Vascular Surgery: Principles and Practice,

Vascular Surgery Principles and Practice Third Edition, Revised and Expanded

Robert W Hobson I& M B . UMDNJ-New Jersey Medical School Newark, New Jersey, U.S.A.

Samuel E. Wilson, M B . University of California Irvine Orange, California, U.S.A.

Frank$ Veith, M B . Montefiore Medical Center-Albert Einstein College of Medicine New York, New York, U.S.A.

m MARCEL

DEKKER

MARCEL DEKKER, INC.

NEWYORK BASEL

The previous edition was published as Vascular Surgery: Principles and Practice, Second Edition, q 1994, McGraw-Hill, Inc. Although great care has been taken to provide accurate and current information, neither the author(s) nor the publisher, nor anyone else associated with this publication, shall be liable for any loss, damage, or liability directly or indirectly caused or alleged to be caused by this book. The material contained herein is not intended to provide specific advice or recommendations for any specific situation. Trademark notice: Product or corporate names may be trademarks or registered trademarks and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress. ISBN: 0-8247-0819-9 This book is printed on acid-free paper. Headquarters Marcel Dekker, Inc. 270 Madison Avenue, New York, NY 10016, U.S.A. tel: 212-696-9000; fax: 212-685-4540 Distribution and Customer Service Marcel Dekker, Inc. Cimarron Road, Monticello, New York 12701, U.S.A. tel: 800-228-1160; fax: 845-796-1772 Eastern Hemisphere Distribution Marcel Dekker AG Hutgasse 4, Postfach 812, CH-4001 Basel, Switzerland tel: 41-61-260-6300; fax: 41-61-260-6333 World Wide Web http://www.dekker.com The publisher offers discounts on this book when ordered in bulk quantities. For more information, write to Special Sales/Professional Marketing at the headquarters address above. Copyright q 2004 by Marcel Dekker, Inc. All Rights Reserved. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher. Current printing (last digit): 10 9 8 7 6 5 4 3 2 1 PRINTED IN THE UNITED STATES OF AMERICA

Foreword

The third edition of Vascular Surgery is a thoroughly revised and expanded work. Ten chapters have been rewritten by new contributors and 15 chapters on current developments have been added. Much of the new material was written by the new generation of leaders in vascular surgery. As an appropriate reflection of the interests and expertise of the editors, the endovascular section is entirely new. The relevance of venous pathology in a vascular practice translates into six new chapters on this subject. This is not an encyclopedic treatise but rather a manageable textbook focused on the diagnosis and treatment of vascular disease. It is a handsome compilation of the vascular surgery field as it now stands. It is accessible, mercifully concise, and to the point. It provides an excellent tool to review the vascular field or to brush up on a specific subject for discussion or presentation. The editors and the contributors are to be congratulated for this accomplishment. Ramon Berguer, M.D., Ph.D. Professor and Chief of Vascular Surgery Wayne State University Detroit Medical Center Detroit, Michigan, U.S.A.

iii

Preface

Vascular surgery is a challenging and exciting discipline that has redefined itself during the last decade. Our interface with colleagues from vascular medicine, cardiology, and interventional radiology has resulted in new treatments and the performance of less invasive procedures for management of carotid occlusive disease, abdominal aortic aneurysm, and peripheral vascular insufficiency. Including coronary artery disease, observed in many of our patients, vascular disease is the major cause of morbidity and mortality in this country. In the third edition of Vascular Surgery: Principles and Practice, our approach has been to present a single comprehensive source of information on pathophysiology, diagnosis, and therapeutic options for surgeons and other specialists in our field. Chapters from the second edition have been extensively revised and new chapters have been added on the evolving practice in endovascular surgery. Insofar as possible, technical updates and descriptions have been added to each chapter detailing new techniques used in surgical and endovascular procedures. However, we have also retained the popular final chapter describing the classical operations for correction of vascular disorders. Contributions have been received from nearly 200 acknowledged authorities in vascular surgery and associated specialties. This effort has achieved a balance that we believe will be useful to the surgeon caring for patients with vascular disease. We have also added an introductory chapter outlining the specialty’s future and its aspirations for independence, as supported by a substantial majority of all recognized vascular societies in this country. Our specialty’s commitment to the noninvasive diagnosis of vascular disease is also emphasized in this textbook and should provide the reader with an authoritative review of current diagnostic modalities. This textbook could not have become a reality without supervision from our publisher, Marcel Dekker, Inc. We are indebted to its staff including Geoff Greenwood, Joseph Stubenrauch, and Kerry Doyle for their organizational talents and much appreciated recommendations. Furthermore, the editors are personally indebted to Estrellita Alejo-Broadie in Irvine, California, Katherine Turlington in Newark, New Jersey, and Jackie Simpson and Julie Harris in New York. Their countless hours of work and devotion to the completion of this textbook have been remarkable and most appreciated. Robert W. Hobson II, M.D. Samuel E. Wilson, M.D. Frank J. Veith, M.D.

v

Contents

Foreword Ramon Berguer Preface Contributors

I.

iii v xiii

Assessment of Vascular Disease

1.

The Evolution of Vascular Surgery James C. Stanley

1

2.

Pathophysiology of Atherosclerosis Russell Ross

15

3.

Pathophysiology of Human Atherosclerosis Christopher K. Zarins and Seymour Glagov

31

4.

Epidemiology of Atherosclerosis and Its Modification Allen W. Averbook and Samuel E. Wilson

55

5.

Hemodynamics of Abnormal Blood Flow David S. Sumner

81

6.

Clinical Examination of the Vascular System Joshua A. Beckman and Mark A. Creager

103

7.

Noninvasive Studies of Peripheral Vascular Disease James S. T. Yao

113

8.

Noninvasive Cerebrovascular Diagnostic Techniques Thomas G. Lynch and Robert W. Hobson II

123

9.

Noninvasive Diagnosis of Venous Disease J. Leonel Villavicencio, David L. Gillespie, and Sandra Eifert

153

10.

Angiography Timothy M. Koci, Frances Chiang, and C. Mark Mehringer

169

11.

Design of Clinical Trials for Evaluation of New Treatments and Methodology James M. Cook and Robert W. Barnes

211

vii

viii

Contents

12.

Outcomes Assessment for the Vascular Surgeon John V. White

221

13.

Computers and Vascular Surgery Richard F. Kempczinski

227

II.

Medical Treatment

14.

Medical Management of Atherosclerotic Vascular Disease Ralph G. DePalma and Donna L. Kowallek

235

15.

Regression and Stabilization of Atherosclerosis by Medical Treatment Howard N. Hodis, Wendy J. Mack, and Albert E. Yellin

249

16.

Hyperthrombotic States in Vascular Surgery Jonathan B. Towne

273

17.

Anticoagulants Timothy K. Liem and Donald Silver

285

18.

Thrombolytic Therapy Sunita Srivastava and Kenneth Ouriel

297

19.

Antiplatelet Agents Richard M. Green and James A. DeWeese

303

20.

Pentoxifylline, Vasodilators, and Metabolic Agents Samuel R. Money and W. Charles Sternbergh III

309

21.

Perioperative Evaluation and Management of Cardiac Risk in Vascular Surgery Piotr Sobieszczyk, Joshua A. Beckman, and Michael Belkin

315

22.

The Biology of Restenosis and Neointimal Hyperplasia Robert A. Larson and Michael A. Golden

325

III.

Endovascular Intervention

23.

Basic Nomenclature Edward B. Diethrich

341

24.

Peripheral Atherectomy Samuel S. Ahn and Kyung M. Ro

351

25.

Endovascular Grafts for Aneurysms, Occlusive Disease, and Vascular Injuries Takao Ohki, Evan C. Lipsitz, and Frank J. Veith

363

26.

Adjunctive Endovascular Procedures: Techniques to Facilitate Operative Vascular Surgery Reese A. Wain and Frank J. Veith

395

Contents

ix

IV.

Peripheral Occlusive Disease

27.

Acute Arterial Insufficiency F. William Blaisdell and James W. Holcroft

405

28.

Microcirculatory Dysfunction in the Pathophysiology of Skeletal Muscle Ischemia Walter N. Dura´n, Mauricio P. Boric´, Peter J. Pappas, and Robert W. Hobson II

413

29.

Arterioarterial Atherothrombotic Microemboli of the Lower Limb Dhiraj M. Shah, R. Clement Darling III, Benjamin B. Chang, Philip S. K. Paty, Paul B. Kreienberg, Sean P. Roddy, and Robert P. Leather

427

30.

Aortoiliofemoral Occlusive Disease K. Wayne Johnston and Peter G. Kalman

439

31.

Femoral-Popliteal-Tibial Occlusive Disease Frank J. Veith and Evan C. Lipsitz

455

32.

In Situ Saphenous Vein Arterial Bypass Robert P. Leather, Dhiraj M. Shah, R. Clement Darling III, Benjamin B. Chang, Philip S. K. Paty, and Paul B. Kreienberg

485

33.

Combined Aortoiliac and Femoropopliteal Occlusive Disease David C. Brewster and Frank J. Veith

495

34.

Adventitial Cystic Disease and Entrapment Syndromes Involving the Popliteal Artery Norman M. Rich, George J. Collins, Jr., Jerry R. Youkey, James M. Salander, Hugh J. Donohue, and Bruce M. Elliott

513

35.

Extraanatomic Bypasses Steven M. Hertz, Bruce J. Brener, Donald K. Brief, and Frank J. Veith

527

36.

Surgery of the Deep Femoral Artery: Profundaplasty Jonathan B. Towne

545

37.

Amputation in the Dysvascular Patient James M. Malone

555

38.

Rehabilitation of the Vascular Amputee Sudesh Sheela Jain and Joel A. DeLisa

575

39.

Lumbar Sympathectomy James S. T. Yao

595

40.

Diabetes and Peripheral Vascular Disease Cameron M. Akbari and Frank W. LoGerfo

601

41.

Biologic and Synthetic Prosthetic Materials for Vascular Conduits William M. Abbott and Thomas F. Rehring

611

42.

Prevention and Management of Prosthetic Graft Infection P. Allen Hartsell, Keith D. Calligaro, Matthew J. Dougherty, and Frank J. Veith

621

x

Contents

V.

Aneurysms

43.

Abdominal Aortic Aneurysms Peter G. Kalman and K. Wayne Johnston

631

44.

Thoracoabdominal Aortic Aneurysms Larry H. Hollier, Marcus D’ayala, and Alfio Carroccio

641

45.

Popliteal Artery Aneurysm Timothy P. Connall and Samuel E. Wilson

653

46.

Splanchnic Artery Aneurysms Russell A. Williams and Samuel E. Wilson

659

47.

Infected Aneurysms Bruce A. Perler and Calvin B. Ernst

669

VI.

Cerebrovascular Disease

48.

Symptomatic Extracranial Vascular Disease: Natural History and Medical Management William S. Fields and James C. Grotta

695

49.

Carotid Pathology Anthony M. Imparato

711

50.

Management of Ulcerative Lesions of the Carotid Artery: Symptomatic and Asymptomatic Hugh A. Gelabert and Wesley S. Moore

729

51.

Cerebral Protection During Carotid Artery Surgery Allan Callow

737

52.

Extracranial Carotid Artery Occlusive Disease Samuel E. Wilson and Robert W. Hobson II

745

53A. Occlusive Disease of the Branches of the Aortic Arch Ramon Berguer

765

53B. Vertebrobasilar Ischemia: Reconstruction of the Vertebral Artery and Proximal Portion of the Subclavian Artery Ramon Berguer

771

54.

Carotid Arterial Tortuosity, Kinks, and Spontaneous Dissection J. Timothy Fulenwider and Robert B. Smith III

783

55.

External Carotid Endarterectomy Karl A. Illig, Richard M. Green, and James A. DeWeese

795

56.

Extracranial Carotid Artery Aneurysms James A. Gillespie and Samuel E. Wilson

803

57.

Carotid Body Tumors Frank T. Padberg, Jr., and Alfred V. Persson

811

Contents

VII.

xi

Visceral Arterial Disease

58.

Renovascular Disease Richard H. Dean and Kimberley J. Hansen

823

59.

Acute Mesenteric Vascular Disease Ronald Nathaniel Kaleya and Scott J. Boley

839

60.

Chronic Visceral Ischemia: A Surgical Condition Darren B. Schneider, Louis M. Messina, and Ronald J. Stoney

861

61.

Sexual Function and Vascular Surgery Ralph G. DePalma

877

VIII.

Vascular Disorders of the Upper Extremity and Vasculitis

62.

Thoracic Outlet Disorders: Thoracic Outlet Compression Syndrome and Axillary Vein Thrombosis Herbert I. Machleder

889

63.

Raynaud’s Syndrome and Upper Extremity Small Artery Occlusive Disease James M. Edwards, Lloyd M. Taylor, Jr., and John M. Porter

903

64.

Vasculitis and Dysplastic Arterial Lesions Hisham S. Bassiouny and Bruce L. Gewertz

915

IX.

Venous and Lymphatic Disorders

65.

Natural History of Deep Venous Thrombosis and Its Implications for Sequelae in the Involved Limb Matthew Waltham, Alberto Smith, and Kevin G. Burnand

929

66.

Pathophysiology of Chronic Venous Insufficiency Peter J. Pappas, Walter N. Dura´n, and Robert W. Hobson II

937

67.

Etiology and Surgical Management of Varicose Veins John J. Bergan

949

68.

Deep Vein Thrombosis: Prevention and Management Lazar J. Greenfield and Mary C. Proctor

963

69.

Chronic Venous Insufficiency: Natural History and Classification Robert L. Kistner, Bo Eklof, and Elna M. Masuda

979

70.

Surgical Management of Lower Extremity Chronic Venous Insufficiency Jae-Sung Cho and Peter Gloviczki

991

71.

Lytic Therapy and Venous Stenting: Indications and Results Anthony J. Comerota

1003

72.

Management of Portal Hypertension Atef A. Salam and Tarek A. Salam

1015

xii

Contents

73.

The Lymphatic System Timothy A. Miller and Andrew E. Turk

X.

Vascular Trauma

74.

Thoracic and Abdominal Vascular Trauma David V. Feliciano and Kenneth L. Mattox

1049

75.

Vascular Injuries in the Neck and Thoracic Outlet Malcolm O. Perry

1071

76.

Vascular Injuries of the Extremities Robert W. Hobson II and Norman M. Rich

1081

77.

Iatrogenic Vascular Injuries Charles D. Franco, Jamie Goldsmith, Takao Ohki, and Frank J. Veith

1095

78.

Vascular Complications Related to Drug Abuse Richard A. Yeager, Robert W. Hobson II, and Creighton B. Wright

1107

79.

Complex Regional Pain Syndromes (Posttraumatic Pain Syndromes: Causalgia and Mimocausalgia) Ali F. AbuRahma

1123

XI.

Compartment Syndrome, Vascular Access, Malformations, and Transplantation

80.

Compartment Syndrome David A. Kulber, Geoffrey S. Tompkins, and Jonathan R. Hiatt

1133

81.

Principles of Vascular Access Surgery Robert S. Bennion and Samuel E. Wilson

1145

82.

Vascular Anomalies: Hemangiomas and Malformations Hugh H. Trout III and Sandra Eifert

1161

83.

Vascular Aspects of Organ Transplantation Jorge Ortiz, T. S. Dulkanchainun, and D. K. Imagawa

1173

XII. 84.

Index

1037

Surgical Techniques Vascular Surgical Techniques Frank J. Veith

1187

1261

Contributors

William M. Abbott, M.D. [41] Department of Surgery Harvard Medical School Chief of Vascular Surgery Division of Vascular Surgery Massachusetts General Hospital Boston, Massachusetts, U.S.A.

Hisham S. Bassiouny, M.D. [64] Department of Surgery The University of Chicago Chicago, Illinois, U.S.A. Joshua A. Beckman, M.D. [6, 21] Cardiovascular Division Department of Medicine Brigham and Women’s Hospital Boston, Massachusetts, U.S.A.

Ali F. AbuRahma, M.D. [79] Chief of Vascular Surgery Division of Vascular Surgery Department of Surgery Robert C. Byrd Health Sciences Center of West Virginia University Charleston, West Virginia, U.S.A.

Michael Belkin, M.D. [21] Chief of Vascular Surgery Department of Surgery Brigham and Women’s Hospital Boston, Massachusetts, U.S.A.

Samuel S. Ahn, M.D. [24] Director, Endovascular Surgery Division of Vascular Surgery UCLA School of Medicine Los Angeles, California, U.S.A.

Robert S. Bennion, M.D. [81] Department of Surgery UCLA School of Medicine Los Angeles, California, U.S.A. John J. Bergan, M.D. [67] Department of Surgery University of California, San Diego La Jolla, California, U.S.A.

Cameron M. Akbari, M.D. [40] Department of Surgery Washington Hospital Center Washington, D.C., U.S.A.

Ramon Berguer, M.D., Ph.D. [53A, 53B] Chief of Vascular Surgery Wayne State University Detroit Medical Center Detroit, Michigan, U.S.A.

Allen W. Averbook, M.D. [4] Pinehurst Surgical Clinic Pinehurst, North Carolina, U.S.A. Robert W. Barnes, M.D. [11] Professor and Chairman Department of Surgery University of Arkansas for Medical Sciences Little Rock, Arkansas, U.S.A.

F. William Blaisdell, M.D. [27] Department of Surgery University of California Davis School of Medicine Sacramento, California, U.S.A.

The numbers in brackets following the contributor name refer to chapter(s) authored or co-authored by the contributor.

xiii

xiv

Contributors

Scott J. Boley, M.D. [59] Montefiore Medical Center Bronx, New York, U.S.A. Mauricio P. Boric´, Ph.D. [28] Departamento de Ciencias Fisiolo´gicas Facultad de Ciencias Biolo´gicas P. Universidad Cato´lica de Chile Santiago, Chile Bruce J. Brener, M.D. [35] Director, Peripheral Vascular Surgery Department of Surgery Newark Beth Israel Medical Center Newark, New Jersey, U.S.A. David C. Brewster, M.D. [33] Department of Vascular Surgery Massachusetts General Hospital Boston, Massachusetts, U.S.A. Donald K. Brief, M.D. [35] Director of Surgery Department of Surgery Newark Beth Israel Medical Center Newark, New Jersey, U.S.A.

Benjamin B. Chang, M.D. [29, 32] Department of Vascular Surgery Albany Medical College Albany, New York, U.S.A. Frances Chiang, M.D. [10] Department of Radiology Harbor – UCLA Medical Center Torrance, California, U.S.A. Jae-Sung Cho, M.D. [70] Division of Vascular Surgery Department of Surgery University of Pittsburgh Pittsburgh, Pennsylvania, U.S.A. George J. Collins, Jr., M.D. [34] Department of Surgery Uniformed Services University of the Health Sciences Bethesda, Maryland, U.S.A. Anthony J. Comerota, M.D. [71] Director Jobst Vascular Center Toledo, Ohio Professor of Surgery University of Michigan Ann Arbor, Michigan, U.S.A.

Kevin G. Burnand, M.S., F.R.C.S. [65] Division of Vascular Surgery Department of Surgery St. Thomas’ Hospital London, England

Timothy P. Connall, M.D. [45] Chief, Division of Plastic Surgery Department of Surgery USAF Medical Center Wright-Patterson Air Force Base Dayton, Ohio, U.S.A.

Keith D. Calligaro, M.D. [42] Chief, Division of Vascular Surgery Department of Surgery Pennsylvania Hospital Philadelphia, Pennsylvania, U.S.A.

James M. Cook, M.D. [11] Division of Vascular Surgery Department of Surgery The Everett Clinic Everett, Washington, U.S.A.

Allan Callow, M.D. [51] Departments of Medicine and Surgery Boston University School of Medicine Boston, Massachusetts, U.S.A.

Mark A. Creager, M.D. [6] Cardiovascular Division Department of Medicine Brigham and Women’s Hospital Boston, Massachusetts, U.S.A.

Alfio Carroccio, M.D. [44] Department of Surgery Mount Sinai Medical Center New York, New York, U.S.A.

Marcus D’ayala, M.D. [44] Department of Surgery Mount Sinai Medical Center New York, New York, U.S.A.

Contributors

R. Clement Darling III, M.D. [29, 32] Department of Vascular Surgery Albany Medical College Albany, New York, U.S.A. Richard H. Dean, M.D. [58] President and CEO Wake Forest University Health Sciences Winston-Salem, North Carolina, U.S.A. Joel A. DeLisa, M.D., M.S. [38] Professor and Chairman Department of Physical Medicine and Rehabilitation UMDNJ—New Jersey Medical School Newark, New Jersey, U.S.A. Ralph G. DePalma, M.D., F.A.C.S. [14, 61] National Director of Surgery Department of Veterans Affairs Washington, D.C. Uniformed Services University of the Health Sciences Bethesda, Maryland, U.S.A. James A. DeWeese, M.D. [19, 55] Chair Emeritus, Cardiothoracic Surgery and Vascular Surgery University of Rochester Medical Center Rochester, New York, U.S.A. Edward B. Diethrich, M.D. [23] Medical Director Department of Cardiovascular Surgery Arizona Heart Institute and Foundation Phoenix, Arizona, U.S.A. Hugh J. Donohue, M.D. [34] Department of Surgery Medical College of Virginia Richmond, Virginia, U.S.A. Matthew J. Dougherty, M.D. [42] Division of Vascular Surgery Department of Surgery Pennsylvania Hospital Philadelphia, Pennsylvania, U.S.A. T. S. Dulkanchainun, M.D. [83] Division of Transplantation Department of Surgery University of California Irvine Orange, California, U.S.A.

Walter N. Dura´n, Ph.D. [28, 66] Professor Department of Pharmacology and Physiology Director, Program in Vascular Biology Division of Vascular Surgery UMDNJ—New Jersey Medical School Newark, New Jersey, U.S.A. James M. Edwards, M.D. [63] Division of Vascular Surgery Oregon Health and Science University Portland, Oregon, U.S.A. Sandra Eifert, M.D. [9, 82] Department of Surgery Uniformed Services University of the Health Sciences Bethesda, Maryland, U.S.A. Bo Eklof, M.D. [69] Department of Vascular Surgery Straub Clinic and Hospital University of Hawaii Honolulu, Hawaii, U.S.A. Bruce M. Elliott, M.D. [34] Head of Vascular Surgery Medical University of South Carolina Charleston, South Carolina, U.S.A. Calvin B. Ernst, M.D. [47] Wayne, Pennsylvania, U.S.A. David V. Feliciano, M.D. [74] Chief of Surgery Grady Memorial Hospital Department of Surgery Emory University School of Medicine Atlanta, Georgia, U.S.A. William S. Fields, M.D. [48] Department of Neurology University of Texas Health Science Center at Houston Houston, Texas, U.S.A. Charles D. Franco, M.D. [77] New Brunswick, New Jersey, U.S.A. J. Timothy Fulenwider, M.D. [54] Northwest Georgia Surgical Associates Gainesville, Georgia, U.S.A.

xv

xvi

Contributors

Hugh A. Gelabert, M.D. [50] Division of Vascular Surgery Department of Surgery UCLA Medical Center Los Angeles, California, U.S.A.

Lazar J. Greenfield, M.D. [68] Interim Vice President for Medical Affairs and Chief Executive Officer University of Michigan Ann Arbor, Michigan, U.S.A.

Bruce L. Gewertz, M.D. [64] The Dallas B. Phemister Professor and Chairman Division of Vascular Surgery Department of Surgery The University of Chicago Chicago, Illinois, U.S.A.

James C. Grotta, M.D. [48] Department of Neurology University of Texas Health Science Center at Houston Houston, Texas, U.S.A.

James A. Gillespie, M.D. [56] Department of Surgery St. George’s Hospital London, England David L. Gillespie, M.D. [9] Chief, Division of Vascular Surgery Department of Surgery Uniformed Services University of the Health Sciences Bethesda, Maryland, U.S.A. Seymour Glagov, M.D. [3] Department of Pathology University of Chicago Chicago, Illinois, U.S.A. Peter Gloviczki, M.D. [70] Vice-Chair, Division of Vascular Surgery Gonda Vascular Center Mayo Clinic Rochester, Minnesota, U.S.A. Michael A. Golden, M.D. [22] Division of Vascular Surgery Department of Surgery University of Pennsylvania Medical Center Philadelphia, Pennsylvania, U.S.A. Jamie Goldsmith, M.D. [77] Montefiore Medical Center—Albert Einstein College of Medicine New York, New York, U.S.A. Richard M. Green, M.D. [19, 55] Department of Surgery University of Rochester Medical Center Rochester, New York, U.S.A.

Kimberley J. Hansen, M.D. [58] Division of Surgical Services Wake Forest University Health Sciences Winston-Salem, North Carolina, U.S.A. P. Allen Hartsell, M.D. [42] Department of Surgery Texas A&M University Temple, Texas, U.S.A. Steven M. Hertz, M.D. [35] Division of Vascular Surgery Department of Surgery Newark Beth Israel Medical Center Newark, New Jersey, U.S.A. Jonathan R. Hiatt, M.D. [80] Department of Surgery Cedars-Sinai Medical Center Los Angeles, California, U.S.A. Robert W. Hobson II, M.D. [8, 28, 52, 66, 76, 78] Director, Division of Vascular Surgery UMDNJ—New Jersey Medical School Newark, New Jersey, U.S.A. Howard N. Hodis, M.D. [15] Departments of Medicine and Preventive Medicine Atherosclerosis Research Unit University of Southern California School of Medicine Los Angeles, California, U.S.A. James W. Holcroft, M.D. [27] Department of Surgery University of California Davis School of Medicine Sacramento, California, U.S.A.

Contributors

Larry H. Hollier, M.D. [44] Franz W. Sichel Professor and Chairman Division of Vascular Surgery Department of Surgery Mount Sinai Medical Center New York, New York, U.S.A. Karl A. Illig, M.D. [55] Department of Surgery University of Rochester Medical Center Rochester, New York, U.S.A. D. K. Imagawa, M.D. [83] Division of Transplantation Department of Surgery University of California Irvine Orange, California, U.S.A. Anthony M. Imparato, M.D. [49] Division of Vascular Surgery Department of Surgery New York University Medical Center New York, New York, U.S.A. Sudesh Sheela Jain, M.D. [38] Consultant Kessler Medical Rehabilitation Research and Education Corporation West Orange, New Jersey, U.S.A. K. Wayne Johnston, M.D. [30, 43] Department of Surgery Toronto General Hospital Toronto, Ontario, Canada Ronald Nathaniel Kaleya, M.D. [59] Department of Surgery Montefiore Medical Center Bronx, New York, U.S.A. Peter G. Kalman, M.D. [30, 43] Division of Vascular Surgery Department of Surgery Loyola University Medical Center Maywood, Illinois, U.S.A. Richard F. Kempczinski, M.D. [13] Professor Emeritus University of Cincinnati Medical Center Cincinnati, Ohio, U.S.A.

Robert L. Kistner, M.D. [69] Department of Vascular Surgery Straub Clinic and Hospital University of Hawaii Honolulu, Hawaii, U.S.A. Timothy M. Koci, M.D. [10] Department of Radiology Washoe Medical Center Reno, Nevada, U.S.A. Donna L. Kowallek, R.N., M.S.N., C.V.N.† [14] VA Sierra Nevada Health Care System Reno, Nevada, U.S.A. Paul B. Kreienberg, M.D. [29, 32] Department of Vascular Surgery Albany Medical College Albany, New York, U.S.A. David A. Kulber, M.D. [80] Division of Plastic Surgery Department of Surgery Cedars-Sinai Medical Center Los Angeles, California, U.S.A. Robert A. Larson, M.D. [22] Division of Vascular Surgery Department of Surgery University of Pennsylvania Medical Center Philadelphia, Pennsylvania, U.S.A. Robert P. Leather, M.D. [29, 32] Professor Emeritus Department of Vascular Surgery Albany Medical College Albany, New York, U.S.A. Timothy K. Liem, M.D. [17] Division of Vascular Surgery Department of Surgery University of Missouri –Columbia Columbia, Missouri, U.S.A. Evan C. Lipsitz, M.D. [25, 31] Department of Surgery Montefiore Medical Center Bronx, New York, U.S.A.

†

Deceased.

xvii

xviii

Contributors

Frank W. LoGerfo, M.D. [40] William V. McDermott Professor of Surgery Harvard Medical School Chief, Division of Vascular Surgery Department of Surgery Beth Israel Deaconess Medical Center Boston, Massachusetts, U.S.A. Thomas G. Lynch, M.D. [8] Chief, Section of Vascular Surgery Department of Surgery University of Nebraska Medical Center Omaha, Nebraska, U.S.A. Herbert I. Machleder, M.D. [62] Division of Vascular Surgery Department of Surgery UCLA Medical Center Los Angeles, California, U.S.A. Wendy J. Mack, M.D. [15] Department of Preventive Medicine Atherosclerosis Research Unit University of Southern California School of Medicine Los Angeles, California, U.S.A. James M. Malone, M.D. [37] Chairman, Department of Surgery Scottsdale Healthcare Shea Scottsdale, Arizona, U.S.A. Elna M. Masuda, M.D. [69] Department of Vascular Surgery Straub Clinic and Hospital University of Hawaii Honolulu, Hawaii, U.S.A. Kenneth L. Mattox, M.D. [74] Vice Chairman of Surgery Department of Surgery Baylor College of Medicine Houston, Texas, U.S.A. C. Mark Mehringer, M.D. [10] Department of Radiology Harbor – UCLA Medical Center Torrance, California, U.S.A.

Louis M. Messina, M.D. [60] Chief of Vascular Surgery University of California Medical Center San Francisco, California, U.S.A. Timothy A. Miller, M.D. [73] Chief, Division of Plastic and Reconstructive Surgery Department of Surgery UCLA Medical Center Los Angeles, California, U.S.A. Samuel R. Money, M.D. [20] Head, Section of Vascular Surgery Department of Surgery Ochsner Clinic Foundation New Orleans, Louisiana, U.S.A. Wesley S. Moore, M.D. [50] Division of Vascular Surgery Department of Surgery UCLA Medical Center Los Angeles, California, U.S.A. Takao Ohki, M.D. [25, 77] Chief, Vascular and Endovascular Surgery Department of Surgery Montefiore Medical Center—Albert Einstein College of Medicine Bronx, New York, U.S.A. Jorge Ortiz, M.D. [83] Division of Transplant Surgery Department of Surgery Albert Einstein Medical Center Philadelphia, Pennsylvania, U.S.A. Kenneth Ouriel, M.D. [18] Chairman, Department of Vascular Surgery The Cleveland Clinic Foundation Cleveland, Ohio, U.S.A. Frank T. Padberg, Jr., M.D. [57] Division of Vascular Surgery Department of Surgery UMDNJ—New Jersey Medical School Newark, New Jersey, U.S.A. Peter J. Pappas, M.D. [28, 66] Associate Professor of Surgery Department of Surgery Chief, Section of Vascular Surgery UMDNJ—University Hospital Newark, New Jersey, U.S.A.

Contributors

Philip S. K. Paty, M.D. [29, 32] Department of Vascular Surgery Albany Medical College Albany, New York, U.S.A.

Sean P. Roddy, M.D. [29] Department of Vascular Surgery Albany Medical College Albany, New York, U.S.A.

Bruce A. Perler, M.D. [47] Chief, Division of Vascular Surgery Department of Surgery The Johns Hopkins University School of Medicine Baltimore, Maryland, U.S.A.

Russell Ross, M.D.† [2] University of Washington School of Medicine Seattle, Washington, U.S.A.

Malcolm O. Perry, M.D. [75] Professor Emeritus Department of Surgery University of Texas Southwestern Medical Center Dallas, Texas, U.S.A. Alfred V. Persson, M.D. [57] Metrowest Medical Center Framingham, Massachusetts, U.S.A. John M. Porter, M.D.† [63] Division of Vascular Surgery Oregon Health and Science University Portland, Oregon, U.S.A. Mary C. Proctor, M.D. [68] Department of Surgery University of Michigan Ann Arbor, Michigan, U.S.A. Thomas F. Rehring, M.D. [41] Department of Vascular Surgery Massachusetts General Hospital Boston, Massachusetts, U.S.A. Norman M. Rich, M.D. [34, 76] Chairman, Department of Surgery Uniformed Services University of the Health Sciences Bethesda, Maryland, U.S.A. Kyung M. Ro, M.P.H., M.S. [24] Division of Vascular Surgery Department of Surgery UCLA School of Medicine Los Angeles, California, U.S.A. †

Deceased.

Atef A. Salam, M.D. [72] Department of Surgery Emory University School of Medicine Atlanta, Georgia, U.S.A. Tarek A. Salam, M.D. [72] Department of Surgery Ain-Shams University Cairo, Egypt James M. Salander, M.D. [34] Department of Surgery Uniformed Services University of the Health Sciences Bethesda, Maryland, U.S.A. Darren B. Schneider, M.D. [60] Divisions of Vascular Surgery and Interventional Radiology University of California Medical Center San Francisco, California, U.S.A. Dhiraj M. Shah, M.D. [29, 32] Director, Institute for Vascular Health and Disease Albany Medical College Albany, New York, U.S.A. Donald Silver, M.D. [17] Chairman, Department of Surgery University of Missouri –Columbia Columbia, Missouri, U.S.A. Alberto Smith, Ph.D. [65] Department of Surgery St. Thomas’ Hospital London, England Robert B. Smith III, M.D. [54] Associate Chairman of Surgery Department of Surgery Emory University School of Medicine Atlanta, Georgia, U.S.A. †

Deceased.

xix

xx

Contributors

Piotr Sobieszczyk, M.D. [21] Cardiovascular Division Department of Medicine Brigham and Women’s Hospital Boston, Massachusetts, U.S.A. Sunita Srivastava, M.D. [18] Department of Vascular Surgery The Cleveland Clinic Foundation Cleveland, Ohio, U.S.A. James C. Stanley, M.D. [1] Head, Section of Vascular Surgery Department of Surgery University of Michigan Ann Arbor, Michigan, U.S.A. W. Charles Sternbergh III, M.D. [20] Program Director Vascular and Endovascular Surgery Department of Surgery Ochsner Clinic Foundation New Orleans, Louisiana, U.S.A. Ronald J. Stoney, M.D. [60] Professor Emeritus Division of Vascular Surgery Department of Surgery University of California Medical Center San Francisco, California, U.S.A. David S. Sumner, M.D. [5] Chief, Division of Peripheral Vascular Surgery Department of Surgery Southern Illinois University School of Medicine Springfield, Illinois, U.S.A. Lloyd M. Taylor, Jr., M.D. [63] Division of Vascular Surgery Oregon Health and Science University Portland, Oregon, U.S.A. Geoffrey S. Tompkins, M.D. [80] Division of Orthopaedic Surgery Department of Surgery Santa Rosa Memorial Hospital Santa Rosa, California, U.S.A. Jonathan B. Towne, M.D. [16, 36] Chief, Vascular Surgery Medical College of Wisconsin Milwaukee, Wisconsin, U.S.A.

Hugh H. Trout III, M.D. [82] George Washington Medical Center Bethesda, Maryland, U.S.A. Andrew E. Turk, M.D. [73] Department of Plastic Surgery Cleveland Clinic, Naples Naples, Florida, U.S.A. Frank J. Veith, M.D. [25, 26, 31, 33, 35, 42, 77, 84] The William J. von Liebig Chair of Vascular Surgery Division of Vascular Surgery Department of Surgery Montefiore Medical Center—Albert Einstein College of Medicine New York, New York, U.S.A. J. Leonel Villavicencio, M.D. [9] Department of Surgery Uniformed Services University of the Health Sciences Bethesda, Maryland Director, Venous and Lymphatic Teaching Clinics Walter Reed Army and National Naval Centers Washington, D.C., U.S.A. Reese A. Wain, M.D. [26] Chief of Vascular Surgery Weiler Hospital of the Albert Einstein College of Medicine New York, New York, U.S.A. Matthew Waltham, M.A., F.R.C.S. [65] Department of Surgery St. Thomas’ Hospital London, England John V. White, M.D. [12] Clinical Professor of Surgery University of Illinois at Chicago Department of Surgery Advocate Lutheran General Hospital Park Ridge, Illinois, U.S.A. Russell A. Williams, M.D. [46] Department of Surgery University of California Irvine Orange, California, U.S.A.

Contributors

Samuel E. Wilson, M.D. [4, 45, 46, 52, 56, 81] Department of Surgery University of California Irvine Orange, California, U.S.A. Creighton B. Wright, M.D. [78] Cardiovascular & Thoracic Surgeons, Inc. Cincinnati, Ohio, U.S.A. James S. T. Yao, M.D., Ph.D. [7, 39] Magerstadt Professor of Surgery Division of Vascular Surgery Northwestern University The Feinberg School of Medicine Chicago, Illinois, U.S.A. Richard A. Yeager, M.D. [78] Surgical Service Portland VA Medical Center Portland, Oregon, U.S.A.

Albert E. Yellin, M.D. [15] Associate Chief of Staff Department of Surgery University of Southern California School of Medicine Los Angeles, California, U.S.A. Jerry R. Youkey, M.D. [34] Department of Surgery Uniformed Services University of the Health Sciences Bethesda, Maryland, U.S.A.

Christopher K. Zarins, M.D. [3] Chairman, Division of Vascular Surgery Department of Surgery Stanford University Medical Center Stanford, California, U.S.A.

xxi

CHAPTER 1

The Evolution of Vascular Surgery James C. Stanley from India, where Sushruta used hemp fibers for blood vessel ligations around 700 B.C.[5] Celsius made an important contribution in the 1st century, when he ligated vessels both above and below the site of injury, then transected the involved vessel so that it might retract from the wound, thus lessening the risk of hemorrhage which often accompanied wound infections. A century later Galen had ligated many vessels and Antyllus ligated both entering and exiting vessels of an aneurysm, but infection continued to compromise such efforts. Venous disease was also well recognized by the ancients, including Hippocrates, who recommended treating venous varicosities with compressive dressings and avoidance of standing.[3] Celsius used bandages and plasters to treat venous ulcerations in the 1st century and Galen suggested multiple ligations as a therapeutic intervention in the 2nd century. Little change occurred in the management of venous disease over the next 1500 years. The dark ages of European history witnessed few advances in vascular surgery. It wasn’t until the 16th century that Ambrose Pare´ successfully ligated vessels in the battlefields at Danvilliers and used stringent agents to lessen wound infections.[6] This was a major contribution in the treatment of controlling hemorrhage from arteries and veins. During the 18th century considerable efforts were extended to the treatment of aneurysms, led by John Hunter, who made many extraordinary contributions to the scientific classification and treatment of vascular diseases.[7 – 10] One of his more noteworthy accomplishments involved ligation of the femoral artery for the treatment of a popliteal artery aneurysm. This procedure provided the impetus for his interest in the relevance of the collateral circulation in the extremities. During the ensuing 19th century many other physicians described arterial ligature in the management of aneurysms. One of the most inventive of those practitioners was Ashley Cooper,[11,12] a student of Hunter, who ligated the carotid artery for an aneurysm in 1805.[13] The patient subsequently died, but he undertook a second successful ligation for the same disease 3 years later in 1808.[14] Cooper also ligated the aorta for an iliac artery aneurysm and treated a femoral artery aneurysm by ligation during this same era. Shortly thereafter

Contemporary vascular surgery has evolved slowly over many years with notable exceptions that catapulted new paradigms into clinical practice. Most landmark contributions occurred during the last half of the 20th century, resulting from a better understanding of the physiologic consequences of vascular disease, the availability of heparin anticoagulation, the introduction of synthetic grafts, development of noninvasive testing, improved anatomic imaging, and the maturation of technical skills from simple vascular ligations to complex open surgical and endovascular procedures. Although vascular surgery had its beginning in many other disciplines, it has evolved into an independent medical specialty with a defined body of knowledge and established standards of practice. The history of vascular surgery is best addressed by reviewing four specific time periods: antiquity to the end of the 19th century, the early 20th century, the last half of the 20th century, and the early 21st century. A select group of listings of landmark contributions have been created as a reference to the historical events affecting certain aspects of vascular surgery, including aortic occlusive disease (Table 1), nonanatomic revascularization of the lower extremities (Table 2), endovascular therapies for arterial disease (Table 3), femoral, popliteal, and tibial arterial occlusive disease (Table 4), aortic aneurysms (Table 5), femoral and popliteal artery aneurysms (Table 6), splanchnic and renal artery disease (Table 7), cerebrovascular disease recognition (Table 8), cerebrovascular disease-surgical treatment (Table 9), and venous disease (Table 10). Many contributors not included in the aforenoted listings because of this review’s brief nature have added both depth and breadth to our knowledge of vascular surgery. Four excellent works on the history of vascular surgery have been published that offer further insight into the evolution of this discipline.[1 – 4]

ANTIQUITY TO THE END OF THE 19TH CENTURY Arterial disruptions due to trauma and ruptured aneurysms were confronted by the ancients, whose earliest vascular surgical procedures related to controlling bleeding from these vessels.[3] Perhaps the first recorded reports on this topic were

Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024969 Copyright q 2004 by Marcel Dekker, Inc.

1

www.dekker.com

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Part One. Assessment of Vascular Disease

in 1817 Valentine Mott ligated the innominate artery for a subclavian aneurysm.[15] Mott also ligated the common iliac artery for an external iliac artery aneurysm in 1820. His work, performed in New York City, was some of the earliest vascular surgery undertaken in the United States. Rudolph Matas was the most widely recognized contributor to vascular surgery towards the end of the 19th century.[16] In 1888 he successfully performed a brachial artery aneurysm endoaneurysmorrhaphy.[17] His technique of ligating the entering and exiting vessels from within the aneurysm proved essential in preserving collateral vessels and maintaining the viability of distal tissues. Matas applied this procedure to the treatment of aortic aneurysms in the next century. Chronic occlusive disease came to the forefront during the 19th century, when Barth described claudication for the first time in 1835, affecting a patient with an aortic thrombosis.[18] His report went unrecognized for many decades, but clearly established the concept that arterial obstructions could cause chronic symptoms amenable to later reconstructive procedures. In 1896 a critical contribution to the understanding of vascular diseases came about with Wilhelm Roentgen’s initial discovery of x-rays,[19] followed 3 months later by an actual arteriogram performed in an amputated upper extremity.[20] It would be decades before the usefulness of arteriography would become apparent in clinical practice. Jaboulay and Briau successfully performed an end-to-end reanastomosis of the carotid artery in 1896.[23] This was remarkable, given the previously held belief that sutures placed in a vessel would result in its early thrombosis. John Murphy, a year later in 1897, described a successful end-toend arterial anastomosis of a femoral artery that had been injured with a gunshot wound with development of a pseudoaneurysm.[22] His case followed considerable experimental work with vascular anastomoses in both canine and bovine subjects and set the stage for subsequent advances in the succeeding century.

EARLY 20TH CENTURY Alexis Carrel, a student of Jaboulay, had an early interest in vascular anastomoses.[23,24] Carrel came to the United States shortly after the turn of the century and joined Charles C. Guthrie in the Department of Physiology at the University of Chicago.[25,26] These two individuals took the concept of inserting a vein into the arterial circulation and demonstrated that such was feasible in animal experiments.[27 – 29] Together they coauthored 28 papers. This work was the basis of Carrel’s receiving the Nobel Prize in Medicine and Physiology in 1912. Given an awareness of the novelty of successful vascular anastomoses performed in the laboratory, Jose´ Goyanes resected a patient’s popliteal artery aneurysm and replaced it with a popliteal vein graft in 1906.[30] This was considered the first clinically successful arterial reconstruction using a vein graft. The treatment of aortic aneurysms at the beginning of the 20th century continued to involve nonreconstructive procedures. Instillation of large amounts of wire into an aneurysm as a means of inducing thrombosis and external

wrapping to limit aneurysmal expansion proved inadequate and were soon discarded as acceptable therapies. Rudolph Matas, who successfully ligated the infrarenal aorta for treatment of an aortic aneurysm in 1923,[31] reported his life’s experience in 1940 with 62 similar lesser operations for aneurysms with a commendable mortality of only 15%.[32] Although the natural history of untreated aortic and peripheral aneurysms became better defined during the early 20th century, adequate treatment would not become commonplace until the second half of the century. The management of lower extremity ischemia advanced quickly toward the end of the first half of the 20th century. In 1946 Joa˜o Cid dos Santos undertook a number of extensive endarterectomies for arteriosclerotic arterial occlusions.[33,34] He is often credited as the founder of arterial endarterectomy, although similar procedures had been performed earlier by Bazy and colleagues for aortic occlusive disease.[35] Endarterectomy was a landmark contribution to the evolution of vascular surgery. In 1948, Jean Kunlin performed a successful femoropopliteal bypass with reversed autogenous saphenous vein and established a therapeutic approach that continues to present times.[36] William Holden, 6 months following Kunlin’s achievement, was first in the United States to perform a lower extremity bypass with vein,[37] and his success was followed by that of many others. Although not directly related to treating lower extremity ischemia, the surgical therapy of thoracic isthmic coarctations during the early mid-20th century established the feasibility of clamping the aorta and undertaking its operative reconstruction. Clarence Crafoord in 1944 first resected the coarcted segment and reconstructed the aorta with an end-toend anastomosis.[38] Robert Gross did the same in 1945,[39] and in 1948 he replaced the coarctated aortic segment with a homograft.[40,41] These achievements allowed others to treat aortoiliac occlusive disease later with much greater confidence. Attention to diseases of the distal aorta followed Rene´ Leriche’s 1923 report on the clinical manifestations of thrombotic occlusion of the arteriosclerotic aortic bifurcation.[42] His experience with the treatment of this disease was later described in a widely heralded report of 1948.[43] The treatment of aortoiliac occlusive disease by operative means progressed rapidly thereafter in the early days of the last half of the century. Recognition of diseases affecting the renal artery during the first half of the 20th century would wait many years before they were successfully treated surgically. Harry Goldblatt in elegant studies performed in the 1920s and 1930s documented that renal artery constrictions in experimental animals caused hypertension.[44] In 1938 the clinical relevance of his observations became apparent when Leadbetter and Burkland removed a small ischemic kidney in a child with renal artery occlusive disease and cured his severe hypertension.[45] Unfortunately, the next few decades saw many kidneys removed without benefit, namely because the careful selection of patients having a renin-mediated form of hypertension was undeveloped and vascular procedures for reconstructing the renal arteries were nonexistent. The classic description of occlusive disease of the splanchnic arteries causing intestinal angina was proposed

Chapter 1.

in J. Englebert Dunphy’s classic paper of 1936.[46] He recognized the importance of postprandial abdominal pain as a manifestation of arteriosclerotic narrowings of the major arteries to the gut and noted its potential to eventuate in intestinal infarction. As was the case with renal artery disease, many years would pass before the successful vascular surgical treatment of intestinal angina occurred. During the first half of the 20th century the role of the extracranial internal carotid artery as a cause of stroke received little attention. There were a number of reasons for this. First, cerebral angiography, initially performed by Egas Moniz in 1927,[47] was not to be used as a diagnostic test for many decades to come. Second, neck vessels were rarely examined during routine autopsy studies, and the existence of extracranial carotid artery arteriosclerosis was usually overlooked. In fact, the most commonly perceived cause of a cerebrovascular accident during the midcentury was thrombosis of the middle cerebral artery, with no understanding that thromboembolism from the region of the carotid bulb may have played a role in the occlusive process. The treatment of venous diseases was one of the mainstays of practice among physicians caring for vascular diseases during the first half of the 20th century. Varicose veins were known to have plagued man since antiquity, and external compression continued to be the basis of most therapies at the close of the century. A noteworthy contribution was the plaster dressing introduced by Unna, which became the forerunner of the dressing carrying his name a century later.[48] In 1905 Keller undertook stripping of extremity veins,[4] and Babcock in that same year developed an intraluminal stripper for vein removal.[49] John Homans subsequently made many observations that advanced our understanding of venous disease. During the century’s second decade he emphasized the importance of saphenofemoral vein ligation in the prevention of varicosities.[50,51] A little more than 20 years later, in 1938, Robert Linton described the importance of incompetent communicating veins and subsequently developed a technique for subfascial ligation of these veins.[52] More direct surgical interventions on the veins themselves to prevent venous hypertension would await another 3 decades. The lethal nature of pulmonary emboli was well known in the early 20th century, and prevention of this complication of venous thrombosis became important. In 1934 Homans advocated femoral vein ligation to prevent pulmonary embolism.[53] By 1945 ligation of the inferior vena cava Table 1-1.

The Evolution of Vascular Surgery

was reported by Northway, Buxton, and O’Neill as a means of preventing fatal pulmonary embolism.[54,55] Ligation of the cava for prevention of septic emboli had been reported a few years earlier.[56] A major advance in the evolution of vascular surgery during the early 20th century was the introduction of translumbar aortography in 1929 by Raynaldo dos Santos.[57] Imaging of blood vessels was to prove essential to the continued advancement of vascular surgery. A second major advance was the use of heparin anticoagulation to prevent perioperative thromboses that affected the vast majority of vascular interventions during the very early 20th century. Although heparin had been discovered in 1918 by Jay McLean in W. H. Howell’s laboratory,[58] it was not purified and readily available for use until the 1930s and 1940s. It was only then that its value in treating arterial thromboses became widely recognized.[59,60] Thus, the first half of the 20th century witnessed the ability to approximate injured vessels, remove arteriosclerotic plaque by the technique of endarterectomy, and replace chronically diseased arteries with bypass grafts, all under the influence of anticoagulation. These achievements laid the foundation for the many advances of the last half of the 20th century in vascular surgery.

THE LAST 50 YEARS OF THE 20TH CENTURY The second half of the century witnessed profound changes in the practice of vascular surgery. These events are best discussed by addressing those contributions unique to specific disease entities.

AortoiliacArteriosclerotic OcclusiveDisease Treatment of arteriosclerotic aortic disease was first successfully undertaken by Jacques Oudot in 1950 with a homograft replacement of a thrombosed aortic bifurcation.[61,62] With the recognition of homograft degeneration and the initial use of synthetic grafts, this form of aortic reconstruction fell into disuse. Although the earliest aortoiliac endarterectomy may have been performed by Bazy and colleagues,[35] this technique was first undertaken in 1951 in the United States by Norman

Aortic Occlusive Disease

Raynaldo dos Santos Clarence Crafoord Rene´ Leriche

1929 1944 1948

Robert Gross Jacques Oudot

1949 1950

Norman Freeman

1951

3

Translumbar aortography Thoracic coarctation resection, aortic reanastomosis Treatment of thrombotic occlusion of atherosclerotic ortic bifurcation, first described in 1923 Homograft replacement of thoracic aortic coarctation Homograft replacement of thrombosed aortic bifurcation Aortoiliac endarterectomy; followed shortly thereafter in 1951 by Wylie, who popularized the open technique first described by Bazy and colleagues in 1949

4

Part One. Assessment of Vascular Disease Table 1-2. Nonanatomic Revascularization of the Lower Extremities Jacques Oudot Norman Freeman

1951 1952

J.J. McCaughan Jr., S.F. Kahn R. Mark Veto F. William Blaisdell, A.D. Hall Lester Savage P.M. Guida, S.W. Moore

1958 1960 1962 1966 1969

Freeman,[63] and shortly thereafter popularized by his former colleague in practice, Edwin Wylie.[64,65] The introduction of synthetic bypass grafts for the treatment of aortic diseases changed the treatment paradigm dramatically, and for the next 40 years these grafts, serving as aortofemoral bypasses, were the most common means of treating aortoiliac occlusive diseases.[66 – 73] Nonanatomic revascularization procedures also evolved during the 1950s and 1960s for the treatment of aortoiliac occlusive lesions in high risk situations. These unconventional interventions were used most often in reoperations for an infected or failed earlier bypass, avoidance of a hostile abdomen, or concerns about the operative hazards of a more extensive procedure. Many types of nonanatomic procedures evolved over a short period of time. The first of these nonanatomic reconstructions was by Jacques Oudot in 1951, who performed a cross-over ilioiliac arterial bypass.[74] Subsequently, Norman Freeman used an endarterectomized superficial femoral artery in 1952 to perform a femorofemoral arterial cross-over bypass.[75] An iliac artery to contralateral popliteal artery bypass was constructed by McCaughan and Kahn in 1958.[76] Little attention was paid to these operations by most practitioners in the earlier days of contemporary vascular surgery. It was only in the 1960s that nonanatomic procedures became popular, after reports by Veto of a femorofemoral arterial cross-over bypass in 1960,[77] as well as by Blaisdell and Hall of an axillofemoral bypass using a synthetic graft in 1962.[78] An important contribution to the latter procedure came from Lester Savage, who in 1966 introduced the addition of a cross-over femorofemoral arterial bypass to a unilateral axillofemoral bypass as a means of revascularizing

Table 1-3.

Ilioiliac bypass Femorofemoral bypass with endarterectomized superficial femoral artery Iliopopliteal bypass Femorofemoral bypass Axillofemoral bypass Axillobifemoral bypass Obturator bypass

both lower extremities.[79] Although unrelated to the primary treatment of aortoiliac occlusive disease, the performance of an obturator bypass, first reported by Guida and Moore in 1969,[80] allowed lower extremity revascularizations with avoidance of an otherwise hostile groin area. Endovascular balloon dilation provided a major advance in the treatment of aortoiliac occlusive disease during the past quarter century, becoming widely used in the 1990s. This technology evolved from the pioneering work of Charles Dotter using percutaneous coaxial dilation of peripheral arteries first reported in 1964,[81] and Andreas Gruntzig, who introduced percutaneous balloon angioplasty in 1974.[82] Treatment of iliac artery stenoses by less invasive percutaneous means markedly reduced the frequency with which open aortobifemoral bypass procedures were performed. The use of balloon-assisted intraluminal stents, developed by Palmaz in 1988,[83] lessened complications associated with balloon-related dissections. The rapid application of stent technology to angioplasty of many arterial stenoses, in addition to iliac artery lesions, followed during the next decade.

Infrainguinal Arteriosclerotic Occlusive Disease Jean Kunlin reported 17 patients who had undergone autogenous vein lower extremity revascularizations in 1951,[84] just 3 years after he performed the first such operation. This was followed by similar bypass procedures in the United States by many surgeons including Julian, Lord, Dale, DeWeese, Linton, Darling, and Szilagyi, that confirmed the utility of reversed saphenous vein femoropopliteal

Endovascular Therapies for Arterial Disease

Arteriosclerotic occlusive disease Charles Dotter Andreas Gruntzig Julio Palmaz Thromboembolism Thomas Fogarty Aneurysmal disease Juan Parodi Frank Veith, Michael Marin Frank Veith, Takao Ohki

1964 1974 1988

Percutaneous coaxial dilation Percutaneous transluminal balloon angioplasty Balloon-assisted stent placement

1963

Balloon catheter for embolectomy

1991 1994 1999

Aortic endograft Endograft exclusion of traumatic arterial disruptions and pseudoaneurysms Aortic endograft treatment of ruptured aneurysms

Chapter 1. Table 1-4.

The Evolution of Vascular Surgery

5

Femoral, Politeal, and Tibia1 Arterial Occlusive Disease

Joa˜o Cid dos Santos Jean Kunlin

1946 1948

Eduardo Palma Karl Hall Peter Martin Herbert Dardik

1956 1962 1971 1976

Robert Leather

1979

Frank Veith, John Bergan, Victor Bernhard

1982, 1985

reconstructions. Extension of vein graft procedures to the more distal infrageniculate arteries was first reported by Palma, who undertook a femorotibial bypass in 1956.[85] This too was followed with similar revascularizations by many others. The use of the saphenous vein in situ after rendering its valves incompetent was first reported by Karl Hall in 1962.[86] This technology saw limited use until 1979, when Robert Leather and his colleagues introduced a new valve cutter for in situ revascularizations.[87] Subsequently, the procedure became widely used during the next decade. Although some have questioned the advantage to these reconstructions, their use in many distal revascularization procedures appeared valid. An alternative biologic graft for use instead of autogenous vein was the tanned human umbilical vein, reported initially by Herbert Dardik in 1976.[88,89] Although utilization of Dacron grafts for lower extremity reconstructions waned with the success of vein revascularizations, the introduction of extruded polytetrafluroethylene (PTFE) grafts caused a resurgence in synthetic graft use for the treatment of lower extremity ischemia. In two hallmark papers, John Bergan, Frank Veith, Victor Bernhard and their colleagues demonstrated the utility of PTFE grafts for femoropopliteal reconstructions, with lesser benefits when used for distal infrageniculate procedures.[90,91] The importance of the profunda femoris artery was initially reported in 1971 by Peter Martin, who described an extended profundoplasty as a means of improving blood flow to the ischemic extremity.[92] Although unrelated to his report, the importance of the profunda femoris artery in completing the distal anastomosis of an aortofemoral bypass was well recognized during the same time period, and an extension of the graft limb onto this vessel became standard practice.

Embolic Arterial Occlusions of the Lower Extremity One of the major advances in vascular surgery was introduced in Thomas Fogarty’s 1963 report on balloon catheter

Femoral endarterectomy Reversed autogenous saphenous vein femoral popliteal bypass Femoral-tibial bypass with vein In situ saphenous vein bypass Extended profundoplasty Use of human umbilical vein grafts in lower extremity revascularizations In situ saphenous vein bypass popularized with introduction of new valve cutter Comparison of PTFE and saphenous vein grafts in lower extremity revascularizations

extractions of thromboembolic material from distant vessels.[95] Given the risks of open procedures for saddle aortic emboli that often followed a myocardial infarction and the difficulties in removing emboli originating from atrial fibrillation in the smaller arteries of the leg, the ability to remove occlusive material through a femoral artery under local anesthesia must be considered a sentinel contribution to the discipline of vascular surgery.

Aortic Aneurysms The lethal nature of aortic aneurysms led to many direct therapeutic advances, once clamping of the aorta proved tolerable and the postoperative management of these patients became better recognized. Charles Dubost was the first to successfully treat an abdominal aortic aneurysm in 1951.[94] He replaced the aneurysm with a thoracic aortic homograft in a relatively complex procedure. Shortly thereafter, in 1953, Michael DeBakey and Denton Cooley replaced a thoracic aortic aneurysm with a similar homograft.[95] These reconstructions occurred during a time of considerable interest in the use of homografts for a variety of vascular procedures. The inevitable degenerative changes affecting these conduits led to their later abandonment in the clinical practice of aortic surgery. Aortic aneurysm treatment changed dramatically shortly after Arthur Voorhees, Arthur Blakemore, and Alfred Jaretzki reported the successful implantation of Vinyon-N cloth grafts in animals in 1951.[72] Two years later, in 1953, they used this type of graft in a patient with a ruptured aortic aneurysm who subsequently died of a myocardial infarction. However, their case was made, and in 1954 they described the use of this type of synthetic graft in 17 patients.[96] Unfortunately, this nylon material proved too brittle. These grafts were replaced by conduits constructed of Teflon and Dacron, with the latter being popularized by DeBakey in the mid-1950s. Subsequent refinements involved lessening the risk of graft-enteric erosions by covering the implanted graft with the aneurysm shell, which in earlier times was usually excised en toto, and using synthetic sutures rather than silk, which with its deterioration led to late anastomotic separations of the graft

6

Part One. Assessment of Vascular Disease Table 1-5.

Aortic Aneurysms

Rudolph Matus

1923

Charles Dubost

1951

Arthur Voorhees, Arthur Blakemore, Alfred Jaretzki

1952

Michael DeBakey, Denton Cooley

1953

Michael DeBakey

1955

E. Stanley Crawford

1974

from the vessel and eventual development of pseudoaneurysms. A major innovation in the therapy of aortic aneurysmal disease was the 1974 reported success of E. Stanley Crawford in using intraluminal grafts to treat thoracoabdominal aneurysms that involved the renal and splanchnic arteries.[97] Although improvements in conventional open aortic aneurysm repair occurred during the succeeding years, the next major advance would not be until 1991 when Juan Parodi reported using an endograft to treat an abdominal aortic aneurysm.[98] This single contribution revolutionized the management of aortic aneurysms, and the subsequent decade witnessed many contributions to this new paradigm of vascular surgery. In the following years Veith and his colleagues extended the use of endografts to treatment of traumatic arterial disruptions,[99,100] and recently they reported the successful treatment of ruptured abdominal aortic aneurysms with endografts.[101,102] It would be an understatement to note that this technology has had a major impact on patient care and indeed the very definition of vascular surgery. The common association of femoral and popliteal artery aneurysms with aortic aneurysms, especially in male patients, was clearly established in the last half of the 20th century.[103 – 105] Few changes in the clinical management of these peripheral aneurysms occurred during recent decades, other than for lytic therapy for thrombosed popliteal artery aneurysms before their operative exclusion and bypass.

First successful ligation for treatment of abdominal aortic aneurysm; unsuccessful attempt by Ashley Cooper in 1817 Homograft replacement of abdominal aortic aneurysm Development of synthetic aortic graft (Vinyon-N) in experimental subjects. First clinical results with these grafts reported in 1953 Homograft replacement of thoracic aortic aneurysm Repair of abdominal aortic aneurysms with prosthetic grafts Intraluminal graft repair of thoracoabdominal aneurysms

performed by Marion S. DeWeese in 1958, was subsequently more widely used than endarterectomy.[108] Stoney and his colleagues favored using autologous iliac artery for reconstructing the renal arteries,[109] and DeCamp’s first successful nonanatomic renal revascularization by a splenorenal bypass in 1957 offered yet another alternative means of renal revascularization.[110] Despite these early contributions, the surgical treatment of renal artery occlusive disease was uncommon until after a series of publications from the Cooperative Study of Renovascular Hypertension in the mid-1970s. [111 – 115] Shortly thereafter large surgical series appeared from Vanderbilt University[116] and the University of Michigan[117] which firmly established the appropriateness of operation for renovascular hypertension. During the same time period a definitive classification of renal artery occlusive disease followed two publications, one from the Mayo Clinic in 1971[118] and the other from the University of Michigan in 1975.[119] Andreas Gruntzig and his colleagues reported the first successful percutaneous balloon dilation of an arteriosclerotic renal artery occlusive lesion in 1978.[120] This technology had revolutionized the treatment of renovascular hypertension by the close of the 20th century. Recent experiences suggest that percutaneous angioplasty is preferred for the treatment of most fibrodysplastic disease, and with the use of stents is efficacious in treating many arteriosclerotic ostial stenoses.

Renal Artery Occlusive Disease The first renal artery endarterectomy was performed by Norman Freeman in 1953,[106] a procedure popularized later by Edwin Wylie and his colleagues.[107] Nevertheless, aortorenal bypass using autogenous saphenous vein, first

Splanchnic Artery Occlusive Disease Acute intestinal ischemia, usually a consequence of embolism to the superior mesenteric artery, continued to be a lethal illness throughout latter half of the 20th century. Klass in

Table 1-6. Femoral and Popliteal Artery Aneurysms Ashley Cooper Jose´ Goyanes

1808 1906

Femoral aneurysm ligation (patient lived 18 years) Popliteal aneurysm excision, replaced with vein (first vein bypass graft used in clinical practice)

Chapter 1.

The Evolution of Vascular Surgery

7

Table 1-7. Splanchnic and Renal Artery Disease Renal artery disease Harry Goldblatt W.F. Leadbetter, G.E. Burkland Norman Freeman Marion DeWeese Andreas Gruntzig Splanchnic artery disease J. Englebert Dunphy J. Klass R.S. Shaw, E.P. Maynard W.P. Mikkelsen

1929 1938 1953 1958 1978

Established importance of renal artery occlusion and secondary hypertension Nephrectomy for renovascular hypertension (First treated case of renovascular hypertension) Renal artery endarterectomy Aortorenal bypass with autogenous vein Percutaneous renal artery balloon dilation

1936 1951 1958 1959

Description of chronic intestinal ischemia Superior mesenteric artery embolectomy Operative treatment of acute and chronic intestinal ischemia Operative treatment of chronic intestinal ischemia

1951 was the first to successfully treat acute intestinal ischemia by performance of a superior mesenteric artery embolectomy.[121] The operative treatment of both acute and chronic intestinal ischemia leading to today’s endarterectomy and bypass procedures was subsequently advanced by Shaw and Mikkelsen with their colleagues in the late 1950s.[122,123] Additional experience during the last few decades of the 20th century affirmed the generally accepted tenets that aortomesenteric bypasses with synthetic grafts were preferable to vein graft reconstructions, and that multiple vessel revascularizations were more likely to provide greater longterm benefits than single vessel reconstructions. However, no large clinical studies existed that properly compared the differing vascular options. Thus the surgical management of intestinal ischemia due to splanchnic arteriosclerosis must be considered somewhat anecdotal compared to treatment of other vascular diseases. The same conclusion applies to the therapy of many splanchnic artery aneurysms, with few definitive experiences reported since two widely quoted reviews were published in the 1970s.[124,125]

Cerebrovascular Disease Miller Fisher reported autopsy findings in 1951 that for the first time presented irrefutable evidence that extracranial

Table 1-8.

carotid artery bifurcation arteriosclerosis was likely to be a common cause of a stroke.[126] This led to a series of remarkable advances in the surgical treatment and prevention of stroke. The first reported operation for carotid artery stenotic disease was in 1951 by Raul Carrea, Mahelz Molins, and Guillermo Murphy, who resected the affected carotid artery and reanastomosed the internal carotid artery to the external carotid artery.[127] Three years later, in 1954, Felix Eascott, George Pickering, and Charles Rob reported a similar procedure with resection of the diseased carotid bifurcation and a reanastomosis of the internal carotid artery to the common carotid artery.[128] In 1953, the first conventional carotid endarterectomy was performed by Michael DeBakey.[129] One year later, in 1954, Davis, Grove, and Julian reported having performed the first innominate artery endarterectomy,[130] and in 1958 E. Stanley Crawford, Michael DeBakey, and William Fields reported endarterectomy as a means of treating vertebral artery occlusive disease.[131] The benefits of treating cerebral ischemic syndromes with a bypass was also first recognized during the mid-1950s. Lyons and Galbraith in 1956 performed a subclavian-tocarotid artery bypass,[132] and in 1958 Michael DeBakey and his associates reported an innominate artery-to-subclavian and carotid arterial bypass.[133] A vertebral artery bypass was also reported by Crawford, DeBakey, and Fields that same

Cerebrovascular Disease: Recognition

Egas Moniz Miller Fisher

1927 1951

Henry Barnett

1991, 1998

Robert Hobson

1993

James O’Toole

1995

Cerebral angiography Postmortem exam of 373 patients suggested arteriosclerosis of the extracranial carotid artery bifurcation might be a common cause of cerebrovascular accident North American Symptomatic Carotid Endarterectomy Trial (NASCET) documented benefit of surgical therapy for symptomatic stenotic lesions greater than 50% Surgical benefit documented for select treatment of asymptomatic carotid artery stenoses Asymptomatic Carotid Artery Study (ACAS) documented surgical benefit for asymptomatic lesions greater than 70%

8

Part One. Assessment of Vascular Disease

Table 1-9. Cerebrovascular Disease: Surgical Treatment Raul Carrea, Mahelz Molins, Guillermo Murphy Michael DeBakey H.H.G. (Felix) Eascott, George Pickering, Charles Rob C. Lyons and G. Galbraith J.B. Davis, W.J. Grove, O.C. Julian Michael DeBakey, George Morris, G.L. Jordan, Denton Cooley Stanley Crawford, Michael DeBakey, William Fields M. Gazi Yasargil, Hugh A. Krayenbuhl, Julius H. Jacobson II

1951

Resected arteriosclerotic carotid, with external to internal carotid reanastomosis (first operation for carotid stenotic disease) Carotid artery endarterectomy Resected carotid bifurcation, with common carotid to internal carotid reanastomosis Subclavian-carotid artery bypass Innominate artery endarterectomy Innominate-subclavian-carotid arterial bypass Vertebral artery endarterectomy and bypass Extracranial-intracranial arterial bypass

1953 1954 1956 1954 1957 1958 1970

year.[137] A more dramatic approach to these diseases was by an extracranial –intracranial arterial bypass, championed by Yasargil and his colleagues in the early 1970s.[134] This has been used infrequently following a still-controversial clinical study of the technique published by Henry Barnett and his colleagues in 1989.[135] One of the most important effects on the surgical treatment of carotid artery arteriosclerosis resulted from a series of welldesigned and -conducted prospective clinical studies initially published in the 1990s that better defined the indication for operative intervention. The first, the North American Symptomatic Carotid Endarterectomy Trial (NASCET), led by Henry Barnett, was published initially in 1991 and updated in 1998.[136,137] These studies documented the benefit of carotid endarterectomy in lessening the risk of subsequent stroke in patients with symptomatic stenotic lesions greater than 50%. Two other studies, one from Europe[138] and the other from Veterans Hospitals in the United States,[139] supported the NASCET conclusions. The beneficial effects of carotid endarterectomy in preventing stroke in patients with

Table 1-10.

asymptomatic carotid stenoses greater than 70% was subsequently reported by James O’Toole and Robert Hobson.[140,141] Although some may dispute the details of any of these studies, the benefits of a carefully performed carotid endarterectomy in a properly selected patient were definitively established. At the conclusion of the 20th century carotid endarterectomy was the most common vascular operation performed in the United States. At the close of the last century the introduction of percutaneous carotid artery dilation and stenting was touted as an appropriate alternative to carotid endarterectomy. However, its proper place in preventing stroke will only be established by yet-to-be-performed controlled clinical trials, not by individually reported series.

Venous Disease Prevention of embolization and venous hypertension arising from deep venous thromboses led to a number of

Venous Disease

Removal of varicose veins W.W. Babcock John Homans Correction of venous hypertension Robert Linton Jean Kunlin Eduardo Palma E.A. Husni Robert Kistner S.A. Taheri G. Hauer Prophylactic prevention of pulmonary embolism John Holmans O. Northway, Robert Buxton, E. O’Neill Marion S. DeWeese Kazi Mobin-Uddin Lazar J. Greenfield

1905 1916

Intraluminal stripper for vein removal Saphenofemoral vein ligation

1938 1952 1958 1970 1975 1982 1985

Subfascial division of incompetent perforating veins Saphenous vein bypass of obstructed external iliac vein Saphenofemoral vein crossover bypass Saphenopopliteal vein bypass Valvuloplasty Vein-valve transplant Endoscopic interruption of incompetent perforating veins

1934 1944 1958 1967 1974

Femoral vein ligation IVC ligation Suture plication of the IVC Transvenous IVC umbrella filter Percutaneous IVC conical-strut filter

Chapter 1.

important surgical interventions during the last half of the 20th century. Although ligation of the inferior vena cava had been performed earlier for prevention of pulmonary embolism, and often was used as the treatment of choice for septic emboli, the morbidity of this therapy was considerable. In 1958 Marion S. DeWeese was the first to partially interrupt the vena cava for the prevention of pulmonary emboli, using a suture plication technique.[142,143] In 1967 Kazi Mobin-Uddin introduced an umbrella device to trap emboli in transit.[144,145] This remarkable innovation was followed by Lazar Greenfield’s conical vena cava filter,[146] which was initially placed through the jugular vein with an open procedure, but was later inserted percutaneously through a femoral vein route. Subsequently, other caval devices have been developed to trap emboli from the lower body veins. The reduction in fatal pulmonary embolism using vena cava filters represents a major accomplishment of vascular surgeons. Treatment of venous hypertension in the last half of the 20th century focused on both direct venous reconstructive surgery and on less invasive procedures for interrupting incompetent perforating veins. In 1952 Jean Kunlin performed a saphenous vein bypass of an obstructed external iliac artery vein,[147] and 6 years later in 1958, Eduardo Palma performed a saphenofemoral vein crossover bypass.[148] A more distal decompressive procedure, a saphenopopliteal vein bypass, was accomplished by Husni in 1970.[148] More direct means of reducing elevated venous pressures in the lower extremity were introduced by Robert Kistner, who was the first to perform venous valvuloplasty procedures.[150,151] Taheri was the first to undertake transplantation of a vein valve to reduced venous hypertension.[152] Hauer in 1985 reported on the endoscopic interruption of incompetent perforating veins.[153] This less invasive means of interrupting perforating veins is undergoing current clinical study.[154] Durable treatment of venous diseases continued to challenge the surgical skills of vascular surgeons at the close of the 20th century.

THE EARLY 21ST CENTURY The diagnosis of vascular disease in the early years of the current millennium will evolve in two primary arenas. The first relates to genetic analysis technology that will identify patients at risk for various arteriosclerotic disorders, matrix problems leading to aneurysms, and other vascular diseases. This will revolutionize the selection of patients for early

The Evolution of Vascular Surgery

9

interventions, both medical and surgical, and will affect vascular surgery more than any other advance since the introduction of vascular grafts and heparin. The second relates to new modalities of imaging that will define both the anatomic presence or absence of disease, as well as the functional relevance of vascular lesions. These changes will occur within years. The therapy of vascular diseases will also change dramatically, with the most immediate change related to the endovascular treatment of many diseases heretofore amenable only to open surgical procedures. Two other events are on the horizon, but have not come to fruition. The first relates to the production of antithrombotic biologic vascular prostheses through the cloning of human tissues. Although the ethics of this may be questioned, the benefits are too important to patients who have no available conduits for treatment of their diseases to believe that the technology will not rapidly become available to practitioners. Lastly, gene therapy with the introduction of DNA responsible for specific proteins that will affect the status of a vascular disease or improve the outcome of an interventional procedure will likely become available within the first half of this century. Again, the ethical concerns regarding this are important, but are unlikely to slow the introduction of this therapy for somatic cell treatment of vascular diseases, The practice of vascular surgery, especially in industrial nations during the early decades of the 21st century, will be impacted by increasing costs of technology, a greater number of patients needing therapy as the population ages, and the involvement of third parties in controlling affordable medical practice. Given society’s greater medical literacy and availability of the internet there will also be an increasing patient demand for better care in relation to outcomes. Vascular surgery, because of its easily documented clinical endpoints, should be the beneficiary of evidence-based care. Lastly, there will be complementary and competing practices in the new millennium. This will likely result in the establishment of true multidisciplinary care and the elimination of those disciplines that are unable to adapt to new paradigms of practice. Vascular surgery can ill afford to not adapt to change. This relates to training and certification in a bureaucratic era, where benefits of treatment, and surgical intervention in particular, must outweigh the risk of alternative therapies. Durable benefits must be afforded patients. The evolution of vascular surgery during the last half of the 20th century was one of enormous success. The challenge now is to enhance the knowledge base and practice patterns enacted by our discipline’s forebears as we enter the 21st century.

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Part One. Assessment of Vascular Disease Palma, E.C. The Treatment of Arteritis of the Lower Limbs by Autogenous Vein Grafts. Minerva. Cardioangiol. Eur. 1960, 8, 36– 49. Hall, K.V. The Great Saphenous Vein Used In Situ as in Arterial Shunt After Extirpation of the Vein Valves. Surgery 1962, 51, 492– 495. Leather, R.P.; Powers, S.R., Jr.; Karmody, A.M. The Reappraisal of the In Situ Saphenous Vein Arterial Bypass: Its Use in Limb Salvage. Surgery 1979, 86, 453–461. Dardik, H.; lbrahim, I.M.; Sprayregan, Dardik, II. Clinical Experiences with Modified Human Umbilical Cord Vein for Arterial Bypass. Surgery 1976, 79, 618– 624. Dardik, H.; Miller, N.; Dardik, A.; Ibrahim, I.M.; Sussman, B.; Silvia, M.; Berry, M.; Wolodiger, F.; Kahn, M.; Dardik, I. A Decade of Experience with the Glutaraldehyde-Tanned Human Umbilical Cord Vein Graft for Revascularization of the Lower Limb. J. Vasc. Surg. 1988, 7, 336– 346. Bergan, J.J.; Veith, F.J.; Bernhard, V.M.; Yao, J.S.T.; Flinn, W.R.; Gupta, S.K.; Scher, L.A.; Samson, R.H.; Towne, J.B. Randomization of Autogenous Vein and Polytetrafluoroethylene Grafts in Femoral Distal Reconstruction. Surgery 1982, 92, 921– 930. Veith, F.J.; Gupta, S.K.; Ascer, E.; White-Flores, S.; Samson, R.H.; Scher, L.A.; Towne, J.B.; Bernhard, J.J. Six-Year Prospective Multicenter Randomized Comparison of Autologous Saphenous Vein and Expanded Polytetrafluoroethylene Grafts in Infrainguinal Arterial Reconstructions. 1985, 3, 104– 114. Martin, P.; Renwick, S.; Stephenson, C. On the Surgery of the Profunda Femoris Artery. Br. J. Surg. 1971, 55, 539–542. Fogarty, T.J.; Cranley, J.J.; Krause, R.J.; Strasser, E.S.; Hafner, C.D. A Method for Extraction of Arterial Emboli and Thrombi. Surg. Gynecol. Obstet. 1963, 116, 241– 244. Dubost, C.; Allary, M.; Oeconomos, N. Resection of an Aneurysm of the Abdominal Aorta: Reestablishment of the Continuity by a Preserved Human Arterial Graft, with Results After Five Months. Arch. Surg. 1952, 64, 405–408. DeBakey, M.E.; Cooley, D.A. Successful Resection of Aneurysm of Thoracic Aorta and Replacement by Graft. J. Am. Med. Assoc. 1953, 152, 673– 676. Blakemore, A.H.; Voorhees, A.B., Jr. The Use of Tubes Constructed from Vinyon “N” Cloth in Bridging Arterial Defects—Experimental and Clinical. Ann. Surg. 1954, 140, 324– 334. Crawford, E.S. Thoraco-Abdominal Aortic Aneurysms Involving Renal, Superior Mesenteric and Celiac Arteries. Ann. Surg. 1974, 179, 763– 772. Parodi, J.; Palmaz, J.C.; Barone, H.D. Transfemoral Intraluminal Graft Implantation for Abdominal Aortic Aneurysms. Ann. Vasc. Surg. 1991, 5, 491– 499. Marin, M.L.; Veith, F.J.; Cynamon, J.; Panetta, T.F.; Bakal, C.W.; Kerr, A.; Parodi, J.C. Transfemoral Endoluminal Repair of a Penetrating Vascular Injury. J. Vasc. Intervent. Radiol. 1994, 5, 592– 594. Marin, M.L.; Veith, F.J.; Panetta, T.F.; Cynamon, J.; Sancez, L.A.; Schwartz, M.L.; Lyon, R.T.; Bakal, C.W.;

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Suggs, W.D. Transluminally Placed Endovascular Stented Graft Repair for Arterial Trauma. J. Vasc. Surg. 1994, 20, 466– 472. Ohki, T.; Veith, F.J.; Sanchez, L.A.; Cynamon, J.; Lipsitz, E.C.; Wain, R.A.; Morgan, J.A.; Zhen, L.; Suggs, W.D.; Lyon, R.T. Endovascular Graft Repair of Ruptured Aortoiliac Aneurysms. Am. Coll. Surg. 1999, 189, 102– 112. Ohki, T.; Veith, F.J. Endovascular Grafts and Other Image-Guided Catheter-Based Adjuncts to Improve the Treatment of Ruptured Aortoiliac Aneurysms. Ann. Surg. 2000, 232, 466– 479. Diwan, A.; Sarkar, R.; Stanley, J.C.; Zelenock, G.B.; Wakefield, T.W. Incidence of Femoral and Popliteal Artery Aneurysms in Patients with Abdominal Aortic Aneurysms. J. Vasc. Surg. 2000, 31, 863– 869. Graham, L.M.; Zelenock, G.B.; Whitehouse, W.M., Jr.; Erlandson, E.E.; Dent, T.L.; Lindenauer, S.M.; Stanley, J.C. Clinical Significance of Arteriosclerotic Femoral Artery Aneurysms. Arch. Surg. 1980, 115, 502– 507. Whitehouse, W.M., Jr.; Wakefield, T.W.; Graham, L.M.; Kazmers, A.; Zelenock, G.B.; Cronenwett, J.L.; Dent, T.L.; Lindenauer, S.M.; Stanley, J.C. Limb Threatening Potential of Arteriosclerotic Popliteal Artery Aneurysms. Surgery 1983, 93, 694– 699. Freeman, N.E.; Leeds, F.H.; Elliott, W.G.; Roland, S.I. Thromboendarterectomy for Hypertension Due to Renal Artery Occlusion. J. Am. Med. Assoc. 1954, 156, 1077– 1079. Wylie, E.J.; Perloff, D.L.; Stoney, R.J. Autogenous Tissue Revascularization Techniques in Surgery for Renovascular Hypertension. Ann. Surg. 1969, 170, 416– 428. Stanley, J.C. Surgical Treatment of Renovascular Hypertension. Am. J. Surg. 1997, 174, 102– 110. Stoney, R.J.; DeLuccia, N.; Ehrenfeld, W.K.; Wylie, E.J. Aortorenal Arterial Autografts, Long-Term Assessment. Arch. Surg. 1981, 116, 416– 422. DeCamp, P.T.; Snyder, G.H.; Bost, R.B. Severe Hypertension due to Congenital Stenosis of Artery to Solitary Kidney: Correction by Splenorenal Arterial Anastomosis. Arch. Surg. 1957, 75, 1023– 1026. Bookstein, J.J.; Abrams, H.L.; Buenger, R.E.; Reiss, M.D.; Lecky, J.W.; Franklin, S.S.; Bleifer, K.H.; Varady, P.D.; Maxwell, M.H. Radiologic Aspects of Renovascular Hypertension: Part 2. The Role of Urography in Unilateral Renovascular Disease. J. Am. Med. Assoc. 1972, 220, 1225– 1230. Bookstein, J.J.; Abrams, H.L.; Buenger, R.E.; Reiss, M.D.; Lecky, J.W.; Franklin, S.S.; Bleifer, K.H.; Varady, P.D.; Maxwell, M.H. Radiologic Aspects of Renovascular Hypertension Part 3. Appraisal of Arteriography. J. Am. Med. Assoc. 1972, 221, 368– 374. Bookstein, J.J.; Maxwell, M.H.; Abrams, H.L.; Buenger, R.E.; Lecky, J.; Franklin, S.S. Cooperative Study of Radiologic Aspects of Renovascular Hypertension. Bilateral Renovascular Disease. J. Am. Med. Assoc. 1977, 237, 1706– 1709. Foster, J.H.; Maxwell, S.S.; Bleifer, K.H.; Trippel, O.H.; Julian, O.C.; DeCamp, P.T.; Varady, P.D. Renovascular Occlusive Disease: Results of Operative Treatment. J. Am. Med. Assoc. 1975, 231, 1043– 1048.

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Franklin, S.S.; Young, J.D.; Maxwell, M.H.; Foster, J.H.; Palmer, J.M.; Cerny, J.; Varady, P.D. Operative Morbidity and Mortality in Renovascular Disease. J. Am. Med. Assoc. 1975, 231, 1148– 1153. Foster, J.H.; Dean, R.H.; Pinkerton, J.A.; Rhamy, R.L. Ten Years Experience with Surgical Management of Renovascular Hypertension. Ann. Surg. 1973, 177, 755– 766. Ernst, C.B.; Stanley, J.C.; Marshall, F.F.; Fry, W.J. Autogenous Saphenous Vein Aortorenal Grafts. A TenYear Experience. Arch. Surg. 1972, 105, 855– 864. Harrison, E.G., Jr.; McCormack, L.J. Pathology Classification of Renal Arterial Disease in Renovascular Hypertension. Mayo. Clin. Proc. 1971, 46, 161–167. Stanley, J.C.; Gewertz, B.L.; Bove, E.L.; Sottiurai, V.; Fry, W.J. Arterial Fibrodysplasia. Histopathologic Character and Current Etiologic Concepts. Arch. Surg. 1975, 110, 551– 556. Gruntzig, A.; Kuhlmann, U.; Vetter, W.; Lutolf, U.; Meier, B.; Siegenthaler, W. Treatment of Renovascular Hypertension with Percutaneous Transluminal Dilatation of a Renal-Artery Stenosis. Lancet 1978, 1, 801– 802. Klass, J. Embolectomy in Acute Mesenteric Occlusion. Ann. Surg. 1951, 134, 913– 917. Shaw, R.S.; Maynard, E.P. Acute and Chronic Thrombosis of the Mesenteric Arteries Associated with Malabsorption. Report of Two Successful Cases Treated by Thromboendarterectomy. N. Engl. J. Med. 1958, 258, 874– 878. Mikkelsen, W.P.; Zaro, J.A. Intestinal Angina: Report of a Case with Preoperative Diagnosis and Surgical Relief. N. Engl. J. Med. 1959, 260, 912– 914. Deterling, R.A. Aneurysm of the Visceral Arteries. J. Cardiovasc. Surg. 1971, 12, 309– 322. Stanley, J.C.; Thompson, N.W.; Fry, W.J. Splanchnic Artery Aneurysms. Arch. Surg. 1970, 101, 689– 697. Fisher, M. Occlusion of the Internal Carotid Artery. Arch. Neurol. Psychiatry 1951, 65, 346– 377. Carrea, R.; Molins, M.; Murphy, G. Surgical Treatment of Spontaneous Thrombosis of the Internal Carotid Artery in the Neck. Carotid-Carotideal Anstomosis. Report of a Case. Acta Neurol. Latinoamer 1955, 1, 71– 78. Eastcott, H.H.G.; Pickering, G.W.; Rob, C.G. Reconstruction of Internal Carotid Artery in a Patient with Intermittent Attacks of Hemiplegia. Lancet 1954, 2, 994– 996. DeBakey, M.E. Successful Carotid Endarterectomy for Cerebrovascular Insufficiency: Nineteen Year Follow-Up. J. Am. Med. Assoc. 1975, 233, 1083– 1085. Davis, J.B.; Grove, W.J.; Julian, O.C. Thrombotic Occlusion of the Branches of the Aortic Arch; Martorll’s Syndrome: Report of a Case Treated Surgically. Ann. Surg. 1956, 144, 124– 126. Crawford, E.S.; DeBakey, M.E.; Fields, W.S. Roentgenographic Diagnosis and Surgical Treatment of Basilar Artery Insufficiency. J. Am. Med. Assoc. 1958, 168, 514. Lyons, C.; Galbraith, G. Surgical Treatment of Atherosclerotic Occlusion of the Internal Carotid Artery. Ann. Surg. 1957, 146, 487– 498. DeBakey, M.E.; Morris, G.C.; Jordan, G.L.; Cooley, D.A. Segmental Thrombo-Obliterative Disease on Branches

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of Aortic Arch. J. Am. Med. Assoc. 1958, 166, 998– 1003. Yasargil, M.C.; Krayenbuhl, H.A.; Jacobson, J.H., II. Microneurosurgical Arterial Reconstruction. Surgery 1970, 67, 221– 233. Extracranial/Intracranial Bypass Study Group; Failure of Extracranial—Intracranial Anterior Bypass to Reduce the Risk of Ischemic Stroke. N. Engl. J. Med. 1985, 313, 1191– 1200. North American Symptomatic Carotid Endarterectomy Trial Collaborators; Beneficial Effect of Carotid Endarterectomy in Symptomatic Patients with High-Grade Carotid Stenosis. N. Engl. J. Med. 1991, 325, 325– 453. Barnett, H.J.; Taylor, D.W.; Eliasziw, M.; Fox, A.J.; Ferguson, G.G.; Haynes, R.B.; Rankin, R.N.; Clagett, G.P.; Hacinski, V.C.; Sackett, D.L.; Thorpe, K.E.; Math, M.; Meldrum, H.E. Benefit of Carotid Endarterectomy in Patients with Symptomatic Moderate or Severe Stenosis. N. Engl. J. Med. 1998, 339, 1415– 1425. European Carotid Surgery Trialists’ Collaborative Group; MRC European Carotid Surgery Trial: Interim Results for Symptomatic Patients with Severe (70 – 99%) or with Mild (0 – 29%) Carotid Stenosis. Lancet 1991, 337, 1235 – 1243. for the Veterans Affairs Cooperative Studies Program 309 Trialist Group; Mayberg, M.R.; Wilson, S.F.; Yatsu, F.; Weiss, D.G.; Messina, L.; Hershey, L.A. Carotid Endarterectomy and Prevention of Cerebral Ischemia in Symptomatic Carotid Stenosis. J. Am. Med. Assoc. 1991, 266, 3259– 3295. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study; Endarterectomy for Asymptomatic Carotid Artery Stenosis. J. Am. Med. Assoc. 1995, 273, 1421– 1428. The Veterans Affairs Cooperative Study Group; Hobson, R.W., II.; Weiss, D.G.; Fields, W.S.; Goldstone, J.; Moore, W.S.; Towne, J.B.; Wright, C.B. Efficacy of Carotid Endarteretomy for Asymptomatic Carotid Stenosis. N. Engl. J. Med. 1993, 328, 221–227. DeWeese, M.S.; Hunter, D.C., Jr. A Vena Cava Filter for the Prevention of Pulmonary Emboli. Bull. Soc. Int. Chir. 1958, 1, 1 – 19. DeWeese, M.S.; Kraft, R.O.; Nichols, K.W. Fifteen-Year Clinical Experience with Vena Cava Filter. Ann. Surg. 1973, 178, 247– 257. Mobin-Uddin, K.; Smith, P.E.; Martinez, L.D.; Lombardo, C.R.; Jude, J.R. A Vena Cava Filter for the Prevention of Pulmonary Embolus. Surg. Forum 1967, 18, 209– 211. Mobin-Uddin, K.; McLean, R.; Bolooki, H.; et al. Caval Interruption for Prevention of Pulmonary Embolism. Long-Term Results of a New Method. Arch. Surg. 1969, 99, 71l– 715. Greenfield, L.J.; Peyton, M.D.; Brown, P.P.; Elkins, R.C. Transvenous Management of Pulmonary Embolic Disease. Ann. Surg. 1974, 180, 461– 468. Kunlin, J. The Reestablishment of Venous Circulation with Grafts in Cases of Obliteration from Trauma or Thrombophlebitis. Mem. Acad. Clin. 1953, 79, 109. Palma, E.C.; Esperon, R. Vein Transplants and Grafts in the Surgical Treatment of the Post Phlebitic Syndrome. J. Cardiovasc. Surg. 1960, 1, 94– 107.

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Husni, E.A. In Situ Saphenopopliteal Bypass Graft for Incompetence of the Femoral and Popliteal Veins. Surg. Gynecol. Obstet. 1970, 2, 279– 284. 150. Kistner, R. Surgical Repair of a Venous Valve. Straub. Clin. Proc. 1968, 34, 41– 43. 151. Kistner, R. Surgical Repair of the Incompetent Femoral Vein Valve. Arch. Surg. 1975, 110, 1336– 1342. 152. Taheri, S.A.; Lazar, L.; Elias, S.; Marchand, P.; Heffner, R. Surgical Treatment of Posphlebitic Syndrome with Vein Valve Transplant. Am. J. Surg. 1982, 144, 221– 224.

153. Hauer, G. The Endoscopic Subfascial Division of the Perforating Veins—Preliminary Report. Vasa 1985, 14, 59– 61. 154. The North American Study Group; Gloviczki, P.; Bergan, J.J.; Rhodes, J.M.; Canton, L.G.; Harmsen, S.; Ilstrup, D.M. Mid-Term Results of Endoscopic Perforator Vein Interruption for Chronic Venous Insufficiency: Lessons Learned from the North American Subfascial Endoscopic Perforator Surgery Registry. J. Vasc. Surg. 1999, 29, 489– 502.

CHAPTER 2

Pathophysiology of Atherosclerosis Russell Ross†

number of T lymphocytes together with varying numbers of smooth-muscle cells. Both the macrophages and smooth muscle contain deposits of cholesterol and cholesterol oleate. Fatty streaks can be found in increasing numbers between the ages of 8 and 18 years. Fatty streaks appear in the coronary arteries at about the age of 15 years and continue to increase in amount in these vessels through the third decade of life.[4] The lesions are yellowish and sessile and cause little or no obstruction of the affected artery and no clinical sequelae. The fatty streak is ubiquitous in young people and even in those populations that do not appear to develop severe atherosclerosis. This observation suggests that lipid deposition does not inevitably lead to the advanced lesions of atherosclerosis but that a number of other factors are associated with the progression of the lesions and with the development of the more complex form of atherosclerosis, the fibrous plaque.

THE DISEASE PROCESS The lesions of atherosclerosis take different forms depending upon their anatomic site; the age, genetic, and physiological status of the affected individual; and the so-called risk factors to which each individual may have been exposed. The examination of atherosclerotic lesions with modern techniques of cell and molecular biology has revealed that each lesion contains significant elements of a specialized chronic inflammatory fibroproliferative response. These consist of accumulated monocyte/macrophages and T lymphocytes followed by smooth-muscle proliferation; the formation by the proliferated cells of large amounts of connective tissue matrix, including collagen, elastic fibers, and proteoglycans; and the accumulation of intracellular and extracellular lipid.[1,2] In each instance, the relative degree to which each of the cells responds to different atherogenic stimuli determines the unique combination of these three elements that defines the type and extent of the resulting lesion. The lesions of atherosclerosis occur principally within the innermost layer of the artery wall, the intima. They include the fatty streak, the fibrous plaque, and the so-called complicated lesions.[2,3] Secondary changes have been noted in the media of the artery underlying the lesion, principally in association with the more advanced lesions of atherosclerosis.

The Fibrous Plaque More advanced lesions begin to develop around the age of 25 in those populations in which there is a high incidence of atherosclerosis and its clinical sequelae. The fibrous plaque is grossly white; it becomes elevated and therefore may protrude into the lumen of the artery. If this lesion progresses sufficiently, it can occlude the lumen and compromise the vascular supply of the involved tissue. The principal change that occurs within the arterial intima during the development of the fibrous plaque consists of the proliferation of smoothmuscle cells. These cells usually form a fibrous cap due to the deposition by the cells of new connective tissue matrix and to the accumulation of intracellular and extracellular lipids. The fibrous cap covers a deeper deposit of varying amounts of extracellular lipid and cell debris.[5] It has been suggested that fibrous plaques are derived from fatty streaks that continue the process of cell proliferation, lipid accumulation, and connective tissue formation and that the deep core of lipid and cell debris results from inadequate blood supply and cell necrosis. Such a relationship has not been proved, since—although fatty streaks in young persons are often found at the same

The Lesions The Fatty Streak The process of atherosclerosis begins in childhood with the development of flat, lipid-rich lesions called fatty streaks. These lesions consist of lipid-laden macrophages and variable

Portions of this chapter are reprinted from Hurst JW (ed): The Heart, 7th ed., q 1990 by McGraw-Hill, Inc. Used with permission of J. Willis Hurst and McGraw-Hill, Inc. †

Deceased.

Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024885 Copyright q 2004 by Marcel Dekker, Inc.

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anatomic location in the coronary and extracranial cerebral arteries as fibrous plaques in older persons—fatty streaks can also occur at anatomic sites that are different from those at which fibrous plaques appear. The reasons for these differences are not understood. It has been suggested that in those instances in which their location is different, the fatty streaks have simply regressed and disappeared, whereas in the instances in which the anatomic location is the same, lesion progression has occurred. This remains a matter of controversy.[6]

The Complicated Lesion The complicated lesions of atherosclerosis occur with increasing frequency with increasing age. The fibrous plaque can become vascularized from both the luminal and medial aspects. In the complicated lesion, the necrotic “lipid-rich core” increases in size and often becomes calcified. The lesions may become increasingly complex as a result of hemorrhage and calcification, and the intimal surface may disintegrate, fissure, or ulcerate and become involved with thrombotic episodes that may lead to occlusive disease. Such thrombi may then organize and further increase the thickness of the plaque while progressively reducing the size of the arterial lumen. Sometimes, as the intimal lesions progress, the number of smooth muscle cells in the underlying media decreases and the media atrophies; this can result in aneurysmal changes rather than thrombotic occlusion of the artery. There is quite a range in the degree of severity of the atherosclerotic lesions in different arteries. The recognition that smooth-muscle proliferation, connective tissue formation, and lipid accumulation represent the key elements of the developing lesions of atherosclerosis has led to the use of a number of models of experimentally induced atherosclerosis to study this process in different animal species.

Plaque Rupture Plaque rupture and the thrombosis that usually results from the rupture have been shown to be responsible for 50% or more of the cases of acute coronary syndromes, myocardial infarction, and sudden death.[7,8] Plaque erosion and rupture usually occur from irregular thinning of the fibrous cap that covers the necrotic core in most advanced lesions. Thinning often happens at the shoulder of the lesion where monocytederived macrophages accumulate and elaborate metalloproteases.[9] These proteins can degrade the matrix, lead to instability of the fibrous cap, and cause rupture at sites of high stress. Macrophages may be activated by numerous factors, including activated T cells. Macrophage activation is often accompanied by increased levels of tissue factor and other hemostatic factors, which help to increase the probability of blood coagulation and, ultimately, thrombosis. These dangerous plaques present a formidable problem because they may be no more than 40% occlusive and not necessarily picked up on angiographic examination.[7,10,11] Control of macrophage activation is an important part of dealing with

the chronic inflammatory response that represents every phase of the process of atherogenesis.[10]

Studies in Experimental Animals Five species have been widely used in studying atherogenesis: rabbits, chickens, swine, mice, and nonhuman primates. Most early work was performed in rabbits; however, swine and nonhuman primates are generally considered to develop lesions that correspond more closely with those that occur in human beings. Atherosclerosis has been induced in most of the animal models by a high-fat, high-cholesterol diet. A principal shortcoming of this approach, however, is that to produce more advanced lesions, it is necessary to maintain animals on such diets for years. Even though it is possible to induce the lesions in a relatively short period (1– 3 years in the monkey), it is not clear that the lesions produced in this manner actually simulate those that may require 20– 30 years to form in human beings. On the other hand, the rate at which the lesions form in humans is not entirely clear; some may progress more rapidly than had heretofore been considered to be possible.[12] Other approaches to studying the smooth-muscle proliferative changes associated with atherosclerosis have included endothelial injury resulting from mechanical trauma from various types of intraarterial catheters,[13,14] chemically induced injury from sources such as chronic hypercholesterolemia[15] or chronic homocystinemia,[16] immune-type injury from exposure to antigen-antibody complexes,[17] and, more recently, virally induced injury in diseases such as Marek’s disease.[18] In a recent study of diet-induced hypercholesterolemia in nonhuman primates, Faggiotto et al.[19,20] and Masuda and Ross[21,22] described the changes that lead to fatty streak development and the manner in which some fatty streaks progress to become more complicated fibrous plaques. Within 12 days after the induction of high levels of plasma cholesterol (. 700 mg/dL), numerous monocytes and T lymphocytes were observed attached to the surface of the endothelium throughout the arterial tree. These leukocytes probe between junctional complexes of the endothelium, migrate, and localize subendothelially, where they accumulate lipid and become foam cells that establish the initial fatty streak. These fatty streaks form at branches and bifurcations and accumulate increasing numbers of macrophages, T cells, and smooth-muscle cells and in the process create a markedly uneven surface contour and stretch the overlying endothelium exceedingly thin. After about 5 months, breaks occur between endothelial cells, exposing the lipid-filled macrophages, some of which appear to enter the circulation. Many of the exposed macrophages serve as sites where platelets adhere and form mural thrombi. These sites of platelet-macrophage interactions were first observed in the iliac arteries; after longer periods of hypercholesterolemia, similar changes occur at higher levels in the abdominal and then the thoracic aorta and finally in the coronary arteries. Interestingly, the sites that are first involved with platelet-macrophage interactions are the same sites that 1–2 months later contain the proliferative smooth-muscle lesions of atherosclerosis. These findings further support observations that endothelial injury and

Chapter 2.

platelet-macrophage interactions may be important in atherogenesis. Some of the most recent advance in the use of experimental animals has come with the development of genetically modified mice. With the development of the homozygous apolipoprotein E –deficient (ApoE -/-) and the homozygous low-density lipoprotein receptor – deficient (LDL-R -/-) mice, small murine models of atherogenesis have opened remarkable opportunities to study and understand the process of atherogenesis. The ApoE -/- mouse, in particular, has been of great benefit because it develops lesions of atherosclerosis at sites analogous to those in humans.[23,24] The cellular events at every stage of lesion formation and progression are identical to those in humans. Thus, upregulation of adhesion molecules in outflow tracks, branches, and bifurcations leads to lymphocyte and monocyte adhesion and entry. Fatty streaks form and then develop into intermediate lesions and, finally, advanced lesions.[24,25] It is possible to examine the impact of the addition or removal of specific factors in mice. For example, one can mate the ApoE -/- mouse with the M-CSF – deficient mouse[26] or with mice that lack vascular adhesion molecules. One can make mice chimerically deficient in a growth factor in subsets of their hematopoietic precursor cells or in sitespecific alterations to make a tissue or organ, such as the arterial system, devoid of given molecules. The development of such mice represents a powerful approach that may rapidly shed light on the process of atherogenesis, which can be confirmed in larger animals, such as nonhuman primates, and, ultimately, in humans.

HYPOTHESES OF ATHEROGENESIS Atherosclerosis has been recognized in humans for thousands of years. Lesions of atherosclerosis were identified in Egyptian mummies as early as the fifteenth century B.C. Long[27] discussed the development of clinical-pathological correlations during the era when autopsy permitted an understanding of the relationship between the degree of atherosclerosis and the incidence of myocardial infarction and stroke. In the mid-nineteenth century, Virchow[28] proposed that some form of injury to the artery wall associated with an inflammatory response results in what was then considered to be the degenerative lesion of atherosclerosis. This idea was subsequently modified by Anitschkow[29] and further included the role of platelets and thrombogenesis in atherosclerosis, as expounded by Duguid[30] in 1948. Many of the modern views of atherogenesis stem from the work of John French,[31] who suggested that the structural integrity of the endothelial lining of the artery represents a key element in the maintenance of normal arterial function and that alterations in endothelial integrity may precede a sequence of events that lead to the various lesions in atherosclerosis. Thus, over the years, a number of theories concerning the etiology and pathogenesis of atherosclerosis have been developed. At least one of these deserves elaboration and comment: the response-to-injury hypothesis.

Pathophysiology of Atherosclerosis

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The Response-to-Injury Hypothesis One basis for the response-to-injury hypothesis of atherosclerosis[2,15,32] lies in the marked similarity, observed by many investigators, between the ubiquitous fibromusculoclastic lesions noted at autopsy and a similar lesion that can be induced in a number of animal species—including nonhuman primates, rabbits, and swine—after experiencing different forms of arterial endothelial injury. This hypothesis states that some form of “injury” to the endothelium results in structural and/or functional alterations in the endothelial cells. Factors such as chronic hypercholesterolemia,[15] decreased shear stress from the flow of blood over the endothelial cells, as may occur at branch points or bifurcations in arteries in hypertension,[33] and dysfunction induced by toxins or other injurious agents may lead to changes in the nature of the permeability barrier established by the endothelial cells. In the normal artery, the endothelial cells form a continuous monolayer that regulates the passage of substances from the plasma to the underlying artery wall. Injury to the endothelial cells may alter their permeability characteristics and change endothelial cell-cell or endothelial cell –connective tissue relationships, permitting hemodynamic forces to induce focal endothelial cell dysfunction and thus permit interactions to occur between elements from the blood and the wall of the artery. Not only do the endothelial cells play an important role as a permeability barrier, but they also form a thromboresistant surface that promotes the continuous flow of blood throughout the vascular tree. The thromboresistant character of the endothelium appears to be due principally to three factors produced by the cells. These have been identified, but their physiological roles are relatively poorly understood. They are nitric oxide (NO), the glycoproteins and proteoglycans, which form the surface coat of the endothelial cells, and a prostaglandin derivative, prostacyclin (PGI2).[34] Nitric oxide and prostacyclin are two of the most potent vasodilatory agents thus far isolated, as well as being potent inhibitors of platelet aggregation. Both of these substances can be formed by endothelium and smooth muscle. Nitric oxide appears to be responsible for the normal vasodilatory tone maintained in arterial homeostasis.[35] This is discussed in greater detail below. Endothelial injury that results in alterations in permeability would permit plasma constituents such as lipoproteins to have more ready access to the artery wall. Endothelial dysfunction could also alter the thromboresistant character of the lumen of the artery so that leukocytes and platelets could interact directly at the sites of endothelial injury. If the injury were sufficiently severe, the endothelial cells might detach and be lost into the bloodstream, exposing the underlying connective tissue to platelets and to other elements in the circulation. The response-to-injury hypothesis suggests that the interaction between leukocytes and the endothelium and between platelets and the subendothelial connective tissue, principally collagen, can result in entry of monocytes into the intima and/or platelet adherence, platelet aggregation, and the release of contents normally stored within the granules of the platelets, in particular a mitogen, the platelet-derived growth factor (PDGF). At the sites of injury the exposure of the artery wall to factors derived from

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Part One. Assessment of Vascular Disease

the activated monocyte-derived macrophages and/or platelets, together with components from the plasma, such as lipoproteins and hormones, would then lead to the focal proliferation of arterial smooth-muscle cells. According to the hypothesis, this smooth-muscle proliferation would be derived from two sources: preexisting intimal smooth-muscle cells and medial smooth-muscle cells that are attracted to and

migrate and proliferate within the intima at the sites of injury. Such a local stimulus could also lead to the formation of new connective tissue matrix constituents by the proliferating smooth-muscle cells and to the deposition of lipids both within and around the proliferated cells (Fig. 2-1). According to this hypothesis, if the injury to the endothelium were a self-limited event and endothelial

Figure 2-1. The response-to-injury hypothesis. Advanced intimal proliferative lesions of atherosclerosis may occur by at least two pathways. The pathway demonstrated by the clockwise long arrows has been observed in experimentally induced hypercholesterolemia. Injury to the endothelium (A) may induce growth factor secretion (short arrow ). Monocytes attach to endothelium (B ), which may continue to secrete growth factors (short arrow ). Subendothelial migration of monocytes (C ) may lead to fatty-streak formation and release of growth factors such as platelet-derived growth factor (PDGF) (short arrow ). Fatty streaks may become directly converted to fibrous plaques (long arrow, C to F ) through release of growth factors from macrophages or endothelial cells or both. Macrophages may also stimulate or injure the overlying endothelium. In some cases, macrophages may lose their endothelial cover and platelet attachment may occur (D), providing three possible sources of growth factors—platelets, macrophages, and endothelium (short arrows ). Some of the smooth-muscle cells in the proliferative lesion itself (F ) may form and secrete growth factors such as PDGF (short arrows ). An alternative pathway for the development of advanced lesions of atherosclerosis is shown by the arrows from A to E to F. In this case, the endothelium may be injured but remain intact. Increased endothelial turnover may result in growth factor formation by endothelial cells (A ). This may stimulate migration of smooth-muscle cells from the media into the intima, accompanied by endogenous production of PDGF by smooth muscle as well as growth factor secretion from the “injured” endothelial cells (E ). These interactions could then lead to the formation of fibrous plaques and further progression of the lesion (F ). (Reproduced from Ross.[2])

Chapter 2.

functional integrity were restored, the proliferative lesions would be capable of regressing. If this were the case, the lesions would be reversible, and if they had not reached a critical size, they would be clinically silent. There is evidence both in experimental animals and in human beings that the lesions of atherosclerosis can, under certain conditions, regress.[36] On the other hand, if the injury at focal sites in the artery wall is either sufficiently long-standing or chronically repeated over periods of many years, the lesions could continue to progress, become increasingly complex in composition, and eventually lead to the principal clinical sequelae of atherosclerosis, myocardial infarction, and cerebral infarction. The capacity of the endothelium to regenerate and to restore functional integrity at sites of injury may be critical in determining whether the lesions of atherosclerosis enlarge, remain relatively constant in size, or regress. The superimposition of risk factors possibly affects this balance by providing a chronic source of injury or by somehow altering the normal balance so that lesions become slowly progressive. As an example, the increased levels of plasma low-density lipoproteins (LDL) associated with hypercholesterolemia may provide a source of injury to the endothelial cells and may also convert what might otherwise be a limited tissue response to injury to the frank progressive lesions of atherosclerosis. This hypothesis has stimulated a great deal of experimental work that has led to an increase in our understanding of factors that determine the capacity of the endothelial cells to maintain themselves as an integral continuous functional cell layer; the hypothesis has also led to studies of those factors that control the normal function and growth of endothelium. Of equal importance, many studies have elucidated factors that modify the capacity of arterial smooth-muscle cells to form connective tissue proteins, to synthesize and metabolize lipids and lipoproteins, and to proliferate in response to different mitogenic factors. One of the most important observations that has resulted from the examination of this hypothesis is the discovery that platelets contain a potent mitogen, the platelet-derived growth factor.[37] It has been suggested that this factor may play an important role in inducing the intimal smooth-muscle proliferation seen in experimentally induced atherosclerosis and in atherosclerosis in human beings. This is discussed in greater detail below. A number of important questions have arisen about the factors that promote the proliferation of smooth-muscle and endothelial cells and about the mechanisms whereby the lesions of atherosclerosis may regress. More is becoming known about the factors responsible for the turnover of connective tissue matrix within the artery wall and about the mechanisms responsible for removing either this matrix or cholesterol from the lesions. A factor known as transforming growth factor-beta (TGFb) has been shown to be a potent stimulator of connective tissue formation and inhibitor of matrix degradation.[38 – 40] This factor can be made by all of the cells involved in the process of atherogenesis. The response-to-injury hypothesis has provided potential explanations for some of these phenomena. However, much remains to be learned, for example, with respect to the activity of endothelium, smooth muscle, and macrophages in their

Pathophysiology of Atherosclerosis

19

interactions with each other in the complex microenvironment of the lesions of atherosclerosis.

The Role of Lipids In many persons, both the initiation and the progression of atherosclerotic lesions appear somehow to be associated with markedly increased levels of plasma LDL. The accumulation of lipid within proliferated smooth-muscle cells, within macrophages in the lesions, and within the extracellular connective tissue matrix is a common finding, particularly in the lesions of atherosclerosis.[41] The presence of elevated levels of LDL suggests that cholesterol internalization and esterification by cells may be accelerated to such a degree that proliferated smooth-muscle cells and macrophages within the lesions become filled with cholesterol oleate. Many of the cells may go on to become necrotic and may release their lipid into the extracellular spaces. In the presence of excess plasma LDL, which is relatively rich in cholesterol linoleate, the debris may be a mixture of both types of cholesteryl esters. Some studies have suggested that in hyperlipemic animals there are changes in LDL that may promote endothelial injury, the proliferation of smooth-muscle cells, and the production of new connective tissue components by these cells.[42] Thus a sequence of events involving endothelial injury by chronic elevated levels of LDL, oxidation or other modifications of LDL, and the continuing progression of atherosclerotic lesions by exposure to modified LDL [and presumably to decreased levels of high-density lipoproteins (HDL)] could lead to the development of advanced atherosclerotic lesions. LDL can be modified not only by oxidation but by glycation (as occurs in many diabetics), by binding as a complex with proteoglycans, or by incorporation into immune complexes. This “modified” LDL is characteristically taken up by various scavenger receptors on the surfaces of macrophages and, thus, plays a major role in foam cell development and inducing the inflammatory response.[43 – 45]

Risk Factors A number of risk factors of atherosclerosis have become reasonably well established on the basis of their relationship in epidemiologic studies to the incidence of clinically manifest disease. Unfortunately, there is no basis for comparison between risk factors and the severity or extent of the lesions of atherosclerosis. Among many factors that are considered to be important are hyperlipidemia, hypertension, cigarette smoking, male sex, and diabetes mellitus. These have in general been associated with an increased incidence of fibrous plaques and their sequelae. The associations are relatively strong when they are made on a group basis, although all the studies have demonstrated a high degree of variability among individuals within even the most homogeneous groups.[46]

Hypercholesterolemia Dietary lipids are considered to be among the most important environmental agents responsible for severe

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atherosclerosis and for the high frequency of atherosclerotic disease in industrially developed parts of the world. Saturated fats became known to be associated with an increased incidence of atherosclerosis when it was found that they elevate the concentration of plasma cholesterol. The specific contributions of cholesterol, saturated fats, polyunsaturated fats, and total fats in atherosclerosis have become clarified. It has been possible to demonstrate an unequivocal association between dietary cholesterol or plasma cholesterol levels and the incidence and prevalence of coronary disease within population groups.[47] Unfortunately, there is a great deal of daily variation from individual to individual in terms of the dietary intake of fats and plasma cholesterol levels. There is also intrinsic variation in plasma cholesterol levels among individuals who consume the same diet and respond differently to it. This has increased the difficulty of relating this factor in individuals to the incidence of atherosclerosis, but it does not negate the clear association between hyperlipidemia and atherosclerosis that has been demonstrated by numerous epidemiologic studies. There is little question that dietary cholesterol directly affects the levels of plasma cholesterol.[48] However, only recently has it been suggested that dietary cholesterol may affect the incidence of atherosclerosis by altering the profile of plasma lipoproteins and possibly by changing the structural or functional properties of these lipoproteins.[49] Increased dietary cholesterol generally results in an increase in LDL cholesterol levels, with a lesser increase in HDL cholesterol levels. As the role of these two lipoproteins in atherogenesis becomes clearer, it can be stated that elevated HDL levels appear to be protective, whereas the reverse is true for elevated LDL levels. There are many differences in the ways in which animals and humans respond to dietary cholesterol, and there are limits to the extent to which information concerning responses to dietary intake in experimental animals can be applied to human beings. Nevertheless, the epidemiologic association between the increased incidence of atherosclerosis and the increased intake of saturated fat is very strong. The means by which these fats affect the incidence of atherosclerosis at the cellular and molecular levels is probably related to the formation of “modified” LDL, as discussed above.

Hypertension Hypertension has been established unequivocally as an associated risk factor in that persons with elevated blood pressure show accelerated atherogenesis, an increased incidence of coronary heart disease, and, in particular, an increased incidence of cerebrovascular disease. The effects of hypertension appear to be independent of other risk factors in an epidemiologic sense; however, it does not appear to be a primary cause of advanced atherosclerosis in those populations in which the incidence of clinically manifest atherosclerosis is less than average. The means by which hypertension induces atherogenesis are not clear, although there are many humoral mediators of blood pressure which may participate in this process. For example, renin and other hypertensive agents may induce cellular changes that lead to atherogenesis. Fry[33] and his

colleagues, as well as others, have suggested that the altered shear stress of the flow of blood, particularly in hypertensive persons, at selected anatomic sites within the arterial tree may result in focally altered endothelium and in the development of atherosclerotic lesions very much as suggested in the response-to-injury hypothesis discussed earlier. Angiotensin II (AII), the principal product of the reninangiotensin system, is a potent vasoconstrictor and may contribute to elevated blood pressure. Interestingly, AII can increase the activity of smooth-muscle lipoxygenases, which can participate in the oxidation of LDL and augment the inflammatory response.[50] Hypertension has a pro-inflammatory capacity; in hypertensive individuals there is an increase in the formation of hydrogen peroxide and other free radicals, such as superoxide anion.[51,52] These substances can negate the effects of nitric oxide on the endothelium and serve to augment the process of atherogenesis by pro-inflammatory means.

Cigarette Smoking Cigarette smoking provides perhaps the strongest and most consistent correlation with the increased incidence of atherosclerotic disease and appears to be a major contributor to the increased risk of disease, generally in combination with other risk factors. Unfortunately, there is relatively little information about how cigarette smoking exerts an impact at the cellular level. Free radicals that form in the plasma and interstitial fluid as a result of smoking may induce endothelial injury and participate in modifying LDL. Becker et al.[53] identified agents derived from cigarette smoke that may be injurious to the artery wall. They also suggested that the inhalation of cigarette smoke may result in the exposure of arterial cells to mutagens that transform the smooth-muscle cells, which are stimulated to proliferate. Apparently, the cessation of cigarette smoking decreases the risk for the development of the clinical sequelae of atherosclerosis and may augment the regression of lesions. Further research is clearly required to identify the factors in cigarette smoke that are responsible for its cardiovascular effects and to determine the mechanisms by which it alters cellular metabolism.

Male Sex Perhaps one of the best-documented and most consistent risk factors for coronary atherosclerosis is male sex. This differential is accentuated in nonwhite populations, and it has been suggested that women have a decreased incidence because estrogens exert a protective function. Paradoxically, large doses of estrogenic hormones appear to increase cardiovascular mortality in men who have had one myocardial infarct and in men under treatment for prostatic cancer. Consequently, the reasons for the sex differential are not yet understood.

Diabetes Another risk factor known to be associated with an increased incidence of atherosclerosis and myocardial infarction is diabetes mellitus. The mechanisms involved are poorly understood. There is, unfortunately, no consistency

Chapter 2.

in the evidence related to whether elevated concentrations of plasma cholesterol and lipoproteins occur in diabetics whose concentrations of blood and urine glucose are carefully regulated. There is some evidence suggesting a decreased concentration of HDL cholesterol in diabetics and a high prevalence of hypertension associated with hyperglycemia. The basic mechanisms associated with the proliferation of smooth-muscle-type cells in the mesangium of the kidney in the renal complication of diabetes and in the increased thickness of capillary basement membranes in diabetics with microvascular disease may bear some similarity to the mechanisms of smooth-muscle proliferation in atherogenesis. However, the alterations in the arterial tree that precede the lesions of atherosclerosis in diabetics are not well documented and are poorly understood. Although a great deal is known (see below) about endothelial cells, smooth-muscle cells, macrophages, platelets, and their interactions, the specific role of each of the risk factors associated with atherosclerosis remains, for the most part, to be investigated. This information is critical if we are to improve the means of diagnosis, prevention, and intervention in this disease process.

CELLULAR MODIFICATIONS IN ATHEROSCLEROSIS Endothelium Endothelial cells provide a selective permeability barrier, a blood-compatible interface, and a thromboresistant lining to the artery wall, and they are also metabolically active. A number of studies of endothelial permeability using various tracer molecules have demonstrated the presence of pinocytotic vesicles, transendothelial channels, and intracellular clefts in different kinds of endothelium. The junctional complexes between endothelial cells and the artery wall appear to be functionally dynamic structures that can respond to stimuli such as pharmacologic agents and changes in blood pressure. At the molecular level, the surface components of the endothelial cells appear to influence the selective permeability of the endothelium.[54,55] Endothelial cells have been shown by the Steins[56] to be capable of transporting plasma lipoproteins of certain sizes into the artery wall via vesicles. Thus molecules like HDL are transported, but larger lipoproteins the size of very-lowdensity lipoproteins (VLDL) or chylomicrons have difficulty crossing the endothelial barrier without some kind of alteration in these lipid-rich particles. In a number of experimental animals, the disruption of this barrier has been shown to permit interactions between platelets and the artery wall at the sites of endothelial injury; this interaction results in an intimal smooth-muscle proliferative response. Stemerman and Ross[13] observed that if endothelial cells are removed by abrasion with an intraarterial catheter, the sites of exposure of the subendothelial connective tissue are quickly coated with a “carpet” of degranulated platelets. At such sites of endothelial injury, the interaction of plasma constituents with products released from the platelets is followed by focal smooth-muscle migration

Pathophysiology of Atherosclerosis

21

and proliferation that eventually lead to the development of a fibromusculoelastic lesion. If this mechanical injury is accompanied by a high-fat, high-cholesterol diet, the hyperlipemic animals develop intimal proliferative lesions essentially identical to fibrous plaques. In the normocholesterolemic animals, such endothelial injury leads to fibromusculoelastic proliferative lesions that, over a period of 6 months, may undergo regression, whereas in hypercholesterolemic animals, the lesions become slowly progressive and show no signs of regression. Ross and Harker,[15] Faggioto et al.,[19,20] and Masuda and Ross[21,22] observed that monkeys that received no mechanical injury but were only fed a high-fat, high-cholesterol diet for a year or longer showed signs of endothelial injury as determined morphologically and by measurements of endothelial cell turnover at selected sites in the arterial tree (Fig. 2-2). The intimal smooth-muscle proliferation that accompanies the functional alteration in the endothelial cell barrier has been shown to be associated with the interaction between monocytes and endothelium and between platelets and the exposed subendothelium at such sites of injury. This is further discussed below.

Endothelial Cell Culture Arterial endothelial cells have been successfully cultured from a number of species, including the cow, rabbit, swine, nonhuman primate, and human being.[57,58] Endothelial cells from each of these species demonstrate a number of common characteristics. They grow, as they do in vivo, in a unique, continuous monolayer and, unlike other cells such as smoothmuscle cells or fibroblasts, appear to be truly contactinhibited. That is, the cells become quiescent when they become confluent and remain quiescent as long as they

Figure 2-2. A scanning electron micrograph demonstrating an area over a fatty streak in the iliac artery of a monkey that had been hypercholesterolemic (600 mg/dL) for 5 months. Several exposed macrophages are visible. One of them is covered by a mural collection of platelets (arrow ). A lesion such as this is found in the same anatomic site that 1 or 2 months later is occupied by a smooth-muscle proliferative lesion of atherosclerosis.

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Part One. Assessment of Vascular Disease

remain in contact. If the monolayer is disrupted, for example, by wounding, the cells are stimulated to synthesize new DNA, to migrate, and to proliferate and restore the continuity of the monolayer. Only those cells next to the margins of the wound appear to undergo DNA synthesis and proliferation, whereas those in the monolayer at a distance from the wound appear to remain relatively quiescent. This peculiar characteristic of the growth of endothelium is so strikingly different from that of smooth-muscle cells that it has been suggested that these two different cell types are under different sets of growth controls and that somehow cell-cell contact is important in determining the state of quiescence of endothelial cells. Endothelial cells grown in a culture have been shown to be capable of forming a number of connective tissue matrix macromolecules, including particular types of collagen;[59] of transporting lipids; of synthesizing PGI2,[34] factor VIII,[60] and angiotensin-converting enzyme;[61] and of maintaining many aspects of their differentiated phenotype through several passages.

Endothelial Responses Endothelial cells have been shown to be capable of forming mitogens, or growth factors, in culture. One of the earliest detectable responses of the endothelial cells to “injurious agents” such as hyperlipidemia or oxidized LDL is to increase the transport of lipoproteins through the endothelial cells, where they localize subendothelially. At the same time, the endothelial cells participate in a specialized type of chronic inflammatory response by developing specific cell-surface glycoproteins that are adhesive for monocytes and T lymphocytes. These adhesive glycoproteins, or endothelial leukocyte adhesion molecules (ELAM), bind to other glycoproteins on the surfaces of the monocytes and lymphocytes in receptor-ligand –type interactions.[62,63] Concurrently, monocyte chemotactic factors can be formed either by the endothelial cells or subendothelially by smooth muscle, and these can induce monocytes to migrate between endothelial cells and localize subendothelially. Activation of the endothelial cells can not only lead to the formation of new adhesive glycoproteins on their surfaces but may possibly stimulate the endothelial cells to make growthregulatory molecules including PDGF, TGFb, and possibly fibroblast growth factor (FGF).

Smooth Muscle Smooth-Muscle Proliferation Smooth-muscle cells have long been recognized to possess a number of features important to normal arterial function, including their capacity to contract, maintain arterial tone, and synthesize connective tissue proteins. Perhaps the most important phenomenon associated with the smooth-muscle cell is cell proliferation in atherogenesis. Since intimal smooth-muscle proliferation is an important early feature in atherogenesis, the factors responsible for this proliferative response are under intensive investigation in vivo and in vitro. In cell culture, it is well known that whole blood serum provides all the factors necessary for smooth-muscle proliferation. Arterial smooth-muscle cells from a large

number of species can be grown in culture and are able to maintain their differentiated phenotype under these conditions.[64,65] Ross and coworkers[37] together with several other research groups [66,67] demonstrated that the principal component that is present in whole-blood serum and missing in cell-free, plasma-derived serum and that is responsible for the proliferation of arterial smooth-muscle cells in culture is a mitogen derived from the platelet, the platelet-derived growth factor. The observation that smooth-muscle proliferation in culture is stimulated principally by this mitogen led to a series of studies to examine the role of this factor, PDGF, in smoothmuscle proliferation induced in vivo. As described above, several forms of endothelial injury result in the adherence of macrophages and platelets at the sites of injury. Platelet adherence is followed by degranulation and then material stored in the platelet granules is released into the artery wall. When activated, macrophages can also release PDGF. Together with plasma constituents, these platelet products have far-reaching effects upon the smooth-muscle cells of the artery wall. Harker et al.[16] demonstrated that in homocystinuria, a genetic disease of childhood commonly associated with a markedly increased incidence of arteriosclerosis, platelets appear to interact at sites where the endothelium has somehow been injured by increased levels of plasma homocysteine. Harker et al. demonstrated this association by measuring the survival of autologous 51Cr-labeled platelets in homocystinuric children and observed that the greater the levels of plasma homocysteine, the greater the decrease in platelet survival. As a result of these observations, they developed an animal model of homocystinuria by chronically infusing homocysteine in baboons. In this model they showed a similar correlation between elevated levels of plasma homocysteine and decreased rates of platelet survival (or increased rate of platelet utilization). When they maintained the baboons on a homocystinemic regimen for 3 months, they observed an increased incidence of missing endothelial cells by morphometric examination of whole-mount preparations of the aorta. Their studies established a correlation between the amount of injured endothelium, the rate of platelet survival, and the formation of proliferative smooth-muscle atherosclerotic lesions at the sites of endothelial injury. Harker and colleagues[16] went on to demonstrate that if they administered to the homocystinemic baboons a pharmacologic agent that could inhibit platelet interactions with the injured artery wall, they could prevent the intimal smoothmuscle proliferative lesions that could otherwise develop. One agent, dipyridamole, returned platelet survival rates to normal. This drug is known to have the capacity to inhibit platelet phosphodiesterase activity and to inhibit platelet adherence. Another agent, sulfinpyrazone, appears to somehow protect the endothelial cells, since the sulfinpyrazonetreated homocystinemic baboons demonstrated fewer areas of endothelial injury. In both approaches, platelet survival rates were normalized and the proliferative lesions of atherosclerosis were prevented. These were the first data to correlate a requirement for platelet function with experimentally induced atherosclerosis. Other approaches to examining these same phenomena were taken by Moore and colleagues[68] and by Friedman

Chapter 2.

et al.[69] In both their studies, atherosclerosis was induced in rabbits by injuring the endothelium with an intraarterial catheter. In each case, the investigators induced a thrombocytopenia by the administration of a specific antiplatelet antiserum. They found that the animals made thrombocytopenic in this manner had no proliferative atherosclerotic lesions, whereas the control animals had extensive lesions. Using a different approach, Fuster and colleagues[70] examined the incidence of atherosclerosis in the aortas of swine fed a high-fat, high-cholesterol diet. They were able to study the role of platelets by trying to induce atherosclerosis with a high-cholesterol diet in a group of swine that were homozygous for von Willebrand’s disease and then comparing them with a group of normal swine on the same diet. The swine with severe von Willebrand’s disease have essentially no factor VIII—von Willebrand factor—in their plasma. Normally this factor is required for platelet adherence and release. Fuster et al. showed that the control animals on the high-lipid diet developed extensive proliferative lesions of atherosclerosis, whereas the von Willebrand swine developed intimal infiltrates of lipid but no smooth-muscle proliferative lesions. In the absence of the von Willebrand factor, platelet interactions may be inhibited in the hypercholesterolemic von Willebrand swine. The ability of the smooth-muscle cell to migrate and proliferate gives it a central role in the development of the advanced lesions of atherosclerosis and, in particular, in the formation of the fibrous cap that covers the necrotic core. Recent data have demonstrated that the matrix with which the smooth muscle cells interact can play a critical role in determining whether the cells respond to mitogens, such as PDGF, as they do in the intima where the lesions develop, or are nonresponsive, as they are in the media of the artery.[71,72] Atherosclerosis is an inflammatory response, and activated macrophages can secrete metalloproteases that can profoundly affect both the smooth muscle cells and the form taken by the matrix surrounding them.[10] As we achieve a clearer understanding of the importance of these interactions, the process of lesion formation and progression may be modifiable in part by paying closer attention to the form and nature of the matrix formed by the smooth-muscle cells.

Lipid Metabolism Lipids are essential components of all cells; it is not surprising that they are involved in a number of cell functions and metabolic processes, as they represent the principal constituent of all cell membranes. Both the plasma membrane and the internal membranous compartments of all cells, including smooth muscle, are composed of phospholipids, proteins, and cholesterol, principally unesterified cholesterol. Esterified cholesterol is found in smooth muscle only under abnormal conditions. Accumulations of cholesteryl ester in smooth-muscle cells and macrophages lead to the development of foam cells, which are found in the lesions of atherosclerosis. Recent experiments have shown that smoothmuscle cells can acquire cholesterol both by de novo synthesis[73] and from an exogenous source of cholesterolcarrying lipoproteins.[74] Such a dual mechanism may help the cell to protect itself against possible deficits in cholesterol.

Pathophysiology of Atherosclerosis

23

Smooth-muscle cells and many other cells can also protect themselves against excess cholesterol. The mechanism that has evolved for this purpose is the surface-located, highaffinity LDL receptor.[75,76] These receptors bind LDL, and the cell then internalizes the bound LDL by endocytosis and transports it to lysosomes, where the LDL is degraded and free cholesterol is liberated for use by the cell. If the cell is exposed to excess LDL, there is a feedback-inhibitory pathway in the cell that inhibits the synthesis of LDL receptors. In addition, the presence of excess cholesterol within the cell inhibits cholesterol synthesis by the ratelimiting intracellular enzyme hydroxymethylglutaryl –coenzyme A reductase (HMG-CoA reductase). Under normal circumstances, sterol balance in the cell maintains a given level of receptor for LDL at the cell surface. In this way the requirements for extracellular cholesterol are met by concentrations of plasma LDL that are not atherogenic. Increased concentrations of plasma LDL may alter the endothelial barrier and bring large amounts of LDL, much of which may be modified (oxidized), in direct contact with the smooth-muscle cell, which may ingest much of the oxidized LDL by bulk-phase endocytosis and by special highaffinity receptors; this leads to the increased esterification and storage of cholesteryl esters and the development of foam cells (Fig. 2-3). The metabolism of lipoproteins is sufficiently complex that it will not be covered in this chapter. Nevertheless, recent data suggest that at least two alterations of lipoproteins may be important in the process of atherogenesis. The first of these, as referred to earlier, is the modification or oxidation of LDL. Low-density lipoprotein can be modified by the endothelium, by macrophages, or perhaps even by smoothmuscle cells. Such modified LDL can be taken up by macrophages via scavenger receptors on the cell surface and can lead to foam-cell formation. The oxidized forms of LDL, however, can also be quite toxic to the endothelial cells, to smooth muscle, and perhaps to the macrophages themselves. When Watanabe heritable hyperlipidemic (WHHL) rabbits or hypercholesterolemic monkeys were treated with antioxidants such as probucol, the lesions that formed in these animals were much smaller. This has led to an exciting series of experiments suggesting that antioxidants might perhaps be useful in the treatment and prevention of the process of atherogenesis. It is now widely appreciated that HMG-CoA reductase inhibitors (statins) have been enormously successful in preventing the clinical consequences of atherosclerosis, such as myocardial infarction.[77,78] They effectively lower LDL cholesterol by inhibiting the rate-limiting enzyme of cholesterol synthesis. Nevertheless, it has recently become apparent that these interesting pharmacologic agents have a broad array of effects in addition to lowering LDL cholesterol. Some of these effects may directly inhibit the inflammatory response that represents the earliest phase of the process of atherogenesis. The use of these agents and ones in development will have profound effects on the incidence of atherosclerosis and its clinical sequelae. Evidence is accumulating in favor of the notion that HDL, in contrast to LDL, is a negative factor in the development of atherosclerosis. Two hypotheses have been proposed to explain how HDL might be a deterrent against

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Part One. Assessment of Vascular Disease

Figure 2-3. A transmission electron micrograph of part of an atherosclerotic lesion from the iliac artery of an 8-month-old hypercholesterolemic monkey. The smooth-muscle cell in the center of this micrograph contains numerous lipid droplets and is surrounded by connective tissue.

atherosclerosis. The first suggests that HDL augments the removal of cholesterol from cells such as smooth-muscle cells. The second mechanism involves the apparent ability of HDL to influence the binding and absorption of LDL by cells such as smooth-muscle cells. However, neither of these mechanisms has been shown to be responsible for the control of cellular cholesterol levels.

The Macrophage Macrophages represent the principal cell in early lesions of atherosclerosis and are present in all stages including advanced lesions like the fibrous plaque. These cells could conceivably play several roles in lesion progression and possibly in regression as well. In tissue culture, macrophages have been shown to release into the culture medium a mitogen as potent as that derived from platelets.[79] Platelet-derived growth factor is the principal mitogen that can be released from activated macrophages. However, macrophages also make a large number of cytokines and growth factors, including interleukin 1 (IL-1), tumor necrosis factor-alpha (TNFa), TGFb, and numerous others. Thus the macrophage represents a potent source of growth-regulatory

molecules that can affect its surrounding neighbors. It can also form colony-stimulating factor, a mitogen for macrophages themselves. It has recently been shown that macrophage replication may be as important a component of cell proliferation in the lesions of atherosclerosis as is smooth-muscle proliferation. Replicating macrophages have been observed in experimental animals and recently in human lesions of atherosclerosis. Macrophages have long been known to be largely responsible for tissue debridement. There is increasing evidence in experimental studies and in human beings[32] that some lesions of atherosclerosis are capable of regression. The role of the macrophage in this phenomenon remains to be elucidated. Not only monocytes are ubiquitous in all of the lesions of atherogenesis, but so are subsets of T lymphocytes.[80] The monocyte-derived macrophage is not only a scavenger cell, it is also an antigen-presenting cell. The presence of monocytederived macrophages, together with T cells, suggests that some form of immune response may be responsible for the development of the lesions of atherosclerosis. Hansson and colleagues have shown that oxidized LDL can serve as such an antigen.[81] Also, some infectious organisms, such as herpesvirus or Chlamydia pneumoniae, may play such

Chapter 2.

a role.[82 – 84] There are increasing data suggesting that, in some cases, infection, together with other components associated with risk factors, may be involved in the process of atherogenesis. The macrophage as the hallmark of chronic inflammation, together with the lymphocytes, can not only be a phagocytic cell but can provide cytokines, chemokines, metalloproteases, and other hydrolytic enzymes, and the growth factors noted above in the process of atherogenesis. Macrophages also multiply and are potentially important as proliferating and replicating cells, as are smooth-muscle cells.[85]

Platelets Platelet-Derived Growth Factor Platelet-derived growth factor is a mitogen that is stored in the alpha granule of the platelets. The factor has been purified to homogenicity. It has a molecular weight of approximately 32,000 and is a highly cationic (pI 9.8), stable, disulfidebonded protein. This growth factor is extremely potent; it causes the proliferation of connective tissue cells such as smooth muscle in culture at levels of 5 ng/mL of culture medium (equivalent to the addition of 5% whole-blood serum). As discussed earlier, in whole-blood serum, PDGF is the principal mitogen to which cells characteristically respond by cell proliferation. When susceptible cells are exposed to this factor, the result is a sequence of events that includes the binding of the molecule to specific receptors on the surface of the cell. This causes the cell to undergo cell-cycle traverse leading to DNA synthesis and cell multiplication. Upon exposure to smooth-muscle cells, the plateletderived growth factor stimulates a number of phenomena in addition to DNA synthesis. It causes increases in pinocytosis, protein synthesis, RNA synthesis, and lipid metabolism. Chait et al.[74] have observed that the exposure of arterial smoothmuscle cells to this growth factor results in the increased binding of LDL to the cells because of the formation of an increased number of high-affinity receptors for LDL at the cell surface. This increased binding of LDL permits the cells to more effectively utilize exogenous sources of cholesterol for cell multiplication. Habenicht et al.[73] have demonstrated that this mitogen also simulates increased cholesterol synthesis by cells if an exogenous source of cholesterol is not available to them. Davies and Ross[86] observed that smooth-muscle cells exposed to the platelet-derived growth factor undergo a marked increase in the rate of endocytosis of tracer molecules. In other words, exposure to this mitogen results in an increase in a number of cellular activities, many of which are associated with cell proliferation and with new protein syntheis, and therefore with connective tissue formation.[87] Thus exposure to this factor could trigger the initiation of all the components of a proliferative lesion. The role of functional platelets in inducing experimental atherosclerosis in vivo is unquestioned. The role of the platelet-derived growth factor in stimulating mitogenesis in cell culture is also clear. The question remains whether this factor is active in vivo (Fig. 2-4). Since activated platelets can play a role not only in the genesis of the lesions of atherosclerosis but also in

Pathophysiology of Atherosclerosis

25

thrombosis, one of the principal clinical sequelae of the advanced lesions, thrombus formation and its prevention have become integral to approaches to treatment and prevention of lesions of atherosclerosis. Activated platelets express on their surfaces a glycoprotein, the IIbIIIa receptor, which is a member of the integrin superfamily of adhesion molecules that plays a key role in thrombosis. These receptors normally serve an important hemostatic function. Clinical antagonists have been developed into pharmacologic agents, which are used to prevent thrombus formation, particularly in individuals who have had myocardial infarction.[88]

Other Factors Possibly Involved in Atherogenesis During the past several years, a host of new factors has been uncovered which may play roles that either aggravate the process of atherogenesis or are important in its inhibition. Endothelial cells have been shown to form vasodilatory factors called endothelial-derived relaxing factors (EDRF), which represent a thiolated form of nitric oxide. This factor is very important in maintaining the arteries in a dilated state and thus maintaining patent arterial lumina. In addition, all three cell types associated with the lesions of atherosclerosis—endothelium, smooth muscle, and macrophages—are capable of converting the fatty acid arachidonic acid into prostaglandin endoperoxides. Studies of these endoperoxides identified a number of unstable intermediates in the metabolic pathway of arachidonic acid that leads to the formation of two important end products: thromboxane A2 (formed by platelets) and PGI2 (formed by endothelium and smooth muscle). Understanding these two end products has greatly expanded our view of the role played by platelets in thrombosis and by endothelium and smooth muscle in the prevention of thrombosis and atherosclerosis. Arachidonic acid is derived either from linoleic acid, an essential fatty acid in the membranes of cells, or from the diet. Thromboxane A2 is a powerful vasoconstrictor and is capable of stimulating smooth-muscle contraction and platelet aggregation. It has a short half-life (30 s) and breaks down spontaneously into a stable substance, thromboxane B2. A number of inhibitors of thromboxane synthesis markedly reduce platelet aggregation. These include aspirin and indomethacin.[89,90] PGI2 is the principal product of cyclooxygenase activity in the walls of arteries and veins. Endothelium and smooth muscle synthesize PGI2 from arachidonic acid may also be able to synthesize this prostaglandin derivative from endoperoxides released from platelets. PGI2 is unstable and is an extremely potent vasodilator, as well as an inhibitor of platelet aggregation. It is possible that an imbalance in the relative amounts of thromboxane A2 and PGI2 may partly explain the involvement of platelets in cardiovascular diseases. Since platelets contain thromboxane synthetase, the enzyme responsible for the synthesis of thromboxane A2, and since the inhibition of the activity of this enzyme does not interfere with cyclooxygenase activity, it has been speculated that thromboxane synthetase –inhibited platelets could donate endoperoxides to endothelial cells, which could then use them as substrates for PGI2 production. Therefore, attempts are

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Part One. Assessment of Vascular Disease

Figure 2-4. A diagram illustrating the proposal that smooth-muscle cells are susceptible to at least two potential growth factors: PDGF, which can stimulate smooth muscle proliferation, and TGFb, which can inhibit proliferation and increase connective tissue formation and LDL. The particular importance of each of these as a cause of smooth-muscle proliferation in the genesis of the lesions of atherosclerosis must be better defined for each special set of circumstances; this provides important opportunities for further research.

being made to develop specific inhibitors of thromboxane synthesis that do not affect PGI2 production by cells of the blood vessel wall. Prostaglandin biosynthesis may be important not only in thrombosis (in terms of platelet adherence and aggregation) but also in the prevention of atherogenesis (by the formation of PGI2). This had led to the speculation that alterations in the contents of the fatty acids in the diet might offer some protection against the development of atherosclerosis. Populations that consume diets principally composed of marine animals often replace arachidonic acid, the normal substrate for prostaglandin synthesis, with eicosapentaenoic acid. This fatty acid is not completely metabolized by platelets and instead produces a relatively inert form of thromboxane, thromboxane A3. Eicosapentaenoic acid appears to inhibit the capacity of platelets to metabolize arachidonic acid. When eicosapentaenoic acid is exposed to cells of the blood vessel, they form an analogue of PGI2, PGI3. PGI3 appears to be as effective as PGI2 in preventing platelet aggregation and in inducing vasodilation. Thus further studies of the role of this fatty acid derived from marine animals could be important in terms of protecting persons who

consume a marine diet against atherogenesis. Clearly, there is much to be learned about prostaglandin metabolism before the agents that have thus far been discovered, and those that are yet undiscovered, can be understood in relation to both atherogenesis and protection against this disease process.

FUTURE DIRECTIONS The fields of atherosclerosis research has changed dramatically within the last decade. The emphasis has shifted to probing the fundamental roles of the cells of the artery wall as well as the roles of those in the blood, particularly the platelet and the monocyte. The developments of cell and molecular biology, experimental pathology, and immunology have provided tools that will lead to new approaches to diagnosis, intervention, and prevention. Since it is now apparent that the process of atherogenesis is an inflammatory process and the lesions of atherosclerosis are lesions of an inflammatory disease,[10] it may be possible to

Chapter 2.

treat and prevent the disease with anti-inflammatory agents that are specific for the response sin the artery wall. If, for example, it can be demonstrated unequivocally that PDGF plays a role either in the initiation of the lesions of atherosclerosis or in their progression or in both, the development of specific inhibitors of this factor and the development of specific diagnostic tests to measure increased activity would greatly alter present approaches to diagnosis, treatment, and prevention. Future research at the cellular and molecular levels could provide important diagnostic tools that may be of use clinically.

Pathophysiology of Atherosclerosis

27

The process of atherogenesis is highly complex, involving many cellular interactions as well as interactions between cells and constituents in the fluid phase of the blood, the plasma. The importance of these interactions is undoubtedly modified by the genetic makeup of each individual. Consequently, from individual to individual, the differences in susceptibility to each of the risk factors, and at the cellular level to the various components considered to be important in atherogenesis, will have to be understood if we are to make further progress not only in diagnosis and treatment but ultimately also in prevention.

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30. Duguid, J.B. Thrombosis as a Factor in the Pathogenesis of Coronary Atherosclerosis. J. Pathol. Bacteriol. 1948, 58, 207. 31. French, J.E. Atherosclerosis in Relation to the Structure and Function of the Arterial Intima, with Special Reference to the Endothelium. Int. Rev. Exp. Pathol. 1966, 5, 253. 32. Ross, R.; Glomset, J. Atherosclerosis and the Arterial Smooth Muscle Cell. Science 1973, 180, 1332. (32 References). 33. Fry, D.L. Cerebrovascular Disease; Raven Press: New York, 1976; 77. 34. Moncada, S.; Higgs, E.A.; Vane, J.R. Human Arterial and Venous Tissue Generate Prostacyclin, a Potent Inhibitor of Platelet Aggregation. Lancet 1977, 2, 18. 35. Vanhoutte, P.M.; Boulanger, C.M. Endothelium-Dependent Responses in Hypertension. Hypertension Res. 1995, 18, 87. 36. Brown, B.G.; Albers, J.J.; Fisher, L.D.; et al. Treatment Study: A Randomized Trial Demonstrating Coronary Disease Regression and Clinical Benefit from Lipid Altering Therapy Among Men with High Apolipoprotein B. N. Engl. J. Med. 1990, 323, 1289. 37. Ross, R.; Glomset, J.; Kariya, B.; Harker, L.A. A PlateletDependent Serum Factor That Stimulates the Proliferation of Arterial Smooth Muscle Cells In Vitro. Proc. Natl Acad. Sci. USA 1974, 71, 1207. 38. Ignotz, R.A. Massague´: Transforming Growth Factor-b Stimulates the Expression of Fibronectin and Collagen and Their Incorporation into the Extracellular Matrix. J. Biol. Chem. 1986, 261, 4337. 39. Roberts, A.B.; Sporn, M.B.; Assoian, R.K.; et al. Transforming Growth Factor Type b: Rapid Induction of Fibrosis and Angiogenesis In Vivo and Stimulation of Collagen Formation In Vitro. Proc. Natl Acad. Sci. USA 1986, 83, 4167. 40. Laiho, M.; Saksela, O.; Andreasen, P.A.; Keski-Oja, J. Enhanced Production and Extracellular Deposition of the Endothelial-Type Plasminogen Activator Inhibitor in Cultured Human Lung Fibroblasts by Transforming Growth Factor-b. J. Cell. Biol. 1986, 103, 2403. 41. Geer, J.C.; McGill, H.C., Jr.; Strong, J.P. The Fine Structure of Human Atherosclerotic Lesions. Am. J. Pathol. 1961, 38, 263. 42. Steinberg, D.; Parthasarathy, S.; Carew, T.E.; et al. Beyond Cholesterol: Modifications of Low-Density Lipoprotein That Increase Its Atherogenicity. N. Engl. J. Med. 1989, 320, 915. 43. Steinberg, D. Low Density Lipoprotein Oxidation and Its Pathobiological Significance. J. Biol. Chem. 1997, 272, 20963. 44. Khoo, J.C.; Miller, E.; McLoughlin, P.; Steinberg, D. Enhanced Macrophage Uptake of Low Density Lipoprotein After Self-Aggregation. Arteriosclerosis 1988, 8, 348. 45. Khoo, J.C.; Miller, E.; Pio, F.; Steinberg, D.; Witztum, J.L. Monoclonal Antibodies Against LDL Further Enhance Macrophage Uptake of LDL Aggregates. Arterioscler. Thromb. 1992, 12, 1258. 46. McGill, H.C. Risk Factors for Atherosclerosis. Adv. Exp. Med. Biol. 1977, 104, 273.

47. NHLBI Consensus Development Conference: Lowering Blood Cholesterol to Prevent Heart Disease. J. Am. Med. Assoc. 1985, 253, 2080. 48. Grundy, S.M. Nutrition, Lipids, and Coronary Heart Disease; Raven Press: New York, 1979; 89. 49. McGill, H.C., Jr. The Relationship of Dietary Cholesterol to Serum Cholesterol Concentration and to Atherosclerosis in Man. Am. J. Clin. Nutr. 1979, 32 (Suppl.), 2664. 50. Griendling, K.K.; Alexander, R.W. Oxidative Stress and Cardiovascular Disease. Circulation 1997, 96, 3264. 51. Lacy, F.; O’Connor, D.T.; Schmid-Scho¨nbein, G.W. Plasma Hydrogen Peroxide Production in Hypertensives and Normotensive Subjects at Genetic Risk of Hypertension. J. Hypertens. 1998, 16, 291. 52. Swei, A.; Lacy, F.; DeLano, F.A.; Schmid-Scho¨nbein, G.W. Oxidative Stress in the Dahl Hypertensive Rat. Hypertension 1997, 30, 1628. 53. Becker, C.G.; Dubin, T.; Wiedemann, H.P. Hypersensitivity to Tobacco Antigen. Proc. Natl Acad. Sci. 1976, 73, 1712. 54. Simionescu, N.; Simionescu, M.; Palade, G.E. Permeability of Muscle Capillaries to Small Hemepeptides. Evidence for the Existence of Patent Transendothelial Channels. J. Cell. Biol. 1975, 64, 586. 55. Renkin, E.M. Multiple Pathways of Capillary Permeability. Circ. Res. 1977, 41, 735. 56. Stein, Y.; Stein, O. Biochemistry of Atherosclerosis; Marcel Dekker: New York, 1979; Vol. 7, 313. 57. Gimbrone, M.A., Jr. Progress in Hemostasis and Thrombosis; Grune & Stratton: New York, 1976; Vol. 3, 1. 58. Jaffe, E.A.; Nachman, R.L.; Becker, C.G.; Minick, C.R. Culture of Human Endothelial Cells Derived from Umbilical Veins. J. Clin. Investig. 1973, 52, 2745. 59. Jaffe, E.A.; Adelman, B.; Minick, C.R. Synthesis of Basement Membrane by Cultured Human Endothelial Cells. Circulation 1975, 51 (Suppl. 2), 11. 60. Jaffe, E.A.; Hoyer, L.W.; Nachman, R.L. Synthesis of Antihemophilic Factor Antigen by Cultured Human Endothelial Cells. J. Clin. Investig. 1973, 52, 2757. 61. Gimbrone, M.A., Jr.; Alexander, R.W. Angiotension II Stimulation of Prostaglandin Production in Cultured Human Vascular Endothelium (Abstract). Science 1975, 189, 219. 62. Springer, T.A. Adhesion Receptors of the Immune System. Nature 1990, 346, 425. 63. Bevilacqua, M.P.; Stengelin, S.; Gimbrone, M.A., Jr.; Seed, B. Endothelial Leukocyte Adhesion Molecule 1: An Inducible Receptor for Neutrophils Related to Complement Regulatory Proteins and Lectins. Science 1989, 243, 1160. 64. Ross, R.; Kariya, B. Handbook of Physiology—Circulation, Vascular Smooth Muscle; American Physiological Society: Bethesda, MD, 1980; 69. 65. Chamley-Campbell, J.; Campbell, G.R.; Ross, R. The Smooth Muscle Cell in Culture. Physiol. Rev. 1979, 59, 1. 66. Kohler, N.; Lipton, A. Platelets as a Source of Fibroblast Growth-Promoting Activity. Exp. Cell. Res. 1974, 87, 297. 67. Heldin, C.-H.; Wasteson, A.; Westermark, B. Partial Purification and Characterization of Platelet Factors Stimulating the Multiplication of Normal Human Glial Cells. Exp. Cell. Res. 1974, 87, 297.

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Hypercholesterolemia. N. Engl. J. Med. 1995, 333, 1301. Leibovich, S.J.; Ross, R. A Macrophage-Dependent Factor That Stimulates the Proliferation of Fibroblasts In Vitro. Am. J. Pathol. 1976, 84, 501. Hansson, G.K.; Libby, P. Atherosclerosis and Coronary Artery Disease; Lippincott-Raven: Philadelphia, 1996; 557. Stemme, S.; Faber, B.; Holm, J.; Wiklund, O.; Witztum, J.L.; Hansson, G.K. T Lymphocytes from Human Atherosclerotic Plaques Recognize Oxidized Low Density Lipoprotein. Proc. Natl Acad. Sci. USA 1995, 92, 3893. Libby, P.; Egan, D.; Skarlatos, S. Roles of Infectious Agents in Atherosclerosis and Restenosis. An Assessment of the Evidence and Need for Future Research. Circulation 1997, 96, 4095– 4103. Hajjar, D.P.; Fabricant, C.G.; Minick, C.R.; Fabricant, J. Virus-Induced Atherosclerosis. Herpesvirus Infection Alters Aortic Cholesterol Metabolism and Accumulation. Am. J. Pathol. 1986, 122, 62. Thom, D.H.; Wang, S.P.; Grayston, J.T.; et al. Chlamydia pneumoniae Strain Twar Antibody and Angiographically Demonstrated Coronary Artery Disease. Arterioscler. Thromb. 1991, 11, 547. Rosenfeld, M.E.; Ross, R. Macrophage and Smooth Muscle Cell Proliferation in Atherosclerotic Lesions of WHHL and Comparably Hypercholesterolemic Fat-Fed Rabbits. Arteriosclerosis 1990, 10, 680. Davies, P.F.; Ross, R. Mediation of Pinocytosis in Cultured Arterial Smooth Muscle and Endothelial Cells by PlateletDerived Growth Factor. J. Cell. Biol. 1978, 79, 663. Burke, J.; Ross, R. International Review of Connective Tissue Research; Academic Press: New York, 1979; Vol. 8, 119. Badimon, J.J.; Meyer, B.; Feigen, L.P.; et al. Thrombosis Triggered by Severe Arterial Lesions Is Inhibited by Oral Administration of a Glycoprotein IIb/IIIa Antagonist. Eur. J. Clin. Investig. 1997, 27, 568. Moncada, S.; Vane, J.R. Arachidonic Acid Metabolites and the Interactions Between Platelets and Blood Walls. N. Engl. J. Med. 1979, 300, 1142. Moncada, S.; Vane, J.R. Mode of Action of Aspirin-Like Drugs. Adv. Intern. Med. 1979, 24, 1.

CHAPTER 3

Pathophysiology of Human Atherosclerosis Christopher K. Zarins Seymour Glagov determine human lesion composition, rate of lesion enlargement, lesion organization, and lesion disruption remain to be elucidated. In this chapter we discuss both the structural features of the artery wall and the hemodynamic factors which may relate to the pathogenesis, localization, and disruption of plaques, and we review the principal features of human lesion composition and configuration. These considerations should help to provide insight into the clinical consequences of differences in plaque localization and composition and serve as a basis for the critical evaluation of currently available methods for the quantitative assessment of human lesions.

Atherosclerosis is a degenerative process of the major human elastic and muscular arteries. It is characterized by the formation of intimal plaques consisting of lipid accumulations, smooth-muscle and inflammatory cells, connective tissue fibers, and calcium deposits. Morbidity associated with atherosclerosis arises from plaque enlargement or degeneration. Plaque enlargement may obstruct the lumen, resulting in stenosis and impairment of blood flow. Sudden obstruction of the lumen may result from the dissection of blood from the lumen into or under the plaque or hemorrhage within the plaque from vasa vasorum. Plaque ulceration may result in embolization of plaque elements or thrombus formation on the disrupted intima. Thrombosis may also occlude atherosclerotic vessels without obvious plaque disruption due to local modifications of flow. Finally, atrophy of the media, often associated with atherosclerotic disease, may result in weakening of the artery wall with aneurysmal dilatation, mural thrombosis, and rupture. Atherosclerosis is a generalized disorder of the arterial tree associated with a number of recognized predisposing risk factors, including altered serum lipid and lipoprotein profiles, hypertension, cigarette smoking, diabetes mellitus, and lifestyle. However, the clinical expression of atherosclerosis tends to be focal, with clinical symptoms caused by localized interference with circulation occurring in several critical sites. In addition, the morphologic features underlying morbidity and mortality vary somewhat depending on location. In the coronary arteries, for example, stenosis and thrombosis tend to reduce flow or cause sudden catastrophic occlusion, principally at the site of lesion formation, while at the carotid bifurcation, plaque ulceration and thrombosis often cause characteristic symptoms by embolization to distal cerebral vessels. Extensive disease, often with multiple focal occlusive stenoses, is characteristic of peripheral vascular disease of the lower extremities, while aneurysm formation is a major feature of abdominal aortic disease. While there is a large body of descriptive clinical and experimental knowledge with regard to the general appearance of atherosclerotic lesions, the precise initiating and perpetuating pathogenic mechanisms in human beings remain obscure, and the factors which

STRUCTURE OF THE ARTERY WALL The artery wall consists of three concentric layers or zones. From the lumen outward, these are the intima, the media, and the adventitia (Fig. 3-1).

Intima The intima extends from the luminal endothelial lining to the internal elastic lamina. The endothelium is formed by a continuous monolayer of flat, usually elongated polygonal cells, which tend to be aligned in the direction of blood flow. In areas of slow, reversing, or nonlaminar flow, endothelial cells tend to assume a less clearly oriented configuration.[1] Edges of adjacent endothelial cells overlap, with the downstream edges of most endothelial cells overriding their immediate downstream neighbors much like the shingles on a roof. Cytoplasmic bridges, surface ridges, and microvillus projections as well as interendothelial gaps, stomata, or open junctions between endothelial cells have been described. These features are, however, largely absent from vessels which have been fixed while distended and which have not been manipulated prior to fixation.[2] A protein coating, the glycocalyx, overlies the luminal surface. Immediately beneath the endothelium is a closely associated fibrillar

Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024886 Copyright q 2004 by Marcel Dekker, Inc.

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Figure 3-1. Transverse section of a normal human superficial femoral artery. Note intima (I), media (M), and adventitia (A). The intima and media are separated by the internal elastic lamella (IEL).

layer, the basal lamina. This structure is thought to form a continuous bond between the endothelial cells and the subendothelial connective tissue matrix. Numerous focal attachments are also present between endothelial cells and the underlying internal elastic lamina,[3] while less prominent focal attachments are also formed with other fibers in the intima. The extensive basal lamina provides a supple, pliable junction well adapted to permit bending and changes in diameter or configuration associated with pulse pressure without disruption or detachment of the endothelium. The focal, tight, relatively rigid junctions may prevent downstream slippage or telescoping, which could result from the shear stresses imposed by blood flow. Between the basal lamina and the internal elastic lamina, the intima in most locations normally contains a few scattered macrophages, smooth-muscle cells, and connective tissue fibers. Since the endothelial cell layer is the immediate interface between the bloodstream and the underlying arterial wall, it is subjected to normal forces exerted by blood pressure and to shearing or drag forces resulting from blood flow. Experimentally imposed shearing stresses in excess of 400 dyn/cm2 in canine aortas have resulted in morphologic evidence of endothelial injury or disruption and in increased endothelial permeability.[4] Other observations have failed to reveal evidence of endothelial injury in areas normally subjected to comparable or higher levels of shear stress,[5] suggesting that endothelial cells may withstand relatively high shearing stresses without ill effect in some locations (Fig. 3-2). The endothelial layer has been considered to function as a thrombosis-resistant surface as well as a selective interface for diffusion, convection, and active transport of circulating

Figure 3-2. Scanning electron micrograph of a monkey aortic ostial flow divider (FD). The flow divider is an area subjected to high shear stress. The endothelial cells are intact and elongated in the direction of flow with no disruption. Arrows indicate direction of blood flow.

Chapter 3. Pathophysiology of Human Atherosclerosis

substances into the underlying artery wall. Endothelial cells play a critical role in the physiology and pathophysiology of vascular disorders.[6] They respond to hemodynamic stresses and may transduce an atheroprotective force[7] by regulating the ingress, egress, and metabolism of lipoproteins and other agents that may participate in intimal plaque initiation and progression.[8,9] Endothelial cells have been shown to participate in an array of metabolic and biosynthetic functions related to thrombosis, prostaglandin formation, and smoothmuscle contraction.[10] Detachment of endothelial cells with persistence of the basal lamina does not necessarily result in occlusive thrombus formation. Although a layer of thrombocytes appears to deposit on the denuded basal lamina, large aggregates and fibrin deposits may require the exposure of collagen fibers and other deeper mural components.

Media The media extends from the internal elastic lamina to the adventitia. Although an external elastic lamina demarcates the boundary between media and adventitia in many vessels, a distinct external elastic lamina may not be present, particularly in vessels with a thick and fibrous adventitial layer. The outer limit of the media can nevertheless be distinguished in nearly all intact arteries, for in contrast to the adventitia, the media consists of closely packed layers of smooth-muscle cells in close association with elastin and collagen fibers. Elastic fibers of the media are predominantly wavy or undulating on cross sections of collapsed arteries but appear as relatively straight bands or lamellae in fully distended vessels (Fig. 3-3). The smooth-muscle cell layers are composed of groups of similarly oriented cells, each

Figure 3-3. Tracing of elastic fibers in transverse sections of rabbit aortic media. (A ) A transverse section of a collapsed aorta demonstrating wavy elastic lamellae and increased thickness of each lamellar unit and increased total thickness of the media. (B ) A rabbit aorta fixed while distended. Note the straight elastic fibers and thickness of the media.

33

surrounded by a common basal lamina and a closely associated interlacing basketwork of collagen fibrils, which tighten about the cell groups as the media is brought under tension.[11] This configuration tends to hold the groups of cells together and prevents excessive stretching or slippage. In addition, each cellular subgroup or fascicle is encompassed by a system of similarly oriented elastic fibers. Focal tight attachment sites between smooth-muscle cells and elastic fibers are normally abundant. In the aorta, the juxtaposition of similarly oriented musculoelastic fascicles results in the appearance on transverse sections of layers of continuous elastic lamellae and intervening smooth-muscle layers. In addition to the pericellular network of fine collagen fibrils, thicker, crimped collagen bundles weave between adjacent lamellae. The elastic fibers are relatively extensible and allow for some degree of compliance; they recoil during the cardiac cycle and tend to distribute mural tensile stresses uniformly. The thick collagen fiber bundles provide much of the tensile strength of the media and, because of their high elastic modules, limit distension and prevent disruption (Fig. 3-4). The aortic elastin lamella and its corresponding smoothmuscle layer has been termed a lamellar unit. With increasing mammalian species size, the adult aortic radius increases, with a corresponding increase in medial thickness and in the number of transmural lamellar units (Fig. 3-5).[12] The total tangential tension exerted on the wall is closely approximated by the product of the distending pressure and the radius (law of Laplace). Since aortic pressure is similar for most adult mammals and individual medial layers tend to be of similar thickness regardless of species, there is a very nearly linear relationship between adult aortic radius and the number of medial fibrocellular lamellar units. On the average, the tangential tension per aortic lamellar unit is close to 2000 dyn/cm. Smaller muscular arteries contain relatively less collagen and elastin and more smooth-muscle cells than the aorta and the proximal, larger elastic arteries. The musculoelastic fascicles, which are very prominent in elastic arteries, are also present in muscular arteries and are generally aligned in the direction of the tensile forces (Fig. 3-6). However, because of the preponderance of smooth-muscle cells, they are less clearly demarcated and the layering of the media is less distinct.[13] Medial thickness and the number of layers is nevertheless closely related to the radius, and the average tension per layer tends to be constant for homologous vessels in mammals.[14] In addition, the relative proportion of collagen and elastin varies between muscular and elastic arteries. The media of the proximal aorta and that of the major brachiocephalic elastic arteries contain a larger proportion of elastin and a lower proportion of collagen than the abdominal aorta or the distal peripheral vessels.[15] The proximal major vessels are therefore more compliant than the abdominal aorta but also are more friable and prone to tear with suturing. Medial smooth muscle cells, in addition to synthesizing the collagen and elastin fibers, which determine the mechanical properties of the aortic wall, are actively engaged in metabolic processes that contribute to wall tone and may be related to suceptibility to plaque formation.[16] Under conditions of increased pulse pressure, increased wall motion, and increased wall tension, such as exist proximal to

34

Part One. Assessment of Vascular Disease

Figure 3-4. Diagrammatic representation of the microarchitecture of the media of the aortic wall. The long axes of the smooth muscle cells (C) are oriented circumferentially or perpendicular to the long axis of the artery. Each cell is surrounded by a matrix (M) consisting of basal lamina and a fine meshwork of collagen fibrils. Groups or layers of smooth-muscle cells are surrounded by circumferentially oriented elastic fibers (E), which appear as almost continuous sheets on transverse section of the artery. Wavy collagen bundles (F) course between the successive facing elastic fiber layers. (Adapted from Clark JM, Glagov S: Transmural organization of the arterial media: The lamellar unit revisited. Arteriosclerosis 5:19, 1985. With permission.[11])

an aortic coarctation, medical smooth muscle cell metabolism is increased, as is plaque formation.[17] Conversely, when wall motion, pulse pressure, and smooth-muscle cell metabolism are decreased, as in areas distal to a severe arterial stenosis, intimal plaque formation is inhibited, despite the continued presence of strong atherogenic stimuli such as marked hyperlipidemia.[18] In vitro studies have revealed that cyclic stretching of smooth-muscle cells grown on elastin membranes results in increased biosynthetic activity,[19] and acute arterial injury experiments have revealed that an intact, metabolically active media may be required for intimal plaque formation.[20] The composition and microarchitecture of the media are designed to ensure stability, whereas the metabolic state of the media appears to be an important factor in the pathogenesis of atherosclerotic lesions.

Adventitia Although the boundary between media and adventitia is usually distinct, even in the absence of a well-defined external elastic lamina, the outer limit of the adventitia may be difficult to identify, for it is often continuous with the surrounding perivascular connective tissues. Although the aorta and pulmonary trunk are normally invested by relatively little adventitial fibrous connective tissue and are closely associated with mediastinal or retroperitoneal adipose tissue and lymph nodes, the adventitia of some of the major arteries, such as the renal and mesenteric branches, are composed of prominent layers of elastic and collagen fibers and may be thicker than the associated media. Compared to the media, cells in the adventitia are relatively sparse and most are fibroblasts. For the normal aorta, removal of the adventitia has

Chapter 3. Pathophysiology of Human Atherosclerosis

35

Figure 3-5. Aortic lamellar architecture in three mammals. With increasing species size, the aortic radius increases. There is a corresponding increase in medial thickness due to an increase in the number of medial lamellar units. (A ) Higher-power view of transverse section of media demonstrating lamellar architecture.

little effect on static pressure-volume relationships. In muscular arteries, however, where connective issue fibers are relatively sparse in the media and smooth muscle contraction may regulate vessel diameter and play a role in maintaining circumferential tensile support, a thick, structured adventitia may serve to provide significant tethering and axial tensile support, prevent excessive dilatation, and dampen the cyclic changes in tangential tension associated with the pulse pressure wave. In instances where a large, intimal atherosclerotic plaque overlies an atrophic media, a thickened adventitia may be the principal mural structural component of the artery wall (see Fig. 3-7). During carotid or femoral endarterectomy, the entire intima and extensive portions of remaining media may be removed, leaving only the adventitia to provide support. The adventitia is also the primary source of vasa vasorum and may play a prominent role in arteritis and periaortitis[21] as well as in the inflammatory component of atherosclerosis.[22] Adventitial responses may also be important in the artery wall response to balloon injury and angioplasty.[23,24]

ARTERY WALL NUTRITION The adventitia of all of the major elastic and muscular arteries contains vasa vasorum—i.e., small arteries, arterioles,

capillaries, and venous channels—which are presumed to participate in nutrition of the artery wall. Except for the aorta, however, precise relationships among vasa supply, vessel location, diameter, wall thickness, and architecture have not been established. The aortic media is nourished directly from the lumen and may also be perfused by means of vasa vasorum from the adventitial side. Passage through the lining endothelium is apparently sufficient to nourish the inner 0.5 mm of the adult mammalian aortic media, which corresponds to approximately 30 medial fibrocellular layers.[25] Thus, the aortic media of a small mammal such as the rat or rabbit, which is less than 0.5 mm thick and has fewer than 30 medial lamellar layers, contains no medial vasa vasorum and is nourished largely from the intimal side. Large mammals such as pigs, sheep, and horses have an aortic media with more than 30 medial lamellar layers. The inner 30 aortic layers in such species are avascular, but the remaining outer medial lamellar units contain vasa vasorum (Fig. 3-8). Aortic vasa vasorum arise from major arterial branches close to their origins and usually enter the media at right angles. Within the media, the vasa tend to be oriented axially in several branching levels. The average tension per medial lamellar unit for aortas that contain medial vasa tends to be somewhat higher than for aortas without vasa, suggesting that the presence of nutritive vessels within the media permits each lamellar unit to function at a somewhat higher level of tensile stress. The human abdominal aorta appears to be exceptional

36

Part One. Assessment of Vascular Disease

Figure 3-6. Diagrammatic representation of microarchitecture of the wall of a muscular artery. The long axes of the smooth muscle cells (C) of the media are oriented circumferentially or perpendicular to the long axis of the artery. Cells are surrounded by a matrix (M) of basal lamina and collagen fibrils. Elastin fiber systems (E) are less prominent. Collagen bundles (F) are interspersed. Compared to elastic arteries (see Fig. 3-4), muscular arteries have a greater number of smooth-muscle cells and relatively fewer collagen and elastin fibers. (Adapted from Clark JM, Glagov S: Transmural organization of the arterial media: The lamellar unit revisited. Arteriosclerosis 5:19, 1985. With permission.[11])

when compared to aortas of other mammals, since it is more than 0.5 mm thick but contains fewer than 30 layers.[26] It is not furnished with medial vasa vasorum, although the estimated tensile stress per layer is in the range of those aortas with medial vasa (Fig. 3-9). The implication of this situation with respect to atherosclerosis and aneurysm formation are discussed below. Although mural stresses and deformations associated with hypertension may impair medial vasal flow,[27] the details of aortic media microarchitecture, which permit intramural vasa vasorum to remain open under normal conditions despite the cyclic compressive and shearing stresses within the artery wall, have not been clarified. Vasa vasorum have been identified in atherosclerotic arteries and, in particular, within atherosclerotic plaques. Although vasa vasorum in atherosclerotic plaques have been supposed to underlie disruptive lesion hemorrhages,[28] relationships

among lesion size, composition, and complications and the presence of vasa vasorum are not clear.

AGE-RELATED CHANGES IN THE ARTERY WALL Focal intimal thickenings, including cushions or pads at or near branch points, have been observed in infants and fetuses. Many of these tend to be modified and incorporated into the media during growth, and most are therefore likely to represent local changes in vessel wall organization related to redistributions of tensile stress associated with developmental changes in diameter, length, and geometric configuration.

Chapter 3. Pathophysiology of Human Atherosclerosis

37

thickened intima or in plaques may result in the accumulation of many layers of elastic fibers in the intima. In general, arteries tend to increase in diameter, elongate, and become tortuous with age. This diffuse, apparently irreversible enlargement, when marked, is called ectasia. The common form of diffuse and extensive ectasia of the aorta and large arteries parallels a relative overall increase in matrix fiber accumulation,[32] including an increase in collagen content, a decrease in elastin content, a calcification of the elastic fibers, and a decrease in compliance of the wall. While elongation and tortuosity of the vessel may be quite marked, the diffuse and extensive form of moderate ectasia is not necessarily associated with serious consequences. When complications occur, they are generally attributable to associated atherosclerosis and/or the formation of aneurysms.

STRUCTURE OF ATHEROSCLEROTIC LESIONS

Figure 3-7. Transverse section of superficial femoral artery. Note prominent adventitial (A) thickening and vasa vasorum (arrow ) penetrating through media (M) into plaque (P).

Progresssive fibrocellular diffuse intimal thickening, on the other hand, proceeds from infancy to old age, differing considerably in both extent and degree in different locations in the arterial tree.[29,30] This process tends to be more or less uniform about the vessel circumference and is not limited to areas about branch ostia, bifurcations, or the inner aspects of curves. Although the component cells tend to be oriented axially in straight portions of arteries, the organization and composition of thickened intima resemble to some extent that of the underlying media (Fig. 3-10). The lumen may not, however, be significantly narrowed by this process, for while the condition may produce an artery wall with an intima thicker than the media, the process tends to be concentric, accumulation of lipid is not a prominent feature, there is no focal stenosis, and the vessel lumen may actually be larger than normal. Diffuse intimal thickening is, nevertheless, especially evident in those vessels that tend to be susceptible to clinically significant atherosclerotic disease.[31] There is, however, little evidence to indicate that diffuse intimal thickening is necessarily a precursor of the formation of atherosclerotic lesions. With advancing age, the internal elastic lamina of the aorta and of the large arteries may show gaps, splits, and fragmentation as well as calcium salt deposits. In addition, neoformation of elastin within the

Atherosclerotic lesions may begin in childhood or adolescence and enlarge progressively over years or decades without associated symptoms. Although intimal plaques are evident in arteries of nearly all adults coming to autopsy in much of the world, little is known concerning the factors which determine individual differences in plaque morphology or govern the gradual or sudden transition from asymptomatic plaques to those which enlarge sufficiently to cause obstruction to flow, ulcerate, or induce occlusive thrombosis or aneurysm formation. On the basis of morphologic appearance and composition, human lesions are usually classified as fatty streaks or fibrous “raised” plaques. Transitional forms have also been identified. While fatty streaks are not associated with symptoms, raised plaques are more complex and are associated with the alterations which underlie circulatory compromise.

Fatty Streaks Fatty streaks are relatively flat, fairly well-demarcated patches or minute yellow foci which may appear soon after birth and are seen on the luminal surface of most aortas of individuals over the age of 3 years (Fig. 3-11).[33] Fatty streaks are found with increasing frequency between the ages of 8 and 18, becoming most numerous around puberty. These formations are not, however, limited to young persons and may be seen at any age adjacent to or even superimposed upon fibrous plaques. Fatty streaks consist largely of intimal lipid-laden cells (foam cells) and variable quantities of matrix materials beneath an intact endothelium. The extent to which fatty streaks are precursors of subsequent complex, fibrous, progressive atherosclerotic lesions remains unresolved.[34] There is evidence that many human fatty streaks may be evanescent, for the distribution of fatty streaks seen in young individuals does not coincide entirely with the distribution of fibrous plaques seen later in life. It has also been found that cells in human fatty streaks are not monotypic with respect to isoenzyme content, [35] but that advanced lesions are composed of cells which contain extensive regions of cellular

38

Part One. Assessment of Vascular Disease

Figure 3-8. Relationship between aortic medial lamellar architecture and vasa vasorum blood supply to outer portion of the media in different species. (From Glagov S: Hemodynamic risk factors: Mechanical stress, mural architecture, medial nutrition and the vulnerability of arteries to atherosclerosis. In Wissler RW Geer, JC (eds): The Pathogenesis of Atherosclerosis. Baltimore, Williams & Wilkins, 1972, pp 166 – 199. Reproduced by permission.[14])

Figure 3-9. The human thoracic aorta has medial vasa vasorum in the outer lamellae, and each lamellar unit supports approximately 2095 dyn/cm. The human abdominal aorta, however, has 28 lamellar units, has no medial vasa, and each lamellar unit supports about 3180 dyn/cm. This architectural difference may be important in the vulnerability of the abdominal aorta to atherosclerosis and aneurysm formation. (From Glagov S: Hemodynamic risk factors: Mechanical stress, mural architecture, medial nutrition and the vulnerability of arteries to atherosclerosis. In Wissler RW. Geer JC (eds): The Pathogenesis of Atherosclerosis. Baltimore, Williams & Wilkins, 1972, pp 166– 199. Reproduced by permission.[14])

Chapter 3. Pathophysiology of Human Atherosclerosis

Figure 3-10. Transverse section of coronary artery of 18-yearold accident victim demonstrating diffuse intimal thickening (I). Note that the organization and composition of the thickened intima resembles the underlying media (M). IEL represents the internal elastic lamina.

[36]

monotypia. These findings have suggested that focal events occurring in some fatty streaks may result in cellular proliferation with the persistence of lesions and the subsequent formation of the more complex fibrous plaques, while other fatty streaks resolve. Intimal thickening can reflect an adaptive response to diminish lumen caliber under conditions of reduced flow or can be a response designed to augment wall thickness when tensile stress increases.[37,38] Focal intimal thickenings have been observed in infants and fetuses at or near branch points and probably represent local remodeling of vessel wall organization related to growth and the associated redistribution of tensile stress.[39] Diffuse fibrocellular intimal thickening can occur as a more generalized phenomenon without a clear relationship to branches or curves and may result in a diffusely thickened intima that is considerably thicker than the media. Lipid accumulation is not a prominent feature in such intimal thickening, and the lumen remains regular and normal or slightly larger than normal in diameter.[40] Although there is little direct evidence that diffuse intimal thickening is a precursor of lipid-containing atherosclerotic plaques, both intimal thickening and plaques tend to occur in similar locations, and intimal thickening is

39

Figure 3-11. Fatty streaks in aorta of 45-year-old patient.

most evident in vessels that are especially susceptible to atherosclerosis.[41,42] Evidence has also been presented that diffuse forms of intimal thickening do not develop uniformly and that foci of relatively rapid thickening undergo dystrophic changes, which give rise to necrosis and other features characteristic of plaques.[43] The relationship of these findings to usual atherosclerosis remains to be defined.

Fibrous Plaques Fibrous plaques do not usually appear until the second decade of life and may not become the predominant lesion type until the fourth decade. The endothelial lining appears to be intact over most uncomplicated lesions, i.e., lesions without evidence of disruption, ulceration, hemorrhage, or thrombus formation. Although plaque composition varies considerably with respect to the relative proportions of the usual lesion components, a predominant mode of composition and organization can be discerned. There is frequently a relatively compact zone of connective tissue fibers and smooth-muscle cells immediately beneath the endothelium known as the fibrous cap (Fig. 3-12). Deeper in the central portion of the plaque and beneath the fibrous cap is a zone of variable composition and consistency known as the necrotic core or

40

Part One. Assessment of Vascular Disease

Figure 3-12. (A ) Transverse section of superficial femoral arteries demonstrating fibrous plaque with prominent fibrous cap (F). Note thinning of media below the thickest portion of the plaque. Note the formation of a new elastic lamina (arrow ) near the lumen. (B ) Plaque with prominent necrotic center (N) medial thinning, and thickened adventitia (A). Note vasa vasorum (arrow ) penetrating into plaque and fibrous cap.

center. It contains amorphous debris, lipid-containing cells with morphologic and functional characteristics of either smooth-muscle cells or macrophages,[44] extracellular lipids including droplets and cholesterol crystals, calcium salts, and myxoid deposits. In addition, matrix fibers, including elastin, collagen, finer fibrillar material, and structures resembling basal lamina as well as amorphous ground substance, are evident. The fibrous cap may become quite thick and form a well-organized fibrocellular, layered structure, which may even include a subendothelial elastic lamina. Thrombi formed on lesions as well as librin deposits are also incorporated into lesions. Vasa vasorum penetrate from the adventitia or from the lumen to supply the plaque[45] and fibrous cap (Fig. 3-7) and to organize thrombotic deposits. There may be thinning and attenuation of the media below the intimal lesion such that the atheromatous deposit and the media bulge outward toward the adventitia. Some advanced lesions, particularly those associated with aneurysms, may appear to be atrophic and relatively acellular, consisting of dense fibrous tissue, prominent calcific deposits, and only minimal evidence of a necrotic center. Calcification is a prominent feature of advanced plaques and may be quite extensive, involving both the superficial and deeper reaches of the plaques. Although there is no consistent relationship between plaque size or complexity and the degree of calcification, calcific deposits are most prominent in plaques of older individuals and in areas, such as the abdominal aortic segment and coronary

arteries, where plaques form earliest.[46] Advanced lesions are called fibrocalcific, lipid rich, fibrocellular, necrotic, myxomatous, etc., depending on their morphologic features. The presence of large quantities of lipid, necrotic material, and cells would tend to make a lesion soft and friable, in contrast to the hard or brittle consistency of a mainly fibrocalcific lesion with an intact and prominent fibrous cap.

Lesion Complications Although it tends to isolate the advanced lesion from the lumen, the fibrous cap may be very thin or virtually absent. It may also be interrupted or disrupted focally, exposing underlying lesion contents to the bloodstream and favoring the formation of thrombi or the penetration of blood from the lumen into the lesion. Since advanced atherosclerotic lesions often contain vasa vasorum, these vessels may rupture and result in hemorrhage into the lesion and degeneration of plaque contents. Degeneration and ulceration of plaques is most common at the sites at greatest risk of advanced lesion formation. Thus, the consequences to the circulation of lesions in those areas derive not only from the tendency to progressive stenosis but also from the effects of lesion complications, leading to rapid or sudden local occlusion or to distal embolization of thrombi or atheromatous fragments. Direct relationships among lesion composition, age of the

Chapter 3. Pathophysiology of Human Atherosclerosis

lesion, lesion complication, and the presence of particular risk factors remain to be demonstrated. Excision of lesions obtained during surgical procedures and at autopsy have revealed complications which may be related spatially and temporally to documented clinical manifestations.[47] It should also be noted, however, that lesions studied at autopsy and not associated with known clinical manifestations may show evidence of earlier complications, including hemosiderin deposits from hemorrhages, partially organized thrombi, and inflammatory cells such as macrophages, lymphocytes, plasma cells, and giant cells.[48,49] These findings indicate that lesions may progress through stages potentially severe enough to induce clinical morbidity but that local tissue reactions may be adequate, at least temporarily, to contain the injury.

CONFIGURATION OF LESIONS The perception that advanced atherosclerotic lesions protrude or bulge into the arterial lumen is suggested by angiographic or ultrasonic views of arteries in longitudinal projections which reveal narrowing of the lumen. En face observations of the luminal surface of arteries opened at operation or autopsy also reveal plaques as projecting elevations, and transverse sections of unopened but undistended atherosclerotic arteries may show narrow, crescentic or slitlike arterial lumens. These perceptions may be somewhat misleading, for the absence of distending pressure results in partial collapse of the arterial lumen and corresponding deformation of both the artery wall and the plaque. Progressive distension of the normal aorta from zero to diastolic pressure results in a nearly twofold

41

increase in aortic radius, a fourfold increase in lumen crosssectional area, and a 50% reduction in wall thickness (see Fig. 3-3).[50] Similar findings are evident for other arteries. Beyond diastolic pressure there is little change in artery wall configuration or lumen diameter in keeping with the mechanical properties related to the connective tissue fiber content and organization of the media as outlined above. Examination of atherosclerotic arteries fixed while distended reveals that the lumen on transverse section is almost always round or oval and only rarely irregular, triangular, or slitlike.[51] Sequential transverse sections through distended vessels with narrowings on axial projections reveal that the lumen is round even in areas of marked stenosis. In addition, plaques are most often eccentric with respect to the cross section of the artery wall and, under conditions of normal distension, do not usually protrude into the lumen as moundlike projections but tend instead to bulge outward from the lumen. The luminal surface of the fibrous cap is therefore usually concave on transverse section, corresponding to the curvature of the adjacent uninvolved artery wall. As a consequence, the external or outer contour of the artery tends to become oval while the corresponding lumen remains circular (Fig. 3-13). As long as the fibrous cap is intact, the necrotic center is effectively sequestered from the lumen and the circular configuration of the lumen is preserved. Thus, while plaques may appear as focal projections into the lumen on angiographic images, cross-sectional views reveal rounded lumen contours and a concave luminal profile of the plaque.[52] Circular lumen profiles may also be evident in excised undistended and unopened rigid atherosclerotic arteries when plaques are completely encircling and largely fibrocalcific. Irregular transverse lumen contours on sonograms or distended arteries examined in cross section

Figure 3-13. Multiple transverse sections at 0.5-cm intervals through a 10-cm segment of superficial femoral artery. Despite the presence of large intimal plaques, the lumen remains rounded. The external vessel contour becomes oval as the artery locally dilates to accommodate the enlarging lesion.

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Part One. Assessment of Vascular Disease

generally correspond to recent or resolving plaque disruptions ulcerations, or thrombus deposition.

ENLARGEMENT OF ATHEROSCLEROTIC ARTERIES The formation of intimal plaque does not necessarily lead to stenosis and obstruction of the arterial lumen. Atherosclerotic arteries may compensate for increasing plaque deposits by enlarging, and such enlargement can maintain a normal or near-normal lumen caliber when the cross-sectional area of the intimal plaque does not exceed approximately 40% of the area encompassed by the internal elastic lumina.[53] Larger plaques tend to be completely encircling and result in lumen stenosis. Compensatory arterial enlargement has been demonstrated in human coronary arteries,[53 – 57] carotid arteries,[58,59] superficial femoral arteries,[60,61] and abdominal aortas.[62,63] Enlargement has also been demonstrated in experimental atherosclerosis in primates in the coronary,[64,65] carotid,[66] and superficial femoral arteries and in the coronary artery of pigs.[67,68] However, different segments of the arterial tree respond differently to increasing intimal plaque.[69] In the distal left anterior descending coronary artery, arterial enlargement occurs more rapidly than intimal plaque deposition. This may result in a net increase in lumen area rather than lumen stenosis in the most severely diseased arteries.[70] Individual variation has also been demonstrated in the superficial femoral artery.[71] Thus, it appears that the development of lumen stenosis, the maintenance of a normal lumen cross-sectional area, or the development of an increase in lumen diameter is determined by the relative rates of plaque growth and artery enlargement.[72] Reduction in artery size can also result in the development of lumen stenosis, and this phenomenon has been demonstrated in vivo with intravascular ultrasound.[73] Further study of this phenomenon of artery enlargement, or reduction in size, particularly in regions associated with great morbidity related to plaque deposition, is needed in order to fully understand the processes involved in the development of atherosclerotic stenoses and aneurysms. Although plaques may occur in straight vessels away from branch points, they are usually located at bifurcations or bends, where variations in hemodynamic conditions are especially likely to occur.[74] The mechanism by which this enlargement occurs is not clear. Possible explanations include the effects of altered blood flow on the segment of artery wall which is free of plaque formation or direct effects of the plaque on the subjacent artery wall. Normal arteries respond to changes in wall shear stress[75,76] with increase[77] or decrease[78,79] in lumen diameter. This response appears to be dependent on the presence of an intact endothelial surface[80] and may be mediated through endothelial-derived vasoactive agents.[81] Whether enlargement of atherosclerotic arteries in response to increasing intimal plaque occurs by a similar mechanism is unknown. Focal narrowing of the lumen caused by intimal plaque may result in a local increase in wall shear stress, which may stimulate endothelial-dependent arterial

dilation.[82] Since most atherosclerotic plaques are eccentric, the relatively uninvolved sections of artery wall may respond normally to shear stress stimuli despite an extensive lesion on the opposite wall. Under these circumstances, enlargement of the free wall would act to promote the further development of eccentricity. Adaptive enlargement may fail if the plaque becomes concentric and rigid with no responsive free wall. Alternatively, atherosclerotic artery enlargement may develop as a result of plaque-induced involutional changes in the underlying media. Thinning of the media is commonly seen beneath atherosclerotic plaques, and dissolution of the support structure of the artery wall may result in outward bulging of the plaque.[83] Under these circumstances, direct effects of the plaque on the underlying wall promote enlargement. The observation of apparent overcompensation with excess enlargement in the distal left anterior descending coronary artery in humans[54] is consistent with a direct effect of the plaque on the artery wall, as are morphologic evidences of outward plaque bulging. The balance between plaque deposition and artery enlargement is likely to be an important determinant whether lumen caliber remains normal or whether lumen stenosis or ectasia develops. In experimentally produced arteriovenous fistulae, the afferent artery has been shown to enlarge just enough to restore shear stress to baseline levels.[84] Wall shear stress thus appears to act as a regulating signal to determine artery size, and this response in dependent on the presence of an intact endothelial surface.[85 – 88] The response is mediated by the release of endothelial-derived relaxing factor or nitric oxide.[89,90] Thus the endothelium functions as a mechanically sensitive signal-transduction interface between the blood and the artery wall.[91,92] Nitric oxide (NO) plays an important role in both the acute and chronic increase in vessel caliber in response to increased flow.[93,94] Inhibition of NO synthesis by means of long-term oral administration of LNAME can inhibit flow induced arterial enlargement.[95,96] Atherosclerotic arteries are also capable of enlarging in response to increases in blood flow and increase in wall shear stress, but this process may be limited.[97] Atherosclerotic artery enlargement is further discussed later in this chapter. The nature and mechanisms of the artery wall –adaptive processes which allow arteries to adjust lumen diameter are currently being actively investigated. Understanding the mechanism and limits of the adaptive process and identification of the consequences for the vessel wall of shear stress that is persistently higher or lower than normal will be of value in clinical efforts to maintain normal lumen caliber.

LOCALIZATION OF ATHEROSCLEROTIC LESIONS Several major arterial sites are particularly prone to the development of advanced atherosclerotic lesions, while others are relatively resistant. The coronary arteries, carotid bifurcation, infrarenal abdominal aorta, and iliofemoral vessels are particularly susceptible, while the mesenteric, renal, intercostals, and mammary arteries tend to be spared.[98]

Chapter 3. Pathophysiology of Human Atherosclerosis

The apparently selective localization of plaques which evolve to cause clinical symptoms has been attributed to local differences in vessel wall metabolism, structure, and permeability and to differences in local hemodynamic patterns. Since many plaques tend to form in relation to branch points and bends where flow profiles have been shown to undergo deviations from unidirectional laminar flow, various flow features related to these changes have been implicated in plaque localization. These include elevated shear stress,[4] turbulence,[99,100] flow separation,[101] and low shear stress.[102,103] Elevated shear stress has been thought to contribute to plaque initiation by causing endothelial injury. The resulting exposure of intimal connective tissue to the bloodstream would favor platelet deposition and release of platelet growth factor, thereby including focal intimal thickening by stimulating smooth-muscle cell proliferation.[104] Variations in shear stress direction associated with pulsatile flow may favor increased endothelial permeability by direct mechanical effects on cell junctions, whereas relatively high unidirectional shear stresses may not be injurious[105] and may even favor endothelial mechanical integrity.[106] Endothelial cells are normally aligned in the direction of flow[107] in an overlapping arrangement.[108] Cyclic shifts in the relationship between shear stress direction and the orientation of intercellular overlapping borders may disturb the relationships between ingress and egress of particles through junctions. This hypothesis agrees well with reports of increased permeability of cultured, confluent endothelial cells subjected to changes in shear stress[109] as well as increased permeability to Evans blue dye in relation to differences in endothelial cell orientation,[110] which may be associated with different flow patterns. Oscillatory shear stress has also been shown to influence endothelium and nitric oxide synthase expression[111] as well as stimulate adhesion molecule expression in cultured human endothelial cells.[112] Heart rate has been implicated as an independent risk factor in coronary atherosclerosis and is discussed further in the section dealing with the coronary arteries. Reduction in heart rate in experimental atherosclerosis has been shown to retard carotid plaque progression.[113,114] Turbulence may, however, develop in association with stenoses and irregularities of the flow surface caused by atherosclerotic plaques, but turbulence is located distal to the lesion, not at the lesion. Experimentally produced stenoses reveal that turbulence is greatest two to four vessel diameters distal to the stenosis in an area that frequently develops poststenotic dilatation but does not readily develop diet-induced plaques.[115 – 117] Thus, turbulence per se has not been shown to be an initiating factor in atherogenesis. Nevertheless, turbulence may play a role in plaque disruption or thrombogenesis. Further investigation is needed to establish these relationships. Evidence that these are major initiating or sustaining mechanisms in human or experimental plaque formation has not been forthcoming. Experimental observations reveal no evidence of endothelial damage or disruption over early developing experimental foam cell lesions,[118] suggesting that endothelial denudation is not an important initiating factor in plaque pathogenesis.

43

Clinical observations suggest that plaques localize first in areas of low shear stress, such as on the upstream rather than downstream rim of aortic ostia (Fig. 3-14). Quantitative correlative studies of flow profiles and early plaque formation in the human carotid bifurcation suggest that flow separation, reduced flow rate, reduced shear stress, and departures from unidirectional laminar flow may be the important hemodynamic factors in plaque pathogenesis.[119] At the carotid bifurcation, for example, plaques do not begin in the vicinity of the flow divider where flow velocity is high, laminar, and unidirectional throughout the cardiac cycle. Plaques are formed earliest and are most advanced opposite the flow divider, where flow velocity and shear stress are low (Fig. 315). Under conditions of pulsatile flow, flow reversal occurs in the same area, particularly during the downstroke of systole with oscillation in wall shear stress direction.[120] These flowfield disturbances may be associated with prolonged residence time of atherogenic particles such as lipids or mitogens at sites which are prone to plaque formation. Although reduced velocity and shear stress, departures from unidirectional laminar flow, and flow reversal appear to favor plaque

Figure 3-14. Celiac (CEL) and superior mesenteric (SMA) ostia of human aorta. Note prominent plaque formation at upstream rim of the ostia with no plaque formation on the flow divider (arrows ), which is exposed to high shear stress.

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Part One. Assessment of Vascular Disease

mortality on both men and women.[124] The combined protective effects of increased flow velocity and reduced heart rate are consistent with the known protective effects of regular exercise against coronary artery disease in humans.

CAROTID BIFURCATION PLAQUES

Figure 3-15. Blood flow patterns in the human carotid bifurcation. There is a large area of show flow, flow separation, low shear stress, and disordered flow patterns in the internal carotid sinus opposite the bifurcation flow divider. Plaques localize in this area. The area of high shear stress at the flow divider is relatively spared of plaque formation. (From Zarins CK, Giddens DP, Glagov S: Atherosclerotic plaque distribution and flow velocity profiles in the carotid bifurcation. In Bergan JJ. Yao JST (eds): Cerebrovascular Insufficiency. New York, Grune & Stratton, 1983, pp 19 – 30. Reproduced by permission.)

formation, turbulence as such does not appear to be a factor. Areas of high turbulence such as occur immediately distal to experimental stenoses are not sites of preferential lesion formation.[121] Such findings also suggest that an increase in flow velocity and shear in a developing atherosclerotic stenosis could tend to retard further plaque formation. Since the development of complex flow patterns and shear stress reversal occurs during systole, an elevated heart rate may be expected to be associated with the acceleration of plaque formation at sites of predilection, for increased heart rate would prolong the relative time spent in systole. This effect would be expected to be particularly important in the coronary arteries, where systolic flow is biphasic. Experimental studies reveal that lowered heart rate has a profound effect on retarding the development of diet-induced coronary artery[122] and carotid artery[66,123] plaques. Clinical epidemiologic studies have revealed heart rate to be a primary independent risk factor for coronary and cardiovascular

Intimal thickening is found in the carotid sinus or carotid bulb early in life, and atherosclerotic lesions are common at this site in adults. Although extensive, complex, and complicated plaques may be present in the carotid bifurcation, particularly within the sinus, there is little plaque formation in the immediately proximal common carotid artery or the internal carotid artery immediately distal to the sinus. Within the bony canal in the base of the skull, lesions are unusual, but the basilar artery as well as the proximal segments of the cerebral arteries about the circle of Willis are commonly involved. The distribution of lesions about the bifurcation is probably associated with hemodynamic conditions which derive from the special geometry at this site.[119] The internal carotid sinus is a localized region which has a cross-sectional area twice that of the immediately distal internal carotid segment. This configuration in combination with the branching angle results in a flow profile in which a large area of flow separation is formed along the outer wall of the sinus (Fig. 3-15). Secondary and tertiary flow patterns, vortex formation, and oscillations in the angle of the flow vector occur at the side walls of the sinus.[120] Intimal plaques are deposited early in life in this region. As plaques enlarge at the outer wall, the geometric configuration of the lumen is modified so that other flow patterns may develop which favor plaque formation on the side and inner walls. In its most advanced and stenotic form the disease may involve the entire circumference of the sinus, including the region of the flow divider, but plaques are commonly largest and most complicated at the outer and side walls of the carotid bifurcation (Fig. 3-16). The hemodynamic conditions which exist at the carotid bifurcation may also influence the surface characteristics of existing carotid plaques and contribute to their tendency to ulcerate and embolize. Carotid plaques producing high-grade stenosis exhibit features of intraplaque hemorrhage, ulceration, thrombosis, lumen surface irregularity, and calcification.[125] These microanatomic features are present in plaques removed from symptomatic and asymptomatic patients and appear to be related to plaque size. Ulceration and surface thrombi that may lead to cerebral embolization are prominent features in markedly stenotic plaques even when symptoms are absent. These observations indicate that the disruptive processes that underlie plaque instability appear to be closely associated with plaque size rather than plaque composition.[126] Quantitative morphologic studies of human carotid bifurcations have demonstrated increased intimal thickness in association with lumen enlargement with resultant preservation of normal tangential mural tension.[127,128] The factors that differentiate a normal adaptive intimal thickening from an inappropriate intimal hyperplastic response resulting in lumen stenosis at a vascular anastomosis are not well understood. Techniques to precisely measure stresses in the

Chapter 3. Pathophysiology of Human Atherosclerosis

Figure 3-16. Longitudinal section of carotid endarterectomy specimen. Note marked plaque formation (P) on outer wall of internal carotid (IC) sinus. This corresponds to the area which is exposed to low flow velocity and low shear stress. The inner wall (arrow ) has minimal intimal thickening. External carotid (EC), common carotid (CC).

artery wall are now available and will help define the role of mechanical forces in artery wall response.[129,130]

AORTIC ATHEROSCLEROSIS Plaques are regularly found in the adult human thoracic aorta, but they are often less abundant, more discrete, less complicated, and less calcific than in the abdominal aortic segment of the same individual. Although plaques tend to deposit about intercostal branch ostia, significant occlusive lesions of the thoracic aorta do not develop and thoracic aorta aneurysms are unusual. The infrarenal abdominal aortic segment, on the other hand, is particularly prone to the early occurrence of plaques and occlusive disease as well as to the development of marked medial atrophy, calcification, and aneurysmal dilation with mural thrombus formation.

45

The differing susceptibilities of the thoracic and abdominal aorta to atherosclerosis and to aneurysmal dilation may be due to differences in architecture, composition, and nutrition of the artery wall as well as to differences in the distribution of mechanical stresses. As noted previously, the thoracic aorta is thicker and has a greater number of medial lamellar units than the abdominal aorta, in keeping with its greater diameter and tangential wall tension.[131] The thoracic aorta contains a greater relative proportion of elastin and a lower proportion of collagen than the abdominal aorta.[132] The increased stiffness of the abdominal aorta is associated with an elevated pulse pressure that could result in altered medial smooth muscle metabolism and increased susceptibility to plaque deposition.[133,134] In addition, differences exist with respect to wall nutrition that could result in different propensities to atherogenesis and to different responses of the media to mechanical stress.[135] The outer two thirds of the thoracic aortic media is well perfused by intramural vasa vasorum, whereas the inner 30 lamellar units are nourished by diffusion from the lumen. The abdominal aorta, however, is nourished only from the lumen and lacks medial vasa vasorum; moreover, the tension per layer is much larger than for the thoracic segment.[2] These factors may place the medial smooth muscle cells of the abdominal aorta at a relatively higher risk for ischemic injury. Intimal plaque formation may increase the diffusion distance from the lumen and induce reparative and healing processes, which may promote lipid uptake and further plaque formation. Penetration of vasa vasorum into atherosclerotic plaque has been demonstrated and may further promote a proliferative response in the artery. Thus, the composition and microarchitecture of the media and the metabolic state of the media smooth muscle cells may be important factors in determining differential susceptibilities of the aorta to atherosclerosis.[133] Flow conditions in the aorta may also predispose it to plaque formation. The thoracic aorta is exposed to relatively high rates of flow, with obligatory flow to the cerebral, upperextremity, and visceral arterial beds, including the renal arteries, which deliver one quarter of the cardiac output at rest. By contrast, blood flow in the infrarenal aorta may be highly variable, with volume flow largely dependent on muscular activity of the lower extremities. Under modern conditions of motorized transport and an increasingly sedentary lifestyle, the abdominal aortic segment is likely to be subjected to relatively reduced blood flow velocities over the long term. The abdominal aorta would therefore be exposed to the adverse hemodynamic forces of low flow velocity, low wall shear stress, prolonged particle residence time, and oscillation of wall shear.[136,137] Each of these factors would act to favor plaque formation.[138] Experimental flow studies in models of the human abdominal aorta reveal that these adverse hemodynamic conditions can be eliminated or minimized by hemodynamic conditions that prevail during exercise.[139]

ANEURYSM FORMATION The association between atherosclerosis and abdominal aortic aneurysm formation has long been recognized in humans. However, the mechanisms by which the atherosclerotic

46

Part One. Assessment of Vascular Disease

process may be associated with aneurysmal dilation are not well defined. A number of other etiologic factors have been proposed, including increased proteolytic enzyme activity[140 – 142] and genetic abnormalities leading to deficiencies in connective tissue structure and function.[143] Although some investigators have questioned a role for atherosclerosis in aneurysm formation, evidence for its importance is increasing. Most aneurysms are localized to the infrarenal abdominal aortic segment, where aortic atherosclerosis is usually most advanced. Plaque formation in this region may further impair diffusion of nutrients to the aortic wall, resulting in atrophy of the underlying aortic wall. Plaque deposition is accompanied by compensatory enlargement of the aorta, as described

earlier in this chapter. Under these circumstances, the plaque may provide structural support to the aortic wall. Subsequent plaque atrophy may leave an enlarged aorta with a thinned wall unable to support wall tension as aneurysmal enlargement progresses. Ingrowth of vasa vasorum into the media and plaque occurs commonly in occlusive aortic atherosclerosis (Figs. 3-17 and 3-18). However, under conditions where vasa vasorum are absent, impaired nutrition of plaque and media may result in atrophy of both the plaque and the artery wall with aneurysmal enlargement.[144] Experimental studies confirm the importance of the medial lamellar architecture in the pathogenesis of aneurysms[145] and reveal that diet-induced atherosclerosis may result in destruction of the media and in aneurysm formation.[146,147]

Figure 3-17. (A ) Transverse section of abdominal aorta demonstrating intimal plaque (P) with preservation of underlying media (M) with its lamellar architecture. Vasa vasorum (arrow ) are present in the media. (B ) Aneurysm with marked medial atrophy (M), delineated by arrows, fibrous plaque (P), and large mural thrombus (T).

Chapter 3. Pathophysiology of Human Atherosclerosis

47

SUPERFICIAL FEMORAL ARTERY STENOSIS

Figure 3-18. Obstructing plaques in the abdominal aorta are characterized by ingrowth of vasa vasorum to nourish the media and plaque. Aneurysms are relatively devoid of vasa with atrophy of the aortic wall. A deficiency of medial nutrition may be a factor in aneurysm pathogenesis. (From Zarins CK, Glagov S: Aneurysms and obstructive plaques: Differing local responses to atherosclerosis, in Bergan JJ, Yao JST (eds): Aneurysms: Diagnosis and Treatment. New York, Grune & Stratton, 1982, pp 61– 82. Reproduced by permission.[144])

A controlled trial of cholesterol-lowering therapy in monkeys revealed plaque regression, thinning of the media, and aneurysmal dilation of the abdominal aorta.[148] These observations suggest that the formation of abdominal aortic aneurysms may complicate the atherosclerotic process under special experimental and human clinical conditions. Aneurysms appear at a relatively late phase of plaque evolution, when plaque regression and medial atrophy predominate, rather than at earlier phases when cell proliferation, fibrogenesis, and lipid accumulation characterize plaque progression. Macrophages and proteolytic enzymes during this phase of atherosclerotic artery wall degeneration may provide the mechanisms whereby dissolution of the aortic wall occurs. Individual differences in plaque evolution reflecting differences in both the rate and duration of plaque formation and plaque regression and in tissue and cell responses to the atherogenic process are likely to be major determinants of individual susceptibility to aneurysm formation. Microarchitectural differences in artery wall structure as well as local mechanical conditions related to geometry, blood flow, and blood pressure are likely to be major determinants of aneurysm localization.[149] These factors may be modulated by genetic predisposition and by local injurious,[150] hemodynamic,[151] metabolic, and tensile stresses.

The arteries of the lower extremities are frequently affected by atherosclerotic plaques, while vessels of similar size in the upper extremities are spared. In addition to differences in hydrostatic pressure, the arteries of the lower extremities are subjected to more marked variations in flow rate, depending on the level of physical activity. Similar to the situation that prevails in the abdominal aorta, sedentary lifestyles would tend to favor low flow rates and lead to increased plaque deposition in vessels of the lower extremities. Cigarette smoking and diabetes mellitus are the risk factors most closely associated with atherosclerotic disease of the lower extremities.[152] The manner in which these factors and the special hemodynamic conditions are mutually enhancing in the vessels of the lower extremities remains to be elucidated. Of the arteries of the lower extremity, the superficial femoral artery is most commonly the site of multiple stenotic lesions, while the profunda femoris tends to be spared. The superficial femoral artery is a major conduit with relatively few proximal branches, and flow velocity is likely to be relatively slow on the average, varying in relation to activity of the calf muscles during walking or running. The profunda femoris is a smaller, muscular vessel with many branches to lower extremity muscles; flow velocity is likely to be relatively high under normal conditions. Plaques in the superficial femoral artery have not been shown to occur preferentially at branching sites, but stenotic lesions tend to appear earliest at the adductor hiatus, where the vessel is straight and branches are few (Fig. 3-19). Repeated mechanical trauma, limitations on vessel compliance, or alterations in the adaptive enlargement process associated with the closely applied adductor magnus tendon[60] may contribute to the selective localization of occlusive disease in this position.

CORONARY ARTERY ATHEROSCLEROSIS The coronary arteries are particularly prone to develop atherosclerosis.[153] The special hemodynamic features of the coronary circulation, including the marked excursions in flow rate during the cardiac cycle, the geometric configuration of the vessels and their branches, the mechanical torsion and flexions of the vessels associated with cardiac motion, and the special reactivity of coronary artery smooth muscle to vasoactive substances and nervous impulses, have been suggested as predisposing factors that could underlie individual differences in lesion distribution. The selective involvement of the left coronary artery opposite the flow divider at the bifurcation of the left circumflex indicates that hemodynamic relationships similar to those that prevail at the carotid bifurcation also occur in the coronary arteries. In addition, compared to other vessels, there are two pulses of flow during systole. Since the oscillatory changes in fluid shear are related to the downstroke phase of the systolic pulse,[120] an increase in heart rate may exert a greater effect

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Part One. Assessment of Vascular Disease

but related aspects of involvement.[155] These include the extent of the disease process, i.e., the degree to which a given artery segment or arterial bed is involved by the disease and/or the number of distinguishable lesions present in a vessel or group of vessels (Fig. 3-20). Irregularities and strictures of lumen contour on angiograms as well as on ultrasonic and axial tomographic images and the presence of calcifications have been considered to be major indicators of extent of disease. A second quantifiable feature that bears directly on the consequences to the circulation is the severity of the disease, as reflected in the degree of luminal stenosis. Usual estimates are expressed as percent stenosis, based on comparisons between lumen diameter at a definite narrowing and an immediately adjacent segment which appears to be uninvolved. Another discernible index of the atherosclerotic process, independent of both extent of involvement and severity of stenosis, is lesion complication. This includes ulceration, necrosis, thrombosis, and plaque hemorrhage. Finally, quantitative information concerning lesion composition may be obtained. This includes calcification, frequently revealed by clinical visualization methods, and estimates of

Figure 3-19. Focal stenosis of superficial femoral artery at adductor hiatus.

on atherogenesis in the coronary arteries than elsewhere in the arterial tree. Recent studies suggest that reduced heart rate retards the development of experimental, diet-induced plaques.[66,122,123,154] These observations are consistent with clinical observations of a reduced risk of cardiovascular mortality in men and women with a lower heart rate.[124]

QUANTITATIVE EVALUATION OF ATHEROSCLEROSIS Quantitative clinical assessment of atherosclerosis by modern diagnostic methods may include evaluation of several distint

Figure 3-20. Quantifiable aspects of atherosclerotic lesions. In light of developing techniques for assessing plaque size, configuration, and composition in vivo, use of more precise terms for the description of lesions could improve validation and clinical pathologic correlative studies. Extent implies degree of involvement of a particular vessel or arterial bed, while severity implies interference with flow and reduction of perfusion. Both stenosis (narrowing of the lumen) and complication (plaque disruption, hemorrhage, or thrombosis) determine severity regardless of the extent of disease. Lesion composition may be important in predisposing to complication.

Chapter 3. Pathophysiology of Human Atherosclerosis

lipid, cell, and matrix fiber content, usually estimated from histological sections. Most often, quantitative descriptions of atherosclerosis deal with the severity of disease, or percent stenosis, of a lesion imaged by angiography. Since angiography can only demonstrate the opacified artery lumen, the degree of stenosis is calculated by comparing lumen diameter at the narrowest point to an apparently “disease-free” area in the same vessel. In addition to errors in projection, resolution, and magnification, errors may arise if the apparently normal zone is involved by advanced intimal plaques. In comparing sequential angiograms, further errors may result if arteries dilate as atherosclerosis progresses. Such a response to progressing disease has been demonstrated in experimental[156] and human atherosclerosis.[52] Ultrasonic imaging of arteries has the capability of visualizing not only the lumen of the vessel but also the artery wall.[157] Other imaging techniques such as computed tomography and nuclear magnetic resonance have similar potential to visualize the plaque. It is important, however, to recognize the difference in definition of percent stenosis by these imaging techniques compared to angiography (Fig. 321) when assessing validation studies. Gross morphologic and histologic examinations of atherosclerotic arteries have the advantage of direct visualization and inspection of the lumen, plaque, and artery wall. However, redistension of the collapsed artery wall during fixation is necessary in order to restore in vivo configuration.[52] Failure to do so has led to a misperception that angiography “underestimates” the degree of stenosis when compared to postmortem examination.[158] Calculation of percent stenosis from histologic cross sections of arteries is usually performed by comparing the lumen cross-sectional area to the area encompassed by the internal elastic lamina, the presumed lumen size before the plaque developed (Fig. 321). This difference in definition of percent stenosis may make comparison to other methods difficult. In addition, if vessel enlargement occurred during plaque enlargement, the internal elastic lamina landmark may not accurately represent the “true lumen.” Furthermore, accurate quantitative correlation of plaque cross-sectional area as measured on histologic sections with in vivo clinical measurements requires corrections to account for tissue shrinkage during fixation and processing.[52] Although plaques may vary a good deal in composition, methods for assessing the distribution of plaque components in vivo are not yet sufficiently sensitive or specific to permit the establishment of criteria for predicting which lesions are likely to enlarge or ulcerate and which lesions will remain relatively stable. Methods that provide direct information about actual plaque size and composition are developing rapidly and are likely to gain increased application. These include real-time ultrasound imaging, reconstructions from computerized tomography, and nuclear magnetic reasonance and positron imaging. Thus, more accurate assessments of the extent of disease may be available in the future,

49

Figure 3-21. Different methods of measuring and defining percent stenosis.

including more quantitative in vivo measurements of lumen diameter, plaque and artery wall thickness, plaque composition, plaque disruption, and thrombosis. For the present, attempts to quantitate atherosclerotic disease in the living patient or from histologic sections in order to evaluate treatment programs dealing with prevention, regression, or early detection must take appropriate account of the features of plaque and vessel morphology outlined above. In particular, the outward sequestration effect, the persistence of a circular lumen which may approximate normal dimensions despite the presence of a large plaque, the association of plaque formation with enlargement of the vessel, and the need for fixation under pressure must be considered.

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Part One. Assessment of Vascular Disease Growth, and Compensatory Vessel Enlargement in Coronary Arteries of Miniature Pigs. Arterioscler. Thromb. Vasc. Biol. 1998, 18 (3), 415. Birnbaum, Y.; Fishbein, M.C.; Luo, H.; Nishioka, T.; et al. Regional Remodeling of Atherosclerotic Arteries: A Major Determinant of Clinical Manifestations of Disease. J. Am. Coll. Cardiol. 1997, 30 (5), 1149. Zarins, C.K.; Weisenberg, E.; Kolettis, G.; et al. Differential Enlargement of Artery Segments in Response to Enlarging Atherosclerotic Plaques. J. Vasc. Surg. 1988, 7, 386. Wong, C.B. Atherosclierotic Arterial Remodeling in the Superficial Femoral Artery: Individual Variation in Local Compensatory Enlargement Response. Circulation 1997, 95 (1), 279. Keren, G. Compensatory Enlargement, Remodeling, and Restenosis. Adv. Exp. Med. Biol. 1997, 430, 187. Smits, P.C.; Bos, L.; Quarles van Ufford, M.A.; Eefting, F.D.; et al. Shrinkage of Human Coronary Arteries Is an Important Determinant of De Novo Atherosclerotic Luminal Stenosis: An In Vivo Intravascular Ultrasound Study. Heart 1998, 79 (2), 143. Ravensbergen, J.; Ravensbergen, J.W.; Krijger, J.K.; Hillen, B.; et al. Localizing Role of Hemodynamics in Atherosclerosis in Several Human Vertebrobasilar Junction Geometries. Arterioscler. Thromb. Vasc. Biol. 1998, 18 (5), 693. Zarins, C.K.; Zatina, M.A.; Giddens, D.P.; et al. Shear Stress Regulation of Artery Lumen Diameter in Experimental Atherogenesis. J. Vasc. Surg. 1987, 5, 413. Kamiya, A.; Togawa, T. Adaptive Regulation of Wall Shear Stress to Flow Change in the Canine Carotid Artery. Am. J. Physiol. 1980, 239, H14. Masuda, H.; Bassiouny, H.S.; Glagov, S.; Zarins, C.K. Artery Wall Restructuring in Response to Increased Flow. Surg. Forum 1989, 40, 285. Guyton, J.R.; Hortley, C.J. Flow Restriction of One Carotid Artery in Juvenile Rats Inhibits Growth of Arterial Diameter. Am. J. Physiol. 1985, 248, H540. Singh, T.M.; Zhuang, Y.J.; Masuda, H.; Zarins, C.K. Intimal Hyperplasia in Response to Reduction of Wall Shear Stress. Surg. Forum 1997, 48, 445. Langille, B.L.; O’Donnell, F. Reductions in Arterial Diameter Produced by Chronic Decreases in Blood Flow Are Endothelium-Dependent. Science 1986, 231, 405. Furchgott, R.F. Role of Endothelium in Responses of Vascular Smooth Muscle. Circ. Res. 1983, 53, 557. Zarins, C.K. Adaptive Responses of Arteries. J. Vasc. Surg. 1989, 9, 382. Glagov, S.; Zarins, C.K.; Giddens, D.P.; Ku, D.N. Hemodynamics and Atherosclerosis: Insights and Perspectives Gained from Studies of Human Arteries. Arch. Pathol. Lab. Med. 1988, 112, 1018. Masuda, H.; Bassiouny, H.S.; Glagov, S.; Zarins, C.K. Artery Wall Restructuring in Response to Increased Flow. Surg. Forum 1989, 40, 285. Langille, B.L.; O’Donnell, F. Reductions in Arterial Diameter Produced by Chronic Decreases in Blood Flow Are Endothelium-Dependent. Science 1986, 231, 405. Pohl, U.; Holtz, J.; Busse, R.; Bassenge, E. Crucial Role of Endothelium in the Vasodilator Response to Increased Flow In Vivo. Hypertension 1986, 8, 37.

87. Hull, S.S.J.; Kaiser, L.; Jaffe, M.D.; Sparks, H.V.J. Endothelium-Dependent Flow-Induced Dilatation of Canine Femoral and Saphenous Arteries. Blood Vessels 1986, 23, 183. 88. Rubanyi, G.M.; Romero, C.J.; Vanhoutte, P.M. Flow Induced Release of Endothelium-Derived Relaxing Factor. Am. J. Physiol. 1986, 250, H1145. 89. Furchgott, R.F. Role of Endothelium in Responses of Vascular Smooth Muscle. Circ. Res. 1983, 53, 557. 90. Koller, S.; Sun, D.; Huang, A.; Kaley, G. Corelease of Nitric Oxide and Rotaglandins Mediates Flow-Dependent Dilatation of Rat Gracilis Muscle Arterioles. Am. J. Physiol. 1994, 267, H326. 91. Davies, P.F. Flow-Mediated Endothelial Mechanotransduction. Physiol. Rev. 1995, 75, 519. 92. Cooke, J.P.; Rossitch, E.J.; Andon, N.A.; Localzo, J.; Dzau, V.J. Flow Activates an Endothelial Potassium Channel to Release an Endogenous Nitrovasodilator. J. Clin. Investig. 1991, 88, 1663. 93. Holtz, J.; Fostermann, U.; Pohl, U.; Giesler, M.; Bassenge, E. Flow-Dependent, Endothelium-Mediated Dilatation of Epicardial Coronary Arteries in Conscious Dogs: Effects of Cyclooxygenase Inhibition. J. Cardiovasc. Pharmacol. 1984, 6, 1161. 94. Miller, V.M.; Burnett, J.C.J. Modulation of NO and Endothelin by Chronic Increases in Blood Flow in Canine Femoral Arteries. Am. J. Physiol. 1992, 263, H103. 95. Tronc, F.; Wassef, M.; Esposito, B.; Henrion, D.; Glagov, S.; Tedgui, A. Role of NO in Flow-Induced Remodeling of the Rabbit Common Carotid Artery. Arterioscler. Thromb. Vasc. Biol. 1996, 16 (10), 1256. 96. Guzman, R.J.; Abe, K.; Zarins, C.K. Flow-Induced Arterial Enlargement Is Uninhibited by Suppression of Nitric Oxide Synthase Activity In Vivo. Surgery 1997, 122, 273. 97. Glagov, S.; Weisenberg, E.; Zarins, C.K.; et al. Compensatory Enlargement of Human Atherosclerotic Coronary Arteries. N. Engl. J. Med. 1987, 316, 1371. 98. Roberts, J.C., Jr.; Moses, C.; Wilkins, R.H. Autopsy Studies in Atherosclerosis: I Distribution and Severity of Atherosclerosis in Patients Dying Without Morphologic Evidence of Atherosclerotic Catastrophe; II. Distribution and Severity of Atherosclerosis in Patients Dying with Morphologic Evidence of Atherosclerotic Catastrophe. Circulation 1959, 29, 511, 520. 99. Stehbens, W.E. The Role of Hemodynamics in the Pathogenesis of Atherosclerosis. Prog. Candiovasc. Dis. 1975, 18, 89. 100. Bharadvaj, B.K.; Mabon, R.F.; Giddens, D.P. Steady Flow in a Model of the Human Carotid Bifurcation. Part II. Laser Doppler Anemometer Measurements. J. Biomech. Eng. 1982, 15, 363. 101. Scharfstein, H.; Gutstein, W.H.; Lewis, L. Changes of Boundary Layer Flow in Model Systems, Implications for Initiation of Endothelial Injury. Circ. Res. 1963, 18, 580. 102. Caro, C.G.; Fitz-Gerald, J.M.; Schroter, R.D. Atheroma and Arterial Wall Shear: Observation, Correlation and Proposal of a Shear Dependent Mass Transfer Mechanism for Atherogenesis. Proc. R. Soc. Lond. [Biol.] 1971, 117, 109.

Chapter 3. Pathophysiology of Human Atherosclerosis 103.

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53

Ku, D.N.; Giddens, D.P. Pulsatile Flow in a Model Carotid Bifurcation. Arteriosclerosis 1983, 3, 31. Bomberger, R.A.; Zarins, C.K.; Taylor, K.E.; Glagov, S. Effect of Hypotension on Atherogenesis and Aortic Wall Composition. J. Surg. Res. 1980, 28, 402. Beere, P.; Glagov, S.; Zarins, C.K. Retarding Effect of Lowered Heart Rate on Coronary Atherosclerosis. Science 1984, 226, 180. Bassiouny, H.S.; Zarins, C.K.; Hovanessian, A.; Glagov, S. Heart Rate and Experimental Carotid Atherosclerosis. Surg. Forum 1992, XLIII, 373. Kannel, W.B.; Kannel, C.; Paffenbarger, R.S., Jr.; et al. Heart Rate and Cardiovascular Mortality: The Framingham Study. Am. Heart J. 1987, 113, 1434. Glagov, S.; Zarins, C.K. What Are the Determinants of Plaque Instability and Its Consequences? J. Vasc. Surg. 1989, 9, 389. Bassiouny, H.S.; Davis, H.S.; Masawa, N.; et al. Critical Carotid Stenoses: Morphologic and Biochemical Similarity of Symptomatic and Asymptomatic Plaques. J. Vasc. Surg. 1989, 9, 202. Masawa, N.; Glagov, S.; Zarins, C.K. Quantitative Morphologic Study of Intimal Thickening at the Human Carotid Bifurcation: I. Axial and Circumferential Distribution of Maximum Intimal Thickening in Asymptomatic Uncomplicated Plaques. Atherosclerosis 1994, 107, 137. Masawa, N.; Glagov, S.; Zarins, C.K. Quantitative Morphologic Study of Intimal Thickening at the Human Carotid Bifurcation: II. The Compensatory Enlargement Response and the Role of the Intima in Tensile Support. Atherosclerosis 1994, 107, 147. Vito, R.P.; Choi, H.S.; Seitferth, T.A.; Zarins, C.K.; Glagov, S.; Bassiouny, H.S. Measurement of Strain in Soft Biological Tissue. Dev. Theor. Appl. Mech. 1990, 536. Vito, R.P.; Whang, M.C.; Giddens, D.P.; Zarins, C.K.; Glagov, S. Stress Analysis of the Diseased Arterial CrossSection. Adv. Bio-Eng. ASME 1990, 4, 273. Clark, J.M.; Glagov, S. Transluminal Organization of the Arterial Wall: The Lamellar Unit Revised. Arteriosclerosis 1985, 5, 19. Clark, J.M.; Glagov, S. Structural Integration of the Arterial Wall: I Relationships and Attachments of Medial Smooth Muscle Cells in Normally Distended and Hyperdistended Aortas. Lab. Investig. 1979, 40, 587. Stehbens, W.E. Hemodynamics and the Blood Vessel Wall; Charles C Thomas: Springfield, Illinois, 1979. Cozzi, P.J.; Lyon, R.T.; Davis, H.R.; et al. Aortic Wall Metabolism in Relation to Susceptibility and Resistance to Experimental Atherosclerosis. J. Vasc. Surg. 1988, 7, 706. Lyon, R.T.; Runyon-Hass, A.; Davis, H.R.; et al. Protection from Atherosclerotic Lesion Formation by Reduction of Artery Wall Motion. J. Vasc. Surg. 1987, 5, 59. Klocke, F.J.; Mates, R.E.; Canty, J.M.; et al. Coronary Pressure-Flow Relationships. Controversial Issues and Probable Implications. Circ. Res. 1985, 56, 310. Granata, L.; Olsson, R.A.; Huvos, A.; et al. Coronary Inflow and Oxygen Usage Following Cardiac Sympathetic Nerve Stimulation in Unanesthetized Dogs. Circ. Res. 1965, 16, 114.

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Part One. Assessment of Vascular Disease Zarins, C.K.; Glagov, S.; Giddens, D.P.; Ku, D.N. Hemodynamic Factors and Atherosclerotic Change in the Aorta. In Aortic Surgery; Bergan, J.J., Yao, J.S.T., Eds.; Saunders: Philadelphia, 1988; 17 –25. Ku, D.N.; Glagov, S.; Moore, J.E., Jr.; Zarins, C.K. Flow Patterns in the Abdominal Aorta Under Simulated Postprandial and Exercise Conditions: An Experimental Study. J. Vasc. Surg. 1989, 9, 309. Dobrin, P.B.; Baker, W.H.; Gley, W.C. Elastolytic and Collagenolytic Studies of Arteries: Implications for the Mechanical Properties of Aneurysms. Arch. Surg. 1984, 119, 405. Menashi, S.; Campa, J.S.; Greenhalgh, R.M.; Powell, J.T. Collagen in Abdominal Aortic Aneurysm: Typing, Content, and Degradation. J. Vasc. Surg. 1987, 6, 578. Cohen, J.R.; Mandell, C.; Margolis, I.; et al. Altered Aortic Protease and Antiprotease Activity in Patients with Ruptured Abdominal Aortic Aneurysm. Surg. Gynecol. Obstet. 1987, 164, 355. Tilson, M.D. A Perspective on Research in Abdominal Aortic Aneurysm Disease with Unifying Hypothesis. In Aortic Surgery; Bergan, J.J., Yao, J.S.T., Eds.; Saunders: Philadelphia, 1989; 1st ed., 355 – 358. Zarins, C.K.; Glagov, S. Aneurysms and Obstructive Plaques: Differing Local Responses to Atherosclerosis. In Aneurysms: Diagnosis and Treatment; Bergan, J.J., Yao, J.S.T., Eds.; Grune & Stratton: New York, 1982; 61 – 82. Zatina, M.A.; Zarins, C.K.; Gewertz, B.L.; Glagov, S. Role of Medial Lamellar Architecture in the Pathogenesis of Aortic Aneurysms. J. Vasc. Surg. 1984, 1, 442. Zarins, C.K.; Glagov, S.; Wissler, R.W.; Vesselinovitch, D. Aneurysm Formation in Experimental Atherosclerosis: Relationship to Plaque Evolution. J. Vasc. Surg. 1990, 12, 246. Strickland, H.L.; Bond, M.G. Aneurysms in Large Colony of Squirrel Monkeys (Saimiri sciureus ). Lab. Anim. Sci. 1983, 33, 589.

148. Zarins, C.K.; Xu, C-P.; Glagov, S. Aneurysmal Enlargement of the Aorta During Regression of Experimental Atherosclerosis. J. Vasc. Surg. 1992, 15, 90. 149. Glagov, S.; Zarins, C.K. Pathophysiology of Aneurysm of Formation. In Aneurysms; Kerstein, M., Moulder, P.V., Webb, W.R., Eds.; Williams & Wilkins: Baltimore, 1983; 1 – 18. 150. Bomberger, R.A.; Zarins, C.K.; Glagov, S. Medial Injury and Hyperlipidemia in Development of Aneurysms or Atherosclerotic Plaques. Surg. Forum 1980, 31, 338. 151. Zarins, C.K.; Runyon-Hass, A.; Zatina, M.A.; et al. Increased Collagenase Activity in Early Aneurysmal Dilatation. J. Vasc. Surg. 1986, 3, 238. 152. Gordon, T.; Kannel, W.B. Predisposition to Atherosclerosis in the Head, Heart and Legs: The Framingham Study. J. Am. Med. Assoc. 1972, 221, 661. 153. Glagov, S.; Rowley, D.A.; Kohut, R. Atherosclerosis of Human Aorta and Its Coronary and Renal Arteries. AMA Arch. Pathol. 1961, 72, 558. 154. Beere, P.A.; Glagov, S.; Zarins, C.K. Retarding Effect of Lowered Heart Rate on Coronary Atherosclerosis. Science 1984, 226, 180. 155. Strandness, D.E.; et al. Workshop Overview. In Clinical Diagnosis of Atherosclerosis; Bond, M.G., Insull, W., Jr., Glagov, S., Eds.; Springer-Verlag: New York, 1983; 1 – 9. 156. Bond, M.G.; Adams, M.R.; Bullock, B.C. Complicating Factors in Evaluating Coronary Artery Atherosclerosis. Artery 1981, 9, 21. 157. Greene, E.R.; Eldridge, M.W.; Voyles, W.F.; et al. Quantitative Evaluation of Atherosclerosis Using Doppler Ultrasound. In Clinical Diagnosis of Atherosclerosis; Bond, M.G., Insull, W., Jr., Glagov, S., Eds.; SpringerVerlag: New York, 1983; 8 – 168. 158. Isner, J.M.; Kishel, J.; Kent, K.M.; et al. Accuracy of Angiographic Determination of Left Main Coronary Arterial Narrowing. Circulation 1981, 63, 1056.

CHAPTER 4

Epidemiology of Atherosclerosis and Its Modification Allen W. Averbook Samuel E. Wilson findings. The International Atherosclerosis Project (IAP), 1960–1965, confirmed findings from previous reports that the occurrence of raised arterial lesions ranged from a high of 18% for the white population in New Orleans to a low of 6% in African blacks.[12 – 14] Populations with a higher incidence of raised arterial lesions also showed a higher incidence of extensive coronary atheroma. Comparisons among geographic locations suggest that the extent of atherosclerotic lesions on postmortem examination reflects CHD mortality in the respective populations. The severity of atherosclerosis therefore is closely related to the frequency of clinically apparent CHD.[6] These early population studies also hinted at the varying influences of different risk factors that, at the time, were not well defined. The expression of atherosclerotic vascular disease is influenced by underlying racial differences as well as by the specific risk-factor differences between these groups.[15,16] Results comparing atherosclerotic lesions in 25- to 44-yearold men from Tokyo and New Orleans support the findings of earlier studies.[17,18] The coronary arteries and abdominal aorta of both black and white men from New Orleans showed significantly more raised, atherosclerotic lesions than did those of men from Tokyo. These results parallel the reported differences in mortality from CHD between the two countries. Other studies indicate that atherosclerosis is relatively milder in the Japanese living in Japan than among those living in Hawaii or among western whites.[14,19 – 21] These differences in severity of atherosclerosis between men in different geographic locations but of the same racial stock demonstrate the important contributions that environmental factors make in the development and expression of the disease between and within populations. The strong role that socioeconomic status plays in the development and progression of atherosclerotic vascular disease and the fact that this effect appears mediated through known atherosclerotic risk factors has been well documented.[22,23] Importantly, lower socioeconomic status can impact on the manifestations of atherosclerotic vascular disease early in its natural history. Genetics also plays a significant role in determining the degree, time course, severity, and anatomic pattern of the

INTRODUCTION Atherosclerosis has a predilection for the critical arterial beds: coronary, cerebral, renal, and aortoiliac. Its complications are the major cause of death in North America as well as in other economically developed societies.[1] Coronary heart disease (CHD) and cerebrovascular disease join cancer as the three leading causes of death in the United States.[2,3] The development of atherosclerotic lesions follows a variable course dependent on multiple influences. In the past decade much has been learned about these factors through study of the epidemiology, pathophysiology, clinical progression, and therapy of the disease in humans. An early study by Strong and McGill[4] demonstrated that atherosclerosis is the significant determinant of CHD in a population, a crucial underlying assumption of many studies that have used the severity of clinically manifested CHD as representative of the severity and extent of atherosclerotic disease. Risk factors for the development of the arterial lesions of atherosclerosis have been shown to be similar to those for clinically overt CHD, peripheral vascular disease and cerebrovascular disease.[5 – 11] The implication then is that many of the risk factors for these clinically diagnosed disease states are shared concomitants of atherosclerosis. More so, the outcomes derived from measurements of CHD have been considered applicable to other manifestations of atherosclerotic vascular disease in many studies. Although there is some variation of magnitude and role between the different risk factors identified and the various arterial beds affected by atherosclerotic changes, these associations have provided a useful tool for assessing risk factors and their potential modification.

SEXUAL AND RACIAL PREDISPOSITION Extensive studies of geographic differences in the prevalence of atherosclerotic lesions support Strong and McGill’s early

Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024887 Copyright q 2004 by Marcel Dekker, Inc.

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atherosclerotic process.[24] The extent to which environmental and genetic factors each influence the development and expression of atherosclerotic disease is unclear; an interaction of both, though, is certain, as is demonstrated in studies of endothelial function and the different physiologic responses between races to various stimuli.[25,26]

RISK FACTORS AND ATHEROSCLEROSIS While never denying the role that genetic factors must play, epidemiologic studies have indicated the role of diet, lifestyle, and personal habits as being strongly influential in the pathogenesis and progression of vascular disease. As early as 1980, a decreasing incidence of coronary atherosclerosis in association with declines in mortality rates from CHD became evident.[27 – 29] Between 1968 and 1976, CHD mortality decreased by over 20% in adults aged 30 –74 in the United States.[30] The Minnesota Heart Survey[31,32] suggested that both preventive efforts and improved medical care had an impact on reducing CHD mortality in the Minneapolis – St. Paul area between 1970 and 1990 (Fig. 4-1). The downward trend in CHD mortality may be related to the concomittant improvement seen in multiple cardiovascular risk factors,[33] but a recent computer simulation analysis of the U.S. population between the ages of 35 and 84 years suggests that the decline in CHD-related mortality from 1980 to 1990 was only 25% related to primary prevention, whereas improvements in the treatment of patients with CHD contributed significantly more to this trend.[34] These statistics raise questions about the nature of risk factors and which ones are important influences on the development of atherosclerosis, as well as what are the most cost-effective methods to manage and prevent the development of vascular disease. Despite these encouraging trends, the death rate from complications of atherosclerosis in the United States is still very high. Risk factors may be independent causal agents, intervening variables, or indicators of other, more fundamental associations. The Pooling Project[35] described three principal risk factors: hypercholesterolemia, hypertension, and cigarette smoking. Other important risk factors have emerged, including diabetes mellitus, male sex, age, obesity, physical inactivity, specific behavioral patterns, familial history, hypertriglyceridemia, amount of alcohol consumption, hyperhomocystinemia, prothrombotic factors, and plasma fibrinogen. In evaluating an individual’s risk for atherosclerotic disease, the presence of risk factor clusters correlates with a particularly high risk of CHD. In the Pooling Project, the presence of more than one risk factor for CHD in men aged 30 –59 was found to have a synergistic effect (Table 4-l).[36,37]

Age There is a close relationship between age and the incidence and severity of atherosclerosis in both sexes.[12,38,39] This association is evident in all arterial beds affected by atherosclerosis.[40 – 42] Lower extremity arterial disease is associated with a 4–5 relative risk for all-cause mortality and

Figure 4-1. Age-adjusted death rates (per 100,000) for coronary heart disease in the population 30 – 74 years old. (From Gillum et al.[31] Reproduced by permission.)

progresses over time.[43] In a recent population study, the development of the fibrous plaque of the aorta was seen to be associated with advancing age.[44] In another study, the effects of aging on aortic morphology in populations with high and low prevalence of hypertension and atherosclerosis was performed via postmortem exam.[45] It was apparent that aging itself had a marked effect on aortic morphology (aortic circumference and intimal thickness) separate from but modified by both hypertension and the presence of atherosclerotic changes. This study also suggested that a decrease in tensile strength with advancing age rather than atherosclerosis alone contributes to the formation of abdominal aortic aneurysm. In contrast to aortic aneurysmal, femoropopliteal, and combined segmental disease, studies have demonstrated that atherosclerotic aortoiliac disease occurs more often in a younger population.[46] Death rates from CHD rise with each decade of life up to age 85. The death rate from CHD among white males aged 25 –34 is about 10 per 100,000; by ages 55 –64, it has increased 10-fold to nearly 1,000 per 100,000. It is interesting that death due to acute myocardial infarction (MI) seems to decline slightly after age 75. The relationship between the prevalence of atherosclerosis and age may be due to the time required for

Table 4-1. Ten-Year Age-Adjusted CAD Mortality Rates in Men Aged 30–59 at Entry by Number of Risk Factors Presenta—The National Cooperative Pooling Project No. of risk factors 0 1 2 3

Predicted additive rate/1000

Observed rate/1000

– – 33 43

13 23 44 82

Risk factors were any use of cigarettes, serum cholesterol $ 250 mg/dL, and diastolic blood pressure $ 90 mmHg. CAD = coronary artery disease. Source: From Criqui et al.[37] Reproduced by permission.

a

Chapter 4. Epidemiology of Atherosclerosis and Its Modification

the lesions to develop, but the duration of exposure to risk factors possibly accelerates atherogenesis.[12]

57

Ischemic Heart Disease Death Ratesa in the United States

Table 4-2.

Male

Female

Male Sex In a study of the populations of six different countries, variations across cultures were compared and the sex difference in high-density lipoprotein (HDL) cholesterol levels usually assumed to be related to biologic factors seemed related to environmental factors.[47] Nonetheless, the association between sex and risk for atherosclerosis is not a trivial one (Table 4-2). Fabris et. al.[48] studied 457 patients and found that the prevalence of carotid atherosclerosis was greater in men than in women in all age groups, as was the number of plaques and the severity of vascular narrowing. There was a high prevalence of asymptomatic carotid atherosclerosis in the general population, especially among the very old. One of the few prospective studies of a general population that evaluated cardiovascular disease in female as well as male subjects was the Framingham Study.[49] On the average, symptomatic coronary artery disease appeared 10 years later in U.S. women than in men. When this comparison was made on the basis of proven myocardial infarction (MI), the difference between the sexes increased to approximately 20 years. Also, the factors that influence the development of raised atherosclerotic lesions seem to act differently in the coronary arteries and in the aorta as well as in the two sexes.[38,39,50] While the incidence of CHD is much lower in women than in men for each of the four leading risk factors considered in the Framingham Study, the relationship of these risks to incidence of CHD is at least as strong for women as for men.[51] Interestingly, the sex differential is less apparent in nonwhites.[49,50] Sex differences in the extent of atherosclerotic lesions are striking in the white race and minimal in the black race. These differences are probably related to the influence of other ethnic or racially related risk factors. Myocardial infarction is uncommon in premenopausal women, but the rate of CHD is increased in women with a history of heavy cigarette smoking and diabetes, indicating the influence and complex interactions of other risk factors on the relative risk of CHD. Multiple studies evaluating estrogen use in postmenopausal women have suggested less of a risk for developing CHD than is seen in those who do not use hormone therapy. A recent clinical trial however, has challenged this hypothesis by showing an increase in cardiovascular events with a specific hormone replacement regimen. Indeed, large doses of estrogens also appear to increase cardiovascular mortality in men who have had one myocardial infarction as well as in men being treated for prostatic cancer with exogenous estrogens. Also, some investigators contend that oral contraceptives increase a female’s risk for cardiovascular disease. A large prospective study,[52] though, demonstrates that the use of oral contraceptive agents in the past does not raise a woman’s risk of subsequent cardiovascular disease. As we write in 2002, much needs to be discovered in this important area.

Hypertension Elevated blood pressure (BP), systolic or diastolic, is related to an increased incidence of CHD as well as to other

Age group

1960

1985

1960

1985

44– 54 55– 64 65– 74 75– 84 .85

347 885 1863 3637 6931

170 475 1111 2545 2659

72 296 915 2503 6009

43 163 514 1548 4643

a

Per 100,000 population. Source: Adapted from Levy, R. I. and Feinleib, M: Risk factors for coronary artery disease and their management, in Braunwald, E. (ed): Heart Disease: A Textbook of Cardiovascular Medicine. Philadelphia, Saunders, 1984, p 1205.

manifestations of atherosclerotic disease.[21,53 – 56] The Framingham Study suggested that hypertension is the principal vascular risk for all the complications of atherosclerosis, including arterial disease of the lower limbs.[57] It is an independent risk factor for claudication, approximately doubling the risk, and has been strongly associated with CHD after stratifying for other risk factors.[54,58] In the Framingham Study,[53] men aged 45 –62 with BP exceeding 160/95 had more than five times the incidence of CHD than did normotensive men (BP 140/90 or less). Also, the relationship between BP and the risk of developing CHD was found to be as strong in women as it is in men. Hypertension is a consistent and powerful contributor to coronary disease, with casual BP readings at any age being potent predictors of CHD.[35,49] The risk of cardiovascular death increases stepwise with the level of BP, beginning at quite low levels. There is a smooth, direct, linear relationship between the levels of BP and the risk of morbidity and mortality from cardiovascular disease (as well as from other atherosclerotic diseases) over the entire range of values measured under casual conditions; there is no specific critical value above which the risk of atherosclerotic disease increases and below which it decreases (Fig. 4-2).[51] It is noteworthy, then, that in the VA Cooperative Study,[59] antihypertensive therapy for diastolic BP exceeding 104 mmHg was shown to reduce the incidence of strokes and possibly also of CHD. But the benefits, measured as decreased morbidity and mortality, of treating mild hypertension (defined as a diastolic BP between 90 and 104 mmHg) were not demonstrated.[60,61] Whether or not lowering BP in those with mild hypertension will reduce mortality from MI and coronary disease in general remains unclear. However, in the Tecumseh study,[62] it was demonstrated that borderline hypertension is clearly associated with other risk factors for cardiovascular disease and with structural changes of the heart and blood vessels. The controversy persists as to whether, individually systolic or diastolic BP is more influential. The traditional teaching that the diastolic measurement is the more important component may no longer be valid (Table 4-3).[56,59,63,64] One study identified systolic hypertension as a risk factor of early

Part One. Assessment of Vascular Disease

58

significance. For example, obesity and alcohol intake both cause a significant increase in BP, while regular exercise in men of age 20 or above is associated with a decrease in BP.[41] The means by which hypertension induces atherogenesis is unclear. Various mechanisms have been hypothesized. Humoral mediators of BP may induce cellular changes or the shear stress of the flow of blood at selected anatomic sites within the arterial tree may result in focally altered endothelium and in the development of atherosclerotic lesions.

Cigarette Smoking

Figure 4-2. Actual and smoothed probability of cardiovascular disease (CVD) according to BP level: men and women aged 45– 64 years, Framingham Study. (From Kannel et al.[49] Reproduced by permission.)

atherosclerosis in the carotid artery by measuring intimalmedial thickness with ultrasonography.[65] As an individual predictor, BP has been found to be more reliable than cholesterolemia or cigarette smoking, especially after the age of 45. Other risk factors associated with CHD, though, also affect BP and its prognostic

The risk of cardiovascular death is high in the smoking population (Fig. 4-3), correlating with a strong and independent link to CHD.[55,56,66] The association of tobacco use with the extent and character of atherosclerotic peripheral arterial occlusive disease, aortic disease, and cerebrovascular disease is also well documented. When smoking is combined with other risk factors, there is a notable synergy yielding increased mortality from CHD.[67] The association between passive exposure to cigarette smoke and CHD mortality and morbidity is also becoming increasingly apparent.[68] Recent large trials have demonstrated the significant association of passive smoke exposure to CHD risk and the strong association between active smoking and acceleration of coronary disease along with new arterial lesion formation.[69,70] In the Framingham Study’s 30-year follow-up,[71] men who smoked one or more packs of cigarettes per day had a two to three times greater risk of having a first-time major

Table 4-3. Risk Factors: Systolic BP Versus Diastolic BP Study Veterans Administration Cooperative Study Group on Antihypertensive Agents[35]

Findings Persons with diastolic BP $ 115 mmHg have greater risk of developing organic complications associated with atherosclerosis

Subjects: male veterans Duration: varied The Western Collaborative Group Study[34]

Risk of CHD more strongly associated with systolic than diastolic BP

Subjects: 3154 males Duration: 8.5 years The Framingham Study[31] Subjects: 5209 male/female Duration: 20 years The Framingham Study of the Evolution of Atherothrombotic Brain Infarction[37]

Declining importance of diastolic BP relative to systolic BP with advancing age

Risk of stroke and CHD most closely linked to systolic BP or mean arterial pressure

Subjects/duration: as above The Pooling Project[23]

Risk for developing CHD proportional to BP over twofold range for both systolic and diastolic BP individually

Chapter 4. Epidemiology of Atherosclerosis and Its Modification

Figure 4-3. Age-adjusted mortality rates/thousand in men after 6 years for coronary artery disease (CAD) and cardiovascular disease (CVD) by smoking status. (From Criqui et al.[37] Reproduced by permission.)

coronary event than did nonsmokers, especially younger men (Table 4-4). As stated earlier, atherosclerotic aortoiliac disease occurs more often in a younger population as compared to other potentially involved segments. This may be due to the critical role that tobacco use plays in its development in the younger population (,60 years old).[72] The effect of smoking on peripheral vascular disease is also well documented.[73] There is an increased risk of developing intermittent claudication among smokers, and the risk is higher in diabetic smokers. The risk of peripheral arterial occlusive disease is increased two- to threefold among smokers and smoking correlates more closely with the

59

development of intermittent claudication than any other cardiovascular risk factor.[58] Importantly, smoking cessation is associated with an improvement in the symptoms of claudication.[73] In both peripheral arterial occlusive disease and CHD, the current number of cigarettes smoked each day is directly related to the risk of development and progression of the disease. Smoking tobacco is also significantly and independently related to the development and progression of carotid atherosclerosis and stroke.[74,75] The 1986 Honolulu Heart Program[76] study firmly demonstrated a strong relationship between cigarette smoking and stroke in men. It was not until the publication of two subsequent studies, however, that a significant causal role for cigarette smoking in stroke in middle-aged women was demonstrated. The relative risk for fatal stroke was found to be consistent in magnitude with that reported for men.[77] As in peripheral arterial occlusive disease and CHD, a graded dose-response relationship between smoking and cerebrovascular disease in both sexes independent of age and hypertensive status has been well established.[78] Those smoking more than 40 cigarettes per day have nearly twice the risk of stroke as those smoking fewer than 10 cigarettes per day. The risk of stroke is still high among ex-smokers as compared to nonsmokers, especially in the first 2 years after stopping, although it is lower than that for current smokers (Fig. 4-4). By 2 years after quitting, the risk decreases significantly; within 5 years after stopping, the risk reverts to the lower levels seen in nonsmokers, sooner than that noted in CHD.[78] These relationships between the development of carotid atherosclerosis and tobacco use and the significance of the number of pack-years smoked have been corroborated by studies utilizing carotid duplex in large samples.[41,79] It has also been demonstrated through B-mode ultrasonography that the development of carotid atherosclerosis may progress more slowly in people who have quit smoking as compared to those who continue to smoke, even after taking into account the effect of other risk factors.[80] Cessation of smoking will also dramatically reduce the rate of cardiovascular death in persons of all ages.[81 – 84]

Table 4-4. Risk of Cardiovascular Diseasea by Cigarette Smoking: 30-Year Follow-Up of the Framingham Study Men Age 35– 64 Years No. of cigarettes per day None 1 – 10 11– 20 21– 40 41– 90 All a

Women Age 65 – 94 Years

Age 35 – 64 Years

No. of events

Age-adjusted rate/1000b

No. of events

Age-adjusted rate/1000b

No. of events

Age-adjusted rate/1000c

No. of events

Age-adjusted rate/1000c

236 47 212 143 27 665

12 13 23 21 27 17

237 32 43 26 3 341

38 36 39 33 81 38

276 60 86 33 3 458

8 8 10 11 26 9

326 35 40 5 0 406

26 25 34 12 – 26

Cardiovascular disease: coronary heart disease, stroke, cardiac failure, peripheral arterial disease. p , 0:001: c Not significant. Source: Kannel et al.[71] Reproduced by permission. b

Age 65 – 94 Years

60

Part One. Assessment of Vascular Disease

Figure 4-4. Survival free of stroke in male and female cigarette smokers (dotted line ), nonsmokers (solid line ), and former smokers (dashed line ) aged 60 years, using Cox proportional hazard regression model. (From Wolf et al.[78] Reproduced by permission.)

There is consistent evidence that within 1 year of quitting tobacco, the risk of CHD attributable to smoking drops to about half that of those who continue to smoke. However, this reduced risk only approximates but never quite equals that of lifelong nonsmokers, and then only after a decade or more, according to most studies.[67,85] The cardiovascular risk declines more rapidly than that of lung cancer or emphysema.[67] The effect of cigarette smoking on both stroke and cardiovascular disease previously appeared to be due predominantly if not entirely to current or very recent smoking.[77] In the large population –based ARIC Study,[86] environmental tobacco smoke and active smoking were both found to increase the rate of progression of atherosclerosis by 20% and 50%, respectively. This may be a direct manifestation of cigarettes’ effect on blood coagulation by increasing levels of fibrinogen or other clotting factors or by enhancing platelet aggregability, as suggested by the observed relationship between cigarette smoking and acceleration of atherosclerosis via an effect on platelets.[87] Nonetheless, the ARIC Study demonstrated that the number of years smoking and that past smoking were less important than the total number of pack-years, suggesting that the adverse affects of smoking are cumulative and some progression of atherosclerotic disease appears irreversible.[86] The development of an abdominal aortic aneurysm (AAA) is also strongly associated with tobacco use, with an eightfold increased risk in heavy smokers as compared to nonsmokers. The findings of Witteman et al.[88] in a female population – based cohort regarding the association between smoking and AAA were supported and expanded by Lederle et al.’s ADAM Study.[89] In this large ongoing screening program designed to assess the appropriate management of moderatesized AAA, 1031 patients with AAA . 4.0 cm were identified. Smoking was the risk factor most strongly associated with the presence of AAA. This association increased significantly with the number of years of smoking and decreased significantly with the number of years after quitting. In Witteman’s study, a residual effect of smoking on atherosclerosis appeared to be present for at least 10 years following the cessation of smoking.[88]

Contrary to popular belief, cigarettes that are low in tar and nicotine have not been shown to lessen the cardiovascular morbidity and mortality associated with smoking.[90] In fact, in the Framingham Study, smokers who used filtered cigarettes possibly had an even higher incidence of CHD than did smokers of nonfiltered cigarettes. This was probably related to deeper and larger inhalations, thus compensating for the lower level of nicotine and negating the advantage of the filter. Also, the delivery of carbon monoxide has not been shown to be reduced by filters. A definite relationship between cigarette smoking and fibrinogen has been established.[91] Age-adjusted fibrinogen values in the Framingham Study were significantly higher in cigarette smokers than in nonsmokers, and they increased with the amount of tobacco smoked in each sex.[71] The risk of CHD increased with increasing fibrinogen values in both smokers and nonsmokers. There was no evidence of a greater impact in smokers than in nonsmokers (Table 4-5). Interestingly, multivariate analysis indicates that fibrinogen makes a stronger independent contribution than cigarettes to the occurrence of cardiovascular disease. A direct reversible relationship, though, was suggested, in that fibrinogen values increased in proportion to the amount smoked. The relationship of cigarette smoking to the occurrence of atherosclerotic cardiovascular disease must be attributable to some extent to the effect of smoking on fibrinogen levels, which in turn enhances thrombotic tendencies leading to occlusive clinical events. Cigarette smoking exerts a long-term effect (possibly via an atherogenic mechanism)[92] as well as a short-term triggering effect; it appears to exert this short-term effect by its influence on the incidence of lethal events that trigger sudden death in those who already have a compromised coronary circulation. This may occur through a thrombotic or hypoxic mechanism.[85] Nonetheless, cigarette smoking should still be considered an independent risk factor in the development of atherosclerosis. The epidemiologic data reviewed thus far is very compelling, and direct effects of tobacco’s by-products on the tissue of the heart, the vascular tree, and the blood have been demonstrated.[85,93 – 97] A dose-related and potentially revers-

Chapter 4. Epidemiology of Atherosclerosis and Its Modification

61

Risk of Cardiovascular Disease by Fibrinogen Level and Smoking Status: 14-Year Follow-Up of the Framingham Study (Subjects 48–80 Years of Age)

Table 4-5.

14-Year Age-Adjusted Rate/1000 Men Fibrinogen (mg/dL) 126– 264 265– 310 312– 696

Women

Nonsmokersa

Cigarette smokersb

Nonsmokersb

Cigarette smokersb

318 295 397

230 421 486

176 209 297

213 165 343

a

Trend not significant. Trend significant at p , 0:05: Source: Kannel et al.[71] Reproduced by permission. b

ible impairment of endothelium-dependent arterial dilation in asymptomatic young adults, consistent with endothelial dysfunction, was seen using noninvasive assessment of 200 subjects aged 15 –57 years old.[98] This phenomenon has also been demonstrated in a smaller sample of subjects in association with passive smoking.[99] The effect of long-term cigarette smoking on impairment of endothelium-dependent coronary vasodilatation is well documented. [100] The mechanism by which cigarette smoking stimulates atherogenesis is, however, controversial. High-density lipoprotein levels, which are associated with a decreased risk of atherosclerosis, are reduced in cigarette smokers in a doseresponse manner, but evidence suggests that cigarette smoking mainly influences the HDL3 subfraction, which is considered to be unrelated to CHD.[85,101,102] The Lipid Research Clinics Follow-Up Study[103] supported these findings by demonstrating via multivariate analysis that cigarettes are strongly linked to coronary artery disease and cardiovascular mortality while being independent of an HDL mechanism.

not been supported by studies of population groups.[109] The level of plasma cholesterol is measurably influenced by the dietary intake of total calories of cholesterol, saturated fat, and polyunsaturated fat. There are five major groups of cholesterol-bound lipoproteins, each with a different prognostic significance. The three that are of most concern are as follows:

Hyperlipidemia

The development, progression, and regression of atherosclerosis is closely related to the plasma cholesterol level. There is a direct relationship between diet, hyperlipidemia, and the development of CHD.[111] Dietary cholesterol intake from 0 to 600 mg/day correlates closely with plasma cholesterol levels. A high consumption of saturated fat is directly related to an increase in coronary artery disease; dietary saturated fatty acids elevate plasma cholesterol levels and detrimentally affect other coronary risk factors, whereas polyunsaturated and, more recently, monounsaturated fatty acids have been found to reduce them.[112 – 114] Proteins and carbohydrates are preferred substitutes for fat calories, being associated with a significantly decreased risk of new atherosclerosis lesions as compared to poly- and monounsaturated fat when total saturated fat intake is reduced.[115] Interestingly, emigrants from populations having low plasma cholesterol levels attain higher cholesterol levels, presumably because of the new diet, and an associated increase in the incidence of coronary disease comparable to those of their host populations within a few years of their emigration, as is been seen in Japanese e´migre´s to the United States.[116] It is still unclear whether beans, oat bran, and other forms of

Multiple prospective population studies have supported the thesis that elevated serum lipid concentrations contribute to the development of atherosclerosis.[55,56,104,105] Elevated total serum cholesterol level is an independent risk factor for the development of stroke as well as CHD.[106] Populations with relatively high levels of cholesterol have a higher mortality from CHD, and the probability of developing a myocardial infarction increases in proportion to the plasma cholesterol level. In the Honolulu (Hawaii) Heart Program,[107] 1480 men aged 65 years and older and free of coronary heart disease were followed up for an average of 12 years. In this study, serum cholesterol level was shown to be an independent predictor of coronary heart disease among men older than 65 years, disputing other reports that there is a diminished association between serum cholesterol level and coronary heart disease in the elderly. High serum total cholesterol levels have been identified as a risk factor for the development of atherosclerosis in the carotid, coronary, and peripheral arteries.[41,108] The theory that genetic factors are the predominant determinants of plasma lipid metabolism has

1.

2. 3.

LDL (low-density lipoprotein), which is about 70% total cholesterol and, when elevated, has the strongest association with CHD in both men and women.[110] Patients with increased LDL-C levels, and particularly increased LDL apolipoprotein B, have the greatest risk of premature atherosclerosis and present the greatest therapeutic challenge.[111] VLDL (very-low-density lipoprotein), which is strongly correlated with triglyceride levels. HDL (high-density lipoprotein), which is about 30% cholesterol and plays a role in transporting cholesterol away from the peripheral tissues—an action opposite that of LDL.

62

Part One. Assessment of Vascular Disease

soluble fiber lower total cholesterol or lipoprotein subfractions; only short-term data are available, and the results are inconclusive.[117 – 122] The North American population’s intake of cholesterol has declined since 1970 as a result of increased public awareness, and the polyunsaturate/saturate ratio in dietary fat has been increasing. Concurrently, there has been a definite downward trend in the plasma cholesterol levels of adult Americans. These trends have all coincided with a significant reduction (25–27%) in CHD mortality among persons 36 –74 years of age, further supporting the possibility of a causal relationship.[123 – 125] Dietary therapy can play a major role in reducing CHD events and decreasing progression of coronary atherosclerosis. Dietary modification studies have demonstrated that sustained decreases in serum cholesterol levels of 10–20% can be achieved by diet manipulation alone in dissimilar study groups.[104,126,127] Increased dietary cholesterol usually results in an increase in LDL cholesterol levels, with a lesser increase in HDL cholesterol levels. Serum levels of HDL are inversely related to the risk of coronary disease—the higher the level, the lower the risk of death from heart disease (Table 4-6).[110,128 – 130] In the Framingham Study, HDL cholesterol was a more important predictor of CHD than either total or LDL cholesterol. This was true for both men and women, where for each 1% rise in HDL there was a 2% reduction in the incidence of coronary artery disease.[110] More recently, findings have suggested that total LDL and HDL cholesterol levels in men 40 – 69 years of age with and without preexisting cardiovascular disease predict subsequent mortality.[131] The hypothesis that increased triglycerides is an independent cause of CHD remains controversial. While some studies did not initially support this relationship, more recent prospective studies do—the difference between the studies being related more to methodological concerns and statistical interpretations.[110,132 – 140] Triglycerides have also been shown to be an independent risk factor for stroke and coronary arterial disease in a Taiwanese population.[141] Elevated LDL cholesterol and triglyceride levels as well as low HDL levels are also strongly correlated with the development and progression of peripheral atherosclerosis. Elevated LDL cholesterol and triglyceride levels as well as low HDL levels are strongly correlated with development and progression of peripheral atherosclerosis.[142 – 145] The epidemiologic association between increased incidence of atherosclerosis and the increased intake of fat with concomitant changes in plasma LDL and HDL levels is very strong. Aside from dietary influences on HDL, alcohol consumption, cigarette smoking, obesity, and exercise may influence the serum level of HDL.[94] The HDL2 subfraction of the HDL lipoprotein is considered to be the protective subfraction.[128,146] It is this subfraction of HDL that is markedly elevated in women undergoing postmenopausal estrogen therapy, suggesting the mechanism by which estrogen exerts its documented cardioprotective effect in the postmenopausal female.[147 – 151] The cardiovascular death rates in the Lipid Research Clinics Follow-Up Study[152] were significantly lower for women taking postmenopausal estrogen; the protective effect appeared to be mediated by HDL (Table 4-7). However, lowered levels of plasma

Coronary Artery Disease Incidence per 1000 after 4 Years in Men and Women by Level of HDL Cholesterol— The Framingham Study

Table 4-6.

HDL, mg/dL

Men

Women

,25 25– 34 35– 44 45– 54 55– 64 65– 74 $75 All levels

176.5 100.0 104.5 51.0 59.7 25.0 0.0 77.1

0.0 164.2 54.5 49.2 39.7 13.9 20.1 43.6

Source: From Criqui.[37] Reproduced by permission.

cholesterol, triglycerides, LDL, and VLDL are also associated with postmenopausal estrogen use, suggesting a more complicated relationship.[150] The clinical utility of these findings is limited at this time, given the controversial association between postmenopausal estrogen use and endometrial cancer as well as the contradictory results denying any protective effect of estrogens on the incidence of CHD in men and in menopausal female smokers.[153 – 155] Population studies have also shown that HDL levels are increased by alcohol consumption in a dose-response manner, and alcoholics often have very high HDL levels (Table 4-8).[156,157] This may explain the protective effect for CHD observed in some studies with moderate alcohol consumption (Table 4-9). It is not clear, however, which HDL subfraction is most affected by alcohol; while some studies report an effect on HDL2, others find alcohol intake to affect only the HDL3 subfraction.[102,158] One prospective study suggests that with moderate alcohol consumption in middleaged women, the risks of CHD and ischemic stroke are decreased but the risk of subarachnoid hemorrhage is increased.[159] This does not imply that it is healthy to drink heavily. Coronary heart disease and related cardiovascular deaths as well as stroke and hypertension are more commonly observed with excessive alcohol consumption than with moderate drinking, probably indicating a complex interaction

Age-Specific and Age-Adjusted Cardiovascular Death Rates per 10,000 Person-Years by Estrogen Use at Baseline

Table 4-7.

Estrogen

Age, years 40– 49 50– 59 60– 69 70– 79 Crude rate, all ages Age-adjusted rate, all ages

Nonusers, n ¼ 1676

Users, n ¼ 593

0.0 19.0 46.3 159.6 30.9 41.8

0.0 5.5 8.1 67.8 10.1 12.4

Source: From Criqui et al.[37] Reproduced by permission.

Chapter 4. Epidemiology of Atherosclerosis and Its Modification 4-8. Mean High-Density and Low-Density Lipoprotein Cholesterol Levels According to Alcohol Consumption

Table

Alcohol, oz/week 0 1–3 4–9 10– 19 20+

No. of men

HDL-C,a mg/dL

LDL-C,b mg/dL

849 320 354 166 24

42.2 44.8 48.3 52.2 56.7

147.0 148.5 138.6 125.8 97.7

63

reduction in cholesterol was observed, correlating with a 39% decrease in coronary disease (Fig. 4-5). The reduction in cardiovascular risk was greatest in those patients with the greatest decreases in total cholesterol levels.[162] Some aspects of this study lead to questions about its full significance, since total mortality was similar in the two groups and the actual difference in CHD incidence after 7 years was only 7% in the treatment group compared with 8.6% in the placebo group. This amounts to an absolute difference in endpoints of only 1.7%—a very modest difference, despite the initial appearance of a major decrease in CHD incidence in the treatment group early in the study. Also, strict application of the results is limited to middle-aged men with type II hyperlipidemia. Despite some methodological concerns, this study strongly demonstrated the relationship between serum cholesterol and CHD. The results of this and other clinical trials were in agreement with predictions from some much longer running epidemiologic studies such as the Framingham Study. In the World Health Organization Cooperative Trial,[163] a reduction of total cholesterol was associated with a significant reduction in nonfatal myocardial infarction after 5 years. Despite the reduction in cardiovascular events, though, there was a significant increase in noncardiovascular morbidity and mortality with clofibrate therapy. In the Coronary Drug Project (CDP),[164] an excessive cancer and cardiovascular mortality was noted with the use of either estrogen or dextrothyroxine. Clofibrate and niacin were also evaluated in this study. Unlike the WHO Cooperative Trial, the short-term and long-term studies of clofibrate showed no beneficial effects on mortality or other cardiovascular events, although clofibrate therapy was associated with a reduction in total cholesterol levels similar to that seen in the WHO Cooperative Trial. Despite poor patient compliance with the niacin regimen (3 g/day), this therapy was associated with a significant reduction in total cholesterol levels and a significant reduction in nonfatal MI, although nearly identical death rates were noted for the niacin- and placebo-treated groups in the initial report. After a mean follow-up of 15 years,[165] almost 9 years after termination of the trial and possibly of niacin therapy, mortality from all causes was 11% lower in the niacin-treated patients than in the placebo group. These results may suggest a potential long-term benefit from a relatively short course of niacin therapy, with a significant

a

HDL-C = high-density lipoprotein cholesterol. LDL-C = low-density lipoprotein cholesterol. Source: From Kagan et al.[160] Reproduced by permission. b

of mechanisms and multiple risk factors, especially hypertension.[160] The full extent of the effect of alcohol consumption on cholesterol levels remains to be elucidated in a study designed specifically to address the role of alcohol in CHD. Many intervention trials have been conducted to determine whether reducing total cholesterol and, specifically, LDL, with diet and/or drug therapy can lower the incidence of CHD. In showing that this can be done, such studies further strengthen the thesis that there is a relationship between hypercholesterolemia and CHD (Table 4-10). A multicenter controlled study, the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT),[161] evaluated the efficacy of the bile acid sequestrant cholestyramine (an agent effective in reducing cholesterol) on morbidity and mortality from CHD in middle-aged hypercholesterolemic men. All participants were placed on a cholesterol-lowering diet that reduced plasma total cholesterol by 3 –5%. A random half of the men were then given cholestyramine, while the remainder received placebos. Initially, with cholestyramine use after optimizing diet control, a reduction of plasma LDL and total cholesterol was seen as compared with the control group. Significant reductions in risk for fatal CHD or nonfatal MI were seen. A graded effect was observed. In those individuals who did not take the medication and had no reduction in cholesterol, there was no reduction in coronary risk. In the subgroup able to take the full dose of medication, a 19%

Table 4-9. Alcohol Consumption and Incidence of Coronary Heart Disease 6-Year CHD incidence, age-adjusted rate/1000 Alcohol consumption, oz/month 0 1–6 7 – 15 16– 39 40+ a

No. of men at risk

Total CHDa

CHD death and MIb

Acute CIc and angina

3565 1034 962 1024 1006

46.0 41.2 30.7 26.7 21.2

28.0 28.3 18.2 19.6 7.2

18.0 12.9 12.5 7.1 14.0

CHD = coronary heart disease. MI = myocardial infarction. c CI = coronary insufficiency. Source: From Kagan et al.[160] Reproduced by permission. b

64

Part One. Assessment of Vascular Disease

Table 4-10.

Intervention Trials

Trial

No. of subjects Duration (yr)

Drug used

Mean cholesterol reduction (%)

Reduction in CHD (%), endpoint

9 6 Clofibrate 10 Niacin 9

20 (nonfatal MI) 27 (nonfatal MI)

WHO CDP

15,745 3908

5 5

LRC-CCPT

3806

7.4

Clofibrate Niacin, estrogens, clofibrate Cholestyramine

Helsinki Heart Study

4081

5

Gemfibrozil

8

NHLBI Type II CIS

116

5

Cholestyramine

15

CLAS

162

2

CARE

4159

5

4S

4444

5.4

Colestipol þ niacin 26 (57% reduction in LDL/HDL ratio) Pravastatin 20% (mean LDL lowered by 28% and triglyceride by 14%; mean HDL increased by 5%) Simvastatin 25% (LDL lowered by 35%, triglyceride by 8%, HDL increased by 8%)

19 (nonfatal MI) 24 (CHD death) 37 (nonfatal MI) 34 (CHD events) 26 (CHD death) Outcomes determined by coronary angiogram only (see text)

WHO = World Health Organization Cooperative Trial;[163] CDP = Coronary Drug Project;[164] LRC-CCPT = Lipid Research Clinics Coronary Primary Prevention Trial;[161,162] Helsinki Heart Study;[168,182] NHLBI Type II CIS = National Heart, Lung, and Blood Institute Type II Coronary Intervention Study;[166,167] CLAS = Cholesterol-Lowering Atherosclerosis Study;[178] CARE = the Cholesterol and Recurrent Events Trial;[173] 4S = Scandinavian Simvastatin Survival Study.[172,309]

reduction in mortality evident years after discontinuation of therapy. The National Heart, Lung, and Blood Institute (NHLBI) Type II Coronary Intervention Study[166] was the first major report to indicate that pharmacologic intervention directed at lipids and an increase in the HDL/LDL ratio is associated with a decreased progression of coronary artery atherosclerosis. As demonstrated by serial angiograms, coronary artery disease progressed in 49% of placebo-treated patients as compared with 32% of cholestyramine-treated patients. Independent of the specific treatment group, progression of coronary disease was inversely associated with an increase in HDL-C and a decrease in LDL-C levels.[167] In the Helsinki Heart Study,[168] gemfibrozil therapy was extremely well tolerated; side effects were no more likely than with placebo therapy. The level of HDL-C increased by 10% and total cholesterol, LDL-C, and triglyceride levels decreased 8, 8, and 35%, respectively. Total deaths and cancer rates were no different in the two groups, but gemfibrozil was associated with a strongly significant reduction in CHD events. Similar to the LRC-CPPT results, total mortality during the study period was not reduced by gemfibrozil therapy, with only a 1.4% absolute difference in endpoints between study groups. Most of the early treatment studies were conducted using a population of middle-aged hypercholesterolemic men, and although epidemiologic data has always supported the role of hypercholesterolemia in CHD in most patient subgroups, the vigorous management of lipids for the prevention of CHD in women or in elderly persons was not supported by these intervention trials. More recent trials have included an older population and both sexes.[169 – 171]

The Scandinavian Simvastatin Survival Study (4S) evaluated a large cohort of patients with coronary artery disease for the effects of cholesterol reduction with simvastatin on mortality and morbidity.[172] The participants were started on lipid-lowering diets and randomized to receive either simvastatin or placebo. Another large secondary prevention trial, the Cholesterol and Recurrent Events (CARE) trial,[173] enrolled 2081 patients, including patients with usual cholesterol levels rather than elevated levels as was done in the other studies. The results of these studies further supported and elucidated those of their predecessors in that the reduction of cardiovascular risk was greatest in those patients with the greatest decreases in total cholesterol levels in a graded fashion. In the more recent trials this risk reduction was shown to apply even to a population of both sexes over the age of 59 years. These results strengthened the earlier findings of The Honolulu Heart Program [107] that elevated total cholesterol level is a risk factor for coronary artery disease in the elderly population, a conclusion that has been further substantiated by a recent population-based prospective study.[174] Of great importance, these statin drug trials demonstrated a reduction in total mortality with lipidlowering therapy, something that the earlier studies could not demonstrate.[169,173] Long-term results of coronary artery bypass operations are hampered by progression of disease in the native coronary circulation and by closure of saphenous vein grafts. Data from the Montreal Heart Institute[175] demonstrated a saphenous vein graft closure rate of 2% annually for the first 5 years and then 5.3% annually between years 5 and 10; at 10 years, the patency of saphenous vein grafts is only about 50%.[176] In a

Chapter 4. Epidemiology of Atherosclerosis and Its Modification

Figure 4-5. Relationship of reduction in low-density lipoprotein cholesterol (LDL-C) levels to reduction in coronary heart disease (CHD) risk (logarithmic scale). Risk reduction was estimated by comparing distribution of percent change in LDL-C levels among CHD cases to that among all participants in same treatment group. Dashed line represents reduction in CHD risk predicted by proportional hazards model for given decrease in LDL-C level in cholestyramine group. Estimates of percent reduction in CHD risk for men in cholestyramine group (solid circles ) and placebo (open circles ) group with differing degrees of LDL-C level reduction are compared with this line. Each point (except those at either extreme) is plotted at center of 5% interval of percent change in LDL-C levels that it represents. Points for open-ended strata at extremes are plotted at their approximate median values of percent change in LDL-C levels. (From Lipid Research Clinics Program.[161] Reproduced by permission.)

study of 82 patients 10 years after a bypass procedure, plasma levels of LDL, apolipoprotein B, HDL-C, LDL-C, and triglycerides were found to be strong predictors of both saphenous vein graft patency and progression of disease in the native circulation.[177] A subsequent study, the CholesterolLowering Atherosclerosis Study (CLAS),[178] evaluated whether aggressive lowering of LDL-C with a concomitant increase in HDL-C would affect the growth of atherosclerotic lesions in the native coronary arteries as well as in saphenous vein grafts. Through the use of diet, colestipol, and niacin in the treatment group, total cholesterol was reduced by 26%, LDL-C decreased 43%, and HDL-C increased 37%—in conjunction with a 57% reduction in the LDL/HDL ratio. By serial coronary angiography, the treatment group had a statistically significant reduction in progressive lesions in the native coronary arteries and saphenous vein grafts. Deterioration in overall coronary status was less in the drug-treated patients, and a significant regression in coronary atherosclerosis was also noted. The results of the statin trials are also now being correlated with angiographically proven slowing and in some cases prevention of development of coronary atherosclerosis in both native coronary vessels and saphenous vein bypass grafts.[179] Aggressive management of lipids in the secondary prevention of ischemic heart disease is thus

65

justified. A double-blind, randomized clinical trial with progression of early extracranial carotid atherosclerosis as an outcome variable was performed using 151 patients with coronary disease being randomized to placebo or pravastatin. B-mode ultrasound quantification of carotid artery intimalmedial thickness (IMT) was followed. Total cholesterol and LDL cholesterol plasma levels were both decreased in the pravastatin-treated patients while HDL2 cholesterol levels were higher. A nonsignificant 12% reduction in progression of the mean-maximum IMT and a statistically significant 35% reduction in IMT progression in the common carotid artery was seen along with a significant reduction in nonfatal and fatal coronary events.[180] In the Asymptomatic Carotid Artery Progression Study (ACAPS),[181] reduction of LDL cholesterol levels with lovastatin was seen in 919 men and women with asymptomatic corotid artery disease. This was a randomized, double-blind, placebo-controlled, factorially designed study in which the LDL cholesterol levels were reduced by 28% in the lovastatin group as compared to the placebo-controlled group. Concomitantly, a significant reduction in the progression of mean maximum IMT of the carotid arteries along with a decreased incidence of cardiovascular events was observed. Results of the major clinical trials of cholesterol lowering are consistent in showing that the greater the degree of cholesterol lowering, the greater the reduction in CHD risk. The results of these studies can be fitted to a regression line relating cholesterol reduction to decreased CHD risk. As a rough rule of thumb, a 1% reduction in cholesterol reduces the risk of developing CHD by 2%. Interestingly, in the Helsinki Heart Study,[182] there was a 4% fall in coronary artery disease for every 1% fall in cholesterol. This correlated with a 10% rise in HDL levels and an 8% fall in LDL. Therefore, in men with elevated LDL levels who were at high risk for coronary heart disease, a reduction of total cholesterol through a decrease in LDL levels diminished morbidity and mortality from CHD. Many early dietary studies gave suggestive but inconclusive results. Changes in recent diet habits that do not represent lifetime patterns may have little overall impact. Development of atherosclerosis occurs over a decade, diluting the significance of many studies that analyze diet and other factors over brief intervals. Some authors believe that the early prospective intervention studies failed to demonstrate statistically significant associations between diet and CHD risk. They felt that reduced mortality from CHD might have been due to a reduction in a variety of risk factors not accounted for, such as cigarette smoking.[183] The more current intervention studies are not without flaws, but the results are powerful. Old lipid-lowering drugs (fibrates, resins, niacin) have proven morbidity benefits, but the statins are efficacious and safe with proven mortality benefits. For these reasons, it has become apparent that lipid profiling as well as assessment of total cholesterol levels is very important. All but a few of the intervention trials looked at patients with significantly elevated plasma cholesterol levels. They demonstrated that a reduction of plasma cholesterol level is beneficial in a high-risk population. Most of the attributable cases of CHD, though, arise from people whose cholesterol values are average, not from the few in whom the

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concentration is conspicuously high. The CARE trial[173] and the Air Force/Texas Coronary Atherosclerosis Prevention Study[184] both demonstrate the significance of average total cholesterol levels in patients with coronary arterial atherosclerotic disease and describe the risk benefits of cholesterollowering therapy in these patients. These results supported and extended the findings of earlier epidemiologic studies that found the incidence of coronary atherosclerosis in a specific population to vary directly with the mean serum cholesterol level, regardless of the population examined.[185] Early in the Framingham Study, serum cholesterol levels of 265 mg/dL or above in men and women 35–44 years of age were associated with a five times higher risk of developing coronary artery disease than in those with levels below 220 mg/dL.[186] The Pooling Project[35] supported these findings and suggested that rates of CHD are relatively constant for cholesterol levels up to 200 –220 mg/dL, but above this threshold range the risk for CHD increases as cholesterol concentrations rise. These findings have been qualified by the Multiple Risk Factor Intervention Trial (MRFIT),[187] which studied a large male sample. The results showed unequivocally that the relationship between serum cholesterol and CHD is not a threshold one but rather a continuously graded one in which the risk of fatal CHD increases with serum cholesterol levels of about 180 mg/dL and above in a gradual manner; the threshold of 220 mg/dL is no longer accurate (Fig. 4-6). Importantly, in a recently published mortality follow-up of the MRFIT, 16 years after randomization, a continued mortality benefit of the multifactor intervention program, which included serum cholesterol reduction, was confirmed.[188]

Fish Consumption and Omega-3 Fatty Acids Another dietary concern is the relationship of omega-3 fatty acids, or fish oils, to the prevention of heart disease. Much of the interest in these fish oils began with the observation that despite their high-fat, high-cholesterol, low-carbohydrate diet, Greenland Eskimos, who eat cold-water fish, have a low incidence of cardiovascular disease, low plasma triglyceride and total cholesterol levels, and high concentrations of HDL cholesterol.[189,190] The fat found in cold-water fish is rich in long-chain, highly unsaturated omega-3 fatty acids. It has also been reported that Eskimos have decreased platelet aggregation and reactivity and a lower thrombotic tendency than do Danes, who eat a dairy- and meat-rich diet.[191] In addition to their lipid-lowering, antiaggregating, and viscosity effects, omega-3 fatty acids also decrease blood pressure, the magnitude of the change being dependent upon the dose given.[192,193] Thus, ingestion of omega-3 fatty acids shifts the physiologic balance in the direction of vasodilation and antiaggregation. Omega-3 fatty acids may also exert antiinflammatory effects via their inhibition of production of some leukotrienes as well as other immunomodulators, such as interleukin-1 and tumor necrosis factor.[194] The effects of these fish oils on lipid levels have been examined in a few studies with varying results. The hypolipidemic effect

Figure 4-6. Actual and smoothed probability of cardiovascular disease (CVD) according to serum cholesterol level: men and women aged 45 –64 years, Framingham Study. (From Kannel et al.[49] Reproduced by permission.)

observed varies with the dosage used. The evidence that cardiovascular disease can be prevented by the ingestion of fish oils taken in regular doses, however, has not been borne out. Reports in the literature are inconsistent regarding fish consumption and the risk of CHD. The effects of fish consumption on the development of myocardial lesions separate from the extent of atherosclerosis were assessed in a recent autopsy study. The protective effects of fish consumption appeared to extend to individuals relatively free of coronary atherosclerosis, possibly through hemostatic mechanisms.[195] Another recent study[196] demonstrated an inverse association between fish consumption and death from CHD. This observed relationship may not be due to omega-3 fatty acids since other studies have not demonstrated any evidence of omega-3 fatty acids affecting the progression of coronary atherosclerosis.[197] Components other than omega3 fatty acids may be contributing to the CHD risk reduction seen with fish consumption. The Honolulu Heart Program[198] questioned the discrepancy seen in the strength of cigarette smoking as a risk factor for CHD observed between populations. In looking at a cohort of Japanese men, a population with strong smoking habits but relatively fewer CHD risks as compared to some other smoking populations, a significant interaction of cigarette smoking/day and fish intake on CHD mortality was identified. The manner in which fish consumption may impact on cigarette smoking to lessen its risk for promoting atherosclerosis is unknown, but may be related to a diminution of tobacco’s prothrombotic effects.

Diabetes Mellitus More peripheral arterial, coronary, and cerebrovascular disease develops in diabetics than in nondiabetics. There is a twofold increase in the incidence of MI among diabetics as compared with nondiabetics as well as an increased tendency toward cerebral thrombosis. There is a two- to fourfold increased risk of developing intermittent claudication as compared to nondiabetics and an 8- to 150-fold increased frequency of gangrene of the lower extremity.[199] The association between diabetes mellitus (DM) and an increased incidence of myocardial infarction, atherothrombotic brain infarction, and intermittent claudication is well

Chapter 4. Epidemiology of Atherosclerosis and Its Modification

documented.[51,199,200] The Framingham Study showed that the risk of cardiovascular disease and death was greater in diabetic women than in men.[201] It appears that risk is mediated in part by the association of DM with hypertension and hyperlipidemia. Nonetheless, DM is also an independent risk factor for CHD and stroke.[201,202] Along with cigarette smoking, diabetes is one of the strongest risk factors for peripheral arterial disease.[203,204] The degree of glycemic control is not well correlated with the presence or severity of peripheral arterial disease,[205] but the associated risk factors of smoking and hyperlipidemia correlate strongly with disease severity.[205,206] The mechanism by which DM contributes to atherogenesis is poorly understood. Some prospective population studies on nondiabetic subjects have suggested that high plasma insulin levels are associated with an increased risk of CHD; other studies have suggested a relationship between the level of plasma insulin in patients with impaired glucose tolerance or NIDDM and atherosclerotic vascular disease.[207 – 211] Through ultrasonographic measurements of carotid intimal-medial wall thickness (an accepted and reproducible indicator of atherosclerosis), the ARIC study[212] demonstrated a positive association with diabetes (abnormal glucose metabolism). The nature of this relationship, whether hyperinsulinemia is an independent risk factor or dependent upon other factors such as hypertriglyceridemia in promoting the development and progression of atherosclerotic vascular disease, remains unanswered. It has been known for some time that there is a relationship between plasma insulin and triglyceride concentrations.[213] There appears to be an increased risk of CHD in persons with hyperinsulinemia associated with elevated plasma triglycerides, low plasma HDL, and elevated blood pressure.[214,215] Plasma insulin level has been shown to be a strong predictor of the HDL2 cholesterol level in specific populations, suggesting a causal relationship, although this may be more related to the obese rather than the diabetic state.[216] In support of an association between known coronary artery risk factors and non – insulin-dependent diabetes mellitus (NIDDM), a recent case-control study found that patients with a predominance of LDL subclass phenotype B, a known risk factor for coronary heart disease, had an increased risk for the future development of NIDDM.[217] This association was independent of age, sex, glucose intolerance, but not fasting triglyceride or insulin levels. Lipoprotein(a) [Lp(a)] levels appear to be independently associated with the development of coronary artery atherosclerosis in NIDDM.[218] Overall, there is no consistency in the studies evaluating whether elevated concentrations of plasma cholesterol and lipoproteins occur in diabetics whose concentrations of blood and urine glucose are carefully regulated. Also, some evidence suggests a decreased concentration of HDL levels in diabetics and a high prevalence of hypertension associated with hyperglycemia. This obviously raises doubts as to the independent influence that the hyperglycemia of diabetes has on the progression of atherosclerosis. It is even less clear whether borderline hyperglycemia is a risk factor, as evidenced by the equivocal results in numerous studies.[219,220] Some studies indicate that the fasting plasma glucose level, when measured as a continuous variable in nondiabetic patients, appears to be an independent risk factor

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for cardiovascular mortality in men, but not in women.[220] No controlled clinical trials have been conducted to assess the effect of risk factor modification on the regression of vascular disease in the diabetic person, and much remains to be learned about the relationship between hyperglycemia, hyperinsulinemia, and the progression of atherosclerosis.

Obesity and Physical Inactivity Obesity is correlated with an increased risk of dying from the clinical complications of atherosclerosis. Obese individuals tend to have severe hyperlipidemia, with decreased HDL levels, sedentary lifestyles, hypertension, and DM.[128,221] The Framingham Study, though, suggests that obesity is a risk factor independent of such associations—a finding that has been inconsistently supported in the literature.[222,223] Prospective studies have demonstrated the influence of obesity on the development of CHD in women. After controlling for multiple risk factors, even mild to moderate overweight increased the risk of coronary disease in middleaged women.[224] The ARIC study looked at the association between body mass, waist-to-hip circumference ratio, and physical inactivity and asymptomatic carotid artery wall thickness.[212] It found that physical inactivity and abdominal adiposity were both positively associated with carotid intimal-medial wall thickness, suggesting a contribution by these factors to the atherogenic process. Of note, it is upperbody obesity rather than total body weight alone that is associated with an increased risk of CHD, possibly through an HDL2 mechanism.[216] There is little doubt that obese persons have an increased risk for CHD, but obesity is not as consistently predictive of ischemic heart disease in white men as would be expected if it were an independent risk factor.[225] A significant gain in weight may indirectly affect the atherosclerotic process by worsening one or more of the many atherogenic traits with which it has been associated, this effect being more pronounced in whites than in blacks.[226] Also, the debate continues as to whether obesity paradoxically has a protective effect against cardiovascular disease in persons with hypertension.[227,228] The loss of substantial body fat through either dieting or exercising alters plasma lipoprotein concentrations favorably, decreases triglyceride levels, and raises HDL and HDL2 cholesterol levels.[229] This has great significance, given the findings of the Helsinki Heart Study. Even without any associated weight loss, the beneficial effect of fitness, if not moderate exercise alone, in decreasing the mortality rate from heart disease was demonstrated.[230,231] In the Framingham Study,[232] the most sedentary men had about three times the risk for cardiovascular disease as compared to 15% of the most physically active. There was a trend of improved overall cardiovascular and coronary mortality with increased levels of physical activity among those of all ages, including the elderly. Properly prescribed physical activity can affect atherosclerosis and its sequelae. More energy expenditure seems to be associated with greater benefits in achieving regression of coronary atherosclerosis, but any activity is good. The benefits of exercise, though, are much less apparent

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if modification of other coronary risk factors is not also achieved.[233] Elevation of serum HDL—specifically the protective HDL2 subfraction—is seen with both weight loss and exercise.[102,146,221,234] This may account for the frequent observation in population studies that higher activity levels appear to be protective against CHD.[235] It is also known that other consequences of physical activity may protect from the effects of ischemic change, including increases in heart volume and mass, development of collaterals, and a decrease in heart rate.

Other Potential Risk Factors In addition to the major risk factors already discussed, studies have identified others, including elevated levels of apolipoprotein B and lipoprotein(a), homocysteine and fibrinogen, low antioxidant ingestion, periodontal disease, infectious agents, stress and behavior patterns, and blood viscosity.[236 – 238] Many of the associations of these factors with the development and progression of atherosclerotic disease appear to be mediated either independently or through their impact on different systems, such as lipid metabolism or the coagulation cascade.

Stress and Behavior Patterns The specific coronary-prone behavior profiles and the physiologic mechanisms linking behavior to CHD are still unclear. Stress, behavior patterns, and personality traits have received considerable attention for their possible roles in atherosclerosis. Statistical evidence appears to validate the commonly held belief that stressful life events influence the risk of coronary disease.[239] Several epidemiologic studies have described men with a type A personality (characterized by a chronic sense of urgency, competitiveness, ambitiousness, and hostility) as having a higher rate of CHD than men judged to be of the less competitive type B behavior pattern.[240 – 243] In these studies, a synergistic relationship between type A behavior and other coronary risk factors is postulated in the development of CHD. Other studies have not confirmed an association between this behavioral type and the incidence of CHD and cardiovascular death.[244,245] In a large study looking at the prevalence, incidence, and risk factors for intermittent claudication, stress and psychosocial coping factors were found along with more traditional risk factors to be associated with the development of intermittent claudication and therefore presumably peripheral vascular arterial disease.[246]

Hyperhomocystinemia Individuals with homozygous homocystinuria have abnormally elevated homocysteine levels and suffer from multiple medical problems including an accelerated form of atherosclerosis. In recent years it has become increasingly evident that a large percentage of patients with premature atherosclerosis have less dramatic elevations in plasma homocysteine levels that may arise from nutritional deficiencies and subtle genetic abnormalities.[247] Enzymes involved in the metabolism of homocysteine are dependent

upon the availability of vitamin B6 (pyridoxal phosphate) or B12 and folate. Deficiencies of any of these factors can induce homocystinemia and are probably the most common and easily corrected causes of homocystinemia. A strong association has been noted between increases in plasma homocysteine concentration and the risk of developing peripheral arterial disease.[248] A study that analyzed the possible association between homocysteine and the risk of ischemic stroke was inconclusive.[249] Noninvasive examination of the endothelium-dependent, flow-mediated dilation of the brachial artery have shown that hyperhomocystinemia is an independent risk factor for arterial endothelial dysfunction in healthy middle-aged adults.[250,251] Whether or not this is a mechanism by which premature atherosclerosis develops has not been defined, although as stated earlier, endothelial dysfunction has been hypothesized as one mechanism by which atherosclerosis develops and progressess. Hyperhomocystinemia is associated with smoking and low levels of vitamin B12 and folate.[252] A higher level of homocysteine is seen in patients with multilevel disease as compared to suprainguinal or infrainguinal disease.[252] In two large studies, the independent association of elevated plasma homocysteine levels with manifestations of vascular disease in the various arterial beds and the potential prevention of CHD in women by folate and vitamin B6 intake in doses greater than the current recommended daily allowances was significantly demonstrated.[253,254] Also, plasma homocysteine levels have been shown to strongly predict mortality in patients with angiographically confirmed coronary artery disease, even after adjusting for other significant cardiovascular risk factors.[255] Hyperhomocystinemia appears to be an independent risk factor for premature vascular disease in the coronary, cerebral, and peripheral arteries.

Antioxidant Vitamins Vitamin antioxidants include vitamins A, C, E, and b-carotene. The results from different studies have not been conclusive and the role of each of these antioxidants alone or in combination is unclear when looking at all the studies. The evidence strongly suggests a role for them in the development of atherosclerosis when their plasma levels are low. Some epidemiologic studies have demonstrated an inverse relation between coronary artery disease and especially vitamin E supplementation.[256,257] For example, the Prospective Basel Study[258] suggested that low plasma antioxidant levels contribute to an increased risk for developing ischemic heart disease and cerebrovascular disease. The variety of roles by which antioxidants might prevent clinical manifestations of CHD is still unclear, but a tendency to thrombosis, plaque stability, vasomotor function/endothelial dysfunction, and a reduced oxidation of LDL are all mechanisms that have been proposed by which antioxidants may play a protective role.[259] Elevated levels of LDL cholesterol is a major risk factor for atherosclerosis. The oxidative susceptibility of LDL and its proatherogenic role has been demonstrated in recent studies and is enhanced by known cardiovascular risk factors including diabetes,

Chapter 4. Epidemiology of Atherosclerosis and Its Modification

smoking, and hypercholesterolemia.[260] Antioxidant therapy may confer a benefit by decreasing LDL oxidation.[261] Randomized trial data are not yet sufficient to fully assess the risk-to-benefit ratios for antioxidant supplements. The possible role of antioxidants such as vitamins C and E and b-carotene in the primary prevention of cardiovascular disease is supported by basic research and various clinical studies, but results from several large-scale randomized trials are not consistent, and there is no definitive answer as to the value of antioxidant therapy in modifying atherosclerotic risk. Of the different antioxidant vitamins, vitamin E currently seems to hold the most promise.[256,262,263]

Miscellaneous Factors Controversy exists as to the possible association between total body iron stores (TBIS) measured as serum ferritin levels and the development and progression of atherosclerosis. In some studies, a declining ferritin level is associated with improvements in atherosclerotic disease, while a rising ferritin level is associated with disease progression.[264] Increased TBIS appeared associated with an increased risk for CHD and stroke.[265] The level of TBIS seemed to be a predictor of carotid atherosclerosis and has also been proposed to account for gender differences in the expression of atherosclerotic vascular disease.[266,267] The reduced risk of CHD in premenopausal women may be related to lower levels of TBIS rather to variations in sex hormones.[268,269] The ARIC[270] study investigated this possible relationship between body total iron stores and cardiovascular disease indirectly by sonographically looking at carotid arterial intima-media thickening as described earlier in this chapter. Using a matched case-control design with major cardiovascular risk factors, it concluded that increased body iron stores did not increase the risk of atherosclerotic cardiovascular disease. Infectious etiologies of atherosclerotic vascular disease development and progression have also been proposed including both viral and bacterial agents.[271,272] A relationship between cytomegalovirus (CMV) and other infectious agents in the development and progression of atherosclerosis has been demonstrated, but the nature of this association remains to be elucidated.[273 – 275] Immunologic mechanisms modulating atherosclerosis may relate to the infectious causes identified in some studies as contributing to the development and progression of atherosclerosis.[276,277] The identification of a relationship between dental caries, periodontal disease, and atherosclerosis also suggests possible mediation by infectious pathways.[278 – 280] Whether or not infectious/ inflammatory changes affect atherosclerosis via fibrinogen as an acute phase reactant or by other means is unclear.[281]

Thrombosis A thrombotic tendency may also be associated with the development of atherosclerosis, as already alluded to in this chapter. A relationship between fibrinogen and cardiovascular disease development and progression has been established.[209,282] The Framingham Study strongly supports the finding that elevated fibrinogen level is a predictor of the same magnitude as other well-accepted risk factors for cardiovascular

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disease and stroke.[283] The findings of the ARIC[284] study also support the role that thrombosis and defective fibrinolysis play in the progression of atherosclerotic lesions. Moderate alcohol consumption may affect the clotting system, and exercise may stimulate fibrinolysis.[285] Certain fish oils may reduce platelet aggregation and exert favorable effects on lipoprotein levels. The omega-3 fatty acids competitively inhibit synthesis of thromboxane A2 (a vasoconstrictor that promotes platelet aggregation) in the membrane of platelets.[286,287] The net effect is decreased platelet reactivity and documented increased bleeding times, as is seen in Eskimos. In one large population study comparing Japenese men and women to American men and women of mixed races, there was a statistically significant difference in plasma fibrinogen levels, with the Americans having higher plasma levels.[288] In this study, women’s plasma fibrinogen level was positively associated with menopause and inversely associated with the use of hormone replacement therapy.[288] Also, total fish intake was inversely associated with plasma fibrinogen in all sex-race groups with a statistically significant association seen in Caucasian men.[288] The antiplatelet effects of fish oils appear to be dose-dependent, but the overall effect of the omega-3 fatty acids on hemostasis remains unclear. Growing evidence points to the interdependence between clotting factors and lipids. Increased blood viscosity and plasma fibrinogen, along with the major fibrinolytic inhibitor a2-antiplasmin, have been reported in type II hyperlipoproteinemia.[289] Fibrinogen levels have also been correlated with serum cholesterol.[290] Arachidonic acid, a stimulator of platelet aggregation, has been noted to be released in greater concentrations from platelets incubated with cholesterol-rich liposomes as opposed to cholesterol-poor platelets.[291] The relationships are far from clear. Another risk factor associated with premature atherosclerosis, atherothrombotic disease, and a greater tendency for restenosis after interventional procedures is lipoprotein(a) [Lp(a)].[292 – 295] The addition of apoprotein(a) to a molecule that is otherwise identical to LDL cholesterol confers a property of adhering to fibrinogen and inhibiting fibrinolysis. This is not surprising because apoprotein(a)’s structure is very similar to that of plasminogen. Lp(a) is very atherogenic, and high levels seem to be a stronger predictor of peripheral arterial disease than reduced levels of HDL cholesterol or elevated levels of LDL cholesterol. Estrogen given to postmenopausal women does seem to reduce Lp(a) levels, as do high doses of niacin.[292,293] Most of the antilipid agents and dietary intervention alone seem, however, to be ineffective in modifying Lp(a) levels. Gender difference exists in the expression of serum lipoprotein levels in patients with advanced coronary artery disease.[296] In patients studied who had a similar severity of coronary disease, 60% of the women and only 39% of the men had serum Lp(a) levels higher than 25 mg/dL. Based on these findings and the age of the sample population, Lp(a) level seemed to be a risk factor for coronary artery disease mostly in older (postmenopausal) women.[296] Lipoprotein(a) is a recently described lipoprotein fraction that is an independent risk factor for atherosclerosis in coronary and peripheral beds.[297 – 300] This association may be racially dependent in that the studies done have shown that

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elevated plasma concentration of Lp(a) is not an independent risk factor for coronary artery disease in African-Americans as it seems to be in the Caucasian populations.[301]

CONCLUSIONS Clinical research in atherosclerotic epidemiology has focused on cardiovascular disease, specifically CHD. The same risk factors, however, apply in general to cerebrovascular disease, aortoiliac disease, and other forms of peripheral vascular disease. The preponderance of data compiled to date has demonstrated a common set of precursors to all the major atherosclerotic diseases, whether manifest in the brain, the heart, or peripherally. In assessing risk for cardiovascular disease, consideration of only a single risk factor to detect persons at high risk may not be sufficient. Further, the relative importance of different risk factors varies according to the anatomic location and morphology of the lesion. Atherosclerotic changes appear in the coronary arteries years or decades before the age at which CHD becomes a clinically

recognized problem.[302] Atherosclerotic lesions in the coronary arteries, some causing narrowing or even occlusion, are found in young men in their 20s and 30s who have no symptoms of CHD. The lesions were commonly located at or near points of bifurcation. The occlusive process assumes distinctive characteristics in the four major arterial beds, and the development of these patterns is based on an interplay between genetics, environment, and physiologic forces.[303 – 308] Atherogenesis is a multifactorial process involving the interaction of blood lipids, metabolism of the arterial wall, and hemodynamic factors. The atherosclerotic process increases with age and is influenced by racial, geographic, and dietary factors. Risk factors, including hyperlipidemia, hypertension, diabetes mellitus, smoking, and obesity, determine to what extent the disease will manifest clinically. Anatomic distribution of the lesions follows reproducible patterns in most patients, with changes in plaque morphology contributing to the development of complications and symptoms. Current management concepts favor prevention, by minimizing risk factors, even for patients treated successfully by operation, since regression of the disease is unusual in the continuing presence of these readily identifiable risk factors.

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Venous Occlusion in Healthy Adults. N. Engl. J. Med. 1980, 302, 987. Thorngren, M.; Gustafson, A. Effects of 11-Week Increases in Dietary Eicosapentaenoic Acid on Bleeding Time, Lipids, and Platelet Aggregation. Lancet 1981, ii, 1190–1193. Knapp, H.R.; Reilly, I.A.; Allessandrini, P.; FitzGerald, G.A. In Vivo Indexes of Platelet and Vascular Function During Fish-Oil Administration in Patients with Atherosclerosis. N. Engl. J. Med. 1986, 314, 937–942. Iso, H.; Folsom, A.R.; et al. Plasma Fibrinogen and Its Correlates in Japanese and U.S. Population Samples. Arterioscler. Thromb. 1993, 13 (6), 783– 790. Lowe, G.D.O.; Stromberg, P.; Forbes, C.D.; et al. Increased Blood Viscosity and Fibrinolytic Inhibitor in Type II Hyperlipoproteinaemia. Lancet 1982, 1, 472. Korsan-Bengtsen, K.; Willhelmsen, L.; Tibblin, G. Blood Coagulation and Fibrinolysis in a Random Sample of 788 Men 54 Years Old. Thromb. Diath. Haemorrh. 1972, 28, 99. Stuart, M.J.; Gerrard, J.M.; White, J.G. Effect of Cholesterol on Production of Thromboxane B2 by Platelets In Vitro. N. Engl. J. Med. 1980, 302, 6. Hajjar, K.A.; Nachman, R.L. The Role of Lipoprotein(a) in Atherogenesis and Thrombosis. Annu. Rev. Med. 1996, 47, 423– 442. Maher, V.M.; Brown, B.G. Lipoprotein(a) and Coronary Heart Disease. Curr. Opin. Lipidol. 1995, 6, 229– 235. Liu, A.C.; Lawn, R.M. Vascular Interactions of Lipoprotein(a). Curr. Opin. Lipidol. 1994, 5, 269– 273. Kario, K.; Matsuo, T.; et al. Close Relation Between Lipoprotein(a) Levels and Atherothrombotic Disease in Japanese Subjects .75 Years of Age. Am. J. Cardiol. 1994, 73 (16), 1187– 1190. Stiel, G.M.; Reblin, T.; et al. Differences in Lipoprotein (a) and Apolipoprotein(a) Levels in Men and Women with Advanced Coronary Atherosclerosis. Coron. Artery Dis. 1995, 6 (4), 347– 350. Valentine, R.J.; Kaplan, H.S.; et al. Lipoprotein(a), Homocysteine, and Hypercoabulable States in Young Men with Premature Peripheral Atherosclerosis: A

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Prospective, Controlled Analysis. J. Vasc. Surg. 1996, 23 (1), 53 – 61. Takami, S.; Kubo, M.; et al. High Levels of Serum Lipoprotein(a) in Patients with Ischemic Heart Disease with Normal Coronary Angiogram and Thromboangiitis Obliterans. Atherosclerosis 1995, 112 (2), 253– 260. Budde, T.; Fechtrup, C.; et al. Plasma Lp(a) Levels Correlate with Number, Severity, and Length-Extension of Coronary Lesions in Male Patients Undergoing Coronary Arteriography for Clinically Suspected Coronary Atherosclerosis. Arterioscler. Thromb. 1994, 14 (11), 1730. Schreiner, P.J.; Morrisett, J.D.; et al. Lipoprotein[a] as a Risk Factor for Preclinical Atherosclerosis. Arteioscler. Thromb. 1993, 13 (6), 826– 833. Moliterno, D.J.; Jokinen, E.V.; et al. No Association Between Plasma Lipoprotein(a) Concentrations and the Presence or Absence of Coronary Atherosclerosis in African-Americans. Arterioscler. Thromb. Vasc. Biol. 1995, 15 (7), 850– 855. Enos, W.F.; Holmes, R.H.; Beyer, J. Coronary Disease Among United States Soldiers Killed in Action in Korea. J. Am. Med. Assoc. 1953, 152, 1090. Strong, J.P.; Restrepo, C. Coronary and Aortic Atherosclerosis in New Orleans. Lab. Investig. 1978, 39, 358. DeBakey, M.E.; Lawric, G.M.; Glaeser, D.H. Patterns of Atherosclerosis and Their Surgical Significance. Ann. Surg. 1985, 201, 115. The Progression of Atherosclerosis. Lancet 1985, i, 791. Montenegro, M.R.; Eggen, D.A. Topography of Atherosclerosis in the Coronary Arteries. Lab. Investig. 1968, 18, 586. Solberg, L.A.; Eggen, D.A. Localization and Sequence of Development of Atherosclerotic Lesions in the Carotid and Vertebral Arteries. Circulation 1971, 43, 711. Haimovici, H. Atherogenesis: Recent Biological Concepts and Clinical Implications. Am. J. Surg. 1977, 134, 174. Scandinavian Simvastatin Survival Study Group; Baseline Serum Cholesterol and Treatment Effect in the Scandinavian Simvastatin Survival Study (4s). Lancet 1995, 345, 1274– 1275.

CHAPTER 5

Hemodynamics of Abnormal Blood Flow David S. Sumner kinetic energy and vice versa with each change in velocity and direction. All along the way—but in some regions more than others—energy is converted into heat and is thus “lost.” By the time the blood returns to the right atrium, it has given up most of its potential energy but still retains some kinetic energy. Arterial obstruction accelerates the dissipation of energy and interferes with the smooth operation of this system by creating discontinuities in the energy gradient (Fig. 5-1).

To remain viable and to maintain proper function, all living cells depend on an adequate supply of nutrients and the efficient removal of metabolic products. In all except the most primitive organisms, blood is the vehicle for transporting these substances and the blood vessels are the conduits. Lesions within the human arterial tree produce symptoms and signs only when the integrity of the vessel wall is violated, allowing blood to escape, or when transportation is impaired sufficiently to compromise the viability or function of the tissues. A level of blood flow that suffices under resting conditions may be inadequate under conditions of stress, such as exercise, trauma, or infection. Thus, while the physical dimensions of an obstructing lesion place limitations on the ability of the arteries to transport blood and the strength of the arterial wall determines its resistance to leakage, the needs of the recipient organs ultimately dictate the threshold for the appearance of symptoms. Like all hydraulic systems, the motion of blood and the behavior of the arterial wall adhere to the laws of physics.[1 – 6] A basic knowledge of the principles of fluid transportation and vessel wall mechanics is, therefore, fundamental to the understanding of arterial disease and to the formulation of a rational approach to treatment.

Potential Energy In addition to the dynamic pressure PD produced by the heart, blood is subjected to pressure due to the elastic recoil of the vascular walls and to the effect of gravity (Fig. 5-2). Both of these pressures are present even when the circulation is completely static. While they are not ultimately responsible for the motion of blood, they are pertinent to our understanding of vascular physiology. Although elastic recoil is an important mechanism for storing energy produced during systole for discharge during diastole, the static filling pressure is ordinarily quite small, around 7 mmHg, and can be neglected for most practical purposes. On the other hand, hydrostatic pressure—which represents the weight of a column of blood extending from the right atrium to the point of measurement—may be appreciable. Hydrostatic pressure PH depends on the density of blood r, about 1.056 g/cm3; the acceleration due to gravity g, 980 cm/s2; and the distance h from the right atrium:

BASIC HEMODYNAMICS Because blood vessels are not ideal conduits and blood is not a frictionless fluid, the motion of blood from one site to another in the vascular tree involves the dissipation of energy. Consequently, to maintain blood flow, energy must be supplied continuously. Most of this requirement is met by the heart, which transforms chemical energy into mechanical energy. To a lesser degree, some energy is also contributed by the muscles of respiration and locomotion, but for the most part it is sufficient to focus on the heart as the major source. Blood leaving the left ventricle is given a potential energy boost in the form of hydraulic pressure and a kinetic energy boost in the form of increased velocity (Fig. 5-1). As the blood traverses the intricate network of tubes that make up the circulatory system, potential energy is transformed into

PH ¼ 2rgh

ð5-1Þ

At a point 100 cm below the heart, PH would be 103,488 dyn/cm2. Since 1.0 mmHg is equal to 1333 dyn/cm2, the pressure in more familiar terms would be 77.6 mmHg. In general, therefore, hydrostatic pressure in millimeters of mercury can be predicted by multiplying the vertical distance in centimeters from the heart by 20.78. Distances above the heart are given a plus sign, those below, a minus sign. As shown in Fig. 5-3, the total pressure at any point in the arterial tree is the sum of the dynamic and hydrostatic pressures. Below the heart, these pressures are additive, while above the heart, the hydrostatic component acts to reduce the

Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024888 Copyright q 2004 by Marcel Dekker, Inc.

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Figure 5-1. Potential energy (pressure) gradient from the left ventricle to the right atrium. Normally, the greatest pressure drop is across the arterioles. Note that discontinuities produced by arterial obstructions at the iliac and superficial femoral levels are largely rectified by a reduced gradient across the arterioles.

total pressure. In collapsible structures, such as veins or capillaries, intraluminal pressure cannot fall below that of the surrounding tissue (, 1 to 5 mmHg); otherwise the lumen would be obliterated and no blood would flow.[7] In a standing subject, blood flows from a lower pressure in the aortic arch to a higher pressure at the ankle (Fig. 5-3). To explain this apparently paradoxical situation requires consideration of gravitational potential energy. Gravitational potential energy is not manifest as pressure but represents the energy that any particle of matter (such as blood) acquires merely because of its distance from the center of the earth (Fig. 5-2). A useful artificial convention is to designate the left atrium as the reference point, calling this the point of “zero” gravitational potential energy. Using this convention, the formula for gravitational potential energy EG is identical with that for hydrostatic pressure but has the opposite sign: EG ¼ þrgh

Therefore, hydrostatic pressure and gravitational potential energy tend to cancel, explaining how blood may move against a pressure gradient but not against an energy gradient.

Kinetic Energy Like any other matter in motion, blood flowing in the vascular tree possesses kinetic energy (Fig. 5-4). In fluid systems, kinetic energy EK is proportional to the density of the fluid and the square of its velocity v (in centimeters per second): 1 EK ¼ rv 2 2

ð5-3Þ

ð5-2Þ

Total Fluid Energy At any point in the vascular system, the total fluid energy E, in ergs per milliliter of blood, is the sum of the potential and kinetic energy: E ¼ P D þ PH þ E G þ E K 1 ¼ PD 2 rgh þ rgh þ rv 2 2

Figure 5-2. Forms of potential energy acting on blood. Dynamic pressure is produced by cardiac contraction and is ultimately responsible for the blood circulation. Note that hydrostatic pressure and gravitational potential energy have opposite signs.

ð5-4Þ

Neglecting hydrostatic pressure and gravitational potential energy, most of the energy at the aortic arch is manifested in the form of dynamic pressure, with only a small fraction being kinetic, while in the thoracic venae cavae, most of the energy may be kinetic. According to Bernoulli’s principle, the total energy at one point in a closed system is equal to that at another under ideal conditions of steady flow and no frictional losses. In reality, blood always flows down an energy gradient, since energy is

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Figure 5-3. Effect of hydrostatic pressure on total arterial and venous pressure at various anatomic levels in the standing position. [From Sumner, D.S.: Hemodynamics and pathophysiology of venous disease. In Rutherford, R.B. (ed): Vascular Surgery, 4th ed. Philadelphia, Pennsylvania, Saunders, 1995, pp 1673 –1695. With permission.]

continuously dissipated in the form of heat: E1 ¼ E2 þ heat P1 þ rgh1 þ 12 rv1 ¼ P2 þ rgh2 þ 12 rv2 þ heat

ð5-5Þ

Because the mechanical equivalent of heat is so great, only about 16 cal would be generated per minute in moving 5 L of blood from the left ventricle to the right atrium when the mean pressure differential between these two sites is 100 mmHg. If there were no heat loss to the environment, this would raise the temperature of a 70 kg person only 2:6 £ 1024 8C=min: Figure 5-5 illustrates the interchange between one form of energy and another. Fluid flows from a reservoir (1) with a low pressure but high gravitational potential energy to a horizontal tube (2) where the pressure is higher but the gravitational potential energy is lower. In the aneurysmal area (3), velocity is decreased, since flow Q is the product of velocity v and cross-sectional area A: Q ¼ nA

Conversely, in the stenotic area (4), velocity increases. When velocity decreases, pressure tends to rise as kinetic energy is transformed into potential energy; but when velocity increases, the reverse change occurs—pressure falls as potential energy is converted into kinetic energy. Thus, at several points in the system, fluid may flow against a pressure gradient but never against an energy gradient. For most practical purposes, total fluid energy can be considered to be roughly equivalent to the dynamic pressure. Neglecting kinetic energy introduces an error that seldom

ð5-6Þ

Figure 5-4. Blood, like other fluids, gases, or solid bodies in motion, possesses kinetic energy.

Figure 5-5. Hydraulic model illustrating Bernoulli’s principle (Eq. 5-5): P, pressure; K, kinetic energy; E, total fluid energy. Although there is a sequential decline in total fluid energy from point 1 to point 5, fluid flows against a pressure gradient in several areas owing to an interchange between pressure and gravitational potential energy or between pressure and kinetic energy.

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exceeds 2 mmHg and is ordinarily much less; hydrostatic pressure and gravitational potential energy cancel each other out. Bernoulli’s principle has been used to estimate pressure drops (DP ) across stenoses. When the patient is horizontal in a supine position, the rgh terms on both sides of Eq. 5-5 are equal and can be eliminated. If energy losses (heat) are neglected, Eq. 5-5 can be rearranged to obtain: 1 DP ¼ P1 2 P2 ¼ rðv22 2 v21 Þ 2 Velocity of blood flow proximal (v1) and distal (v2) to a stenosis can be measured transcutaneously with a Doppler instrument. Predictions of pressure drops are fairly accurate across cardiac valves, because v1 in the cardiac chamber is low and can be neglected and because viscous losses are minimal, owing to the short length of the stenosis (see below).[8] Attempts to use the formula in other areas have met with little success.[9] Pressure gradients across low-grade stenoses tend to be overestimated, especially when the distal velocity (v2) is relatively low and when velocity above the stenosis (v1) is not measured.[10] Moreover, pressure below the stenosis may be recovered downstream as v2 decreases and kinetic energy is transformed into pressure. On the other hand, when viscous and kinetic energy losses (heat) are high (as they frequently are in relatively long arterial stenoses), the formula underestimates the pressure gradient.[10] It is evident, therefore, that this simplified formula is not adequate when applied to the relatively complex lesions that predominate in the peripheral circulation.

Energy Losses Viscosity, or the friction between contiguous layers of fluid, accounts for much of the transformation of energy into heat. In an idealized situation (steady, nonpulsatile, laminar flow in a straight cylindrical tube with rigid walls), the energy losses due to viscosity are described by Poiseuille’s equation: DP ¼ v



8Lh 8Lh ¼ Q
4 r2 pr

ð5-7Þ

where v ¼ mean flow velocity, cm/s, across a tube with inside radius r, cm Q ¼ flow, cm3/s DP ¼ pressure drop, dyn/cm2, over a length of tube L, cm h ¼ coefficient of viscosity P (poise ¼ dyn · s/cm2) That DP is directly related to flow, length, and viscosity comes as no surprise, but the inverse relationship to the fourth power of the radius is less intuitively evident. As shown in Fig. 5-6, diminishing radius has little effect on DP until a critical point is reached; thereafter, even small reductions in radius cause a major increase in DP. With increasing flow, the point of inflexion occurs at a greater radius, and at any given radius, DP is proportional to flow. Large vessels, such as the iliac arteries with diameters of 7 mm, can sustain massive flows of 3000 cm3/min (50 cm3/s) over a 10 cm segment with only a 2 mmHg DP due to viscous losses (h ¼ 0:035 P ). In contrast, the DP across a similar length of a 2-mm vessel, such

Figure 5-6. Curves depicting viscous energy losses DP across a 1.0-cm-long tube at various radii and flow rates (Eq. 5-7). Viscosity is assumed to be 0.035 P.

as the posterior tibial artery, would exceed 3 mmHg at a flow of only 30 cm3/min (0.5 cm3/s). Diameters of normal vessels are, therefore, consistent with the loads they are expected to carry. Viscous losses, however, may be overshadowed by those due to inertia. Velocity is a vector quantity; consequently, inertial losses occur any time the speed or direction of blood flow is altered. Because of the pulsatile nature of blood flow, velocity is continuously changing throughout the cardiac cycle and across the vascular lumen (Fig. 5-7). Direction changes occur at all branches or bifurcations, in areas of curvature, at the entrance and exit of stenoses or aneurysms, and even during systole and diastole as the vessel wall expands and contracts (Fig. 5-8). Turbulence, which creates a multitude of velocity vectors, is a major source of energy loss.* Inertial losses are proportional to the density of blood r and to the square of the change in velocity Dv: 1 DP ¼ k rðDvÞ2 2

ð5-8Þ

The constant k varies depending upon the nature and rapidity of the velocity change. For example, at the exit from a stenosis, k approaches 1.0 when the orifice is abrupt but is less than 0.2 when the orifice expands gradually at a 68 angle.[11] It should be emphasized that Dv may imply a change in *Frictional losses due to flow in directions other than the long axis of the tube are neglected in Eq. 5-7, but are incorporated in a general way in the constant k in Eq. 5-8. Thus, “inertial energy loss” is a term of convenience; it should be understood that all these losses are ultimately due to molecular interaction.

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Figure 5-7. (A ) Femoral arterial flow pulse. (B ) Velocity profiles across the vascular lumen at various phases of the pulse cycle (indicated by lowercase letters). At the wall, velocities are zero. During peak systole b, the profile is nearly parabolic; at other times it is quite blunt. When the overall direction of flow is changing rapidly, forward and reverse flow may occur simultaneously. [From Sumner, D.S.: Essential Hemodynamic Principles. In Rutherford RB (ed): Vascular Surgery, 4th ed. Philadelphia, Pennsylvania, Saunders Co., 1995, pp 18 – 44. With permission.]

“direction” of a blood particle without necessarily a change in its “speed.” As a result of inertial losses, the relationship of pressure gradients and flow in the arterial system never adheres to Poiseuille’s law. For a given flow, pressure gradients are always larger than those predicted; likewise, for a given

pressure gradient, flows are always less (Fig. 5-9). Instead of a linear relationship between pressure gradient and flow, the curve is concave toward the pressure axis and is best described by equations in which flow appears as a squared term. This, of course, would be anticipated from Eq. 5-8, since velocity and flow are interdependent. A curve depicting the inertial energy losses for the artery shown in Fig. 5-9 could be obtained by subtracting the line representing Poiseuille’s equation from the experimentally determined values. The resulting equation ðP ¼ 144Q þ 11Q 2 Þ emphasizes the relationship between inertial losses and flow. Reynolds number (Re) defines the ratio between destabilizing inertial forces and stabilizing viscous forces acting on a fluid: Re ¼

Figure 5-8. Factors responsible for energy “losses” due to inertia. All affect either the speed or direction of blood flow. The energy given up by a baseball bouncing off a hard surface provides a rough analogy.

2rvr h

ð5-9Þ

Although laminar flow disintegrates into turbulent flow when Reynolds number exceeds 2000, numbers of this magnitude seldom occur in the circulation under normal circumstances. Yet the pattern of blood flow in a large part of the arterial tree can be characterized as disturbed for the reasons mentioned above.[12]

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Figure 5-9. Flow versus pressure drop across a 9.45 cm length of canine femoral artery. The dashed line represents the pressureflow curve predicted from Poiseuille’s law (Eq. 5-7). Note that the formula for the curve that best approximates the experimental data has both a linear and a squared term. [From Sumner, D.S.: Essential Hemodynamic Principles. In Rutherford, R.B. (ed): Vascular Surgery, 4th ed. Philadelphia, Pennsylvania, Saunders. 1995, pp 18– 44. With permission.]

Indeed, energy losses calculated with turbulent friction factors more closely approximate those observed experimentally than they do when Poiseuille’s equation is employed.[13]

Arterial Stenoses Energy losses caused by stenoses in the arterial system are due to both viscous and inertial factors.[14,15] Viscous losses depend on the length of the stenosis and the fourth power of its diameter. According to Poiseuille’s law, a reduction in luminal diameter of 50% would increase the pressure gradient by a factor of 16, and a reduction of 75% would increase DP by a factor of 256—provided flow remained constant (Eq. 57). The diameter of the stenosis, therefore, is far more important than its length.[14,16,17] Energy losses due to inertia occur at the entrance to a stenosis and also at its exit.[3,15,16,18,19] Less flow disturbance occurs at the entrance than at the exit, where much of the excess kinetic energy resulting from the increased fluid velocity within the stenosis is dissipated in a turbulent jet. Just beyond the stenosis, areas of flow separation develop near the arterial wall. In these areas, flow may actually reverse. That inertial losses ordinarily exceed those due to viscous factors is illustrated in Fig. 5-10. Viscous factors predominate only at low flow rates or in relatively long stenoses. Because flow disturbances are concentrated at the ends of a stenosis, doubling the length of a stenosis—which affects only the viscous factors—will not double the energy loss. Based on Poiseuille’s law (Eq. 5-7) and Eq. 5-8, one would predict that narrowing of the arterial lumen would have little

Figure 5-10. Calculated energy losses experienced by nonpulsatile blood flow through a 60% stenosis. Flow velocity before and after the stenosis is 50 cm/s. Inertial losses are based on Eq. 5-8. At the entrance, k is 0.5, and at the exit, 1.0. [From Sumner, D.S.: Essential Hemodynamic Principles. In Rutherford, R.B. (ed): Vascular Surgery, 4th ed. Philadelphia, Pennsylvania, Saunders, 1995, pp 18 – 44. With permission.]

effect on the pressure gradient across or the flow through a stenosis until the cross-sectional area is reduced by about 75%. These predictions have been substantiated by numerous experimental studies.[20,21] As shown in Fig. 5-11, in an isolated system with a fixed peripheral resistance and no collateral input, changes in DP and flow are mirror images of each other. Flow decreases are commensurate with increases in the pressure gradient. When the peripheral resistance is low and initial flow rates are high, the curves are shifted to the left; in other words, changes in pressure and flow are perceived a lesser degree of narrowing when initial flow rates are high.[20,21] In part, this explains why a lesion that does not appear particularly severe on arteriography may cause no symptoms at rest but causes significant disability during exercise.[22] When the lesion responsible for a stenosis is axisymmetric, a 75% area reduction corresponds to a 50% diameter reduction. Stenoses of this magnitude seen on arteriography are frequently labeled “critical” or “hemodynamically significant.” While this is a clinically useful concept, permitting the surgeon to predict physiological changes from the arteriographic picture, it must be used cautiously. Because many lesions are not axisymmetric, the anteriographic picture may overestimate or underestimate the degree of stenosis. Moreover, as pointed out above, a lesion may or may not be critical, depending upon the rate of flow.

Hemodynamic Resistance Hemodynamic resistance (R ) is defined as the ratio of the energy gradient between two points along the vessel to the

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87

Figure 5-12. Electrical analogue showing effect on total resistance R of isolated resistances R1, R2, and R3 arranged in series and in parallel.

CIRCULATORY EFFECTS OF ARTERIAL OBSTRUCTIVE LESIONS

Figure 5-11. Effect of increasing stenosis on pressure and flow in isolated segment of canine femoral artery. Peripheral resistance was modified by means of an arteriovenous communication. [From Sumner, D.S.: Essential Hemodynamic Principles. In Rutherford, R.B. (ed): Vascular Surgery, 4th ed. Philadelphia, Pennsylvania, Saunders, 1995, pp 18–44. With permission.]

mean blood flow through the vessel: R¼

E 1 2 E2 P1 2 P2 ð<Þ Q Q

ð5-10Þ

Stenotic or obstructed arteries are part of a complex hemodynamic circuit that includes the involved artery, a parallel system of collateral arteries, and the peripheral runoff bed (Fig. 5-13).[3,25] The parallel resistances of the collaterals Rc and the involved artery Rs constitute a “segmental” resistance Rseg, which is in series with the resistance of the runoff bed Rp. Therefore, the total blood flow QT to the peripheral tissues is determined by the central arterial pressure Pa, the venous pressure Pv, and the sum of the segmental and runoff resistances: QT ¼

Pa 2 Pv Pa < Rseg þ Rp Rseg þ Rp

ð5-12Þ

For most purposes, R can be roughly approximated by the ratio of DP to Q. It must be recognized that the resistance of any vascular segment is not fixed and is not determined exclusively by the diameter of the segment. Because of inertial factors, resistance increases as flow increases. The minimum possible resistance is given by Poiseuille’s law*: Rmin ¼

8Lh pr 4

ð5-11Þ

Analogous to electrical circuitry, resistances in series are roughly additive (Fig. 5-12).[23,24] Arranged in parallel, the reciprocal of the total resistance is equal to the sum of the reciprocals of the resistance of each component part (Fig. 512). The total resistance of vessels in parallel must, therefore, be less than that of the vessel with the least resistance.

*Since blood is a non-Newtonian fluid, its viscosity (h ) decreases as its shear rate increases. (Shear rates are directly proportional to velocity and inversely proportional to the vessel diameter.) At very low velocities, when blood is practically stagnant, viscosity may be several times higher than that at normal flow velocities, but throughout the wide range of velocities normally present in human arteries, viscosity is nearly constant.[3] Therefore, the minimal resistance calculated from Eq. 5-11 varies little with changes in flow rate.

Figure 5-13. Diagram illustrating components of a hemodynamic circuit containing an arterial occlusion or stenosis. Shown below is an electrical analogue, in which the battery represents the left ventricle and ground potential represents the right atrium.

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(Because the venous pressure is ordinarily quite low, it can be neglected for the purpose of the following discussion.) To maintain adequate tissue perfusion in the face of a developing stenosis, the body has three options: reduce the segmental resistance, reduce the runoff resistance, or reduce both. The success in accomplishing this task and the mechanisms involved depend not only on the extent and severity of the lesion, but also on its location and the rapidity with which it develops. Collateral arteries are preexisting pathways consisting of intercommunications between terminal branches of distributing arteries that originate both above and below the obstructing lesion.[26] Their recruitment and subsequent enlargement are stimulated by an increased pressure gradient across the involved segment and an increased demand to carry blood flow.[27 – 29] This response is probably mediated by the release of nitric oxide (endothelium-derived relaxing factor).[30] In some areas of the body, the collaterals are sufficiently developed to sustain tissue viability even in the event of an acute obstruction, provided the obstruction does not block the inflow or reentry vessels. In most cases, however, preexisting collaterals are inadequate to prevent ischemia. As a rule, collateral development occurs over a prolonged period; even when they have attained their maximum dimensions, their resistance almost always exceeds that of the major artery whose function they are called upon to supplement or replace. For example, 256 collaterals, each with a diameter of 2.5 mm, or 10,000 collaterals with a diameter of 1.0 mm would be required to reduce the segmental resistance to that of a major vessel with a diameter of 10 mm (Eq. 5-11 and Fig. 5-12). Although the resistance of the collateral bed is relatively fixed, that of the runoff bed is quite variable and acutely responsive to various exigencies.[25,31,32] Most of the resistance is concentrated in the terminal arterioles and precapillary sphincters, which, because of their small diameter and muscular walls, are ideally suited for regulatory functions (Fig. 5-1). Their tone is controlled by the sympathetic nervous system, circulating catecholamines, local products of metabolism, and myogenic influences. These vessels have the remarkable ability to autoregulate, dilating in response to a fall in blood pressure and constricting in response to a rise.[33,34] By this mechanism, blood flow is maintained within tolerable limits despite wide variations in perfusion pressure. In skeletal muscles, autoregulation ceases when perfusion pressure drops below about 20 – 30 mmHg.[34,35] Beyond this point, flow becomes pressuredependent. When flow drops to the point that ischemia results, metabolic products accumulate. These substances are powerful vasodilators, their influence overcoming the vasoconstrictive effects of sympathetic nerve impulses.[36,37] As the segmental resistance rises, the resistance of the runoff bed falls. At first, the fall in resistance is due to autoregulation, but once blood flow to the periphery is compromised, the products of ischemia play a role. Peripheral vasodilatation, therefore, is immediately available to compensate for an acute elevation of the segmental resistance. With persistence of the obstruction, the collateral arteries dilate, allowing the peripheral resistance to rise. However, peripheral resistance never returns to normal levels as long as arterial obstruction persists.

Pressure-Flow Relationships At Rest The pressure distal to an arterial obstruction Pd depends on the central arterial pressure Pa and the product of the segmental resistance and the total blood flow (Fig. 5-13): Pd ¼ Pa 2 QT Rseg

ð5-13Þ

In subjects without arterial disease, Rseg is so low that the mean Pd is only a few millimeters of mercury below Pa. Because pulse waves are reflected from the periphery, the systolic pressure distal to the segment may actually be higher than the central systolic pressure; the diastolic pressure, however, will be less.[3,38] (This accounts for the observation that systolic blood pressure at the ankle normally exceeds that in the arm.[39]) Segmental resistance becomes appreciable only when the stenosis in the major artery becomes “critical,” and, even then, well-developed collaterals may provide adequate compensation. As the segmental resistance rises, arterioles in the runoff bed dilate, thereby maintaining total blood flow QT constant. Because Rseg is elevated, the product QTRseg increases, and the distal pressure Pd falls (Fig. 5-14). Thus, a fall in distal pressure is the earliest objective evidence of arterial obstruction. This explains why blood flow in a limb with well-advanced arterial obstruction is usually normal but the peripheral pressure is reduced.[3,39 – 42]

Figure 5-14. Relationship between increasing segmental resistance, distal pressure, and distal blood flow. Although flow is maintained at normal levels until maximal peripheral vasodilatation is reached, pressure begins to drop immediately. [From Sumner, D.S.: Correlation of lesion configuration with functional significance. In Bond, M.C., Insull, W. Jr., Glagov, S., Chandler, A.B., Cornhill, J.F. (eds): Clinical Diagnosis of Atherosclerosis: Quantitative Methods of Evaluation. New York, Springer-Verlag, 1983. With permission.]

Chapter 5.

With increasing disease, poor collateral development, lesions that block collateral inflow or outflow, or multilevel involvement, Rseg becomes quite high and the peripheral pressure Pd drops below the limits where autoregulation is possible. Total limb resistance rises; total blood flow QT falls, and the peripheral tissues become ischemic at rest (Eq. 512).[43] Despite the fact that QT is decreased, the product QTRseg continues to rise, and the peripheral pressure Pd continues to fall, albeit at a slower rate (Eq. 5-13 and Fig. 514). Noninvasive studies suggest that ischemic signs and symptoms—such as rest pain, ulcers, gangrene, and poor healing—usually become manifest only when the pressure drops below 30 mmHg.[44 – 47] It is important to recognize that a level of blood flow adequate to maintain tissue viability under normal conditions may not be sufficient to supply the additional nutrients and other blood-borne factors required to heal traumatic wounds or ulcers, especially in the presence of diabetes and infection. Therefore, it is impossible to state precisely what the critical level of tissue perfusion might be in a particular situation. In most patients with ischemic feet, elevating the legs increases rest pain and impedes healing, while placing the feet in a dependent position often provides relief from pain and may encourage healing. These effects are the result of changes in hydrostatic pressure. Consider a patient who, when lying supine, has an arterial pressure of 25 mmHg and a venous pressure of 10 mmHg in the toes. In this position, the pressure gradient determining blood flow across the arterioles, capillaries, and venules is 15 mmHg. A 20 cm elevation of the feet would decrease the hydrostatic pressure 16 mmHg (Eq. 5-1), causing the arterial pressure to fall to 9 mmHg. Since the venous pressure cannot fall below tissue pressure ( t 1–5 mmHg), the gradient across the capillary bed decreases from 15 to 4–8 mmHg; nutritive flow suffers by a like amount; and the patient develops paresthesias or pain in the elevated foot.[48] On the other hand, if the patient were to sit up, allowing the feet to rest on the floor, the vertical distance from the heart to the toes would increase by perhaps 80 cm, and the hydrostatic pressure would rise by 62 mmHg. Although both the arterial and the venous pressures increase by the same amount and perfusion pressure across the capillaries remains unchanged (87 mmHg – 72 mmHg – 15 mmHg), the capillary bed dilates in response to the increased intraluminal pressure. This reduces the resistance of the capillaries and venules, thereby augmenting tissue perfusion despite the fact that the transcapillary pressure gradient has not changed.[49,50] If the patient contracts the calf muscles and if the venous valves are intact, the venous pressure in the foot will fall from 72 mmHg to some lower value (often to 5– 10 mmHg). Since arterial pressure is unaffected by calf motion, the pressure gradient across the capillaries will be augmented proportionate to the drop in venous pressure, and tissue perfusion will be similarly enhanced. This explains the somewhat paradoxical observation that ischemic rest pain may be relieved by walking a few steps. Last, in considering the mechanism of ischemic rest pain, one must not forget that the central pressure Pa also plays a role in determining tissue perfusion (Eq. 5-12). Rest pain occurs primarily at night, when the cardiac output falls and arterial pressure decreases. The stimulation of sitting up or

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moving about usually raises the mean blood pressure, thus augmenting tissue perfusion.

Pressure-Flow Relationships During Exercise During exercise, the terminal arterioles supplying the involved muscles dilate, reducing the peripheral resistance Rp. In normal limbs which have a high resting peripheral resistance, exercise produces a marked decrease in total limb resistance and a similarly marked augmentation of limb blood flow (Eq. 5-12). Blood flow to the muscles increases commensurate with the vigor of the exercise, often by a factor of 5 or more.[3,42,51,52] Despite the marked increase in blood flow, the product QTRseg remains low, and there is little drop in peripheral pressure Pd (Eq. 5-13). These relationships are illustrated in Fig. 5-15. In limbs with arterial obstruction, the terminal arterioles— already partially dilated to compensate for the increased segmental resistance—dilate further in response to exercise, but, because of the elevated segmental resistance, the total limb resistance remains relatively high (Fig. 5-15). Although exercise induces an increase in blood flow to the muscles, the increase may be inadequate to meet metabolic demands.[3,42,50 – 53] Consequently, the by-products of metabolism accumulate, provoking the symptoms of intermittent claudication. Because blood flow through the elevated segmental resistance increases, peripheral pressure falls (Eq. 5-13). This drop in peripheral pressure, usually measured at the ankle level, is one of the most sensitive methods for detecting obstruction of the arteries supplying blood to the legs.[39,42,54 – 56] Even when the resting ankle pressure is imperceptibly reduced, exercise may induce an unequivocal pressure drop, thus establishing the diagnosis.[57] The effects of exercise for a given degree of arterial stenosis are often more severe when the obstruction is located in the proximal arterial segments. A stenosis of the terminal aorta or common iliac artery may impair walking tolerance to a greater degree than a similar stenosis of the superficial femoral artery. Since the iliac artery supplies a much larger muscle mass than that supplied by the superficial femoral artery, the metabolic demands for increased blood flow are correspondingly greater. The central blood pressure Pa frequently rises during exercise, especially in patients with peripheral vascular disease. This seldom provides much relief from claudication but may disguise small drops in peripheral pressure (Eq. 513). Consequently, to detect subtle falls in ankle pressure during exercise, one must measure the brachial and ankle pressure simultaneously. When obstructions involve more than one arterial segment, the hemodynamic situation becomes far more complex (Fig. 5-16).[58,59] An arterial segment is composed of a major artery and its collaterals, which supply a more or less well-defined peripheral vascular bed. The major artery of a given segment may also constitute the primary inflow source for another more distally located segment. For example, the iliac segment consists of the common and external iliac arteries, which function as major arteries, and the internal iliac system, which make up the collateral

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Figure 5-15. Relationship between total resistance RT, segmental resistance Rseg, peripheral resistance Rp, blood flow QT, and distal blood pressure Pd in normal limbs and limbs with single-level arterial obstruction. Central arterial pressure Pa is 100 mmHg. PRU = mmHg/mL/min. (Theoretical curves based on Fig. 5-13 and experimental observations.)

channels. These vessels supply not only the buttock and thigh muscles but also provide inflow to the superficial femoral artery, which in turn—with its collaterals— supplies the calf muscle via the popliteal artery. Thus, the leg may be divided into iliac, femoral, calf, and pedal segments. Walking exercises buttock, thigh, and calf muscles and thus simultaneously involves the iliac, femoral, and calf segments. In a limb with both iliac and superficial femoral disease, exercise provokes increased pressure drops across both segments (Fig. 5-17). Because blood flow to the thigh and buttocks increases due to arteriolar vasodilatation, the femoral arterial pressure drops; and the superficial femoral artery and its collaterals will be perfused—not by the central arterial pressure, but by a reduced pressure. Although dilation of the arterioles in the calf muscle decreases the peripheral resistance, the reduction in pressure at the upper end of the femoral segment will further restrict the increase in calf blood flow. Therefore, claudication occurs with less exercise when there is multiple segment disease than when disease is limited to a single segment. In severe cases, the

foot and toes, which are at the end of the line, may have virtually no blood flow.[39,52,55,60] Thus, in limbs with multilevel obstruction, the proximal segments “steal” blood from those more distally located. This explains why multilevel disease is far more physiologically devastating than disease confined to a single segment. Even with a single obstruction at the iliac level, the proximal muscle compartments may steal blood from the calf, since the superficial femoral artery, though widely patent, is perfused by a reduced common femoral pressure. Return of blood to the heart is facilitated during walking by the venous pump mechanism. As mentioned earlier, in normal limbs with functioning venous valves, contraction of the calf muscles forces blood cephalad, reduces the effective length of the hydrostatic column, and decreases venous pressure. Since the hydrostatic component of arterial pressure is not affected, the pressure gradient across the capillaries of the exercising muscles is increased and blood flow is augmented. Therefore, one might expect that claudication would occur earlier in limbs with arterial obstruction when chronic venous insufficiency is also present.

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91

Figure 5-16. Components of a hemodynamic circuit with two levels of obstruction (Rseg1, Rseg2) and two runoff beds (Rp1, Rp2). Electrical analogue is shown below.

Pressure-Flow Relationships After Exercise Following exercise, the greatly increased blood flow in normal limbs rapidly replenishes any nutritional deficiencies that might have developed during muscular contraction and rapidly removes any accumulated products of metabolism. As a result, the dilated arterioles constrict to their resting diameter and blood flow falls to preexercise levels within a few minutes (see Fig. 5-15).[3,25,40] Limbs with arterial obstruction, on the other hand, develop a much larger “flow debt” during exercise, the extent of which is roughly proportional to the severity of the obstruction and the duration and magnitude of the muscular work. A prolonged period, therefore, is required to restore the metabolic state to that existing prior to exercise. As a result, postexercise blood flow remains elevated and peripheral pressure remains decreased until the arterioles once again return to their preexercise state (see Fig. 5-15).[25,39,40,54 – 56,58] In limbs with multilevel disease, repayment of the flow debt of the distal muscular compartments may be delayed until that of the more proximal compartment is satisfied.[55,58] For example, in a limb with combined iliac and superficial femoral arterial obstruction, hyperemia of the thigh and buttock muscles must decrease before the femoral pressure can rise (Fig. 5-17). As the femoral pressure rises, blood flow to the calf will initially increase and then gradually decrease as the flow debt of the calf muscle is eradicated. Peripheral pressure remains low until calf blood flow begins to fall, returning to preexercise levels only after the hyperemia has subsided. Recording the ankle pressure after exercise, therefore, provides an excellent method for assessing the severity of

arterial obstruction and for predicting the changes occurring in blood flow to the calf and thigh.[55] Given an equivalent amount of exercise, one can assume that the greater the decrease in ankle pressure and the longer it remains below preexercise levels, the more severe the obstructive process. An ankle pressure that remains low or undetectable for a prolonged period implies multilevel disease and a diversion of blood flow into the more proximal muscular compartment (Fig. 5-17).

PRESSURE AND FLOW PULSES The periodic discharge of blood from the left ventricle into the arterial system during the systolic phase of the cardiac cycle is basically responsible for the pulsatile nature of blood flow. Energy developed during systole is stored within the arterial wall. During diastole, the elastic recoil of the expanded arteries continues to propel blood into the various vascular beds; otherwise, flow would be intermittent and pressure would fall to zero. Many factors affect the contour of flow and pressure pulses. Among these are resistance to outflow, inertia and viscosity of blood, stiffness of the arterial wall, pulse rate, and wave reflections—all of which are incorporated into the concept of input impedance.[3,61] The effect of resistance and wave reflections is perhaps the most easily understood (Fig. 518). In the normal arterial system, the major site of resistance is in the arterioles. When the surge of blood constituting the flow pulse meets this high resistance, part of the blood is

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Figure 5-17. Relationships between pressure in the common femoral and popliteal arteries and flow in the thigh and calf in a limb with severe occlusive disease of the iliac and superficial femoral segments. Central arterial pressure is 100 mmHg. Note that calf blood flow may drop during exercise and that popliteal pressure remains low for 10 min: ankle pressure would be undetectable during this time. (Theoretical curves based on Fig. 5-16 and experimental observations.)

transmitted into the capillaries and part is reflected back up the arterial tree.[3,62] The relative magnitude of the reflected wave is therefore a function of the peripheral resistance, being accentuated by vasoconstriction and attenuated by vasodilatation.[63] The reflected wave explains the characteristic appearance of the normal flow pulse, which has a large forward flow component in systole, followed by a reverse flow component (representing the reflected wave) in early diastole (Fig. 5-18). Finally, another—but much smaller—forward flow wave is often present in late diastole. When the arterioles are dilated, as in exercise, there may be no perceptible reflected wave, and flow is antegrade throughout the cardiac cycle. This configuration is also typical of the pulse in arteries (such as the internal carotid) that supply low resistance vascular beds. The normal pressure pulse has a sharp upslope and a dicrotic wave on the downslope (Fig. 5-18). This wave is produced by the return of potential energy reflected from the periphery. Plethysmographic pulses (which represent the interaction of arterial pressure and vessel wall compliance) have contours that are roughly the same as that of the pressure pulse.[64,65] Distal to a critical stenosis, pulse waves are attenuated due to energy losses incurred in the vicinity of the lesion and within the high-resistance collateral pathways

Figure 5-18. Effect of reflected waves on the contour of flow and pressure pulses. Reflected waves subtract from forward flow waves but add to pressure waves. Vasoconstriction accentuates the reflected wave, producing flow reversal in diastole and a prominent dicrotic notch in the pressure tracing. Vasodilatation minimizes pulse wave reflection.

(Fig. 5-19).[66,67] The combination of high resistance and arterial compliance functions as a low-pass filter. While the lower frequency harmonics are passed with relatively little change, the energy in the higher frequency harmonics is markedly diminished. This produces a characteristic damping of the pulses. The pressure pulse becomes rounded, develops a slow upslope and a downslope that bows away from the baseline, and loses the dicrotic wave. Similarly, the flow pulse displays a slow upslope, a rounded peak, a gradual decline during diastole, and no reverse flow. Palpation of the peripheral pulse is an essential part of the physical examination in patients with suspected arterial disease. Reduction or absence of palpable arterial pulses distal to an obstruction is the result of both the decrease in mean pressure and the attenuation of the pressure pulse. While gross changes in the flow pulse can be easily recognized with an electromagnetic or Doppler flowmeter, various mathematical manipulations have been introduced to enhance diagnostic accuracy. The simplest of these is the pulsatility index, which is defined as the ratio of the maximum excursion of the velocity pulse wave (from peak systole to the lowest diastolic point) and the mean velocity.[68,69] Reduction of the pulsatility index below established normal values indicates proximal stenosis.[70,71] Since the accuracy of this test may be compromised by distal obstruction—which also affects the contour of the wave—other more complicated methods, including the use of Laplace transforms, have been

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93

Figure 5-19. The combination of a hemodynamically significant stenosis and compliant vessels functions as a “low-pass” filter, attenuating high-frequency components of pulse waves. Arterioles are represented by the faucet and the variable resistance. Mean pressure (dashed line ) is reduced, but mean flow (dashed line ) remains unchanged distal to a stenosis. [From Sumner, D.S.: Correlation of lesion configuration with functional significance. In Bond, M.C., Insull, W. Jr., Glagov, S., Chandler, A.B., Cornhill, J.F. (eds): Clinical Diagnosis of Atherosclerosis: Quantitative Methods of Evaluation. New York, Springer-Verlag, 1983. With permission.]

devised.[72] The relative merits of these calculations have as yet not been established. Although changes in the envelope of the pulse waves do not become evident until the stenosis reaches critical dimensions, even minor lesions generate turbulent eddies and areas of flow separation.[73,74] These disturbances produce a variety of velocity vectors that “broaden” the Doppler frequency spectrum, providing a sensitive method for detecting low-grade stenoses.

applicability and subjects the patient to additional hazards.[75] On the other hand, restoring blood pressure to normal levels by improving the cardiac output of hypotensive patients with pump failure and extensive arterial disease may reverse severe ischemia of the feet and toes. In most cases, however, eliminating the cause of increased resistance is the only rational approach.

Direct Arterial Surgery THERAPY Improvement of peripheral perfusion is the objective of all methods for treating obstructive arterial disease. When the obstruction is severe and the goal is to eliminate ischemia at rest, a small increase in blood flow may suffice, but when the obstruction is less severe and the goal is to secure relief from claudication, it is necessary to provide a large increase in blood flow during exercise. To increase blood flow, two basic mechanisms are possible: elevation of perfusion pressure Pa and reduction of hemodynamic resistance (Eq. 5-12). While temporary relief of severe ischemia can sometimes be achieved by inducing systemic hypertension, this approach has limited

Since the site of increased resistance is the diseased arterial segment and not the peripheral runoff bed (which almost invariably has a decreased resistance), restoration of normal hemodynamics requires removing or bypassing the obstruction. Depending on the nature, extent, and location of the obstructing lesion, it can be removed by embolectomy, thrombectomy, endarterectomy, atherectomy, angioplasty, replacement grafting, or lytic therapy. Bypass grafting is preferred when the lesions are quite extensive or difficult to remove, or when preservation of collateral channels might be jeopardized by attempts to disobliterate the involved artery. When the obstruction is confined to one arterial segment, it is often possible to return inflow resistance to normal levels and completely restore normal function.[76] Peripheral pressures at rest and during and following exercise return to

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normal levels, and blood flow under the same conditions becomes normal. The same results can be achieved in multisegmental disease when all diseased segments are bypassed. Restricting the operation to one or more segments (usually the more proximal segments), but leaving residual disease, will effect only partial restoration of hemodynamic function. The degree of improvement will depend on the relative reduction in resistance.[77] Although peripheral pressures are improved, they continue to be abnormal at rest and to fall during exercise; however, the postexercise decrease in pressure is reduced and recovery time is lessened. Likewise, partial repair is often sufficient to return blood flow to normal levels at rest and to provide sufficient blood flow to prevent claudication during moderate exercise. In cases being operated on for ischemia, it is only necessary to raise the peripheral perfusion pressure to a level that permits autoregulation to occur—about 40 mmHg at the ankle or 30 mmHg at the toe. In cases being operated on for claudication, this degree of improvement would not provide much relief; peripheral pressures need to reach levels that allow some constriction of the intramuscular arterioles at rest. Only then can the arterioles dilate under the influence of exercise to provide the additional flow required to ameliorate claudication. Even when disease is confined to one segment, the operative procedure may not completely return the resistance of that segment to normal levels. For example, stenosis can occur during closure of an endarterectomy site or at the proximal or distal ends of a bypass graft. Aside from these technical errors, the buildup of pseudointima within a prosthetic graft or the development of fibrodysplastic thickening at the ends of an autogenous graft or within the recipient vessels can narrow the lumen. While these changes may not be clinically evident, they can often be recognized by a less than perfect result in terms of objective hemodynamic data.[78,79] Peripheral pressures may not return to normal or, if normal at rest, will show reduction following exercise, and flow disturbances may be detected with a Doppler survey or by the presence of a bruit. To provide sufficient blood flow at a minimal pressure drop, the diameter of the graft must be selected with its proposed function in mind. Like other blood conduits, the resistance of a graft is directly related to its length and inversely related to the fourth power of its diameter. Thus the minimal resistance of a graft can be estimated from Poiseuille’s law (Eq. 5-11). This, of course, neglects the inertial energy losses that occur at the graft-host artery junctions—losses that can be appreciable. Table 5-1 lists the minimal pressure gradients that would occur across grafts of various diameters at various flow rates. At flow rates normally observed at rest in a femoropopliteal bypass (about 60 – 150 mL/min), a graft diameter of less than 4 mm would be associated with an appreciable pressure drop; the gradient during exercise, when flow rates of 300–500 mL/min are required, would be unacceptably high. While a 3-mm femoropopliteal graft might relieve ischemic symptoms, it would provide little benefit in claudicating limbs. A 7-mm aortofemoral graft having a length of 20 cm would be capable of carrying flows of 3000 mL/min with a pressure drop of only 4.5 mmHg. Due to additional inertial losses, the actual experimental values are considerably

Table 5-1.

Minimal Pressure Gradient Across Grafts,

mmHga Flow, mL/min Aortofemoral, length = 20 cm Diameter, mm 10 7 6 5

300

500

1500

3000

0.1 0.5 0.8 1.7

0.2 0.7 1.4 2.9

0.5 2.2 4.1 8.6

1.1 4.5 8.3 17.1

Flow, mL/min Femoropopliteal, length = 40 cm Diameter, mm

50

150

300

500

6 5 4 3

0.3 0.6 1.4 4.4

0.8 1.7 4.2 13.2

1.7 3.4 8.4 26.4

2.8 5.7 13.9 44.0

Flow, mL/min Femorotibial, length = 80 cm Diameter, mmb 6– 4 5– 3 4– 2 a b

50

100

150

200

1.3 3.5 13.0

2.6 6.9 26.0

3.9 10.4 39.0

5.2 13.8 52.0

Based on Eq. 5-7, h ¼ 0:035 P. Evenly tapered grafts, largest diameter to smallest.

higher, about 7–20 mmHg at flows of 1200 mL/min.[80,81] Nonetheless, grafts of this size should suffice in most circumstances. A 5 mm graft, however, would develop a rather large gradient during exercise and could restrict flow. Long grafts (80 cm) from the femoral to the tibial regions are ordinarily employed for the treatment of ischemic symptoms. Resting flow rates are not high, and pressure drops of 10 mmHg or more may be acceptable. Still, long segments of such grafts with small diameters (, 3 mm) are inefficient blood conduits. After implantation, prosthetic grafts develop a pseudointima. A thin (0.5 mm) fibrinous layer applied circumferentially to the interior of the graft would reduce the diameter by 1 mm, a reduction that could be of hemodynamic significance if a graft of borderline dimensions had been chosen. On the other hand, if the diameter of the graft is too large, clots tend to form on the inner walls as the flow stream tries to mold itself to the diameter of the recipient vessel. As in the case of aneurysms, this lining has little tensile strength, is loosely attached, and may embolize, causing the graft to fail. A highflow velocity is conducive to the formation of a thin, tightly adherent pseudointima. Because mean flow velocities are directly related to the flow rate and inversely related to the square of the radius, the velocity in a 7 mm graft would be 1.3 times that in an 8 mm graft and 2.0 times that in a 10 mm graft (Eq. 5-6). To reduce inertial losses, it is important to make the transition from graft to host vessel as smooth as possible. End-to-end anastomoses, therefore, cause the least flow

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disturbances.[3] End-to-side anastomoses are usually tailored to enter the recipient artery or leave the donor artery at an acute angle. While this diminishes flow disturbances at the entrance to the graft and in the antegrade recipient limb, it accentuates disturbances in the retrograde recipient limb, where the flow vectors are almost completely reversed. No matter what construction is used, there will always be regions of flow separation that contribute to energy losses and, more importantly, to the development of initial thickening or thrombus formation (Fig. 5-20).[82,83] Thus, grafts of all sorts always introduce new hemodynamic problems while they decrease others.

Vasodilators and Sympathectomy Vasodilators and sympathectomy have little effect on collateral arteries and, therefore, can do little to reduce an elevated segmental resistance. Their function is to dilate the peripheral arterioles, principally in the skin of the more distal parts of the extremity. Since these arterioles are already maximally dilated in ischemic tissues, administration of vasodilators does not enhance blood flow to the critical areas. By dilating arterioles in nonischemic tissues distal to a proximal arterial obstruction, these drugs may actually cause a steal, which, at least theoretically, could be detrimental. Sympathectomy has the advantage of exerting its effect in a more limited area, thus minimizing the likelihood of a steal. Some surgeons feel that sympathectomy hastens demarcation of ischemic tissues, encourages healing of minor skin lesions, and decreases rest pain. The evidence, however, that sympathectomy has a beneficial effect is scant.[84 – 87] In patients with claudication, sympathectomy and vasodilator drugs do increase blood flow at rest in the nonischemic peripheral tissues. Since resting blood flow is already adequate in these limbs, the only potentially beneficial effect would be to increase the rate of flow through an arterial reconstruction, reducing the chance of thrombosis in the early postoperative period. Exercise itself is the most powerful dilator of intramuscular arterioles.[36,85,88,89] Because further dilatation is not possible, these measures are not helpful in the treatment of intermittent claudication (Fig. 5-21).[85,90,91]

Reducing Viscosity Blood with a hematocrit of 50% is about twice as viscous as that with a hematocrit of 30%; consequently, it is possible to augment blood flow somewhat by hemodilution.[92 – 94] Lowmolecular-weight dextran, which expands blood volume, raises cardiac output, decreases hematocrit, and reduces erythrocyte aggregation, has been used for this purpose. The effects, however, are unpredictable, difficult to control, and do not offer a long-term solution to the problems associated with chronic arterial obstructive disease. Pentoxifylline, a drug that increases erythrocyte flexibility and decreases plasma fibrinogen and platelet aggregation, has been shown to increase walking tolerance in claudicants, but again the results are variable.[95]

Figure 5-20. Flow patterns at end-to-side and side-to-end anastomoses. Note that blood may reverse and travel circumferentially to reach the recipient conduit. Areas where the mainstream flow is separated from that at the wall are prone to neointimal hyperplasia. (Based on studies by LoGerfo, F.W. et al.[82] and Crawshaw, H.M. et al.[83] With permission.)

Collateral Dilatation Collateral development can be stimulated by exercise therapy, thus reducing segmental resistance. Not only are walking times increased appreciably when the patient adheres to an exercise program, but there may also be some improvement in the postexercise ankle pressure response.[75,94 – 98] Most of the beneficial effects, however, are probably metabolic and not hemodynamic in origin. But this mode of therapy is not applicable to patients with rest pain, and the beneficial effects are variable and are lost when the program is discontinued.

ARTERIOVENOUS FISTULAS The components of a typical vascular circuit containing an arteriovenous fistula are illustrated in Fig. 5-22. With appropriate modifications, all arteriovenous fistulas, regardless of their complexity, conform to this basic model. Collateral arteries connect the proximal and distal arteries,

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Figure 5-21. Contrasting effects of sympathectomy and bypass grafting on blood flow during exercise. Peripheral resistance (represented by the faucet) is maximally decreased during exercise, and sympathectomy cannot further reduce resistance. Grafts, bypassing the obstruction, reduce segmental resistance and permit increased blood flow even when there is less peripheral vasodilation. [From Sumner, D.S.: Pathophysiology of arterial occlusive disease. In Hershey, F.B., Barnes, R.W., Sumner, D.S. (eds): Noninvasive Diagnosis of Vascular Disease. Pasadena, California, Appleton Davies, 1984, pp. 2 – 15. With permission.]

bypassing the abnormal communication. Similarly, on the venous side, collaterals connect the proximal and distal veins. The critical component of the circuit is the fistula itself, which can be classified as “large” or “small,” depending on its resistance relative to that of the contributing vessels. Fistulas with a narrow diameter or those that are quite long (e.g., a graft between the radial artery and brachial vein) have a high resistance, whereas those with a diameter approaching or exceeding that of the donor artery have a low resistance.[3,99] Blood always traverses the fistula from its arterial to its venous end, the rate of flow being determined by the resistance of the fistula and the arteriovenous pressure gradient (Fig. 5-22). Although flow is always directed distally in the proximal artery and proximally in the proximal vein, flow direction varies in the distal artery and vein, depending on the relative resistance of the components of the circuit.[3,99 – 102] When the fistula is “small,” a portion of the blood from the proximal artery continues past the fistula, flowing in the normal distal direction in the distal artery, where it joins the collateral inflow to supply the peripheral vascular bed. When the fistula is “large,” part of the collateral inflow is diverted into the distal artery, flowing retrograde up the artery to enter the fistula. In this event, the peripheral tissues are nourished only by input from the collateral arteries.

Figure 5-22. Diagram of typical H-type or side-to-side arteriovenous fistula.

In other words, the fistula “steals” blood from the peripheral vascular bed. The situation is duplicated on the venous side. Normal flow direction persists in the distal vein when the fistula is small, but the volume of flow is reduced.[99] When the fistula is large, there may be no reverse flow in the distal vein if the communication is acute and the valves remain competent. When, however, the fistula is chronic, the distal veins tend to expand, the valves become incompetent, and blood flows retrograde in the distal veins, returning to the central veins via collateral channels.[103,104] Peripheral arterial pressures (point 3 in Fig. 5-22) are always reduced in the presence of an arteriovenous communication, the extent of the pressure reduction increasing as the resistance of the fistula decreases.[3,99,105,106] When flow is reversed in the distal artery, the peripheral pressure (point 3) exceeds the pressure at the arterial end of the fistula (point 2).[100] Peripheral venous pressures (point 4) are always elevated, especially when there is reversed flow in the distal veins. The pressure at the venous end of the fistula (point 5) exceeds that at the periphery (point 4) when venous flow is retrograde; otherwise, the normal gradient is maintained.[100,105 – 107] In summary, all fistulas, regardless of size, tend to impair peripheral perfusion, decrease peripheral arterial pressure, and elevate peripheral venous pressure. Steals associated with “large” fistulas can seriously compromise blood flow to the distal tissues, producing ischemia and venous congestion.

Therapy Surgical obliteration of the abnormal communication restores normal hemodynamics and is the optimum form

Chapter 5.

of treatment. Ligation of the proximal artery, a procedure sometimes attempted in the past, is the worst approach.[3] This operation ensures that all flow through the fistula will be derived from the collateral arteries; thus an increasing proportion of the collateral input is diverted into the distal artery, further depriving the peripheral tissues of nutrition. On the other hand, quadruple ligation (ligation of all proximal and distal arteries and veins) may be an acceptable compromise. Although this procedure blocks the major inflow arteries and the major outflow veins, it eliminates the devastating effects of the steal. If the fistula is chronic, the collateral arteries and veins are usually well developed and are capable of sustaining peripheral perfusion. In fact, quadruple ligation usually increases peripheral arterial pressure and reduces peripheral venous pressure.[3] These parameters, however, seldom return to normal levels, unless the collateral supply is truly excellent (as it may be when the ulnar artery represents the collateral supply for a radial artery – cephalic vein fistula). When a significant steal accompanies a side-to-side arteriovenous fistula constructed for vascular access, relief can often be obtained by ligating the distal artery, provided the collateral arteries are well developed.[108] This operation maintains adequate flow through the fistula and ensures that the collateral input will be totally devoted to peripheral perfusion.

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shown that expansion of the coronary arterial wall may partially compensate for a reduction in the radius of the lumen produced by arteriosclerotic plaques.[112] Low shear rates, on the other hand, promote the development of atherosclerotic plaques and fibromuscular dysplasia.[113] This may explain the tendency for atherosclerotic plaques to develop in the carotid bulb, where expansion of the lumen results in flow separation, flow reversal, decreased velocity, and a low wall shear rate.[114] Similar flow disturbances leading to a reduction in shear rate occur in the vicinity of atherosclerotic plaques and at arterial graft anastomoses, again predisposing to dysplastic wall thickening.[82,83,115,116]

ANEURYSMS The circumferential stress t developed within an arterial wall is directly proportional to the transmural pressure P.[3,4] Transmural pressure is the difference between the blood pressure within the artery and the surrounding tissue pressure. Wall stress is also directly related to the inside radius ri of the artery and is inversely proportional to its wall thickness d:

t¼P

ri d

This explains why large aneurysms are more apt to rupture than small ones and why the risk of rupture is increased in hypertensive patients (Fig. 5-23). Rupture is more likely to

EFFECT OF SHEAR ON THE ARTERIAL WALL When flow is laminar, the velocity profile in a cylindrical vessel is parabolic, being maximal at the center and decreasing to zero at the wall. The ratio of the incremental decrease in velocity (2 dv ) to the incremental increase in radius (dr ), as measured from the center of the flow stream, is known as the shear rate (D ): D¼2

dv dr

ð5-14Þ

Shear stress (t ), which represents the force required to overcome the friction between contiguous layers of fluid, is the product of shear rate and viscosity (h ). At the arterial wall, shear rate (I )w) and shear stress (tw) are given by Dw ¼

4
v ri

ð5-15Þ

tw ¼

4hv
ri

ð5-16Þ

where v¯ represents the mean velocity across the flow stream and ri is the radius of the arterial lumen. Endothelium is capable of sensing shear. When shear is increased by an increasing velocity or by a decreasing radius, nitric oxide is released from the endothelium, promoting relaxation of the arterial wall.[109,110] This results in an increased radius, which tends to normalize shear. Thus, arteries proximal to an arteriovenous fistula dilate to compensate for an increased flow rate.[111] It has also been

Figure 5-23. Effect of increasing arterial diameter on tangential stress t. Original diameter (2.0 cm) and wall thickness (0.2 cm) correspond to that of a terminal aorta. Solid line assumes that cross-sectional area of the wall remains constant as the artery expands (wall thickness decreases). Broken line assumes constant wall thickness. Aneurysmal rupture occurs when stress exceeds tensile strength.

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occur when the wall is thin. Although most aneurysms have thicker walls than normal arteries, the collagen content, which is primarily responsible for tensile strength, may be diminished[117] or degraded.[118] In other words, the functional thickness of an aneurysmal wall may be less than that of a normal artery. According to recently reported computer simulations, the thick layer of clot that develops in most aneurysms may reduce wall stress by as much as 50% and provide some protection against rupture.[119 – 121] While collagen degradation weakens the aneurysm wall and is responsible for rupture, expansion is most likely a function of decreased elastin content.[117,118,122]

CONCLUSION A basic knowledge of hemodynamic principles is necessary to understand the adverse effects that obstructive arterial disease has on the circulation to the multiple organs of the body. Although the factors governing pressure-flow relationships, velocity profiles, blood flow patterns, arterial wall properties, and metabolic interactions are exceedingly complicated and remain a fertile area for investigation, one can work with the knowledge currently on hand to enhance diagnostic accuracy and therapeutic capabilities.

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CHAPTER 6

Clinical Examination of the Vascular System Joshua A. Beckman Mark A. Creager than those supplying the upper extremities. Approximately 9% of the population over the age of 55 have evidence of peripheral arterial disease as assessed by noninvasive testing, but only 2.5% of them are symptomatic.[1,2] The subclinical presence of atherosclerosis is important to discern for it conveys information about the probability of co-existing coronary artery disease and prognostic information about the patient’s survival. There are two cardinal symptoms: claudication and rest pain. The word claudication derives from the Latin and French, claudicatio and claudico, respectively, and was commonly used to describe a lame horse. Claudication is exertion-induced discomfort described as pain in the extremity that is exacerbated with further exercise and relieved with rest. As such, it occurs intermittently, hence the term intermittent claudication. The discomfort is commonly described as a cramping, burning, aching, or fatigue. Both lower and upper extremities may develop these symptoms. The discomfort recurs in the same area with each provocation. Typically, specific activities like walking or brushing one’s hair will cause discomfort at the same level of exertion each time in the legs and arms, respectively. The location of discomfort is a clue to the site of greatest stenosis. Symptoms generally occur in the most proximal muscle area with inadequate perfusion. Thus, severe iliac stenoses often will cause discomfort in the buttock or thigh, while superficial femoral and infrapopliteal arterial disease cause calf and pedal symptoms, respectively. Symptoms may develop in more than one area, like the thigh and calf, depending on the location and severity of the stenoses. Patients with chronic occlusive disease may occasionally be unaware of a specific limitation or progression in their symptoms. Subconsciously, patients may accommodate their lifestyle to the limitations imposed by the limited blood flow. Specific questioning about the discomfort should exact a reliable amount of exercise required. Certain activities can act as benchmarks to follow disease progression. Examples include flights of stairs climbed or blocks walked prior to onset of pain. Each of these may be compromised, however, by a slowing of pace. Thus, while questioning the patient

INTRODUCTION Vascular diseases comprise disorders of the arteries, veins, and lymphatics. This chapter will review the salient features of the history and physical examination of common circulatory diseases such as peripheral arterial disease, chronic venous insufficiency, and lymphedema. Complete examination of the patient with vascular disease requires an appreciation of the whole patient with focus on specific findings. As will be apparent later in the chapter, multi-system diseases can easily be missed with a limited perspective. Adequate synthesis of signs and symptoms necessitates generating a broad differential diagnosis. The confines of this chapter preclude a full discussion of the comprehensive history and physical exam, but accurate diagnosis and treatment depend on it.

ARTERIAL DISEASES Arterial disease can be classified as occlusive or aneurysmal. Arterial occlusive disease can be caused by atherosclerosis, inflammation (vasculitis), external compression (e.g., popliteal artery entrapment), or thrombo-embolism. There may be similarities among the complaints upon presentation, but each has specific historical and clinical features that enable the examiner to focus in on the correct diagnosis. The arterial vascular examination should be performed consistently with special examinations performed as dictated by the history. This chapter will describe the historical features of the disease processes and then the physical exam to match the physicianpatient encounter.

Peripheral Arterial Disease Peripheral arterial disease (PAD) is a term generally applied to atherosclerosis of the limb vasculature. The arteries supplying the lower extremities are affected more frequently

Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024889 Copyright q 2004 by Marcel Dekker, Inc.

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about the activities that provoke discomfort, the physician should try to formulate an understanding about the patient’s activity level in general and whether it is changing. Relief from discomfort with a discrete period of rest is a hallmark of claudication. Just as the pain should develop with a predictable amount of exertion, relief should require a consistent period on each occasion. Whether that relief comes with sitting, standing, or reclining, the patient will be able to quantify it. Pain that is relieved immediately upon cessation of activity is not claudication and not related to inadequate perfusion. Pain that results from specific positional changes, occurs while lying, or can be relieved by activity is not a consequence of peripheral arterial disease and may be neuropathic or musculoskeletal in origin. Age of onset and disease progression can also provide clues to the cause of the arterial occlusive disease. The presence of arterial occlusive disease in younger patients should prompt examination for etiologies that can exacerbate the development and progression of atherosclerosis like hyperhomocysteinemia and familial hypercholesterolemia and for other causes like vasculitis or arterial entrapment. Atherosclerosis is usually a disease of slow progression. The time course for disease evolution is over years. The initial symptoms generally occur during periods of extreme exertion and may remain undiagnosed. As the disease progresses, the process of plaque rupture and thrombosis may lead to periods of waxing and waning symptom progression. Disease processes that proceed more rapidly may indicate the presence of exacerbating factors like diabetes mellitus. A thorough history that acquires a complete set symptoms is usually the most sensitive means to diagnose a condition. Several questionnaires have been devised and evaluated for the diagnosis of claudication. The Rose questionnaire was the first device created to assess claudication.[3] Its low diagnostic sensitivity has decreased its use. These devices provide a written standard to accompany exercise testing for changes in the disease. The Walking Impairment Questionnaire evaluates both the extent of walking impairment and its etiology. Six questions characterize the patient’s difficulty in walking a defined distance and four the walking speed. Specific symptoms are also evaluated to infer the source of walking limitation including aching in the calf or thigh (claudication), joint pain or stiffness (arthritis), leg weakness (neurologic), and chest discomfort and shortness of breath (cardiovascular). The disease-specific Walking Impairment questionnaire has been validated and can be used to assess baseline functioning and changes after therapy.[4] The San Diego questionnaire is another valid assessment device.[5] Rest pain occurs when the perfusion pressure during inactivity is inadequate to meet basal requirements. The lack of blood flow may affect all of the structures of the extremity including cutaneous, muscular, nervous, and bony. The pain affects the most acral part of the limb, usually the toes or foot. The most severe pain occurs at the site of tissue breakdown. Other complaints include sensitivity to cold, weakness, joint stiffness, and hypesthesia. When perfusion pressure drops low enough to cause rest pain, gravity plays an important role in blood supply. Patients will report more pain at night when the leg is elevated and mitigation of pain with leg dependency, as occurs when dangling from the bed.

Vasculitis Inflammation of the blood vessel wall can cause the development of stenotic lesions, aneurysmal dilation, and constitutional symptoms. Important clinical entities that affect large and medium sized arteries include Takayasu’s arteritis, giant cell (temporal) arteritis, and Buerger’s disease (thromboangiitis obliterans). Takayasu’s arteritis (TA), also known as pulseless disease, was first described by and named for a Japanese ophthalmologist. At one time thought to be a disease primarily of the East Asian rim, TA has been described worldwide. This large vessel vasculitis affects elastic arteries, specifically the aorta and its branches. Women are more commonly affected than men. This is a disease of younger adults. The most common age of onset is the third to fifth decades of life, although it has been diagnosed beyond this range. Early in the course of the disease, patients may report nonspecific constitutional symptoms like fever, weight loss, malaise, arthralgias, and myalgias. These may last months and occasionally years. The continuing arterial inflammation causes progressive stenosis yielding upper more commonly than lower extremity claudication, strokes, renal artery stenosis, and myocardial infarction. The ostial portion of the coronary and renal arteries, as an extension of aortic disease, is the most likely affected area. Any secondary or tertiary branch from the aorta may develop a stenotic or aneurysmal lesion. The presentation of upper extremity symptoms out of proportion to lower extremity complaints should prompt an investigation into large vessel vasculitis. Giant cell (temporal) arteritis (GCA) is another elastic artery vasculitis that tends to involve the secondary and tertiary branches of the thoracic aorta, but may present with abdominal aortic disease. GCA is a disease of the elderly. The incidence climbs from 1.5 per 100,000 age 50 –59 years to nearly 30 per 100,000 age 70–79 years.[6] Women are more likely to be affected than men. Up to 15% of patients with GCA may have their most significant stenosis or aneurysm in the aorta, arch vessels, coronary arteries, or even lower extremities. Presenting complaints may include arm or leg claudication. More commonly patients report visual changes like amaurosis fugax, headaches, and jaw claudication. However, it is not unusual that the primary complaints concern constitutional changes like fever and malaise. About half of patients will have symptoms of polymyalgia rheumatica, including proximal muscle stiffness and pain on active motion. In contrast to the two previous vasculitides, thromboangiitis obliterans (Buerger’s disease) is a bland inflammation of the extremities that occurs in the distal, small to medium arteries. Larger vessel involvement has been reported, but occurs rarely in the absence of small vessel disease. Symptoms of ischemia are the most common complaint. Patients describe hand or foot claudication. As the disease progresses, claudication may develop proximally and finger or toe ulceration may occur. Patients may complain of cold sensitivity, painful red nodules (i.e., superficial phlebitis), or report symptoms compatible with Raynaud’s phenomenon. The typical patient is a young male heavy smoker.

Chapter 6.

Acute Arterial Occlusion Sudden occlusion of an artery of the lower extremity may result from local thrombus formation or from an embolism originating at a more proximal site. Plaque rupture and its resultant thrombosis may occlude an atherosclerotic vessel. In patients with hypercoagulable states, thrombus formation may occlude an otherwise normal artery. Aortic dissection may occlude the vessels of the lower extremities because of the intimal flap from aortic dissection or propagation of the dissection into the limb. Trauma may damage the vessel directly and incite thrombosis in situ or cause a hematoma or compartment syndrome and occlude the vessel from external compression. The heart may be the source of emboli from dysrhythmias like atrial fibrillation, valvular abnormalities like mitral stenosis or prosthetic valves, and structural abnormalities like atrial myxoma. Patients with congestive heart failure are at greater risk for left ventricular thrombus which may embolize. Patients with lower extremity bypass grafts may develop graft occlusion at anastomotic sites and within the conduit. The usual time course for symptom development and progression in a patient with an acute arterial occlusion is hours. Sudden and dramatic decreases in perfusion cause symptoms that are related to ischemia of skin, musculature, and nerves. The range in clinical outcome, however, remains broad. New thrombosis may cause the asymptomatic loss of a pulse, a decreased threshold for claudication, or the sudden onset of severe pain at rest. The pain does not change locations, however, certain patients may present several days after the signal event with symptomatic progression and exacerbation caused by thrombus propagation. The decrease in blood flow can impair nerve function creating paresthesias and then numbness. In addition, paralysis may develop. The severity of the blood flow decrement dictates the symptoms appreciated. Sudden but moderate changes may not cause rest pain acutely but only decrease the exercise required for claudication. Severe changes may be associated with a sudden loss of limb strength and induce a fall. The presence of nervous complaints like paresthesias and muscular symptoms, like weakness or paralysis, indicate a greater severity of disease. The symptomatology of the presentation does not necessarily discriminate among etiologies.

Atheroembolism Atheroembolism arises from the atherosclerotic plaques of the aorta and its branches and is derived from the components of the plaques. These atheromatous emboli, variably composed of cholesterol crystals and fibrin and platelets, may occlude arteries and arterioles, often lodging in distal arteries, such as the plantar arch and digital arteries. The most common causes of atheroemboli are catheterization, aortic manipulation in surgery, and idiopathic. Nearly half of the presentations for atheroemboli have an unknown cause. Warfarin anticoagulation has been posited to cause atheroembolism at the case report level, but not proved. Thrombolytic agents do not necessarily increase the incidence of cholesterol embolization.[7] Patients will present with painful blue-violet spots on their toes (blue toe syndrome) and pain in their calves

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representing focal areas of ischemia. Depending on the site of origin, distal or proximal to the bifurcation of the aorta, symptoms may develop on one side or bilaterally, respectively. The symptoms are usually sudden in onset, may recur, and are slow to heal. The skin around the affected area may feel cool and demonstrate livedo reticularis.

Miscellaneous Thoracic Outlet Syndrome The patient that presents with upper extremity complaints reminiscent of claudication or vascular insufficiency, but reports that it is positional, may have thoracic outlet syndrome. In this syndrome, the axillo-subclavian artery is compressed, usually by a cervical rib, abnormal insertion of the scalene anticus muscle, or apposition of the clavicle and first rib during arm lifting, arm extension, or head turning. Patients may complain of weakness, fatigue, or heaviness with activities performed above the shoulder. Common complaints include difficulty with hair washing or brushing and cleaning high places. This complex of symptoms may be mimicked by nerve compression instead of diminished arterial flow. The physical exam can discern between these two processes. Repetitive stress on the artery may damage the intimal lining of the artery and lead to aneurysm formation and its sequelae.

Popliteal Artery Entrapment Intermittent claudication is unusual among patients under the age of 50. One cause among this population is popliteal artery entrapment. The artery may be displaced or compressed by the medial head of the gastrocnemius muscle. The popliteal artery usually courses along the popliteal veins in between the medial and lateral heads of the gastrocnemius vein. Less common sources of entrapment include fibrous bands or the popliteus muscle. In addition to intermittent claudication, patients may complain about tingling and pain at rest, depending on the severity of compression.

Reflex Sympathetic Dystrophy Reflex sympathetic dystrophy (RSD), or causalgia, is a progressive painful disorder that usually stems from an injury to the soft tissue or neural tissue of an extremity, although there are nontraumatic etiologies, including malignancy and myocardial infarction. After the precipitant, the patient develops complaints consistent with autonomic nervous dysfunction including color changes, alterations in limb temperature, and edema. Three stages have been described in the disease. Each stage may last from weeks to years, but 3 –6 months is the common duration of each stage. Initially, in the acute or hyperemic stage, the area of injury is warm, erythematous, and swollen. In the second or dystrophic (ischemic) stage, the skin may be cool, pale or cyanotic, and clammy. The nails may develop ridges and become brittle while the hair on the extremities coarsens. During the third or atrophic stage, patients may report wasting in the entire extremity including the muscles, skin, and subcutaneous tissues. Attendant to this wasting is marked weakness, a cold sensation, and limited

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motion of the joints. The changes may become permanent during this stage. Pain is commonly the most prominent and enduring element in each stage of RSD. The pain is described as burning that is worse distally, diffuse, and occurs with little or no provocation. It tends to be palmar or plantar, and the subsequent symptoms are usually out of proportion to the severity of the initial injury. Small stimuli such as touch may provoke symptoms. Patients may report either hypersensitivity or diminished sensitivity to touch. Tissue ulceration may occur.

Raynaud’s Phenomenon Episodic vasospasm of the digital arteries in response to cold or emotional stress is the hallmark of Raynaud’s phenomenon. The classic description of the phenomenon includes three phases: digital pallor associated with arterial spasm and ischemia, cyanosis from the deoxygenated blood collecting in the dilated arterioles and venules, and rubor from rewarming and the subsequent hyperemia. Patients may report a sensation of cold or numbness during the first two phases and throbbing with hyperemia. All three phases do not need to be present to confer a diagnosis; some patients develop only pallor and/or cyanosis. Reproduction of the color response is usually difficult to induce in the office, and the diagnosis is usually made on the basis of historical information. These changes occur additionally in the toes in 40% of the patients, and rarely in the nose, earlobes, and tongue. The range of severity is wide from intermittent, mild attacks to the prolonged vasospasm with development of ulceration and gangrene. The primary form of Raynaud’s disease is typically benign with a rate of , 1% of tissue loss. The diagnostic criteria for the idiopathic form include intermittent attacks of ischemic discoloration of the extremities, absence of an arterial occlusion, a bilateral distribution, trophic changes limited to the skin, the absence of any symptoms or signs of a systemic disease that may cause Raynaud’s phenomenon, and the presence of symptoms for more than 2 years. Women comprise 70–80% of patients. The onset of symptoms may occur between menarche and menopause, but typically occurs before the age of 40. The secondary form of the phenomenon should be suspected in patients that present with symptoms that do not occur evenly in all digits, have prolonged vasospasm despite rewarming, or develop tissue loss. The secondary causes of Raynaud’s phenomenon include vasculitides like scleroderma, arterial occlusive disease including atherosclerosis, neurologic disorders, blood dyscrasias, trauma, and drug reaction. The development of symptoms unilaterally or after the age of 45 should prompt an investigation for a primary cause.

review. The patient should be in a comfortable position to avoid muscle tensing. The examiner should use the fingertips of the hand and avoid the thumb. The thumb pulse may be large enough to transmit sensation great enough to cause a misperception of the patient’s pulse. Palpation should begin lightly and increase in pressure gradually. Pulses may be palpated in the neck, arms, legs, and trunk. Subtle changes in pulse contour may be defined by comparing each pulse bilaterally. In the neck, the carotid pulse may be palpated between the trachea and the sternocleidomastoid muscles. It may be examined from the base of the neck to the angle of the jaw. In addition to impulse strength, pulse contour can impart information concerning proximal stenosis, valvular heart disease, and ventricular abnormalities. Palpation should be performed lightly at first, especially in older patients, for the carotid body may be sensitive and promote bradycardia and hypotension. The subclavian pulse may be palpated in two locations: in the supraclavicular fossa and between the lateral clavicle and pectoralis muscle. Upper extremity pulses typically examined include the brachial, radial, and ulnar pulses. The brachial pulse is found in the medial third of the antecubital fossa. The pulse is superficial and requires only a mild pressure. It may be traced back along the inferior border of the biceps muscle. The radial pulse is palpated in the wrist at the base of the first digit (Fig. 6-1). It is a superficial, usually brisk pulse and easy to appreciate. The ulnar pulse, in contrast, courses deeper and may be obscured by muscle. It requires deeper palpation and may be difficult to detect. Detection of both pulses in the wrist may be improved by supporting the subject’s hand to relax the muscles in the wrist with one hand while palpating the pulses with the other. Pulses may be examined at three levels in the lower extremities. The common femoral artery pulse can be examined just below or above the inguinal ligament. It lies medial to the quadriceps muscle. Obesity may obscure local landmarks. Lateral rotation of the leg, retraction of the overhanging pannus, and palpation using four fingers across can aid in detection. The common femoral artery can be palpated several centimeters proximal to the inguinal ligament in thin patients. The popliteal artery pulse is more

ARTERIAL PHYSICAL EXAM Pulse Examination of the arteries begins with the pulse examination. The pulse examination should be performed in a consistent manner by the examiner to ensure a complete

Figure 6-1.

Palpation of the radial pulse.

Chapter 6.

difficult to palpate. Generally located between the medial and lateral third of the popliteal fossa, the pulse is commonly obscured by the overlying muscle. The patient’s leg should be mildly flexed and relaxed. The examiner should use four fingers from both hands to palpate in the fossa while applying a moderate counter pressure via the thumbs on the knee cap. The pulse is a transmitted impulse and generally not discrete. The posterior tibial pulse can be found below the medial malleolus (Fig. 6-2). Gentle pressure with three or four fingers from above usually allows adequate palpation. Increased application of pressure may be counterproductive in patients with poor arterial perfusion, for examiners may confuse their own pulse for the patients. Relaxation and dorsiflexion of the foot improve detection. The dorsalis pedis pulse is found on dorsum of the foot between the second and third digital ligaments. It is usually 3–4 cm above the digits. In some cases, it may be found more laterally. Laying the fingers from both hands across the dorsum of the foot can help in the detection of difficult pulses. Because it is absent congenitally in approximately 10% of patients, its absence may not be pathological.[8] Certain clinical conditions require the palpation of additional pulses. The temporal arteries, which extend anteriorly and superiorly from the ear, can be palpated with gentle pressure applied by three fingers. Induration, warmth, erythema, and tenderness of this pulse may indicate temporal arteritis. The occipital arteries may be palpated approximately 2 cm laterally from the midline at the base of the occiput and should be examined for the same abnormalities as the temporal arteries. Coarction of the aorta causes excess blood flow through the costal arteries. Pulses, generally not appreciable, may be palpated at the base of the scapula and subcostally in the upper ribs.

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extrinsic compression, aneurysmal dilation, or arteriovenous connection. The proximal location of a bruit defines the location of turbulent flow, but auscultation of the bruit may propagate for an additional five centimeters. The transmitted sound is reflective of the originating vessel and the severity of the stenosis. Larger vessels like the femoral, carotid (Fig. 6-3), and subclavian arteries will usually transmit lower-pitched bruits in smaller vessels in the abdomen will be higher. As the severity of stenosis progresses, the pitch of bruits increases. Thus, severely stenotic large arteries may convey a high-pitched sound. As a stenosis progresses to near occlusion, the intensity of the bruit may decrease and then disappear. The span of the bruit also carries significance. Continuation into diastole implies an advanced stenosis. Continuous bruits traverse both systole and diastole and are pathognomonic for arterio-venous connections. These may be found in the fistulas of Osler-Weber-Rendu disease and at the sites of percutaneous catheter interventions.

Aneurysms

Auscultation of the normal vessel should reveal no sound. The presence of a bruit, sounds caused by turbulence of blood flow, represent alteration in flow because of arterial stenosis,

The abnormal increase in size of a blood vessel can augment its pulse. Abnormal enlargement is called ectasia, while expansion greater than 150% of a proximal segment is defined as an aneurysm. Most aneuryms of the chest and abdomen are discovered via incidental radiographic imaging. Abdominal aortic aneuryms may be detected on physical examination. Examination of the abdominal aorta requires cooperation of the patient. The examiner should gradually increase pressure in the midline using all eight fingers. Attempts should be made to relax the patient and the abdominal musculature. Both sides of the aneurysm are generally pulsatile. Once the pulse is identified, the lateral borders should be approximated using both hands and the diameter estimated. Detection is directly related to aneurysm size and inversely related to patient abdominal girth. Pulsatile expansion detected below the umbilicus indicates extension into the iliac arteries. Significant discomfort during the exam is unusual and may represent recent expansion, an inflammatory aneurysm, or a

Figure 6-2. Palpation of the posterior tibial pulse with three fingers from above applying mild to moderate pressure with counterpressure from the thumb.

Figure 6-3. Auscultation of bruits should be performed using the bell of the stethoscope to ensure an adequate skin seal and amplify their lower pitch.

Bruit

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contained rupture. A seroma may obscure the pulse on one side. Abdominal ultrasound is usually required to differentiate among the varying causes. The next two most common locations for aneurysms, the femoral and popliteal arteries, are readily palpable. Popliteal aneurysms are commonly bilateral and frequently are associated with abdominal aortic aneurysms. Both of these lesions commonly embolize and may present with claudicatory symptoms or blue toe syndrome. Femoral aneurysms are commonly detected by patients. As the aneurysms grow, they may compress first the adjacent vein to produce edema and then cause neuropathy. The carotid pulse is also readily palpable, allowing for aneurysm detection. Carotid artery tortuosity is a more common cause of an increased pulse than aneurysm, and ultrasound differentiation is usually required.

FURTHER EXAMINATIONS

arterial occlusive disease and allow for quantification of exercise tolerance. As the patient exercises, there is an incremental drop in perfusion pressure and ankle-brachial index across the lesion as energy is lost into the lesion and resistance vessels relax. Patients may be exercised on a treadmill using any standard protocol. Ankle pulse pressure should be obtained in both foot locations prior to exertion. Upon discontinuation of exercise, the patient should immediately lie supine on a stretcher and the ankle pulses palpated and ankle pressures examined by Doppler ultrasound (Fig. 6-4). In patients with peripheral arterial diseases, assessment following exercise cessation should reveal a decreased or near absent pulse and a decrease in anklebrachial index by more than 20%. As the severity of the lesion progresses, the time to return to baseline levels increases. To demonstrate the same phenomenon in the office, the examiner can have the patient stand on his toes repeatedly until symptoms develop and remeasure the distal pulses.

The Allen Test

Examination of the Skin

The circulation of the hand is supplied by the radial and ulnar arteries. These arteries, in most people, form two ends of the palmar arches. Thus adequate hand blood supply can arise from either vessel. Five to 10% of the population has a congenitally incomplete arch. Rheumatologic diseases like the CREST variant of scleroderma, vasculitides like thromboangiitis obliterans, and emboli from subclavian artery aneurysms preferentially affect the distal vessels. The Allen test can demonstrate the presence of an incomplete palmar arch. Occlusive pressure is applied over the radial and ulnar pulses. The patient is asked to open and close the fist several times and create palmar pallor. The examiner then releases one pulse. Normal skin color should return within seconds. The other branch of the arch is then tested in the same manner. Slowly resolving or persistent palmar pallor reveal an incomplete arch or occluded artery distal to the pulse.

Variations in the skin may render clues to the underlying vascular pathology. The patient with chronic occlusive disease may demonstrate absence of hair, thickened toe nails, mild pallor, and cool limbs. Chronic hypoperfusion may result in loss of muscle size and subcutaneous atrophy. Skin temperature is best assessed with the back of the hand. The examiner sequentially places a hand on each arm or leg. Even subtle differences in temperature, as low as 0.58C, may be appreciated. Arterial occlusive disease or embolic phenomena may lead to the formation of ischemic ulcers. The ulcers tend to be small, annular, pale, and desiccated because of inadequate perfusion (Fig. 6-5). They are usually located in the acral areas of the limbs, specifically the toes, heel, and finger tips, but may be found more proximally particularly at sites of trauma. Ischemic ulcers may be as small as 3 mm in diameter.

Leg Elevation Elicited changes in skin color can aid in the determination of perfusion. The patient should lie supine on the examining table. Lower extremity pallor while horizontal is indicative of markedly low perfusion and critical ischemia. If pallor is not evident in the horizontal position, the patient’s leg is elevated to 608 for one minute. Severe occlusive disease is suggested if pallor develops within 15 seconds. At one minute, the leg is lowered and the patient sits up. The pedal veins are examined for refill time. Normal patients have pedal venous refill in less than 15 seconds. Arterial occlusive disease subserved by collateral vessels is suspected if refill requires 30– 45 seconds, while severe disease with poor collateral development is likely present if venous filling time is longer than one minute.

Exercise Testing On occasion, a patient will present with complaints typical of arterial occlusive disease yet have a normal physical examination. Exercise can bring out signs consistent with

Figure 6-4. Systolic pressures may be obtained in either the dorsalis pedis or posterior tibial positions. A blood pressure cuff is inflated to suprasystolic pressure and slowly released. The systolic pressure is considered to be the first appreciable Doppler ultrasound signal.

Chapter 6.

Figure 6-5. Arterial ulcers are small, annular, and pale, usually occurring in the acral region of the lower extremity.

The ulcers show postural changes in hue. Ischemic ulcers are painful in contrast to the painless neurotrophic ulcers of diabetes. Diabetic ulcers, which frequently occur in the setting of lower extremity arterial occlusive disease, occur in the area of callus formation, bony prominence, or areas exposed to trauma such as those caused by ill-fitting shoes. Progression of ulceration leads to tissue necrosis and gangrene. Gangrene represents an area of dead tissue that blackens, mummifies, and sloughs. Prolonged leg dependency for pain amelioration may cause foot and ankle swelling in patients with critical limb ischemia. Skin hue can provide clues to the type and severity of disease. Livedo reticularis is a discoloration of the skin in a lace-like pattern. The “laces” vary from red to blue and surround a central clear area. It is usually found in the extremities, is associated with cool skin, and may be painful. The color changes are augmented by cold exposure. Both primary and secondary forms may occur and may be complicated by ulceration. The benign form is more common in women. The secondary forms may be seen accompanying vasculitis, atheroemboli, hyperviscosity syndromes, endocrine abnormalities, and infections. In the secondary form the lesions are more diffuse. Patients may develop purpuric lesions and cutaneous nodules that progress to ulceration in response to cold. The microcirculation frequently provides clues in the skin for diagnosis. Punctate violaceous lesions, splinter hemorrhages, and focal areas of cyanosis are indicative of microemboli. Lesions may be single or multiple, involve single or multiple territories, and may be associated with new onset unilateral Raynaud’s phenomenon. The lesions are usually approximately 1 mm in diameter and painful. Microcirculatory infarcts may lead to digital pitting. Whether the cause is persistent vasospasm in Raynaud’s disease or microemboli, the microinfarcts present as punctate areas of skin loss that resemble pits in the skin of the distal digit.

Thoracic Outlet Maneuvers The thoracic outlet is the site of possible interruption of any component of the neurovascular bundle as they exit

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the chest to each arm. Paresthesias and numbness of the arm in the absence of edema or a diminished pulse point to a neuropathic origin, and electromyographic testing may be necessary for diagnosis. Compression of the subclavian artery may be detected by several bedside maneuvers. Palpation of the supraclavicular fossa or neck may reveal the presence of a seventh cervical rib. To demonstrate the positional interruption of arterial flow, the examiner should hold the radial pulse in one hand and maneuver the arm with the other. The subclavian artery should be auscultated in the supraclavicular fossa. The presence of thoracic outlet syndrome is suspected by the development of a subclavian bruit and loss of the radial pulse during these maneuvers. The right and left sides should be examined in sequence. The hyperabduction maneuver calls for the arm to be raised above the head without rotation of the shoulder while the patient is seated and looking forward (Fig. 6-6). The Adson maneuver has the patient maneuver the neck. While seated with hands in the lap, the patient is asked to rotate the head toward the symptomatic side and extend the neck, thus looking up and over the shoulder, and simultaneously to perform exaggerated respiration. For the costoclavicular maneuvers, the patient both actively and passively thrusts his shoulders back and inferiorly. The maneuvers may be combined in the evaluation of specific symptoms. However, general application of these examinations are not warranted for they may be positive in up to 50% of the population and therefore carry significance only in symptomatic patients.

THE VENOUS SYSTEM In contrast to the stark signs and symptoms of arterial insufficiency, venous disease is more passive and demonstrates fewer signs. The complaints are less common, and the physical exam is more subtle. Objective testing is commonly required for diagnosis.

Figure 6-6. The hyperabduction maneuver is considered positive if, during arm raise, either a new bruit is appreciated in the subclavian fossa or the radial pulse disappears.

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History Varicose Veins Varicose veins are dilated and tortuous segments of superficial veins. They occur in up to 20% of the population. The inciting event may be an incompetent venous valve, structural abnormality of the venous wall, or elevated intraluminal venous pressures. Varicose veins may be primary or secondary. The primary form is more common in women, and approximately half of the patients will report a family history. The presence of a genetic component implies an inherited abnormality of the venous wall. Varicose vein development is incremental. An initial dilation may cause valvular incompetence, thus increasing intraluminal pressure. The superficial venous ectasia progresses as valvular incompetence increases the orthostatic pressure exerted on the distal valves. Secondary varicose veins occur as a result of deep vein thrombosis or insufficiency in concert with perforator vein incompetence. Initially competent collateral channels, the superficial veins are subjected to increased flow and pressure and progressively dilate. The dilation causes insufficiency, increased intraluminal pressures, and yields varicose veins. Obesity, pregnancy, and prolonged standing exacerbate both primary and secondary forms of the disease. Common complaints include pruritus, burning, and aching. Relief can usually obtained with leg elevation. Women may report premenstrual exacerbation of symptoms. The greater saphenous veins are involved in about 80% of patients. Sequelae include dermatitis, ulceration, superficial phlebitis, and rupture with hemorrhage. The hemorrhage may be dangerous for it is usually painless, although it is rarely fatal. Superficial thrombophlebitis is not uncommon in these vessels. The poor cosmetic appearance provokes most office visits.

Chronic Venous Insufficiency The presence of persistent venous thrombosis or valvular insufficiency results in the development of chronic edema and characterizes chronic venous insufficiency. The most common cause of chronic venous insufficiency is deep vein thrombosis, although a primary abnormality of the venous valves may also cause the syndrome. Approximately 30% of all patients with deep vein thrombosis have symptoms, signs, or laboratory evidence of venous insufficiency within 5 years.[9] The inciting deep vein thrombosis may be asymptomatic, thus making a definitive diagnosis difficult. Increased proximal pressure in the venous system results in chronic hypertension, edema, and hyperpigmentation from hemosiderin deposition in the skin. The deposition of hemosiderin arises from red blood cell lysis and is preferentially deposited around the malleloli and pretibial regions. Swelling of the extremity is the most common complaint. Patients will report that the edema nadirs in the morning after a night of elevation and progresses with time spent upright with the extremity in a dependent position. Muscular contraction can exacerbate venous hypertension by augment-

ing venous reflux. Walking may cause a reproducible deep pressure or bursting sensation in the calf that is relieved with rest. Venous insufficiency related to valvular incompetence may cause burning, itching, eczema, or pain. Superficial varicosities in the medial aspect of the calf and ankle may develop as perforator veins become incompetent. The persistent presence of edema decreases perfusion pressure to the skin and may result in ulceration, typically at the level of the malleolus.

Thrombosis Superficial Vein Thrombosis Superficial vein thrombosis may present with a warm, erythematous, tender streak or cord that courses along the path of a superficial vein. The symptoms are a result of the local inflammation associated with the venous thrombosis (i.e., phlebitis). In contrast to the secondary signs of infection present in lymphangitis, such as including fever, chill, and regional lymphadenopathy, local complaints predominate in phlebitis. Superficial vein thrombosis often complicates venous varicosities. The most common cause of superficial thrombophlebitis is iatrogenic, specifically indwelling catheters. Several syndromes are associated with recurrent or migrating superficial thrombophlebitis. Trousseau’s syndrome or migratory superficial phlebitis is seen in pancreatic cancer. Venulitis is common to two rheumatologic diseases, Bechet’s and Buerger’s disease (thromboangiitis obliterans). The latter commonly presents as an annular lesion, instead of as an erythematous streak.

Deep Vein Thrombosis Lower extremity deep vein thrombosis (DVT) may be asymptomatic. The most common complaints include swelling, pain, pressure, or fullness in the affected extremity, although each and all of these may be absent. Patients may complain of pain with walking, specifically with pressure on the ball of the foot. Leg elevation ameliorates the symptoms. Most lower extremity deep vein thromboses are secondary and occur in the setting of immobilization, malignancy, or trauma. The most common cause of primary deep vein thrombosis is the resistance to breakdown of factor Va by activated protein C. This point mutation in the factor V Leiden is found in 30–40% of patients with primary deep vein thrombosis. Other causes include endogenous factor deficiencies like protein C or S, anticardiolipin antibody syndrome, and hyperhomocysteinemia. Other diagnoses whose presentation may be similar to deep vein thrombosis include ruptured Baker’s cyst, hematoma, muscle tear, or cellulitis. One variant of deep vein thrombosis that always manifests symptoms is phlegmasia. In phlegmasia cerulea dolens and phlegmasia cerulea alba, the great extent of thrombosis and its attendant inflammation cause enough edema and an increase in compartmental pressure in the leg to impair blood flow. A leg with phlegmasia cerulea dolens is cyanotic, painful, markedly swollen, and tender. Phlegmasia cerulea alba is further along the spectrum. Arterial inflow is severely limited and the leg is pallid from

Chapter 6.

ischemia. This condition is not uncommonly confused with acute arterial occlusion, but may be differentiated by the physical exam. Effort-induced axillo-subclavian thrombosis, the PagetSchroetter syndrome, presents in a different population than classic lower extremity DVTs. The patient is usually young, athletic, and muscular. These patients complain of activityinduced swelling, heaviness, and early fatigue in the affected arm. The thrombosis is associated with repeated upper extremity physical exertion and presents with recurrent complaints of repeated swelling with effort. As venous collaterals develop, the extent of edema with activity will diminish, but the feelings of early fatigue and arm heaviness do not. The syndrome results from compression of the axillosubclavian vein, usually from a scalene tendon or a bony hyperostosis.

PHYSICAL EXAM Varicose Veins Superficial varicosities appear as dilated, tortuous, superficial veins. In some cases, multiple venous varicosities may feel and appear like a cluster of grapes. Dependent position increases their size with blood reflux. Once filled, the veins may demonstrate a fluid wave with balloting. “Spider veins” or venous telangiectasias are commonly confused for superficial venous varicose veins. The spider veins are small, cutaneous veins that manifest in a caput medusa pattern. Also known as spider hemangiomas, they may occur individually or in clusters.

Venous Insufficiency Superficial venous varicosities may result from superficial venous incompetence or from deep venous thrombosis or insufficiency. The examiner can distinguish superficial from deep/perforator venous incompetence at the bedside using the Brodie-Trendelenburg test. With the patient supine, the leg is elevated and a tourniquet applied after the veins have drained. Upon standing, veins below the tourniquet will fill slowly. Venous refill in less than half a minute is evidence of an incompetent deep and perforator system. If refill is slower, the superficial system should be examined after tourniquet release. Rapid retrograde superficial venous filling indicates superficial venous incompetence. The Perthes test can evaluate the cause of deep vein incompetence. A tourniquet is applied at mid-thigh or the proximal calf. The patient then walks. If the varicosities become visible, perforator and deep vein insufficiency are the cause. If there is proximal obstruction to flow, the patient develops claudication because the superficial return is eliminated. With chronic venous insufficiency, the physical examination may demonstrate fibrosis, tenderness, excoriation, skin induration from hyperkeratosis, cellulitis, and ulceration. The chronic inflammation causes fibrosis and induration of the skin. Hemosiderin deposition results in a brownish pigmentation. These yield the characterization of

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the limb as “brawny.” The ulcers, in contrast to the welldefined, pallid arterial ulcers, are large with irregular borders, erythematous, and moist. They are usually located near the medial or lateral malleolus. The base of the ulcer is composed of granulation tissue. The skin around the ulcer may be shiny.

Thrombosis The patient with superficial vein thrombosis may present with venous distension, a palpable venous cord, erythema, warmth, or tenderness, findings that are usually sufficient to make the diagnosis. The bedside diagnosis of deep vein thrombosis is more difficult. During the examination of a patient suspected of having a deep vein thrombosis, the examiner must scrutinize the extremities carefully in the supine and standing positions. Patients need to be examined both lying and standing since venous distension will be exacerbated in the upright position. The routinely associated physical exam maneuver, the Homan’s sign of pain with passive foot dorsiflexion, misses the diagnosis as commonly as it makes it. The most common physical findings of deep vein thrombosis include unilateral leg swelling, warmth, and erythema. The patient may have tenderness over the involved vein, and a cord may be palpable. Cords are most frequently palpated in the common femoral vein just below the inguinal ligament and in the superficial femoral vein along the anteromedial aspect of the thigh. The examiner may be able to detect unilateral superficial engorgement, alteration of the contours of the thigh, calf, or ankle, and compressive masses in the popliteal space or groin. The leg may be frankly edematous or the calf or thigh muscles may feel boggy and engorged. There may be palpable temperature difference between the warmer affected and normal lower extremity. Superficial venous prominence is more likely to be demonstrated in the standing position. The patient with phlegmasia cerulea dolens will have a painful, edematous, cyanotic limb. The development of this severe form of deep vein thrombosis requires an overwhelming thrombotic burden to impair venous return and cause stasis of deoxygenated blood. The casual examiner may mistake phlegmasia cerulea alba for an acute arterial occlusion. The extreme edema and inflammation of phlegmasia cerulea alba results from impedance of arteriolar and capillary flow causing pallor. The leg, however, will be edematous, turgid, and improved with elevation unlike a limb with arterial occlusive disease.

LYMPHATIC DISEASE History Lymphedema Lymphedema results from production of interstitial fluid that exceeds the drainage capacity of the lymphatics. Thus lymphedema may result from excess interstitial fluid sequestration from the veins and impaired lymphatic return.

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The former is commonly related to venous insufficiency. The latter is described as lymphedema and may result from lymphatic absence, underdevelopment, or obstruction. There are three types of primary lymphedema: congenital lymphedema appears near or at birth; lymphedema praecox develops around puberty; and lymphedema tarda begins after age 35. Primary lymphedema is also associated with Turner’s and Noonan’s syndrome. Secondary lymphedema may be acquired from a variety of conditions including recurrent bacterial lymphangitis, malignant obstruction of the lymphatics, nodal and lymphatic resection in cancer surgery, filariasis, contact dermatitis, tuberculosis, and pregnancy. Early in the course of lymphedema, the extravasated interstitial fluid is similar to venous insufficiency, feeling soft and improving with elevation. With time, the leg begins to feel wooden and stiff. The persistence of the edema allows for the development of cellulitis, lymphangitis, and proximal progression of the swelling.

Lymphangitis Infection of the lymphatic vessels results from extension from an infected or necrotic lesion. Patients may develop erythematous patches or a streak that extends proximally from the lesion. The infected vessel is associated with both pain and tenderness. Patients will usually have a high fever and shaking chills associated with bacterial infections. The chills commonly occur in the absence of other precipitating factors and recur frequently. The small red streak commonly expands to involve the entire limb. Injuries or fungal foot infections are common portals of entry. Recurrent attacks of lymphangitis result in lymphedema.

Physical Examination The patient with lymphedema will demonstrate edema similar to venous insufficiency early in the course. The edema is pitting and soft. At this stage, the “square toe” sign may aid in differentiating lymphedema from venous edema. In contrast to edema in venous insufficiency, lymphedema in the lower limbs

Figure 6-7. The “square-toe” sign and diffuse, nonpitting edema of lymphedema.

tends to extend to the boundary of the toes (Fig. 6-7). Over the course of years, the limb becomes wooden with progressive induration and fibrosis of the affected tissues. The skin becomes thickened with increased production of subcutaneous and adipose tissue. The edema at this stage is no longer pitting. The limb is clearly enlarged. The skin may appear verrucous at the toes. Examination of the patient with lymphangitis reveals a red streak that extends proximally from an inciting lesion. Later in the course, the entire limb may be erythematous, enlarged, and warm. There should not be evidence of venous congestion nor impairment of arterial flow. Usually there is induration of the regional lymph nodes.

REFERENCES 1. Murabito, J.M.; D’Agostino, R.B.; Silbershatz, H.; Wilson, W.F. Intermittent Claudication. A Risk Profile from The Framingham Heart Study. Circulation 1997, 96 (1), 44– 49. 2. Fowkes, F.G.; Housley, E.; Cawood, E.H.; Macintyre, C.C.; Ruckley, C.V.; Prescott, R.J. Edinburgh Artery Study: Prevalence of Asymptomatic and Symptomatic Peripheral Arterial Disease in the General Population. Int. J. Epidemiol. 1991, 20 (2), 384– 392. 3. Rose, G. The Diagnosis of Ischemic Heart Pain and Intermittent Claudication in Field Surveys. Bull. WHO 1962, 27, 645–658. 4. Regensteiner, J.; Steiner, J.; Panzer, R.; Hiatt, W. Evaluation of Walking Impairment Questionnaire in Patients with Peripheral Arterial Disease. J. Vasc. Med. Biol. 1990, 2, 142– 156.

5. Criqui, M.; Denenberg, J.; Bird, C.; Fronek, A.; Klauber, M.; Langer, R. The Correlation Between Symptoms and Noninvasive Test Results in Patients Referred for Peripheral Arterial Disease Testing. Vasc. Med. 1996, 1 (1), 65 – 71. 6. Huston, K.; Hunder, G.; Lie, J.; Kennedy, R.; Elveback, L. Temporal Arteritis: A 25 Year Epidemiologic, Clinical, and Pathologic Study. Ann. Int. Med. 1978, 88, 162– 167. 7. Blankenship, J.C.; Butler, M.; Garbes, A. Prospective Assessment of Cholesterol Embolization in Patients with Acute Myocardial Infarction Treated with Thrombolytic vs Conservative Therapy. Chest 1995, 107 (3), 662– 668. 8. Barnhosrt, D.; Barner, H. Prevalence of Congenitally Absent Pedal Pulses. N. Engl J. Med. 1968, 278, 264– 265. 9. Prandoni, P.; Lensing, A.; Prins, M. Long-Term Outcomes After Deep Venous Thrombosis of the Lower Extremities. Vasc. Med. 1998, 3 (1), 57– 60.

CHAPTER 7

Noninvasive Studies of Peripheral Vascular Disease James S. T. Yao the blood velocity. This is expressed mathematically as follows:

During the past two decades, noninvasive tests have emerged as routine laboratory procedures to provide diagnostic information and follow patients after reconstructive arterial surgery. In most hospitals, a noninvasive vascular laboratory is now an integral part of the diagnostic service. The purpose of this chapter is to describe the noninvasive techniques currently available for the evaluation of patients with peripheral arterial occlusive disease.

Change in frequency ðDoppler shiftÞ ¼ 2 fv cos u=C where f = frequency of incident sound beam, v = velocity, u = angle of incident sound beam to the vessel being examined (60 degrees), and C = velocity of sound in tissue. Since sound beam frequency, the angle of incidence, and the velocity of the sound in tissue are considered constant, the frequency shift is proportional to the blood flow velocity. It is important to note that the shift is directly related to the velocity of red blood cells and the cosine of the angle between the direction of blood flow and the ultrasound beam. When the Doppler angle approaches 90 degrees (cosine 908 = 0), the detection of the Doppler shift is jeopardized. The ideal Doppler angle is 0 degrees (cosine 08 = 1), but this angle can rarely be achieved. In practice, Doppler angles between 45 and 60 degrees produce satisfactory clinical results. The instrument provides audible and recordable information and can be used in the office, at the bedside, and in the vascular laboratory. Basic arterial testing by Doppler includes flow velocity recording and segmental pressure measurement. The vessels examined in the lower extremity are the femoral, popliteal, posterior tibial, and dorsalis pedis arteries, or, alternatively, the lateral tarsal and digital arteries. For the recording of lower limb pressure, the bladder cuff should be 20% wider than the diameter of the limb. Examination of the upper extremity involves the subclavian, axillary, brachial, radial, and ulnar arteries and the digital vessels. Positional changes (military position, abduction and external rotation, hyperabduction) are utilized to determine the presence of thoracic outlet syndrome. In the normal artery, the audible signals consist of three sounds. The first sound is louder and of longer duration than the second and third components. Flow signals detected distal to an occlusion where collateral flow is present consist of a single sound and are low-pitched in character. When the flow probe is placed over a stenosis where high velocity is present, again, the second and third sounds are absent, and the sound is high-pitched with a hissing character. In the presence of turbulent flow, such as arteriovenous communication, the

INSTRUMENTATION Although plethysmography has played a role in noninvasive testing, ultrasound technology appears to dominate the field. Most vascular laboratories are now equipped with ultrasound equipment ranging from the simple transcutaneous Doppler to a duplex scanner or color flow imager.

Transcutaneous Doppler The transcutaneous Doppler flow velocity detector is the most commonly used instrument for arterial examination. A piezoelectric crystal will vibrate under the influence of an electric current, radiating energy in the form of sound waves. Such a crystal will also change dimension when hit by a moving sound wave, developing a voltage across the crystal. These properties allow the crystal to generate and also to detect sound waves. The waves emanating from the crystal are in the low-frequency ultrasound spectrum (1 –10 mHz) and do not harm living tissue. Lower frequency provides better tissue penetration and is best suited for the examination of deep arteries. Doppler instruments are based on the Doppler effect and on the properties of the piezoelectric crystal. Generated ultrasound waves penetrate the tissue and are backscattered by moving red blood cells. The Doppler shift in frequency between the transmitted and reflected sound is proportional to

Supported in part by the Alyce F. Salerno Foundation.

Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024890 Copyright q 2004 by Marcel Dekker, Inc.

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sound is mixed, with high and low pitches, and is continuous in nature. In analog display, the flow velocity waveforms of the normal artery, like the audible sounds with three components, should be triphasic with a diastolic reverse flow (Fig. 7-1A). Once arteriosclerotic changes occur, the first change is turbulence during systole (Fig. 7-1B), followed by the loss of reverse flow (Fig. 71C through E). The systolic flow is progressively lost from stenosis to complete occlusion. In the presence of severe ischemia, the systolic flow waveforms flatten and become broader and nonpulsatile (Fig. 7-1F through H). The use of the Doppler flow probe has greatly facilitated the measurement of lower limb pressure. With this technique, recording of penile pressure with a small cuff (2.5 cm) is now also feasible.

Figure 7-1. Different patterns of flow velocity waveforms. (A ) Normal. (B ) Atherosclerotic changes of artery causing turbulence during systole (high frequency). (C and D ) Loss of reverse flow due to progression of degree of stenosis. (E to H ) With increasing arterial stenosis, the flow velocity waveform becomes progressively damped. [From Johnston, K.W.; Maruzzo, B.C.; Kassam, M. et al.: Methods of obtaining, processing and quantifying Doppler blood velocity waveforms. In Nicolaides, A.N.; Yao, J.S.T. (Eds): Investigation of Vascular Disorders. London, Churchill Livingstone, 1981, p 543. Reproduced by permission.]

Ankle pressures are slightly higher than arm pressures. On comparing lower extremity pressures with brachial pressures, the ratio (ankle/brachial) should be greater than or equal to 1 in normal patients; less than this suggests stenotic disease. Diabetic or other patients with calcified vessels are an exception because these vessels are not compressible; therefore, the ratios are not useful for interpretation. Claudicants generally have a pressure index (ankle-brachial) of 0.5–0.7. Patients with rest pain or other severe ischemic symptoms generally have a ratio of 0.3 or less. In diabetics with calcified arteries, inspection of flow velocity waveform recording from the pedal arteries in conjunction with toe pressure measurement will help to determine the degree of ischemia. The normal toe/brachial pressure ratio is 0.85 or greater. A penile/brachial ratio of less than 0.6 is consistent with vasculogenic impotence. The absolute pressure can be helpful in determining segmental occlusions both in the upper and lower extremities, as suggested above. A pressure level less than 40 mmHg is often associated with limb-threatening ischemia. As one observes pressures from low thigh to ankle, a 30 mmHg pressure drop indicates a severe stenotic or occlusive process. Therefore, if one observes a 30 mmHg pressure drop from the low thigh to the calf and a flattening of the waveform with lack of reverse flow, a popliteal occlusion is highly probable. Study of the upper extremity has shown that a 15 mmHg segmental drop is significant. Ischemic indices are greater than or equal to 0.9 for normal patients, average 0.6 for exertional pain patients, and are 0.3 for those with severe ischemia. It has been shown that a greater than 29 mm/s delay in the onset of stenotic flow is present in unilateral subclavian artery stenosis when brachial arteries are monitored. Distal fingertip ischemia is suggested by a 30 mmHg wrist-to-digit difference or a 15 mmHg finger-to-finger differentiation. Stress testing by treadmill exercise is done by having the patient walk on a treadmill at 4 km/h on a 12% grade or at 2.5 km/h for 5 min or until the patient must stop due to leg pain. The patient then resumes the supine position and brachial and ankle pressures are taken every minute or until they reach baseline level (10– 15 min). If treadmill exercise testing is not possible, an alternative stress test is by reactive hyperemia. The blood pressure cuff is inflated to 50 mmHg above the systolic pressure for 5 min, and ankle and brachial pressures are then recorded at 1-min intervals after deflation of the cuff until baseline is reached. Table 7-1 shows the normal values of lower limb pressure measurement at various levels.

Duplex and Color-Encoded Technology Recent development of duplex Doppler technology has made it possible to evaluate not only anatomic features of vessels but also physiologic aspects of blood flow in vessels in a variety of locations, including the renal, mesenteric, penile, and peripheral arteries. Duplex technology combines conventional B-mode imaging with range-gated pulsedwave Doppler analysis. The method enables the examiner to obtain precise Doppler information from any vessel identifiable on the cross-sectional image and thereby to determine the presence, direction, and velocity of flow in that

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Table 7-1. Normal Values of Systolic Pressure of the Lower Extremity Pressure measurement Ankle systolic pressure Ankle pressure index (ankle/brachial ratio) Thigh systolic pressure High (narrow cuff) Low (wide cuff) Pressure gradients Toe pressure index

Treadmill exercise test (2 mph, 12% grade)

vessel. The color-encoded technology combines real-time ultrasound imaging with semiquantitative color encoding of the Doppler shift. The color assignment depends on the mean velocity and direction of flow. Whenever flow is detected, it is color-encoded and superimposed on the gray-scale real-time image. In general, arterial flow is usually displayed in red and venous flow in blue (Fig. 7-2; see also color plate). The hue or color saturation also reflects the relative blood velocity—slow flow has a deeper hue or saturation and fast flow has a lighter tone. Color flow imaging makes it easier to find and follow the vessel of interest and identifies regions with disturbed or turbulent flow, which facilitates placement of the sample volume for spectral analysis. Artery tortuosity can be recognized readily, and minor wall irregularities not affecting center-stream flow are detected instantly by a color flow imager. Spectral analysis is now a standard procedure to grade the degree of stenosis. Duplex instruments provide both audible and computed frequency information related to the velocity of moving red blood cells. An atherosclerotic plaque may change the pattern of blood flow velocities to produce

Normal values .brachial systolic pressure .1.0 30 – 40 mmHg . brachial systolic pressure 20 – 30 mmHg . brachial systolic pressure ,30 mmHg between adjacent sites 0:7 ^ 0:19 0.35 ^ 0.15 = claudication 0.11 ^ 0.10 = rest pain Elevated or no decrease of ankle pressure after 5 min walking time

frequency spectral broadening, defined as an increase in the range of frequencies present in the Doppler signal. In the normal artery, most of the energy during systole parallels the frequency envelope, with a narrow spectrum of frequencies and a clear “window” (Fig. 7-3A and B). In the presence of stenosis, the resulting flow disturbance causes disruption of the narrow spectrum; thus, the clear window no longer is seen. The flow spectrum becomes broadened, with the various frequencies filling in the window (Fig. 7-3C and D). Also, there is an increase of high-frequency components. Further narrowing is associated with increase in peak systolic velocities relative to the proximal arterial segment. When arterial stenosis exceeds 50% diameter reduction, the peak systolic velocity is increased by more than 100% relative to the proximal arterial segment, and there is spectral broadening throughout the pulse cycle. Lesions that decrease the luminal diameter by more than 75% are associated with increases in end-diastolic velocity (Fig. 7-4). Table 7-2 shows the diagnostic criteria for determining the degree of stenosis in peripheral artery segments.

Plethysmography Several types of plethysmographs are now available for clinical use in the evaluation of arterial occlusion. These are air-filled, strain-gauge, and photoelectric plethysmographs.

Air-Filled Plethysmograph

Figure 7-2. Color Doppler image of normal artery (red ) and adjacent vein (blue ). (See color plate.)

One of the popular instruments used in the vascular laboratory is the pulse volume recorder. In essence, this is an air-filled segmental plethysmograph designed to measure segmental pressure of the leg. The air-filled plethysmograph uses a pneumatic cuff placed around the part being examined, often at several levels. By injecting a known volume of air in the toe cuff bladder, instantaneous volume changes in the limb segment beneath the cuff can be calibrated and recorded with a sensitive pressure transducer to provide pulsatile flow tracings. Changes in the configuration of such pulse-volume tracings indicate proximal arterial occlusion. By visual inspection, the pulse waveforms can be related to different degrees of ischemia.The instrument can be used to record penile pulse waveforms.

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Figure 7-3. (A ) Normal laminar flow with parabolic curve. (B ) Normal spectral band with acoustic window present. (C ) Turbulent flow due to stenosis. (D ) Spectral display at the distal site. Frequencies are markedly elevated; there is total loss of acoustic window (spectral broadening) and an increase of end-diastolic velocity. [From Blackburn, D.R.; Peterson, L.K.: Noninvasive vascular testing. In Fahey, V.A. (ed.): Vascular Nursing. Philadelphia, Pennsylvania, Saunders, 1988, p 99. Reproduced by permission.]

Strain-gauge Plethysmograph Strain-gauge plethysmographs use fine-bore rubber tubes filled with mercury or a liquid-metal alloy that makes contact with copper electrodes at either end. The gauge is wrapped around the part being studied. As the part (calf or forearm) expands or contracts, the length of the gauge increases or decreases by a corresponding amount. The changes in the length of the gauge reflect changes in the circumference of the part and are interpreted as volume changes. Because the resistance of the liquid-metal column varies with its length, changes in voltage across the gauge, when amplified, can be calibrated to reflect changes in circumference (volume) of the circumscribed part. Changes in the strain-gauge length can be calibrated mechanically to reflect volume flow, or electrical calibration by a bridge circuit can be used to measure voltage drop across the gauge. The strain gauge can be used for recording pulse waveform of digits and to record systolic pressure of the extremity. In conjunction with the venous occlusion principle, the strain-gauge plethysmograph has been applied to record calf or skin blood flow expressed in mL/100 g/min. In the clinical practice of vascular surgery, the use of calf (muscle) or skin (foot) flow is of limited value. Flow measurement may be useful in the evaluation of the acute effect of various pharmacologic agents.

Photoelectric Plethysmograph Early instruments included the use of a photocell for pulse recording by means of alternating current (ac) signals. Recently, an infrared sensor has been used in the new generation of photoelectric plethysmographs. In this newer instrument, a direct current (dc) coupling technique is also provided. The dc signal is not related to the pulse, is slow to change, and depends on changes in the total blood volume in the skin. With refinement in probe design, the photoplethysmograph has become a standard instrument for the recording of pulse waveforms in most laboratories. The technique is of particular value in the evaluation of thoracic outlet compression. The use of dc mode to detect volume changes is helpful in recording finger or toe pressure.

CLINICAL APPLICATIONS Peripheral Arterial Occlusive Disease Diagnosis A thorough history taking combined with a careful and skillful physical examination will establish the diagnosis of

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Figure 7-4. Typical velocity spectra for four categories of stenosis: (A ) normal (no stenosis); (B ) 1 – 19% diameter reduction; (C ) 20–49% diameter reduction; (D ) 50– 99% diameter reduction. [From Kohler, T.R.; Nace, D.R.; Cramer, M.M.; et al. Duplex scanning for diagnosis of aortoiliac and femoropopliteal disease: A prospective study. Circulation 76: 1074, 1987. Reproduced by permission.]

peripheral arterial occlusive disease. The role of noninvasive testing in establishing a diagnosis lies in those cases where palpation of a pulse is in doubt or in those patients with intermittent claudication in the presence of a palpable pedal pulse. In these circumstances, the use of systolic pressure measurement allows instant confirmation of the presence of arterial occlusive disease. Intermittent claudication in patients with palpable pedal pulses is a well-known syndrome; it is frequently seen in patients with iliac artery stenosis. However, the ankle pressure is always abnormal, and this abnormality

will become more pronounced after treadmill exercise. Treadmill exercise is also useful to differentiate neurogenic pseudoclaudication from claudication of vascular origin.

Degree of Ischemia. Both the pressure index and the absolute ankle pressure are useful to grade the degree of ischemia, but the pressure index correlates well with presenting symptoms. In patients with claudication, the pressure index often ranges from 0.50 to 0.70, and a marked

Table 7-2. Duplex Criteria for Peripheral Arterial Stenosis Diameter reduction 19% or wall irregularity 20– 49% 50– 75% 76– 99% Occlusion

Velocity spectral characteristics No increase in peak systolic velocity relative to proximal arterial segment, but mild spectral broadening during systole Greater than 30% increase in peak systolic velocity relative to proximal arterial segment; spectral broadening throughout the pulse cycle Peak systolic velocity ratio at stenosis relative to segment proximal to stenosis . 2; uniform spectral broadening over the entire pulse cycle with simultaneous forward and reverse flow components Similar velocity rate as in 50 – 75% category but end-diastolic velocity greater than 100 cm/s No flow signal from visualized segment

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decrease in the pressure index, often to less than 0.30, is seen in patients with rest pain, ischemic ulcer, or gangrene. The absolute pressure alone, however, is more useful to determine limb viability. Chronic critical leg ischemia in both diabetic and nondiabetic patients has recently been defined by several working groups.[1 – 3] The criteria are an ankle systolic pressure less than or equal to 50 mmHg and/or a toe systolic pressure less than or equal to 30 mmHg, or ulceration or gangrene of the foot or toes with an ankle systolic pressure of less than 50 mmHg or a toe systolic pressure of less than 30 mmHg. There is a spectrum of ankle pressure in patients with skin ulcers and/or rest pain. However, to standardize the description of these patients, the level of 50 mmHg is recommended because this includes the majority of patients for whom rest pain or ulcers do not improve spontaneously without intervention. For diabetics, the toe systolic pressure measurements should be performed because a falsely high ankle systolic pressure is frequently found in these patients. A cutoff pressure of 30 mmHg is based on the fact that a majority of diabetic patients with a toe systolic pressure of less than 30 mmHg have a very poor prognosis.[4]

color flow imaging as a surveillance program to follow in situ and other grafts.[5,6] Because the in situ graft is superficially situated, it is readily accessible for blood flow velocity measurement and waveform recording. Transformation of the triphasic graft velocity waveform to a biphasic or monophasic configuration coupled with a decrease in peak velocity to less than 45 cm/s has been found to be highly suggestive of a remote occlusive lesion.[5,6] The major advantage of color Doppler is the reduction of examination time required to completely map a femorotibial bypass graft. The visual feedback afforded by the color flow imaging enables areas of flow abnormalities to be rapidly identified. To accurately determine the site of stenosis, velocities immediately proximal and distal to the site of disturbed color flow must be compared using pulsed-Doppler spectral analysis. A velocity ratio greater than 2.0 or peak systolic velocity in excess of 150 cm/s is evidence that a stenosis is present.[6] With a combination of ankle systolic pressure measurement and duplex scanning, stenosis of the graft can be detected and corrected surgically prior to thrombosis. This type of surveillance program is now a standard practice for the first 2 years after most infrainguinal vein grafts.

Immediate and Late Follow-Up After Arterial Reconstruction

Adequacy of Aortoiliac Inflow

The Doppler flow detector provides a simple way to monitor the patency of a bypass graft during the postoperative period in both the recovery room and intensive care unit. The degree of improvement in ankle pressure depends upon whether or not there is a residual occlusion distal to the site of reconstruction. If multiple occlusions are present, correction of the proximal lesion will significantly elevate the ankle pressure, often to double the preoperative level, but will not convert it to normal. Frequent monitoring of the ankle pressure is helpful to detect graft failure. For late follow-up, the ankle pressure remains the simplest method to detect graft failure. A decrease of pressure index of 0.15 is considered a significant change, and further investigation is necessary. The ankle pressure measurement is useful to detect hemodynamic failure of a bypass graft (a failing graft). Hemodynamic failure is defined as a graft that is patent by arteriography and yet fails to provide hemodynamic improvement. A hemodynamically failed graft, if recognized early, may be corrected by surgery prior to graft occlusion by thrombosis. Postoperative study can determine whether an additional reconstructive procedure is necessary in order to achieve the desired result. Need for a further bypass procedure is commonly seen in patients who have multiplelevel disease and in whom a proximal reconstruction is performed in the presence of a distal occlusion. If there is no improvement in the ankle pressure after aortoiliac or profunda femoris reconstruction, a distal bypass graft to relieve symptoms is often warranted. Although ankle systolic pressure is a simple test, several investigators have claimed that this test is less sensitive to detect graft stenosis, especially in patients with in situ saphenous vein grafts. To deal with this shortcoming, most vascular laboratories have added either duplex scan or

The correct assessment of aortoiliac occlusive disease is often a challenge, especially in multilevel occlusive disease, in which the decision to perform an inflow or outflow operation depends primarily on the hemodynamic significance of the proximal lesion. However, a careful physical examination aided by segmental pressure measurement and common femoral waveform recording will help to resolve the dilemma. A small percentage of cases will need further testing to evaluate the adequacy of aortoiliac inflow. This circumstance includes cases in which one must determine adequate inflow to support a femorofemoral bypass graft or cases in which one must decide whether the disease is located predominantly in the aortoiliac segment or in the femoropopliteal tract, when the results of clinical examination or segmental pressure measurement are ambiguous. In recent years, several techniques ranging from simple waveform inspection to sophisticated computer analysis have been proposed to aid in the assessment of the hemodynamic significance of an inflow tract lesion. The simplest method is waveform amplitude calculation[7] followed by a higher level of sophistication such as pulsatility index[8] to LaPlace transform damping and principal component analysis.[9 – 11] Because of the complicated nature of computer analysis technique, pulsatility index, LaPlace transform, and principal component analysis have not yet been adapted as routine tests in most vascular laboratories, and many vascular surgeons rely on femoral pressure measurements before and after papaverine or before and after the distal bypass is completed (see Chap. 32). Since most laboratories are now equipped with a color flow Doppler or duplex scanner, several investigators have advocated the use of velocity data to assess the degree of aortoiliac lesion in a fashion similar to the analysis of carotid stenoses. While resting Doppler frequency spectrum analysis may offer useful diagnostic information, some investigators have advocated

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the use of reactive hyperemia to increase the diagnostic accuracy.[12]

Vascular Pathology of the Popliteal Fossa Vascular problems in this anatomic region include popliteal aneurysm, cystic degeneration of the popliteal artery, and popliteal artery entrapment syndrome. Diagnosis can now readily be accomplished with duplex technology.[13] The technique is of particular use in the diagnosis of popliteal entrapment. The patient is placed in the prone position and the popliteal fossa is then scanned. Compression of the artery with decreased or absent flow signals when the leg is placed in hyperextension is diagnostic of popliteal entrapment syndrome. The technique is more accurate than the positional testing technique with the Doppler pulse detector. For aneurysm and cystic degeneration, the B-mode image of the duplex scan is also helpful to establish the diagnosis.[14]

Arteriovenous Fistula or Pseudoaneurysm With the proliferation of interventional procedures, arteriovenous fistula or pseudoaneurysm of the femoral artery is now a common vascular complication. The diagnosis can be readily made with duplex scan—in particular, a color flow imager. Unlike the gray-scale B-mode scan, the color imager identifies the jet stream from the puncture site and follows it into the lumen of the pseudoaneurysm. The flow pattern of the pseudoaneurysm is characterized by swirly flow mixed with red and blue color changes. This technique is of particular value if there is a broad-based defect in the artery. In using this technique to evaluate 27 patients with groin pulsatile masses, Schwartz and coworkers reported 100% sensitivity and specificity.[15] The color-encoded imager is useful in the detection of arteriovenous fistula. Diagnostic features for fistula detection include persistent intra-arterial flow throughout the cardiac cycle at the site of the fistula and disorganized color flow pattern as the high-velocity flow jet enters the more compliant venous system. The technique is not only diagnostic but may also be therapeutic, as some investigators have used the imager to identify the communication and to use manual compression to eliminate the aneurysm or fistula.[16] Although compression treatment may help in treating small, acute aneurysms, spontaneous thrombosis of these aneurysms or fistulas has also been reported.[17] The color flow imager appears to help to determine the natural course of these aneurysms.

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Renovascular Hypertension With continuous refinement of duplex technology, diagnosis of renal artery stenosis is now possible by this technique. Duplex technology represents a new screening test in patients suspected of having renovascular hypertension. The colorencoded technique permits a more rapid identification of renal artery origins and anatomic course to the kidney. The size of the kidney can be accurately determined. Normal renal artery flow signals are of low resistance and have continuous flow in diastole, similar to the internal carotid artery and the celiac artery. In addition, flow signals from interlobar arteries may help to determine renal parenchymal disease. When there is stenosis of the renal artery, the peak velocity is increased, and the peak frequency ratio (compared with the aorta) has been suggested as the diagnostic criterion for renal artery stenosis. In the presence of renal artery stenosis (60% or greater), the renal/aortic ratio is 3.5 or greater.[18] This degree of stenosis was chosen because it appears to be the point at which the renin-angiotensin system is activated.[18] This increased frequency is also associated with loss of the acoustic window and turbulent flow. Hansen et al.[19] found that the ratio is not accurate. Instead, they found focal renal artery peak systolic velocity of 2 m/s or more in combination with distal poststenotic turbulence to be a more accurate diagnostic criterion (Table 7-3). Using this criterion, they found a high correlation with the angiographic presence of a 60% or greater diameter-reducing stenosis of the renal artery. In 122 kidneys studied, they reported a sensitivity of 93% and a specificity of 98% with an overall accuracy of 96% when compared with angiography.

Mesenteric Ischemia As with renovascular hypertension, until the introduction of duplex technology, there was no convenient noninvasive test for the detection of mesenteric artery stenosis in patients suspected to have mesenteric ischemia. Over the years, the technique has evolved to be a reliable screening test for mesenteric ischemia (Fig. 7-5 see also color plate). In addition to resting measurement, the physiologic changes of blood flow in response to oral consumption of a standard test meal or pharmacologic stimulation have added more hemodynamic information to the understanding of mesenteric ischemia.[20 – 22] For resting measurement of mesenteric circulation, the hemodynamic (velocity) criteria to establish the degree of ischemia vary slightly among several investigators.[23,24] The variation is due to the use of the threshold of angiographic

Table 7-3. Doppler Velocity Criteria for Renal Artery Stenosis B-Mode defect , 60% diameter-reducing defect . 60% diameter-reducing defect Occlusion Inadequate study for interpretation Note: RA = renal artery; PSV = peak systolic velocity. Source: Adapted from Hansen et al.[19] Reproduced by permission.

Criteria RA-PSV from entire RA, 2.0 m/s or less Focal RA-PSV .2.0 m/s, distal turbulent velocity waveform No Doppler shift signal from B-mode image Failure to obtain Doppler samples from entire main renal artery

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Figure 7-5. Oblique view of the aorta and celiac axis. The flow signal from the celiac axis is one of low resistance with absence of reverse flow. (See color plate.) [From Blackburn, D.R.: Color duplex imaging of the mesenteric and renal arteries. J. Vasc. Technol. 15:140, 1991. Reproduced by permission.]

stenosis (50% or 70%) as the standard for comparison. In general, peak systolic velocity, end-diastolic velocity, color flow image, and presence of reverse flow in the hepatic artery are diagnostic of celiac axis and mesenteric artery stenosis. In a validation study of a cohort of 243 patients, Zwolak and colleagues found the following criteria in patients with angiographic evidence of 75% stenosis.[25] For superior mesenteric artery stenosis, an end-diastolic velocity (EDV) of $45 cm/s or the absence of flow signals has a sensitivity of 90%, specificity of 91%, positive predictive value of 90%, negative predictive value of 91%, and an overall accuracy of 91%. Peak systolic velocity (PSV) was less accurate than EDV: a threshold of $ 300 cm/s resulted in the highest attainable PSV accuracy of 81% with low sensitivity (60%) but high specificity (100%). Doppler velocity criteria were accurate in the diagnosis of celiac axis stenosis: for identification of $50% stenosis or occlusion, an EDV of .55 cm/s or the absence of flow signal resulted in a sensitivity of 93%, specificity of 100%, and overall accuracy of 95%. These velocity data are accurate in the identification of mesenteric ischemia. Color flow image is also helpful to identify anatomic variants that may influence the study interpretation. Also, retrograde common hepatic artery flow direction is diagnostic for severe celiac axis stenosis or occlusion. Duplex scan is a useful screening test and is ideal for follow-up study after mesenteric revascularization.[26]

Infrainguinal Bypass Graft Surveillance Duplex scan is now readily available for direct examination of the entire length of the graft, the proximal and distal anastomoses, and the adjacent inflow and outflow arteries. Graft surveillance helps to identify hemodynamically failing

graft, especially in in situ graft, prior to failure by total occlusion. Graft surveillance is of particular value in in situ vein graft. The advent of color-flow technology has greatly simplified the scanning of the bypass graft. Color-flow scanning, which superimposes a color-coded flow map on the B-mode image, greatly shortens the scanning time. With color-flow mapping, the proximal anastomoses are always indentified and distal anastomoses are visualized in about 90% of the studies. Arteriovenous fistulae, hematomas, fluid collections, false aneurysms, kinks, and other defects related to bypass grafting are readily identified. The B-mode image of normal segments of bypass graft has a smooth contoured appearance. Color saturation is determined by the Doppler frequency shift. Because stenoses are associated with increased flow velocities, a localized change in color (red to white or blue) is a sensitive indicator of the presence of a stenosis. Once the stenotic lesion is identified, it is necessary to evaluate the Doppler flow spectrum and to determine the degree of stenosis. Both peak systolic velocities (PSV) and velocity ratio are helpful to determine the degree of stenosis. Velocity ratio is calculated by dividing the PSV obtained at the stenotic site by the PSV in the adjacent “normal” segment. As recommended by Sumner and Mattos,[27] a velocity ratio greater than 2.0 is predictive of a 50% diameter-reducing lesion. Higher ratios are indicative of more severe diameter reduction. For peak systolic velocity, several investigators have suggested that a PSV greater than 150– 180 cm/s is also indicative of a greater than 50% diameter reduction.[28,29] High-grade stenoses (greater than 70% or 80% diameter reduction) are usually associated with PSV exceeding 170–300 cm/s and end-dissection velocities of 20– 100 cm/s or more. Additionally, Bandyk et al. reported an increase of graft occlusion when the PSV measured at the innermost segment of a graft (either the upper end of a reversed vein graft or the lower end of an in situ graft) was less than 45 cm/s.[28] Graft surveillance by duplex scan is now a recommended routine examination following bypass graft. Approximately 10–34% of infrainguinal grafts developed hemodynamically significant stenoses.[27] The duplex scan examination detects early hemodynamically failing graft (pseudo occlusion), and early correction of stenosis extends graft patency. An increase in secondary graft patency of approximately 10–25% can be achieved with duplex scan over that with routine clinical follow-up or ankle pressure alone. Routine graft surveillance is cost-effective and should be a standard follow-up test for infrainguinal bypass grafts.

Vein Mapping for Infrainguinal Bypass It is uniformly acknowledged that autogenous vein is the choice for bypass grafts. Unfortunately, an adequate long saphenous vein is present in only 67% of patients.[30] The availability of duplex scan has made vein mapping a valuable preoperative evaluation of the adequacy of long saphenous vein or for other potential venous conduits such as the cephalic vein or the short saphenous vein. In repetitive infrainguinal bypass, vein mapping is helpful to locate

Chapter 7.

residual veins or the short saphenous vein. This information helps to determine whether a composite-sequential graft may be used as a limb salvage procedure. Vein mapping is done in a warm room with the patient resting in the supine position with 10– 208 tilt in the reversed Trendelenburg position. With the extremity externally rotated, the long saphenous vein is examined from the groin to the ankle. For short saphenous vein scan, the patient is best examined in a prone position. Duplex mapping of the cephalic and basilic veins is performed with the patient in the supine position, the upper extremity externally rotated. A transverse and longitudinal view of the vein can be obtained and marked with permanent ink for identification. Vein mapping is indicated in patients with (1) previous history of infrainguinal bypasses in which a portion of long saphenous vein has been removed; (2) history of vein ligation or stripping; (3) history of superficial thrombophlebitis; (4) drug abuse; and (5) obesity. Although an absolute vein diameter to be used as a conduit remains unclear, most vascular surgeons would accept an internal diameter of 2 mm at resting condition as suitable for distal anastomosis of an infrainguinal bypass onto the infrapopliteal vessels. Vein mapping extends the usage of autogenous vein, and the technique is useful to detect anatomic variation, which is rather common with the venous system. Vein mapping by duplex scan is now an integrated

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preoperative assessment for patients who are candidates for infrainguinal bypass.

Sexual Impotence The status of pelvic blood flood can now be assessed by recording penile pressure in males. Such pressure recording helps to evaluate sexual potency in patients with aortoiliac occlusive disease. In general, with a pressure index below 0.60, vasculogenic impotence is suspected. Several authors using the current duplex technology have reported that the color flow imager and velocity measurement of the cavernosal arteries provide more diagnostic information. A peak systolic velocity of 25 – 30 cm/s can correctly distinguish patients with normal cavernosal arteries from those with severe arterial disease. The color Doppler imager can be used to evaluate the deep arteries of the corpora cavernosa in the flaccid state and after erection induced by direct injection of 60 mg of papaverine. The degree of arterial dilatation is evaluated, as well as the increase in peak systolic velocity after injection. A lack of arterial dilatation or minimal velocity increase is evidence of arterial insufficiency.[31,32] This approach is helpful in selecting patients for pudendal arteriography for further diagnosis and possible treatment.

REFERENCES 1.

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Bell, P.R.F.; Charlesworth, D.; DePalma, R.G.; et al. The Definition of Criteria Ischaemia of a Limb: Working Party of the International Vascular Symposium (Editorial). Br. J. Surg. 1982, 69 (suppl), S2. Rutherford, R.B.; Flanigan, D.P.; Gupta, S.K.; et al. Suggested Standards for Reports Dealing with Lower Extremity Ischemia. J. Vasc. Surg. 1986, 4, 80– 94. European Working Group on Critical Leg Ischaemia; Second European Consensus Document on Chronic Critical Leg Ischemia. Circulation 1991, 84 (suppl), IV1– IV2. Carter, S.A. The Definition of Critical Ischemia of the Lower Limb and Distal Systolic Pressure. Br. J. Surg. 1983, 70, 188– 189. Bandyk, D.F. Postoperative Surveillance of Infrainguinal Bypass. In Noninvasive Diagnosis of Vascular Disease; Yao J.S.T., Pearce W.H., Eds.; Surg. Clin. North. Am. 1990, 70, 71– 85. Blair, J.-F.; Bandyk, D.F. Real-Time Color Doppler in Arterial Imaging. In Technologies in Vascular Surgery; Yao, J.S.T., Pearce, W.I.I., Eds.; Saunders: Philadelphia, Pennsylvania, 1991; 129 – 149. Fronck, A.; Coel, M.; Bernstein, E.F. Quantitative Ultrasonographic Studies of Lower Extremity Flow Velocity in Health and Disease. Circulation 1976, 53, 957– 960. Johnston, K.W.; Kassam, M.; Gobbold, R.S.C. Relationship Between Doppler Pulsatile Index and Direct Femoral Pressure Measurements in the Diagnosis of Aortoiliac Occlusive Disease. Ultrasound Med. Biol. 1983, 9, 271–281.

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Macpherson, D.S.; Evans, D.H.; Bell, P.R.F. Common Femoral Artery Doppler Waveforms: A Comparison of Three Methods of Objective Analysis with Direct Pressure Measurements. Br. J. Surg. 1984, 71, 486– 493. Baker, J.H.D.; Machleder, M.I.; Skidmore, R. Analysis of Femoral Doppler Signals by LaPlace Transform Damping Method. J. Vasc. Surg. 1984, 1, 520–524. Baird, R.N.; Bird, D.R.; Cliffort, P.C.; et al. Upstream Stenosis: Its Diagnosis by Doppler Signals from the Femoral Artery. Arch. Surg. 1980, 115, 1316– 1322. Van Astern, W.N.J.; Beijneveld, W.J.; Pieters, B.R.; et al. Assessment of Aortoiliac Obstructive Disease by Doppler Spectrum Analysis of Blood Flow Velocities in the Common Femoral Artery at Rest and During Reactive Hyperemia. Surgery 1991, 109, 633– 639. Marzo, I.D.; Cavallaro, A.; Sciacca, V.; et al. Diagnosis of Popliteal Entrapment Syndrome: The Role of Duplex Scanning. J. Vasc. Surg. 1991, 13, 434– 438. Hoyne, R.F. Ultrasonographic Findings in a Case of Adventitial Cystic Disease of the Popliteal Artery, with a Review of the Literature. J. Cardiovasc. Technol. 1991, 10, 7987. Schwartz, R.A.; Kerns, D.B.; Mitchell, D.G. Color Doppler Ultrasound Imaging in Iatrogenic Arterial Injuries. Am. J. Surg. 1991, 162, 4 – 8. Fellmeth, B.D.; Roberts, A.C.; Bookstein, J.J.; et al. Postangiographic Femoral Artery Injuries: Nonsurgical Repair with US-Guided Compression. Radiology 1991, 178, 671– 675.

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17. Kresowik, T.F.; Khoury, M.D.; Miller, B.V.; et al. A Prospective Study of the Incidence and Natural History of Femoral Vascular Complications After Percutaneous Transluminal Coronary Angioplasty. J. Vasc. Surg. 1991, 13, 328–336. 18. Strandness, D.E. Duplex Scanning in Diagnosis of Renovascular Hypertension. In Noninvasive Diagnosis of Vascular Disease; Yao, J.S.T., Pearce, W.I.I., Eds; Surg. Clin. North Am. 1990, 70, 109– 117. 19. Hansen, K.J.; Reavis, S.W.; Dean, R.H. Use of Duplex Scanning in Renovascular Hypertension. In Technologies in Vascular Surgery; Yao, J.S.T., Pearce, W.H., Eds.; Saunders: Philadelphia, Pennsylvania, 1991; 174 – 184. 20. Flinn, W.R.; Sandager, G.P.; Lilly, M.; et al. Duplex Scan of Mesenteric and Celiac Arteries. Arterial Surgery: New Diagnostic and Operative Techniques; Grune and Stratton: Orlando, Florida, 1988; 367 – 375. 21. Jager, K.; Bollingber, A.; Valli, C.; et al. Measurement of Mesenteric Blood Flow by Duplex Scanning. J. Vasc. Surg. 1986, 3, 462– 469. 22. Lilly, M.P.; Harward, T.R.S.; Flinn, W.R.; et al. Duplex Ultrasound Measurement of Changes in Mesenteric Flow Velocities with Pharmacologic and Physiologic Alteration of Intestinal Blood Flow in Man. J. Vasc. Surg. 1989, 9, 18– 25. 23. Moneta, G.L.; Lee, R.W.; Yeager, R.A.; et al. Mesenteric Duplex Scanning: A Blinded Prospective Study. J. Vasc. Surg. 1993, 17, 79– 86. 24. Harward, T.R.S.; Smith, S.; Seeger, J.M. Detection of Celiac Axis and Superior Mesenteric Artery Occlusive

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Disease with Use of Abdominal Duplex Scanning. J. Vasc. Surg. 1993, 17, 738– 745. Zwolak, R.M.; Fillinger, M.F.; Walsh, D.B.; et al. Mesenteric and Celiac Duplex Scanning: A Validation Study. J. Vasc. Surg. 1998, 27, 1078– 1088. McMillan, W.D.; McCarthy, W.J.; Bresticker, M.R.; et al. Mesenteric Artery Bypass: Objective Patency Determination. J. Vasc. Surg. 1995, 21, 729– 741. Sumner, D.S.; Mattos, M.A. Influence of Surveillance Programs on Femoral-Distal Bypass Graft Patency. In The Ischemic Extremity: Advances in Treatment; Yao, J.S.T., Pearce, W.H., Eds.; Appleton & Lange: East Norwalk CT, 1995; 455–474. Bandyk, D.F.; Cato, R.F.; Towne, J.B. A Low Flow Velocity Predicts Failure of Femoropopliteal and Femorotibial Bypass Grafts. Surgery 1985, 98, 799– 809. Bandyk, D.F.; Schmitt, D.D.; Seabrook, G.R.; et al. Monitoring Functional Patency of In Situ Saphenous Vein Bypasses: The Impact of a Surveillance Protocol and Elective Revision. J. Vasc. Surg. 1989, 9, 284– 296. Mattos, M.A.; Sumner, D.S. Vein Mapping for Infrainguinal Bypasses. In Practical Vascular Surgery; Yao, J.S.T., Pearce, W.H., Eds.; Appleton & Lange: Stamford CT, 1999; 79 – 90. Paushter, D.M. Role of Duplex Sonography in the Evaluation of Sexual Impotence. Am. J. Roentgenol. 1989, 153, 1161– 1163. Schwartz, A.N.; Lowe, M.; Berger, R.E.; et al. Assessment of Normal and Abnormal Erectile Function: Color Doppler Flow Sonography Versus Conventional Techniques. Radiology 1991, 180, 105– 109.

CHAPTER 8

Noninvasive Cerebrovascular Diagnostic Techniques Thomas G. Lynch Robert W. Hobson II (Fig. 8-2A). In the presence of a hemodynamically significant internal carotid artery stenosis or occlusion, flow in the distal internal carotid artery is augmented by collateral circulation from the superficial temporal, facial, and infraorbital branches of the external carotid artery. Blood flow reaches the distal internal carotid artery through the nasal, frontal, and supraorbital branches of the ophthalmic artery (Fig. 8-2B). Early experience with a cerebrovascular Doppler examination was reported by Brisman et al.[1] They observed that stenosis or occlusion of the internal carotid artery was associated with a reduction in the amplitude and velocity of common carotid artery flow. Maroon et al.[2] employed a Doppler velocimeter to assess ophthalmic artery flow velocity transorbitally and were able to predict the presence of an internal carotid artery occlusion or a significant stenosis by evaluating the amplitude and velocity of ophthalmic artery flow (Fig. 8-3). Their accuracy, however, decreased when there was adequate collateral circulation through the branches of the external carotid artery. Evidence of this collateral circulation was demonstrated by Muller.[3] Using a directional Doppler velocimeter, he observed that an internal carotid artery stenosis or occlusion was associated with flow reversal in the frontal and ophthalmic arteries (Fig. 8-4). As subsequently refined by Bone and Barnes[4] and by Barnes et al.,[5,6] the cerebrovascular Doppler examination was performed using a 10 mHz directional Doppler. The supraorbital and/or frontal arteries were identified and the direction of flow determined, as well as the response to superficial temporal, facial, infraorbital, and common carotid artery compression. The study was abnormal if the direction of the flow was reversed in either or both arteries or if flow decreased with external carotid artery branch compression. The directional Doppler velocimeter used to perform the CDE was relatively inexpensive, and there were no contraindications to the technique. The accuracy, however, was variable and could be influenced by the skill of the examiner, the technique employed, the definition of hemodynamically significant disease, and the relative distribution of stenotic and occluded arteries in the study population. The technique is no longer commonly employed, but it remains valuable as

INTRODUCTION The hemodynamic changes associated with internal carotid artery stenosis and occlusion have provided the basis for a wide range of noninvasive diagnostic techniques. The cerebrovascular or periorbital Doppler examination (CDE), supraorbital photoplethysmography, oculoplethysmography, and ocular pneumoplethysmography (OPG) were sensitive to alterations in collateral circulation, ocular pulse delay, or decreased end-ophthalmic (distal internal carotid) artery pressure. They provided indirect evidence of hemodynamically significant carotid artery stenosis or occlusion. These indirect techniques, however, were unable to quantify the degree of stenosis, distinguish between stenosis and occlusion, or detect nonstenotic ulcerative disease. Techniques that directly assess the cervical carotid artery, such as real-time B-mode imaging and spectral analysis, provide additional information relative to the morphology of the plaque and the degree of obstruction. More recently, these techniques have also been employed to obtain information regarding the flow profile and its relationship to atherogenesis; the composition and morphology of atherosclerotic plaques and their relationship to symptomatic cerebrovascular disease; and the natural history of carotid atherosclerosis and atherogenesis.

HISTORICAL PERSPECTIVE Early noninvasive techniques developed from an understanding of the carotid circulation and its potential collateral pathways (Fig. 8-1). The ophthalmic artery is the first branch of the internal carotid artery. It divides into the frontal, supraorbital, and nasal arteries that communicate through collateral pathways with the superficial temporal, facial, and infraorbital branches of the external carotid artery. In the absence of obstruction, flow passes from the internal carotid artery through the ophthalmic artery and its branches

Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024891 Copyright q 2004 by Marcel Dekker, Inc.

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The technique also yielded additional physiologic data. Gee et al.[10] calculated ocular blood flow from the pulse rate and amplitude of the ocular pulse wave, demonstrating a significant decrease in flow in those patients with hemodynamically significant obstruction. Further, the pulse wave morphology provides noninvasive correlation with intracranial pressure. Morphologically, the normal pulse wave obtained using the OPG lacks a dicrotic notch, reflecting the low resistance of the intracranial circulation and the damping effect of the carotid siphon. In a study of 81 head-injured patients,[11] Gee et al. observed a consistent relationship between increased intracranial pressure measurements and the presence of a dicrotic notch (Fig. 8-6). While no longer routinely employed as part of the noninvasive cerebrovascular evaluation, the technique does provide objective physiologic data regarding the

Figure 8-1. The common carotid artery and its bifurcation, demonstrating the branches of the internal and external carotid arteries.

a framework on which to discuss the anatomy and hemodynamics of the carotid circulation and the collateral pathways that are associated with stenosis or occlusion of the internal carotid artery. Ocular pneumoplethysmography employed a system of induced and controlled ocular hypertension to measure ophthalmic artery pressure. Ocular pulse volume changes were recorded using hemispherical cups (15 mm in diameter) applied to the sclera of each eye and held in place by a vacuum. As the vacuum was increased, the intraocular geometry was distorted and the intraocular pressure increased. The amount of vacuum applied correlated with the intraocular pressure, and thus it was possible to determine the pressure at which ophthalmic artery flow ceased—which corresponded to the ophthalmic artery systolic pressure (OAP). As initially conceived, measurement of ophthalmic artery pressure was combined with ipsilateral common carotid artery compression, as a means of measuring collateral cerebral blood flow.[7] In 1977, Gee and associates[8] first reported use of the OPG as a screening device to determine the presence of hemodynamically significant carotid disease (Fig. 8-5). While the OPG could neither distinguish between stenosis and occlusion nor quantitate the degree of stenosis, the sensitivity of the technique was a direct function of the percentage stenosis. As the OPG provided a measure of the extent of collateral circulation, it was also possible to document the increase in distal internal carotid artery pressure following carotid endarterectomy. In 14 of 15 patients[9] with a hemodynamically significant stenosis and a contralateral occlusion, endarterectomy of the stenotic artery resulted in hemodynamic improvement on the ipsilateral side, with an average increase in the OAP of 17 mmHg. In addition, 12 of 15 patients also demonstrated improvement on the contralateral side, with an average increase in the OAP of 12 mmHg.

Figure 8-2. The direction of flow is indicated in the absence (A) and presence (B) of a hemodynamically significant stenosis.

Chapter 8.

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Figure 8-3. Experimental data obtained from the monkey (Macaca speciosa) demonstrating the source of the transorbital Doppler signal. Illustrated is a continuous recording of the electrocardiogram (ECG) and mean amplitude (AMP) and frequency (FREQ) of the ophthalmic artery Doppler signal. There is a marked decrease in the amplitude and frequency of the Doppler signal with common carotid (A), internal carotid (C), and ophthalmic artery (D) compression. There were no changes with external carotid artery compression. (From Maroon JC, Pieroni DW, Campbell RL. Ophthalmosonometry: An ultrasonic method for assessing carotid blood flow. J Neurosurg 30:238 –246, 1969.)

hemodynamic significance of a stenosis and the extent of collateral circulation, which cannot be obtained with direct imaging techniques. In those patients with a high carotid bifurcation, which may prevent direct visualization of the distal internal carotid artery, indirect techniques may indicate the presence of distal obstructive disease.

DOPPLER ULTRASOUND Most early noninvasive techniques were dependent upon Doppler ultrasound. In theory, when transmitted ultrasound strikes a moving interface, the frequency of the reflected wave is shifted in proportion to the velocity of that interface. The Doppler velocimeter was the practical application of this principle. The Doppler transducer, a polarized, synthetic, ceramic crystal with piezoelectric properties, emits a high-frequency, ultrasonic pressure wave with the application of an electrical field.[12 – 14] When the transmitted ultrasonic waves are reflected from moving red blood cells, the frequency of the transmission is altered, or shifted, in proportion to the velocity

of the blood cells. The reflected ultrasonic wave then strikes the same, or a second, piezoelectric crystal, producing a voltage that is proportional to the frequency of the wave. The resulting frequency shift, relative to the transmitted frequency, may then be interpreted as an audible signal or an analogue recording. The Doppler effect is used to explain the frequency shift that occurs when transmitted ultrasound is reflected from a moving interface, such as red blood cells. The velocity of blood flow (V) can then be determined from the following relationship: V¼

DF m 2 cos Q f o

where DF is the frequency shift; m is the speed of sound through blood; Q is the probe angle relative to the longitudinal axis of the blood vessel; and fo is the transmitted frequency. If the above relationship is rewritten, it is evident that the magnitude of the frequency shift is related not only to the velocity of blood flow, but also to the transmitted frequency

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Figure 8-4. Normal ophthalmic artery Doppler tracing (A), demonstrating forward (+) flow. Common carotid artery compression (B) results in a decrease in forward flow, and intraoperative clamping of the internal carotid artery (C) results in flow reversal. (From Muller HR. The diagnosis of internal carotid artery occlusion by directional Doppler sonography of the ophthalmic artery. Neurology 22:816– 823, 1972.)

( fo) and the probe angle (Q): DF ¼

2 cos QV f o m

While the magnitude of the frequency shift is directly related to the transmitted frequency ( fo), absorption of the

ultrasound by tissue is proportional to the square of the transmitted frequency ð f 2o Þ: Thus greater tissue penetration is achieved at lower frequencies, but at the expense of a decrease in the magnitude of the frequency shift.[13,14] The optimum frequency ( fopt) is related to the depth (d) in centimeters, by the following relationship:[15] f opt ¼ 9=d The Doppler transducer can be modified to permit continuous or pulsed (gated) sampling of the reflected ultrasound. The continuous-wave transducer has two piezoelectric crystals, one of which transmits the ultrasound while the other continuously receives a reflected, Doppler-shifted sound wave. The ultrasound is reflected from red blood cells across the diameter of the vessel, so that the reflected and Doppler-shifted frequencies represent a range of red cell velocities within the plane of insonation. The pulsed Doppler

Figure 8-5. Study obtained using the OPG-G. The ophthalmic artery pressures are determined using the center scale, The left ophthalmic artery pressure (52 mmHg) is less than two-thirds of the brachial systolic pressure (L. arm, 134 mmHg £ 0:66 ¼ 88), indicating a hemodynamically significant obstruction of the left common or internal carotid artery.

Figure 8-6. Two tracings obtained with the OPG-G illustrating a normal pulse wave contour (A) and one with catacrotic or dicrotic notching (B, arrow).

Chapter 8.

transducer has a single crystal, which alternately transmits and receives ultrasound. The time during which reflected ultrasound is received, relative to the preceding transmission, determines the depth, or distance from the probe, at which the reflected ultrasound is sampled. This permits flow velocity measurements within a discrete sampling area, such as the midstream of an artery (Fig. 8-7). While the magnitude of the frequency shift is directly related to flow velocity, the direction of the frequency shift is a function of the direction of flow. Flow toward the transducer results in a Doppler-shifted frequency that is greater than the transmitted frequency, while flow away from the transducer results in a decrease relative to the transmitted frequency. A continuous-wave directional Doppler velocimeter was employed in the cerebrovascular Doppler examination to determine the direction and amplitude of periorbital blood flow. Both continuous-wave and pulsed Doppler velocimeters have also been used in an attempt to quantify, noninvasively, the degree of stenosis. Since flow (Q) is a function of velocity (V) and cross-sectional area (A), Q ¼ VA velocity is directly related to flow and indirectly related to cross-sectional area:

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visualization of the artery. Identification of the branches of the carotid artery is dependent upon the relationship of the transducer to the bifurcation. When the transducer can be positioned so that the scanning plane includes the internal and external carotid arteries, an image demonstrating the bifurcation and its branches is obtained (Fig. 8-8; see also color plate). In 70% of cases, however, the probe must be moved laterally from the bifurcation to visualize the internal carotid artery or medially to visualize the external carotid artery. The spatial relationship of the bifurcation to the external and internal carotid arteries is illustrated in Fig. 8-9. Early data published by Hobson and associates[16] demonstrated that real-time B-mode imaging had an 89% specificity for the absence of significant carotid disease. There was a 58% sensitivity to the presence of stenoses exceeding 50% and only an 18% sensitivity to carotid occlusion. In this early study, B-mode imaging was particularly useful in excluding disease in those patients with normal arteries and in characterizing hemodynamically insignificant stenoses. The real-time instrument provided images of high resolution that defined the relationship between the arterial wall and the atherosclerotic plaque, characterizing as well the size and ultrasonic morphology of the plaque. The presence of calcification and shadowing interfered with the characterizatican of high-grade stenoses or carotid occlusion.

V ¼ Q=A If flow is constant, then the velocity of flow must increase as the cross-sectional area of the artery is reduced by stenosis. The Doppler frequency shift is directly related to flow velocity. Velocity may be derived from the measured frequency shift if the insonant angle, relative to the axis of the artery, is known. Using spectral analysis, the arterial flow velocity profile can be characterized using the output of continuous-wave and pulsed Doppler velocimeters. Spectral data may be expressed as the Doppler shifted frequency or as velocity.

REAL-TIME B-MODE IMAGING Depending upon the signal processing algorithm, ultrasound may be used not only to determine the direction and velocity of a moving interface, but also to sense the depth and amplitude of signals reflected from a stationary interface, thus creating a visual image of subjacent structures. The amplitude of the reflected signal is proportional to the difference in density of two adjacent media. B-mode ultrasonic imaging employs time relationships to sense the depth of the interface and brightness variations to express differences in amplitude. If the changes in the reflected ultrasound can be displayed at a sufficient rate (greater than 15 frames per second) then a realtime image can be obtained. Real-time B-mode imaging of the cervical carotid artery is routinely performed with the patient in a supine position, with the neck slightly extended and the head rotated away from the side of examination. Longitudinal scans are obtained in planes anterior, lateral, or posterior to the carotid artery. The transducer is then rotated 90 degrees for cross-sectional

DUPLEX ULTRASONOGRAPHY Using a position sensing arm and a storage oscilloscope, continuous-wave or pulsed Doppler instruments could be used to generate a static, flow-dependent image of the carotid artery and its branches (Fig. 8-10). Hobson and associates[16] demonstrated that pulsed Doppler ultrasonic imaging had a 100% sensitivity to carotid occlusion in the same group of patients in which B-mode imaging alone had only an 18% sensitivity. These results can be explained by the differences in approach to vascular imaging. Pulsed Doppler imaging is based on the presence of flow and might reasonably be expected to demonstrate occlusion or absence of flow with a high degree of accuracy. Images produced by real-time Bmode ultrasonography, which demonstrate anatomical relationships rather than flow, might not be as accurate. Similarly, analysis of the Doppler spectral profile might provide a more quantitative assessment of high-grade stenoses, which morphologically can be associated with calcification, shadowing and varying degrees of organization. Duplex ultrasonography is the result of combining pulsed Doppler velocimetry (and spectral analysis) with real-time Bmode imaging. Spectral data may be expressed as the Doppler shifted frequency or as velocity. Both values increase in direct relationship to the percentage stenosis or reduction in cross sectional area. Theoretically some authors have concluded that spectral data, expressed as velocity, are of greater predictive value and more reproducible because they take into account and normalize for differences in probe angle which may effect frequency measurements. Beach,[17] however, has suggested that Doppler-derived velocity measurements are less significant at the carotid bifurcation because flow at

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changes in spectral distribution than is the continuous-wave Doppler. Spectra obtained using a continuous-wave Doppler reflect the velocity profile across the diameter of the artery. Because the normal, laminar flow profile is parabolic, lowvelocity flow at the periphery is insonated along with midstream high-velocity flow resulting in relative spectral broadening. The pulsed Doppler, on the other hand, reflects the velocity profile within a discrete sample area. Thus the midstream profile demonstrates a discrete spectral envelope without significant spectral broadening.

DOPPLER QUANTITATION OF CAROTID STENOSIS Figure 8-8. Longitudinal scan of the carotid bifurcation demonstrating the common carotid artery (Common), the proximal internal carotid artery (INT) and the external carotid artery (EXT). The scan was obtained with the probe imaging from top (superficial tissues) to bottom. (See also color plate.)

the bifurcation can be helical. The question of whether to use Doppler-shifted frequency or velocity as the measure of carotid stenosis remains unsettled. Of 54 duplex imaging devices evaluated at study sites prior to the Asymptomatic Carotid Atherosclerosis Study (ACAS),[18] the primary Doppler measure was reported as velocity, expressed in centimeters per second, from 24 devices and as frequency, expressed in hertz, from 30. The normal internal carotid artery has a prominent diastolic flow component. The velocity profile reflects the laminar flow pattern and is tightly distributed about the midstream velocity[19,20] (Fig. 8-11). This results in an open area, or “window,” beneath the peak systolic envelope. In addition to the increase in peak systolic velocity (frequency) that occurs with increasing stenosis, there is also poststenotic turbulence. This loss of the laminar flow profile results in disordered, low-velocity flow patterns. These are reflected in a shift in the spectral distribution, with increased low-velocity flow and an opacification of the “window” (Fig. 8-12). The shift, or abnormal spectral distribution, associated with increasing stenosis is also referred to as spectral broadening. When interpreting the spectral profile, differences between pulsed and continuous-wave Doppler instrumentation need to be considered. The pulsed Doppler is more sensitive to

Arteriography is the standard against which all noninvasive studies are commonly compared. While arteriography is the only practical standard at present, it is not a perfect standard. Since arteriography yields a two-dimensional image of a three-dimensional process, the extent of disease may be overor underestimated, depending upon which plane or planes of the artery are imaged. (Fig. 8-13). Sensitivity and specificity are used to express the accuracy of a technique relative to a standard, in this case arteriography. The sensitivity of a technique is defined as the percentage of those arteries with arteriographically demonstrated disease that are correctly identified noninvasively. Specificity is defined as the percentage of those arteries without arteriographically demonstrated disease that are correctly identified noninvasively (Table 8-1). Early noninvasive studies focused on the diagnosis of hemodynamically significant disease. May et al.[21] had shown experimentally that the cross-sectional area of the internal carotid artery must be reduced by 75% before flow is decreased distal to the obstruction. This is equivalent to a 50% reduction in diameter as visualized arteriographically. Initially, the peak systolic velocity (frequency), the relative distribution of velocities (frequencies) within the spectral profile, and the end-diastolic velocity (frequency) were used in an attempt to characterize the extent of disease. Using pulsed Doppler spectral analysis, Blackshear and associates from the University of Washington[22] first constructed a relationship between spectral broadening, peak systolic frequency, and the percentage stenosis. In the normal artery, the midstream spectral profile shows no opacification of the peak systolic window (Fig. 8-12, left). There were lesser degrees of spectral broadening, but no

Figure 8-7. The sampling range of the continuous-wave Doppler velocimeter (A, top) encompasses the entire diameter of the insonated vessel. The range of the pulsed Doppler velocimeter (B, top), however, is limited to a small sample volume, the relative position of which is dependent upon the time relationship between the transmitting and the receiving modes of the single piezoelectric crystal. In the example, an ultrasonic wave is emitted at time t ¼ 0; only at time t ¼ 18 msec does the crystal receive a wave, which was reflected from the midstream of the vessel. A parabolic profile characterizes laminar flow at peak systole. The midstream spectral profile obtained with a pulsed instrument (B, bottom) reflects the well-defined spectral envelope and window which are characteristic of midstream flow velocity. The spectral profile obtained with a continuous-wave instrument (A, bottom), however, is characterized by a relative spectral broadening. Because the continuous-wave velocimeter reflects the velocity profile across the entire diameter of the vessel, the spectral envelope is more divergent and the window less well defined.

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Figure 8-9. Spatial relationships are relevant to the appearance of real-time images. An artist’s conception of various anatomical examples. (From Hobson RW, Berry SM, Lynch TG. Applications of B-mode ultrasonography and ocular pneumoplethysmography in the diagnosis of carotid occlusive disease. In Bergan JJ, Yao JST (eds), Cerebrovascular Insufficiency. New York, Grune and Stratton, 1983, pp 165–177.)

increase in peak systolic frequency, when stenoses ranged from 10 to 49%. Total opacification of the spectral window and an increase in peak systolic frequency were associated with hemodynamically significant 50–99% stenoses (Fig. 8-12, right). Using these criteria, they correctly identified 88% ðn ¼ 8Þ of normal arteries, 78% ðn ¼ 23Þ of those arteries with 10–49% stenoses, and 100% ðn ¼ 22Þ of those with 50–99% stenoses. The University of Washington categories were subsequently modified[23] to classify disease as absent (normal artery), mild (1 –15% diameter reduction), moderate (16–49% diameter reduction), severe (50 – 99% diameter reduction), and occluded. In an attempt to characterize more

precisely those stenoses from 50 to 99%, Roederer et al.[24] used pulsed Doppler ultrasound and measured the enddiastolic frequency. Using 4.5 KHz as a cutoff they correctly identified 88% of stenoses less than 80% and 84% of those greater than 80%. While some authors attempted to further narrow the categories within which stenotic disease was classified, refinements in the classification initially appeared useful only in studies attempting to characterize the natural history of carotid disease. The duplex criteria as initially defined by the group at the University of Washington remained useful until publication of the results of the European Carotid Surgery

Figure 8-10. A continuous-wave Doppler ultrasonic image (right) of a normal carotid artery bifurcation. The image is relative and is not useful in quantitating the degree of stenosis. Diagnostic implications are drawn from an analysis of the spectral profile.

Chapter 8.

Figure 8-11. Spectral profile of laminar flow in a normal internal carotid artery obtained using a continuous-wave (left) and pulsed (right) Doppler probe. The profiles demonstrate a well-defined spectral envelope and window (see Fig. 8-7). (Right, from Zierler RE, Roederer GO, Strandness DE. The use of frequency spectral analysis in carotid surgery. In Bergan JJ, Yao JST (eds), Cerebrovascular Insufficiency. New York. Grune and Stratten, Inc., 1983, pp 137 – 163.)

Trial (ECST), the North American Symptomatic Carotid Endarterectomy Trial (NASCET), and the Asymptomatic Carotid Atherosclerosis Study. The ECST concluded that the risks of surgery were significantly outweighed by later benefits in those patients with a 70–99% stenosis of the carotid artery. The risk of surgical morbidity and mortality and subsequent stroke was 12.3% in the surgical arm of the study and 21.9% for the control group.[25] The NASCET demonstrated an early and significant benefit associated with carotid endarterectomy in symptomatic patients with an ipsilateral internal carotid artery stenosis greater than 70%. The cumulative risk of ipsilateral stroke at 2 years was 26% in the medically managed patients and 9% in the surgical group.[26] A second publication from the NASCET group demonstrated a benefit to carotid endarterectomy in symptomatic patients with a 50 –69%

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stenosis. Compared to those patients who had a 70 –99% stenosis, the benefits of surgery in this group required a longer period of follow-up to achieve significance. The 5-year rate of ipsilateral stroke was 15.7% in those patients treated surgically and 22.2% in those treated medically.[27] The ACAS concluded that asymptomatic patients with an internal carotid artery stenosis $ 60%, could benefit from carotid endarterectomy. The aggregate five-year risk of ipsilateral stroke and perioperative stroke and death was 5.1% for the surgical group and 11.0% for the medical group.[28] These three trials introduced clinically relevant criteria for the pharmacological and surgical management of symptomatic and asymptomatic carotid occlusive disease. The new criteria did not correspond to the categories initially defined by researchers at the University of Washington. To further complicate decision making, the three groups of trialists had not adopted a uniform method for the quantification of angiographically defined carotid occlusive disease (Fig. 8-14). Researchers working at the University of Washington had compared Doppler spectral parameters to angiographic stenosis determined relative to the estimated normal diameter of the carotid bulb. While this definition had been adopted in the ECST, it was not the definition that had been employed in the NASCET and ACAS trials. The latter two had determined angiographic stenosis by comparing the least transverse diameter of the carotid artery at the stenosis, with the diameter of the distal uninvolved internal carotid artery. This resulted in an underestimation of stenoses relative to the criterion initially proposed at the University of Washington and that adopted by the ECST. Yet a third methodology proposed that the percentage stenosis be determined relative to the diameter of the visible, disease-free distal common carotid artery.[29 – 33] Eliasziw et al.[31] found the relationship between the percentage stenosis calculated according to the NASCET protocol and that using the common carotid artery diameter to be linear. Rothwell et al.[33] found no significant difference between the three methods in their ability to predict ipsilateral ischemic stroke, but did find that the method employing a common carotid artery reference was consistently the most

Figure 8-12. Normal spectral profile characteristic of the pulsed Doppler velocimeter (left) and profiles demonstrating the changes that occur with progressive stenoses (right). (From Zierler RE, Roederer GO, Strandness DE. The use of frequency spectral analysis in carotid artery surgery. In Bergan JJ, Yao JST. (eds), Cerebrovascular Insufficiency. New York, Grune and Stratton, Inc., 1983, pp 137 – 163.)

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Statistical Calculations Used in the Evaluation of Noninvasive Cerebrovascular Diagnostic Techniques

Table 8-1.

Noninvasive examination Carotid arteriography

Abnormal

Normal

Positive (stenosis or occlusion) Negative Sensitivity Specificity Positive predictive value Negative predictive value Accuracy

A C B/A+B D/C+D A/A+C D/B+D A+D/A+B+C+D

B D

CURRENT CLINICAL APPLICATIONS OF DUPLEX IMAGING

Figure 8-13. (A) The assumed, or apparent, degrees of diameter and area stenosis when an asymmetrical lesion is visualized in different projections. (From Sumner DS, Russell JB, Miles RD. Pulsed Doppler arteriography and computer assisted imaging of the carotid bifurcation. In Bergan JJ, Yao JST (eds), Cerebrovascular Insufficiency. New York, Grune and Stratton, Inc., 1983, pp 115 – 135.) (B) The relationship between area stenosis and diameter stenosis when the artery is asymmetrically narrowed (upper and lower lines) and when it is symmetrically narrowed (middle line). Arrows indicate the direction of the x-ray beam in the projection that shows the greatest degree of narrowing. (From Sumner DS, Russell JB, Miles RD. Pulsed Doppler arteriography and computer assisted imaging of the carotid bifurcation. In Bergan JJ, Yao JST (eds), Cerebrovascular Insufficiency. New York, Grune and Stratton, Inc., 1983, pp 115 –135.)

reproducible. The Committee on Standards for Noninvasive Vascular Testing of the Joint Council of the Vascular Societies[34] recognized that any approach to estimating the angiographic degree of stenosis was a compromise and would have inherent limitations. Nonetheless, the committee recommended that% diameter reduction should be determined relative to the distal internal carotid artery.

Initially noninvasive studies were used to screen individuals for evidence of atherosclerotic involvement of the cervical carotid artery. Such patients included those with asymptomatic cervical bruits; those with symptoms of posterior circulation or vertebrobasilar insufficiency; candidates for major cardiac and vascular reconstructive procedures; those with associated risk factors predisposing to atherosclerotic occlusive disease; and those symptomatic patients with a history of transient ischemic events or stroke. Asymptomatic and symptomatic patients without evidence of significant disease could be treated on the basis of imaging studies alone, but those with evidence of significant disease required arteriographic confirmation of disease prior to surgery. While contrast arteriography has been a prerequisite to surgical intervention, the role of preoperative noninvasive imaging is being critically reevaluated based on criteria established by the ECST, NASCET, and ACAS groups. As a screening test, sensitivity to the presence of disease was of critical importance; as a preoperative study in lieu of arteriography it may of value to modify noninvasive diagnostic criteria based on the risk of surgery (and arteriography) and the expected benefits of the procedure. Thus the positive and negative predictive values of a criterion become important and Doppler criteria are frequently evaluated relative to receiver operator characteristic curves. The positive predictive value represents the percentage of noninvasively abnormal studies which are also abnormal by contrast arteriography, while the negative predictive value represents the percentage of negative noninvasive studies which are associated with normal arteriograms. Unlike sensitivity and specificity, which characterize the percentage of arteriographic studies that are correctly classified noninvasively, the positive and negative predictive values yield the percentage of noninvasive studies that are in agreement with arteriography. Thus the predictive value represents the probability that a given noninvasive test result will accurately reflect arteriographic findings. Receiver operator characteristic (ROC) curves are used to demonstrate the relationship of sensitivity, specificity, positive predictive value, negative predictive value, and accuracy across a spectrum of criteria used to classify the presence or absence of disease (Table 8-2, Fig. 8-15).

Chapter 8.

Noninvasive Cerebrovascular Diagnostic Techniques

Figure 8-14. Measurements used for calculation of the percentage stenosis employing the University of Washington/ ECST method, the NASCET method, and common carotid artery reference (CC).

Attempts to redefine Doppler criteria relative to the significant ranges of carotid disease defined by clinical trials have demonstrated that multiple factors can influence the resulting criteria, including parameters measured, manufacturer specific equipment, individual laboratories, and associated (contralateral) disease. Doppler measures correlated with angiographic stenosis have included the peak systolic velocity (PSV) and end-diastolic velocity (EDV) in the internal carotid artery and ratios of the PSV or EDV measured in the internal carotid artery (at the point of stenosis) and from the common carotid artery (i.e., ICA PSV/CCA PSV). Using ROC curves to compare sensitivity, specificity, PPV and NPV, Faught et al.[35] concluded that the combination of a PSV greater than 130 cm/s and an EDV greater than 100 cm/s

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provided the optimal criteria for diagnosis of a 70 –99% stenosis. Figure 8-15 and Table 8-2 illustrate the ROC curve, and the statistical measures of accuracy generated from the curve, for differentiating a less than 70% stenosis from one equal to or greater than 70%. These demonstrate that a PSV of 210 cm/s yields the highest overall accuracy (93%), but a poor PPV (75%). By combining PSV and EDV, the authors were able to achieve an overall accuracy of 95%, with a sensitivity of 81%, a specificity of 98%, a PPV of 89%, and a NPV of 96%. Using a similar approach, but arriving at a different criterion, Moneta et al.[36] concluded that an ICA PSV/CCA PSV ratio greater than 4.0 provided the best combination of sensitivity (91%), specificity (87%), PPV (76%), NPV (96%), and overall accuracy (88%) for the diagnosis of a 70 –99% stenosis. Yet a third set of criteria were proposed by Carpenter et al.[37] They suggested that a combination of PSV (. 210 cm/s), EDV (. 70 cm/s), ICA PSV/CCA PSV (. 3.0), and ICA EDV/CCA EDV (.3.3) provided optimal criteria for detection of a greater than 70% stenosis. Recent publications clearly demonstrate that Doppler criteria are equipment (manufacturer) and laboratory specific and may explain this variability in published criteria. Alexandrov et al.[38] compared two independent laboratories using similar equipment. Eighty-seven patients (174 bifurcations) underwent imaging in both laboratories, as well as intra-arterial digital subtraction angiography. Applying criteria from one laboratory to studies performed in the second resulted in a 43% reduction in sensitivity and a 15% reduction in PPV. Fillinger et al.[39] compared the duplex criteria for a 60% angiographic stenosis from two laboratories, employing four different scanners. Doppler criteria to obtain a PPV greater than 90% and an accuracy greater than 90% differed, with ICA PSV/CCA PSV ratios varying from 2.6 to 3.3 and PSV in the internal carotid artery varying from 190 to 240 cm/s. Ranke et al.[40] recorded peak systolic velocity in 21 patients using color-flow duplex systems from two different commercial manufactures.

Relationship Between Sensitivity, Specificity, PPV, NPV, and Accuracy of Varying ICA PSVs Differentiating 70% Stenosis from Stenosis $ 70%

Table 8-2.

ICA PSV . (cm/s) 140 150 160 170 180 190 200 210 220 230 240 250

Sensitivity

Specificity

PPV

NPV

Accuracy

96.2 96.2 94.7 94.7 94.0 94.0 91.0 88.7 82.7 75.2 63.9 53.4

84.6 85.9 87.4 89.0 90.6 90.9 92.6 93.9 94.4 95.5 96.4 97.3

56.6 58.7 61.2 64.3 67.6 68.3 72.0 75.2 75.3 77.5 78.7 80.7

99.1 99.1 98.8 98.8 98.6 98.6 98.0 97.6 96.3 94.9 92.8 90.9

86.6 87.7 88.7 90.9 91.2 91.4 92.3 93.0 92.3 92.0 90.8 89.7

(From Faught WE, Mattos MA, van Bemmelen PS, Hodgson KJ, Barkmeier LD, Ramsey DE, Sumner DS. Color-Flow Duplex Scanning of Carotid Arteries: New Velocity Criteria Based on Receiver Operator Characteristic Analysis for Threshold Stenosis Used in the Symptomatic and Asymptomatic Carotid Trials. J. Vasc. Surg. 1994, 19, 818 –828.)

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Figure 8-15. ROC curve of the peak systolic velocity (cm/s) for differentiating between a stenosis of less than 70% and one that is equal to or greater than 70%. The curve demonstrates the relationship between the sensitivity and specificity for the range of velocities from 290 cm/s to 110 cm/s. Table 8-2 expands the measures to show the relationship between peak systolic velocity and the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy. (From Faught WE, Mattos MA, van Bemmelen PS, Hodgson KJ, Barkmeier LD, Ramsey DE, Sumner DS. Color-Flow Duplex Scanning of Carotid Arteries: New Velocity Criteria Based on Receiver Operator Characteristic Analysis for Threshold Stenosis Used in the Symptomatic and Asymptomatic Carotid Trials. J. Vasc. Surg. 1994, 19, 818– 828.)

The peak systolic velocity was significantly higher when measured with one unit compared to the other ð218 ^ 156 cm=s versus 169 ^ 114 cm=sÞ; resulting in a 10% difference in predicted stenosis. Contralateral disease has also been correlated with an increase in carotid volume flow and flow measures, resulting in an overestimation of the severity of disease. Van Everdingen et al.[41] measured mean volume flow in the internal carotid artery using magnetic resonance angiography flow quantification. They demonstrated that flow in an artery with less than 70% stenosis was increased, relative to controls, contralateral to an artery with a greater than 70% stenosis. Busuttil et al.[42] identified 146 patients in whom duplex criteria overestimated disease contralateral to a highgrade stenosis or occlusion. Following carotid endarterectomy, the average peak systolic frequency decreased by 1175 Hz and the end-diastolic frequency by 475 Hz in 44 (of 128) unoperated contralateral stenoses. This resulted in a reduction in the estimate of disease by at least one duplex category.

across the diameter of the artery. Color flow imaging employs a real-time color overlay, superimposed on the gray scale duplex image, which visually demonstrates changes in flow velocity and direction. The diagnostic significance of color-flow duplex imaging continues to be evaluated. It has been demonstrated that colorassisted duplex imaging increases the speed of examination. Polak and associates[43] reported that the determination of peak systolic velocities was 40% faster using color-flow imaging. The peak systolic velocity, measured with and without color assistance, was not significantly different. On average it took 54 seconds to determine velocities using color-assisted techniques compared to 90 seconds with nonassisted techniques. Steinke et al.[44] have suggested that the color-assisted visualization of hemodynamic disturbances increases sensitivity to lesser degress of disease. In comparison to conventional duplex imaging, color flow techniques identified 72 small plaques and 8 minor stenoses in 159 arteries considered normal by conventional techniques. While color imaging may provide the flow image necessary to identify echolucent or anechoic lesions (Fig. 8-16; see also color plate), further information needs to be derived regarding the relationship between the plaque morphology, surface characteristics, and hemodynamic alterations. Only 51% of smooth plaques and 36% of irregular plaques were associated with turbulence. Color-flow techniques have also increased the overall accuracy of duplex imaging in the diagnosis of internal carotid artery occlusion. Bornstein et al.[45] evaluated data from a pooled series representing 2095 arteries. The sensitivity of gray-scale duplex imaging to 248 occluded arteries was 85%; the specificity for 1847 arteries without occlusion was 98%. The positive predictive value of grayscale imaging was 89% and the negative predictive value was 99%. AbuRahma et al.[46] compared the results of color-flow imaging and arteriography for 520 arteries, 103 of which had

COLOR-FLOW DUPLEX IMAGING The development of duplex imaging provided the technology to image arteries in real time, as well as to assess the Doppler velocity (frequency) profile. Color duplex imaging permits the integration of morphologic and hemodynamic information

Figure 8-16. An echolucent plaque in the proximal internal carotid artery. The color-flow image accentuates the luminal reduction and demonstrates increased flow velocities (see color scale to the left) and turbulence distal to the plaque. (See also color plate.)

Chapter 8.

a duplex diagnosis of occlusion or suspected high-grade stenosis/occlusion. The diagnosis of occlusion was based on the absence of flow in the internal carotid artery for at least 1 inch beyond the bifurcation. Near-total or total occlusion was suspected if the internal carotid artery could not be seen beyond the difurcation and there was damping of the common carotid artery signal or internalization of flow in the external carotid artery. In optimal studies, the accuracy of imaging to carotid occlusion was 97%, with a sensitivity of 91%, a specificity of 99%, a positive predictive value of 96%, and a negative predictive value of 98%. Of 12 suspected neartotal/ total occlusions, there were 4 occluded arteries and 8 with stenosis. Mansour et al.[47] evaluated color-flow duplex images of 596 internal carotid arteries for which arteriographic correlation was available. Defining total occlusion as the absence of flow in the internal carotid artery and preocclusive lesions as demonstrating only a trickle of flow, they reported a 98% sensitivity to occlusion, with a negative predictive value of 99%. Eighty-seven percent of preocclusive lesions were correctly identified, with a positive predictive value of 84%. Using color-flow imaging techniques, it has also been possible to assess flow dynamics across the artery in a dynamic fashion. This allows visualization of flow separation within the bulb (Fig. 8-17; see also color plate) as well as identification of turbulent flow profiles distal to stenoses. Ku and associates[48] compared in vitro and in vivo flow studies of the carotid bifurcation using laser Doppler anemometry and Doppler velocity measurements obtained with a Duplex scanner. Within the carotid bulb or sinus it was possible to identify areas of high flow velocity near the inner wall approximating the flow divider. Using a three-dimensional representation of velocity in a model of the proximal internal carotid artery, it was also possible to identify flow reversal in the carotid sinus. The implications of these findings with respect to vessel wall injury and the subsequent development of atherosclerotic plaque remains uncertain, but atherosclerotic involvement of the carotid artery initially involves the posterior and lateral aspect of the bulb and appears to develop in those areas where there is transient flow reversal.

CAN DUPLEX IMAGING REPLACE CAROTID ARTERIOGRAPHY? The logical extension of the advances in technology associated with carotid imaging and spectral analysis is decreased reliance on contrast arteriography in the preoperative assessment and evaluation of patients with suspected carotid obstructive disease. While arteriography may seem to be a reasonable adjunct in this evaluation, issues of cost, the incidence of complications, and patient discomfort become significant considerations. Carotid arteriography has been estimated to cost between $1,000 and $4,000 and can represent approximately 15% of the total expense associated with carotid endarterectomy.[49 – 53] Complications may result from direct arterial injury, contrast reaction, dye-induced renal failure, and embolic events. The

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reported incidence of complications associated with carotid arteriography varies from 0.2 to 2%. The best-documented data come from the ACAS and NASCET trials. In the ACAS, the incidence of cerebral infarction associated with arteriography was 1.2%, representing almost half of the operative risk.[28] There were four strokes and one death among the 414 patients who underwent arteriography. There was a 0.65% stroke rate among 2320 patients undergoing angiography in the NASCET.[26] In order to determine the value of carotid arteriography, it is first necessary to consider the information provided by an arteriogram. Arteriography was the standard used to quantify the percentage stenosis in the three studies validating the role of carotid endarterectomy in the treatment of symptomatic and asymptomatic carotid obstructive disease. In addition to quantifying the extent of atherosclerotic disease involving the carotid bifurcation, bulb and proximal internal carotid artery, arteriography also provides evidence of associated disease involving the arch, the origin of the great vessels, and the intracranial circulation. Eliasziw and associates,[54] writing for the NASCET group, concluded that the accuracy of ultrasonography and spectral data was “moderate” in the quantification of carotid stenosis. They felt that arteriography remained an essential component of the assessment prior to carotid endarterectomy. The NASCET, however, had randomized patients based on arteriographic data, and Eliasziw and associates had assigned duplex criteria for the diagnosis of a 70% stenosis retrospectively based on a review of the literature. Sensitivity and specificity varied from 0.65 to 0.71 using peak systolic velocity, peak frequency shift, and the ratio of peak velocity or frequency change in the internal carotid and the common carotid arteries. The authors did not account for laboratory or machine specific differences. Howard and associates[55] came to a different conclusion based on the ACAS data. Prior to the study an attempt was made to establish machine-specific criteria for each of the instruments that might be used in the study. Criteria were set to provide a 90% positive predictive value of a 60% angiographic stenosis. Using those criteria, sensitivity varied from excellent (80+%) in 21% of instruments to marginal (50–80%) in 51%. In 14% of instruments the sensitivity was less than 50%, and in 14% criteria could not be established. Despite the variation in sensitivity, Doppler-defined stenoses of greater than 60% were confirmed in 92% of 395 patients coming to angiography. The authors concluded that using protocols for standardization, the results of duplex ultrasonography could be used as the sole basis for carotid endarterectomy. Published series reporting carotid endarterectomy without preoperative arteriography have generally been small and uncontrolled. The surgical indications cited have frequently provided a relative (potential) contraindication to arteriography, including contrast allergy, disease progression on serial imaging, preocclusive lesions, crescendo TIAs, concurrent and acute surgical problems, unstable angina, and aortoiliac disease. Validation of the practice has been based on perioperative morbidity and mortality and operative confirmation of preoperative imaging studies. Several retrospective studies, however, have compared the relative value of noninvasive imaging and arteriography prior to carotid endarterectomy. Ricotta et al.[56]

Figure 8-17. A color image of the carotid bifurcation during systole (A) demonstrating flow in the internal (I) and external (E) carotid arteries. Color assignments are arbitrary, with shades of red generally representing forward arterial flow and shades of blue representing venous flow. During late systole and early diastole (B), there is evidence of flow reversal (blue/white shaded area) in the carotid bulb. (See also color plate.)

Chapter 8.

reviewed the records of 111 consecutive patients undergoing evaluation who had noninvasive assessment and arteriography. Of those patients with hemispheric symptoms, angiography was necessary in 11%, useful in 20%, and unnecessary in 69%. In asymptomatic patients, arteriography was necessary in 7%, useful in 20%, and unnecessary in 73%. For patients with nonhemispheric symptoms, arteriography was necessary in 31%, useful in 50%, and unnecessary in 19%. The study by Ricotta and associates employed early noninvasive techniques including OPG and continuous-wave Doppler ultrasonography. Moore et al.[57] reported on a prospective study in which history, physical findings, and duplex imaging were used to develop a proposed anatomic diagnosis. The anatomic diagnosis demonstrated a 94% correlation with arteriography. Preoperative assessment was 100% predictive of carotid occlusion and hemodynamically significant disease, 96% predictive in asymptomatic patients, and 91% predictive in symptomatic patients. Preoperative assessment was least effective in patients with nonstenotic ulceration (64% predictive). Mattos et al.[58] compared color-flow duplex imaging and arteriography in 167 patients being evaluated for possible carotid endarterectomy. The two diagnostic methods agreed exactly in 82% of patients. Duplex diagnosis was within one category of the arteriographic standard in 99% of cases. More importantly, however, clinical management was altered by arteriography in only 4% of cases. Similarly, Dawson and associates[59] prospectively evaluated the clinical decisionmaking process in 103 patients. Of the 94 patients undergoing arteriography, duplex imaging was diagnostic in 93%. If technically inadequate scans were excluded, arteriography affected clinical management in only one case. Technically inadequate studies were associated with disease that extended distally beyond the proximal internal carotid artery, anatomic or pathologic features that interfered with carotid imaging, or an inability to distinguish internal carotid artery occlusion from high-grade stenosis. Since duplex imaging techniques could be used to quantify the extent of carotid disease present, what is the incidence and significance of associated atherosclerotic involvement of the arch and great vessels or of the intracranial arteries? Akers et al.[60] evaluated the arteriographic studies of 1000 patients who underwent arch and four-vessel arteriography for suspected carotid occlusive disease. Eighteen patients (1.8%) had involvement of the arch and great vessels. In 12 of the patients the presence of the obstruction could be suspected on the basis of unequal brachial pressures. Eighty-seven had absence or stenosis of one or both vertebral arteries. Kadwa et al.[61] prospectively evaluated 129 consecutive patients undergoing evaluation for carotid endarterectomy. Pulse and blood pressure were recorded in both upper extremities, supraclavicular bruits were noted, and duplex flow velocity was assessed in the common carotid arteries. Nineteen patients (14.7%) had aortic branch disease, including 6 with disease involving the common carotid artery, 3 with involvement of the innominate artery, and 10 with involvement of the subclavian artery. Involvement of the arch branches was identified on physical examination or with duplex imaging in all cases.

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The incidence of intracranial disease varies depending upon the definition employed. Akers et al.[62] reported a 6% incidence of siphon stenosis in a series of 784 patients. The stenoses ranged from 5 to 70%, and no stenosis greater than 75% was identified. Roederer et al.[63] reported an 84% incidence of siphon stenosis involving 282 sides in 141 patients. Only 9% of lesions exceeded 50%, and 10% of the arteries were occluded. Mackey et al.[64] identified complete angiographic data on 597 patients. Significant intracranial disease was classified as identifiable plaque (, 80% stenosis), stenosis (. 80% stenosis), and occlusion. Two hundred lesions were present in 134 patients. Sixty-six% of the lesions involved the siphon, 20% the posterior communicating artery, 6% the anterior communicating artery, 4% the middle cerebral artery, and 4% the basilar artery. While the incidence of significant intracranial disease (greater than 50%) is generally low, it is variable. The critical question, however, is not the incidence but the effect of concurrent disease on outcome. Schuler et al.[65] demonstrated increased morbidity and mortality in 35 patients (44 endarterectomies) with associated intracranial disease. There was a 4.5% incidence of intraoperative stroke, a 6.8% incidence of perioperative stroke, and a 9.1% mortality. There were no intraoperative or perioperative strokes and a 2.1% mortality in a group of 44 patients (47 endarterectomies) without associated intracranial disease. These differences were not significant, but the number of patients was small. In a larger series reported by Mackey et al.,[64] there were 134 patients with associated intracranial disease and 463 without evidence of intracranial disease. The authors demonstrated no significant difference in perioperative stroke or mortality associated with intracranial disease. The incidence of perioperative stroke and mortality in the group of patients with intracranial disease was 1.9% and 0.5%, respectively, and that associated with the absence of intracranial disease was 1.8% and 0.7%, respectively. The consideration of intracranial disease must also take into account the incidence of intracranial aneurysms. Akers et al.[62] reported a 2% incidence of intracranial aneurysms in 784 patients. Ladowski et al.[66] reported on the results of carotid endarterectomy in 19 patients, with a symptomatic carotid stenosis and an associated intracranial aneurysm, undergoing 20 operations. The aneurysm was ipsilateral to the symptomatic stenosis in 10 patients, contralateral in 9, and involved the basilar artery in one. There was no perioperative stroke or mortality and no perioperative complications associated with rupture of the intracranial aneurysm. The data would suggest that those patients with significant disease involving the proximal branches of the aortic arch can be identified on the basis of physical examination or noninvasive assessment. Such patients could undergo arteriography on a selective basis. While the incidence of intracranial disease is variable, the presence of an intracranial stenosis or aneurysm does not appear to significantly increase the morbidity and mortality associated with carotid endarterectomy. Thus it would appear that arteriography could be supplanted by duplex imaging if criteria for the quantification of disease involving the carotid bifurcation could be developed and validated. While criteria for the quantification of carotid stenosis are variable, suitable

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laboratory-specific criteria can be developed using ROC curves. This statistical technique, in addition, allows criteria to be tailored to the indication for evaluation and endarterectomy. Criteria for screening tests can be adjusted to achieve a high sensitivity and positive predictive value so as not to miss disease. Sensitivity can be sacrificed in favor of a high positive predictive value and specificity when validating the presence of operative disease in an asymptomatic patient who will not undergo arteriography. In those patients with symptomatic disease, sensitivity could be maximized at the expense of overall accuracy.

OPERATIVE AND POSTOPERATIVE IMAGING Postoperative surveillance has heightened awareness, and demonstrated an increased incidence, of recurrent stenosis. The reported incidence of restenosis is variable, dependent upon the technique employed for diagnosis and whether asymptomatic as well as symptomatic recurrences are involved. Stoney and String[67] reported a 1.9% incidence of recurrent disease based upon a recurrence of symptoms, while Nicholls et al.[68] and O’Donnell and Callow[69] have documented recurrence rates of 12 –22% based upon the results of noninvasive assessment. Technological improvements in noninvasive diagnostic methods have provided a safe and practical means of serial follow-up after carotid endarterectomy. The use of real-time B-mode imaging has permitted the identification of lesser, hemodynamically insignificant, degrees of restenosis. On the basis of serial noninvasive examinations, utilizing the OPG, spectral analysis, and real-time B-mode imaging, DeGroote et al.[70] identified 69 (28%) arteries with evidence of restenosis following 248 endarterectomies. Thirteen% had hemodynamically significant restenosis and 15% had hemodynamically insignificant recurrence. O’Donnell and Callow[69] employed a combination of Doppler ultrasound and real-time B-mode imaging, and reported a 29% recurrence rate, with a 12% incidence of hemodynamically significant restenosis and a 17% incidence of hemodynamically insignificant restenosis. Recent data from the ACAS trial[71] have demonstrated a 16% incidence of recurrent stenosis over 5 years of follow-up. Evidence of recurrence was based on instrument specific criteria adjusted to achieve a 90% positive predictive value of a stenosis equal to or exceeding 60%. Recurrence in those arteries closed primarily was 21%, but only 7% in those arteries closed using a patch angioplasty technique. The ACAS data demonstrated that there was a 5.7% incidence of recurrent stenosis in the first 3 months following endarterectomy, an 8.5% incidence from 3 to 18 months and a 3.2% incidence from 18 to 60 months. Ouriel and Green[72] reported an 8.9% incidence of recurrence following 281 carotid endarterectomies and a 4% incidence of occlusion. There was a 5% incidence of restenosis in the first year and a 2% incidence per year thereafter. In an effort to reduce the incidence of postoperative recurrence, Sigel and colleagues[73] recommended intrao-

perative B-mode imaging to evaluate the adequacy of carotid endarterectomy and to identify the presence of unsuspected technical errors. Wall surface abnormalities and intimal flaps can be localized using real-time B-mode imaging. Spectral abnormalities, including elevated peak systolic velocity and spectral broadening, can be used to identify carotid obstruction occlusion. It would appear that small intimal defects can be safely observed. Sawchuk et al.[74] evaluated 80 endarterectomy sites using intraoperative ultrasound. Eighteen arteries had a total of 21 minor defects. Nineteen of these were small, intimal flaps of less than 3 mm, and two were described as minor stenoses. Sixteen of the 19 intimal flaps were no longer apparent at the time of the first postoperative evaluation, a mean of 27 12 months after carotid endarterectomy. Both stenotic lesions resolved within a month. Dorffner et al.[75] studied 50 patients intraoperatively. Abnormalities were identified in 19 cases and were classified as residual plaque, stricture, or a flap. In nine cases the endarterectomy was revised. No flap was associated with the subsequent development of a stenosis, and the authors concluded that intimal flaps less than 10 mm in size could be safely observed. Residual plaque, however, was associated with postoperative thrombosis in one case and stenosis in three cases. One of the strictures was also associated with postobstructive thrombosis. Unlike minimal disease, stenotic lesions should be corrected. While Jackson and associates[76] did not employ intraoperative imaging, early postoperative imaging following 206 carotid endarterectomies identified abnormalities in 5.8%. Two of the patients with greater than 60% stenosis by velocity criteria had a perioperative stroke, and four underwent reoperation. Of four uncorrected defects representing less than 60% stenosis, three had resolved on subsequent imaging; of two defects resulting in greater than 60% stenosis, one had resolved at the time of subsequent imaging and one persisted. Schwartz and associates[77] evaluated 84 arteries in 76 patients following carotid endarterectomy. Eighty% of the arteries studied demonstrated no evidence of a technical defect. Eighteen abnormalities were identified in the 84 arteries studied. Nine involved the internal carotid artery, of which 7 were repaired. There was no evidence of a recurrent stenosis at the end of 4 months. Two patients had evidence of a 50% stenosis at the time of intraoperative evaluation. Neither was repaired, and both lesions persisted at the time of follow-up examination. In addition to the identification of technical defects, intraoperative imaging can be predictive of subsequent postoperative recurrence. Johnson et al.[78] found that the luminal cross-sectional area of arteries closed using a vein patch increased in the first three months post-operatively and patents with a mean cross-sectional area greater than 1.77 cm2 developed evidence of mural thrombus. They recommended tailoring patches to achieve a luminal diameter of less than 1 cm. Golledge et al.[79] imaged patients one day and one week following carotid endarterectomy. They found that restenosis (. 50%) was associated with decreased luminal diameter. The diameter of the distal internal carotid artery was 4.8 mm in those arteries without restenosis and 3.4 mm in those with restenosis ðp ¼ 0:03Þ.

Chapter 8.

Postoperative surveillance also has been used to assess disease in the contralateral internal carotid artery following endarterectomy. In 496 patients, Ricotta and DeWeese[80] reported a 30% incidence of a 50% or greater stenosis in the contralateral internal carotid artery at the time of initial endarterectomy. In those patients with an initial contralateral stenosis that was less than 50%, progression of disease to a greater than 50% stenosis occurred in 10% of the overall population. The rate of progression was 5% at 3 years, 18% at 5 years, and 30% at 7 years. Lafrati et al.[81] attempted to evaluate the cost-effectiveness of postoperative surveillance of the contralateral internal carotid artery following carotid endarterectomy. Duplex scans were obtained in 324 patients, with 19.5% of patients progressing to a critical (.75%) stenosis over 5 years. Patients over age 65 and those with initial stenoses greater than 50% progressed to a critical stenosis at rates of 27 and 39%, respectively. The cost of each stroke prevented was $392,562 if the initial stenosis was less than 25% and $143,522 if the initial stenosis was 50–74%. The cost was $148,320 for patients 65 years of age and older.

MORPHOLOGY/PATHOLOGY It is apparent that certain atherosclerotic patterns are associated with the occurrence of cerebrovascular events. Moore and associates[82] demonstrated a relationship between angiographically identified carotid ulceration and focal neurologic symptoms. It has also been suggested that the presence of intraplaque hemorrhage is associated with a high incidence of symptoms. Imparato et al.[83] reported a relationship between the presence of intraplaque hemorrhage and focal neurologic symptoms. In addition, they further noted that atherosclerotic morphology tended to be symmetrical, observing that the pathologic characteristics of one carotid bifurcation were not dissimilar to those of the contralateral bifurcation. Persson and colleagues[84] reported that 33 of 34 (97%) symptomatic patients had intraplaque hemorrhage, while asymptomatic patients demonstrated similar pathological findings in only 11 of 21 (52%) patients. Lusby et al.[85] subsequently published a prospective study of carotid endarterectomy specimens. Acute or recent intraplaque hemorrhage was present in 46 of 53 symptomatic patients. As a result of this correlation between pathological characteristics and symptomatic events, attempts have been made to identify ultrasonic characteristics that correlate with pathologic morphology. The sensitivity of duplex imaging techniques to carotid ulceration has been variable. O’Donnell and associates[86] have had the greatest success noninvasively identifying carotid ulcerations. In their study, ultrasonic imaging and selective four-vessel arteriography were compared with pathologic specimens. Compared with 89 endarterectomy specimens, angiography demonstrated a 59% sensitivity to the presence of ulceration, while B-mode imaging demonstrated an 89% sensitivity, identifying 24 of 27 ulcerations. Arteriography had a 73% specificity and B-mode imaging an 87% specificity. Ulceration was defined as the presence of an isolated crater, proximal and distal

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lipping, with sharp demarcation of the overhanging echogenic borders, and visualization in two of three planes of insonation. Katz et al.[87] were unable to consistently identify ulcerative plaques using real-time B-mode ultrasonography. These investigators reported a 33% sensitivity to ulcerations of less than 2 mm, while there was a 58% sensitivity for ulcerations greater than 2 mm. O’Leary and associates[88] evaluated images in 55 patients who had undergone carotid endarterectomy. Compared with the pathologic specimen, an ulceration was identified by ultrasound with an accuracy of 60%, a sensitivity of 39% and a specificity of 72%. Sitzer et al.[89] evaluated 43 consecutive patients who underwent carotid endarterectomy. Each patient had a highgrade ($ 70%) stenosis of the internal carotid artery and had been imaged preoperatively with color-flow duplex ultrasonography. Compared with the pathoanatomic characteristics recorded for each endarterectomy specimen, ultrasonography had a 33% sensitivity to carotid ulceration, with a 67% specificity and a 46% positive predictive value. The interobserver reliability for a duplex defined ulcer had a kappa value of 0.57. While surface characteristics can be described as smooth, irregular, and ulcerative, plaques can also be described as echogenic or echolucent. Fibrous plaques, with an increased collagen content, are highly echogenic and homogeneous in character. Calcification is also echogenic or echoreflective and is generally associated with evidence of shadowing (Fig. 8-18). Echolucency is associated with intraplaque hemorrhage, as well as increased lipid deposition (Fig. 8-19). Echolucency associated with lipid deposition tends to be more homogeneous in character, while that associated with intraplaque hemorrhage is often characterized by irregular borders and scattered echoreflectivity. In their study, O’Donnell and associates[86] were able to identify evidence of plaque hemorrhage with a 93% sensitivity. Gray-Weale et al.[90] classified plaque morphology into four categories: dominantly echolucent, with a thin echogenic cap; substantially echolucent, with small areas of echogenicity; dominantly echogenic, with small areas of echolucency (less than 25%); and uniformly echogenic. Two hundred and forty-four specimens, obtained at the time of endarterectomy, were pathologically examined and classified as exhibiting intraplaque hemorrhage only, ulceration only, intraplaque hemorrhage and ulceration, or fibrous changes. The majority of operations, 236 of 244, were performed for symptomatic disease. In this group of predominately symptomatic patients, the majority had a plaque showing evidence of ulceration and/or intraplaque hemorrhage. Of these, 73% were characterized as dominately or substantially echolucent. Evaluated in another fashion, of the 179 specimens which were classified as dominantly or substantially echolucent, 174 or 97% contained evidence of interplaque hemorrhage or ulceration. More recently, AbuRahma et al.[91] classified the ultrasonic morphology of 152 plaques by surface characteristics and echodensity. Intraplaque hemorrhage was present in 90% of the plaques with evidence of surface irregularity and 90% of those characterized as heterogeneous. Eighty-four% of the irregular plaques and 80% of the heterogeneous plaques were symptomatic. Polak et al.[92] investigated the relationship between first stroke and plaque echogenicity in a cohort of 4886

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Figure 8-18. An echoreflective plaque (single arrow) is seen on the near wall of the common carotid artery, proximal to the bifurcation. The associated shadowing (double arrow), which obscures the deep wall of the artery, suggests the presence of calcification.

individuals and found the relative risk of stroke was 1.72 ðp ¼ 0:015Þ for hypoechoic plaque and 2.32 ðp ¼ 0:004Þ for stenoses of at least 50%. Using the Gray-Weale classification system, Golledge et al.[93] categorized plaque morphology in 350 patients with

Figure 8-19.

60–99% stenosis of the internal carotid artery. Echolucent type I and II plaques were most common in symptomatic patients (83% versus 44%). Ulceration was seen in 23% of symptomatic patients and 14% of those without symptoms ðp ¼ 0:04Þ: Recently the reproducibility of morphologic classifications has been questioned in two publications. de Bray et al.[94] found interobserver and intraobserver reproducibility for echostructure and luminal surface classifications varied from 0.41 to 0.64. Arnold and associates[95] came to similar conclusions, observing that interobserver and intraobserver reproducibility were not consistently achievable. They evaluated the Gray-Weale classification as well as a simpler two-category classification (homogeneous and heterogeneous). They found reduced variability with the twocategory grading scheme. Studies evaluating the influence of plaque morphology on presentation or outcome will need to carefully evaluate the reproducibility of their models. Recent reports have begun to employ computer models, which may ultimately provide more reproducible results. El Barghouti et al.[96] used an image analysis program to classify 209 plaques by echogenicity and heterogeneity. Symptomatic plaques and those associated with computed tomography (CT) evidence of infarction were more echolucent and less heterogeneous.

NATURAL HISTORY In addition to defining the relationship between plaque pathology/morphology and clinical presentation, early studies

An area of central echolucency (arrow) within an atherosclerotic echoreflective plaque.

Chapter 8.

have suggested that real-time B-mode imaging could also be used to study the natural history of atherosclerosis and, by extension, could be used to follow the progression and regression of atherosclerotic disease in response to therapeutic interventions. Senin et al.[97] evaluated 118 atherosclerotic lesions in 70 patients. The patients were scanned and the plaques defined on the basis of echoreflectivity, surface characteristics, and the degree of stenosis. Echoreflectivity was defined as soft, intermediate, hard, and mixed. Soft lesions were homogeneous and echolucent, consistent with lipid deposition. Intermediate lesions were homogeneous and moderately reflective, corresponding to a fibrous plaque, while hard lesions were homogeneous and highly reflective with evidence of shadowing. Mixed lesions demonstrated a heterogeneous pattern with areas of high and low reflectivity, suggesting thrombus and/or hemorrhage. Surface aspects were characterized as regular or irregular. After 2 years, the authors observed that 68% of lesions remained unchanged while there was an increase in the degree of stenosis in 32%. Regression was not observed in any of the lesions. Factors associated with increasing stenosis were hard and mixed echogenic patterns, an irregular surface, and an initial stenosis of greater than 50%. Henerici and associates[98] evaluated ultrasonic characteristics and patterns, relative to pathologic findings, in 54 carotid arteries examined in vitro in a postmortem study. The normal carotid artery was characterized by parallel echoreflective lines, enveloping an echolucent core (Fig. 8-20). The distance between the echoreflective lines corresponded to the thickness of the media. The inner echoreflective contour represented the intima/lumen interface, while the outer corresponded to the media/adventia interface. The authors identified a progression of disease from flat plaques to soft plaques to hard plaques. The flat plaque was an eccentric fibrous thickening adjacent to the arterial lumen, with a soft friable center secondary to decreased cellularity. By ultrasound these lesions were characterized by the appearance of heterogeneous echoes within the normally echolucent media (Fig. 8-21). Pathologically, the atherosclerotic process increased by a layering of fibrous tissue, calcific deposits, thrombus, or hemorrhage. By ultrasound this progression was characterized by laminated echoes of different intensities which began to encroach on the lumen. With progression, echoreflective or hard plaques were produced by further compaction of fibrous materials or microcalcification. In a subsequent study, the senior author and others[99] evaluated 43 extracranial carotid plaques (less than 30% diameter stenosis) in 31 patients over 18 months. Regression was restricted to a volume reduction in soft plaques. Fibrous and hard plaques remained unchanged or progressed. Extending these observations, Poli and associates[100] ultrasonically evaluated the thickness of the intima/media complex of the common carotid artery in a group of hypercholesterolemic patients, comparing this with a group of controls. The thickness was significantly increased in those patients with hypercholesterolemia. In the control patients the thickness of the intima/media complex increased with age. In the hypercholesterolemic group, the thickness of this complex increased in male patients and smokers. Pignoli and associates[101] had previously

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evaluated the abdominal aorta and common carotid artery, removed at autopsy, in 18 male subjects. The specimens were evaluated by ultrasound as well as pathologic and histologic examination. The authors concluded that B-mode estimates of the intima-media thickness did not differ significantly from the thickness of the intima and media measured microscopically. Gnasso et al.[102] demonstrated a relationship between intima-media thickness and hyperlipidemia. Fifty hyperlipidemic and 50 control patients were evaluated using real-time B-mode imaging techniques. The intima-media thickness of the common carotid artery ranged from 0.52 to 1.24 mm in hyperlipidemic patients and 0.46 to 0.82 mm in controls. O’Leary et al.,[103] reporting for the Cardiovascular Health Study Collaborative Research Group, demonstrated that the risk of myocardial infarction or stroke increased with intimamedia thickness. The relative risk of a cardiovascular event increased by a factor of 3.87 when patients with the greatest thickness were compared to those with the least. The Cholesterol Lowering Atherosclerosis Study[104] demonstrated a reduction in coronary artery disease and carotid intima-media thickness at 2 and 4 years with colestipal/niacin therapy. A reduction in intima-media thickness was apparent after one year of therapy. Untreated controls showed increasing intima-media thickness at a rate of 0.018 mm/year.

Figure 8-20. A demonstration of the parallel echoreflective lines that characterize the wall of the carotid artery. These are best seen on the far wall of the artery and envelop an echolucent core, which corresponds to the media. The inner echo reflective strip represents the intima/lumen interface and the outer corresponds to the media/adventitia interface.

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Figure 21. An area of intimal thickening (single arrow) is characterized by heterogeneous echoes within the normally echolucent media. Pathologically, the atherosclerotic process progresses with a layering of fibrous tissue, calcific deposits, thrombus, or hemorrhage. By ultrasound this progression is characterized by laminated echoes of different intensities that begin to encroach on the lumen (double arrow).

The transcranial Doppler (TCD) technique has found varied clinical application because it is portable, noninvasive, and can be used for continuous monitoring. It can provide information regarding flow direction and normal and collateral intracranial flow patterns as well as flow velocity and intracranial obstructive disease. While significant experience is required to develop the proficiency necessary to evaluate all major intracranial arteries, identification of the middle cerebral artery is relatively simple. Insonnation of the middle cerebral artery has been used to assess the vasospasm associated with subarachnoid hemorrhage,[106,107] the changes in cerebral perfusion that occur in patients with closed head injuries,[108,109] for continuous intraoperative monitoring[110,111] (Fig. 8-22), and perioperative evaluation of patients undergoing carotid endarterectomy.[111 – 116] Continuous intraoperative monitoring of the middle cerebral artery can demonstrate changes in blood flow velocity with carotid artery clamping, which may indicate the need for shunting. A decrease in flow while shunted may indicate shunt occlusion. Additionally, it has been possible to identify periods of interaoperative embolization. This information can be used to modify operative technique and decrease the incidence of perioperative morbidity.[111] Postoperative evaluation following endarterectomy has demonstrated early hyperperfusion followed by a normalization of velocities. Araki and associates[117] evaluated anterior and middle cerebral artery flow velocity prior to and following carotid endarterectomy. They demonstrated a sustained increase in middle cerebral artery flow up to 3 weeks following surgery in those patients with evidence of a hemodynamically significant stenosis (greater than 75% by diameter or OPG positive).

FUTURE PERSPECTIVES Newer imaging techniques, as well as advancements in the use of ultrasound and image processing, are being evaluated in an effort to increase the diagnostic range and resolution of current noninvasive methodologies. These include the transcranial application of Doppler ultrasound, the use of intravenous echoenhancement agents and three-dimensional ultrasonic imaging techniques, and the extention of magnetic resonance and CT imaging technology. With advancements in the use of ultrasound it has become possible to directly insonnate the major intracranial arteries through the thin, bony windows of the frontal and temporal bones using a 2 MHz transducer, with the capacity to axially gate or focus the signal at specific increments from the transducer. The posterior circulation is accessible through the foramen magnum. Since the position of the major arteries is relatively constant and their distance from the probe fixed by the skull, the distal internal carotid, anterior and middle cerebral, anterior and posterior communicating, and the vertebral and basilar arteries can be identified and studied. Although the angle of insonnation cannot be precisely determined for the branches of the circle of Willis, it is limited by the bony windows of the frontal and temporal bones to between 0 and 30 degrees. Thus, minimal error is introduced (, 15%) by variation in this angle, allowing for accurate and reproducible determination of blood flow velocity.[105]

Figure 8-22. Doppler velocity profiles from the middle cerebral artery, ipsilateral to the side of carotid endarterectomy, prior to (A) and following (B) the application of vascular clamps, following the insertion of a shunt (C) and following the restoration of flow after endarterectomy (D) of a hemodynamically significant obstruction. Corresponding systolic and diastolic velocities are provided below each figure.

Chapter 8.

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Figure 8-23. Magnetic resonance angiogram (MRA, center) demonstrating minimal atherosclerotic disease in the area of the right carotid bulb (R) and occlusion of the left internal carotid artery (L). Corresponding selective carotid arteriograms appear to the right and left of the MRA.

Intravenous echoenhancement agents and three-dimensional imaging algorithms are being used in an effort to improve the resolution of current duplex imaging techniques. Sitzer et al.[118] found that qualitative measures of crosssectional area and plaque length were comparable before and after echoenhancement, but visualization of the stenotic flow lumen was significantly improved. The authors speculated that this improved visualization of the residual flow lumen might increase ultrasonic sensitivity to internal carotid artery occlusion. Abildgaard et al.,[119] however, observed that there was a relative increase in peak systolic and end-diastolic velocities associated with ultrasound contrast media. Spectral intensity was also accompanied by spectral broadening. The authors concluded that intravenous contrast agents may facilitate flow detection, but can also produce spectral and color artifacts. As plaque morphology becomes increasingly important in the natural history of carotid atherosclerosis and atherogenesis, three-dimensional imaging may provide greater correlation with pathoanatomic studies. Yao et al.[120] reported that three-dimensional ultrasound had excellent reproducibility and acceptable intraobserver and interobserver variability with respect to plaque length and volume measurements. In the future, magnetic resonance angiography (MRA) may provide noninvasive images of the extracranial (Fig. 823) and intracranial (Fig. 8-24) cerebral circulation that offer even greater resolution than echoenhanced or three-dimensional ultrasound. Spiral CT imaging is yet another technique that provides high-quality images, three-dimensional visualization, and the opportunity for digital manipulation, facilitating assessment of plaque morphology and luminal characteristics. Magnetic resonance angiography is an extension of magnetic resonance imaging and provides a means of visualizing the aortic arch and proximal great vessels as well as the carotid bifurcation and the intracranial internal carotid artery. Currently, two techniques are utilized. Phase contrast MRA is based on the movement of flowing blood along magnetic field gradients and the resulting phase shifts.

Equal and opposite gradients are applied to the imaging slice. Stationary tissue will produce no net phase shift, while moving blood will produce a positive phase shift. The magnitude of the shift correlates with the velocity of blood flow and a velocity map or phase contrast angiogram is produced. Time-of-flight MRA is based on the principle of “flow-related enhancement.” When tissue is “excited” by a radio frequency (RF) pulse, the tissue produces a weak RF echo, which is used to obtain an image. After emitting an echo, the tissue must relax before it can be reexcited to produce a signal. Tissue that is not fully relaxed or “saturated” does not produce a signal. Blood entering the imaging field, however, has not experienced prior RF pulses and is fully relaxed. Flowing blood will produce a high signal, while

Figure 8-24. Magnetic resonance arteriogram of the intracranial circulation, demonstrating the circle of Willis. (R, L, and P designate right, left, and posterior, respectively.)

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the stationary tissue will produce little signal. This phenomenon is called “flow-related enhancement” and is the basis for time-of-flight MRA. Regardless of the technique, images are computer generated based on maximum intensity projection (MIP) algorithms. The computer surveys all of the cross-sectional

Figure 8-25. MRA of the carotid bifurcation demonstrating the common carotid artery, the internal carotid artery (curved arrow), the external carotid artery (open arrow), and the vertebral artery (arrowhead). Cross-sectional data images (A) and the computer reconstructed MIP image of the carotid bifurcation in a lateral projection (B).

Figure 8-26. MRA of the aortic arch and origin of the great vessels. The upper image (A) was obtained using surface coils, and the lower image (B) was obtained using intravascular contrast agents.

Chapter 8.

images (Fig. 8-25A) and selects the brightest coordinates or pixels in each section. The cross-sectional images are then stacked, producing an angiographic-like display (Fig. 8-25B) that can be viewed in multiple projections. Studies[121,122] have demonstrated good correlation with conventional arteriography, suggesting the usefulness of this technique in the noninvasive evaluation of carotid atherosclerosis (Fig. 8-23). Published series evaluating magnetic resonance angiography have generally been small, evaluating the technique relative to duplex imaging or conventional angiography. Blakeley et al.[123] abstracted multiple articles comparing carotid noninvasive techniques and concluded that duplex ultrasonography and MRA had comparable sensitivities to carotid occlusion, varying from 0.82 to 0.86. The sensitivity of these techniques to high-grade stenoses ($ 70%) was 0.83 –0.86, with specificities of 0.89 –0.94. Pan et al.[124] compared ultrasonography, MRA, and conventional angiography with ex vivo measurement of plaque stenosis. The series included 28 patients and 31 endarterectomy specimens. The correlation with ex vivo measurements was 0.80 for ultrasound, 0.76 for MRA, and 0.56 for angiography. MRA offers some unique advantages in comparison to conventional arteriography. It is dependent on the intrinsic properties of blood flow. As such, it is noninvasive and does not utilize intravenous contrast for visualization. This is an important advantage in patients who may have a contrast allergy or renal dysfunction. Like conventional magnetic resonance imaging, magnetic field gradients are used to generate images so that the patient receives no ionizing radiation during this procedure. As the MRA is generated from many cross-sectional views, the image may be viewed in multiple projections following a single acquisition, rather

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than the single projection provided by standard angiographic techniques. There are also disadvantages compared to conventional arteriography. Patients with metallic implants, such as cardiac pacemakers, certain heart valves, and aneurysm clips, are prohibited from undergoing MR examination. Claustrophobic patients may be uncomfortable in the scanner, although usually this can be overcome with reassurance or sedation. Artifacts can result from patient motion, swallowing, and excessive arterial pulsation. These artifacts can generally be minimized through meticulous patient instruction and alterations in scanning methods. The intracranial circulation and the circle of Willis were the first areas to be explored with MRA. Considerable research has resulted in images of remarkable quality (Fig. 822). Less work has been done in the evaluation of the aortic arch and proximal great vessels.[125] Initial problems encountered in visualizing these arteries were related to the orientation of the arteries, making it difficult to maximize the arterial signal while minimizing signal from the venous return. Patient positioning, newer chest surface coils, and intravenous enhancement agents show promise in circumventing these problems, permitting good quality images (Fig. 8-26) to be obtained in selected patients. The spatial resolution of MRA is less than that of conventional arteriography, and high-grade stenosis and turbulence may produce artifacts, resulting in an overestimation of the degree of stenosis (Fig. 8-27). Because of these limitations, preliminary applications have employed MRA in combination with duplex ultrasonography. While the current resolution of MRA does not approach that of standard arteriography, it does provide a means of confirming the presence of an ultrasonically defined high-grade stenosis. In addition, it permits visualization of the aortic arch, proximal

Figure 8-27. MRA (center) of the right (R) and left (L) carotid arteries. The arrows demonstrate flow voids in the region of the bulb and proximal internal carotid artery, bilaterally. The corresponding arteriogram of the right internal carotid artery demonstrates only a minimal stenosis, indicating that the MRA has overestimated the degree of stenosis. The arteriogram demonstrates a high-grade stenosis (.75%) of the left internal carotid artery consistent with the high-grade stenosis predicted by the flow void on the MRA.

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Figure 8-28. Severe stenosis of the proximal left internal carotid artery (arrow) shown by conventional arteriography (center). A twodimensional (2-D) MRA demonstrates a void in the region of the bulb and proximal internal carotid artery, characteristic of a severe stenosis (left). This area is better defined in the three-dimensional (3-D) MRA (right).

great vessels, and the distal intracranial internal carotid artery. Newer three-dimensional imaging techniques excite or saturate a volume of tissue, rather than the linear slice saturated with earlier two-dimensional techniques. The threedimensional studies provide a greater number of crosssectional images and increased resolution (Fig. 8-28). Using a three-dimensional time-of-flight (TOF) technique, Patel et al.[126] found that MRA had a 94% sensitivity to 70 – 99% stenoses, with a specificity of 85% and an accuracy of 88% relative to contrast arteriography. Doppler ultrasound had a sensitivity of 94%, a specificity of 83% and an accuracy of 86%. MRA accurately differentiated 16 high-grade (90–99%) stenoses from 17 carotid occlusions. Recently spiral CT imaging techniques have permitted three-dimensional reconstruction of contrast enhanced CT images (Fig. 8-29). While this technique does require the use of a contrast agent, it may be administered intravenously and does not carry the risks associated with the introduction of arterial catheters. Spiral CT arteriography can accurately depict the degree of carotid stenosis in comparison to standard carotid arteriography, and three-dimensional reconstructions provide images that can be viewed in multiple projections.[127] This technique may offer an alternative to arteriography or MRA in those patients with ultrasonic evidence of minimal (, 50%) stenosis or ulceration. Data evaluating the results of CT angiography are sparse, but at least one reference has also suggested[128] that the technique has a higher positive predictive value for carotid occlusion than that of duplex imaging (95% versus 77%). With the exception of indirect techniques such as the OPG, none of the current noninvasive methods provide specific information regarding the hemodynamic consequences of extracranial or intracranial carotid occlusive disease. Xenon CT imaging (Fig. 8-30) may provide a means with which to assess flow (mL/100g tissue/min) in the anterior and posterior cerebral circulations. Venninan et al.[129] have also

evaluated MR phase-contrast flow quantification. The technique allows measurement of PSV and volumetric flow rate (VFR). In a series of 55 patients and 10 normal volunteers there was a significant correlation between PSV obtained using duplex ultrasound and MR flow quantification in those volunteers without disease (0.73) and in the study population (0.64). VFR was significantly reduced in arteries with stenoses equal to or greater than 70%. While early techniques evaluated the patency of the carotid circulation indirectly based upon the presence of abnormal collateral flow patterns or decreased end-ophthalmic artery pressures, newer technologies permit the direct assessment of the cervical carotid artery using real-time B-mode ultrasound, pulsed and continuous wave Doppler

Figure 8-29. An image of the carotid bifurcation, generated by spiral CT imaging, demonstrating the internal and external carotid arteries, with an area of stenosis just distal to the carotid bulb.

Chapter 8.

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Figure 8-30. Computer generating reproduction of a CT scan with superimposed flow profiles. The circles represent specific areas of interest and the corresponding table provides the flow wind cc per 100 grams of tissue per minute in the selected areas. Flow estimates can be obtained using the color comparison gradient on the right. Xenon-enhanced CT scan at the level of the occipital lobes (arrows). Cerebral blood flow (cc/100 g of tissue/min) can be calculated for a specific area (mean ^ SD) or displayed visually relative to a color code. The scan demonstrates decreased flow (, 15 mL/100 g tissue/min) in the posterior circular (areas 9, 10, 11, 21, 22).

spectra, and duplex imaging. Current technology now permits accurate quantification of carotid stenoses, and these estimates can be correlated with recent reports defining clinically significant asymptomatic and symptomatic carotid obstructive disease. Using protocols for standardization, the results of duplex ultrasonography can be used as the basis for carotid endarterectomy in selected cases. Recent innovations have resulted in the integration of realtime color flow velocity and B-mode images, the construction of three-dimensional ultrasonic images, and the use of intravascular echocontrast agents. In time these advances may provide greater information regarding atherogenic flow patterns and the flow velocity patterns and turbulence that

result from minimal wall surface irregularities as well as highgrade stenoses. Transcranial techniques have permitted the characterization of intracranial flow patterns, demonstrating increased poststenotic flow velocities, abnormal collateral flow profiles resulting from proximal obstructive disease, and abnormal velocity profiles consistent with decreased cerebral perfusion. In the future, magnetic resonance and CT angiography may provide high-resolution noninvasive images of the extracranial and intracranial cerebral circulation. At present, however, such techniques have technical limitations, and further evaluation will be necessary in order to determine their eventual role in the assessment of patients with atherosclerotic cerebrovascular disease.

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Artery Occlusion: A Prospective Study. Eur. J. Vasc. Endovasc. Surg. 1998, 16, 133– 136. 129. Vanninen, R.L.; Manninen, H.I.; Partanen, P.L.; Vainio, P.A.; Soimakallio, S. Carotid Artery Stenosis: Clinical Efficacy of MR Phase-Contrast Flow Quantification as an Adjunct to MR Angiography. Radiology 1995, 194, 459– 467.

CHAPTER 9

Noninvasive Diagnosis of Venous Disease J. Leonel Villavicencio David L. Gillespie Sandra Eifert

INTRODUCTION

CLINICAL MANIFESTATIONS OF DEEP VENOUS THROMBOSIS OF THE LOWER EXTREMITIES

It has been estimated that each year, nearly 200,000 people in the United States die from complications from venous thrombosis of the lower extremity.[1] The figures from Great Britain are no less impressive, with an estimated annual mortality rate of 21,000.[2] Lower extremity venous thrombosis frequently accompanies other disease processes, and several conditions predispose to its development (Table 9-1). Procedures such as transjugular and transsubclavian catheterization and infusion lines, transvenous pacemaker insertions, and intravenous hyperalimentation have led to a remarkable increase in the incidence of brachiocephalic and upper extremity venous thrombosis. This iatrogenic thrombosis is superimposed on a generally low, but potentially crippling incidence of upper extremity venous occlusion associated with thoracic outlet syndrome. While it was formerly believed that pulmonary embolism rarely occurred in patients with brachiocephalic or upper extremity venous thrombosis, an incidence of pulmonary embolism of 12% has now been documented.[3 – 5] Despite a great deal of experience with lower extremity venous thrombosis, uncertainty continues regarding the optimum treatment during the acute stages and optimum methods of long-term management. However, there has been significant progress over the last several years in the development of noninvasive techniques for diagnosing both venous obstruction and venous insufficiency. As will be discussed in subsequent sections, these techniques have significant advantages over the invasive counterparts, such as contrast phlebography, and they have been shown to have comparable cost-effectiveness.[6]

The most common symptom reported by patients with lower extremity deep venous thrombosis (DVT) is pain. The pain may be mild and insidious in patients with thrombosis of the calf veins, or it may be acute and excruciating in patients with iliofemoral thrombosis and extensive venous occlusion such as phlegmasia cerulea dolens. Most commonly, it is described as a dull ache, throbbing sensation, feeling of tightness, or a feeling that the leg is about to burst. These symptoms are present at rest and may be aggravated by walking. Unfortunately, many patients, particularly those who are postoperative or critically ill from other diseases, have no symptoms related to the leg and their first manifestation of venous thrombosis is an episode of pulmonary embolism. When signs of toxicity such as severe temperature elevation or tachycardia are present, one should suspect the presence of septic thrombophlebitis or massive iliofemoral venous thrombosis. The presence or absence of these signs of inflammation was previously thought to be quite important, and distinctions were made between phlebothrombosis, in which there was little or no inflammation of the vein and therefore few clinical manifestations, and thrombophlebitis, in which inflammation of the vein was prominent and the clinical signs and symptoms were quite evident.[7] Patients with phlebothrombosis were thought to be at much greater risk of pulmonary embolism than those with thrombophlebitis. While these distinctions may have enhanced the basic pathophysiological course of the disease,

Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024892 Copyright q 2004 by Marcel Dekker, Inc.

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Part One. Assessment of Vascular Disease Table 9-1. Conditions Associated with or Predisposing to Development of Venous Thrombosis Cardiovascular disease Coagulopathies (including the use of birth control pills) Immobility Malignancy Obesity Old age Operations

the categorizations are almost impossible to make on the basis of clinical findings. The term phlebothrombosis is rarely used nowadays, and all patients with venous thrombosis should be considered to be at significant risk of pulmonary embolism. Some patients seek medical care only after the onset of leg swelling. Leg swelling and edema may also be a subtle clue to the onset of venous thrombosis in bedridden patients. Edema fluid may collect behind the malleoli before it becomes more diffuse. This subtle finding of retromalleolar edema in bedridden patients should alert one to the possibility of deep venous thrombosis.[8] In searching for leg swelling and edema, one should remember that there is normally some discrepancy between the sizes of the two lower extremities. However, size discrepancies greater than 1 cm are considered significant.[9] In comparing sizes between the two extremities, it is necessary to use fixed landmarks as reference points and to make sequential measurements at the same distance from this fixed reference point (medial malleolus, anterior tibial spine, and anterior superior iliac spine). Local heat and erythema are common in superficial thrombophlebitis, but not in thrombosis of the deep veins. Superficial tenderness and the presence of a palpable cord are also common is superficial thrombophlebitis. It is important to recognize these signs, since it is not unusual for superficial thrombophlebitis to advance into the deep system and result in a deep venous thrombotic episode. The most important physical findings of deep venous thrombosis are leg swelling, dilatation of superficial veins, and tenderness. In iliofemoral thrombosis, the area of maximum tenderness is generally in the thigh or groin. At times, however, it may be in the lower abdominal quadrants, and it may mimic the tenderness elicited in conditions such as appendicitis and diverticulitis. This is especially true in the young female patient in whom an episode of acute iliac venous thrombosis may resemble acute appendicitis or adnexitis. When calf tenderness is present, one must try to determine whether it arises from the underlying muscles or veins. Tenderness due to a partial tear of the gastrocnemius muscle or rupture of the plantaris tendon is usually elicited by side-toside compression of the muscle bellies. Ecchymosis, either at the calf or retromalleolar, should be investigated. A history of recent participation in athletics provides a further clue to the diagnosis of these acute muscular disorders. Calf tenderness due to venous thrombosis is usually elicited by compression of the muscle bellies directly against the tibia. A common physical finding in cases of calf venous thrombosis is the tightening or induration in the area of the calf muscles. This should be investigated with the patient in the supine position with the knees slightly flexed and the calf muscles relaxed.

Pregnancy Previous deep venous thrombosis Sepsis Thrombocytosis Trauma Varicose veins

Gentle palpation of the calf muscles will detect localized induration or tightening of the areas involved in the thrombotic process and will elicit pain. The position adopted by the patient with acute deep venous thrombosis of the lower extremity is classic. The patient lies down with the thigh flexed over the hip and the knee flexed over the thigh. Any efforts to stretch the extremity will produce excruciating pain.

CLINICAL MANIFESTATIONS OF CHRONIC VENOUS INSUFFICIENCY The clinical manifestations of chronic venous insufficiency will vary depending on the pathophysiology of the problem. The clinical types of venous problems seen most often are summarized in Table 9-2. This is a useful classification that aids in the understanding of the pathophysiology of venous insufficiency and constitutes the basis for the selection of treatment.[10] The current classification of chronic venous insufficiency of the SVC/ICVS (CEAP classification) is described in another chapter of this book. Congenital, essential, familiar, or primary varicose veins are all terms used for the same problem, namely, varicose veins that appear early in life, sometimes in childhood, and that are usually present in one or more members of the family. Venous stars, spiders, telangiectases, venous lakes, and venules are all ordinary small veins in the skin that have a striking familial tendency. They appear especially in women on the medial, posterior, and lateral aspects of the thigh and less often on the lower leg and calf (Fig. 9-1). Secondary, acquired, or

Table 9-2. Clinical Classification of Varicose Veins Primary or familial varicose veins Greater saphenous incompetence Lesser saphenous incompetence Perforator vein incompetence Venous spiders Internal iliac venous insufficiency (pelvic varices) Secondary varicose veins Postphlebitic syndrome with severe varicosities Congenital venous malformations with or without AV fistulas (Klippel-Trenaunay and Parkes-Weber syndromes) Acquired arteriovenous fistulas (posttraumatic, spontaneous, etc.)

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Figure 9-1. Telangiectases or “spider veins,” as illustrated here, are a common manifestation of primary varicose veins. They are an unsightly, cosmetic nuisance that are usually asymptomatic. They appear either alone or in association with incompetence of the superficial venous trunks.

postphlebitic varicose veins are the late consequences of an episode of thrombophlebitis. The clinical manifestations of these sequelae are usually severe and vary widely, depending primarily on the extent and location of the initial damage to the valvular mechanism of the deep and/or superficial venous systems and the degree of incompetence of the perforating or communicating systems (Fig. 9-2). Congenital anomalies of the venous system with or without arteriovenous (AV) fistulas lead to another type of chronic venous insufficiency. The KlippelTrenaunay syndrome is the typical example of congenital venous anomalies without obvious AV fistulas (Fig. 9-3). Patients with this syndrome have varicose veins, a port wine stain, and hypertrophy of soft tissue and bone with overgrowth of the extremity. This type of venous malformation should not be confused with the Parkes-Weber syndrome, in which the major pathological difference seems to be the presence of AV Figure 9-3. A 35-year-old woman with bilateral Klippel – Trenaunay syndrome. Extensive congenital varicose veins and capillary hemangioma localized to the external aspect of the extremities are characteristic features of this syndrome. No AV fistulas were detectable by arteriography. This type of venous malformation should not be confused with the Parkes – Weber syndrome, wherein the major difference is the presence of multiple congenital AV fistulas.

fistulas. In the group of acquired, iatrogenic, or traumatic AV fistulas, varicose veins are secondary to the venous hypertension occurring on the venous side of an AV fistula. The hemodynamic effects on the venous system depend to a great extent on the location, size, and duration of the AV fistula.[11,12]

Figure 9-2. Secondary varicose veins, hyperpigmentation, eczema, induration, and ulceration are the devastating sequelae of an episode of deep venous thrombosis that occurred 10 years before in this 27-year-old woman. Incompetent perforators and deep venous reflux were indentified.

DIAGNOSIS OF VENOUS DISEASES In superficial thrombophlebitis, septic thrombophlebitis of the lower extremities, phlegmasia alba dolens, and phlegmasia

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cerulea dolens, diagnosis based solely on symptoms and physical findings should be relatively easy. The diagnosis of varicose veins is also straightforward, but additional studies are needed to define its pathophysiology. In superficial thrombophlebitis, in particular, the diagnosis can usually be made with a high degree of accuracy on clinical grounds and special diagnostic tests are not usually needed. However, conditions such as gout, bacterial cellulites, lymphangitis, fat necrosis, vasculitis, and underlying malignancy must be kept in mind and ruled out. Phlegmasia alba dolens refers to severe iliofemoral thrombosis in which there is marked pain and swelling of the involved extremity. Skin color ranges from white to bluish. Despite the ominous appearance, there is no immediate threat of limb loss. In phlegmasia cerulea dolens,

however, the entire venous outflow from the leg becomes blocked by the thrombotic process and the leg becomes massively swollen and violaceous (Fig. 9-4A). Arterial pulsations are initially present but are later either diminished or lost as the outflow resistance and intracompartmental pressure increases. Cutaneous blebs and bullae may develop. As the process worsens, cardiovascular collapse due to sequestration of fluids in the lower extremity may occur and gangrene will develop unless some degree of venous outflow can be established.[13] This is called venous gangrene (Fig. 94B). Because of the massive venous involvement, the diagnosis is seldom in question in either form of phlegmasia. In the less dramatic but more common variants of deep venous thrombosis, diagnosis is often difficult because of the vague signs and symptoms. Clinical diagnosis is in error in at

Figure 9-4. (A ) Phlegmasia cerulea dolens represents near total obstruction of venous outflow, resulting in massive swelling and violaceous discoloration Cutaneous blebs and bullae may develop. (B ) As shown, limb loss occurs if some degree of venous outflow cannot be established.

Chapter 9.

least 50% of the cases.[9] Venous thrombosis should be suspected and ruled in or out in any patient with lower extremity pain if no other obvious cause is present. Even in the absence of pain or discomfort, it should also be suspected in bedridden patients who develop lower extremity edema. Although unilateral edema makes one more suspicious, the presence of bilateral edema does not rule out the diagnosis. The postthrombotic limb poses special problems for the clinician because of the possibility of combined venous obstruction and venous insufficiency. The limb is usually larger than its counterpart, but distinction must be made between primary and secondary varicosities. Chronic leg edema must be distinguished from that of lymphedema or, in the case of bilateral swelling, from that of congestive heart failure and/or anasarca from other causes. The diagnosis of congenital vascular malformations can usually be made by noninvasive techniques, including computed tomography (CT) and magnetic resonance imaging (MRI). Invasive studies such as phlebography or arteriography are usually indicated when there is a questionable diagnosis or when surgical intervention is contemplated. Continuous wave (CW) bidirectional Doppler study provides bedside information on the presence of deep or superficial venous reflux, including the abnormal lateral marginal vein collector and its large perforators. In patients with hemodynamically active arteriovenous malformations, CW Doppler recordings may identify increased arterial and venous flow signals along the involved vessels. Pulsatile venous signals are detected on the venous trunks of the superficial as well as the deep system, above the site of the malformation. Because of the high rate of inaccuracy of clinical diagnosis in both acute and chronic conditions, physicians initially turned to phlebography as the gold standard for diagnosis of venous thrombosis. Important aspects of phlebography will be discussed in the ensuing paragraphs.

Phlebography Several techniques of phlebography have been described.[14 – 17] Excellent phlebograms are obtained using the technique outlined by Rabinov and Paulin,[18] which is regarded as one of the preferred techniques. In this technique, the patient is in the semi-upright position. No tourniquet is used, and the extremity is not supporting weight. The more common radiographic signs of venous thrombosis are outlined in Table 9-3. Generally speaking, modern phlebography is a safe procedure that is usually done on an outpatient basis. The use of modern low osmolar, nonionic contrast material has made phlebography a very safe procedure with virtually no contraindications or compliTable 9-3.

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cations. Chemical thrombophlebitis, in reaction to the contrast medium that used to be present in roughly 2% of the cases, has been virtually eliminated with the use of lowosmolality contrast medium. Even accidental extravasation of the dye, which often led to tissue necrosis, now produces very few symptoms. The incidence of subclinical chemical phlebitis, which used to be as high as 33%,[19] has not occurred in centers using low osmolar contrast medium.[20,21] The contrast media currently recommended for phlebography are Iopamidol 300 or 370, Iohexol 300 or 350, Sodium –Meglumine Ioxaglate 320, or Iopromide.[22] Even though phlebography is now a much safer procedure, there has been a decline over the past several years in the number of phlebograms performed in major institutions due to the impressive developments of the noninvasive technology. Related techniques that require minor invasiveness and involve little discomfort or risk include several radioisotope techniques, which will be discussed in the next section. Ascending and descending phlebography, as well as select varicography, have been extensively utilized in our centers to outline the anatomy and extension of venous malformations. The phlebographic technique in patients with congenital vascular malformations of venous predominance (Klippel-Trenaunay syndrome) usually requires modification. The large superficial venous bed should be neutralized by the application of an elastic bandage. In this manner, the contrast material preferentially goes into the deep system. This information is of great value when considering the type of treatment and the prognosis of the patient,[2,8 – 11] since agenesia or hypoplasia of deep venous trunks is not an uncommon finding in congenital vascular malformations.

Radioisotope Techniques Radionuclide phlebography refers to a technique in which a radioactive substance is injected into a pedal vein. Dynamic imaging using a scintillation camera is then done over the extremity veins, iliac veins, and inferior vena cava. Some of the substances that have been used are 99mTechnetium (99mTc) macroaggregated albumin, 99mTc macroaggregated fibrinogen, and 99mTc human albumin microspheres (HAM). The basis for the test is that in the presence of venous thrombosis, a portion of intravenously injected macroaggregated albumin particles will become adherent to the thrombus. Thrombi are identified by recognition of delayed clearance of radioactivity from the extremity after intravenous injection of the radiolabeled particles. Compared with contrast phlebography, radioisotope imaging techniques have yielded accuracy rates ranging from 89 to 96%.[23,24] They have a great deal of appeal

Radiographic Signs of Deep Venous Thrombosis

Constant, well-delineated filling defects Abrupt termination of contrast medium at a constant site above or below obstruction Nonfilling of the entire deep system or portions thereof provided that proper technique was used Diversion of flow-through collaterals

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because of a high degree of patient acceptance and the ability to perform a lung scan using the same injection of radioactive substance.[25] However, they also have some drawbacks. In the early studies, the contralateral extremity was used as a reference. Thus, results were difficult to interpret when there was bilateral lower extremity involvement. Furthermore, sluggish blood flow through the popliteal space may lead to false-positive results. Further investigations of these types of imaging techniques are warranted in view of their low risk and potential applications. Another radioisotope technique involves trapping radiolabeled fibrinogen in developing thrombus. Serial counts are obtained over the extremity, but no images are obtained. These techniques were made possible by the recognition that radiolabeled fibrinogen could be incorporated into developing thrombi in sufficient quantity to make it detectable by scintillation counting.[26] 131I was used in the early studies, but a major shortcoming of the technique, related to the short half-life of this isotope,[26,27] was overcome when it was found that the more stable isotope, 125I, gave similar results.[28] Incorporation of 125I-labeled fibrinogen into a developing thrombus now forms the basis of the fibrinogen uptake test. Many of the early studies of the fibrinogen uptake test were done in surgical patients. It was found that in some cases in which venous thrombosis became apparent in the postoperative period, the clotting process actually began either during the operation or as early as the first postoperative day.[29] To perform the fibrinogen uptake test, thyroid uptake of iodine is blocked with 100 mg of sodium iodide, which can be given orally or intravenously, and a 100-Ci dose of 125Ilabeled fibrinogen is given intravenously. Radioactivity counts are then taken at various points over each extremity and expressed as a percentage of reference counts made over the precordium. Based on phlebographic comparisons, accuracy rates ranging from 80 to 93% have been reported.[2,28,30,31] However, the fibrinogen uptake test is not useful in traumatized or recently operated-upon extremities, and it has a low degree of accuracy in the iliofemoral venous segment. Its greatest usefulness has been as an investigation tool in trials comparing various methods for preventing postoperative venous thrombosis. Development of this test also contributed greatly to the identification of categories of patients who are at high risk of developing postoperative venous thrombosis. Thus far, neither phlebography nor radioisotope techniques have provided the degree of clinical usefulness needed for the rapid, safe, and accurate diagnosis of deep venous thrombosis. For this reason, noninvasive tests have gained in popularity and are now widely used as the first diagnostic tests in patients with suspected lower extremity venous thrombosis. The Doppler test, which is discussed further, can also be used to evaluate suspected upper extremity venous thrombosis.[32]

Noninvasive Techniques A number of totally noninvasive techniques for diagnosing venous obstruction and/or venous insufficiency are available. As these techniques have improved, they have begun to

replace contrast phlebography, which is now being used in several institutions only when the diagnosis remains in question after noninvasive testing. The most commonly used techniques will be discussed in the ensuing paragraphs.

Plethysmography There are several techniques of venous plethysmography, including air plethysmography (APG), strain gauge plethysmography (SPG), photoplethysmography (PPG), and foot volumetry (FV). Plethysmography may be used for the detection of venous outflow obstruction or venous reflux. Air plethysmography detects changes in limb volume by using an air-filled cuff from the knee to the ankle. Strain gauge plethysmography uses a mercury-filled silastic strain gauge to encircle the leg at a single point. It detects changes in leg volume following inflation of a thigh occlusion cuff. Foot volumetry is a technique used extensively in Scandanavian countries. This method uses a water-filled container in which the patient stands. Data on volumetric changes are recorded at rest and during exercise by a strip chart recorder. A final noninvasive method of measuring venous hemodynamics is photoplethysmography. This indirect method of measuring volumetry uses a transducer containing an infrared light – emitting diode and an adjacent phototransistor to receive back-scattered light reflected from the superficial layers of the skin. The amount of reflected light varies with the number of red blood cells in the microcirculation.

Venous Outflow Obstruction The investigation of venous outflow obstruction may be performed by APG, PPG, or SPG. In these techniques the patient is placed in the supine position with the leg elevated on a soft heel support and the knee slightly flexed. A proximal thigh occlusion cuff is inflated to a level between arterial and venous pressure (50 –60 mmHg). Limb volume increases and the baseline of the tracing rises. With cuff release, a rapid return toward baseline occurs in normal extremities. The rate of venous emptying in the presence of proximal venous obstruction is retarded. By dividing the fall occurring in the first 1–2 s after release by the total rise, a ratio can be established that will separate extremities with normal venous emptying from those with abnormal venous emptying (Fig. 9-5). In most normal extremities, 50% of venous emptying occurs during the first 2 s after cuff release.[33] Overall accuracy is in the range of 80%. False positives are not common for major obstructing thrombi and have been reported at less than 3.0%.[33] False-positive results are obtained in patients if the leg is improperly positioned. This method cannot detect calf venous thrombosis.[34]

Venous Reflux Competency of the deep system and the perforating veins can be tested using APG, SPG, PPG, and FV. In these tests venous reflux is examined by serially occluding the superficial system with tourniquets. To determine if the reflux comes from the superficial or the deep system, reflux from the superficial vein is eliminated with the use of a tourniquet. If the abnormal plethysmographic tracing is

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Figure 9-5. (A ) In segmental venous occlusion plethysmography, the baseline begins to rise when the occluding cuff is inflated to greater than venous pressure (arrow ). When the capacitance bed is filled, the tracing stabilizes at a higher level (Tf). When the cuff is released (arrow ), the tracing returns to baseline. Venous outflow is calculated by dividing the fall at 2 s (F2) by the total rise (Tr). (B ) Outflow tracing from the normal (left ) and abnormal (right ) lower extremities in a patient with acute deep venous thrombosis.

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corrected with the application of the tourniquet, the abnormality is located in the superficial venous system. On the other hand, if the tourniquet does not correct the abnormal tracing, the abnormality is due to deep venous insufficiency. The location of incompetent perforators can be carefully mapped in a manner similar to the Trendelenburg test by placing the tourniquet at different levels of the extremity. The venous refill time (VRT) is a measurement of venous reflux as measured by strain gauge plethysmography. In this measurement the strain gauge is placed at the ankle of the patient. A series of five plantar flexion/dorsiflexion maneuvers are performed. This empties the leg of blood and then refills over time. Normal refill time is usually longer than 20 s. Venous reflux is defined as a VRT of , 20 s. This method differs from air plethysmography in that it only measures volume changes in a single slice of the leg. In lower extremity venous malformations, SPG has been used to assess the importance and contribution of the large lateral collecting marginalis vein to the venous outflow of the extremity. SPG should be performed under basal conditions and then repeated with compression of the large lateral collector trunk shortly before thigh/cuff deflation. A pattern of venous obstruction is observed if the lateral collector plays an important role in the venous outflow. SPG, in cases of arteriovenous malformations, reveals an increased arterial inflow, a relatively low venous capacitance due to decreased resistance, and a normal venous outflow.[1] Air plethysmography has been shown to be a quantitative method of measuring venous reflux.[35] In this technique, the air-filled chamber is calibrated with the patient in the supine position with the leg elevated and the knee slightly bent. Continuous measurements are taken using a strip chart recorder of the leg volume as the patient moves to a standing position, weight bearing on the opposite leg. The leg volume will increase and plateau at a volume defined as the venous volume (vv). The venous filling index (VFI) is determined as the rate of venous reflux in cc/s. The residual volume fraction (RVF) is a measure of the leg volume after the patient has performed 10 tiptoe maneuvers. Christopoulos et al. have shown this measurement to have a high correlation with invasive measurements of ambulatory venous pressure. The technique of APG has also been shown to be a valuable adjunct to monitor the results of venous surgery[36 – 38] and to assess venous outflow obstruction of the upper extremity. Using foot volume plethysmography, Norgren et al. showed good correlation between venous insufficiency and the ratio of refilling flow to the expelled volume.[39] In this technique the patient starts in a standing position with each foot placed in its own water-filled container. After initial calibration the patient is asked to perform a standard exercise of 20 deep knee bends at a metronomed pace. The PPG examination is performed with the patient in the sitting position with both feet on the floor. The transducer is fixed to the skin above the medial malleolus, using doublefaced clear adhesive tape. Comparison tracings are obtained by examining both extremities at the same time. The examination is performed similarly to the SPG technique of repetitive foot dorsal and plantar flexion. Since the PPG output cannot be calibrated, the quantitative endpoints for this study are related to the recovery time of the baseline skin blood content after active leg muscle exercise. Recovery time

is recorded as the total number of seconds required for the recording to return to the preexercise baseline level or to one half of the preexercise baseline level (t1/2), as shown in Fig. 9-6. Normally, skin blood content decreases in response to active or passive calf muscle exercise due to venous emptying. The recovery time is usually greater than 20 s, and it is not affected by application of a tourniquet.[40,41]

Ultrasound Techniques Doppler ultrasound techniques have been used extensively to detect both venous obstruction and venous insufficiency. The detection of venous obstruction is based on impedance of forward flow and a consequent reduction in transmitted venous flow sounds. Using a bidirectional flow probe, forward flow is recorded as flow away from the probe (Fig. 9-7). Certain maneuvers used to investigate valvular incompetence will augment flow toward the bidirectional probe. For simplicity and ease of application, however, both obstruction and insufficiency can be also detected using a unidirectional probe. With a trained ear, one can rapidly assess the lower extremity veins using the Doppler. Recording of tracings is not entirely necessary but is highly useful for documentation of findings, for physician interpretation of technician’s findings, and for providing a permanent record. Representative tracings are shown in Fig. 9-8. In performing the Doppler ultrasound examination, one needs to assess five elements of the venous Doppler signal: spontaneity, phasicity, augmentation, competence, and pulsatility. Each is discussed in greater detail below. Excellent descriptions are also available in basic texts.[42] Spontaneity: Normally, spontaneous venous flow sounds can be recorded from all the major veins. In vasoconstricted extremities, these sounds may be greatly attenuated or absent over the posterior tibial veins or superficial veins but are still present over the deep veins in the popliteal space and femoral region in the thigh. Absence of spontaneous venous flow signals thus represents an abnormal finding and is one of the early signs of venous obstruction. Phasicity: This refers to the normal waxing and waning of the venous flow signals with respiration. During descent of the diaphragm during inspiration, venous flow is greatly diminished or totally interrupted due to increased intraabdominal pressure. The flow signal then increases maximally during expiration. In the presence of proximal venous obstruction, the venous flow signal becomes high pitched and continuous, and respiratory variations become markedly diminished or absent. The presence of a continuous high-pitched venous flow signal is highly suggestive of venous obstruction and is typical of collateral circulation. Augmentation: The venous flow signal is normally increased by compression of the limb distal to the probe or by release of compression proximal to the probe. Such augmentation is diminished or absent in presence of venous obstruction. Competence: Competent venous valves prevent reflux flow. In cases of congenitally incompetent or absent valves (avalvulia) and in cases of postthrombotic valvular destruction, there will be retrograde flow during compression of the limb proximal to the flow probe. When the venous valves are competent, a Valsalva maneuver causes prompt cessation of

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Figure 9-6. Photoplethysmography is not strictly quantitative, but measurement of the recovery half-time allows one to distinguish between extremities with normal hemodynamics and those with venous insufficiency with a high degree of accuracy. (From Barnes and Yao.[41] Reproduced by permission.)

flow. Contrarily, in the face of valvular incompetence, the Valsalva maneuver augments retrograde flow. Pulsatility: Venous signals are normally nonpulsatile and vary in intensity with respiration but not with the heart beat. When venous pressure is elevated, such as in congestive heart failure, venous sounds may be difficult to distinguish from

arterial sounds. However, limb compression maneuvers and the Valsalva maneuver continue to alter venous flow sounds. These maneuvers have no effect on arterial flow sounds. To perform the Doppler examination, the patient should be positioned supine in a comfortable position with the head of the bed or examining table slightly elevated to increase

Figure 9-7. With the bidirectional probe at a 45-degree angle to the skin and directed toward the heart, forward flow is recorded as flow away from the probe. If reflux occurs with a Valsalva maneuver, there is augmentation of flow toward the probe. This photograph shows the proper orientation of the probe.

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Figure 9-8. Normally, venous flow is nonpulsatile and phasic, as shown in (C ), and valvular competence prevents a venous flow signal during proximal compression, as shown in (E ). When venous obstruction is present, the venous flow signal may be continuous due to flow through collaterals (D ), and proximal limb compression causes an augmented retrograde flow signal due to valvular incompetence (F ). The venous flow signal may also take on a pulsatile arterial quality when venous pressure is elevated as shown in (H ). (From Barnes.[42] Reproduced by permission.)

venous pooling. The legs should be in a comfortable, relaxed position with the hips externally rotated and the knees slightly flexed. Examination of the popliteal veins is best accomplished with the patient in the prone position and the knee slightly flexed. One should routinely examine the posterior tibial, the popliteal, the superficial femoral, and the common femoral veins. Close attention should be paid to the presence of spontaneous venous flow sounds and to the influence of proximal and distal compression. The superficial venous system, especially the greater saphenous vein, can also be tested for incompetence using the Doppler instrument. In this case, the patient should be standing. As mentioned earlier, the Doppler can also be used to detect upper extremity venous obstruction.[32] The accuracy of the venous Doppler examination is observer-dependent, and the test requires time, experience, and practice to learn. However, a competent observer should be able to obtain an accuracy on the order of 90%. Sources of

error, in addition to observer experience, include nonobstructive thrombi, thrombi in parallel veins (duplicated veins), and thrombi in veins that are not in the axial stream. Examples include thrombi in muscular veins, veins of the soleal plexus, and the profunda femoris veins. All the previously mentioned noninvasive tests are subject to the same limitations. The combination of the continuous wave Doppler ultrasound and a B-mode imaging of the veins (Duplex scanning) allows for visualization of both acute and chronic thrombi.[43] It will be described at length in the following sections.

Duplex Scanning Duplex scanning has become the most widely used noninvasive method for the diagnosis of both arterial and venous diseases. As reported by Sumner et al.,[44] a recent survey conducted by the American Registry of Diagnostic

Chapter 9.

Medical Sonographers revealed that 94% of registered vascular technologists use Duplex scanning in their investigations. No other method was used by more than 57% of the respondents. The widespread acceptance of this method is due to its versatility, noninvasiveness, and well-established accuracy. Duplex scanning incorporates two modalities of noninvasive techniques: real-time B-mode scanning and analysis of the Doppler flow signals. The B-mode component scans the echoes reflected from acoustic interfaces in the underlying tissues. At the same time, sound energy is received from a linear array of crystals, thus avoiding the moving parts required by sector scans. At the present time, Duplex imaging offers the most accurate information available for the diagnosis of venous disease including upper and lower extremity venous thrombosis, venous reflux, venous aneurysms, and venous malformations.[45] Each segment of deep venous system from the lower calf to the external iliac vein can be evaluated with the B-mode ultrasonographic imaging. This mode of evaluation provides a three-dimensional assessment of the deep venous system below the external iliac vein. For accurate imaging of the iliac system and the deep venous system, a 3.0 or 4.0 MHz transducer is suggested. For veins below the inguinal ligament, a 7.5 or 8.0 MHz transducer is adequate.

Scanning Technique The patient is placed in the supine position with the shoulders raised approximately 30 degrees. The patient’s knee is slightly flexed, and the entire lower extremity should be rotated externally. A generous amount of transmitting gel is applied over the areas to be scanned. The Duplex probe is placed at the level of the femoral triangle, and the common femoral and superficial femoral veins are visualized along its long axis. In a normal venous segment, gentle pressure applied with the transducers produces approximation of the venous walls. Partial compressibility or incompressibility in both the longitudinal and transverse projections is considered suggestive of thrombosis. The absence of Doppler signals and incompressibility, both in the longitudinal and transverse axis, is strong evidence of thrombosis. Partial compressibility in the longitudinal as well as in the transverse axis, accompanied by weak Doppler signals, suggests the presence of nonocclusive thrombus, partial recanalization, or chronic thrombosis. Duplex scanning of the femoral triangle often reveals the presence of normal valve motion. Valsalva maneuvers can be used to evaluate the changes in venous diameter as well as the presence of venous reflux. In each extremity tested, the entire common and superficial femoral veins are examined. As the scanning is continued to the medial aspect of the thigh, visualization of the superficial femoral vein may be obscured at the level of the Hunter’s canal due to the adductor fascial planes. The popliteal vein is assessed with the patient in the prone position and the knee slightly flexed to reduce tension of ligaments and tendons. In the obese or severely ill patient, the prone position may be difficult. In this situation, flexing the knees and external rotation of the hips usually allows visualization of the popliteal vein. Sitting the patient with the legs dangling at the edge of the examining table is also an acceptable way to investigate the popliteal vein. The popliteal

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vein is examined by moving the probe proximally towards the adductor canal and distally to the popliteal confluence. To assess the personeal veins, the patient should remain in the prone position and the scanning probe placed 1 – 2 cm medial to the edge of the fibula. The anterior and posterior tibial veins can usually be visualized in the proximal and mid-calf. Visualization of the peroneal veins is more difficult because of their anatomical location. One of the drawbacks of the Duplex scanning examination is the impossibility to move the patient from the supine to the prone position to gain optimal access to the popliteal and peroneal veins. In these cases, even though it is not optimal, it is possible to examine the calf veins with the patient in the supine position by elevating the leg and placing support under the heel, allowing the calf muscles to hang away from the bones.[46] The echogenicity of the flowing blood, compared with the thrombus, is quite different. This allows for easy differentiation using Duplex imaging. Fresh thrombus may give the appearance of flowing blood unless motion is detected. Old thrombi are more echogenic and less compressible than fresh thrombus. Because of the difficulty of identifying thrombus by compression in certain anatomic locations, such as the deep femoral vein, the femoral canal, and the personeal veins, compressibility alone should not be used as the single criterium for diagnosis of deep venous thrombosis (DVT) in the absence of other abnormalities. Despite its drawbacks, Duplex scanning has been shown to be highly accurate for the diagnosis of DVT, both in the outpatient population as well as in the screening of high-risk symptomatic or asymptomatic hospitalized patients. In a prospective analysis utilizing Duplex scanning, Lensing et al. studied 220 patients with suspicion of DVT.[47] The sole criterion used for the diagnosis of deep venous thrombosis with Duplex ultrasound was vein compressibility. All patients had contrast phlebography performed 2 hours after the Duplex examination; patients who underwent phlebography were unaware of the Duplex results. These authors found 100% sensitivity and 99% specificity for proximal deep venous thrombosis when using Duplex scanning as compared with phlebography. The sensitivity of Duplex scanning for detecting both proximal and calf venous thrombosis was 91%. In a study of 707 veins examined both by Duplex ultrasonography and phlebography, Montefusco found that Duplex ultrasonography yielded information about the specific thrombus location, extent, and configuration that was similar in detail to the results provided by contrast phlebography. In this study, Duplex ultrasonography had 100% sensitivity and 98.9% specificity. The overall accuracy of duplex ultrasonography in the detection of venous thrombosis, as compared with phlebography, was 97.7%.[46] Because the diagnostic accuracy of traditional noninvasive studies has been shown to be significantly less than that of phlebography for screening asymptomatic, high-risk individuals as compared with screening symptomatic patients, Barnes et al. performed routine preoperative and postoperative Duplex screening and phlebography on 78 patients undergoing total hip or knee arthroplasty with routine anticoagulation for prophylaxis.[48] Of 309 extremity examinations, Duplex scanning had an overall sensitivity of 85.7% and a specificity of 97.3% when compared with

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phlebography. In two instances, Duplex scanning detected thrombi initially overlooked by phlebography. These findings indicate that Duplex scanning is a reliable method for screening perioperative high-risk patients. Duplex scanning has become the preferred examination in many centers for the diagnosis of DVT. However, Hobson et al.[49] currently utilize an algorithm in which IPG is initially performed. In this author’s experience, IPG and serial followup has been sufficiently accurate for the diagnosis of aboveknee thrombi to justify anticoagulant therapy and to avoid treatment in patients with negative studies. As stated by Hobson et al., the final role of B-mode ultrasonography in replacing plethysmographic testing will await further clinical trials. However, there is evidence at the present time that Duplex scanning has enhanced sensitivity and specificity as compared with IPG. The availability of a competent and skilled ultrasonographer is essential to obtain results of comparable accuracy. Kahn and Barnes consider that if acute or recurrent deep venous thrombosis is suspected, Duplex scanning is the diagnostic method of choice.[50] If the Duplex scan is normal, a search for another cause of the patient’s symptoms is begun. If the scanning is clearly abnormal, the findings may be as follows: Thickened, less compressive walls: This is usually a finding in postthrombotic syndrome. Noncompressible vein: If this is found, therapy for DVT should be instituted. Superficial flow and the presence of a floating thrombus: In this situation, therapy should be instituted. If there are any questions in regard to the interpretation of the scanning, a phlebogram should be performed. Color flow Duplex (CFD) imaging of the tibial veins has become increasingly utilized for the detection of infrapopliteal venous thrombi. With the advent of newer, more sensitive Duplex machines, this technique is now possible in the majority of vascular laboratories. Centers have reported the sensitivity and specificity of CFD to detect tibial venous thrombi to be 91% and 93%, respectively.[51,52] Using CFD, Mattos et al. were able to identify acute tibial vein DVT in 110 of 655 (17%) symptomatic limbs.[53] The significance of isolated calf vein thrombus and its relationship to pulmonary embolism has been a subject of debate. Using this newer technology, however, studies have shown that tibial thrombus not only can be identified accurately but also has been shown to propagate.[54]

Venous Reflux Detection with Duplex Scanning and Color Flow Imaging Duplex scanning has provided the ability to quantify reflux in individual veins. This has been demonstrated by several authors. The method of examination to detect venous reflux with duplex scanning requires the use of a pneumatic cuff placed in the calf with standard compression pressure of 70 mmHg and sudden release. The gate of the sample volume is adjusted so that insonation of the vein under examination is from wall to wall. The Doppler spectrum is recorded on video during compression and release. The mean velocity at peak reflux in centimeters per second (cm/s) is determined. The

diameter of the vein is calculated, and this serves to determine the cross-sectional area in square centimeters. The flow in milliliters per second (mL/s) at peak reflux is obtained by multiplying the cross-sectional area by the average flow velocity at peak reflux. The results in 47 limbs of patients who were affected with chronic venous insufficiency problems, studied by Nicolaides et al.,[55] demonstrated that skin changes and ulceration do not occur when the sum of peak reflux in all the veins is less than 10 mL/s. However, the incidence of skin changes and/or ulceration is high when peak reflux exceeds 15 mL/s, whether such reflux is in the superficial or the deep veins. The introduction of color flow imaging (CFI) has simplified the previously tedious procedure of interrogating most vessels by B-mode real-time ultrasound, which used to take approximately 30 minutes per limb. Color flow imaging provides instant visualization of blood flow and its direction. These characteristics are very important for venous assessment. The direction and magnitude of the Doppler frequency shift determine the hue and intensity of the color, respectively. Conventionally, blue indicates flow toward the heart and red, flow away from the heart. The higher the velocity, the paler the color becomes. Previous studies on the arterial system have demonstrated that flow can be quantified using CFI and that flow patterns in specific areas such as the carotid bulb can be visualized accurately. The examination of the venous system for reflux is performed following the same protocol as for duplex scanning, with the patient in the standing position. The veins are initially identified using the gray scale. When the color is switched on, the pulsatile flow in the arteries becomes obvious (red) and distal compression results in augmentation of venous flow and increased Doppler shift frequency, which is assigned a color (blue) for flow toward the heart. In this manner, any shift direction of the venous flow away from the heart would represent reflux, and it will be shown with a different color (red) indicating flow away from the heart. With the introduction of color flow imaging, the detection of reflux in any anatomic position in the superficial or deep system has been simplified and can be seen immediately. The demonstration of venous reflux can be done very quickly and the measurement of reflux (in mL/min) at the time that reflux is occurring is easy to quantify with the available computerized software. Color flow imaging has also made the demonstration of incompetence in the thigh or calf perforators an objective and simple procedure.[56] The examination of tibial, peroneal, and calf-perforating veins is performed with the patient sitting at the end of a table with the legs placed on a low stool. The flow variations during muscle contractions can be studied with CFI. New physiological information has become available as a result of the introduction of this new technology. There is no doubt that color flow imaging is a powerful diagnostic and research tool that will allow us better insight into the hemodynamics and natural history of chronic venous insufficiency. Demonstration of venous valvular reflux has been shown to be a useful adjunct to investigations of patients with severe venous disease. As described by van Bemmelen et al.,[57] a duplex probe is placed over the popliteal, common, or superficial femoral vein with the patient in the standing

Chapter 9.

position. Reverse flow in the popliteal vein is then generated using a rapid cuff inflator placed at a level a few centimeters below the probe. The cuff is inflated to 80 mmHg and then rapidly deflated. Continuous Duplex monitoring reveals a forward jet of venous flow followed by rapid closure of a competent valve. Normal reflux flow duration is less than 0.5 s. Valve closure times (VCT) greater than 2 s are consistent with valvular incompetence.

Congenital Vascular Malformations Duplex scanning of vascular malformations enables us to document the severity of the venous disease and the staging of the malformation.[58 – 61] Even in low-flow venous malformations, duplex may demonstrate an increased venous outflow in comparison to the contralateral extremity. The large venous volume flowing through collateral superficial veins can be traced by duplex scan.[60 – 63] In arteriovenous malformations, there is a

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spectral broadening and continuation of color in diastole in the color flow Duplex scanner. Systolic and diastolic flow velocities, as well as venous flow volume, are also increased above the malformation. Computed tomography and MRI have been extensively utilized in the assessment of the extent and nature of congenital vascular malformations. The combination of MRI and magnetic resonance angiography (MRA) enables the investigator to evaluate the deep and superficial venous channels. MRI and MRA provide basic information regarding the prognosis and treatment of the vascular malformation. Magnetic resonance angiography is usually performed with commercially available pulse sequences, including the time of flight and phase contrast techniques. MRA and MRI are useful, noninvasive, easily repeatable diagnostic and screening methods for the study of peripheral and central venous malformations and have been shown to have excellent correlation with conventional angiography.[64 – 68]

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Bernstein, E.F., Ed.; CV Mosby Co.: St. Louis., MO, 1982; 452– 457. Flanagan, L.D.; Sullivan, E.D.; Cranley, J.J. Venous Imaging of the Extremities Using Real Time B-Mode Ultrasound. In Surgery of the Veins; Bergan, J.J., Yao, J.S.T., Eds.; Grune and Stratton: New York, 1985; 89– 98. Sumner, D.S.; Spadone, D.E.; Colgan, M.P. Duplex Scanning and Spectral Analysis of Carotid Artery Occlusive Disease. In Current Therapy in Vascular Surgery; 2nd Ed. Ernst, C.B., Stanley, J.C., Eds.; B. C. Decker, Inc.: Philadelphia, 1991. Gillespie, D.L.; Villavicencio, J.L.; Gallagher, C.; Chang, A.; Hamelink, J.K.; Fiala, L.A.; O’Donnell, S.D.; Jackson, M.R.; Pikoulis, E.; Rich, N.M. The Presentation and Management of Venous Aneurysms. J. Vasc. Surg. 1997, 26, 845 – 852. Montefusco, C.M.; Bakal, C.W.; Sprayregan, S.; Rhodes, B.; Veith, F.J. Duplex Ultrasonographic Venography: The Definitive Diagnostic Tool for Thrombophlebitis. In Current Critical Problems in Vascular Surgery; Veith, F.J., Ed.; Quality Medical Publishing, Inc.: St. Louis, MO, 1989; 145– 150. Lensing, W.A.; Prandoni, P.; Brandjes, D. Detection of Deep Venous Thrombosis by Real Time B-Mode Ultrasonography. N. Engl. J. Med. 1989, 320, 342. Barnes, R.; Nix, M.; Ferris, E. Perioperative Asymptomatic Venous Thrombosis: Role of Duplex Scanning Versus Venography. J. Vasc. Surg. 1989, 9, 251. Hobson, R.W.; Lynch, T.G.; Jamil, Z. Role of the Vascular Laboratory in the Diagnosis of Venous Disease. In Operative Surgery; DeWeese, J.A., Ed.; Butterworth: London, 1985; 253 – 263. Kahn, M.B.; Barnes, R.W. Noninvasive Methods of Diagnosing Venous Disease. In Current Therapy in Vascular Surgery; 2nd Ed. Ernst, C.B., Stanley, J.C., Eds.; B. C. Decker, Inc.: Philadelphia, 1991; 943 – 949. Prandoni, P.; Lensing, A.W. New Developments in Noninvasive Diagnosis of Deep Vein Thrombosis of the Lower Limbs. Ric. Clin. Lab. 1990, 20, 11. Habsheid, W.; Hohmann, M.; Wilhelm, T.; Epping, J. Real Time Ultrasound in the Diagnosis of Acute Deep Venous Thrombosis of the Lower Extremity. Angiology 1990, 41, 559. Mattos, M.A.; Melendres, G.; Sumner, D.S.; Hood, D.B.; Barkmeier, L.D.; Hodgson, K. et al. Prevalence and Distribution of Calf Vein Thrombosis in Patients with Symptomatic Venous Thrombosis: A Color Flow Duplex Study. Lohr, J.M.; Kerr, T.M.; Lutter, K.S.; Cranley, R.D.; Spirtoff, K.; Cranley, J.J. Lower Extremity Calf Thrombosis: To Treat or Not to Treat? J. Vasc. Surg. 1991, 14, 618. Nicolaides, A.N.; Vasdekis, S. Detection and Quantification of Venous Reflux Using Doppler Ultrasound: The Impact of Color Flow Imaging. In Current Critical Problems in Vascular Surgery; Veith, F.J., Ed.; Quality Medical Publ. Inc.: St. Louis, MO, 1990; 2, 127 – 136. Hanrahan, L.M.; Araki, C.T.; Fisher, J.B.; Rodriguez, A.A.; Walker, G.; Woodson, J.; LaMorte, W.W.; Menzoian, J.O. Evaluation of the Perforating Veins of the Lower Extremity

Chapter 9.

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Using High Resolution Duplex Imaging J. Cardiovasc. Surg. 1991, 32 (1), 87. van Bemmelen, P.S.; Bedford, G.; Beach, K.; Strandness, D.E. Quantitative Segmental Evaluation of Venous Valvular Reflex with Duplex Ultrasound Scanning. J. Vasc. Surg. 1989, 10, 425– 431. Rudofsky, L. Kompaktwissen Angiologie; 2nd Ed. Perimed Verlag: Erlangen, Germany, 1988; 131 – 144. Villavicencio, J.L. Treatment of Varicose Veins Associated with Common Congenital Vascular Malformations. In Complex Problems Involving Varicose Veins. Part IV; Bergan, J.J., Goldman, M.P., Eds.; Quality Medical Publ.: St. Louis, MO, 1993; 329 – 342. Lobato, R.; Martinez, L.; Leal, N.; Diaz, M.; Diez-Pascual, R.; Velasco, B.; Ros, Z.; Lopez-Gutierrez, J.C. Hemangiomas and Vascular Malformations. Review and Update. Circ. Pediatr. (Spain) 1997, 19 (3), 119. Vaghi, M. Apparative Diagnostik der Angeborenen Gefassfehler. In Angeborene Gefassmisbildungen; Loose, D.A.; Weber, J.: Eds. Period. Angiol. 1997, 21, 122. Eifert, S. Clinical and Ultrasonic Diagnosis of Combined Angiodysplasias (Klinische and Sonographische Diagnos-

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tik Kombinierter Angiodysplasien); 29– 34 Univ. Med. Fab. Diss.: Halle, Germany, 1996; 14 – 18. Loose, D.A.; Funk, J. Angeborene Venenfehler—Diagnostische und Therapeutische Mo¨glichkeiten. Akt. Chir. (Germany) 1995, 30 (6), 329. Laor, T.; Burrows, P.E.; Hoffer, F.A. Magnetic Resonance Venography of Congenital Vascular Malformations of the Extremities. Pediatr. Radiol. (Germany) 1996, 26 (6), 371. Allison, J.W.; Glasier, C.M.; Stark, J.E.; James, C.A.; Angtuaco, E.J. Head and Neck MR Angiography in Pediatric Patients: A Pictorial Essay. Radiographics 1994, 14 (4), 795. Villavicencio, J.L.; Papendieck, C. et al. Venous Disorders in Childhood. In Pediatric Surgery; 5th Ed. O’Neill, J.A., Jr., Ed.; Mosby Yearbook Inc.: St. Louis, MO, 1998; 1945–1972. Invasive Diagnostik Angeborener Gefa¨ssfehler. In Angeborene Gefa¨ssmisbildungen; Loose, D.A.; Weber, J.: Eds.; Period. Angiol. 1997, 21, 122–127. Mulliken, J.B.; Fishman, S.; et al. Vascular Anomalies: Hemangiomas and Malformations. In Pediatric Surgery; 5th Ed. O’Neill, R., Ed.; Mosby Yearbook Inc.: St Louis, MO, 1998; 1039– 1052.

CHAPTER 10

Angiography Timothy M. Koci Frances Chiang C. Mark Mehringer monomeric, nonionic monomeric, ionic dimeric (lowosmolality), and nonionic dimeric media. Ionic monomeric compounds are the standard triiodobenzoic acid salts, which dissociate in solution into an iodinated anionic component (diatrizoate or iothalamate) and a cationic component (sodium or meglumine). Agents with a higher proportion of sodium are less viscous (but more toxic), as sodium is a smaller cation. At concentrations necessary for diagnostic angiography, these agents are hypertonic, approximately five to seven times the osmolarity of normal plasma. This high osmolarity accounts for some of the toxicity of these media. Nonionic monomeric agents (iopamidol, iohexol) also feature a triiodinated benzene ring, but the sodium or meglumine cation has been replaced by a nondissociating side chain. Their osmolarity is only two to three times that of blood. An ionic dimeric medium (ioxaglate) is a dimer of two benzene rings (with a total of six iodine atoms) but only a single cation, which results in an osmolarity half that of a standard ionic agent of equal iodine content. The nonionic dimers such as iodixanol (283 mOsm/kg) have nearly the same osmolality as plasma. Properties of several representative agents are summarized in Table 10-1.[6] The adverse effects of intravascular contrast injection are well known. Local sensations of pain and burning as well as flushing (vasodilation) are considered physiologic irritant or chemotoxic effects and are related to high osmolarity. In sensitive areas such as the external carotid territory and peripheral extremities, these local effects can be significantly reduced by the use of low-osmolarity agents.[7 – 9] The addition of local anesthetics to contrast media does not appear to be effective in reducing patient discomfort during aortofemoral angiography.[10] Minor systemic reactions such as nausea and vomiting are not infrequent in arteriography and are common in intravenous contrast injection. Nonphysiologic anaphylactoid or idiosyncratic reactions can manifest as symptoms ranging from urticaria to bronchospasm, laryngospasm, and cardiovascular collapse. The mortality rate in one large series of 300,000 patients was 1:75,000.[11] Pretesting for allergy is of no predictive value and should be abandoned.[12] Patients with a history of previous severe reaction have approximately a 15% change of

INTRODUCTION The history of angiography began only a few months after the discovery of x-rays in 1895 by Roentgen, when contrast agents too toxic for human use were being injected into cadavers, severed limbs, and animals. The next major developments came in the late 1920s, when percutaneous translumbar aortography and cerebral angiography were described by the Portuguese surgeons Dos Santos and Moniz, respectively. Contrast agents were now less toxic, and clinically useful angiography was a reality. In 1953, Seldinger described his technique for percutaneous vascular catheterization,[1] which formed the basis of many catheterization techniques to follow. In the 1970s the development of less invasive methods such as computed tomography (CT) and ultrasound decreased the indications for diagnostic angiography. Vascular imaging progressed rapidly in the 1990s with the addition of color Doppler ultrasound and magnetic resonance imaging (MRI). Magnetic resonance angiography (MRA) is now producing images of striking clarity and resolution. Nonetheless, angiography remains the most important way to demonstrate vascular diseases graphically. The relative decrease in routine diagnostic angiographic procedures has been offset by a proliferation of interventional techniques requiring angiographic guidance, including embolization therapy, angioplasty, thrombolytic therapy, atherectomy, intravascular stenting, intraarterial chemotherapy, caval filter placement, and even hybrid techniques such as intraarterial contrast-enhanced CT angiography.[2] We hope to provide an overview of major areas of angiographic utilization and diagnosis. Interventional techniques will be addressed in other chapters. The basic techniques of arterial puncture and catheterization have been well described elsewhere.[3 – 5]

CONTRAST AGENTS Iodinated radiopaque contrast agents currently used for angiography can be classified into four groups: ionic

Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024893 Copyright q 2004 by Marcel Dekker, Inc.

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170 Table 10-1.

Part One. Assessment of Vascular Disease

Contrast Agents

Trade name Ionic monomeric agents Hypaque 50% (Nycomed) Conray-60 (Mallinckrodt) Renografin-60 (Bracco) Renografin-76 (Bracco) Nonionic monomeric agents Isovue (Bracco) Isovue (Bracco) Omnipaque (Nycomed) Omnipaque (Nycomed) Ionic dimeric (low osmolality) Hexabrix (Mallinckrodt)

Generic name

Concentration, %

Cation

Iodine, mg/mL

Osmolarity, mOsm/kg

Viscosity (cP), 378C

Diatrizoate

Sodium

50

300

1550

2.5

Iothalamate

Meglumine

60

282

1400

4.1

Diatrizoate

Meglumine 52% Sodium 8% Meglumine 66% Sodium 10%

60

288

1420

3.9

76

370

1940

9.1

Iopamidol

61.0

300

616

4.7

Iopamidol

76.0

370

796

9.4

Iohexol

64.7

300

709

6.8

Iohexol

75.5

350

862

11.2

Ioxaglate Meglumine 39.3% Sodium 19.6%

58.9

320

600

7.5

Diatrizoate

Source: Ref. 6.

having another reaction. Corticosteroid premedication reduces the frequency of repeat reactions;[13] additional protection may be afforded by the antihistamines Benadryl (diphenhydramine HCl, an Ht antagonist) and Tagamet (cimetidine HCl, an H2 antagonist). Anesthesia standby should be employed. There has been much recent debate and study regarding the safety, toxicity, expense, and indications for use of the new nonionic contrast agents. The two largest series[14,15] compared reactions to intravenous contrast injection for ionic versus nonionic media. The frequency of severe reaction for nonionic versus ionic were 0.02% versus 0.09%[14] and 0.04% versus 0.22%.[15] To complicate matters, some authors[16] have reported that corticosteroids given 12– 24 h in advance of ionic contrast injection can provide protection against contrast toxicity such that reactions are no greater than those for patients receiving nonionics. Central nervous system complications include seizure, transient cortical blindness (vertebral angiography), and transient global amnesia. “Spinal seizure” can rarely be seen during spinal or aortic angiography.[17] Among the ionic media, pure meglumine salts (no sodium) are tolerated best for cerebral angiography.[18] In a series of 2509 cerebral arteriograms, Skalpe[19] recorded complication rates of 2.0% for ionic contrast and 1.3% for nonionic iohexol. The difference was not statistically significant. Cardiac, coronary, and aortic root injections of contrast can precipitate arrhythmias. If ionic media are used in cardiac

work, agents with a physiologic sodium level should be employed.[20] Myocardial depression and transient blood pressure depression can also occur. The nonionics have fewer cardiac effects[21] and are now in wide use in cardiaccoronary catheterization. Contrast agents are cleared by glomerular filtration, and minor contributions to excretion are made by the liver and small bowel. A few patients may develop impaired renal function following contrast administration, especially those with multiple myeloma or diabetes.[22] Patients of advanced age, those with preexisting renal or cardiac disease, and those receiving large volumes of contrast also appear to be at higher risk for renal compromise.[23] This is usually a self-limited state similar to acute tubular necrosis, but in some cases permanent renal impairment can occur. Contrast may cause sickling in some patients with hemoglobin S. Limiting the contrast dose as much as possible and keeping the patient well hydrated are the best forms of prevention. Animal studies[24] have shown reduced nephrotoxicity for the nonionic iohexol. In a group of high-risk patients, 10% of the ionic group and 5.5% of the nonionic group developed acute renal dysfunction after angiography; however, the difference was not statistically significant.[25] Nonionics, while less toxic, are also less anticoagulant than ionic contrast. Reports of clot formation in angiographic syringes[26] raised a concern that thrombotic complications would increase with nonionics. Attention to meticulous technique has been emphasized, and some authors[27] find no evidence of increased thromboembolic phenomena, while others advocate the addition of

Chapter 10. Angiography

heparin (5 IU/mL contrast) to ensure an anticoagulant medium.[28] Gadolinium chelates (gadopenetate dimeglumine and gadodiamide) are finding increasing use in catheter angiography for patients with renal insufficiency or allergy to iodinated contrast media.[29 – 31] Finally, carbon dioxide is an important radiolucent contrast agent[32] that can provide excellent diagnostic arteriograms when used with digital subtraction technique (Fig. 10-1). It can be used safely “below the diaphragm” in patients with hypersensitivity to iodinated contrast or with renal insufficiency. It has the advantages of low cost, no toxicity, and very low viscosity; moreover, it is resorbed from blood in 1–3 min.

ANGIOGRAPHIC CATHETERS Angiographic catheters are most commonly made of polyethylene, polyurethane, Teflon, or woven Dacron. These can be formed in hot water or steam to a desired shape, but most angiographers now use preformed catheters. Teflon can hold higher injection pressures and therefore deliver higher flow rates, but it takes extreme heat to modify its shape. It is also stiffer than the other materials. The torque control of a catheter is a function of its stiffness, which, in turn, relates to size, wall thickness, and composition. Some “torque control” catheters are braided with a wire mesh being incorporated into the catheter wall. Stiffer catheters are easier to manipulate, but more readily dislodge plaques or injure the vessel wall. It has been said that the stiffness and size of the catheters used are inversely related to the skill of the angiographer. The trend in recent years has been to smaller (usually 4 or 5 French), thinner-walled catheters,[33,34] which

Figure 10-1. CO2 abdominal aortogram (50 cm3 injection CO2) in a patient with renal insufficiency being evaluated for possible renal artery stenosis. The main renal arteries (arrows) are clearly seen and show normal caliber and contour. (Courtesy of Mark Allgood, M.D., Washoe Medical Center, Reno, Nevada.)

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can deliver high rates of flow. The refinement of coaxial systems (usually 2 –4 French selective catheters with 5 –7.5 French guiding catheters) has facilitated superselective catheterizations and the steady advancement of therapeutic interventional techniques. Furthermore, the development of hydrophilic coated catheters and wires has greatly facilitated selective catheterization.

THORACIC AORTOGRAPHY Percutaneous femoral puncture is the most commonly used approach to the aorta and its branches. This technique is most comfortable for the patient, is associated with the lowest rate of puncture complications, and allows the easiest manipulation of the catheter into the desired position, including small aortic branches. Mani et al.[35] cite a rate of 0.1% of damage to the femoral artery in a large series. A prospective sonographic study showed a higher-than-expected incidence of pseudoaneurysm detected by color flow duplex ultrasound following transfemoral catheterization.[36] The study group included patients undergoing diagnostic angiography alone, angioplasty, stenting, or thrombolysis. Initially, pseudoaneurysm incidence ranged from 1.2% for angiography up to 27% for thrombolysis with angioplasty, but in the second part of the study pseudoaneurysms were reduced to 0% for angiography and 8% for thrombolysis combined with angioplasty. This reduction was accomplished merely by prolonging manual compression for an additional 5 minutes beyond visible hemostasis. Obesity and heparinization after sheath removal correlated with higher risk for pseudoaneurysm. All pseudoaneurysms thrombosed with ultrasound compression technique, and none required surgery. In a similar study, a 6.25% incidence of pseudoaneurysm was detected by color flow ultrasound following transfemoral puncture and sheath placement.[37] In addition to pseudoaneurysm formation, dissection of the intima or laceration of the whole arterial wall may cause thrombosis, embolism, or uncontrollable hemorrhage. This results from extraluminal placement of the needle, guidewire, or catheter and may be detected on test injections. An arteriovenous fistula may also develop if the vein is concomitantly punctured. The incidence of these complications clearly increases with the size of the catheter used[35,38] and is higher with an inexperienced angiographer. Thoracic aortography requires a high-flow catheter to achieve a contrast flow rate approaching 40 mL/s, which is needed to opacify this large vessel. Other very uncommon risks are infection at the puncture site and breakage of the catheter or guidewire, requiring snare retrieval or possibly surgical removal. If the femoral artery is not available, we select the axillary artery, which is smaller and deeper and therefore carries a higher risk of local damage than a comparable femoral catheter placement.[35,39] In addition, the musculature in the axilla makes postangiographic hemostasis more difficult, and axillary hematoma may damage the brachial plexus. This may be avoided by careful postangiogram observation and urgent surgical evacuation of any significant hematoma. A recent large study of surgical complications of transaxillary arteriography cited a 2.3% complication rate, of which the

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Part One. Assessment of Vascular Disease

majority were nerve injuries followed by hematomas or pseudoaneurysms.[40] Because the brachial artery is even smaller, we do not advocate its use on a routine basis. Selected, limited cases may be performed using catheters of 4 or 5 French outer diameters or smaller. However, the smaller catheters may not deliver sufficient flow rates for thoracic aortography except with digital subtraction techniques. The most common local complications are loss of the radial pulse from either vasospasm or thrombosis and transient hand paresthesias.[41,42] Damage to the brachial artery with this approach is not uncommon but usually insignificant clinically. If neither axillary nor femoral sites are available, an aortogram can be performed using an intravenous catheter within the superior vena cava and digital subtraction techniques. There is a visible loss of image quality; however, a diagnostic exam can be obtained in most patients with good cardiac output.[43] When a prosthetic graft is in place, puncture is easily accomplished by routine transfemoral technique without a significant increase in complications, in our experience, as long as the graft is mature enough to have a firm neointima. The safety of this procedure has been confirmed in some reports[44] and denied in others.[45] Risks other than those associated with the arterial puncture are uncommon but include cerebral embolus and seizures, since injection is proximal to the brachiocephalic vessels. Dissections may occur with improper positioning of the catheter, as into a coronary artery orifice, under an atheromatous plaque, or with injection recoil into a carotid artery. Arrhythmias, hypotension, and contrast agent – induced renal failure also occur. An exact incidence of complications from thoracic aortography is uncertain, but data from a large series of angiography complications, which included a high proportion of aortograms, cited a mortality rate of 0.032% and a complications rate of 1.7–3.3%, depending on the puncture site.[39]

will identify other causes of mediastinal masses. Early reports on magnetic resonance imaging show similar accuracy as CT, with added flexibility in imaging planes.[48] Traumatic false aneurysms are the second most common type of thoracic aneurysm and have a characteristic angiographic appearance (Fig. 10-2). Although large autopsy series[49] show that only 45% of these aneurysms occur at the site of the ligamentum arteriosum, 95% of radiologically demonstrated aneurysms occur here. As many as 22% of aortic ruptures described on postmortem examination are in the ascending aorta, but they are infrequently diagnosed by angiography because of the much higher mortality rate from aortic root ruptures, associated cardiac injury, or pericardial hemorrhage with tamponade.[50] Fifteen to 20% of isthmus injuries survive hours to days, allowing diagnosis.[49] Chest radiograph findings suggesting aortic rupture include a widened mediastinum, present in the majority of cases of aortic rupture (but also present in 25% of other matched patients),[51] depression of the left main stem bronchus, tracheal and nasogastric tube deviation to the right, pleural fluid, and obliteration of the normal contour of the aortic knob. Widening of the right paratracheal stripe exceeding 5 mm is a sign of mediastinal hemorrhage.[52] In the past, some have advocated routine aortography in all patients with fractures of the first rib because of presumed correlation with aortic and brachiocephalic injuries. [53] Subsequent series[54,55] have demonstrated a low correlation of rib fractures and vascular injuries, which concurs with our experience.[56] Thoracic CT has become a valuable screening test in the evaluation of traumatic aortic injury (TAI) with the advent of high-speed helical/spiral scanners. Chest CT has shown a sensitivity of 100% for TAI [57,58] by virtue of detection of mediastinal hemorrhage. Helical CT was

ANEURYSMS The most common etiology of thoracic aneurysms is arteriosclerosis; 81.6% of aneurysms in DeBakey’s surgical series of 500 descending aortic aneurysms were arteriosclerotic.[46] These aneurysms are usually fusiform but may be saccular and even multiple. They may extend into the brachiocephalic vessels or the abdominal aorta; they are frequently calcified. Other etiologies of thoracic aneurysms are syphilis, bacterial infection, medial degeneration associated with Marfan syndrome or similar disorders, trauma, and aneurysms associated with congenital malformations. Luetic and mycotic aneurysms are usually saccular and more commonly found in the ascending aorta; mycotic aneurysms rarely calcify.[47] Since arteriosclerotic aneurysms may mimic these patterns, the precise etiology of the aneurysm often cannot be determined on the aortogram. Aneurysms create mediastinal masses on chest radiographs and have a diagnostic appearance on CT, which provides the true diameter of an aneurysm, including the amount of thrombosis, but may not demonstrate involvement of branch vessels. It

Figure 10-2. Traumatic false aneurysm (arrows) of the thoracic aorta occurring in its classic location at the level of the ligamentum arteriosum.

Chapter 10. Angiography

more sensitive than aortography (100% vs. 94.4%) but less specific (81.79 vs. 96.3%) in the detection of aortic injuries.[57]

DISSECTING ANEURYSM Aortic dissections arise in the thorax unless they are secondary to trauma or surgery. The chest film, along with the typical history of chest pain and findings of pulse deficits, provides important diagnostic information. Progressive mediastinal widening and haziness or a knobby appearance of the aortic arch or descending aorta is suggestive of dissection. A more specific sign is separation of a calcified intimal plaque from the outer wall of the aorta by 6 mm or more. However, this sign is present in a minority of cases.

173

Furthermore, separation of up to 10 mm has been seen in arteriosclerosis without dissection.[59] In patients with suspected dissection, we approach the aortogram from the femoral route because we have found that entry into the false lumen is just as likely from the axilla. A guide wire with a very flexible tip is carefully advanced ahead of the catheter, and small test injections are used to avoid high-pressure injections into the false lumen. In this way we have been able to demonstrate both true and false lumens without extending the dissection (Fig. 10-3). Signs of dissection on an aortogram include narrowing and distortion of the intraluminal contrast with a parallel linear soft tissue density, which is the unopacified lumen, nonfilling of aortic branches, and associated aortic insufficiency. In other cases, the true and false lumens may fill and empty at slightly different times. If the tear is widely patent and the

Figure 10-3. Type III aortic dissection with retrograde extension. (A) Transfemoral aortogram. The catheter is in the true lumen, which fills the left subclavian artery. There is early filling of the false lumen (arrows) at the site of the tear. (B) Catheterization is now via the left subclavian artery and the false lumen is opacified. The dissection extends retrograde into the ascending aorta and right carotid artery (white open arrows). The true lumen appears as a filling defect (curved arrows) at the arch and descending aorta.

174

Part One. Assessment of Vascular Disease

lumens fill and empty simultaneously, the wall between them may be seen as a thin, linear filling defect in the column of contrast (Fig. 10-3). This dissected wall may be difficult to demonstrate because not only does it assume a spiral configuration, but it also may flap with the heartbeat, changing its appearance or even disappearing on sequential films. Dissections arising at the aortic root within a few centimeters of the valve and extending into the descending aorta (DeBakey type I) or limited to the ascending aorta (DeBakey type II) were most common in autopsy series.[60] In clinical series[61] DeBakey type III dissections have been more frequent; that is, tears arise just distal to the left subclavian artery origin, dissect distally, and often extend proximally as well. Whenever possible, the angiogram will identify the site of the tear by sequential opacification of first the true, then the false lumens (Fig. 10-3). In some cases the tear will not be demonstrated because of rapidity of flow across the tear or multiple reentry sites. A series reported by Abrams[59] demonstrated the tear in only 50% of cases. Intramural hematoma of the thoracic aorta, also known as “noncommunicating aortic dissection” or “aortic dissection without intimal disruption,” may explain many cases of dissection without demonstrable tear on aortography. This important entity can progress to communicating aortic dissection.[62 – 64] High-resolution CT is a valuable tool for diagnosis of dissection. Although demonstration of the tear and reentry or extension into branch vessels or the aortic valve may necessitate angiography, CT is accurate in diagnosing or excluding a dissection and in following up chronic dissections or postsurgical repair.[65] Similarly, transesophageal echocardiography may also demonstrate an intimal flap and false lumen as well as associated pericardial effusions and aortic insufficiency. The position of the trachea may limit evaluation of the aortic arch by ultrasound. Extension into branch vessels or the abdominal aorta is still better assessed with angiography.[66] For the stable and cooperative patient, MRI may provide the greatest anatomic detail, with a reported diagnostic accuracy of 90%.[67] Penetrating atherosclerotic ulcers of the aorta may present similarly to aortic dissections. However, these patients are elderly, with severe underlying atherosclerosis. The ulcerated plaque penetrates the internal elastic lamina, forming a hematoma within the media, which can develop a false aneurysm or rupture. The most common location is in the middle or distal descending thoracic or upper lumbar aorta. The lesion can be demonstrated by either angiography or CT[68] (Fig. l0-4). Occlusive disease of the aorta and brachiocephalic vessels—such as arteriosclerosis, arteritis, and congenital coarctation—is a common indication for arch aortography. Arteriosclerotic plaques of the carotid bifurcation are best demonstrated by selective injection; aortography demonstrates proximal stenoses, collateral vessels, or retrograde flow. The most common example of the latter is so-called subclavian steal: filling the subclavian artery distal to an occluded segment by retrograde flow down the vertebral artery (Fig. 10-5). Retrograde filling of the right carotid may similarly fill an occluded right subclavian artery. Takayasu’s arteritis (Fig. 10-6) occurs typically in premenopausal females who have pulse deficits and

Figure 10-4. Penetrating atheromatous ulcer. CT (not shown) demonstrated periaortic or intramural hemorrhage consistent with aortic dissection. Angiography of the aortic arch and proximal descending thoracic aorta was unremarkable. Penetrating atheromatous ulcer (arrows ) in the distal descending thoracic aorta.

angiographically show long or short segments of smooth stenosis in the aorta itself or any of its branches. Less commonly, there is dilatation of the ascending aorta or arch, or aneurysms in the descending aorta. In advanced cases, superimposed arteriosclerosis may mask the diagnosis of aortitis.[69] Most other types of arteritis cause dilatation and irregularity of the aorta and do not have a diagnostic radiologic picture. These include giant cell arteritis, which may also cause stenosis, and arteritis associated with syphilis, rheumatic fever, rheumatoid arthritis, ankylosing spondylitis, and Reiter’s syndrome.[70] Congenital coarctation appears in one of three patterns: (1) a short-segment stenosis in the high thoracic aorta near the origin of the left subclavian artery (Fig. 10-7), which is most common; (2) distal thoracic segmental narrowing, which is

Chapter 10. Angiography

175

Figure 10-5. Subclavian “steal.” (A) Arch aortogram showing nonfilling of the right subclavian and right vertebral arteries as well as stenoses at the origins of all the other brachioccphalic vessels. (B) Delayed film shows retrograde filling of the right vertebral artery (arrows), which fills the right subclavian artery (open arrows).

probably a form of Takayasu’s arteritis; and (3) complete interruption of the aortic arch or hypoplasia over a long segment involving the brachiocephalic origins.

PULMONARY ANGIOGRAPHY The two most common approaches to the pulmonary artery are percutaneous femoral or antecubital vein (preferably basilic vein) puncture, although axillary, subclavian, or internal jugular routes can also be used. Because the right heart and pulmonary arteries are relatively thin-walled and delicate, we almost exclusively use catheters with a pigtail shape to minimize the risk of cardiac or vessel perforation. Multiple side holes and large caliber (7 or 8 French) help prevent recoil on injection and allow high injection rates, up to 30 – 40 mL/s. The Grollman reversed-curve pigtail catheter[71] used from the transfemoral approach often passes easily through the heart and into the pulmonary artery, although a tip-deflecting wire may be needed to traverse the tricuspid valve in some cases. If pulmonary artery pressure is acceptable (see discussion below), a pulmonary arteriogram can be obtained with the catheter in the main pulmonary artery, or the right or left pulmonary artery can be selected, depending on which side shows the most suspicious findings on the ventilation/perfusion lung scan. Alternative catheters include the Van Aman right-angled pigtail,[72] which easily

crosses the tricuspid valve and is then passed over a wire into the pulmonary artery. The Ledor downward-turned pigtail catheter[73] may be helpful in lower lobe catheterization. Multiple-side-hole balloon-tipped Berman catheters (Arrow, Reading, Pennsylvania) can be flow-directed into the pulmonary arteries, and flow rates up to 27– 30 mL/s can be achieved. Two major risks complicate pulmonary arteriography. The first is arrhythmia induced by passage of the catheter into the right ventricle. ECG monitoring is mandatory during the procedure. Patients with preexisting left bundle branch block (LBBB) should have placement of a temporary pacemaker before pulmonary angiography. Fortunately, arrhythmias usually resolve when the catheter is withdrawn into the right atrium. In Mills et al.’s series of 1350 pulmonary angiograms,[74] 11 serious arrhythmias and 5 cardiac arrests occurred. The second danger is that of acute cor pulmonale. In patients with pulmonary hypertension where right ventricular end-diastolic pressure (RVEDP) reaches 20 mmHg or higher, acute right heart failure can follow even small contrast injections in the pulmonary arteries. Of 10 deaths reported in a series of 4000 pulmonary angiograms, most manifested acute cor pulmonale.[75] In a series of 388 patients with pulmonary hypertension and/or elevated RVEDP, 6 complications and 2 deaths occurred following pulmonary angiography.[76] Pulmonary artery pressures (PAP) and/or RVEDP must be obtained before contrast injection. In Mills et al.’s series,[74] all 3 deaths occurred in patients with PAP

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The most common indication for pulmonary arteriography is documentation of pulmonary emboli. The results from the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) cooperative study[85] set a perspective for the value of the ventilation/perfusion (V/Q) scan and the role of pulmonary angiography. Of patients with high-probability V/Q scans, 88% had positive pulmonary angiographs: of those with intermediate V/Q scans, 33% had positive angiograms; of those with low-probability V/Q scans, 12% had positive angiograms; those with normal or near normal V/Q scans had an estimated 4 –9% incidence of pulmonary emboli. Of all patients with confirmed pulmonary emboli, only 41% had a high-probability V/Q scan. If clinical criteria were considered, patients with low-probability or normal V/Q scans where clinical impression also indicated embolism to be unlikely had only a remote possibility of pulmonary embolism. Patients with intermediate or indeterminate scans where matching areas of ventilation and perfusion defects are seen require angiography for definitive diagnosis. Undue delay may result in missing the diagnosis because lysis of clots has been documented in 2 days, although most persist longer.[86] The diagnosis is made by

Figure 10-6. Takayasu’s arteritis in 21-year-old woman with absent pulses in both upper extremities. Arch aortogram shows a long smooth stenosis in the right subclavian artery (arrowheads), severe diffuse left subclavian narrowing (curved arrows), and a moderate left common carotid stenosis (small arrows).

greater than 75/28 mmHg or RVEDP greater than 20 mmHg, and the 2 deaths reported by Perlmutt et al.[76] had systolic PAP greater than 70 mmHg. Nonionic contrast agents have less hemodynamic effect on PAP,[77 – 79] and we now use nonionic contrast media for all pulmonary angiograms. Ioxaglate also produces less cough stimulation and thereby reduces patient motion.[80] Our guidelines are that a systolic PAP above 60 mmHg is a contraindication to continuing the study. If the pressure is between 40 and 60 mmHg, we proceed carefully with subselective injections in the areas of highest suspicion, continuing if the first injections are well tolerated. Two recent large studies[81,82] document improved safety of pulmonary angiography with low osmolar contrast. There were no deaths attributed to the procedure in either series. Since straight catheters are no longer used for pulmonary angiography, the complications of subintimal injection, cardiac perforation, and tamponade previously reported[74] have disappeared. It is wise to bear in mind the theoretical danger of dislodging emboli while advancing the catheter or from the proximal pulmonary arteries during injection. We minimize this risk by careful test injections and gentle catheter manipulation. We now use digital subtraction angiography (DSA) for most pulmonary angiograms. Although cut film angiography (CFA) has higher spatial resolution, DSA studies can be viewed subtracted or unsubtracted and reviewed in a “live” cine mode. DSA studies can be performed more quickly, require less contrast media, and have diagnostic accuracy comparable to CFA pulmonary angiograms.[83,84]

Figure 10-7. Congenital aortic coarctation. Arch aortogram showing a focal coarctation (white arrow) distal to the left subclavian artery. Note also the hypertrophied supreme intercostal collaterals (white arrowheads).

Chapter 10. Angiography

demonstrating an intraluminal filling defect in one of the pulmonary arteries (Fig. 10-8). Amputated vessels and avascular areas may be seen, but these also occur in chronic pulmonary embolism, pneumonia, emphysematous bullae, tumors, and other conditions. Superselective injections or oblique projections may be necessary to distinguish emboli from these other types of occlusions. Congenital or acquired arteriovenous (AV) fistulas (Figs. 10-9 and 10-10) are an indication for pulmonary arteriography. Posttraumatic AV fistula or false aneurysms (Fig. 1011) or “Rasmussen” aneurysms[87] associated with tuberculosis (Fig. 10-12) are also diagnosed by pulmonary angiography. Arteriovenous fistulas may be closed with detachable balloon embolization[88] or coils.[89] Balloon placement in large fistulas (greater than 6–8 mm) incurs the risk of balloon escape into the systemic arteries. The Amplatz “spider” occluding device resembles a miniature caval umbrella filter and can be used to anchor the balloon or balloons. Other anomalies of the pulmonary vasculature that may be demonstrated on angiogram include pulmonary artery atresia or stenosis, anomalous pulmonary drainage, or venous obstruction by tumor or mediastinitis. Displacement and encasement of pulmonary arteries may be caused by tumor, but tumor vascularity of both primary and metastatic lung cancers is supplied by systemic vessels.[90] The bronchial arteries are variable in number and configuration, but most commonly there are one right and two left bronchial arteries arising from the descending thoracic aorta. Bronchial arteriography is indicated in lifethreatening hemoptysis.[91,92] Bronchoscopy assists in localizing the side of hemorrhage. Actual extravasation of

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contrast is uncommonly seen angiographically, and embolization is performed empirically provided that no vascular supply to the spinal cord is identified on the arteriogram. We routinely use polyvinyl alcohol sponge particles and occasionally coil emboli. At our institution, massive hemoptysis is most commonly due to tuberculosis or lung carcinoma. Other causes for bronchial bleeding include bronchiectasis, cystic fibrosis, sarcoidosis, pneumoconiosis, and other inflammatory or neoplastic processes.

PORTAL AND MESENTERIC VENOGRAPHY Angiographic methods remain the most reliable means of demonstrating the portal venous system, but the noninvasive imaging techniques of ultrasound/color flow Doppler, CT, MRI, and MRA provide important and often complementary data and can be expected to have an increasing role in the evaluation of patients with portal hypertension.[93 – 100] The development of transjugular intrahepatic portosystemic shunting (TIPS) and proliferation of liver transplantation has driven new innovations in angiographic imaging and intervention in the portal circulation.

ARTERIAL PORTOGRAPHY The portal vein and its tributaries are usually well visualized 8–12 s after selective injection of either the celiac or superior mesenteric artery (Fig. 10-13). An injection of 50 mL over 6 – 7 s is our routine dose, but we have safely used injections or up to 100 mL in large arteries to increase the venous contrast; this is particularly useful in cases of gross splenomegaly for dense opacification of the splenic vein. Venous contrast can be further enhanced by injecting 25– 50 mg of tolazoline (Priscoline) through the catheter immediately prior to the contrast injection. We no longer perform arterial portography to assess patency or provide localization of the portal vein prior to TIPS. In celiac and mesenteric angiography for suspected bowel ischemia or gastrointestinal bleeding, careful attention is given to the portal and venous mesenteric phase images because unsuspected varices or venous occlusive disease may be discovered.

TRANSJUGULAR INTRAHEPATIC PORTAL CATHETERIZATION AND TIPS

Figure 10-8. Pulmonary embolism. Pulmonary angiogram during main pulmonary artery injection shows a large saddle embolus at the bifurcation of the right main pulmonary artery (arrowheads). Filling defects representing emboli are also seen in left lower lobe segmental arteries (small arrowheads and white arrow).

A transjugular intrahepatic approach to portal venography was first described in animal studies in 1969[101] and was first reported in humans as a method of creating an intrahepatic portosystemic shunt in 1982.[102] Initially, portocaval shunts were created by a combined transjugular and transhepatic approach.[103] Transjugular intrahepatic portosystemic shunting has become a safe and effective method of reducing

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Figure 10-9. Right (A) and left (B) pulmonary arteriograms show multiple arteriovenous fistulas. This patient with Osler-Weber-Rendu syndrome presented at the age of 19 years with a brain abscess.

portal venous pressure and arresting variceal hemorrhage, and in some cases it is a successful treatment for intractable ascites.[104] The procedure typically begins with percutaneous puncture of the right internal jugular vein, placement of a long 9-11 French sheath and catheterization of the right hepatic vein (or middle hepatic vein). A wedged hepatic venogram can be performed through a standard catheter or balloon occlusion catheter and can facilitate retrograde opacification of the portal venous system. Carbon dioxide has been an effective contrast agent for this application when used with DSA.[105] This provides a portal vein target. Other techniques to target the portal vein before or during TIPS include arterial portography, ultrasound, and transhepatic placement of a metallic marker or wire adjacent to the portal vein bifurcation (extravascular), within the hepatic artery, or in the portal vein itself.[106] Subsequently, a 55-cm-long curved 16-gauge

Colapinto needle is passed out of the hepatic vein caudad and into the portal vein, targeting the right main portal vein near the portal bifurcation. Over a wire, the portal vein is catheterized, portal and systemic pressures measured, and a portal venogram obtained. An intrahepatic tract is balloondilated and stented, creating the portosystemic shunt (Fig. 1014). A final portosystemic pressure gradient is measured. If a high gradient persists, the stent can be dilated to a larger size or a second parallel shunt constructed (Fig. 10-14a). In cases of active variceal bleeding when angiographic filling of varices persists, sclerosant or coil embolization of varices can be performed at the same session.[107] Several randomized trials comparing TIPS versus endoscopic sclerotherapy/band ligation for variceal bleeding have been published with mixed results.[108 – 111] Three of four studies found significantly lower rates of rebleeding in the

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Figure 10-10. Osler-Weber-Rendu syndrome. The patient has hypoxemia and previous surgical resection of a left lower lobe arteriovenous fistula 9 years eazrlier. (A) Left pulmonary arteriogram. A large left upper lobe arteriovenous fistula is demonstrated. Two major feeding arteries (white arrows) and a large draining vein (white arrowheads) are identified. (B) Two detachable balloons were placed in the medial feeding artery and anchored by an Amplatz “spider” (black arrowhead) to prevent balloon migration. The proximal arterial trunk remains patent, sparing branches to the lateral portion of the left upper lobe.

TIPS group (23%, 12%, and 15% vs. 52%, 48%, and 45%). In one study, rebleeding was equal at 25% for both groups. Since TIPS achieves immediate portal venous decompression, the patients in the endoscopic therapy group are in theory at risk for rebleeding over a longer time since multiple treatments are given over a period of months. Not surprisingly, portosystemic encephalopathy was higher in the TIPS group in three of four studies (33%, 30%, 36% vs. 13%, 12%, 18%), but in one study encephalopathy rates were similar.[110] Overall, the studies showed a lack of significant survival differences between the two therapies.

INTERPRETATION OF MESENTERIC VENOGRAPHY Indications for mesenteric venography include most cases of portal hypertension being considered for surgical or embolic therapy. As well as giving the surgeon a “road map” of the veins available and their calibers, it will demonstrate the venous dynamics; hepatofugal flow in advanced cirrhoses is shown by retrograde flow down a portal tributary toward an

organ whose artery was not injected—that is, superior mesenteric or inferior mesenteric vein filling on a celiac injection or splenic or inferior mesenteric vein filling from the superior mesenteric arteriogram. Also, varices at unsuspected sites such as the ileum (Fig. 10-15) or colon (Fig. 10-16) will be seen; these may be sites of gastrointestinal bleeding not visible on barium studies or endoscopy. Portal vein thrombosis, sometimes an unsuspected etiology of variceal bleeding, will be revealed (Fig. 10-17). In addition, patients with previous surgical portal-systemic shunts may be evaluated for shunt patency (Fig. 10-18). Dynamic CT and MRI can be effective means of noninvasive assessment of shunt patency.[112 – 114] Finally, invasion of the portal vein by hepatic tumors, a grave prognostic sign and usually a contraindication to resection, is well shown by portography.

HEPATIC VENOGRAPHY Hemodynamic information about the portal system can also be obtained by hepatic venography. A wedge pressure may be taken by advancing a catheter from the inferior vena

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Figure 10-11. Subtraction left pulmonary arteriogram showing a posttraumatic false aneurysm at the site of a gunshot wound a year before. Contrast jet into the left atrium (arrows) indicates that an AV fistula is also present.

Figure 10-12. Right pulmonary arteriogram shows a “Rasmussen” aneurysm (arrow) in a patient with tuberculosis and hemoptysis refractory to bronchial artery embolization.

Figure 10-13. Arterial portography in portal hypertension. (A) Splenic artery injection, venous phase. There is splenomegaly. There is good opacification of the splenic and portal veins. Hepatofugal flow is present in a recanalized umbilical vein (arrowheads) with an aneurysmal varix (white arrows). (B) Superior mesenteric artery injection, venous phase. The superior mesenteric vein is well opacified (open arrow). Hepatofugal flow is seen in the inferior mesenteric vein (curved arrow) and again in the umbilical vein (arrowheads).

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Figure 10-14. Transjugular intrahepatic portosystemic shunting (TIPS). (A) A transjugular catheter has been directed into a hepatic vein, traversed liver parenchyma, entered the portal vein, and advanced into the superior mesenteric vein. A venogram shows an enlarged coronary vein (open arrow) and gastroesophageal varices (curved arrows). (B) Superior mesenteric venogram after balloon dilatation of the portosystemic tract and deployment of balloon-expandable stainless steel stents (arrows). Streaming of contrast into the inferior vena cava (IVC) and right atrium is seen (arrowheads). (C) Injection within the stent (arrows) shows rapid flow of contrast into the IVC and right atrium (arrowheads).

cava far into a hepatic vein until it blocks a small hepatic branch. Pressure measurements then accurately reflect the sinusoidal pressure and also the portal pressure in cases of postsinusoidal portal hypertension, as in most cases of alcoholic cirrhosis. Normal portal venous pressure is about 5–10 mmHg. Corrected sinusoidal pressure (wedged hepatic venous pressure minus free hepatic vein pressure) is normally 6 mmHg or less. Injection of contrast will demonstrate distorted hepatic venules in cases of cirrhosis

and even portal radicle filling if cirrhosis has advanced to stage III, where the flow in the portal vein is reversed (hepatofugal). In eases of presinusoidal portal hypertension, such as portal vein thrombosis or schistosomiasis, the wedge study will be normal. However, in Budd-Chiari syndrome or hepatic vein thrombosis, if a hepatic vein can be catheterized, contrast injection reveals a typical “spiderweb” pattern of hepatic vein collaterals (Fig. 10-19). A more detailed discussion of all

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transhepatic and transjugular method was used. Transhepatic puncture into or adjacent to the portal vein is sometimes used to localize the portal vein for TIPS[119] and may facilitate TIPS in cases with anatomy unfavorable for the transjugular approach.[120] Umbilical vein catheterization can also facilitate access to the portal venous system and was described in 1959 in children.[121] Surgical cutdown[122] and percutaneous ultrasound guided punctures have also been used to enter the umbilical vein and localize the portal vein for TIPS.[123] Mesenteric venous catheterization via minilaparotomy has also been used to cannulate the portal venous system for variceal embolization[124] and to facilitate TIPS.[125]

TRAUMA

Figure 10-14a. Two parallel TIPS shunts. Initial placement of TIPS between the right hepatic vein and portal vein achieved little clinical response in this patient with intractable ascites. A second TIPS via the middle hepatic vein resulted in resolution of ascites without encephalopathy.

CT has replaced arteriography in evaluation of blunt trauma to the liver or spleen except in cases where therapeutic embolization is anticipated. Angiographic signs of vascular injury are similar in the liver and spleen and include areas of extravasation or puddling of contrast agent; filling of false aneurysms (Fig. 10-21); avascular clefts; arteriovenous shunting; and displacement of the parenchymal blush away from the body wall, which is a sign of subscapular hematoma. Care must be taken in interpreting the splenic angiogram because congenital lobulations and accessory spleens occur

forms of mesenteric venous pathology may be found in Reuter et al.’s text.[115]

CELIAC AND MESENTERIC ARTERIOGRAPHY The celiac and mesenteric vessels may be approached by the femoral or axillary routes for selective catheterization. Stenosis of the origins of these vessels is best appreciated on the lateral aortogram. Risks of mesenteric arteriography are small; vessel injuries are uncommon with the use of smaller, softer catheters.

TRANSHEPATIC AND OTHER PORTAL VENOUS ACCESS The portal vein can be entered directly via a transhepatic puncture. This approach is now seldom used because the transjugular intrahepatic approach to the portal venous system is preferred. Variceal embolizations (Fig. 10-20), blood sampling in portal vein tributaries for localization of secreting pancreatic tumors (gastrinomas and insulinomas),[116,117] and diagnostic portal venograms have been performed via this route. This has been discussed in further detail in an earlier edition of this text.[118] Direct portal venous puncture was also used early in the development of TIPS when a combined

Figure 10-15. Ileal varix demonstrated on venous phase of superior mesenteric arteriogram. The superior mesenteric vein fills retrograde (open arrows) down to the varix (large white arrow) and up the right ovarian vein (small white arrows) to the interior vena cava.

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commonly and may simulate splenic rupture. Most accessory spleens lie near the hilus, but those below the lower pole can be confusing. CT scans are highly accurate in diagnosing splenic trauma,[126]permitting correct identification of splenic injury in 54 of 55 surgically proved cases. CT is also a reliable indicator of hepatic trauma, playing an important role in patient management.[127,128]

TUMORS Hepatic Tumors Angiography continues to be a valuable modality in the diagnosis, preoperative planning, and therapy of hepatic tumors. Malignant hepatic tumors (primarily hepatocellular carcinoma and cholangiocarcinoma) typically show arterial neovascularity. Angiography can localize tumors with respect to vascular territory within the liver and help determine the possibility and extent of resectability. A hybrid technique of liver CT performed during arterial portography is helpful in preoperative localization of focal lesions to specific liver segments.[129] Portal vein invasion may also be detected. A road map of vascular anatomy and detection of variant vessels (such as origin of the right hepatic artery from the superior mesenteric artery) is a valuable guide to the surgeon. Angiography continues to be of value in presurgical planning for resection of both malignant and benign tumors in children.[130] A new technique of digital subtraction angiography, using the partially opacified late hepatic portogram as the subtraction mask, has shown improved detection of faintly enhanced small hypervascular tumors, including hepatomas and metastases.[131] Finally, hepatic arteriography is necessary to guide effective chemotherapeutic infusion catheter placement for treatment of metastatic and primary liver tumors.[132]

Pancreatic Tumors

Figure 10-16. (A) Transhepatic injection of the splenic vein showing retrograde (hepatofugal) flow down the superior mesenteric vein (arrowheads). (B) Later film of transhepatic splenic venogram showing filling of colonic varix and drainage into the inferior vena cava (arrowheads). (Courtesy of Dr. Robert Conroy, Long Beach Veterans Administration Hospital.)

Angiography is now seldom used to diagnose pancreatic adenocarcinoma, which would usually appear as a hypodense mass within a background of normal parenchymal blush. Currently, angiography is indicated in determining the extent and resectability of tumor particularly as this relates to the encasement and invasion of adjacent vascular structures (Fig. 10-22). Conversely, pancreatic islet cell tumors such as insulinoma (Fig. 10-23) typically manifest themselves as focal highly vascular masses at angiography.[133] Other modalities can be superior to angiography for localization (portal venous sampling, CT, and intraoperative ultrasound),[134] but these tumors can be difficult to identify. In our experience, correlation of several imaging studies including angiography may be necessary to reach a confident diagnosis.

Alimentary Tract Tumors Angiography plays little role in the diagnosis of bowel tumors, as barium studies and endoscopy are highly effective in mass detection. However, bowel tumors are occasionally

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Figure 10-17. Portal vein thrombosis with “cavernous transformation” of the portal vein (curved arrows) demonstrated on the venous phase of a splenic artery injection. The splenic vein (arrow) and coronary vein (open arrow) are normal, but retrograde filling of mesenteric collaterals (arrowheads) indicates portal hypertension.

Figure 10-18. Patent Warren shunt demonstrated on venous phase of high-volume splenic arteriogram. Straight arrows outline the renal vein. Curved arrows show the inferior vena cava.

Figure 10-19. Wedged hepatic venogram in patient with BuddChiari syndrome, showing typical pattern of tortuous hepatic venous collaterals.

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Figure 10-20. (A) Transhepatic portogram showing large esophageal varices. (B) Selective catheterization of the coronary vein for variceal embolization. (C) Postembolization portogram showing occluded coronary vein (arrow). (Courtesy of Dr. Robert Conroy, Long Beach Veterans Administration Hospital.)

noted in the evaluation of gastrointestinal bleeding, identified by virtue of active bleeding, vessel displacement or invasion, tumor vascularity, or early venous drainage. For the interested reader, the text by Reuter, Redman, and Cho[115] contains a complete discussion of angiographic findings for specific bowel tumors.

GASTROINTESTINAL BLEEDING Bleeding into the gut is reliably demonstrated by selective mesenteric arteriography if the patient is bleeding at a rate of at least 0.5– 1.0 mL/min at the moment of contrast

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Figure 10-21. (A) Selective proper hepatic arteriogram showing large hepatic false aneurysm secondary to shotgun wound. (B) Close-up of right hepatic branch after particulate embolization shows stump of occluded vessel at the site of the aneurysm (arrow).

injection.[135] The diagnosis is made by demonstration of extravasation or puddling of contrast agent, which persists beyond the phase of venous emptying (Fig. 10-24). The major problem with arteriographic diagnosis is that bleeding is often intermittent and may have stopped at the time of the injection. In patients with recurrent life-threatening bleeding where standard techniques have failed, provocation of bleeding with intraarterial vasodilators such as tolazoline

(Priscoline), heparinization,[136] or urokinase infusion at the time of angiography may allow localization of the bleeding site.[137] A recent prospective study of provocative intravenous urokinase administration combined with systemic heparin anticoagulation enabled determination of the bleeding source in only 2 of 10 patients with recurrent gastrointestinal bleeding.[138] Within this study group, intraoperative endoscopy subsequently was diagnostic in 2 of 3 patients. Other previous studies utilizing intraarterial thrombolytics have shown a higher diagnostic yield angiographically.[137,139] Endoscopy immediately prior to the angiogram helps to localize the site and limits the number of vessels to be injected. This avoids the long catheter time and high contrast agent load often required to select all possible gut vessels. Recent barium studies preclude arteriography, because the residual barium masks extravasation. Several intravenous isotope studies are available which are more sensitive than the arteriogram to slow or intermittent bleeding. Extravasation at 0.1 mL/min may be visible on scan after injection of 99mTc-labeled sulfur colloid[140] or 99m Tc-labeled red blood cells.[141] For the sulfur colloid scans, bleeding must be active at the moment of injection and bleeding adjacent to the liver is obscured. In areas where upper and lower bowel are superimposed, it may be difficult to tell which segment is bleeding. Gastrointestinal bleeding can be controlled in a high percentage of patients by transcatheter therapy with vasopressin (Pitressin) infusion or embolization. In general, vasopressin infusion is easier because catheter placement is less critical and the risk of bowel infarction is negligible; however, the prolonged presence of the catheter in the femoral artery carries a risk of thrombus formation and embolization in the leg. In the stomach, embolization is an attractive choice, since the left gastric artery can usually be catheterized without difficulty and the risk of stomach infarction is exceedingly low. Control of gastric bleeding by vasopressin has been reported at approximately 80% in multiple series.[142] Pyloroduodenal bleeding is more difficult because of the double blood supply from the pancreaticoduodenal arcade, and the success of vasopressin is correspondingly lower at 40% or less.[142] For better control, selection of the gastroduodenal artery for embolization is desirable. Even after gastroduodenal embolization, bleeding may persist from superior mesenteric artery collaterals. Selective embolization can control bleeding in 65 – 70% of cases.[142] Selective small bowel embolization can be performed safely[143] in cases that cannot be controlled with vasoconstrictive therapy, but cases of bowel infarction have been reported. Colon infarcts after embolization are known to occur in approximately 12% of patients,[144] so that in the lower bowel infusion is the treatment of choice, achieving success in 80–90% of cases (Fig. 10-24).[145] Although intraarterial infusion of vasopressin into the superior mesenteric artery (SMA) reduces splanchnic blood flow, it has been demonstrated that intravenous infusion is just as effective at controlling variccal bleeding;[146] we have therefore abandoned intraarterial therapy in these cases.

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Figure 10-22. Poorly differentiated adenocarcinoma of the pancreas with vessel encasement. (A) Celiac arteriogram demonstrates irregular narrowing of the celiac trunk (straight arrow) and common hepatic artery (curved arrow) consistent with tumor encasement. (B) Superior mesenteric arteriogram shows SMA narrowing (curved arrows) and markedly irregular contour of the gastroduodenal artery (arrowheads) representing encasement. A biliary stent is in place.

MESENTERIC ISCHEMIA Chronic Ischemia Angiography is not a precise diagnostic tool in many cases of suspected chronic mesenteric ischemia because stenoses and occlusions correlate very poorly with ischemic symptoms of bowel infarcts in radiological or pathological series. It is not rare to see proximal stenoses or occlusions of all three mesenteric vessels in asymptornatic patients.[147] The rich

collateral supply of the gut often compensates adequately in slowly progressive stenoses. Proximal occlusions are seen best on the lateral aortogram, while the anterior projection demonstrates the anatomy of collaterals. Collateral flow between the SMA and the inferior mesenteric artery (IMA) develops along the left colic to middle colic anastomoses, along the marginal artery of Drummond (the “functional artery” of the colon), in the mesenteric edge of the descending colon, and along the arc of Riolan between the proximal IMA and SMA. Enlarged pancreaticoduodenal arteries are the most commonly seen

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Figure 10-23. Pancreatic insulinoma. A common hepatic arteriogram (subtraction film) shows the insulinoma in the pancreatic head as an area of blush or “stain” (arrowheads).

collaterals between the SMA and the celiac artery, although routes around the stomach are available. Atherosclerosis is the most common etiology for stenoses; the most frequently affected vessel is the IMA. Other etiologies include Takayasu’s arteritis, dissecting aneurysm, fibromuscular dysplasia, and the controversial median arcuate ligament syndrome wherein the celiac trunk is compressed by this diaphragmatic ligament (Fig. 10-25). Patients with the clinical syndrome of intestinal angina have been successfully treated with balloon angioplasty of the celiac and superior mesenteric arteries.[148]

configuration. The constriction may be precipitated by a variety of insults including hypotension, transient SMA occlusion, pressor agents, digoxin toxicity, or decreased cardiac output, but it may persist after correction of the initial event. Infusion of vasodilators, either papaverine or tolazoline,[150,151] has been successful in relieving symptoms and avoiding bowel resection. Papaverine has been used successfully after demonstrating a clot[151] in a few patients. Acute venous thrombosis is an infrequent cause of bowel infarction and often is not visible on angiography. Nonvisualization of the portal vein or tributaries and delayed washout of the small vessels and mucosal blush are seen with an extensive thrombosis.

Acute Mesenteric Ischemia Angiography is indicated in cases of acute mesenteric ischemia to delineate an obstructive lesion and differentiate obstruction from nonocclusive ischemia; in some cases of nonocclusive ischemia, transcatheter therapy is indicated. Obstructive ischemia is usually caused by either thrombus or embolus or occasionally by an acute aortic dissection (Fig. 10-26). Emboli appear as rounded filling defects in the artery; thrombi are usually associated with atherosclerotic stenoses that are often evident in other vessels as well. Radiologic differentiation between thrombi and emboli may not be possible. Occlusions of the celiac and superior mesenteric arteries have been treated successfully with thrombolytic agents.[149] Nonocclusive ischemia is causes by mesenteric vasoconstriction, which appears on the angiogram as diffusely decreased caliber of the mesenteric arteries, impaired filling of distal branches—giving a “pruned” appearance—and a series of segmental stenoses forming a “string of sausages”

RENAL ARTERIOGRAPHY Either selective renal artery injections or abdominal aortography can be used to evaluate the renal vasculature. The best images result from selective injections; however, when disease is suspected at the renal artery origin, aortography may be used first in lieu of renal artery catheterization. A slight right posterior oblique projection shows the renal artery orifice optimally in most patients (Fig. 10-27). Aortography may also be preferred in cases of renal trauma, for large renal tumors with parasitized blood supply, and for evaluating renal donors. Aortography provides an anatomic overview, which is useful in demonstrating multiplicity of renal arteries, present in 20 – 30% of cases.[152] The left kidney is preferred as a donor kidney because of its longer renal vein, but multiple arteries or early

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branches (renal parenchymal or ureteral) less than 1 cm from the origin would dictate harvest of the right kidney.[153] Renal angiography has been replaced by CT as the preferred method of evaluating acute renal trauma.[154] Even nonvisualization of a kidney on intravenous urogram may not be an indication for arteriography; some feel it merely delays

Figure 10-24. (A) Inferior mesenteric arteriogram showing extravasation of contrast (curved arrow), indicating an active bleeding site in the descending colon. (B) Repeat injection of the interior mesenteric artery after a trial of pitressin infusion. The caliber of all the branches is reduced, and the extravasation is no longer seen.

Figure 10-25. (A) Lateral aortogram in expiration showing narrowing (open arrow) at the origin of the celiac axis typical of median arcuate ligament syndrome. (B) Aortogram in inspiration. The stenosis has disappeared (curved arrow).

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Chapter 10. Angiography

emergent surgical repair.[155] Renal angiography is more apt to be utilized in cases of penetrating injury (as opposed to blunt trauma) or where embolization is anticipated. Selective catheterization of the renal artery is usually straightforward; however, an acute takeoff from the aorta may make a recurved catheter shape or an approach from the axillary artery necessary. Injection of epinephrine into the renal artery immediately prior to filming has been recommended in cases of suspected renal tumor.[156] Normal vessels respond by constricting. Neovascularity does not respond as much and is thereby rendered more prominent. This form of pharmacoangiography does enhance visualization of tumor vessels but has, in our experience, seldom made a diagnosis which was not already possible from routine films. In our practice, the greatest usage of renal angiography currently is for vascular lesions, such as renal artery stenosis, renal arteriovenous fistula or malformation, renal artery aneurysm, fibromuscular dysplasia, and arteritis. When lesions are not primarily vascular in nature, less invasive tests such as intravenous urography, ultrasound, CT, and isotope studies almost always precede angiography. If less invasive procedures are not diagnostic, angiography may demonstrate an etiology in some cases of oliguria, hypertension, hematuria, or hydronephrosis. Arteriography may elucidate the extent of tumor spread in cases of renal cell carcinoma. Venous phase films may reveal tumor thrombus in the renal vein. Inferior venacavography may also be indicated in staging of renal cell carcinoma, but selective renal vein catheterization should be avoided, if possible, as friable tumor could be dislodged. We have found MRI particularly helpful in assessing renal vein or caval tumor invasion. Preoperative ablation of renal tumors with intraarterial absolute ethanol can be effective in reducing blood loss at the time of radical nephrectomy.[157,158] Atherosclerotic narrowing is the most common renal vascular lesion. Atherosclerosis usually involves the proximal third of the renal artery and is seldom present without associated abdominal aortic disease. Since only a small percentage of hypertension is renovascular and patients with renal artery stenosis may be normotensive, the presence of renal artery narrowing alone is rarely appropriate as the sole determinant for angioplasty. If selective renal vein renin samples show a ratio of l.5:1 or greater for the ipsilateral side, it has been considered likely that the renal artery stenosis is the cause of hypertension; however, a prospective study concludes that renal vein renins are unreliable in predicting which patients will respond to revascularization and are not specific enough to exclude patients who do not have renovascular hypertension.[159] Based on arteriography alone, a narrowing of 80% or more is usually significant.[160] Renal artery aneurysms have been incriminated as a cause of pain, hematoma, and hypertension. They may rupture, and an increased incidence of rupture during pregnancy has been

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described.[161] Selected patients can be treated by embolization (Fig. 10-28). Renal arteriovenous fistulas are usually associated with congenital arteriovenous malformations or penetrating trauma or are iatrogenically induced. The most common cause overall is percutaneous needle biopsy. Most postbiopsy fistulas resolve with time, but a few go on to severe hypertension or heart failure. Arteriovenous fistulas and malformations may also be treated by embolization techniques (Fig. 10-29).[162] Renal artery dysplasia or fibromuscular dysplasia occurs most frequently in women in the middle decades of life (Fig. 10-30). Other visceral and cerebral vessels may be involved. Renal artery dysplasia can be associated with spontaneous renal artery dissection, aneurysms, and hypertension. The proximal third of the main renal artery is usually spared, which is not the case with atherosclerotic involvement. A number of classification systems based on location and type of arterial involvement have been described.[163] In some instances, dysplasia may be difficult to differentiate from arteritis. Arteritis of the renal vasculature causes changes that are not specific for the different etiologies. Vessel irregularities, stenoses, occlusions, and aneurysms may be seen. Small aneurysms of medium- and smaller-sized renal artery branches are suggestive of polyarteritis nodosa (Fig. 10-31) and are usually associated with clinically florid disease.[164] Other necrotizing vasculitides may cause similar aneurysms.

ABDOMINAL AORTIC AND LOWER EXTREMITY ARTERIOGRAPHY We routinely use the femoral approach to arteriography of the abdominal aorta and lower extremity. The femoral artery on the least symptomatic side is usually punctured. In patients with absent femoral pulses and iliac occlusion, common femoral artery puncture (with or without ultrasound guidance) may result in successful catheterization of the aorta, as even chronically occluded iliac segments can often be traversed with careful technique and use of steerable hydrophilic wires. In the author’s experience, axillary puncture can be avoided in many of these cases, and in some, thrombolysis or primary stent angioplasty can restore iliac patency. Other safe alternatives include the “high” proximal brachial approach,[165,166] and we occasionally use a percutaneous antecubital brachial approach in cases where a nonselective arteriogram will be performed and a 4 French catheter can be used.[41,167] The translumbar aortic approach can also be employed, and some angiographers prefer this route.[168] The translumbar technique, originally described by Dos Santos et al.[169] in 1929, has been modified by the use of

Figure 10-26. (A) Extension of a thoracic aortic dissection causing acute mesenteric ischemia shown on lateral aortogram. The septum is indicated by arrowheads. There is a tight stenosis of the superior mesenteric artery (open arrow) and no celiac filling. (B) Subtraction of true lumen arteriogram showing superior mesenteric artery stenosis (arrow) and hepatic artery filling via collaterals. (C) Lower portion of severely narrowed true lumen giving rise to normal lumbar arteries.

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Figure 10-27. (A) The proximal right renal artery origin is partially obscured in the straight AP projection (arrow). (B) A right posterior oblique projection more clearly demonstrates the proximal renal artery stenosis (curved open arrow).

Figure 10-28. Traumatic renal artery aneurysm arising from the lower pole artery. (A) Preembolization. (B) Postembolization.

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Figure 10-29. (A) Traumatic renal AV fistula unsuccessfully treated by surgery. White arrow indicates the renal artery, and black arrow shows venous shunting into the left renal vein. (B) A single detachable balloon (white arrow) occludes the fistula with cessation of pain and hypertension.

guidewires and replacement of the needle with a Teflon sheath or catheter after the aortic puncture. Severe hypertension or coagulopathy are firmer contraindications to the use of translumbar aortography than to angiography using peripheral access sites, because the inability to compress the puncture site following catheter withdrawal or to visualize the site makes bleeding more problematic. Thousands of aortograms have been performed using the translumbar approach, with a surprisingly low complication rate, but the approach is lacking in flexibility in that selective catheterizations and interventional techniques such as angioplasty or thrombolytic therapy are not easily performed by this route. The authors have not performed translumbar aortography in many years and currently utilize gadolinium-enhanced magnetic resonance angiography when arterial access difficulties are extreme. It is possible to catheterize mature grafts with a low complication rate, but the tough scar and graft material may make catheter passage difficult. The amounts, rate, and location of contrast agent injection and the sequence and centering of filming vary depending upon the suspected pathology. For example, an arteriovenous fistula would require rapid injection and filming, while the slowed, turbulent flow of an aneurysm would be better demonstrated by slower rates of injection and filming. Atherosclerotic occlusive disease of the lower extremity is one of the most common indications for angiography in our practice; following a cut film abdominal aortogram, the study

is completed by placing the 4 or 5 French catheter in the distal abdominal aorta. Nitroglycerin (200 mg intraarterially) injected through the catheter immediately before contrast injection can improve visualization of distal vessels. Other vasodilators have been shown to be less effective in this regard.[170] Reactive hyperemia following temporary tourniquet application prior to contrast injection is another effective technique for enhancing visualization of distal vessels, but a case of prosthetic graft occlusion immediately following this method has been reported.[171] In cases where exquisite detail of the small runoff vessels, including the plantar arch and foot vessels, is necessary, as in patients being evaluated for distal in situ saphenous vein bypass grafting, a technique of balloon occlusion femoral angiography has been advocated.[172] Contrast (4 mL/s for total 60 mL) is injected via the balloon catheter while the ipsilateral external iliac artery is occluded by the balloon, which is inflated with carbon dioxide (Fig. 10-32). Supplemental selective DSA angiograms may also be very helpful in visualizing small runoff vessels beyond the trifurcations. For our standard aortogram with runoff, contrast agent is injected at a rate of 8 mL/s for 10 s (80 mL total), and films are exposed at intervals for up to 40 s from the beginning of the injection. Because of the generalized nature of atherosclerosis, an abdominal aortogram is included in the study even when symptoms and noninvasive studies suggest disease limited to the lower extremity. Films extend at least down to

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Figure 10-30. Renal artery fibromuscular dysplasia in a 35year-old woman with renovascular hypertension. Characteristic beaded stenosis is seen in the right mid-main renal artery (arrow). The right kidney is small.

the ankle. Long films that cover the entire lower extremity or a programmed moving tabletop are valuable for obtaining films that show all vessels maximally opacified and for minimizing the need for repeat injections. We routinely obtain films with a long-leg changer in both oblique projections. This is particularly helpful in demonstrating the common iliac bifurcations and origins of the superficial femoral and profunda femoris arteries. It is desirable to keep the contrast agent load within limits so as not to impair renal function. Injection of contrast is also uncomfortable for the patient, but nonionic and ionic dimeric low-osmolality agents have considerably decreased the pain effects in peripheral arteriography.[173,174] Ioxaglate (Hexabrix) seems to cause the least pain and heat sensation in angiography of the lower extremity.[175] Conflicting reports regarding pain reduction when local anesthetics are added to contrast media have appeared in previous years,[176,177] but a more recent study[178] concludes that this is an ineffective technique. When aortography is performed to examine the abdominal aorta alone, smaller amounts of contrast agent are adequate; 25 –40 mL injected over 2 s is usually sufficient. Diagnostic quality aortofemoral angiography can also be obtained using carbon dioxide with DSA along with limited selective injections of iodinated contrast. Atherosclerotic occlusive disease is seldom a diagnostic dilemma per se, because the vessel irregularities, stenoses, and occlusions are easily diagnosed. Performance of the examination may be the most challenging aspect of the study. Vascular access may be limited, and plaques that compromise

Figure 10-31. Polyarteritis nodosa. Multiple small aneurysms are evident in (A) the right kidney and (B) the left kidney. (C) Superior mesenteric artery injection in the same patient also reveals several small aneurysms (white and black arrows).

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Figure 10-32. Balloon occlusion femoral arteriography (BOFA), lateral projection. Distal runoff was inadequately demonstrated on conventional aortofemoral arteriogram. There is occlusion (white arrow) of the distal superficial femoral artery, which “continues” via a geniculate collateral. The popliteal artery is occluded, and all three trifurcation vessels are occluded proximally. Well-filled collaterals reconstitute all three runoff vessels in the lower calf. The posterior tibialis artery is occluded at the ankle (curved white arrow). The dorsalis pedis artery is patent and affects filling of plantar vessels.

Figure 10-33. (A) Collateral circulation to the lower extremities in infrarenal aortic occlusion. A prominent inferior mesenteric artery (black arrow) and superior hemorrhoidal branches (white arrows) are seen. (B) A network of perirectal and perineal collaterals gives rise to retrograde filling of pudendal and obturator branches of the hypogastric artery (arrowheads), which reconstitutes the common and external iliac and femoral arteries (black arrows). Note also the left L1 lumbar to iliolumbar collateral (white arrows) contributing to the hypogastric artery.

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the lumen increase the chance of subintimal passage of the guidewire. Distal emboli in the form of dislodged plaque fragments or showers of cholesterol emboli may complicate the procedure. For these reasons we prefer small, soft catheters and soft guide wires such as the 0.032-in. Bentson guide (Cook, Inc., Bloomington, Indiana) as our standard equipment. Certain patterns of atherosclerotic occlusion occur with predictable frequency. The area most often involved is the distal superficial femoral artery at the adductor canal, presumably because of repeated trauma as the artery enters the canal. The calf vessels and popliteal artery are involved in order of decreasing frequency after the superficial femoral artery. Profunda femoris occlusion is uncommon, although there may be stenoses at its origin. This is fortunate, because it is the collateral pathway for superficial femoral disease. The patterns of occlusive disease have been well described for the lower extremity[179,180] as well as for the abdominal aorta and pelvic vessels.[181 – 183] Pathways of collateralization in chronic distal aortic and iliac disease are testimony to the body’s ability to adapt to adversity (Figs. 10-33 and 10-34). If unsuspected or incompletely defined, they can lead to unpleasant surprises.

Figure 10-35. Aortogram with runoff. In situ saphenous vein graft (large white arrow) with multiple persistent “perforators,” which now function as arteriovenous communications (small white arrows), shunting between the arterialized saphenous graft and the superficial femoral vein (black arrowheads), which appears abnormally early on the arteriogram.

Figure 10-34. Collaterals in external iliac occlusion. Iliolumbar branch (arrows) from the hypogastric artery anastomoses with a circumflex iliac artery (arrowheads), which reconstitutes the common femoral artery. Note also the collateralization from the superior gluteal artery (short curved arrows) to the lateral circumflex femoral artery (arrow with tail).

When the aorta is occluded, both parietal and visceral collateral networks may form. The visceral network involves connections between branches of the superior mesenteric to inferior mesenteric to internal iliac to profunda femoris systems. The level of obstruction will determine which portion of the network develops. The parietal network involves aortic branches such as the intercostal, subcostal, lumbar, and middle sacral arteries, anastomosing with external iliac, internal iliac, and profunda femoris branches. The epigastric arteries may be important collaterals in the

Chapter 10. Angiography

form of the Winslow pathway, which is a superior epigastric to inferior epigastric connection linking the internal mammary and intercostal arteries to the internal iliac artery. This pathway should be remembered because it is not evaluated by standard injections in the abdominal aorta. In patients who have had vascular grafts, angiography is indicated when acute symptoms of limb ischemia occur, because these usually indicate graft occlusion. Less abrupt clinical deterioration can represent progression of atherosclerotic disease in native vessels, development of anastomotic site stenoses, or graft occlusion. Selection of puncture site may be influenced by therapeutic options such as thrombolysis, but we prefer to avoid graft puncture. Urokinase infusion directly into graft thrombus can be very effective, as grafts have no side branches or collaterals by which the drug could diffuse away. Following clot lysis, anastomotic stenoses amenable to angioplasty are often revealed. A unique feature of in situ saphenous grafts that may be responsible for graft failure is the persistence of arteriovenous communications (Fig. 10-35).[184] If the small tributaries between the superficial and deep venous systems are not all ligated, shunting may occur when the vein becomes arterialized. This shunting can lead to ischemic symptoms or thrombosis of the distal graft. We have also found color Doppler ultrasound helpful in identifying these AV fistulas. A localizing skin mark can be made preoperatively, guiding the surgeon to the site for ligation. Vascular trauma is the second most frequent indication for lower extremity angiography. The indications for angiography in extremity trauma have been the matter of some debate. Positive findings on physical exam of decreased or absent pulse or blood pressure, cold limb, bruit or murmur, uncontrolled bleeding or expanding hematoma, or neurologic deficit are accepted criteria for emergent arteriography. In patients with negative physical exam where arteriography was performed only because of proximity of the wound to vessels, arteriograms were consistently negative.[185] It has been suggested that patients without signs or symptoms of arterial injury be observed and have elective arteriograms.[186] The injury patterns include vasospasm (arterial narrowing), intimal flap, occlusion, laceration, complete transection, arteriovenous fistula, pseudoaneurysm, and combinations of these. When a pseudoaneurysm, AV fistula, or frank extravasation is seen, diagnosis is straightforward, but an angiogram may not be able to differentiate the others.[187] It is possible to have a complete arterial transection with intact flow. Rose and Moore[188] correlated angiograms, operative findings, and clinical outcome in arterial trauma. Intraluminal defects “typical” for intimal flaps can be misleading and result in false-positive or false-negative angiographic interpretation. Focal luminal widening usually represents partial-thickness injury to the arterial wall. Smooth arterial narrowing was a finding generally associated with a benign clinical course; when combined with slowed arterial flow, however, it indicates compartment syndrome. An irregular beaded pattern of arterial narrowing corresponds to severe vascular injury.[188] Angiography generally underestimates the severity of injury. Penetrating wounds cause the majority of injuries and more commonly cause lacerations and transections. Blunt trauma is more commonly associated with intimal

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flaps.[189,190] Intravascular embolization therapy is useful in arteriovenous fistula, hemorrhage, and some false aneurysms. It is especially useful in traumatic pelvic bleeding, which may be difficult to control surgically. Pelvic and lumbar fractures may also lead to retroperitoneal hemorrhage due to injury to lumbar arteries,[191] so aortography (not merely selective iliac or hypogastric injections) should be performed in these patients. Embolization therapy for pelvic hemorrhage during the postpartum period and from pelvic malignancy can also be effective.[192,193] Abdominal aortic aneurysms are usually atherosclerotic in origin. Thoracic aortic dissection may extend into the abdomen, but a dissecting aneurysm originating in the abdominal aorta is rare. Traumatic, arteritic, and mycotic aneurysms are also rare. Most abdominal aortic aneurysms are fusiform (Fig. 10-36); some are saccular. Ultrasound is an effective method for the detection and serial measurement of abdominal aortic aneurysms.[194] Computed tomography is very accurate in the assessment of abdominal aortic aneurysms with respect to size, extent, and presence of mural thrombus as well as in distinguishing between simple mural thrombus calcification in an aneurysm versus displaced intimal calcification in aortic dissection.[195] CT is also helpful in identifying leaking aneurysms,[196] but it is not sufficiently accurate in defining the origins of the renal arteries relative to the aneurysm.[197] Angiography allows precise definition of which branches are involved. Extension into renal or iliac arteries can be demonstrated. Angiography may fail to demonstrate the full diameter of the aneurysm because of thrombus in the lumen (Fig. 10-37).

LOWER EXTREMITY VENOGRAPHY Many techniques for performing lower extremity venography have been described. The choice depends on the equipment available, the patient’s clinical status, and the personal preference of the radiologist. We routinely perform venography of the lower extremity using the following technique. A superficial vein on the dorsum of the foot is cannulated with a plastic cannula or butterfly needle. Tourniquets are placed at the ankle, below the knee, and above the knee to force flow into the deep venous system. Then 50 mL of nonionic contrast is injected by hand, with careful attention to any signs of extravasation over the dorsum of the foot. Films arc obtained over a longleg film changer at the end of injection, and tourniquets are removed just before final films to better demonstrate the superficial, soleal, and gastrocnemius veins. Placement of a sandbag or manual compression at the groin can help pool the contrast in the lower extremity. Subsequent release of compression, coupled with elevation of the leg prior to final films, can enhance visualization of the iliac vein and inferior vena cava. Immediately after filming, we flush the veins with normal saline. We occasionally use an alternative technique wherein the venous system is filled with 100 mL of contrast (diluted to half concentration) while the patient is semiupright and non–weight-bearing on the leg that is being studied. A tilting fluoroscopic table is used, and spot films are obtained as the table is lowered and contrast advances cephalad.

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Figure 10-36. Fusiform infrarenal abdominal aortic aneurysm. (A) Anteroposterior view. Note the displacement of the superior mesenteric artery. (B) Steep LPO oblique view. (C) Pelvic arteriogram confirms absence of extension into the iliac arteries.

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pool.[204] The reported sensitivity of this technique ranges from 68[205] to 90%.[206] Radionuclide blood pool venography can be helpful in detecting iliac vein thrombosis,[207] which is a difficult area to evaluate with ultrasound. The labeled fibrinogen test may be sensitive for acute thrombi in the calf, but it is not widely available, takes up to 48 h to complete, and is of less use in chronic thrombosis. Results of MRI in the diagnosis of lower extremity and pelvic vein thrombosis using flow-sensitive gradient echo techniques have been impressive. A recent study with venography correlation reported a sensitivity of 100% and specificity of 92.9% for MRI.[208] Contrast venography also plays a role in the evaluation of the patient with chronic venous stasis syndrome. Chronic venous insufficiency occurs when there is valve dysfunction or obstruction of the deep venous system and/or incompetent perforator valves. The ascending venogram performed with a calf tourniquet in place drives contrast into the deep system. Opacified blood flowing from the deep venous system through

Figure 10-37. Saccular abdominal aortic aneurysm. Most of the aneurysm is filled with thrombus.

Major complications of the procedure include contrastagent reaction, contrast-material –induced thrombophlebitis, and skin slough secondary to extravasation at the injection site. Skin slough is rare and usually occurs when skin viability is already compromised by chronic venous or arterial disease. Thrombophlebitis related to the procedure is usually a mild, self-limited phenomenon. The risk of dislodging emboli by venography is negligible. Overall, the risks of lower extremity venography are quite low.[198] The most accurate venographic sign of acute thrombosis is direct demonstration of thrombus as an intraluminal filling defect with a thin layer of contrast agent surrounding the clot (Fig. 10-38). Visualization of collaterals and nonfilling of veins are indirect signs suggesting thrombosis. In cases of chronic venous occlusive disease, collateral pathways, irregular vessel walls, and loss of valvular detail may be seen. Contrast venography is the most invasive of the techniques employed in the diagnosis of deep vein thrombosis, but it is 95% accurate and remains the standard by which other methods are judged. At our institution, the initial evaluation far suspected lower extremity deep venous thrombosis is performed with ultrasound using real-time venous compression technique.[199,200] For detection of thrombus above the knee, sensitivity has been reported at 89, 91, and 96%.[199,201,202] Color flow Doppler can facilitate visualization of the venous anatomy, especially in the calf, and may assist in identification of eccentric thrombus and partially recanalized thrombus.[203] Venography is performed when the ultrasound study is equivocal or suboptimal (usually due to massive edema or obesity) or if there is a high clinical suspicion for thrombosis limited to calf veins. Radionuclide venography can be performed by injection of isotope into a vein on the dorsum of the foot or 99mTc-labeled red blood cells can be injected in any peripheral vein and the venous system imaged “at equilibrium” as the circulating blood

Figure 10-38. Clot causing a serpentine intraluminal filling defect in the femoral vein of a patient with thrombophlebitis.

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effects are most often manifest by signs of ischemia if there is vessel occlusion, an enlarging mass in cases of false aneurysm (Fig. 10-39), and a thrill or bruit in an acquired arteriovenous fistula. An arteriovenous fistula may also cause local ischemia, cardiac failure, and swelling related to venous engorgement. Congenital arteriovenous malformations of the upper extremity may become very large and present with pain, ulceration, and hemorrhage. If they become too large to resect with limb salvage, embolization therapy may palliate symptoms or make surgery possible. Diagnostic evaluation of vasospastic and vasoocclusive diseases in the hand is difficult: the specific etiology may be elusive. Vasospasm may be a component of occlusive disease, may cause thrombosis, or may occur during angiography. Intraarterial administration of vasodilators may help distinguish vasospastic from occlusive disease. An overview of

Figure 10-39. Posttraumatic false aneurysm arising at the origin of the radial artery from the brachial artery (white arrow). This presented as an enlarging pulsatile mass following a stab wound to the antecubital fossa.

perforators to the superficial veins indicates incompetent perforators. The descending venogram is performed by puncture of the common femoral vein and placement of a 5 French catheter at the junction of the common femoral and external iliac veins. Injection of contrast material is made during a Valsalva maneuver, and valvular competence is graded from 0 to 4, with grade 0 indicating no reflux below the common femoral vein and grade 4 representing severe reflux into the calf veins or to the ankle.[209,210]

UPPER EXTREMITY ARTERIOGRAPHY Arteriography of the upper extremity is performed in most cases via retrograde catheterization from the femoral artery. Antegrade puncture of the brachial artery may be utilized when embolization therapy of lesions in the forearm or hand is performed. Upper extremity angiography is most often performed for evaluation of traumatic injuries, arteriovenous malformations or fistulas, vasospastic or vasoocclusive phenomena, and thoracic outlet syndrome. Acute traumatic injuries show a gamut of findings similar to vascular injuries elsewhere. Delayed or chronic traumatic

Figure 10-40. Thoracic outlet syndrome. Vascular compression related to an anomalous 1st rib with a pseudoarthrosis. (A) There is a slight poststenotic dilatation with the arm in neutral position. (B) There is marked compression when the arm is elevated.

Chapter 10. Angiography

the manifold causes of upper extremity and digital ischemia has been presented by Yao et al.[211] Thoracic outlet syndrome may be due to neural compression or vascular compromise, either arterial or venous. Arteriography is probably best limited to patients with a pulse deficit or bruit in the neutral position or in patients in whom a subclavian artery aneurysm or peripheral emboli are suspected. Demonstration of a vascular compression does not prove that it is the cause of symptoms. Many normal, asymptomatic patients will show compression in certain stress positions, and patients with severe outlet syndrome may have normal arteriograms. In our evaluation for thoracic outlet syndrome, whenever possible, we inject the subclavian artery in both the neutral position as well as in the position that recreates symptoms (Fig. 10-40). A more extensive technique has been described by Lang,[212] who also recommends radionuclide flow studies to decrease falsepositive results.

VENOGRAPHY OF THE UPPER EXTREMITY AND SUPERIOR VENA CAVA The technique of upper extremity venography is simple. A vein distal to the suspected site of occlusion is cannulated with a butterfly needle and 50 mL of contrast agent is injected by hand. Tourniquets are not used during injection. Elevation of the arm prior to the final film may give better opacification of the subclavian vein and superior vena cava.

Figure 10-41.

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Manual compression of the jugular vein during filming may improve opacification of the subclavian vein by decreasing filling defects from inflow of unopacified jugular venous return. If examination of the superior vena cava is desired, both upper extremities are injected simultaneously. Alternatively, the superior vena cava and subclavian veins can be visualized by retrograde or antegrade catheterization; however, this is seldom necessary. If a study performed for evaluation of the axillary and subclavian veins in the neutral position is negative, a second injection should be performed with the arm above the head to evaluate for positional compression by muscle, fibrous bands, or the first rib. Color Doppler ultrasonography provides accurate assessment of the axillary vein, but imaging of the adjacent proximal subclavian vein is dependent on body habitus. Patency of the subclavian vein or superior vena cava is evaluated indirectly by response to respiratory maneuvers.[213] Computed tomography with contrast agent infusion is a useful adjunct to image masses responsible for venous occlusion in some patients with superior vena cava or arm vein obstruction. It may also show collateral veins but generally does not demonstrate intraluminal clot as well as does venography. Upper extremity venous thrombosis is usually less symptomatic and more self-limited than venous thrombosis of the lower extremity. Etiologic factors include exertion, penetrating trauma, intravenous drug abuse, congenital venous web, central venous catheter placement, and hypercoagulable states (Fig. 10-41). Significant pulmonary embolism is not common from the upper extremity but is known to occur.[214,215]

Exertional thrombosis of the axillary vein in a young manual laborer.

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Figure 10-41a. Segmental carotid occlusion with collateral reconstitution. Ultrasound (not shown) demonstrated left common carotid occlusion. (A) Selective angiogram shows distal left common carotid occlusion. Prolonged filming showed no “string sign.” Note the carotid bulb calcification (arrow). (B) RAO right common carotid angiogram showing right external carotid collaterals (curved arrow) and left superior thyroid collateralization (open curved arrows) reconstituting the left internal carotid (arrowheads). (C) AP right common carotid angiogram (later phase than B) showing reconstituted left internal carotid (arrowheads). Note the carotid bulb calcification (arrow). Successful surgical endarterectomy repaired this short segment occlusion.

CAROTID-CEREBRAL ANGIOGRAPHY Angiography remains the most graphic method of demonstrating extracranial occlusive disease of the carotid and vertebral arteries as well as intracranial vascular abnormalities. The evaluation of extracranial occlusive disease usually begins with carotid duplex sonography (often with guidance from color Doppler imaging). This is an accurate screening technique for estimating carotid bifurcation stenosis,[216,217] but shadowing from calcified plaques can obscure areas of narrowing, and the carotid origins are not well imaged. The vertebral arteries are partially obscured by their bony canal. Magnetic resonance angiography of the carotid bifurcation has shown very good correlation with digital subtraction angiography[218] and is coming into increasing clinical use. The indications for angiography in carotid bifurcation disease, the interpretation of findings, and patient selection criteria for surgical carotid endartectomy (CEA) continue to be the subjects of debate. CEA remains the standard procedure for carotid stenosis, but many clinical trials of carotid stent-angioplasty are in progress. There is a trend to perform CEA based solely on results of carotid duplex imaging. Proponents of this approach argue that the major multicenter trials have differed in their methods for measuring carotid stenosis, that angiography may underestimate the degree of stenosis,

and that angiography seldom altered management even when intrathoracic and intracranial lesions were identified. The authors conclude that catheter angiography should be reserved for cases with atypical symptoms, suboptimal duplex imaging, or “uncommon vascular abnormalities.”[219] In practice, we frequently perform carotid angiography in such “atypical” cases (Fig. 10-41a). Some familiar examples would include patients with amaurosis fugax with ipsilateral internal carotid occlusion by duplex ultrasound, cerebral hemispheric symptoms contralateral to the “significant” carotid stenosis, or cases of suspected carotid dissection. Advocates of routine preoperative catheter angiography for carotid bifurcation disease cite a prospective study of 100 patients showing incidental concomitant nonatherosclerotic vascular pathology in 14 patients including 9 aneurysms, 2 arteriovenous malformations, 2 cases of subclavian steal, and 1 case of internal carotid fibromuscular dysplasia. In addition, 15 patients had “severe” intracranial atherosclerosis.[220] Another study advocating angiography found satisfactory concordance of ultrasound with angiography in vessels with mild stenoses (0–29%), but in vessels with 70– 99% stenosis, ultrasound was more likely to underestimate stenosis, identifying only 52% of patients with stenosis greater than 70% by angiography.[221] Intuitively, complex irregular or ulcerated lesions would be expected to be associated with a higher risk of stroke.

Chapter 10. Angiography

However, in one blinded control-matched study, there was no significant difference in stroke risk by the various angiographic characteristics other than the degree of stenosis.[222] Ultrasound can classify carotid plaques as homogeneous, heterogeneous (complex), smooth, irregular, or ulcerated. These sonographic findings have been used as criteria for further imaging studies, either MRA or catheter angiography.[223,224] Carotid-cerebral angiography is almost exclusively performed via the femoral approach, with occasional need for the axillary or transbrachial route. Routinely, we begin with placement of a 5 French multiple-side-hole catheter at the aortic root and obtain an arch aortogram in the right posterior oblique projection. This is usually satisfactory for evaluation of the great vessel origins. Occasionally, a left posterior oblique view is necessary if the right common carotid and right subclavian origins are superimposed. We then proceed with selective catheterization of the common carotid arteries with a soft 5 French polyethylene end-hole catheter with a simple “hockey-stick” configuration. Tortuous vessels may require use of more complex or stiffer catheters such as recurved Simmons types or torqueable “headhunter” designs. Visualization of at least the proximal intracranial vessels is desirable when evaluating the extracranial occlusive disease. The presence of unsuspected distal lesions (e.g., at carotid siphon) may alter a treatment plan. Our technique includes three views of the neck with a field of view from above the supraclinoid carotid to below the carotid bifurcation while injecting in the common carotid artery. The results of the four major multicenter trials—the North American Symptomatic Carotid Surgery Trial (NASCET), the European Carotid Surgery Trial (ECST) and the two trials of asymptomatic patients, the Veterans Asymptomatic Carotid Trial (VACT) and the Asymptomatic Carotid Artery Surgery Trial (ACAS)—are discussed in depth elsewhere in this text. In summary, the degree of stenosis correlating with clinical benefit for CEA in each trial is as follows: NASCET, 70%; ECST, 70%; VACT, 50%; ACAS, 60%.[223]

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It is worth mention that the ECST method calculated stenoses at the carotid bulb using estimated full bulb diameter as the reference, while NASCET, VACT, and ACAS used the distal cervical internal carotid as the “normal” reference artery. If more of the intracranial vasculature or superficial temporal artery must be demonstrated, a second series of films can be obtained centered over the head. Although the efficacy of extracranial-intracranial bypass has been controversial,[225] important developments in cerebral revascularization techniques have enabled successful treatment of some cerebrovascular conditions, including vertebrobasilar insufficiency.[226] Specific techniques are discussed in other chapters, and a well-referenced review[227] outlines methods of cerebral revascularization. Vascular trauma is being recognized with increasing frequency as angiography is utilized more often to evaluate trauma patients. The usefulness of angiography in trauma is shown by one study where 42% of patients with clinical evidence of carotid injury had normal arteriograms and 20% of those with no clinical signs subsequently had positive studies.[228] Cranial CT is useful to rule out intraaxial and extraaxial hematomas as a cause of neurologic findings but cannot exclude associated vascular injury, and CT seldom demonstrates infarcts in the first several hours. Injury patterns in the head and neck are the same as elsewhere, but clinical presentations may differ. Blunt trauma to the neck may result in delayed carotid occlusion with a lucid interval of 1 –24 h before symptoms develop. The postulated mechanism is stretching of the vessel, with intimal injury or disruption of a preexistent atheromatous plaque. A wall hematoma or intimal flap then forms, with resultant occlusion or stenosis.[229] The carotid bifurcation and proximal internal carotid are most frequently involved. The vertebral artery is less commonly involved in trauma than the carotid, presumably because it is enclosed in a bony canal for most of its course. Arteriovenous fistulas in the head and neck offer a challenge to the interventional radiologist, especially when they are located in surgically difficult areas such as the cavernous sinus, vertebral canal, and high cervical carotid regions.[230]

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229. Yamada, S.; Kindt, G.W.; Youmans, J.R. Carotid Artery Occlusion Due to Non-Penetrating Trauma. J. Trauma. 1967, 7, 333– 342. 230. Mchringer, C.M.; Grinnell, V.S.; Hieshima, G.B. Therapeutic Embolization of Trauma to the Head and Neck. Am. J. Neuroradiol. 1983, 4, 137– 142.

CHAPTER 11

Design of Clinical Trials for Evaluation of New Treatments and Methodology James M. Cook Robert W. Barnes Well-designed clinical trials have become the “gold standard” for the assessment of new treatments and comparison of alternate therapies in medicine. They have evolved as a joint discipline involving both medical and statistical science, and their rigorous methodology greatly strengthens the scientific foundation of clinical practice. This chapter is designed to review the background and rationale for clinical trials and to discuss principles of sound trial design, including analysis, interpretation, and presentation of results. Also, ethical issues are explored, costs and limitations are considered, and finally, some future trends in clinical trials and their applications are suggested.

medical practice and, in particular, reimbursement for physicians’ services.

TYPES OF CLINICAL TRIALS Clinical trials are only one form of research involving human subjects. Table 11-1 lists the conventional types of clinical studies. Clinical investigation may be classified as either observational or experimental.[4] In observational studies, the investigator does not control major variables but observes relationships among variables and possible causal relationships. Observational studies tend to be “hypothesis seeking,” and, although they often identify potential causal relationships or therapeutic efficacy,[5] the validation of such relationships often requires verification by experimental studies. Clinical trials may be defined as experiments utilizing human subjects in which two or more types of therapy are prospectively compared. They may be uncontrolled or controlled, and the latter may be either nonrandomized or randomized. Controlled trials compare the outcome of one treatment group (“experimental group,” usually a novel drug or procedure) with that of a second group given either traditional therapy or no treatment (control). Random assignment of patients to experimental and control groups assures that potentially important clinical variables (covariates), such as demographic characteristics and comorbidity, are similar between groups. Uncontrolled studies often rely on data from previous research to make assumptions about the value of the procedure or drug in question. In some cases, such use of historical controls may limit the validity of the study, since patients in prior times may not have shared similar diagnostic criteria or treatment regimens with contemporary patients.[4] However, ethical considerations may preclude a true control (i.e., no

RATIONALE Most physicians deliver health care based on practices reflecting their own uncontrolled clinical experience (induction) or on recommendations of authoritative figures (seduction).[1] Only a small proportion of medical practice is based on deduction derived from human experiments (clinical trials). Salzman[2] has indicated that only 10 –20% of health care technologies have been validated by prospective controlled studies. The objective appraisal of burgeoning medical technology, as well as certain traditional medical and surgical practices, is increasingly important in our current fiscal and legal climate. In addition, patients and third-party papers are increasingly concerned about prognosis and outcomes of health care, especially after interventional or surgical procedures.[3] However, as is discussed in the following sections, the bias of physicians and patients alike often leads to perpetuation of therapies that have minimal, if any, efficacy. Despite the complexity, ethical issues, and costs associated with clinical trials, such studies are becoming more commonplace and will probably be the basis for future

Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024894 Copyright q 2004 by Marcel Dekker, Inc.

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Part One. Assessment of Vascular Disease Table 11-1. Types of Clinical Studies Observational studies Epidemiologic studies Cross-sectional studies Retrospective studies (case control) Prospective studies (cohort) Experimental studies Prospective studies (clinical trials) Uncontrolled studies Controlled studies Nonrandomized Randomized Source: Barnes RW.[18] Used by permission.

treatment) group in certain situations, so that some unrandomized or uncontrolled research must continue to be performed in medicine. It is the prospective, randomized clinical trial that represents the most rigorous clinical design to document the efficacy and risk of medical therapies. By controlling major variables and minimizing bias, the clinical trial fulfills the criteria of an experimental study, which permits “hypothesis testing” versus the “hypothesis searching” characteristic of observational studies. The combination of the size of a clinical trial and the degree to which confounding factors are controlled in a study determines, respectively, the precision and internal validity of the trial. These factors have led to an organizational strategy for clinical research termed population-adjusted clinical epidemiology (PACE), which is a mechanism for designing and implementing multicenter observational studies and randomized clinical trials.[6] Clinical trials may be classified as preventative or therapeutic. The former are further categorized as primary or secondary prophylaxis, depending upon whether the intent is to prevent disease occurrence or recurrence. The latter examine the course of active disease when modified by a particular drug or procedure. Therapeutic drug trials are frequently classified in three phases. Phase I trials are designed to study a relatively small number of patients to determine tolerated doses and side effects or risks of new agents (is it dangerous?). These trials may also reveal some potential therapeutic effects. Phase II trials are designed to estimate the efficacy of the new therapy compared with conventional treatment (does it work?). Phase III trials, which are randomized clinical trials, establish the effectiveness or therapeutic value of the new agent compared with controlled or conventional therapy (how well does it work compared with standard treatment?). Both the efficacy and effectiveness of potential therapies may be evaluated. Efficacy refers to the maximal potential or effect of a therapy and is often evaluated in so-called explanatory trials.[7] Effectiveness refers to the general effect or net benefit (risk/benefit) of a therapy and may be evaluated in a management trial.

TRIAL DESIGN AND ANALYSIS The design, performance, analysis, and reporting of a clinical trial should follow the principles of rigorous scientific methodology. These precepts have been well outlined by Salter.[8] First, the investigator should recognize an unsolved clinical problem and take time to think and reflect on it. Next, the scientific literature on the subject should be reviewed. Although such a review is usually integrated in a qualitative or narrative form, consideration should be given to a quantitative research integration by the method of metaanalysis, as reviewed by Thacker.[9] After this background work, one may ask an intelligent question and formulate a hypothesis. A research protocol is then developed with appropriate collaboration, particularly with a biostatistician. The investigator must then apply for and secure funding for the study. After approval by an appropriate institutional review board and/or human use committee, the formal investigation is conducted and data are collected, analyzed, and interpreted. Valid conclusions should be drawn that answer the original questions. Finally, the results are presented and published. The goal of clinical investigation should be the application of new knowledge to the care of patients. The time and effort devoted to planning and securing funding for a clinical trial is considerable. Powell et al.[10] have recommended the following steps to facilitate approval and funding of randomized clinical trials: (1) trials should address an important clinical problem; (2) potential trialists should be surveyed to establish the need for a trial; (3) a multidisciplinary team should be established early in the development phase; (4) professional bodies should endorse the trial; (5) measurement techniques should be validated before trial design is finalized; (6) the costs of multicenter trials should be spread across different funding bodies; (7) funding bodies should provide guidance to preparation of the application, including the need for socioeconomic evolution, the availability of funds, and the review process; and (8) nationally based ethical committees or review boards should be established to minimize the need for multiple local applications. Failure to properly design and analyze the results of a clinical trial will hinder its application to clinical practice. Hall et al.[11] reviewed the nature and methodologic standards of 364 trials reported in 10 prestigious journals between 1988 and 1994. They found that less than 50% of the trials reported unbiased assessment of outcome, provided a description of the randomization technique, or prospectively estimated the required sample size. Economic analyses were carried out in only 6.5% of the studies. Finally, only 2% of the trials measured outcome effects such as quality of life.

Design As previously noted, clinical trials are usually designed to compare two or more groups of patients subjected to a new medical or surgical procedure with groups receiving conventional therapy or no treatment (control or placebo). Such trials usually test the null hypothesis that there is no

Chapter 11.

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significant difference between the two groups. The comparison of outcomes of treatment and control groups usually follows one of three standard design methods: parallel, crossover, or self-controlled. In parallel studies,[12] each patient receives one method of treatment; results are analyzed by comparison between treatment groups. In crossover studies,[13] each patient receives two (or more) treatments, and outcomes are analyzed by within-patient comparisons. In self-controlled studies,[13] each patient receives one treatment, and results are analyzed by within-patient comparison before and after administration of the therapy. An advantage of the latter two designs is that a separate control group need not be recruited, thus decreasing study size requirements. Also, since each patient is his or her own control, there are no covariate differences between experimental and control groups. If the null hypothesis is rejected, a significant difference is said to exist between the treatments. Such a difference may be the result of one of the following four circumstances: (1) a true effect of the new procedure, (2) differences between the treatment and control groups in some important covariate, (3) differences in handling and evaluating the treatment and control groups during the investigation, or (4) sampling variation or chance. The goal of sound trial design is to eliminate all but the first of these possible explanations. The other situations result in a type I error (false-positive study). The second and third circumstances are a result of bias in selection or management of patients in the trials. The fourth situation occurs as a result of random chance that the groups selected for comparison differed significantly but the larger populations from which they were chosen did not differ. The probability of this latter occurrence is set by the investigator by his choice of alpha, as discussed later. Bias refers to systematic error introduced into sampling that selects or encourages one outcome over others. Sackett has described a large number of sampling and measurement biases that must be controlled in designing a clinical trial.[14] Selection or sampling bias includes differences in prognostic factors or covariates of patients in treatment and control groups and is generally controlled by the process of randomization, as discussed below. Measurement bias is minimized by blinding or masking both subjects and observers in the study whose conscious or often unconscious bias may otherwise affect the interpretation of the outcome variables in the study (particularly subjective, decisionrelated endpoints). The combination of randomization and masking leads to internal validity or believability of the study. Careful, unbiased patient selection and treatment compliance improves the external validity or generalizability of the study (clinical relevance and utility). A clinical trial may accept the null hypothesis that there is no significant difference between the treatment and control groups. Although such an outcome may be true, a “falsenegative” trial (type II error) may result from an insignificant sample size. The importance of designing a trial with an adequate sample size to prevent such errors will be discussed below. Some clinical trials are designed to demonstrate the equivalence of two treatments. An equivalence trial may be of value if the standard treatment has been documented to be

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efficacious and the innovative treatment is easier to use, is associated with fewer side effects, or is less costly.[15]

Patient Selection The patient sample, as well as the larger population from which the sample is selected, must be carefully defined. Only by clarifying the characteristics of the patient sample can one extrapolate the results of the study to the larger patient population. Patient selection criteria as well as exclusion criteria must be stated clearly. A register of patients screened and rejected from the study should be maintained to permit subsequent documentation that selection bias has been minimized or eliminated. The period of patient recruitment or enrollment should be stated clearly, and withdrawals prompted by either the investigator or the patient should be described and followed if at all possible. Safeguards for the patient, including informed consent, the right to withdraw, and assurance of privacy, must be delineated.[16] If the study involves an unusual disease or large numbers of patients are required to detect small but important differences in therapeutic efficacy, patients may be recruited from multiple centers. Although this increases the logistical complexity and potential for selection and measurement bias, the results of a carefully performed multicenter study may often be more readily applied to the general population than those of a study from a single institution. Several alternative trial formats have been proposed to enhance patient recruitment and to minimize patient dropouts by taking into account the strong preferences of patients eligible for enrolment.[17] These alternatives include partly randomized trials in which patients without strong preferences are randomized and opinionated patients are assigned the treatment of their choice, with separate analysis of the latter group as a prospective cohort study. Other options include varying the randomizing ratio depending upon patient attitudes as influenced by evidence accumulating during the trial. Finally, patients may be allowed to participate in the randomizing process, such as picking a sealed envelope. A final feature of successful patient recruitment is the ability to “market” clinical trials to clinicians, as emphasized by Macbeth and Stephens.[18] Key features of making a trial attractive to clinicians include (1) addressing an important or interesting clinical question, (2) facilitating patient entry, and (3) simplifying data collection. Strategies must be developed to reduce demands on the clinician, such as time, effort, or increased resources necessary to carry out a study. Finally, rewards for clinician participation in clinical trials should be developed, which may include tangible rewards (financial, resources, travel), academic or professional esteem, group membership, or satisfaction of intellectual curiosity (usually valued in that order).

Therapeutic Regimens The treatment and control groups must be well defined. If “conventional” treatment is used as a control, the exact characteristics of such therapy should be stated. The strategy of dealing with changes in conventional treatment or cointerventions should be anticipated. Ancillary treatments

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or management should be clarified. Placebo treatment, if used, must be described. Finally, the timing of treatments and drug washout periods (in crossover studies) should be stated.[19]

Randomization To avoid bias in treatment assignment and balance covariates between groups, patients are randomly allocated to treatment and control groups.[20] Although fixed randomization (i.e., allocation of patients in a strict order determined precisely by chance alone) is ideal, adjustment procedures are often employed to ensure balance of certain critical prognostic factors. Such adjustments, when carried out before randomization, usually take the form of stratification of important covariates within both treatment and control groups. Blocking to ensure roughly equal numbers of patients in each of these stratified subgroups may also be used. For multicenter trials, it is often wise to stratify by institution to prevent unbalancing if a given institution must be dropped for any reason. The number of stratified groups should be kept to a minimum (usually no more than two to five) to avoid problems with statistical analysis of groups with inadequate sample size. Finally, allocation concealment from both investigator and patient is imperative, because of the bias that may be introduced if deciphering of assignment sequences occurs before ramdomization (a not infrequent occurrence). As Schulz[21] has stated, “randomized controlled trials appear to annoy human nature—if properly conducted, indeed they should.”

Blinding It is clear that randomization alone will not prevent observer bias. This is minimized by masking or blinding participants in the study so that the treatment received by an individual patient is not known. In a review of 145 publications of treatment of acute myocardial infarction, Chalmers et al.[22] demonstrated that positive study results were found in 58.1% of 43 reports of nonrandomized studies, 24.4% of unblinded randomized studies, and only 8.8% of blinded randomized trials. Masking may be single-blind (the patient), double-blind (the patient and physician), or triple-blind (the patient, physician, and those evaluating outcomes, including statisticians). The randomization process should also be masked (quadruple blinding). Although blinding of patients and investigators may not be possible in some studies, particularly in comparison of medical and surgical therapy, observer and statistical blinding may still be appropriate.

Statistical Design Statistical design refers to a series of measurements that should be undertaken before and during a study to ensure statistical validity at the conclusion of the investigation. Because many statistical tests are performed after data have been generated, many clinicians falsely assume that such statistical interventions are most applicable at the conclusion of a study.

One of the most important design considerations is an estimation of the required sample size to achieve the objective of the study.[23] Certain steps are important in calculating sample size. First, the null hypothesis to be tested should be specified clearly, including a precise definition of the outcomes or endpoints of interest. Second, the investigator should decide what statistical tests will be used to accept or reject the null hypothesis and with what probability a positive result might be due to chance (alpha level of a false-positive, type I error). Commonly the level chosen is 0.05. The probability of accepting the null hypothesis (detecting no difference when none exists) is I-alpha and is analogous to the specificity of a diagnostic test. Third, the investigator should specify an alternative hypothesis representing a clinically important difference between treatments that, if the hypothesis is valid, should be detected. The probability of the study not detecting such a difference (beta or type II error) is often accepted at a level of 0.20, but for large trials or studies in which detection of a difference is very important, a level of 0.10 may be chosen. The probability of detecting a difference when one exists (a true positive, or I-beta) is termed the power of a study and is analogous to the sensitivity of a diagnostic test. The sample size of the study should be calculated to ensure adequate power, usually . 0.80. Thus the factors influencing beta and power include the alpha level chosen, the size of difference that treatment makes, the rate events among control patients, and, most important, the number of patients in the trial.[23] The importance of adequate sample size was illustrated by Freiman et al.,[24] who reviewed 71 negative randomized clinical trials. Of these, 67 had a risk of greater than 10% of missing a 25% therapeutic benefit, and 50 had a similar risk of missing a 50% therapeutic benefit. In general the investigator should anticipate screening at least twice the number of patients required for the projected sample size.[25] The number will depend on the entry requirements for the study. Relatively restrictive entry requirements may lead to a more homogeneous study population and, potentially, a greater probability for a positive outcome of a study of a given size. However, such rigid criteria may lead to a large number of screened patients and a limited generalizability to the general patient population. As a group, randomized clinical trials tend to be fairly specific (a low incidence of false-positive results), largely because of the choice of alpha level. They are thus useful to document efficacy of therapy (hypothesis testing). On the other hand, clinical trials often are relatively insensitive (high probability of false-negative results), largely because of inadequate sample size or power. Retrospective or historical control trials are inherently more sensitive than prospective, randomized, controlled trials and are thus useful for screening (hypothesis seeking).[26] However, because of their relatively low specificity, the results of such retrospective studies should be validated when possible by a prospective, randomized controlled trial. Other items of importance in statistical design[16] include a tabular listing of known prognostic factors (covariates ) and their distribution between treatment and control groups. Tests of blinding of both physicians and patients are advisable to determine whether either participant recognized the therapy

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employed. Tests of patient compliance should be specified, such as pill counts, blood or urine levels, or other tests of biologic equivalence. Despite the importance of the aforementioned statistical design of clinical trials, there are certain elements in the statistical analysis of the data generated by a trial that are a reflection of quality control.[16] The statistical significance of differences in major endpoints should present both the test statistic and the observed probability level so that others may verify the statistical conclusion. For negative study results, a discussion of the probability of a type II error should be made, which may include estimating a posterior beta (i.e., determining the statistical power of the study). Statistical inference should be based on appropriate use of confidence limits, life-table or time-series analysis, regression analysis, or correlations. It must be clear how withdrawals or dropouts are handled. It is usually preferable to analyze them in the group to which they were originally assigned (intent-totreat analysis).[27] Ignoring or eliminating such withdrawals is not acceptable. Considering crossover patients in the new treatment arm of the study may not be statistically valid, although it seems logically appealing.[27] Retrospective subgroup analysis (post hoc) should be performed with caution. Such “data dredging” or hypothesisseeking approaches are associated with bias, and the probability of finding significant differences by chance alone increases considerably.[28] Such analysis may be useful to identify possible causal relationships for future study, but inferences should not be drawn or confused with the original aims of the study.[29] Techniques to blind the statistician as well as the data monitoring committee should be encouraged.[16] Finally, repeated significance testing (“multiple looks”) prior to study termination increases the probability that a falsely significant difference will be found.[30] Techniques of sequential design or other methods to reduce the risk of premature termination of a trial should be stated. An excellent summary of common statistical problems and recommendations for avoiding distortions in clinical trials have been reported by Pocock et al.[31]

Presentation of Results The reporting of results of a study should relate to and reflect the original specific objectives of the study.[16] All endpoints should be tabulated, and the timing of outcomes and withdrawals should be presented so that others can reconstruct survival curves for independent validation of the statistical conclusions. Side effects should be reported, analyzed, and discussed. The completeness of reporting trial results will influence the willingness of physicians to incorporate the recommendations into their practice, e.g., from knowledge of relative risk reduction as opposed to absolute risk reduction.[32] Proper design and analysis of a clinical trial should establish[32a] its internal validity or believability and its external validity or clinical applicability (generalizability). Sackett[1] has suggested that a sound clinical trial should answer the following questions in the affirmative: (1) Is patient assignment randomized? (2) Are all outcomes

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reported? (3) Are the patients recognizably similar to one’s own? (4) Are both clinical and statistical significance considered? (5) Is the therapeutic maneuver feasible? (6) Are all patients accounted for? Table 11-2 lists the important elements of design and analysis that should be incorporated into a sound randomized clinical trial.[16] DerSimonian et al.[33] have reviewed 67 articles in leading scientific journals and found that in only 56% were design and analysis methodology clearly reported. In another 10% such design features were ambiguously reported, and in 34% such methodology was lacking. In order to assure greater rigor and uniformity of design, analysis, and reporting of randomized clinical trials, several

Table 11-2.

Design for Clinical Trials

Patient sample/data set Population sampled Selection criteria Exclusion criteria Rejection log Enrollment period Withdrawals, dropouts Patient safeguards (informed consent, privacy) Therapeutic regimens Treatment regimens Control, placebo Cointervention Ancillary management Randomization Complete (fixed) method Stratification/blocking Adaptive allocation Covariate adjustment Sequential design Masking (blinding) Randomization Patients/subject Physician Results (statistical blinding) Statistical design (testing, quality control) Sample size: a, b, power Pretreatment (confounding, covariate) variables Tests of blinding Compliance Biologic equivalent Statistical analysis Significance of major endpoints, adverse effects Posterior b estimates (negative trials) Statistical inference Withdrawals (intent to treat, endpoint) Retrospective (subgroup) analysis Multiple analysis, sequential designs, stopping rules Presentation of results Dates of study Prerandomization data analysis Tabulation of endpoints Timing of events Source: Chalmers TC, et al.[16] Used with permission.

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recommendations for standardized reporting practices have been published recently.[34 – 38] The reader is referred to these reports for current standards of reporting clinical trial results.

ETHICS Research involving human subjects inevitably raises ethical questions that profoundly influence the design and conduct of clinical trials.[39] A number of moral questions of clinical research include those relating to experimental design, funding sources, subject recruitment and selection, informed consent, experimental procedures, patient compensation, and subject injury or harm. The latter concern of subject risk is the central moral problem of clinical research. Clinical trials require a sacrifice of individualized treatment, although recent innovations in research design permit randomized trials in individual patients (“n of 1” trials),[40 – 42] and some novel designs allow a choice of treatment by patient or physician. Also, certain adaptive procedures may be useful to maximize the number of patients allocated to superior treatment.[43] The freedom to withdraw from a study must be ensured, but premature withdrawal from or termination of a study raises ethical questions, and consent should be obtained for such decisions. The role of informed consent for the conduct of human investigation has led to a wide spectrum of ethical opinions.[44] The concept of consent arises from an ethical principle: volenti non fit injuria (he who consents cannot receive an injury).[45] Kanoti[46] has defined the following ideal ethical imperatives of clinical research: freedom (patient and investigator), beneficence (benefit to patient or society), nonmalfeasance (no physical, social, psychologic, or spiritual risk), justice (no financial ruin), and confidentiality (no public scrutiny). Ethical issues in clinical trials are best addressed if the principles of research responsibility are followed as emphasized by Little:[47] realism with avoidance of undue protocol rigidity, accountability by the investigator as well as the review bodies, and purposiveness with research directed to a common good. Unfortunately, the ethical principles embodied in the doctor-patient relationship constitute the leading reason for resistance on the part to physicians to entering patients in clinical trials.[48] Despite the desire of most physicians to provide ethical care based on their own experience, Miller and Perry[49] have made the plea that “the obligation to replace ignorance with knowledge must have priority over the obligation to administer a suspected therapy.” Physicians participating in clinical trials enter into an ethical dilemma in their role as scientists during the investigation.[50] The physician is expected to be a practicing, empathetic professional whose primary concern is the patient. The scientist is concerned with answering questions that may be of benefit to humanity in general. Thus, the physicianscientist encounters conflicting demands between rightsbased and utilitarian moral theories. Passamani[51] responds to this ethical dilemma by noting that “proved therapies involve a consensus of the competent medical community that the

data in hand justify using a treatment in a given disorder. It is this consensus that defies an ethical boundary.” In addition to participating physician and patients, those who govern clinical trials also face ethical dilemmas. Sniderman[52] has recommended that the governance of clinical trials should be modified to permit a greater role of continuing monitoring of the local ethics committee (Institutional Review Board) not only to approve the protocol but also to assure patient safety, to inform patients of successes or failure of similar trials, to be informed of the whole trial, and to communicate with other safety-monitoring committees. A final ethical dilemma has emerged in applying the results of population-based clinical trials to the care of individual patients. This current era of “evidence-based medicine”[53] emphasizes the role of the physician in objectively interpreting the results of a hierarchy of published studies, often randomized clinical trials. There is an ethical danger of choosing care options based upon statistical significance or clinical significance, while overlooking the personal significance of the other partner in the decision making—the patient. Sweeney et al.[54] have emphasized that the practitioner’s role should be to evaluate the research evidence, to explore the patient’s philosophy of health, and to deliver an opinion based on a synthesis of this information. The patient’s role should be to participate actively in his or her health care decisions based upon personal, family, social, and demographic factors. As McCormack[55] has stated: “It is as important to know the patient who has the disease as it is the disease which the patient has.”

COSTS AND LIMITATIONS One of the most frequently quoted reasons for not carrying out a major clinical trial is the cost of such research. Many individuals fail to consider the cost of treating disease, particularly with therapy that has not been validated by appropriate clinical investigation.[56] The cost of clinical trials will vary depending on the type of trial. Although multicenter trials are usually more expensive than single-center trials, Meinert[57] has shown that the median cost per patient studied may actually be lower in multicenter trials. Treatment trials have the merits of providing the greatest initial benefit and are usually better accepted by patient and physician alike.[58] However, such trials suffer the limitations of potential changes in or obsolescence of treatment and the greater cost of treating disease. Prevention trials have the disadvantage of following relatively high-risk patients over a long latent period and often require a change in habits for possibly marginal benefits. However, preventive trials, despite great expense, ultimately offer the greatest reduction in the cost of disease. The sources of funding for clinical trials include the government through grants and contracts, industry, foundations or public funds, academic research institutions, and third-party sources.[57] The National Institutes of Health (NIH) remain the principal source of support for major clinical trials in this country. Despite increasing fiscal restraints, NIH support has increased steadily over the years.

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Design of Clinical Trials for Evaluation of New Treatments and Methodology

Not all medical therapy requires validation by randomized controlled trial. Clinical trials are inappropriate for treatment that favorably influences an otherwise rapidly fatal disease, a rare disease, or a disease that otherwise has a uniform outcome (no variance).[18] Although Spodick[59] has urged that surgical therapy be subjected to randomized clinical trials at the outset of their development, such procedures require a period of technical evolution for their perfection, unlike drugs.[60] Furthermore, operations are subject to variability of skill of different surgeons, which complicates the outcome of surgical trials. Finally, most operations are irreversible, unlike medical therapies, thus precluding crossover or self-controlled studies. Nevertheless, surgical procedures are being subjected increasingly to randomized controlled trials.[61 – 64]

ECONOMIC ANALYSIS Public, governmental, and professional concerns about escalating costs of health care have led to widespread efforts to carry out a variety of economic analyses of medical practice.[65] Economic analysis is based on the principle that choices must be made between alternative uses of resources, and these choices must consider both cost and outcome, in as much as there are insufficient resources to provide all possible medical care that is available or desired by patients. Economic analysis includes different types of analysis, different points of view, and different types of cost.[65] From the perspective of types of analysis, three commonly reported methods include cost-identification, cost-effectiveness, and cost-benefit analysis. Cost-identification analysis is most commonly used by physicians and describes the cost for services provided. Frequently, the true cost of services is difficult to identify, because charges are more readily available to physicians, patients, and third parties. Costidentification analysis, also called minimization analysis, assumes that outcomes are equivalent, because the method does not evaluate what the expenditures bring in terms of health care outcomes. This method applies only to services that provide lower cost and better or equal outcomes. Costbenefit analysis involves making explicit decisions about whether the cost is worth the benefit by measuring both in the same units, such as units of currency. This analysis may calculate the net benefit or net cost by subtracting cost from benefit or, alternatively, determining the ratio of benefits to cost. Cost-benefit analysis requires societal decisions as to what would be done with monies saved by choosing the more cost-beneficial treatment. Cost-effectiveness analysis has been the method most frequently used by health care economists. This technique measures the net cost of providing service (the expenditures minus the savings) as well as the outcomes achieved. Outcomes are reported as a single unit of measurement, such as year of life saved, or as several outcomes on a common scale (utility analysis). The latter often involves calculation of quality-adjusted life-years (QALYs), and such calculations may be termed cost-utility analysis. Economic analysis may be viewed from a number of perspectives, including the payer, the provider, the patient,

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and society at large. Payer costs are the charges for health care allowed by the payer. Provider costs involve the true costs of providing the service and, as mentioned previously, are difficult to establish without detailed analysis, because charges are more frequently evident. Charges measure cost only to those who pay those charges. Charges do not differentiate between fixed and variable costs. Patient costs include the amount paid for service that is not covered by insurance plus other costs incurred by the illness or treatment, such as time missed from work. Societal costs involve the net cost of all different societal components including the patient’s lost productivity and the expenses incurred in providing and receiving the medical care. Societal costs may be viewed as “opportunity costs” resulting from giving up the opportunity to use the resources for other purposes. Medical costs include fixed and variable costs. Fixed costs are those that would not be affected by a change in number of services provided (building maintenance), whereas variable costs are those affected by the volume of services (supplies). Costs may be defined as the consumption of a resource that otherwise could have been used for another purpose, i.e., opportunity cost. Costs may be direct, indirect, or intangible. Direct costs are those transactions or expenditures for medical or nonmedical products and services. Direct medical costs include hospitalization, drugs, physician fees, laboratory tests, radiological procedures, rehabilitation, durable medical equipment, and long-term care. Direct nonmedical costs include food, transportation, lodging, family care, home aides, and clothing for the patient as well as transportation and lodging expenditures by the family. Costs must be corrected for inflation and be discounted to the present in order to consider the effect of time. Future outcomes are often discounted at the same rate as the interest rate, which may be termed the “social rate of time preference.” Indirect costs are those that occur because of loss of life or livelihood (mortality and morbidity). Indirect costs may be calculated by the “human capital approach” or the “willingness-to-pay approach.” The human capital approach refers to the future earnings, in today’s value, that could have been realized had the individual not become prematurely disabled or died. The approach is beset with problems of devaluing individuals with lower income and sensitivity to the rate at which future dollars are handled. The willingness-to-pay approach applies market economy to the value of human life, or what someone would pay to avoid an adverse event. This approach suffers from difficulty in estimating willingness to pay for hypothetical outcomes, sensitivity to the ability to pay, the likelihood of the event, and the likelihood that payment will influence the outcome. Intangible costs include the costs of pain, suffering, grief, and other nonfinancial outcomes of illness and health care. These costs are often incorporated into outcome measures such as QALYs. Cost-effectiveness analysis is often calculated in terms of marginal or incremental effects. Marginal cost-effectiveness refers to the additional cost and effectiveness that can be obtained from one additional unit of service, such as an extra day in the hospital. Incremental cost-effectiveness reflects the additional cost and effectiveness resulting when one option is compared to the next most intensive or expensive alternative,

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such as outpatient surgery versus short-stay surgery (extra units of outcomes per extra dollar spent). Economic analyses also involve sensitivity analysis and decision analysis. Sensitivity analysis identifies the degree to which uncertainty or bias influences the economic results of clinical decisions. These results are calculated separately for different values of the various components of a study. Decision analysis is a method of determining the sensitivity of a decision to the probabilities of various outcomes, their economic effects, and the cost of health care interventions. Cost-effectiveness analysis has become an influential factor in health care policy decisions,[66 – 68] in assessing of the value of clinical trials,[69] and in the evaluation of the effectiveness of surgery,[70] including the cost-effectiveness of various vascular surgical procedures.[71 – 73] However, there are a number of limitations to economic analyses that must be recognized by all parties involved in health care delivery. First, there are a number of misconceptions about the implications of terminology:[74] cost-effective does not necessarily mean cost saving or more effective therapy. Rather, it implies an additional benefit that is worth the possible additional cost, assuming these caveats: (1) less costly and at least as effective; (2) more effective and more costly, with the additional benefit worth the cost; or (3) less effective and less costly, the added benefit not worth the extra cost. Second, clinical trials often fail to substantiate the costs, particularly start-up costs and general overhead.[75] Third, the assessment of outcomes of cost-effectiveness studies often fail to take into account the reasons for given outcomes, such as risk adjustment[76] of patient characteristics that influence the results of health interventions. Fourth, controversy exists about whether clinical trials with concurrent economic analyses should be blinded.[77] Fifth, both professionals and

the lay public often place a greater importance on equity than on cost-effectiveness analysis when making choices about health care priorities in the setting of budget constraints.[78] Finally, and perhaps most important, economic analyses applied at the bedside may disrupt the traditional physicianpatient fiduciary relationship.[79]

FUTURE TRENDS The aforementioned review suggests that clinical trials are serving an increasing role in validating medical and surgical therapies. Nevertheless, considerable resistance to clinical trials exists on the part of physicians and patients alike. Bias, ethics, and costs contribute to this problem. However, education of all parties—physicians, patients, public, and media—will be instrumental in increasing their awareness and acceptance of the value of clinical trials in improving medical practice. Increased participation by physicians in clinical trials is likely, in both academic centers and individual practices. Facilitation of such participation may arise from innovation in trial design, such as increasing use of self-controlled studies or randomized trials in the individual patient. Finally, there may be increasing pressure by various funding agencies to pursue clinical trials in order to validate costly medical and surgical therapies and technologies in an attempt to control spiraling health care costs. Indeed, the future of physician reimbursement may well rest on practicing “validated” medicine. Only by becoming knowledgeable about the rationale and principles of sound clinical trial design can physicians and patients participate meaningfully in this process.

REFERENCES 1. Sackett, D.L. Rational Therapy in the Neurosciences: The Role of the Randomized Trial. Stroke 1986, 17, 1323. 2. Salzman, E.W. Is Surgery Worthwhile? Arch. Surg. 1985, 120, 771. 3. Mahoney, J.E.; Wright, J.G.; McLeod, R.S.; Lossing, A. Prognosis in Surgery: Why They Are Determined, Strategies for Making Them, and Study Design. Surgery 1996, 120, 563. 4. Bourke, G.J.; Daly, L.E.; McGilvray, J., (Eds.) Interpretation and Uses of Medical Statistics; 3rd Ed. Blackwell Scientific Publications: Oxford, 1985. 5. Hu, X.; Wright, J.G.; McLeod, R.S.; Lossing, A.; Walters, B.C. Observational Studies as Alternatives to Randomized Clinical Trials in Surgical Clinical Research. Surgery 1996, 119, 473. 6. Engles, E.A.; Spitz, M.R. PACE-Setting Research. Lancet 1997, 350, 677. 7. Sackett, D.L.; Gent, M. Controversy in Counting and Attributing Events in Clinical Trials. N. Engl. J. Med. 1979, 301, 1410. 8. Salter, R.B. The Philosophy and Nature of Surgical Research. Can. J. Surg. 1980, 23, 349.

9. Thacker, S.B. Meta-Analysis. J. Am. Med. Assoc. 1988, 259, 1685. 10. Powell, J.T.; Greenhalgh, R.M.; Ruckley, C.V.; Fowkes, F.G.R. Prologue to a Surgical Trial. Lancet 1993, 342, 1473. 11. Hall, J.C.; Mills, B.; Nguyen, H.; Hall, J.L. Methodologic Standards in Surgical Trials. Surgery 1996, 119, 466. 12. Lavori, P.W.; Louis, T.A.; Bailar, J.C.; Polansky, M. Designs for Experiments: Parallel Comparisons of Treatment. N. Engl. J. Med. 1983, 309, 1291. 13. Louis, T.A.; Lavori, P.W.; Bailar, J.C.; Polansky, M. Crossover and Self-controlled Designs in Clinical Research. N. Engl. J. Med. 1984, 310, 24. 14. Sackett, D.L. Bias in Analytic Research. J. Chronic. Dis. 1979, 32, 51. 15. Ware, J.H.; Antman, E.M. Equivalence Trials. N. Engl. J. Med. 1997, 337, 1159. 16. Chalmers, T.C.; Smith, H.; Blackburn, B. et al. A Method for Assessing the Quality of a Randomized Controlled Trial. Control. Clin Trials 1981, 2, 31. 17. Silverman, W.A. Patients’ Preferences and Randomized Trials. Lancet 1994, 343, 1586.

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Macbeth, F.; Stephens, R. Marketing Clinical Trials. Lancet 1996, 348, 111. Barnes, R.W. Understanding Investigative Clinical Trials. J. Vasc. Surg. 1989, 9, 609. Byar, D.P.; Simon, R.M.; Friedwald, W.T. et al. Randomized Clinical Trials. N. Engl. J. Med. 1976, 295, 74. Schulz, K.F. Subverting Randomization in Controlled Trials. J. Am. Med. Assoc. 1995, 274, 1456. Chalmers, T.C.; Celano, P.; Sacks, H.S.; Smith, H. Bias Treatment Assignment in Controlled Clinical Trials. N. Engl. J. Med. 1983, 309, 1358. Colton, T. Statistics in Medicine; 1st Ed. Little, Brown: Boston, 1974. Freiman, J.; Chalmers, T.C.; Smith, H.; Kuebler, R.R. The Importance of Beta, the Type II Error and Sample Size in the Design and Interpretation of the Randomized Controlled Trial. N. Engl. J. Med. 1978, 299, 690. Charlson, M.E.; Horwitz, R.I. Applying Results of Randomized Trials to Clinical Practice: Impact of Losses Before Randomization. Br. Med. J. 1984, 289, 1281. Sacks, H.S.; Chalmers, T.C.; Smith, H. Sensitivity and Specificity of Clinical Trials. Arch. Intern. Med. 1983, 143, 753. Feinstein, A.R. Problems, Pitfalls, and Opportunities in Long-Term Randomized Trials. Arzneim.-Forsch./Drug Res. 1989, 39, 980. Smith, D.G.; Clemens, J.; Crede, W. et al. Impact of Multiple Comparisons in Randomized Clinical Trials. Am. J. Med. 1987, 83, 545. Yusuf, S.; Wittes, J.; Probstfield, J.; Tyroler, H.A. Analysis and Interpretation of Treatment Effects in Subgroups of Patients in Randomized Clinical Trials. J. Am. Med. Assoc. 1991, 266, 93. De Klerk, N.H. Repeated Warnings Re Repeated Measures. Aust. N Z. J. Med. 1986, 16, 637. Pocock, S.J.; Hughes, M.D.; Lee, R.J. Statistical Problems in the Reporting of Clinical Trials. N. Engl. J. Med. 1987, 317, 426. Bobbio, M.; Demichelis, B.; Giustetto, G. Completeness of Reporting Trials Results: Effect on Physicians’ Willingness to Prescribe. Lancet 1994, 343, 1209. Rothwell, P.M. Can Overall Results of Clinical Trials Be Applied to All Patients? Lancet 1995, 345, 1616. DerSimonian, R.; Charette, J.; McPeek, B.; Mosteller, F. Reporting on Methods in Clinical Trials. N. Engl. J. Med. 1982, 306, 1332. The Standards of Reporting Trials Group; A Proposal for Structured Reporting of Randomized Controlled Trials. J. Am. Med. Assoc. 1994, 272, 1926. Begg, C.; Cho, M.; Eastwood, S.; Horton, R.; Moher, D.; Olkin, I.; Pitkin, R.; Rennie, D.; Schulz, K.F.; Simel, D.; Stroup, D.F. Improving the Quality of Reporting of Randomized Controlled Trials. The CONSORT Statement. J. Am. Med. Assoc. 1996, 276, 637. Schulz, K.F. Randomized Trials, Human Nature, and Reporting Guidelines. Lancet 1996, 348, 596. Working Group on Recommendations for Reporting of Clinical Trials in the Biomedical Literature; Call for Comments on a Proposal to Improve Reporting of Clinical Trials in the Biomedical Literature. Ann. Intern. Med. 1994, 121, 894.

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63. McLeod, R.S.; Wright, J.G.; Solomon, J.M.; Hu, X.; Walters, B.C. Randomized Controlled Trials in Surgery: Issues and Problems. Surgery 1996, 119, 483. 64. Howard, G.; Chambless, L.E.; Kronmal, R.A. Assessing Differences in Clinical Trials Comparing Surgical vs Nonsurgical Therapy. Using Common (Statistical) Sense. J. Am. Med. Assoc. 1997, 278, 1432. 65. Eisenberg, J.M. Clinical Economics. A Guide to the Economic Analysis of Clinical Practices. J. Am. Med. Assoc. 1989, 262, 2879. 66. Russell, L.B.; Gold, M.R.; Siegel, J.E.; Daniels, N.; Weinstein, M.C. The Role of Cost-Effectiveness Analysis in Health and Medicine. J. Am. Med. Assoc. 1996, 276, 1172. 67. Weinstein, M.C.; Siegel, J.E.; Gold, M.R.; Kamlet, M.S.; Russell, L.B. Recommendations of the Panel on CostEffectiveness in Health and Medicine. J. Am. Med. Assoc. 1996, 276, 1253. 68. Siegel, J.E.; Weinstein, M.C.; Russell, L.B.; Gold, M.R. Recommendations for Reporting Cost-Effectiveness Analyses. J. Am. Med. Assoc. 1996, 276, 1339. 69. Detsky, A.S. Are Clinical Trials a Cost-Effective Investment? J. Am. Med. Assoc. 1989, 262, 1795. 70. Finlayson, S.R.G.; Birkmeyer, J.D. Cost-Effectiveness Analysis in Surgery. Surgery 1998, 123, 151. 71. Katz, D.A.; Cronenwett, J.L. The Cost-Effectiveness of Early Surgery Versus Watchful Waiting in the Management of Small Abdominal Aortic Aneurysms. J. Vasc. Surg. 1994, 19, 980.

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CHAPTER 12

Outcomes Assessment for the Vascular Surgeon John V. White “If the function of a hospital were to kill the sick, statistical comparisons of this nature would be (sufficient).” Florence Nightingale, 1863

The value of these interventions, then, lies in the improvement in overall well-being and productivity derived by the patient. Clinical outcomes parameters do not adequately describe patient benefit from vascular intervention.

The ultimate objective of health care is improvement in the quality of a patient’s life. Though simple in concept, the achievement of this goal is often difficult to substantiate. Despite health care costs exceeding $988 billion in 1996, the United States ranks only 9th in life expectancy and even lower for infant mortality and other health parameters.[1,2] There is little information available regarding the improvement in quality of life. Reflexively, the government has taken steps to assess the quality of health care in the United States. Congress, in 1989, created the Agency for Health Care Policy and Research and charged it with the responsibility to conduct research to identify effective health care and develop clinical guidelines based upon the findings. The government emphasizes that the outcomes of health care should be evaluated on the basis of factors which directly affect the patient, such as pain and functional ability, rather than on intermediate clinical measures, such as laboratory tests.[3] Ultimately, the rising cost of health care in the United States will mandate that therapies which fail to directly increase the well-being and productivity of patients be restricted or eliminated, regardless of technical outcome. This mandate will have a major impact upon the treatment of patients with vascular disease. The vast majority of vascular interventions are performed for palliation or a reduction in immediate mortality. These therapeutic endeavors do not clearly prolong life, and few are directed toward achieving a cure of the underlying cause of disease. Aneurysm resection does not alter the metabolic processes which destroy the structural integrity of the aortic wall. This has been demonstrated for both open surgery and in recent aortic stent-graft trials in which the proximal neck has continued to grow despite aneurysm resection.[4,5] Similarly, endarterectomy and bypass procedures do little to directly control the progression of atherosclerosis. The patient remains susceptible to recurrent disease after vascular surgery.[6,7] Life expectancy of patients with lower extremity ischemia is severely reduced despite revascularization.[8,9]

THE IMPACT OF THE DISEASE AND ITS TREATMENT Evaluation of the effects of vascular surgical intervention requires an understanding of (1) the characteristics of the specific condition, (2) the effect of the specific condition upon the patient’s life and level of functioning, and (3) the impact of therapy upon the patient. Each of these areas provides complementary information about the course of vascular disease and its treatment. Together, these pieces of information permit more reliable interpretation of the data, whether it is clinical or patient-based. Most vascular diseases have been well characterized by physical examination and laboratory testing, providing insight into the clinical characteristics of various vascular diseases. Based solely upon the information gathered during the performance of a complete history and physical examination plus noninvasive laboratory studies, a diagnosis can be made. However, a physician cannot accurately assess the overall impact of vascular disease upon the patient. Moreover, physiologic parameters do not correlate well with patient disability. Evaluating 555 patients with lower extremity ischemia by ankle-brachial index ¼ /(ABI) and patient-reported outcomes measures, Feinglass and colleagues noted only a modest correlation between the anklebrachial index and the patient’s self-reported level of physical functioning and walking ability.[10] Many patients with only slight reductions in ABI to 0.8–0.9 reported significant impairment in physical function. Conversely, many patients with significant reductions in ABI to 0.4–0.6 maintained high levels of physical function and walking ability. Thus, clinical descriptors of vascular disease do not provide a useful guide to the manifestations of the disease experienced by the patient.

Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024895 Copyright q 2004 by Marcel Dekker, Inc.

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Similarly, the impact of the disease upon the patient’s life and level of functioning may be quite variable among patients. A clear understanding of this effect is essential for the appropriate management of the patient. It is as important for patients to completely describe their perception of the impact of the disease upon their life and level of functioning as it is for the physician to characterize the severity of vascular disease by physical examination and laboratory evaluation. This was nicely demonstrated by Pell, who had 201 claudicants rate their quality of life prior to their first visit with a vascular surgeon.[11] After the visit, the surgeon was asked to rate the patient’s quality of life based upon an understanding of the patient’s symptoms and examination. The correlation between these two estimates was poor and the vascular specialist often held an exaggerated concept of the impact of vascular disease on a given patient. Assessing 157 claudicants with treadmill walking distance, ankle-brachial index, and the Euroqol generic quality of life survey, Chetter and colleagues noted a poor correlation between the clinical parameters of treadmill walking distance and ankle-brachial index and the measured quality of life.[12] Barletta and associates evaluated treadmill performance and the quality of life with the McMaster Health Index Questionnaire in 251 patients and 89 age-matched controls.[13] These investigators documented a reduction in physical, emotional, and social function in claudicants compared with controls, but the reduction in these quality of life parameters did not correlate well with treadmill performance. Thus, it is imperative that the vascular specialist assess the impact of vascular disease through patient-based reporting. Once the manifestations of vascular disease and their impact upon the patient’s level of functioning have been documented, the beneficial and adverse effects of treatment can be determined. An optimal technical result represents a step toward the achievement of an improved patient wellbeing, but it is not itself sufficient to enhance a patient’s quality of life. This concept is familiar to most vascular surgeons who, for example, have puzzled over patients with a patent lower extremity revascularization who remain unable to walk because of persistent pain. Currie and associates studied 186 patients treated with an unsupervised exercise program, angioplasty, or surgery for claudication.[14] As might be expected, these investigators documented that angioplasty and surgery reduced the symptoms of claudication and improved functional status and quality of life scores. Strikingly, however, these improvements did not correlate directly with changes in the ankle-brachial index. Schneider and colleagues evaluated the functional status and well-being of 60 patients more than 6 months after aorto-bifemoral bypass grafting.[15] Although complete healing and postoperative recovery had occurred, patients with patent bypass grafts were found to have physical function, role function, and perceived health scores that were worse and bodily pain scores that were greater than those without symptomatic arterial occlusive disease. A similar study has documented greater anxieties and less satisfaction among patients requiring repeat vascular surgical interventions compared to those undergoing their first procedure.[16] These findings indicate that clinical measures, such as ankle-brachial index, patency, and limb salvage, effectively assess the physiologic impact of vascular intervention but do not adequately describe

overall patient benefit or adverse effect. This lack of correlation again underscores the need to use both clinical and patient-based parameters to adequately determine the impact of vascular disease and its treatment on the claudicant. Gibbons and colleagues evaluated the activities of daily living, mental well-being, and symptoms of vascular disease in 156 patients.[17] Though limb salvage was 97% at 6 months, only 45% of patients reported feeling “back to normal.” Nicoloff and colleagues evaluated 112 patients who had undergone infrainguinal bypass 5 – 7 years previously.[18] These investigators found that 30% of patients who were ambulatory preoperatively were not ambulatory at the time of evaluation postoperatively. Only 14.3% of the patients experienced an ideal surgical result of an uncomplicated operation with longterm symptom relief, maintenance of functional status, and no repeat or recurrent operations. Similarly, Abou-Zamzam and associates in a study of 513 patients undergoing lower extremity revascularization for limb salvage noted a primary assisted graft patency of 92%.[9] Despite this impressive success, 79% of patients who underwent revascularization because of inability to ambulate could not ambulate postoperatively although a patent bypass was present. The benefits and adverse effects of vascular surgical interventions, then, must be clearly defined by their ability to improve upon the patient’s quality and quantity of life, not simply by clinical parameters.

PATIENT-BASED OUTCOMES ASSESSMENT PARAMETERS The current approach to patient-based assessment has grown out of the National Health Interview Survey which was established in the late 1950s to characterize the national health.[19] In this survey, people were asked for the first time to rate their health, identify health problems, and describe the impact of the problem on their level of daily activity. In the 1970s the National Center for Health Services Research established a program to develop a survey instrument to measure the effect of illness on people’s lives. From this effort was created The Sickness Impact Profile.[20] During this same period of time, the Health Insurance Experiment developed a 20-question survey tool for patient-based assessment of health status.[21] This broadly applied tool became the foundation for the Medical Outcomes Study undertaken a decade ago to evaluate physician practice patterns and patient outcome after treatment.[22] Through the questioning of many thousands of individuals, these efforts delineated four integral components to the assessment of health-related quality of life: functional ability, perceived health, psychological well-being, and role functioning. Assessment of functional status provides information about how well the patient can perform tasks commonly required in daily life, such as climbing stairs, walking across a room, reading a newspaper, or holding a pen. These activities are basic and generic in nature and are independent of gender and occupation. They reflect the ability of the patient to perform common activities of daily living. Perceived health

Chapter 12.

evaluation describes how healthy a person believes he/she is and those aspects of ill health which most limit the patient. The presence of chronic medical conditions which lead to the development of atherosclerosis can have a profound impact upon a patient’s perceived health. The Medical Outcomes Study documented that diabetes, hypertension, and angina are all associated with a significant reduction in perceived health.[23] Additionally, a patient’s perception of his/her health may be adversely affected by disease even after treatment. Though claudication is not a directly life- or limbthreatening disorder, numerous investigators have documented greater perceived health problems regarding energy, pain, and emotional reactions among claudicants compared to a nonclaudicating control group (Fig. 12-1).[24] In a study of 24 claudicants 1 year after angioplasty, Cook and Galland noted continued improvement in walking distance and quality of life but a deterioration in perceived health because of the development of co-morbid conditions.[25] Duggan and colleagues evaluated 17 patients who had successful lower extremity bypass procedures and found that, at a mean of 18 months after surgery, there was a decline in perceived health despite a patent bypass.[26] Each of these studies documents the complex nature of vascular disease and the challenge which vascular surgeons face in aiding their patients. Assessment of the psychological well-being of a patient yields insight into how worried, anxious, or depressed a patient is about his/her illnesses and treatment. Using carotid artery intimal-medial thickness as an indicator of progression of atherosclerosis, Agewall and colleagues found more rapid progression of disease in patients with poor psychological well-being even after correcting for serum cholesterol and cardiovascular disease.[27] Thompson and colleagues evaluated anxiety and depression in 112 patients with limbthreatening ischemia.[28] They found no difference in anxiety between those who had primary amputation and those who underwent an attempt at revascularization. Primary amputees, however, experienced greater depression. Role functioning evaluation is directed toward the assessment of the impact of a patient’s illness on his/her ability to work and perform obligatory duties. This dimension may provide important information for physicians regarding the goals of treatment. The desired improvement in walking ability is generally greater in younger patients with job-threatening claudication than in more sedentary elderly individuals. For the elderly, the goal of intervention is frequently maintenance of sufficient ambulatory ability to live at home. Nehler and associates studied the impact of lower extremity revascularization for limb-threatening ischemia in 88 patients 80 or more years of age.[29] These investigators found that 80% of those with a patent graft were ambulatory and living at home whereas 67% of those who sustained graft occlusion required amputation and transfer to a nursing home. The assessment of functional status, perceived health, psychological well-being, and rolefunctioning provide invaluable insight for the physician into the specific manifestations of the patient’s vascular disease and the impact of this disease and therapy upon the patient’s life and level of functioning. Other tools have been developed for the evaluation of patient choices, the impact of these choices on overall health, and the costs involved. Used largely for research, three wellestablished tools include the standard gamble,[30] the time

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Figure 12-1. General health status in patients with claudication (dark bars) and without claudication (light bars) as measured by the RAND-36. Note that although the major symptom of claudication is simply calf discomfort with walking some distance, this vascular problem has a pervasive effect upon the overall health status. (From Bosch and Hunink.[24])

tradeoff,[31] and the rating scale.[32] The standard gamble asks patients to choose between an assured intermediate outcome and a gamble between a bad outcome and a good outcome. The time tradeoff requests that a patient choose between a period of time at his/her current health state and an improved health state for fewer years. The rating scale asks the patient to rate his/her health status on a scale of 0 (death) to 100 (perfect health). Quality-adjusted life years is an outcome measure that combines both quantity of life and quality of life values into a single number.[33] Such a patient-based assessment generally uses a 0 (death) – 1 (perfect health) scale from which the patient identifies his/her health state. It is possible to track the patient’s changes in health state over the years subsequent to treatment to determine quality-adjusted life years as depicted in Fig. 12-2. These valuational tools are useful for tracking overall patient health states, the impact of clinical decision making, and the economic burden of treatments. Few are applicable to the assessment of a specific patient.

GENERIC OUTCOMES ASSESSMENT TOOLS There are currently several survey instruments developed in the United States and elsewhere which are capable of assessing functional ability, perceived health, psychological well-being, and role functioning (Table 12-1). Each of these broadly applied instruments has demonstrated both reliability and validity, which are essential properties for the acquisition of meaningful information. Reliability refers to the consistency of measurement of each question within the survey tool. In simplest terms, a reliable question will be answered in

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Figure 12-2. Outcome assessment in claudication.

the same way by most individuals who have the same overall health condition. Answers should be consistent if no changes in the patient’s health condition occur. A reliability measure of 1.0 indicates complete consistency. Many of the current tools, such as the SF-36, have a reliability measure of 0.85 or more.[34] Validity implies that each question actually measures what is intended and that the answers to similar questions are consistent. In the absence of a change in the patient’s condition, answers to specific questions in surveys administered over time should be the same. Assessment of validity is increased through the use of multiple questions on the same topic. The SF-36 is the most commonly used health assessment tool in the United States and has demonstrated excellent reliability and validity in the study of broad populations of patients. This generic quality of life instrument encompasses eight health dimensions (Table 12-2). Each of these dimensions can be interpreted separately. These measures are significantly affected by symptomatic vascular disease, such as claudication (Fig. 12-1). Because the design of the instrument is generic, it does not directly assess the specific impact of vascular disease but of all the co-morbid conditions that accompany it. For example, the successful treatment of claudication in the setting of worsening cardiac function may yield evidence of deterioration of general health status. As with other generic health assessment tools, the SF-36 scores may be affected by patient age.[35] Disease-specific instruments, therefore, are required to specifically identify the impact of therapy.

DISEASE-SPECIFIC INSTRUMENTS There are few disease-specific instruments for the measurement of vascular disease and its treatment. Those that have been constructed and validated involve the assessment of claudication. The most widely utilized is the Walking Impairment Questionnaire (WIQ), which has been designed to elicit information regarding the severity of discomfort experienced while walking, the reason for difficulty walking, walking distance and speed, and stair climbing.[36] The usefulness of this instrument for the assessment of treatment of claudication has been demonstrated in studies of exercise therapy for claudication in which the WIQ scores for walking distances and speed have improved in conjunction with increased treadmill walking distances. Evaluating severe claudicants before and after participation in a supervised exercise training program, Regensteiner and colleagues noted that after 24 weeks WIQ scores improved commensurate with increased treadmill walking distance.[37] There are no validated disease-specific instruments to evaluate the impact of limb-threatening ischemia and its treatment. Also lacking are disease-specific instruments for the evaluation of treatment of critical, asymptomatic vascular disease, such as carotid artery stenosis or abdominal aortic Medical Outcomes Study 36-Item Health Survey (SF-36)

Table 12-2.

Areas of assessment Table 12-1. Generic Quality of Life Instruments Nottingham health profile[38] EuroQol[39] Sickness impact profile[20] Medical outcomes study SF-36[22] Quality of well-being scale[40]

Perception of health Psychological well-being Role limitations due to physical health problems Role limitations due to mental health problems Physical function Social relations Pain Fatigue

Chapter 12.

aneurysm. The development of instruments capable of identifying the benefits and adverse effects of treatment on these asymptomatic vascular problems is essential to vascular surgery.

APPLICATION OF OUTCOMES ASSESSMENT IN VASCULAR SURGERY At this time, practical application of outcomes assessment tools for the vascular surgeon is limited to the claudicant. Because the effect of treatment on the overall status of the patient does not directly correlate with improvement in clinical parameters, a more complete set of endpoints must be used (Table 12-3). The clinical results of any intervention for intermittent claudication should be documented through postrevascularization ankle-brachial indices and imaging studies which detail the area of intervention. A reduction in anklebrachial index should be correlated with the images of the treated segment to determine whether a reduction in index has been caused by problems within the treated segment or by progressive disease proximal or distal to the segment. Additionally, success of an intervention should be associated with an improvement in walking ability, an increase in WIQ score, and improvement in SF-36 scores. Only in this way can the benefit of palliative vascular surgical intervention for the treatment of patients with lower extremity ischemia be clearly demonstrated.

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Recommended Parameters for the Evaluation of Lower Extremity Ischemia and Its Treatment

Table 12-3.

Standard clinical parameters Technical success Morbidity Mortality Vascular examination Ankle-brachial indices Patency of treated arterial segment Changes in walking distance as measured by a treadmill protocol Changes in symptom severity by Rutherford classification Walking impairment questionnaire scores prior to and after treatment SF-36 quality of life scores prior to and after treatment

CONCLUSION Vascular surgical intervention is directed toward improvement in the patient’s quality of life. There are now wellestablished instruments for the assessment of quality of life. Utilization of such tools by physicians is simple and important for the analysis of all forms of palliative treatments of vascular disease. Only in this way can the benefits and adverse effects of intervention on patient quality of life and functional status be adequately documented.

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18. Nicoloff, A.D.; Taylor, L.M.; McLafferty, R.B. et al. Patient Recovery After Infrainguinal Bypass Grafting for Limb Salvage. J. Vasc. Surg. 1998, 27, 256– 263. 19. Fowler, F.J. Using Patients’ Reports to Evaluate Medical Outcomes. U.S. Congress Office of Technology Assessment, Tools for Evaluating Health Technologies: Five Background Papers; BP-H-142, U.S. Government Printing Office: Washington, DC, 1995;. 20. Bergner, M.; Bobbitt, R.A.; Carter, W.B. et al. The Sickness Impact Profile: Development and Final Revision of a Health Status Measure. Med. Care 1981, 19, 787– 805. 21. Brook, R.H.; Ware, J.E.; Davies-Avery, A. et al. Conceptualization and Measurement of Health for Adults in the Health Insurance Study: Vol. VIII—Overview; Publication No. R-1987/8-HEW, RAND Corp.: Santa Monica, CA, 1987;. 22. Ware, J.E.; Sherbourne, C.D. The MOS 36-Item ShortForm Health Survey SF-36-I: Conceptual Framework and Item Selection. Med. Care 1992, 30, 473– 483. 23. Stewart, A.L.; Greenfield, S.; Hays, R.D. et al. Functional Status and Well-Being of Patients with Chronic Conditions. J. Am. Med. Assoc. 1989, 262, 907– 913. 24. Bosch, J.L.; Hunink, M.G.M. The Relationship Between Descriptive and Valuational Quality-of-Life Measures in Patients with Intermittent Claudication. Med. Decis. Making 1996, 16, 217– 225. 25. Cook, T.A.; Galland, R.B. Quality of Life Changes After Angioplasty for Claudication: Medium-Term Results Affected by Co-morbid Conditions. Cardiovasc. Surg. 1997, 5, 424– 426. 26. Duggan, M.M.; Woodson, J.; Scott, T.E. et al. Functional Outcomes in Limb Salvage Vascular Surgery. Am. J. Surg. 1994, 168, 188– 191. 27. Agewall, S.; Fagerberg, B.; Dahlof, C.; Wikstrand, J. Negative Feelings (Discontent) Predict Progress of IntimaMedia Thickness of the Common Carotid Artery in Treated Hypertensive Men at High Cardiovascular Risk. Am. J. Hypertens. 1996, 9, 545– 550. 28. Thompson, M.M.; Sayers, R.D.; Reid, M. et al. Quality of Life Following Infragenicular Bypass and Lower Limb

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Amputation. Eur. J. Vasc. Endovasc. Surg. 1995, 9, 310– 313. Nehler, M.R.; Moneta, G.L.; Edwards, J.M. et al. Surgery for Chronic Lower Extremity Ischemia in Patients Eighty or More Years of Age: Operative Results and Assessment of Postoperative Independence. J. Vasc. Surg. 1993, 18, 618– 624. Torrance, G.W. Measurement of Health State Utilities for Economic Appraisal. J. Health Econ. 1986, 5, 1 – 30. Torrance, G.W. A Utility Maximization Model for Evaluation of Health Care Programs. Health Serv. Res. 1972, 7, 118– 133. Froberg, D.G.; Kane, R.L. Methodology for Measuring Health-State Preferences—II: Scaling Methods. J. Clin. Epidemiol. 1989, 42, 459– 471. Gold, M.R.; Siegel, J.E.; Russel, L.B.; Weinstein, M.C. Cost-Effectiveness in Health and Medicine; Oxford University Press: New York, 1996. Andrews, F.M.; Withey, S.B. Social Indicators of WellBeing: Americans’ Perceptions of Life Quality; Plenum Press: New York, 1976. Bartment, B.A.; Revicki, D.A.; Hochberg, M. et al. Relationship Between Health Status and Utility Measures in Older Claudicants. Qual. Life Res. 1998, 7, 67– 73. Regensteiner, J.G.; Steiner, J.F.; Panzer, R.J.; Hiatt, W.R. Evaluation of Walking Impairment by Questionnaire in Patients with Peripheral Arterial Disease. J. Vasc. Med. Biol. 1990, 2, 142– 152. Regensteiner, J.G.; Steiner, J.F.; Hiatt, W.R. Exercise Training Improves Functional Status in Patients with Peripheral Arterial Disease. J. Vasc. Surg. 1996, 23, 104– 115. Hunt, S.M.; McEwen, J.; McKenna, S.P., (Eds.) Measuring Health Status; Croom Helm: Dover, NH, 1986. EuroQol Group; EuroQol—A New Facility for the Measurement of Health-Related Quality of Life. Health Policy 1990, 16, 199– 208. Kaplan, R.M.; Bush, J.W. Health-Related Quality of Life Measurement for Evaluation and Research and Policy Analysis. Health Psych. 1982, 1, 61– 71.

CHAPTER 13

Computers and Vascular Surgery Richard F. Kempczinski frame computers utilizing the UNIX operating system and “dumb” terminals, most users rely on PCs incorporating the Intel Pentium IV processor running Windows XP (WinTel). A small but devoted minority prefer the Apple Macintosh, which incorporates the Motorola Power PCe chip and is able to run both Apple and IBM software. Since the author has no personal experience with this type of system, the subsequent discussion will focus on the most common WinTel system mentioned above. Hardware is usually the first hurdle the novice computer user must overcome when getting started. However, a good piece of advice that still applies even today is “to first decide what you want to do with your computer and then buy the hardware that best serves that purpose.” Every PC has a “mother board” containing the main processor (the Pentium IV chip), the computer’s volatile, random access memory (RAM), and a variable number of accessory boards depending on the peripheral devices attached to the machine. This integrated system is known as the central processing unit (CPU). There will also be devices for inputting data into the computer, typically a keyboard and a mouse or track-ball. Finally, a monitor is required to visualize the computer’s activity. Additional peripherals attached to most PCs include a printer, speakers, a fax/modem, a scanner, and a microphone. The cost of a complete system keeps coming down. It is generally quite easy to find a powerful system from a reputable manufacturer for less than $2,000. Such a system would typically include the Pentium IV chip running at 2 GHz Gigahertz with at least 512 megabytes (MB) of RAM. Given the size of most major software programs today, 20 gigabytes (GB) of hard disk storage space should be available. The choice of a suitable monitor is a balance between screen size and cost. Given the amount of time you will spend staring at the screen, I would recommend nothing smaller than 15 inches. A 17- or even 21-inch screen may be a worthwhile investment for users facing presbyopia but wishing to avoid the necessity for eyeglasses while using the computer. An internal fax/modem is usually part of most PCs, and current, top-of-the-line machines are being delivered with 56 kilobits (Kbps) modems. These devices are indeed capable of transferring data across the Internet at the rate of 56 Kbps

INTRODUCTION After the International Business Machine Co. (IBM) introduced their “personal computer” (PC) in 1981, computers began sporadically appearing in the offices of some vascular surgeons, where they were generally used for wordprocessing and to a much lesser extent, database management, spreadsheets and communication. This trend received an added boost several years later with the introduction of the graphical user interface called Windowse. However, it was not until 1992 with the emergence of the Internet that the real potential of computers in vascular surgery became apparent and they began appearing in the homes and offices of even the most confirmed computer phobics. In response to this interest and recognizing the potential opportunity to improve communications between vascular surgeons around the world, the Joint Council of the Society for Vascular Surgery and the American Association for Vascular Surgery decided in 1996 to create a home page on the World Wide Web (WWW). By combining the rosters of these two societies with those of all the major regional vascular societies and other affiliated national organizations, a large relational database of vascular surgeons was created as the nucleus for the “page.” Each society was then assigned its own “subpage” and encouraged to be as creative as its needs required. Two years later, the Association of Program Directors in Vascular Surgery mandated regular access of the home page [www.vascularweb.org] by its trainees to ensure that the next generation of vascular surgeons would be cognizant of and comfortable with the potential benefits of computers in their practice. This chapter will review the current status of PCs and will suggest how vascular surgeons might best use this new technology. We will also examine the most popular applications, with a particular emphasis on the Internet.

COMPUTER BASICS Although some academic vascular surgeons and members of large, multispecialty practices might have access to main-

Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024896 Copyright q 2004 by Marcel Dekker, Inc.

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(kilobits per second). However, due to FCC rules that limit power output, current download (receiving information from the Internet) speeds are restricted to 53 Kbps and upload (sending information to the Internet) speeds are limited to 33.6 Kbps. In addition, actual speed may differ significantly depending on the local phone line and Internet traffic. As Internet access becomes increasingly part of the cable service users receive in their homes, line speed will no longer be the limiting factor and the modem can truly perform up to its potential. Some type of backup system is essential for every computer. It’s not a question of whether your system will ever “crash,” but when! A number of manufacturers offer tape systems capable of backing up more than 2 GB on a single tape. Although this operation might take 10– 15 hours, it only needs to be performed periodically, depending on how often major changes are made in your software, and can easily be run overnight. Most PC’s offer inexpensive, optional Iomega built-in zip drives which can back up 250 MB (Megabytes) of data on a single cartridge rapidly and conveniently. These are usually more than adequate to back up individual, and important programs on a daily basis and are highly recommended. The first time your hard drive crashes and you have to restore your computer without a backup, you will be kicking yourself for failing to take this simple precaution. As an alternative to tape which is slow, there are now writable CD drives which feature “removable media” that can be stored away from your computer and used to restore your files following a system crash. Software is the set of instructions that tells the computer how to perform its various functions. First, you will need an operating system, such as Windows XP, which tells the computer how to interact with each of its peripheral devices and with the different programs it will be running. Then, a specific application program will be required for each task the computer is expected to perform, e.g., wordprocessing, database management, spreadsheets/financial management, graphics and communications. The last of these, i.e., communications, is particularly challenging because it brings together computers and peripheral devices, such as modems, cable or telephone connections, usually from different manufacturers and attempts to make them work smoothly together while abiding by certain rules, or protocols, established by a third party, the “line provider.” Because today’s PCs are so powerful and the software programs are generally so well integrated under the operating system, it is possible to run several programs simultaneously. This ability, called multitasking, is limited by the amount of available RAM. Thus, it is generally advisable to have no less than 256 MB of RAM in your machine, but to paraphrase Gloria Vanderbilt’s famous aphorism, “you can never be too thin or too rich,” you can never have too much RAM!

APPLICATIONS Generally, each specific application, or task, requires its own software. However, certain “integrated” programs such as Microsoft Officew or Corel Office Suitew bundle together several programs, typically a wordprocessor, spreadsheet,

graphics program and database manager, into a coherent package that features a consistent interface and easier movement of data between programs. Computer software develops so quickly that it would be impractical and unfair of me to recommend specific programs within each category, especially since I have not personally worked with all of the programs currently on the market. However, I intend to describe the types of software which might be of interest to vascular surgeons and mention the most popular programs in each category. Although even the most complex programs now come with excellent online help, the quality of technical support each developer provides can be quite variable, and it is usually a good idea for novice users to choose programs for which local help is available. There’s nothing more frustrating than settling down in front of your home computer after a long day and then having your program stubbornly refuse to perform some simple task.

Wordprocessing This is probably the most widely used computer application. From simple tasks, such as the composition of individual letters or documents, to more complicated projects like the creation of multipage documents with tables, footnotes and references, every aspect of text processing is facilitated by these programs. When it comes to form letters, merge documents, newsletters, etc., there is simply no practical way to perform these tasks without computers. Although most vascular surgeons have a computer on their secretary’s desk running one of these programs, few have any personal experience working with them. With all the recent interest in the Internet, most of the current wordprocessing programs include the ability to prepare documents in hypertext markup language (HTML) for posting directly online. The most popular programs in this category are Microsoft Wordw and Corel WordPerfectw. For individuals who are not facile typists, voice activated programs such as Dragon System’s Naturally Speaking are capable of transcribing spoken text directly into most word processing programs at greater then 150 words per minute with an accuracy exceeding 90% and greatly facilitate data entry into such programs.

Database Management This is another very important computer application for the vascular surgeon. Even vascular surgeons in private practice who have no intention of reviewing their clinical experience for publication must keep track of their cases and results in order to honestly develop their own set of personal indications and to satisfy the demands of hospital credentialing committees and various certifying boards. Using any of the current database programs, such as Microsoft Accessw, it is easy to store all the relevant information on each case and to retrieve it in a usable fashion, when necessary. Similarly, one could also store references to the vascular literature[1] or organize the retrieval and reporting of vascular laboratory data.[2]

Chapter 13. Computers and Vascular Surgery

Spreadsheets Spreadsheets, such as Microsoft Excelw or Lotus 1-2-3w, are primarily intended for the storage and manipulation on numeric data, such as budgets or research data. In fact, it was the development of Lotus 1-2-3 that is credited with transforming PCs from mere toys intended primarily for playing games into serious business machines. Although you could develop and manage your personal finances with one of these programs, the same task is much more easily accomplished with specific financial management software, such as Microsoft Moneyw or Quickenw. Because so much financial information is available on the Internet and because many banks now permit their depositors to access their accounts online and to download account balances directly into their home computers, it is important to choose a program that automates these operations and works smoothly with the software supplied by your Internet provider.

Communications This software falls into two broad categories. One group of programs allows your computer to scan and fax information over the phone lines or, if your computer is equipped with an appropriate microphone, to actually use your computer as a alternative telephone. A second group is specifically designed for accessing the Internet. Included in this category would be software programs supplied by the Internet provider you select. This software must include a program to connect your computer via the modem with the Internet provider’s server, which, in turn, is physically linked, or hard-wired, to the Internet. If your computer is already so linked, you do not need either a modem or this type of software. However, if you are going to search for and download information or receive email via the Internet, you must have an Internet “browser,” such as Microsoft Internet Explorerw or Netscape Navigatorw. These programs have the ability to store your most frequently visited Internet sites as “bookmarks,” to develop and maintain an address book of email addresses and to download, organize and store your email. Usually, one of the two programs mentioned above will be included with the software you receive from your Internet provider, and although it is usually possible to substitute one for the other, it is generally a good idea to go with the program supplied by your Internet provider, unless you have a strong preference for the competing program. Although there are separate programs, such as Microsoft Outlook or Outlook Expresse, that are specifically designed to manage your email, the simple program included in your Web browser will usually be more than adequate.

Miscellaneous For surgeons who really want to immerse themselves in the digital revolution, there are pocket-sized, digital “assistants,” such as the Palm Pilot, which can store 128 kilobytes (KB) or more of information, such as telephone numbers, daily schedules, reminders, etc. They can be linked to the computer on your secretary’s desk via a small cable and updated at the end of each day with the following day’s activities. Many of

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them are small enough to fit in a shirt pocket and are equipped with small, internal alarms that sound to remind you of imminent meetings or important dates.

THE INTERNET Basic Considerations The Internet began more than a quarter of a century ago as a network of Defense Department computers which was designed to maintain critical communication links, even in the face of a possible nuclear war. Of all its component parts, none has captured the public’s interest more than the World Wide Web, which facilitated the posting and retrieving of information from around the world. Although it was originally conceived as a way for scientists to share data, it now contains information on virtually every imaginable subject. In 1992, the WWW was pushed into the spotlight when the National Center for Supercomputing Applications at the University of Illinois developed Mosaic, a software application that recognized graphics elements and dynamic links embedded directly within Web documents. This software program was the prototype for Netscape Navigator, the Web browser which opened the “information highway” to the general computing public. The power and unique appeal of the Internet derives from several important features. First, hypertext markup language, the language of the Internet, can be understood by most computers currently on the market, thus opening the Web to virtually every machine currently in use. Second, the ability to embed hypertext links within text documents on the Web allows the developers of each site to enrich them with virtually transparent links it to other “pages” within that site or anywhere on the Internet! These links usually appear within the document in a different colored font and are underlined. This gives each site on the Internet a potential richness and complexity usually lacking in two-dimensional documents. Finally, the incorporation of graphic elements (photographs, video clips, audio, animation, etc.) within documents can make them so visually appealing that it has released a creative energy within the Internet that is unmatched in a medium with such immediacy. Because there is so much information available on the Internet, some type of search “engine” is essential if you are going to find what you are looking for. Fortunately, a number of excellent search engines, such as Yahoow, Excitew, Googlew, Infoseekw, Alta Vistaw, and Lykosw, are all available, free of charge, and compete for your business, so there’s usually no problem finding what you are looking for. In fact, the opposite is usually the case, namely you find so many sites that fit your search criteria that winnowing through them becomes the challenge. As you refine your search techniques, your “net browsing” will become much more efficient. Before you venture too far, bear in mind that there is no one charged with the responsibility of policing the Internet or assuring the accuracy of any of the information contained on

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it, so Websurfer beware! There are several general standards you should hold up against data you need to trust. First, the source, or author, of that data should be clearly identified. Second, the date the information was posted should be listed, and finally, if matters of fact are stated, their source should be referenced. The unit of the Internet is a “page.” Since each page that contains information or graphic elements is a discrete, digital file, it has an “address” or uniform resource locator (URL) that precisely pinpoints its place on the Internet. Therefore, it is possible to interconnect all the documents that relate to a particular subject by embedding their URLs within the HTML coding of that document. One might compare this to the myriad, cellular interconnections that occur within the cerebral cortex in response to stimuli and which gives the brain its richness and complexity. To better understand URLs, let’s take a closer look at the Internet address for the vascular home page: http://www.vascweb.org Although this might, at first, seem like gibberish, it follows a precise protocol that is easily decipherable. “http” stands for hypertext transfer protocol and indicates the rules, that we will be expected to follow. “www” stands, as you know, for the World Wide Web and defines that portion of the Internet we will be using. “vascweb” is the unique, registered name for our site. Finally, the extender “org” describes the nature of the site, namely an organization. Some other common extensions that you might see here are: “com” for commercial sites; “edu” for educational sites; and “gov” for governmental sites. To go to any location on the Internet, you merely enter the URL for that site into a “location” box on your Internet browser and hit the , ENTER . key on your computer. If you identify a site that you might want to visit in the future, you can store its URL as a “bookmark” in your browser software. From within the Internet, other related sites can be accessed by merely clicking on the imbedded hypertext links, which are indicated by the change (from an arrow to a hand) in the shape of your mouse cursor when it passes over the word. For someone who has never visited the Internet and especially for someone who is a computer novice and may be a little intimidated by the strange computer jargon and technology, the immediate question that must come to mind is “why should I go to all this trouble to visit a place that I didn’t even know existed until a year or two ago and without which I got along perfectly well all my life?” The answer to that question will differ for each potential Websurfer, but for a vascular surgeon, I would suggest the following reply: “to communicate quickly and efficiently with your colleagues around the world and to get information that is largely unavailable any other way.” Email allows virtually instantaneous communication with your colleagues anywhere in the world. Most Web browsers have email components that automatically insert return addresses and allow mail to be saved, forwarded, etc. With digital address books, storing, retrieving and using a colleague’s email address is far simpler than conventional mail and you can post your communication

any time of the day, 7 days a week. Similarly, retrieving and reading your email can be performed at your convenience. Although each email address is unique, they follow a recognized convention, similar to that used for URLs. Let’s examine my email address as an example. E-mail: [email protected] The “@” separates the address into two parts: to its left we have the “user name or user ID” and to its right we have the “domain” which identifies the file server where that individual receives his/her email. In my case, it’s the local phone company which calls their Internet service “fuse.” The terminal extender “net” identifies this server as a network. These are identical to the terms we used in categorizing URLs, thus “com” stands for a commercial server, “edu” signifies an educational computer, etc. Depending on the naming convention observed on that server, the user name is typically some contraction of the individual’s name, usually in a lowercase font, with quotation marks used to separate words rather than spaces, which are not allowed. If individuals use common sense in choosing their user name, their email address is usually quite simple and descriptive. The ability to attach digital files to an email is a great way to share larger documents and graphic images with colleagues around the world. When a document or manuscript is being prepared by several colleagues in different locations, the electronic wordprocessing file can be passed back and forth, revised and finalized without ever generating a hard copy. For vascular surgeons who are uncomfortable using a keyboard to type their email, there are several “voice recognition” programs which, after a brief training period, can recognize your voice and type your continuous speech directly into your email editor. They do require that your computer be equipped with an appropriate microphone and that your sound card be able to receive input, but the hidden benefit they bring to the process is synchronous spell checking! Because text is entered as whole words, these programs never misspell words already programmed into their extensive vocabularies, although they still have problems with homonyms. Furthermore, new words can be spelled into their vocabularies and memorized so that the next time they are used, they appear automatically. They also accept macros which allow you to store several steps or longer phrases as single word commands thus expediting the whole process of using computers. For example, this chapter was completely prepared, without any manual typing, using a program called Dragon-Dictate for Windowsw.

Communicating with the Vascular Societies’ Administrative Office In the very near future, it will be possible to submit abstracts for consideration by the Program Committee, to register for the annual meeting or to pay your membership dues online. Of course, email communication is always available, night or day. In the reverse direction, if individuals keep their personal listings in the roster database up to date, it will be possible for the Association Offices to send a “broadcast” email to every

Chapter 13. Computers and Vascular Surgery

vascular surgeon in the registry with a few clicks of the mouse. This potentially could be very important in alerting members to unfavorable legislative actions being considered or mobilizing a response from the vascular surgical community, when needed.

Searching for Data Regardless of whether you are looking for a reference in Medline, the contents of an abstract that is going to be presented at an upcoming meeting, the exact dates of a future vascular meeting or the membership requirements for the Western Vascular Society, a wealth of information can now be at your fingertips, night or day! The individual physician database which lies at the heart of Vascular Societies’ home page contains the names, addresses, phone & fax numbers, email addresses, photos and CVs of every member of all the affiliated societies. Since these data are arranged as a relational database, it is searchable by name, location, society, etc. This potentially represents the most comprehensive listing of vascular surgeons in the world and is a valuable demographic resource for our profession. As more and more vascular organizations develop their own Web pages, hypertext links on our home page can quickly take you to other sites of interest such as the Endovascular Forum or the home page for the Inter Societal Commission for the Accreditation of Vascular Laboratories.

Vascular Home Page In June 1996, the Joint Council of the Society for Vascular Surgery (SVS) and the North American Chapter of the International Society for Cardiovascular Surgery (NAISCVS)

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approved the creation of a home page on the World Wide Web that would bring together all the affiliated vascular societies and facilitate communication by vascular surgeons amongst themselves and with the Societies’ administrative offices. Demographic information from the membership rosters of all affiliated vascular societies was combined into a single, searchable, relational database. Subsequently, similar information was collected from the vascular residents in all approved and freestanding training programs in the United States and Canada and a registration form was designed to allow “Guest Physicians” from around the world to add their demographic information to the database. A standardized interface was created for each of the related vascular societies which were encouraged to populate their home page with up-to-date information on their history, officers, organizational structure, membership requirements, annual scientific meeting, etc. A full-text version of the Journal of Vascular Surgery (JVS) was linked to the site and a search engine was developed so all members could interrogate the Medline database as well as the JVS. Hypertext links were created to a large number of related sites which might be of potential interest to vascular surgeons. Although the exact appearance will differ slightly depending on your Web browser and the resolution of your monitor, most users will see an opening screen that looks something like Fig. 13-1 when they first logon. Let’s explore the website in greater detail and demonstrate how it might be used by a busy vascular surgeon. There are three distinct “areas” to the opening screen: a raised “power bar” across the top; a “button bar” down the left side; and the large central area of the screen. The power bar contains links to major vascular sites not directly controlled by the vascular societies themselves. The button bar features links to the major subdivisions of the vascular societies

Figure 13-1. Opening screen of vascular home page.

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Affiliated Vascular Societies That Have Linked Pages on the Vascular

Website American Venous Forum Canadian Society for Vascular Surgery Peripheral Vascular Surgery Society Society for Clinical Vascular Surgery Western Vascular Society

themselves, such as the Joint Council, the Lifeline Foundation, etc. The central area prominently features each of the two sponsoring societies and a link to a directory through which each of the affiliated societies can be reached (Table 13-1). What’s New is a great place to start each visit to the vascular website. It lists all new features that have been added to the page in the past month and contains hypertext links directly to those sites. In addition, whenever a site is significantly updated, a notice is posted here. By visiting this location first you will be certain not to miss any of the new and exciting features that are constantly being added.

Power Bar Currently, there are four power bars that take the user to other areas which should be of significant interest to most vascular surgeons. The first of these is the Journal of Vascular Surgery site. This site offers to subscribers the full text of the Journal online as well as a search engine that allows you to look for any text string and to focus your search on the title, the abstract or the entire text. Although the full text version is

Eastern Vascular Society Midwestern Vascular Surgical Society New England Society for Vascular Surgery Southern Association for Vascular Surgery

only available beginning with 1997, the abstracts for previous years are online. The Association of Program Directors in Vascular Surgery site offers a complete listing of all programs currently approved by the Residency Review Committee for Surgery to provide training in vascular surgery and permits downloading of several extensive documents which would be useful to individual vascular program directors, such as the “Vascular Laboratory Syllabus” (Fig. 13-2). Notice in the upper, left corner of every page “below” the opening screen a Home button. This is intended to facilitate navigation within the website and will take the visitor back to the opening screen with a single click of the mouse button. The Physician Database link provides access to the search engine which allows you to look into the entire database or to focus your member search on a single society (Table 13-2). You can then search for an individual by name or look for all members residing in a particular city, state, etc. In addition, each member, after entering the appropriate user ID and password, can access the individual “page” and update the demographic information in their own records. If members regularly update their records, as necessary, the roster information can be much more accurate than presently possible using conventional techniques.

Figure 13-2. Home page for Association of Program Directors in Vascular Surgery.

Chapter 13. Computers and Vascular Surgery Table 13-2. Categories of “Related Links”

Available Through the Vascular Home Page Other vascular societies Departments and divisions of vascular surgery Journals Evolving vascular technology Major vascular concerns Additional vascular surgery links Government sites Medical decision support Patient support groups General medical information

The Medline link will be described in greater detail below.

Button Bar The Welcome button is a good choice for first-time visitors to the website. It describes the rationale behind the site and directs laypeople to those areas specifically designed for them. The Joint Council page contains an up-to-date, complete list of the current members with hypertext links to their email address thus expediting communication with any member of the Council. It also contains a comprehensive list of all position papers commissioned by the Council and its “Issues & Answers” forum usually posts items of topical interest to vascular surgery. The Annual Meeting brings together on one page links to the annual scientific meeting of the SVS/AAVS. In addition to the current meeting, the dates and location for further meetings are available. Abstracts, posters and the research forum for the meeting are posted as soon as they are chosen by the program committee, which is usually several months prior to their availability through any other means. A complete section was devoted to Research Forum because of its importance to the future of vascular surgery. The complete program of the Research Initiatives Forum is posted each year. There is also a comprehensive section for young researchers giving advice on how to secure research grants with a detailed listing of potential funding sources and the latest deadlines for posting applications. The Lifeline Foundation page lists the current composition of the board and posts the annual recipients who have been chosen to receive research support from the foundation. A comprehensive list of all recent donors is available online and plans are being made to permit online contributions. The Clinical Case Forum features the “Case of the Month” which will be prepared monthly by one of the approved vascular training programs. In addition to a challenging clinical problem, there will be interactive questions through which visitors can compare their management of the case with that of the submitting service and receive feedback on how other respondents would have proceeded. The submitting service will prepare a referenced discussion of each case and the completed cases will be catalogued in a “Teaching Collection” for use by future vascular trainees. We are also planning a mechanism whereby physicians could post

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challenging clinical problems from their own practices and request consultation from colleagues around the world. This could be an extremely popular and unique “consulting service” for uncommon or complicated vascular problems. Frequently Asked Questions are intended for laypeople visiting our website and contains answers to the questions most often asked by our patients in terms they can understand. The list of questions is flexible and visitors are invited to post additional, new questions for future discussion, as long as they are likely to be of widespread interest. Finally, a link is provided for Feedback to the Webmaster in the form of a link to his/her email. Comments on the website, corrections of errors and suggestions for future additions to the page are all welcome.

Future Enhancements The website is a dynamic place that is constantly updating and changing. Hopefully, by the time this chapter is published, we will have added a Calendar of Meetings on which will be posted a complete listing of all meetings around the country offering Continuing Medical Education credits. Each listing will be hypertext linked to individual subpages describing the location, faculty and content of that meeting. We are also planning a Job Opportunity page on which will be posted all vascular job offerings advertised in the Journal of Vascular Surgery. These will be in the form of a searchable relational database which will allow interested job seekers to search by location, type of job (academic vs. private practice), etc. Since this chapter was written the “look of” the vascular website has been redesigned, although all the previously described features are still available. A great advantage of the internet is the ability to continuously modify and update our website to meet the needs of vascular surgeons.

Searching the Medical Literature During the past 30 years, there has been an explosion in the volume of published medical information. The development of the Internet as a highway for worldwide communication, and the emergence of the WWW as a common vehicle for communication have made instantaneous access to much of the entire body of medical information an exciting possibility. The National Library of Medicine (NLM) maintains MEDLINE, a comprehensive, cross-referenced database of citations to the medical literature covering 1966 to the present. Unfortunately, MEDLINE currently contains only abstracts of the medical literature, not the complete text of the articles. In 1996, the NLM began providing free, unlimited access to MEDLINE to all Americans over the World Wide Web. As the volume of cost-free medical information has increased, so has the need for efficient methods for searching the data.[3] Presently, MEDLINE is manually indexed with NLM’s Medical Subject Heading (MeSH) vocabulary. MEDLINE searches use AND/OR/NOT logical searching for “keywords” that have been assigned to each article and for “textwords” included in article abstracts. Using MeSH, a searcher can potentially create powerful and unambiguous

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MEDLINE queries. However, in order to get maximum productivity from your searches, you should be familiar with the MeSH vocabulary. Lowe and Barnett reviewed the structure and use of MeSH, directed toward the nonexpert, and outlined how MeSH may help resolve a number of common difficulties encountered when searching MEDLINE.[4] Recently, the complete text of some scientific journals, including figures and tables, has become accessible electronically. The vascular home page offers two methods for searching MEDLINE. The first is through PubMed, a free, simple search engine created by the National Library of Medicine that can quickly search the 9 million citations it indexes. The second is a search engine developed by Community of Science, the Baltimore-based Internet development company that has been hired by the Joint Council to support the development and maintenance of their website. Both are accessed through the “MEDLINE” link on the Power Bar. Grateful Med is a computer software package developed by the National Library of Medicine which provides access to MEDLINE and other medical databases.[5] The program is available for both IBM and Macintosh computers, is inexpensive, easy to install and has excellent documentation. Health professional in all areas find Grateful Med to be a userfriendly, cost-effective way to search current, worldwide medical literature. The full text of Journal of Vascular Surgery recently became available on CD-ROM. Once several years are available, this will be an alternate way to quickly search the medical literature on vascular topics since most of the important articles on vascular disease are contained in this publication. The advantages of this type of search are its speed and simplicity. However, its effectiveness will depend on the quality of the search engine provided by Mosby. In a study comparing the effectiveness and speed of searching the medical literature via CD-ROM versus the Internet, Smith et al. found a CD-ROM MEDLINE literature search took 60 minutes to find 31 articles (43% of the possible articles) compared with an online search to the Bibliographic Retrieval Services database in Chicago, which produced the same articles when MEDLINE was searched (but took only 16 minutes).[6] When Excerpta Medica was searched, they found 47 articles (with an overlap of only seven). They estimated that the combined MEDLINE and Excerpta Medica search detected 93% of all known relevant articles, based upon an assumed gold standard.

Eventually, conceptual searching in which the computer searches for related ideas, without having to be given all the related keywords, may become a reality. This will free the user from having to learn specific rules about searching, allowing energies to be focused on results of the search, not the search itself.

CONCLUSIONS Following the introduction of powerful, inexpensive personal computers and the development of an user-friendly, graphic interface, computers have become an inevitable part of everyday life and are present in the offices of most vascular surgeons. Because of the ever-growing demands on their time and all proliferation of labor-intensive record keeping, it is essential that all vascular surgeons become familiar with this new technology and take maximum advantage of its laborsaving potential. The Internet has opened up a highway on which vascular surgeons can easily and quickly communicate with their colleagues around the world and have access to medical information not easily obtained in any other way. In 1996, the Joint Council of the two major, national vascular societies created a home page on the World Wide Web. A larger relational database was formed by combining demographic information from the rosters of all affiliated vascular societies, and separate subpages were created for each of the societies on which they could post their annual scientific meetings, poster sessions, etc. Related hypertext links were created to most other major vascular sites on other servers, thus bringing the vascular medical “universe” together under one tent. Using tools provided on the vascular home page, it is now easy for vascular surgeons to access the medical literature quickly and efficiently 24 hours a day, 365 days a year. In addition, the availability of full-text Journal of Vascular Surgery online now makes it possible to search not just key words chosen by some medical librarian but every word that appears in the journal. The responsibility to learn how to use these powerful, new tools to improve the quality of care we provide our patients is no less real than would be our obligation to learn a new procedure for revascularizing the ischemic leg.

REFERENCES 1. Kempczinski, R.F. A Microcomputer-Based System for the Management of Vascular Surgical References. J. Vasc. Surg. 1987, 6, 542– 547. 2. Kempczinski, R.F. Computerized Data Management in the Vascular Non-invasive Laboratory. In The Noninvasive Vascular Laboratory: Current Issues and Clinical Developments; Auer, A.I., Neumyer, M.M., Eds.; Appleton Davies, Inc.: Norwalk, 2002; in press. 3. Kastin, S.; Wexler, J. Bioinformatics: Searching the Net. Semin. Nucl. Med. 1998, 28, 177– 187.

4. Lowe, H.J.; Barnett, G.O. Understanding and Using the Medical Subject Headings (MeSH) Vocabulary to Perform Literature Searches. J. Am. Med. Assoc. 1994, 271, 1103– 1108. 5. Horak, B.B.; Hamasu, C.C. Grateful Med: Gateway to World-Wide Literature. Hawaii Med. J. 1991, 50, 419–420. 6. Smith, B.J.; Darzins, P.J.; Quinn, M.; Heller, R.F. Modern Methods of Searching the Medical Literature. Med. J. Aust. 1992, 157, 603– 611.

CHAPTER 14

Medical Management of Atherosclerotic Vascular Disease Ralph G. DePalma Donna L. Kowallek† as well. Choices among alternatives for individual patients might appear to be superficially clear-cut, but instead are complex and require comprehensive knowledge of the natural history of particular lesions, surgical and endovascular options, and possible efficacy of nonoperative approaches.

Atherosclerosis is the disease most commonly treated by vascular surgeons. It is also the most common cause of morbidity and mortality in modern Western society, in spite of a decreasing cardiovascular mortality in the United States. Forty years ago, arteriosclerosis was believed to be an inevitable consequence of aging. Physicians considered it to be an inexorable arterial degeneration offering little hope for treatment. That atherosclerosis was segmental in nature and that diseased arteries could be treated by bypassing or removing lesions were uniquely surgical insights.[1] Surgical intervention is the most effective means of limiting the lethal consequences of aortic aneurysms, coronary artery disease, and carotid bifurcation plaques. However, atherosclerosis is also a systemic disease remaining dormant in arteries until a complication signals its presence. Operations on the cardiovascular system restore circulation, saving lives previously lost to aneurysmal rupture and limbs once lost to gangrene. With growing technical expertise, it is clear that life expectancy increases after surgical repair of aortic aneurysms and selected coronary lesions. However, a strictly surgical approach to treatment does not prevent disease progression. Life expectancy remains shortened, and many patients need additional vascular operations; about 12% will require another vascular procedure for the same problem that prompted the first operation.[2] Not only does atherosclerosis progress in native arteries, it also tends to occur in newly placed grafts.[3] This chapter discusses medical management of atherosclerotic disease. Surgeons are often required to choose among medical and surgical alternatives. Indeed, often a choice exists about recommending an operation or medical treatment. The surgeon plays a key role in postoperative recommendations

†

THE ATHEROSCLEROTIC PLAQUE Figure 14-1 depicts a typical fibrous plaque containing a central atheromatous core with a fibrous or fibromuscular cup, macrophage accumulation, and round-cell adventitial infiltration. The word atheroma is derived from a Greek word meaning porridge. Sclerosis means induration or hardening. These contrasting characteristics exist in varying degrees in distinct plaques, disease stages, and individuals. According to Haimovici et al.,[4] in 1755 Von Haller applied the term “atheroma” to the common type of plaque, which, on sectioning, exudes yellow pultaceous contents. DeBakey[5] provided a reference to show that such plaques were found in Egyptians as early as 1580 B.C. The plaques contain three components: cholesterol, mainly in the form of cholesterol esters; cells, mainly smooth muscle but also macrophages and other cell types; and fibrous proteins, mainly collagen, elastin, and proteoglycans. In advanced lesions, fibrin, blood components, and calcium also occur. Considerable lesion variability characterizes atherosclerosis. This variability is best illustrated in carotid atheromas.[6] Even in this limited and uniform site, plaques sometimes occur that exhibit mainly smooth-muscle cellular proliferation, collagen, and little fat. Such plaques contrast with commonly occurring carotid atheromas containing a core of friable lipid debris and blood elements. The variable compositional characteristics of atheromas in many sites probably account for difficulties in assessing the effects of treatment. Complicated plaques (i.e., fibrous plaques which

Deceased.

Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024897 Copyright q 2004 by Marcel Dekker, Inc.

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are calcified, ulcerated, or necrotic) are unstable. Thus, there can be dissection from the arterial wall, causing sudden occlusion, expansion due to hemorrhage within the plaque, or overlying thrombosis due to cap rupture, such as often occurs in coronary atheromas. Ulcerated carotid plaques can embolize the porridgelike core material into the brain and retina. It is not yet known whether or not medical therapy might stabilize such intrinsically unstable lesions. The development and role of the atherosclerotic core and its relationship to the cap have been recognized as causing complications. A recent insight[7] is the finding that the “core” develops in early lesions, accumulating in the deep aspects of very early plaques before these become actual fibrous plaques.

It is probable that there are several pathways leading to the lesion depicted in Fig. 14-1. For example, one etiologic hypothesis suggested a role for cytomegalovirus[10] in atherogenesis to explain the onset of abnormal cellular proliferation. Immunologic or mechanical endothelial injury might result in exposure of underlying smooth muscle to a variety of plasma and cellular components which trigger smooth muscle proliferation and subsequently cause lipid accumulation. However, since the early lesion found in children and created experimentally in animals is usually fatty, the most commonly accepted theory of evolution focuses on the entry of low-density lipoprotein (LDL) cholesterol into the arterial wall.

FATTY STREAKS PLAQUE EVOLUTION After long latency periods, atherosclerotic plaques progress through early and more advanced asymptomatic stages to become complicated lesions causing clinical events. The ultimate pathology of advanced atherosclerotic plaques tells little of these early evolutionary events. Stary and colleagues[8] have provided a comprehensive report defining initial fatty streaks and intermediate lesions of atherosclerosis as well as the cellular alterations in early lesions. The advanced lesions of atherosclerosis have also recently been clarified.[9] Pragmatically, the value of hypotheses relating to pathogenesis must be judged by the ability to predict measures that would prevent or control this process. It seems probable that measures to prevent initial plaque formation might be quite different from those later used to control established disease, though in any individual several evolutionary stages of lesions coexist.

Fatty streaks are gross, minimally raised, yellow lesions found frequently in the aorta of infants and children. These lesions contain lipids deposited intracellularly in macrophages and in smooth muscle cells. Type I lesions in children are the earliest microscopic lesions, consisting of an increase in intimal macrophages with the appearance of foam cells. Type II lesions are grossly visible; in contrast to type I lesions, type II lesions stain with Sudan III or IV. Fatty streaks are characterized by foam cells and lipid droplets, also in intimal smooth muscle cells, and heterogeneous droplets of extracellular lipids. Type III lesions are considered intermediate lesions; they are usually the bridge between the fatty streak and the prototypical atheromatous fibrous plaque, the type IV plaque (Fig. 14-1). Type III lesions occur in plaque expression – prone localities in the arterial tree,[11] that is, sites exposed to forces that cause increased LDL influx, particularly low shear

Figure 14-1. Schematic of a typical atheroma. Note central lipid core, fibrous cap, accumulation of macrophages, and zone of synthetically active smooth muscle at the “shoulders” of the core. Note tendency of the media to bulge outward, adventitial neovascularization, and lymphocytic infiltration. (From DePalma, R.G.: Pathology of Atheromas. In Bell, P.R.F.; Jamieson, C.W.; Ruckley, C.V. (eds): Surgical Management of Vascular Disease. London, W.B. Saunders Co. Ltd, 1992, pp. 21 –34.)

Chapter 14.

Medical Management of Atherosclerotic Vascular Disease

stress.[12] The fatty streak type II lipids are chemically similar to those of the plasma,[13] although the plasma lipids might enter the arterial wall in several ways. The plasma threshold level for LDL entry into the arterial wall is unknown. As described in a recent review of pathogenesis,[14] LDL accumulation may occur because of (1) alterations in the permeability of the intima, (2) increases in the interstitial space in the intima, (3) poor metabolism of LDL by vascular cells, (4) impeded transport of LDL from the intima to the media, (5) increased plasma LDL concentrations, or (6) specific binding of LDL to connective tissue components, particularly proteoglycans in the arterial intima. Experimental studies shows that LDL cholesterol accumulates in the intima even before lesions develop and in the presence of intact endothelium. These observations are quite similar to those of early lesion formation described by Aschoff[15] at the beginning of the twentieth century and Virchow[16] in the nineteenth century. A second event in early atherogenesis as shown in animal experiments is binding of monocytes to the endothelial lining, with their subsequent diapedesis into the subintimal layer to become tissue macrophages.[17 – 19] Experimentally, fatty streaks are populated mainly by monocyte-derived macrophages. These lipid-engorged scavenger cells mainly become the foam cells that characterize fatty streaks and other lesions. An important and key observation is that LDL must be altered in some manner,[20] such as by oxidation or acetylation, to be taken up by the macrophages to form foam cells. This concept has become central to thinking about pathogenesis and treatment, as will be seen in subsequent discussion. Oxidized LDL (OxLDL) is a powerful chemoattractant for monocytes. Another aspect of this concept suggests that the endothelium modifies LDL to promote foam cell formation. The interactions of plasma LDL levels with the arterial wall are the subject of intense interest. Low-density lipoproteins traverse the endothelium mostly through receptor-independent transport, but also through cell breaks.[21] Endothelial cells,[22] smooth cells,[23] and macrophages[24] are all capable of promoting oxidation of LDL. OxLDL, in turn, further attracts monocytes into the intima and promotes their transformation into macrophages. Macrophages produce cytokines including platelet-derived growth factor (PDGF), transforming growth factor beta (TGFb), and interleukin-1 (IL-1). The OxLDL also induces gene products ordinarily unexpressed in normal vascular tissue. A notable example is tissue factor (TF), the cellular initiator of the coagulation cascade that is expressed by atheroma monocytes and foam cells.[25] Expression of TF requires the presence of bacterial lipopolysaccharide, suggesting that hypercoagulability in atherosclerosis could be enhanced by endotoxemia.

GELATINOUS PLAQUES The intimal gelatinous lesion, also first described by Virchow in 1856,[16] is an interesting and overlooked lesion. Haust[26] believed that these plaques ranked among the important progenitors of advanced atherosclerosis. Smith[27] stressed their characterization; she and her associates have accumu-

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lated much valuable data about them.[28] It has been shown that virtually all plasma proteins, particularly hemostatic components, are capable of entering the intima. These plaques are not high in lipid content. Gelatinous lesions are translucent and neutral in color, with central grayish or opaque areas. This material separates easily from the underlying arterial wall without entering the usual endarterectomy plane. Gelatinous lesions are most commonly seen in the aorta. The gelatinous plaque is high in fluid and low in lipid content. In transitional stages, cellularity is increased and the plaques contain smooth-muscle cells. These lesions exhibit substantial amounts of cross-linked fibrin, possibly relating to increased plasma fibrinogen levels.

THE FIBROUS PLAQUE Figure 14-1 shows the more advanced atherosclerotic lesion capable of causing complications, the fibrous or type IV plaque. These are composed of large numbers of smoothmuscle cells and connective tissue forming a fibrous cap over an inner yellow atheromatous core. The soft core contains cholesterol esters, mainly cholesterol oleate, thought to be derived from disrupted form cells. A second type of particle contains both cholesterol and cholesterol lineates. The early case, described previously, is associated with lipids derived directly from LDL by enzymes capable of hydrolyzing LDL cholesterol esters.[14] Considerable emphasis has been placed on the composition and integrity of the cap as this structure stabilizes the atheroma, preventing intraluminal rupture of the soft core.[29,30] Chronologically, such lesions are detected after fatty streaks, often in the same anatomic locations, and characterize the clinically apparent stages of atherosclerosis. While other lesions can be precursors of fibrous plaques, the fatty streak is believed to be the most common pathway. Fibrous plaques can arise by conversion of a mural thrombosis into an atheroma.[31] While the fibrous plaque protrudes into the arterial lumen on fixed cut sections, abluminal bulges can also be seen when arteries are fixed at arterial pressures.[32] Such abluminal bulges have characterized early coronary and peripheral lesions in subhuman primates.[33,34] This prestenotic phase of atheroma development can make quantitating plaque evolution difficult, as luminal intrusion is not seen angiographically. Lipid arterial wall interactions are quite important for other reasons. The cholesterol esters in fatty streaks appear in the form of ordered arrays of intracellular lipid crystals. In fibrous plaques, the lipids assume isotropic forms and occur extracellularly.[35] Extracellular cholesterol esters and oxysterols cause severe inflammatory tissue reactions and are probably capable of eliciting the same responses in the arterial wall.[36] As illustrated, arteries with fibrous plaques often exhibit striking periarterial inflammation, fibrosis, and lymphocytic infiltration relating to disease severity.[37] Neovascularization from the adventitia also characterizes advancing intermediate and fibrous plaque lesions. Fibrous plaques protrude into the arterial lumen in fixed cut sections; however, when arteries are fixed at arterial pressure, they produce an albuminal or external bulge. For

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example, coronary plaques in vivo must occupy at least 40% of the arterial wall before angiographic detection is possible,[38] and atheroma growth can be compensated for by arterial enlargement within certain limits.[39] Remodeling of coronary arteries in subhuman primates and humans has been stressed.[40] However, with lesion growth, ulceration, rupture, or overlying thrombosis, the arterial lumen is ultimately compromised. When this occurs, distal ischemia develops. A unique adaptive response involving dilation, with atheromatous involvement of the entire arterial wall and participation of inflammatory cells and immunologically active T lymphocytes, may predispose to aneurysm formation. Atherosclerotic lesions contain immunoglobulin G (IgG) in large quantities along with other immunoglobulins and complement components. The contained IgG recognizes epitopes characteristic of oxidized LDL, indicating that immunologic processes characterize advanced plaques.[41] The process exhibits systemic effects; patients with carotid atherosclerosis have higher antibody levels of anti-oxLDL and IGM than comparable nonatherosclerotic controls.[42]

the younger the afflicted patient, the more likely one is to encounter a risk factor as it coincides with clinical events. Patients with extremity disease are often older than those with coronary disease, but, on careful inquiry, risk factors will be found in the past.[44] The clinical problem in treating patients is choice of modifications in lifestyle or medical interventions in individual stages or patterns of disease. The aim is to prevent progression of disease to lethal endpoints such as myocardial infarction, stroke, and peripheral ischemia. The choices that face the vascular surgeon occur both preoperatively and postoperatively and are somewhat different in each instance, depending upon the coexisting disease patterns.[47] The practical intervention that all vascular surgeons should insist upon is cessation of cigarette smoking. In this author’s opinion, control of this risk factor is paramount for immediate-term results along with control of LDL cholesterol level, an attempt to increase high-density lipoprotein (HDL) cholesterol, and control of diabetes, hypertension, or embolic phenomena in the long term.

LESION ARREST OR REGRESSION PROGRESSION TO COMPLICATED PLAQUES Late complications of fibrous plaques lead to clinical complications. Aneurysms might represent a unique genetic or immune response to atherosclerosis or alternatively be considered as nonspecific degenerative or purely mechanical responses. There clearly exists a high prevalence of risk factors for atherosclerosis in aneurysm patients.[43] The recent classification of advanced lesions[9] takes into account that extracellular lipid is the precursor of the core of the type IV fibrous plaque. Type V lesions contain a thick layer of fibrous tissue, whereas type VI lesions contain fissures, hematoma, or thrombus. Aneurysms are also included within the recent staging of advanced atherosclerosis.

APPROACH TO TREATMENT The complications of atherosclerosis relate to numerous interactive factors and inflammatory mechanisms occurring in complicated plaques. It is useful, but not scientifically rigorous, to view epidemiologically defined risk factors as etiologic factors. As this disease manifests itself as a spectrum of lesions, human atherosclerosis can be considered as a family of related vascular disorders. Interestingly, bodily patterns of involvement relate to particular risk factors and often are associated with distinctly differing rates of progression.[44,45] In an individual with atherosclerosis, it is almost always possible to elicit a past or present history of risk factors. Risk factors are epidemologically defined; their effects on vascular complications and changing disease prevalence have been reviewed.[46] These major risk factors are hyperlipidemia, primarily elevated levels of LDL cholesterol; cigarette smoking; hypertension; and diabetes mellitus. In general,

Regression of atherosclerosis in response to lowered serum cholesterol has been demonstrated in autopsy studies of starved humans,[15] in animals,[48,49] and in angiographic trials.[50] In experimental animals, plaque regression is clear, while in humans arrest is more commonly documented. As experimental plaques regress, bulk is reduced mainly by lipid egress in hypercholesterolemic dogs[51,52] and monkeys.[53,54] The authors and coworkers verified regression using serial direct observations of lessened bulk and lipid content of individual fibro-fatty plaques, which correlated with lessened plaque lipid and altered fibrous protein content.[54] An important operational aspect of this research was confirmation of regressive changes by immediate morphologic measurement and biopsy following angiography. While these observations are difficult to obtain in human atherosclerosis, lessening of luminal intrusion on segmental angiography does coincide with favorable lipid interventions. Experimentally, plaque fibrous protein content may increase in some instances during lipid egress,[53] which may limit regression, but this process also might convert a soft atheromatous plaque into a more stable entity. This process, in fact, has now been shown using pravastatin in an experimental model.[55] To produce consistent arrest or regression, serum cholesterol must be reduced to below 200 mg/dL; conversely, there also exist serum cholesterol levels above which lesions inevitably progress over time.[54,56] This threshold in humans might approximate a total serum cholesterol of 150 –170 mg/dL or an LDL level of 100 mg/dL or less, levels cited in world populations in which atherosclerosis is virtually absent.[57]

MEDICAL MANAGEMENT As can be seen from considerations of plaque evolution and complications, lipid dynamics play an important role in

Chapter 14. Table 14-1.

Medical Management of Atherosclerotic Vascular Disease

239

Diet Trials of Cholesterol Lowering

Trial

Type, years

Lipid change, %

LAVAMC

18 8

TC (14)

MRC Low Fat

28 3

TC (9)

MRC Soya Oil

28 4

TC (13)

OSLO Diet Heart

28 5

TC (15)

n

Fatal plus nonfatal CHD events

T = 424 C = 422 T = 123 C = 129 T = 199 C = 194 T = 206 C = 206

54 71 30 31 45 51 61 81

Note: 18 = primary; 28 = secondary; TC = total cholesterol; T = treated; C = control. Source: Rossouw, J.E.; Rifkin, B.M.[66] Used with permission.

atherogenesis. In late disease, the instability of fibrous plaques has now received increasing attention. As yet, however, among all the interventions intended to stabilize, arrest, or regress plaques, solely lipid interventions (i.e., decreasing LDL cholesterol or increasing HDL cholesterol) have been shown to promote favorable changes in the atheroma itself as well as increasing survival mainly in coronary atherosclerosis. These favorable changes require cessation of smoking. Many thousands of individuals have been studied by serial angiography in regression trials that use mostly lipid reduction,[58] most recently using pravastatin, which has evident effects in reducing cardiovascular events in older and younger patients, men and women, and patients with and without histories of prior infarctions, as well as in those with only modest elevation of serum cholesterol.[59,60] Vessel wall changes have also been measured in the carotid and femoral arteries using the statin drugs.[61] Epidemiologic and interventional studies support the view that it is desirable to keep total serum cholesterol (TC) values below 200 mg/dL, with LDL below 130 mg/dL, fasting triglycerides below 250 mg/dL, and HDL levels above 40 mg/dL;[62] these values may be true for older age groups as well.[63] When TC is greater than 200 mg/dL, calculations of LDL cholesterol are obtained according to the following formula: LDL cholesterol equals TC minus HDL cholesterol minus triglycerides divided by 5. When initial screening is positive—when TC is greater than 200 mg/dL—fasting blood for these determinations is required. This formula is valid only in fasted patients and when the triglycerides are below 400 mg/dL. Small differences in cholesterol concentrations over time have important effects; therefore, screens are repeated periodically in symptomatic patients. In patients in whom LDL cholesterol is above 130 mg/dL, cholesterol-lowering diets are prescribed, as outlined by Luepker[63] and Stone.[64] The Step I Diet recommends a total fat intake of less than 30% of the total caloric intake, with less than 10% of total calories derived from saturated fat and less than 300 mg of cholesterol a day. Total calories are calculated to achieve and maintain desirable weight. With high-risk patients—those whose LDL is above 160 mg/dL and who

have two other risk factors or clinical coronary disease— saturated fat is reduced to less than 7% of the total caloric intake and cholesterol intake to less than 200 mg/day. Dietary consultation and instruction will be needed to achieve these goals, and these have been long recommended by the author.[65] The effects of lipid-lowering diets on coronary heart disease (CHD) can be seen in Table 14-1, from a summary by Rossouw and Rifkin.[66] As the number of fatal CHD endpoints is too small in each trial to detect significant differences, the results for these data are tabulated as fatal plus nonfatal CHD events. Only the Oslo Heart Study demonstrated statistical significance.

DRUG THERAPY FOR HYPERLIPIDEMIAS When dietary therapy fails to achieve goals for lipid lowering (i.e., an LDL level below 130 mg/dL), drug therapy is used. The surgeon undertaking dietary recommendations must recognize that the time and effort required will often exceed that of operative interventions. Drug therapy does not substitute for a concerted and organized dietary approach for a minimum of 6 months or a search for familial dyslipoproteinemia. Drugs currently available include cholestyramine and cholestepol, which are bile acid sequestrants, nicotinic acid (a B-complex vitamin), Gemfibrozil, a fibric acid derivative that acts in the liver to elevate plasma HDL and lower triglycerides and LDL, and the statin drugs referred to previously.[59 – 61] The latter class of drugs are 3-hydroxy-3methylglutaryl coenzyme H – reducing agents and are currently in wide use in trials and clinically for primary and secondary coronary artery disease. This has led Roberts[67] to editorialize that statin drugs are to atherosclerosis what penicillin was to infectious disease. A cautionary note on the carcinogenicity of lipid-lowering drugs has been sounded by Newman and Hulley[68] in that all members of the statin and fibrin classes of drugs have exhibited cancer in rodents, in some cases at levels of animal exposure approaching those prescribed in humans. With regard to the statin drugs, an

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overview of all published trials by Herbert et al.[59] revealed no evidence of either noncardiovascular death increase or cancer incidence. The use of the statin drugs has been shown to be effective in primary prevention as well and likely will become more widespread for this purpose.[69] In addition, lowering LDL cholesterol reduces the cardiovascular risk of lipoprotein, a particle similar to LDL but containing apolipoprotein a, which causes it to promote thrombosis.[70] Niacin and the fibrate drugs are considered better agents for increasing HDL in certain circumstances, but the use of these agents in combination with other measures in various metabolic hyperlipidemic states is a complex issue. The reader is referred to a recent monograph by Grundy.[71] The drug probucol and the natural vitamins E and C are antioxidants which may impact the deleterious effects of oxidized LDL. Recent trials examining the use of vitamin E supplements were reported as yielding an associated 40% risk of coronary disease.[72] The role of antioxidants and correlation with plaque dynamics has emerged as an important new consideration, as these agents might be used as drugs.

ANTIOXIDANTS Oxidative damage to proteins, DNA, and macromolecules occurs with age and has been generally thought to be a major, but not the single factor in endogenous changes leading to aging and degenerative diseases, including atherosclerosis.[73] Experimentally, preservation of endogenous antioxidant activity and inhibition of lipid peroxidation are common mechanisms of antiatherosclerotic attributes of vitamin E as well as the drugs lovastatin and amlodipine based on superoxide dismutase measurements and extent of atherosclerosis.[74] A serial coronary angiographic study of men after bypass surgery indicated less coronary progression among men with supplementary vitamin E intake of 100 IU daily as compared to the use of vitamin C supplements exclusively or use of other multivitamins.[75] Randomized trials have shown questionable benefit in coronary events with vitamin E and not with vitamin A. These potentially new agents, along with the oxidative modification hypothesis of atherogenesis, have been exhaustively reviewed.[76]

CIGARETTE SMOKING This is the most prevalent and the most ominous risk factor in patients presenting with atherosclerotic disease. This habit is directly related to the progression of peripheral atherosclerosis to amputation,[77] high mortality from ischemic heart disease,[78] failure of aortic grafts,[79,80] and the failure of femoral-popliteal grafts,[81] added to the list of woes. For the practicing vascular surgeon, smoking cessation is the most important intervention required both pre- and postoperatively. The means by which cigarette smoking promotes atherosclerosis and graft thrombosis are incompletely understood. Carbon monoxidemia probably predisposes to arterial wall injury by producing increased plasma flux into the arterial

wall and entry of LDL and other proteins. Cigarette smoking causes increased platelet reactivity, promotes peripheral vasoconstriction, and is associated with reduced HDL levels.[82] It is interesting that in populations in whom LDL levels are exceedingly low, cigarette smoking may not be associated with a high incidence of atherosclerotic vascular disease. While it is well known that smoking is the most important factor in both rapid progression of atherosclerosis and graft failure and that cessation has an immediate potent and beneficial effect, a recent report suggested that pack-years of smoking, but not current versus past smoking, was associated with more rapid disease progression.[83] The progression in this study was a measure of intima-medial thickness of the carotid artery assessed by ultrasound and adjusted for demographic characteristics, cardiovascular risk factors, and lifestyle variables. This result from a clinical standpoint seems counterintuitive and should not exclude the vascular surgeon or physician from energetic management attempts at smoking cessation. Smoking cessation clinical practice guidelines have been recommended to identify and treat smokers with cessation and motivational intervention,[84] offer nicotine replacement, and scheduled follow-up contacts. Nicotine-replacement therapy is most effective when used as part of a program.[85] Following personal advice given by physicians to encourage smoking cessation at a single consultation, only an estimated 2% of all smokers stopped smoking with no relapse after one year.[86] With repeated visits, vascular surgeons should be able to improve this. Finally, bupropion therapy at higher dosages has improved results to 44.2% at 7 weeks as compared to placebo therapy with counseling, which yielded 19% at this short interval.[87]

HYPERTENSION Hypertension is a potent cardiovascular risk factor; its adequate control prolongs life. In experimental animals, atherosclerosis associated with hyperlipidemia is accelerated by chronic hypertension.[88] However, as with cigarette smoking, Asian and Caribbean populations exhibit hypertension with a low incidence of atherosclerotic disease in the absence of hyperlipidemia. Treatment of hypertension with thiazide diuretics was disadvantageous in a certain group of men, as shown in a previous trial. Traditionally, sodium reduction and weight loss have been regarded as an important recommendations; these measures in older people have been found to be feasible and safe in recent trial.[89] However, a recent meta-analysis addressing the controversy as to whether or not reduced sodium intake might decrease the blood pressure of a population did not support this general recommendation.[90] A recent issue is whether or not antihypertensive drugs, specifically calcium antagonists and angiotensin-converting enzyme (ACE) inhibitors, exert an antiatherosclerotic effect. Trials have been structured to test antiatherosclerotic actions of an ACE inhibitor versus diuretics in antihypertensive therapy as it affects carotid atherosclerosis.[91] ACE inhibitors may contribute to plaque stabilization by a variety of mechanisms, including inhibition of angiotensin II gener-

Chapter 14.

Medical Management of Atherosclerotic Vascular Disease

ation, antagonists of macrophage function and migration, and inhibition of thrombotic and sympathetic activity.[92] A number of trials using combined therapy to assess plaque stabilization, arrest, or regression are in progress.

DIABETES MELLITUS One of the most important risk or actual pathogenetic factors promoting atherosclerosis is diabetes. In its singular form, diabetes is associated with severe infracrural and coronary atherosclerosis. A current diabetes control trial[93] revealed favorable reduction in microvascular complications with “tight control” using insulin; unfortunately, this trial was not designed to study endpoints of macrovascular atherosclerotic complications. Diabetes as it affects atherogenesis has not been studied extensively in animal models of atherosclerosis. Causes of enhanced atherogenesis in diabetes include abnormalities in apoprotein and lipoprotein particle distributions, particularly elevated levels of lipoprotein(a),[94] an independent thromboatherosclerotic risk factor. In poorly controlled diabetes, a procoagulant state exists; insulin resistance and hyperinsulinemia also might contribute to smooth muscle proliferation. Not only do glycooxidation and oxidation contribute to LDL entry into macrophages, glycation of proteins and plasma in the arterial wall could contribute further to accelerated atherosclerosis in diabetics. Hormones, growth factors, cytokine-enhanced smoothmuscle cell proliferation, and increased foam cell formation are also postulated to be unique aspects of atherogenesis in diabetes mellitus.[95] However, it is not known which of these factors dominates atherogenesis in diabetes and why the distal vessels are more severely affected. In view of the utility of tight control in preventing microvascular and infectious complications, aggressive control of blood glucose on a consistent basis appears advisable. With any given level of LDL, coronary heart disease risk is tripled in patients with diabetes relative to those without,[96] an important consideration in overall management. In the diabetic, elevated triglyceride levels most commonly accompany severely elevated cholesterol levels; this particular combination greatly increases the risk of adverse coronary events.

OTHER RISK FACTORS Lack of exercise, obesity, and psychological factors are also to be considered. The classic retrospective study reported that sedentary London bus drivers had a higher incidence of coronary disease than a matched cohort of their more physically active bus conductors.[97] The Framingham Study[98] showed an inverse relationship of overall mortality, cardiovascular mortality, and CHD mortality as related to physical activity. This effect was small as compared to the major risk factors of smoking, hypertension, diabetes, and hyperlipidemia. Obesity remains a controversial risk factor.[99] Insurance statistics suggest that obesity promotes excess cardiovascular mortality,[100] and that life expectancy

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increases with weight reduction. Other data have been interpreted to suggest that obesity may be benign in the absence of other major risk factors.[101] Framingham prospective studies challenged these results.[102] Psychological studies associate coronary artery disease with type A behavior. These are also controversial.[103] Type A persons are said to exhibit enhanced competitiveness, ambitiousness, and a chronic sense of time urgency. The clinical impression that personality characteristics play a strong role in coronary artery disease was first stated in 1633. Fabrizio Bartoletti described patients with coronary disease to be “dissatisfied with themselves and others, very ill-humored, and easily angered or annoyed.” Clarkson[104] recently quoted Osler,[105] who noted the typical coronary patient to be “the robust, the vigorous in mind and body, the keen and ambitious man; whose engine is always at full-speed ahead.” Clarkson’s experiments[104] showed that highly aggressive monkeys who were kept in chronically unstable social conditions developed more extensive coronary atherosclerosis than dominant monkeys living in unstressed social conditions. These studies link the risk factor of stress to morphologically measured disease severity. It would not appear likely that surgeons would commonly employ psychological intervention, but they might consider behavior modification.

EXERCISE The effects of exercise on any treatment of atherosclerosis must be considered from two viewpoints: preventative or therapeutic for established disease. Epidemiologically, little doubt exists that habitual physical activity decreases the primary incidence of coronary heart disease.[106] The relative risk of physical inactivity is similar to the risk factors of hypertension, hyperlipidemia, and smoking. However, symptomatic improvement of established atherosclerosis, e.g., angina or claudication, appears to relate mainly to muscular tone and conditioning. A direct effect of exercise on the atherosclerotic plaque or on collateral arterial development has yet to be shown. Episodes of sudden death due to coronary atherosclerosis during exercise or emotional stress are believed to result from plaque disruption; this remains a matter of continuing concern[107,108] for clinicians. In evaluating exercise research studies, an operational definition of physical activity should be sought. Exercise is a complex behavior for which no standard measurement exists such as can be done for blood pressure or lipid profiles. Classic epidemiologic studies of CHD focused on occupation, e.g., London bus drivers versus conductors or longshoremen versus sedentary workers. Modern exercise research uses standard aerobic exercise programs. For example, recent research compared dietary weight loss to exercise by measuring enhanced VO2max induced by exercise to a predetermined amount.[109] This study suggested that weight loss by diet was preferred treatment to improve CHD risk factors in overweight middle-aged men, but these conclusions have been questioned.[110] Other studies using exercise combined with multiple

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interventions have shown favorable angiographic effects on rate of coronary plaque progression.[111] The quantitation of exercise in multiple intervention studies is often difficult to assess, as is its contribution to favorable effects observed. Regular exercise improves lipid profile and glucose and insulin metabolism, aids in weight reduction, and improves muscle tone and endurance. Exercise is undoubtedly beneficial in the treatment of claudication,[112 – 116] but direct effects of exercise on blood vessels and atherosclerosis remain to be determined. Experimentally, computer models of flow dynamics of human aortas show that with increased flow, shear stress is normalized, and thus atherosclerosis might be inhibited.[117] Favorable effects in clotting and platelet reactivity have also been shown in humans.[118] The role of exercise needs more study before specific prescriptions can be made for treatment. Recent pragmatic prescriptions suggest the prophylactic utility of moderate exercise such as brisk walking 30 minutes daily; others have warned of deleterious effects of intense exercise due to free radicals.[119] Highly trained athletes showed no ill effects on lipid levels or antioxidant activity after extreme exertion using the iron man triathlon as a model.[120]

ANTIPLATELET AND ANTICOAGULANT THERAPY To date, the only interventions shown to alter intrusive atherosclerotic plaques toward regression or arrest have employed the combination of both serum lipid reduction and cessation of smoking. Antiplatelet therapy has not yet been demonstrated to produce favorable effects on established lesions. In fact, the reverse has been described in some experimental studies.[121 – 123] The use of antiplatelet agents is based on the theory that these drugs might alter atheroma growth due to abnormal platelet kinetics or inhibit platelet-derived growth factors. Such hopes have not yet been fulfilled. The serial demonstration of beneficial effects on plaque morphology has been seen unequivocally in humans and animals only with lipid reduction. A voluminous literature regarding the optimal aspirin dose has been reviewed by Wecksler.[124] Smaller rather than larger doses of aspirin are now considered advantageous. Small doses of aspirin are recommended for certain patients (e.g., those with a asymptomatic carotid lesions or those who have had one transient ischemic attack). The data concerning intraplaque hemorrhage due to antiplatelet therapy are conflicting.[125,126] A number of patients needing vascular surgery have been found to exhibit hypercoagulable states, often manifested by postoperative graft thromboses. These patients may exhibit low antithrombin III levels and abnormalities of proteins C and S as well as plasminogen.[127] In properly selected patients, coumadin treatment will be useful postoperatively. Newer agents for patients at risk for ischemic events include antiplatelet agents such as ticlopidine and clopidogrel; the latter is believed to be safer as compared to aspirin 325 mg once daily[128] for the endpoints of stroke and myocardial infarction.

NEW HORIZONS Homocysteine and Folic Acid Supplementation Among the risk factors identified for cardiovascular disease, an elevated homocysteine level has surfaced.[129 – 131] Folic acid supplementation has been suggested for lowering homocysteine levels, but considerable controversy continues as to whether this should be done as a public health matter.[132] The addition of “either 140 or 350 mg of folic acid per 100 g of grain product”[133] or using folic acid supplements with mandatory addition of 1000 mg of vitamin B12 has been debated. Typical multivitamin supplements contain about 400 mg of folic acid.

Infection: Viral and Chlamydia pneumoniae Herpesviruses are widespread and often systemic in the general population. Antigens and nucleic sequences of herpesviruses have been found in atherosclerotic lesions; herpesvirus-induced atherosclerosis has been produced in animals; the herpesvirus family causes cholesterol ester accumulation in smooth muscle cells, induces growth factors and cytokines by vascular and inflammatory cells, and has procoagulant effects on endothelium.[134] The cytomegalovirus (CMV) relationship to atheroma is another observation previously mentioned.[10] Such circumstantial evidence of potential viral factors requires proof of a causal relationship. Another, perhaps more exciting, observation was the 1992 detection of Chlamydia pneumoniae by immunochemical staining and electron microscopy in coronary atheroma.[135] The organism has since been found in atherosclerotic lesions in the aorta and carotid and femoral arteries. In the peripheral arteries C. pneumoniae was detected in 48% (11/23) patients using several methods.[136] In another important study, coronary atherectomy specimens from 90 patients were definitely positive by direct immunofluorescence in 73% and equivocally positive in 6%, for a total of 79% showing evidence for the presence of these organisms.[137] This result compared with only one of 24 nonatherosclerotic coronaries showing evidence of Chlamydia. The evidence suggests that the first of Koch’s postulates has been fulfilled with regard to Chlamydia in atheromas. Animal studies as well as antibiotic trials are now in progress.

Gene Therapy Although not affecting the atheroma itself, this concept is based on the idea that new blood vessel growth might be induced by the use of direct application of growth factors.[138] These include fibroblast[139] and vascular endothelial growth factors (VEGF). The delivery of these growth factors includes direct gene application of DNA, by a viral vector using intravascular injection, by balloons or stents, and by direct application. Transfer of DNA coding for angiogenesis is a novel approach that will require considerable study to assess

Chapter 14.

Medical Management of Atherosclerotic Vascular Disease

its value for revascularization. The reader is referred to a recent review.[140] Another aspect of gene therapy concerns the control of lipid metabolism. In transgenic mice in whom a rat apolipoprotein E (apo E) gene has been established, overexpression of apo E reduces plasma cholesterol and triglycerides, preventing atherosclerosis.[141] In another example, phenotypic correction of hyperlipidemia in rabbits was achieved by hepatic delivery of the rabbit LDL receptor gene.[142] These therapies are likely to assume importance in the treatment of familial hyperlipidemias.

CONCLUSIONS This chapter has considered the management of atherosclerosis as if it were a single entity. However, the clinical

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presentations of atherosclerosis are varied; a spectrum of lesions, some with differing modes of pathogenesis, exist, and the disease involves distinct patterns of distribution and progression rates. A simplistic approach to management will not suffice; the treating clinician will need to individualize medical and surgical management based on clinical presentations. In certain cases, peripheral vascular interventions in continued smokers will make matters ultimately worse. In coronary disease, interventions directed at lipid lowering appear to now show real primary and secondary benefit. This is of relevance to vascular surgeons since many of our patients succumb to coronary disease. The use of antioxidants promises benefits with little risk, as does dietary supplementation for homocystinemia. Finally, the unstable characteristics of certain atheromatous plaques, in particular arterial segments, have now been clearly recognized; visualization techniques permit quantitative evaluations of treatment of the arterial lesion itself.

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Part Two. Medical Treatment Grandl, V.A.; Galloe, A.M.; Garred, P. Effects of Sodium Restriction on Blood Pressure, Renin Aldosterone, Catecholamines, Cholesterols and Triglyceride. J. Am. Med. Assoc. 1998, 279, 1383. Zanchett, A. Antiatherosclerotic Effects of Antihypertensive Drugs: Recent Evidence and Ongoing Trials. Clin. Exp. Hypertens. 1996, 18, 489. Pepine, C.J. Ongoing Clinical Trials of AngiotensinConverting Enzymes Inhibitors for Treatment of Coronary Artery Disease in Patients with Preserved Left Ventricular Function. J. Am. Coll. Cardiol. 1996, 27, 1048. The Diabetes Control and Complication Trial Research Group; The Effect of Intensive Treatment of Diabetes on the Development and Progression of Long-Term Complications in Insulin-Dependent Diabetes Mellitus. N. Engl. J. Med. 1993, 329, 977. Loscalzo, J. Lipoprotein(a): A Unique Risk Factor for Atherothrombotic Disease. Arteriosclerosis 1990, 10, 672. Bierman, E.I. Atherogenesis in Diabetes. Arterioscler. Thromb. 1992, 12, 647. Stammler, J.; Vaccaro, O.; Nealon, J.D.; Westworth, D. Diabetes and Other Risk Factors and 12 Year Cardiovascular Mortality for Men Screened for MRFIT. Diabetes Care 1993, 16, 434. Morris, J.N.; Heady, J.A.; Raffle, P.A.B.; et al. Coronary Heart Disease and Physical Activity of Work. Lancet 1953, 2, 1053. Dawber, T.R. The Epidemiology of Atherosclerotic Disease: The Framingham Study; Harvard University Press: Cambridge, MA, 1980. Barrett-Connor, E.L. Obesity, Atherosclerosis and Coronary Artery Disease. Ann. Intern. Med. 1985, 102, 1010. Lew, E.A. Importance of Overweight in Life Insurance. 11th International Congress of COINTRA, 1969, p 277. Rosenman, R.; Brand, R.; Shaltz, R.; Friedman, M. Multivariable Prediction of Coronary Heart Disease. Am. J. Cardiol. 1976, 37, 903. Hubert, H.B. The Nature of the Relationship Between Obesity and Cardiovascular Disease. Int. J. Cardiol. 1984, 6, 268. Criqui, M.H. Epidemiology of Atherosclerosis: An Update and Overview. Am. J. Cardiol. 1980, 57, 186. Clarkson, T.B. Personality, Gender and Coronary Atherosclerosis of Monkeys. Arteriosclerosis 1987, 7, 1. Osler, W. The Lumeian Lectures on Angina Pectoris. Lancet 1910, 1, 839. Powell, K.E.; Thompson, P.D.; Casperson, C.J.; Kentrick, J.S. Physical Activity and the Incidence of Coronary Heart Disease. Ann. Rev. Public Health 1987, 8, 253. Curfman, G.D. Is Exercise Beneficial—or Hazardous—to Your Heart? N. Engl. J. Med. 1993, 329, 1730. Ciampricotti, R.; Deckers, J.W.; Tavern, R.; et al. Characteristics of Conditioned and Sedentary Men with Acute Coronary Syndromes. Am. J. Cardiol. 1994, 73, 219. Katzel, L.I.; Bleeker, E.R.; Colman, E.G.; et al. Effects of Weight Loss vs Aerobic Exercise Training on Risk Factors for Coronary Disease in Healthy, Obese, Middle Aged and Older Men. J. Am. Med. Assoc. 1995, 274, 1915. Civish, F.M. Letter. J. Am. Med. Assoc. 1996, 275, 1546.

111. Haskell, W.L.; Alderman, E.L.; Fair, J.M.; et al. Effects of Intensive Multiple Risk Factor Reduction on Coronary Arteriosclerosis. Circulation 1994, 89, 975. 112. Jonason, T.; Jonzon, B.; Ringquist, I.; Oman-Rydbert, A. Effects of Physical Training on Different Categories of Patients with Intermittent Claudication. Acta Med. Scand. 1979, 206, 253. 113. Hiatt, W.R.; Regensteiner, F.G.; Hargarten, M.E.; et al. Benefit of Exercise Conditioning for Patients with Peripheral Arterial Disease. Circulation 1990, 81, 602. 114. Creasy, T.S.; McMillan, P.J.; Fletcher, E.W.L.; et al. Is Percutaneous Transluminal Angioplasty Better Than Exercise for Claudication. Preliminary Results from a Prospective Randomized Trial. Eur. J. Vasc. Surg. 1990, 4, 135. 115. Gardner, A.W.; Poehlman, E.T. Exercise Rehabilitation for the Treatment of Claudication Pain: A Meta Analysis. J. Am. Med. Assoc. 1995, 274, 975. 116. Williams, L.R.; Ekers, M.A.; Collins, P.S.; Lee, J.F. Vascular Rehabilitation: Benefits of a Structured Exercise/Risk Modification Program. J. Vasc. Surg. 1991, 14, 320. 117. Taylor, C.A.; Tropea, B.I.; Hughes, T.J.R.; Zarins, C.K. Effects of Graded Exercise on Aortic Wall Shear Stress. Surg. Forum 1995, 46, 331. 118. Wang, J.; Fen, C.J.; Chen, H. Effects of Exercise Training and Reconditioning on Platelet Function in Men. Arterioscler. Thromb. Vasc. Biol. 1995, 15, 1668. 119. Kanter, M.M. Free Radicals, Exercise, and Antioxidant Supplementation. Int. J. Sport Nutr. 1994, 4, 205. 120. Ginsburg, G.S.; Agil, A.; O’Toole, M.; et al. Effects of a Single Bout of Ultra-Endurance Exercise on Lipid Levels and Susceptibility of Lipids to Peroxidation in Triathletes. J. Am. Med. Assoc. 1996, 276, 221. 121. DePalma, R.G.; Bellom, E.M.; Manalo, P.; Bomberger, R.A. Failure of Antiplatelet Treatment in Dietary Atherosclerosis: A Serial Intervention Study. In Cardiovascular Disease: Molecular and Cellular Mechanisms, Preventions, Treatment; Gall, L.L., Vahouny, G.V., Eds.; Plenum Press: New York, 1987; 407 – 426. 122. Hollander, W.; Kirkpatrick, B.; Paddock, J.; et al. Studies on the Progression and Regression of Coronary and Peripheral Atherosclerosis in the Cynomolgus Monkey: L Effects of Dipyridamole and Aspirin. Exp. Mol. Pathol. 1979, 30, 55. 123. Dembinska-Kiec, A.; Rucker, W.; Schonhofer, A. Effects of Dipyridamole in Experimental Atherosclerosis. Atherosclerosis 1979, 33, 315. 124. Wecksler, B.B. Arterial Thrombosis, Atherosclerosis and Platelet Activity: A Reassessment of Antiplatelet Therapy. In Atherosclerosis Reviews; Hegyeli, R.J., Ed.; Raven Press: New York, 1984; 39. 125. Lennihan, L.; Kuposky, W.J.; Mohr, J.P.; et al. Lack of Association Between Carotid Plaque Hematoma and Ischemic Cerebral Symptoms. Stroke 1987, 18, 879. 126. AbuRahma, A.F.; Boland, J.P.; Robinson, P.; DeCanio, R. Antiplatelet Therapy and Carotid Plaque Hemorrhage and Its Clinical Implications. J. Cardiol. Vasc. Surg. 1990, 31, 66. 127. Donaldson, M.C.; Weinberg, D.S.; Belkin, M.; et al. Screening for Hypercoagulable States: A Preliminary Study. J. Vasc. Surg. 1990, 11, 825.

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CAPRIE Steering; A Randomized Double Blinded Trial of Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events. Lancet 1996, 348, 1329. Boers, G.H.J.; Smals, A.G.H.; Trijbels, F.J.M. Heterozygosity for Homocystinuria in Premature Peripheral and Cerebral Occlusive Arterial Disease. N. Engl. J. Med. 1985, 313, 709. Brattstrom, L.E.; Hardebo, J.E.; Hultberg, B.L. Moderate Homocystinemia: A Possible Risk Factors or Arteriosclerotic Cerebrovascular Disease. Stroke 1984, 15, 1012. Taylor, L.M., Jr.; Porter, J.M. Elevated Plasma Homocysteine as a Risk Factor for Atherosclerosis. Semin. Vasc. Surg. 1993, 6, 36. Boston, A.G.; Mayer, J. Folic Acid Fortification of Food [letter]. J. Am. Med. Assoc. 1996, 275, 9. Boushey, C.J.; Beresford, S.A.A.; Omenn, G.S.; Motulsky, A.G. Quantitative Assessment of Plasma Homocysteine as a Risk Factor for Vascular Disease: Probable Benefits of Increasing Folic Acid Intakes. J. Am. Med. Assoc. 1995, 274, 1049. Nicholson, A.C.; Hajjar, D.P. Herpes Virus in Atherosclerosis and Thrombosis: Etiologic Agents or Ubiquitous Bystanders. Arterioscler. Thromb. Vasc. Biol. 1998, 18, 339. Shor, A.; Kuo, C.C.; Patton, D.L. Detection of Chlamydia pneumoniae in Coronary Fatty Steaks and Atherosclerotic Plaques. S. Afr. Med. J. 1992, 82, 158.

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Kuo, C.C.; Coulson, A.S.; Campbell, L.A. Detection of Chlamydia pneumoniae in Atherosclerotic Plaques of Lower Extremities from Patients Undergoing Bypass Operation for Arterial Obstruction. J. Vasc. Surg. 1997, 26, 29. Muhlestein, J.B.; Hammond, E.H.; Carlquist, J.F. Increased Incidence of Chlamydia Species Within the Coronary Arteries of Patients with Symptomatic Atherosclerotic Versus Other Forms of Cardiovascular Disease. J. Am. Coll. Cardiol. 1996, 27, 1555. Lewis, B.S.; Flugelman, M.Y.; Weisz, A. Angiogenesis by Gene Therapy: A New Horizon for Myocardial Revascularization. Cardiovasc. Res. 1997, 35, 490. Tabata, H.; Silver, M.; Isner, J.M. Arterial Gene Transfer of Acidic Fibroblast Growth Factor for Therapeutic Angiogenesis In Vivo: Critical Role of Secretion Signal in Use of Naked DNA. Cardiovasc. Res. 1997, 35, 470. Melillo, G.; Scoccianti, M.; Kovesdi, I.; et al. Gene Therapy for Collateral Vessel Development. Cardiovasc. Res. 1997, 35, 480. Harada, K.; Shimano, H.; Ishibashi, S.; Yamada, N. Transgenic Mouse and Gene Therapy. Diabetes 1996, 45 (Suppl. 3), S129. Li, J.; Fang, B.; Eisensmith, R.C.; et al. In Vivo Gene Therapy for Hyperlipidemia: Phenotypic Correction in Watanabe Rabbits by Hepatic Delivery of the Rabbit LDL Receptor Gene. J. Clin. Investig. 1995, 95, 768.

CHAPTER 15

Regression and Stabilization of Atherosclerosis by Medical Treatment Howard N. Hodis Wendy J. Mack Albert E. Yellin Anitschkow[4] observed that continued cholesterol feeding was necessary to sustain lesions produced in rabbits, the original animal model for atherosclerosis. Subsequently, reversal of atherosclerosis has been observed to occur after discontinuance of cholesterol feeding in all major species of animals used in atherosclerosis research: dogs,[5] rats,[6] pigs, [7] chickens,[8] pigeons, [9] and nonhuman primates.[2,3,10 – 36] Further, regression of atherosclerosis in the presence of continued cholesterol feeding has been observed to occur in animals treated with cholestyramine,[10 – 18] exercise,[19,20] diets high in polyunsaturated fats,[21] alfalfa meal,[22] clofibrate,[37] ileal bypass,[38] and calcium channel blockers.[39 – 41] Nonhuman primates, principally rhesus (Macaca mulatta ) and cynomolgus (Macaca fascicularis ) monkeys, are preferred animals for regression studies because of anatomic, physiologic, and metabolic similarities to human beings. For example, there are minimal differences between humans and macaques in lipoprotein patterns.[42] Hyperlipidemia of the rhesus monkey can be compared to human acquired type II hyperlipoproteinemia.[10] Although other animal models may not demonstrate the clinical features of advanced human disease, the severely atherosclerotic macaque has been shown to develop xanthomata,[43] myocardial infarction, and severe cerebral ischemia.[44,45] Hypercholesterolemia and atherosclerosis have been most commonly induced in monkeys by feeding 0.37 – 2% cholesterol diets with variable amounts of saturated fat (usually in the form of butter) for 2 –38 months. Total cholesterol levels typically are increased to 6.72 – 25.86 mmol/L (260–1000 mg/dL). Regression phases have ranged from 2 weeks to 48 months with cholesterol levels between 2.46 and 7.76 mmol/L (95 and 300 mg/dL), but mostly below 5.17 mmol/L (200 mg/dL). Typical observations of regression are based upon group comparisons of

This chapter presents evidence that the atherosclerotic process can be altered both in native vascular beds and in various bypass grafts. The rationale for risk-factor reduction is to prevent potential problems from disease progression in vascular grafts and to reduce lesion progression in other vascular beds. The surgeon should be aware of the high probability that if one vascular bed requires surgery, then substantial atherosclerosis is also present in other vascular beds.[1] Postoperative management of patients requiring vascular surgery should therefore include systematic evaluation of all vascular areas where risk of end-organ damage is high as well as immediate normalization of lipid abnormalities, reduction of elevated blood pressure, and smoking cessation.

ATHEROSCLEROSIS REGRESSION IN EXPERIMENTAL ANIMAL MODELS The strictest definition of atherosclerosis reversibility requires normalization of vessel wall anatomy and chemical composition, including (1) restoration of the integrity of the endothelium over plaques; (2) arrest of intimal cell proliferation; (3) decrease in the number of cells within lesions plus decreases in intra- and extracellular lipid; and (4) decrease in the extent of necrotic foci and calcification.[2] Controlled studies in animal models with quantitative histology indicate that regression meeting these criteria except for reduction in calcification can be achieved. A more liberal definition and one appropriate for surgical practice would accept as proof of reversibility any change except plaque rupture which reduces the size of intrusive lesions. Reduction in lesion size does not necessarily imply improvement in all cellular elements of the lesion.[3]

Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024898 Copyright q 2004 by Marcel Dekker, Inc.

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animals sacrificed at different times for morphologic and histochemical exploration of atherosclerosis regression at a cellular level. Physiologic changes induced by regression have also been studied by pulse wave velocity[23] and arterial wall reactivity[24] and relaxation.[25] Absolute establishment of atherosclerotic lesion regression requires that evolution of individual atherosclerotic plaques be studied sequentially over time in the same subject. This has been accomplished in vivo by angiographic examination[18] as well as by serial arteriotomy for direct visualization of change in individual lesions.[5] Portman et al.[26] reported evidence of disease stabilization in squirrel monkeys achieved by returning the animals to regular chow following 3 months on a high-cholesterol diet. Animals returned to the nonatherogenic diet for 3 –5 months showed significantly fewer aortic lesions and less arterial wall lipid content than did those who remained on the atherogenic diet. In the early 1970s, Armstrong et al.[27] demonstrated unequivocal reduction in the size of advancing, stenosing coronary artery lesions in the rhesus monkey. A 17-month induction phase of a high-fat, high-cholesterol diet was followed by 40 months of a cholesterol-free diet, which allowed total cholesterol to return to a baseline level of 3.62 mmol/L (140 mg/dL). The lesions produced during dietary induction were found to average 60% obstruction in all main epicardial coronary arteries. After 40 months on regression diets, average coronary lumen obstructions had decreased to approximately 21%. Stary[28] observed normalization of cell kinetics in arterial lesions during regression after returning monkeys to a basal diet for 3 – 10 months. Reparative changes included a measurable decrease in intracellular lipid and a return to normal cellular proliferative patterns. Initial signs of disease reversibility were seen as soon as 4 weeks after the total cholesterol had returned to baseline levels. Foam-cell production stopped and normalization of smooth muscle cell morphology was observed. Tucker et al.[29] returned rhesus monkeys fed a high-cholesterol, high-fat diet for 2 months to a basal diet for 4 months and found a resulting decrease in the quantity of foam cells and intracellular lipid and an increase in extracellular lipid. Biochemical verification of lipid depletion has been demonstrated by Srinivasan et al.[30] in cynomologus monkeys and by Armstrong et al.[31] in rhesus monkeys. Armstrong et al.[31] observed that in arteries that had undergone regression, arterial wall cholesterol content decreased from 51 to 18 mg/g dry weight and that cholesteryl ester and free cholesterol decreased 69 and 53%, respectively. Regression of the atherosclerotic lesions was also accompanied by measurable reductions in the arterial wall collagen and elastin content.[32] Wissler’s group[11 – 16] has shown that experimental lesions in rhesus monkeys can be reversed by treatment with cholestyramine. Male rhesus monkeys were kept on an atherogenic diet for 1 year and then switched to a lowcholesterol, low-fat diet with or without the addition of cholestyramine. A third group of animals received cholestyramine while remaining on the atherogenic diet. The amount of aortic surface area affected with grossly visible lesions was significantly less at 1 and 2 years in all three treatment groups than among control animals who remained on the atherogenic diet (10–31% vs. 62–84%). Low-cholesterol, low-fat diet

with added cholestyramine produced the most favorable results, particularly in the coronary arteries, where there was 1–5% luminal narrowing versus 12 –36% narrowing among animals remaining on the atherogenic diet. Using female cynomolgus monkeys, Malinow et al.[17] also have shown coronary artery regression in monkeys fed an atherogenic diet for 6 months and then treated with cholestyramine for 18 months. Cholestyramine decreased the plasma cholesterol level to normal 4.24 mmol/L (164 mg/dL) and normalized lipoprotein patterns. Mendelsohn and Mendelsohn[21] studied the effect of polyunsaturated fat on regression of aortic and iliac vessel atherosclerosis. Vervet monkeys were initially placed on a “Western” diet containing 190 mg/day of cholesterol with a polyunsaturated/saturated fat (P/S) ratio of 0.28 for 24 months. One group continued on this diet, while the other had an adjustment of the P/S ratio to 1.5 and received an increase in daily cholesterol to maintain equivalence in the total sterol intake between the two groups. Both diets were continued for 20 additional months. Percentage of atheroma and arterial wall content of total cholesterol and cholesteryl ester were significantly higher than at baseline in the group that continued the Western diet ðP=S ¼ 0:28Þ versus the group with the increased P/S ratio (1.5). These results imply that dietary modification of the types and amounts of fats ingested as a cholesterol carrier can influence lesion regression. Kramsch et al.[19,20] studied the effects of exercise during induction of atherosclerosis. Regular moderate exercise in cynomolgus monkeys comparable to jogging in humans increased coronary vessel caliber and decreased lesion size. A control group fed regular chow for 36 months was compared to a group of monkeys on an atherogenic diet for 36 and 42 months. Half the latter group received regular treadmill exercising three times per week while the other half were sedentary. In the sedentary monkeys on the atherogenic diet, coronary artery mean involvement was 46–60%, compared to 15–20% in the exercising monkeys on the atherogenic diet. Whether there may be a threshold total cholesterol level at which atherosclerotic lesions undergo regression has been considered by several investigators. The threshold-forregression levels of total cholesterol tested in monkeys are well within ranges attainable in human beings. Clarkson et al.[33] induced cholesterol levels of approximately 15.51 mmol/L (600 mg/dL) in rhesus monkeys and then compared regression regimens with levels of 5.17 and 7.75 mmol/L (200 and 300 mg/dL). After 24 months, 13 of 19 animals in the 5.17 mmol/L group and 9 of 18 animals in the 7.75 mmol/L group showed coronary artery lesion regression, a nonsignificant difference between the two groups. At 48 months, 5.17 mmol/L prevented progression in practically all of the animals. The authors also reported an inverse relationship between high-density lipoprotein (HDL) cholesterol and coronary artery lesion progression. Only regression and no progression occurred at a total cholesterol/HDL cholesterol ratio of 2.5. No regression was seen in animals with a total cholesterol/HDL cholesterol ratio greater than 3.5. Changes seen in the abdominal aorta were comparable to those observed in the coronary arteries. Armstrong et al.[27] found that a serum cholesterol level of 3.62 mmol/L (140 mg/dL) resulted in regression of severe atherosclerotic lesions in the coronary artery and aorta in

Chapter 15. Regression and Stabilization of Atherosclerosis by Medical Treatment

rhesus monkeys. Vesselinovitch et al.[34] observed that returning rhesus monkeys to a low-cholesterol, low-fat diet for 18 months after 18 months of a high-cholesterol high-fat diet leads to regression of advanced coronary artery and aortic atherosclerotic lesions when total cholesterol levels are maintained at or below 4.52 mmol/L (175 mg/dL). DePalma et al.[18] found that regression of fatty-fibrous plaques in rhesus monkeys occurred at levels of total cholesterol below 5.17 mmol/L (200 g/dL). Several researchers have shown that atherosclerosis can be prevented if calcium channel blockers are administered concurrently with high-cholesterol diets to rabbits[39] and monkeys.[40] Thiery et al.[41] have shown that calcium channel blockers, without altering elevated plasma lipid levels, can lead to regression of established plaques in rabbits.

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Yokoyama et al.[50] demonstrated complete disappearance of a 90% stenotic renal artery lesion in a 5-year-old homozygous familial hypercholesterolemic patient after 6 years of low-density lipoprotein (LDL) apheresis. Prior to therapy, the patient’s total cholesterol was 18.62 mmol/L (720 mg/dL); during plasmapheresis, it averaged 7.76 mmol/L (300 mg/dL). Atherosclerotic lesions also regressed in the supravalvular region of the ascending aorta and stabilized in the coronary arteries.

Carotid Artery Among three brothers with severe familial hypercholesterolemia treated with plasmapheresis and followed with duplex ultrasound imaging, Keller and Spengel[51] observed regression and stabilization in two who had continuous plasmapheresis and progression in one who discontinued plasmapheresis.

Coronary Artery and Aorta

Uncontrolled Studies and Case Reports Femoral Artery The earliest human angiographic studies, of the femoral ¨ st and Ste´nson,[46] who treated 31 arteries, were reported by O hyperlipidemic men for intermittent claudication with 3 –6 g of nicotinic acid per day. After a mean treatment period of 42 months, 3 patients showed regression and 11 patients arrest of progression of femoral lesions. Barndt et al.[47] in a study conducted on 25 hyperlipidemic patients, reported 9 patients with regression and 3 with arrest in progression after an average of 13 months of treatment with lipid-lowering drugs, principally clofibrate and neomycin. Regression of disease was significantly correlated with reductions in total serum cholesterol levels, triglyceride levels, and systolic and diastolic blood pressures.

Popliteal Artery In one of the first angiographic case studies, DePalma et al.[48] showed plaque regression by serial arteriograms taken 9 months apart in the popliteal artery of a 57-year-old diabetic man who had reduced his total cholesterol from 8.46 to 4.91 mmol/L (327 to 190 mg/dL) after initiating dietary therapy, exercise, and cessation of cigarette smoking.

Renal Artery Basta et al.[49] reported a case of a 49-year-old hypertensive woman with renovascular hypertension due to a 90% occlusion of the right renal artery and a 75% narrowing of the left renal artery. After 3 years of therapy with cholestyramine and clofibrate, total cholesterol was reduced from 8.79 to 3.90 mmol/L (340 to 151 mg/dL) and total triglycerides from 1.77 to 1.37 mmol/L (157 to 121 mg/dL). A repeat arteriogram showed almost complete resolution of the right renal artery occlusion and some regression of the left renal artery lesion, with concomitant normalization of blood pressure and the peripheral vein plasma renin level.

Long-term (1 –2 years) plasma exchange for treatment of familial hypercholesterolemia was evaluated with serial aortograms and coronary angiograms 1 –2 years apart by Thompson et al.[52] Plasma exchange plus nicotinic acid in three homozygous patients produced a reduction in mean total cholesterol from 15.83 to 9.52 mmol/L (612 to 368 m/dL) and angiographic evidence of aortic supravalvular lesion stabilization. In two heterozygous patients, plasma exchange plus cholestyramine reduced mean total plasma cholesterol from 6.36 to 4.65 mmol/L (246 to 180 mg/dL), with coronary artery lesion regression in one patient and stabilization in the other. Stabilization of coronary atherosclerosis for 3 years with plasma exchange and lipid-lowering medication has also been demonstrated in homozygous familial hypercholesterolemia by Stein et al.[53] Rafflenbeul et al.,[54] in an angiographic study of coronary anatomy of 25 patients with unstable angina, noted regression in 5 patients treated after an average interval of 1 year with a low-saturated-fat diet and counseling for cigarette cessation. Lipid-lowering medications were not used. Roth and Kostuk[55] reported a symptomatic patient with a positive exercise thallium stress test and a 90% stenosis of the left anterior descending artery. Dietary modification and increased exercise reduced the total serum cholesterol level from 6.96 to 5.20 mmol/L (269 to 201 mg/dL) and the triglyceride level from 2.21 to 0.03 mmol/L (205 to 93 mg/dL). Repeat angiography 1 year later showed decreased stenosis in the left anterior descending artery and disappearance of retrograde collateral filling from the right coronary artery seen on a first angiogram. The patient was asymptomatic and repeat exercise thallium stress tests were normal. Kuo et al.[56] examined the effect of lipid lowering induced by dietary and colestipol therapy on coronary artery, brachiocephalic, and peripheral arterial lesions in familial type II hyperlipoproteinemia with a 3- to 4-year interval between angiograms. Average total cholesterol level decreased from 10.68 to 6.98 mmol/L (413 to 270 mg/dL) and the LDL cholesterol from 8.56 to 4.86 mmol/L (331 to

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188 mg/dL). Stabilization of lesions was demonstrated in all three vascular beds in 21 of 25 subjects. Nash et al.[57] reported 25 patients who received colestipol hydrochloride and 17 nonresponders to colestipol who were given placebo. All patients were on a low-cholesterol, low-fat diet, and all had baseline serum cholesterol levels greater than 6.46 mmol/L (250 mg/dL). Angiograms were repeated after 2 years, at which time the total cholesterol had decreased 21%, 7.24 to 5.74 mmol/L (280 to 222 mg/dL), with colestipol treatment and 2% 6.77 to 6.64 mmol/L (262 to 257 mg/dL), in the placebo group. In the drug-treated group, 22 of 25 patients had stable coronary artery lesions, in the placebo group, 9 of 17 were stable ðp ¼ 0:011Þ: Nikkila et al.[58] compared 28 patients on lipid-lowering diet and clofibrate and nicotinic acid therapy to 13 nonrandomized controls drawn from another study who were not on lipid-lowering diet or medication. In the dietdrug–treated group, total cholesterol, triglyceride, and LDL cholesterol decreased by an average of 18, 38, and 19%, respectively, and HDL cholesterol increased 10%. More patients showed coronary artery lesion stabilization upon repeat angiography at 2 years in the treated group than in the control group: 9 out of 28 (32%) versus 1 out of 13 (8%). The Leiden Intervention Trial,[59] a 2-year test of vegetarian diet with a P/S ratio greater than 2.0 and cholesterol intake less than 100 mg/day, included 39 patients with angiograms separated by 2 years. There was no control group. Eighteen patients showed no progression in coronary angiograms analyzed both by visual assessment and computerized image processing. Lesion progression was strongly related to the total cholesterol/HDL, cholesterol ratio, and no coronary lesion progression occurred in patients with a total cholesterol/HDL cholesterol ratio below 6.9 throughout the study or in those who had reduced a high ratio at baseline to less than 6.9. An important finding of the Leiden study was the indication that lesion progression can be arrested by dietary modification without weight loss. Atherosclerotic lesions have long been known to decrease with severe, war-related dietary deprivation[60] and wasting disease.[61]

Controlled Clinical Trials Femoral Artery In 1976, Terry et al.[62] reported atherosclerotic lesion stabilization in a randomized double-blind test of pyridinol carbamate versus placebo. After 2 years of treatment, 19 of 22 drug-treated patients showed no progression, while 15 of 16 placebo patients did show progression. This study provided early information on an appropriate treatment interval for angiographic trials because angiograms were obtained yearly and showed a difference in progression at 2 years. In a study of advanced femoral artery disease, Duffield et al.[63] described quantitative evidence of disease stabilization and regression. Twenty-four patients with stable intermittent claudication and baseline total cholesterol levels greater than 6.52 mmol/L (252 mg/dL) and/or triglyceride levels exceeding 1.78 mmol/L (158 mg/dL) were randomly assigned to a usual-care group or a drug treatment group,

which included dietary advice and cholestyramine, nicotinic acid, or clofibrate therapy. All patients received antismoking advice and a weight-reducing diet if indicated. Patients in the usual-care group showed no significant lipid changes. The treatment group exhibited mean plasma reductions in total cholesterol, total triglycerides, LDL cholesterol, and VLDL cholesterol of 25, 45, 28, and 57%, respectively, and a 26% increase in HDL cholesterol. Paired, matched femoral angiograms obtained an average of 19 months apart were analyzed visually and by computerized image processing. The treatment group had 60% fewer arterial segments showing progression than did the control group ðp , 0:01Þ: The mean increment in the arterial surface area covered by plaque (square millimeter per segment per year) among the treated patients was 33% less than that observed among the nontreated patients ðp , 0:01Þ: Regression was observed in 15 of 46 segments in the treatment group compared to 7 of 46 in the control group as determined by an edge irregularity index ðp , 0:05Þ: The Cholesterol-Lowering Atherosclerosis Study, described in more detail in the next section, was a randomized, placebo-plus-diet controlled clinical trial of aggressive colestipol-niacin plus dietary therapy to reduce LDL cholesterol and increase HDL cholesterol. Coronary, carotid, and femoral arterial beds were studied to provide a complete survey of atherosclerosis. These three vascular beds were visualized by angiographic and/or ultrasonographic methodology. The femoral arteries were visualized with angiography at baseline and after 2 years of treatment in 153 subjects. The annual rate of change in a computer-estimated measure of lumen abnormality was used to determine the persegment therapy effect between treatment groups.[64] A significant per-segment treatment effect was found in segments with moderately severe atherosclerosis ðp , 0:04Þ and in proximal segments ðp , 0:02Þ; but not in segments with mild or severe atherosclerosis.

Coronary Artery Lipid-Lowering Antiatherosclerosis Therapies. Cohn et al.,[65] who conducted the earliest controlled coronary angiographic trial, randomized 24 patients to clofibrate therapy and 16 patients to placebo. Total cholesterol and triglyceride levels were minimally reduced 3 and 14%, respectively, in the clofibrate group. No significant reduction in the progression of atherosclerosis was noted after 1 year. The National Heart, Lung, and Blood Institute Type II Coronary Intervention Study[66,67] (NHLBI type II) was a double-blind, randomized, placebo-controlled trial designed to test the effects of cholestyramine on the progression of coronary atherosclerosis. Average entry serum levels for total cholesterol, triglyceride, LDL cholesterol, and HDL cholesterol were 8.35, 1.85, 6.52, and 1.01 mmol/L (323, 164, 252, and 39 mg/dL), respectively. A prerandomization lowcholesterol, low-fat diet reduced LDL cholesterol 6% in both the treatment and control groups. After randomization, this level decreased another 5% in the control group and another 26% in the cholestyramine-treated group. At the end of the 5-year study period, there was a significant difference in total cholesterol, 7.47 versus 6.62 mmol/L (289 vs. 256 mg/dL), and LDL cholesterol, 5.66 versus 4.60 mmol/L

Chapter 15. Regression and Stabilization of Atherosclerosis by Medical Treatment

(219 vs. 178 mg/dL), between the cholestyramine and placebo groups. Triglyceride levels, 1.82 versus 2.18 mmol/L (161 vs. 193 mg/dL), and HDL cholesterol, 1.01 versus 1.06 mmol/L (39 vs. 41 mg/dL), were not significantly different between the two groups. Matched angiograms were evaluated in 116 patients, 57 placebo-treated and 59 cholestyramine-treated, after 5 years. Repeat angiograms were originally scheduled after 2 years, but only 9 out of 31 patients showed any lesion change, and the interval was therefore lengthened to 5 years. Definite progression of disease occurred in 35% (20 of 57) of the placebo-treated group compared to 25% (15 of 59) of the cholestyramine-treated group. Probable progression was found in 14% (8 of 57) of the placebo patients and in 7% (4 of 59) of the drug-treated patients. Definite and probable progression combined occurred in 49% (28 of 57) of the placebo-treated patients compared to 32% (19 of 59) of the cholestyramine-treated patients ðp , 0:05Þ: Definite regression was found in 2% (1 of 57) of the placebo-treated group compared to 3% (2 of 59) of the drug-treated group. After baseline demographic inequalities and lesion severity were taken into account, it was found that lesions with a 50% or more stenosis at baseline progressed more slowly in the cholestyramine-treated group than in the placebo-treated group, 12 versus 33% respectively ðp , 0:05Þ: Increases in ratios of HDL cholesterol/total cholesterol and HDL cholesterol/LDL cholesterol were found to be the best predictors of lesion stabilization.[67] The Cholesterol-Lowering Atherosclerosis Study (CLAS)[68] was the first angiographic trial to demonstrate lesion regression in humans. This was a single-blind, randomized, placebo-controlled angiographic trial consisting of 188 nonsmoking, nondiabetic, normotensive men aged 40– 59 years who all had coronary bypass surgery and entrance fasting cholesterol levels between 4.78 and 9.05 mmol/L (185 and 350 mg/dL). Coronary angiograms were obtained at baseline and repeated 2 years after therapy in 162 patients. The control group films were evaluated first by panels of expert angiographers with a global change score (GCS)[68] and later by quantitative coronary angiography (QCA) using automated computerized image processing.[69,70] The control group followed a diet that provided 26% of energy as fat (10% as polyunsaturated fat and 5% as saturated fat) and contained 250 mg of cholesterol per day. The treatment group received maximal dosage of colestipol (30 g/day) and nicotinic acid (3–12 g/day, average 4.3 g/day) as well as a diet that provided 22% energy as fat (10% polyunsaturated fat and 4% saturated fat) and contained 125 mg/day of cholesterol. After 2 years of intervention, the treatment group showed large decreases in total cholesterol (27%), from an average of 6.36 mmol/L (246 mg/dL) at baseline to 4.65 mmol/L (180 mg/dL); total triglycerides (27%), 1.70 to 1.24 mmol/L (151 to 110 mg/dL); LDL cholesterol (43%), 4.42 to 2.51 mmol/L (171 to 97 mg/dL); and the ratio of LDL cholesterol/HDL cholesterol (58%), 4.0 to 1.7. HDL cholesterol increased 36% from 1.15 to 1.57 mmol/L (44.6 to 60.8 mg/dL). In the placebo group, smaller, statistically significant decreases also occurred: total cholesterol (5%), 6.28 to 6.00 mmol/L (243 to 232 mg/dL); total triglycerides (8%), 1.74 to 1.59 mmol/L (154 to 141 mg/dL); LDL cholesterol (5%), 4.37 to 4.14 mmol/L

253

(169 to 160 mg/dL); and LDL cholesterol/HDL cholesterol (8%), 4.0 to 3.7. HDL cholesterol also increased 2%, from 1.13 to 1.15 mmol/L (43.7 to 44.4 mg/dL). All 162 patients had evaluable GCS end points; 156 of the 162 patients had evaluable end points by QCA. The distribution of angiographic change as determined by GCS (percentage of control group patients vs. percentage of treatment group patients) was regression (4% vs. 16%), progression (59% vs. 39%), and no change (37% vs. 45%) ðp , 0:001Þ: The percentage of patients in the treatment group with new lesion formation in native arteries was reduced compared to the control group (22% vs. 10%; p , 0:03).[68] Also compared to the control group, the drugtreated group showed a significant reduction in the percentage of patients with new lesion formation (30% vs. 12%; p , 0:04) and any adverse changes (39% vs. 24%; p , 0:03) in the venous bypass grafts.[68] The average ^ standard deviation change in percent diameter stenosis (% S) and minimum lumen diameter (MLD) for native arteries plus venous bypass grafts as determined by QCA (control group vs. treatment group) was 2:7 ^ 5:8% S versus 0:3 ^ 5:9% S ðp ¼ 0:02Þ and 20:09 ^ 0:26 mm versus 20:01 ^ 0:22 mm ðp ¼ 0:04Þ; respectively.[70] The evidence for angiographic benefit retained statistical significance after the cohort was divided according to baseline total cholesterol levels, ranging from 4.78 to 6.20 mmol/L (185 to 240 mg/dL) and from 6.23 to 9.05 mmol/L (241 to 350 mg/dL). This implicates the entire range of total cholesterol from 4.78 to 9.05 mmol/L (185 to 350 mg/dL) as a risk factor for arterial lesion progression. In a 2-year continuation study of the CLAS trial (CLAS II)[71] repeat coronary artery angiograms were obtained in 103 patients who continued colestipol –nicotinic acid therapy ðn ¼ 56Þ and placebo ðn ¼ 47Þ for an additional 2 years. Changes in lipid levels obtained in CLAS I were maintained in CLAS II. The repeat angiograms represented 4 years of colestipol–nicotinic acid therapy, which, when compared to the control group, showed a greater percentage of patients with regression (18% vs. 6%), a lesser percentage of patients with progression (48% vs. 88%), and a greater percentage of patients with stabilization (34% vs. 6%). Also compared to the control group, the treatment group showed a significant reduction in the percentage of patients with new lesions (40% vs. 13%) in native arteries. The drug-treated group also showed a significant reduction in the percentage of patients with new lesions in venous bypass grafts as compared to the control group (38% vs. 18%). Overall, the coronary artery lesion status of the drug- and placebo-treated groups grew more divergent over the additional 2 years, with the drugtreated group showing stability of lesions and the placebotreated group showing marked progression.[71] The power of CLAS to detect lesion change was greater than that of previous angiographic trials because more subjects completed sequential angiograms and maintained larger changes in LDL cholesterol (LDL-C) and HDL cholesterol (HDL-C) levels. The Familial Atherosclerosis Treatment Study (FATS) was the first coronary angiographic trial to report reduced cardiac morbidity with medical treatment.[72] One hundred and fortysix men less than 62 years of age with elevated apolipoprotein B levels ð. 125 mg=dLÞ and a family history of coronary artery disease were randomized to lovastatin-colestipol,

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niacin-colestipol, or conventional care. Angiograms were separated in time by an average 2.5 years and analyzed by QCA. In the conventional care group, 46% of the subjects had lesion progression in at least one proximal coronary artery segment. Progression was less frequent in the subjects treated with lovastatin-colestipol (21%) and niacin-colestipol (25%). Regression was more frequent in the lovastatin-colestipol (32%) – and niacin-colestipol (39%) –treated subjects than those in conventional care group (11%). Multivariate analysis indicated reduction in apolipoprotein B (or LDL-C) and systolic blood pressure and an increase in HDL-C correlated with regression of coronary artery lesions. In the conventional care group, average change (mean ^ standard deviation) in % S was 2:0 ^ 3:7% S versus 20:3 ^ 5:0% S in the lovastatin-colestipol group and 21:1 ^ 3:7% S in the niacin-colestipol group ðp ¼ 0:0009Þ: Mean change in MLD in the conventional care group was 20:05 ^ 0:14 mm versus 20:002 ^ 0:14 mm in the lovastatin-colestipol group and 0:04 ^ 0:12 mm in the niacin-colestipol group ðp ¼ 0:003Þ: Clinical events (death, myocardial infarction, or revascularization) occurred in 19% of subjects in the conventional care group compared to 7% of subjects in the lovastatin-colestipol group and 4% of subjects in the niacin-colestipol group. The relative risk of a clinical coronary event during lipid-lowering therapy compared to conventional care was 0.27 (95% confidence interval, 0.10 –0.77). The University of California, San Francisco, Specialized Center of Research (UCSF SCOR) Intervention Trial was the first randomized, placebo-controlled trial to demonstrate statistically significant coronary angiographic lesion regression in women.[73] This trial was conducted in 72 subjects (41 women), 19 –72 years of age with heterozygous familial hypercholesterolemia in which only 3 subjects had objective evidence of coronary artery disease prior to the baseline angiogram. The treatment group received a combination of lipid-lowering agents up to 30 g of colestipol and 7.5 g of niacin daily. When lovastatin became available, 16 subjects were given 40 –60 mg daily in binary or ternary drug combinations. At first the control group was treated with diet alone. Later, 7 control men and 7 control women took 15 g of colestipol per day. The control group was thus comprised of those treated with diet alone and those with diet plus colestipol. After 2 years of treatment, angiograms were evaluated with per-patient averages in percent area stenosis determined by QCA. Mean change in percent area stenosis among controls was +0.80, indicating an average progression, while mean change for the treatment group was 2 1.53, indicating regression ðp ¼ 0:039Þ: When analyzed by gender, treatment group differences in lesion change among women was significant ðp ¼ 0:05Þ; whereas for men it was not ðp ¼ 0:42Þ: Treated women demonstrated a response of 2 2.06 in percent area stenosis, whereas men demonstrated a 2 0.88 change. Change in percent area stenosis was correlated with on-trial LDL-C levels. Because patients randomized to the UCSF SCOR study had heterozygous familial hypercholesterolemia, the baseline average LDL-C level was much higher than that in other serial coronary angiographic trials, 7.32 mmol/L (283 mg/dL) versus 3.52 mmol/L (136 mg/dL) to 5.07 mmol/L (196 mg/dL) (Table 15-1). Although the LDL-C reduction of 39% in the UCSF SCOR drug-treated group was

comparable to other serial coronary angiographic trials, the on-trial LDL-C level remained quite elevated relative to these other studies, 4.45 mmol/L (172 mg/dL) versus 2.46 mmol/L (95 mg/dL) to 3.36 mmol/L (130 mg/dL), respectively (Table 15-1). In fact, the on-trial LDL-C level in the UCSF SCOR drug-treated group was even higher than the on-trial LDL-C level in most of the placebo-treated groups of the other angiographic trials, which ranged from 3.10 mmol/L (120 mg/dL) to 4.65 mmol/L (180 mg/dL). It is often debated whether it is the absolute on-trial LDL-C level or percentage reduction of LDL-C that is important in the treatment of atherosclerosis. Data from the UCSF SCOR indicate that when on-trial LDL-C levels remain high after being reduced from an even greater level, progression of atherosclerosis can be stabilized. These data are also substantiated by the NHLBI type II study,[66,67] which had similar lipid level and angiographic outcome results as the UCSF SCOR study. The St. Thomas’ Atherosclerosis Regression Study (STARS) was a three-arm placebo-controlled study in which 90 men with coronary heart disease were randomized; 74 subjects completed the study with paired angiograms, 24 in the usual care group, 26 in the dietary intervention group, and 24 in the diet-cholestyramine group.[74] Paired angiograms were performed at baseline and after 39 months. Mean absolute arterial width, the primary end point, was measured by QCA. The proportion of subjects who showed overall progression of coronary narrowing was reduced by both interventions, 12% of subjects in the diet-cholestyramine group and 15% in the diet group compared to 46% in the usual care group (p , 0:02 for trend). Regression occurred in 33%, 38%, and 4% of subjects, respectively (p , 0:02 for trend). Per patient average width of coronary segments increased 0.103 mm with diet-cholestyramine and 0.003 mm with diet and decreased 0.201 mm in controls (p ¼ 0:012 for trend). Per patient change in % S did not show a significant effect (p ¼ 0:07 for trend). With segments rather than subjects as the experimental unit, treatment effects were found for mean arterial width, minimum width, % S, and vessel edge irregularity (p , 0:002 for trend in all measures). Improvement in mean absolute arterial width correlated with on-trial LDL-C levels and LDL-C/HDL-C ratios. Both dietcholestyramine and diet interventions reduced the frequency of total cardiovascular events (death, myocardial infarction, revascularization, or stroke). Fourteen subjects had clinical events: 10 (36%) control subjects, 1 (4%) diet-cholestyramine subject (p , 0:01 compared to control subjects), and 3 (11%) diet subjects (p , 0:05 compared to control subjects). The Stanford Coronary Risk Intervention Project (SCRIP) included 300 men and women (13% women) less than 75 years of age; 155 patients were randomized to usual care and 145 patients were randomized to multifactorial risk reduction, which included drug treatment principally with colestipolniacin, low-fat low-cholesterol dietary modification, smoking cessation, weight reduction, and exercise.[75] QCA arterial diameter measurements were made in nonbypassed coronary segments at baseline and 4 years later in 246 patients. The rate of change in MLD was 20:045 ^ 0:073 mm=y in the usualcare group and 20:024 ^ 0:066 mm=y in the risk-reduction group ðp , 0:02Þ: In women, the change was 20.046 mm/y for the usual-care group ðn ¼ 20Þ versus 2 0.016 mm/y for the

2

2.5

Pravastatin

REGRESS [83] Pravastatin

Fluvastatin

Pravastatin

PLAC I [82]

LCASe [84]

CARS [85]

2

4

247/270 (9%)b 37– 67 yrs (58 yrs) 299/331 (19%) 27– 70 yrs (54 yrs) 345/381 (10%) 30– 67 yrs (55 yrs) 320/408 (20%) (57 yrs)d 778/885 (0%) (56 yrs)d 261/319 (19%) 35– 75 yrs (58 yrs) 80/90 (23%) (64 yrs)d 232/159 153/43 250/194 173/41 244/170 169/43 231/166 164/41 233/157 166/36 213/165 137/43 189/126 123/41

156(2 32%)/120(2 22%) 93(2 38%)/46(+9%) 196(2 21%)/173(2 8%) 122(2 29%)/43(+7%) 191(2 23%)/149(2 18%) 117(2 31%)/46(+9%) 187(2 19%)/153(2 8%) 118(2 28%)/44(+7%) 189(2 20%)/129(2 7%) 125(2 29%)/39(+10%) 184(2 14%)/160(2 0.1%) 106(2 23%)/46(+9%) 166(2 11%)/114(7%) 99(2 18%)/45(+10%) CARS

LCAS

REGRESS

PLAC I

MAAS

CCAIT

MARS

b

Percentage of subjects. Percentage of women. c Mean ^ standard deviation, unless indicated. d Age range not reported. e 25% of subjects also received cholestyramine; data reported are based on subjects who received only fluvastatia. MARS = Monitored Atherosclerosis Regression Study. CCAIT = Canadian Coronary Atherosclerosis Intervention Trial. MAAS = Multicenter Anti-Atheroma Study. PLAC I = Pravastatin Limitation of Atherosclerosis in the Coronary Arteries. REGRESS = Regression Growth Evaluation Statin Study. LCAS = Lipoprotein and Coronary Atherosclerosis Study. CARS = Coronary Artery Regression Study. % S = Percent diameter stenosis. MLD = Minimum lumen diameter (mm). Control = Control group. Intervention = Lipid-lowering intervention group.

a

3

Simvastatin

MAAS [81]

2

Lovastatin

CCAIT [78]

2

Lovastatin

MARS [76]

Trial [Ref.]

Trial

Trial No. completed/ duration No. randomized Baseline TC/TG Intervention (y) age range (average) LDL-C/HDL-C (mg/dL)

On-trial TC/TG, LDL-C/HDL-C, mg/dL (% change)

Serial Coronary Angiographic Trials of HMG-CoA Reductase Inhibitor Monotherapy

Table 15-1.

41 29 50 33 32 23 38 26 28 22 36 29 39 18

Progressiona control intervention 12 23 7 10 12 19 14 14 5 8 8 14 2 3

na na na na 43 53 35 48 18 18 na na na na

Regressiona Stabilizationa control control intervention intervention na na 32 16 4 12 30 15 na na na na 12 15

New lesionsa control intervention

MLD change control intervention 2 0.06 ^ 0.21 2 0.03 ^ 0.21 2 0.09 ^ 0.16 2 0.05 ^ 0.13 2 0.13 ^ 0.27 2 0.04 ^ 0.25 2 0.05 mm/y 2 0.03 mm/y 2 0.09 2 0.03 2 0.09 2 0.02 na na

% S change control intervention 2.2 ^ 6.8c 1.6 ^ 6.7 2.89 ^ 5.9 1.66 ^ 4.5 3.6 ^ 9.03 1.0 ^ 7.90 1.12% S/y 0.69% S/y na na 2.5 ^ 9.19 0.5 ^ 9.09 na na

Chapter 15. Regression and Stabilization of Atherosclerosis by Medical Treatment 255

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Part Two. Medical Treatment

risk-reduction group ðn ¼ 10Þ ðp ¼ 0:27Þ: Progression occurred in 49.6% of patients in the usual-care group and 50.4% of the patients in the risk-reduction group; regression occurred in 10.3% of patients in the usual-care group and 20.2% of the patients in the risk-reduction group. In the first study year there were 17 cardiac events in the risk-reduction group and 9 events in the usual-care group ðp ¼ 0:09Þ: Over the next 3 years of the study, there were 8 additional cardiac events in the risk-reduction group and 35 in the usual-care group ðp , 0:003Þ: In more recent coronary angiographic trials, monotherapy with the newest lipid-lowering class of medications, the HMG-CoA reductase inhibitors, has been used. These medications offer certain advantages over the previous class of agents, including a low side effect profile and high tolerability. The Monitored Atherosclerosis Regression Study (MARS) was the first serial coronary angiographic trial of single-drug therapy with an HMG-CoA reductase inhibitor.[76] In this 2year coronary angiographic/carotid ultrasonographic trial, 270 smoking and nonsmoking men and women (9%), 37 –67 years of age, were randomized to lovastatin 40 mg twice daily or placebo. Both treatment groups had daily cholesterol intake targets of ,250 mg and daily fat intake of ,27% of calories, with saturated fat constituting , 7% of total calories and monounsaturated and polyunsaturated fats , 10% of calories each. Because of the minimal side effects of lovastatin, this was the first truly double-blind randomized clinical imaging trial. There were 247 subjects (123 lovastatin, 124 placebo) with baseline and 2-year coronary angiograms available for interpretation. Although mean change in % S by QCA for all lesions was not significant (an average increase of 1.6% S vs. 2.2% S in the lovastatin and placebo groups, respectively), there was a significant response to therapy according to baseline lesion severity. There was no statistical difference between treatment groups for change in lesions , 50% S at baseline (þ2.6% S in the lovastatin group and þ3.0% S in the placebo group). However, for lesions $ 50% S at baseline, there was a mean decrease of 24.1% S with lovastatin therapy compared to þ0.9% S with placebo ðp , 0:01Þ: Minimum lumen diameter (MLD), an absolute measure of lumen width, paralleled % S, providing this latter measure with an internal consistency since MLD is independent of the assumption that adjacent segments are normal. Mean change in MLD evaluated over all lesions was not significant (2 0.03 mm vs. 2 0.06 mm in the lovastatin and placebo groups, respectively). For lesions , 50% S at baseline, there was no statistical difference between treatment groups in change in MLD (2 0.05 mm for lovastatin vs. 20.07 mm for placebo). However, for lesions $ 50% S at baseline, lovastatin increased mean MLD þ0.13 mm compared to 2 0.04 mm with placebo ðp , 0:01Þ: Assessed by QCA, progression was less frequent in lovastatin subjects (29%) than placebo subjects (41%) ðp ¼ 0:07Þ: Regression was twice as frequent in lovastatin subjects (23%) than placebo subjects (12%) ðp ¼ 0:04Þ: Panel evaluation of angiographic change was consistent with the QCA angiographic results. Subgroup analyses of females in the MARS trial indicated two trends: women may have a better lesion response to lipid

lowering than men, and estrogen replacement may enhance lesion response to aggressive lipid-lowering therapy. The % S change after 2 years was þ2.0% S for men on lovastatin, þ0.8% S for women on lovastatin, and 2 2.1% S for women on lovastatin and estrogen. The observation in MARS that women may have a better lesion response to therapy than men has also been reported in the UCSF SCOR,[73] Lifestyle Heart Trial,[77] the Stanford Coronary Risk Intervention Project,[75] and the Canadian Coronary Atherosclerosis Intervention Trial.[78] It is also consistent with evidence indicating that lesions in women appear pathologically younger than those in men.[79] Compared to lesions in men, coronary artery lesions in women consist of more cellular fibrous tissue, found at earlier stages of plaque development, and less dense fibrous tissue, found at later stages of plaque development.[80] This difference in plaque composition suggests a pathological basis for expecting a greater potential for response to therapy in women. Since the MARS trial, there have been six additional published studies[78,81 – 85] examining the effects of HMGCoA reductase inhibitor monotherapy on the progression of atherosclerosis in coronary angiographic trials (Table 15-1). Results from these trials have demonstrated that lipid lowering with HMG-CoA reductase inhibitor monotherapy reduced coronary artery disease progression to a degree similar to the MARS trial (Table 15-1). Summary of Lipid-Lowering Coronary Angiographic Trials. The beneficial effect of slowing coronary artery atherosclerosis progression with LDL-C lowering is irrefutable. Figure 15-1 displays a review of the trials that have used the same angiographic outcome measure—the difference between treatment groups in the change in MLD. Figure 15-1 shows that the beneficial effect of LDL-C lowering is apparent across a broad range of baseline LDL-C levels, 3.36 mmol/L (130 mg/dL) to 5.17 mmol/L (200 mg/dL). Although it is unclear whether it is percentage reduction of LDL-C or the absolute on-trial LDL-C level that is most important in the slowing of coronary artery atherosclerosis, both factors most likely play a role depending on the cohort under study and the duration of intervention. In general, it appears that the longer the intervention, the greater the treatment effect. LDL-C reductions from baseline levels ranged from 20% to 45% and on-trial LDL-C levels from 2.46 mmol/L (95 mg/dL) to 3.36 mmol/L (130 mg/dL) with two exceptions—the Bezafibrate Coronary Angiographic Intervention Trial (BECAIT) and the Lopid Coronary Angiographic Trial (LOCAT). The BECAIT and LOCAT trials, reviewed later in the chapter, demonstrated very similar angiographic outcomes to these trials, although there was essentially no change of LDL-C from baseline, which averaged 4.47 mmol/L (173 mg/dL) and 3.39 mmol/L (130 mg/dL) on-trial, respectively (Fig. 15-1). The BECAIT and LOCAT trials were unique in that a reduction in the total triglyceride level rather than LDL-C was the primary goal. Normalization of all the trials to 2 years of intervention (Fig. 15-1b) reveals several important points. As shown in Fig. 15-1b, the treatment group difference in change in MLD resulting from LDL-C reduction falls into the range of 0.03– 0.06 mm with the majority of trials between 0.04 and 0.06 mm (a range of only 20 mm) with the exception of two trials.

Chapter 15. Regression and Stabilization of Atherosclerosis by Medical Treatment

257

Figure 15-1. Comparison of serial coronary angiographic trials reporting results as minimum lumen diameter measured by quantitative coronary angiography. Results are displayed as treatment group differences in change in minimum lumen diameter by baseline LDL-C levels. LOCAT reported for all native segments. (a) Each data point is labeled by the trial name, the therapeutic intervention, percentage of reduction in the on-trial LDL-C level from baseline, the absolute on-trial LDL-C level, the sample size, and the duration of the intervention. (b) Trials were normalized to a 2-year intervention. BECAIT = Bezafibrate Coronary Angiographic Intervention Trial; CCAIT = Canadian Coronary Atherosclerosis Intervention Trial; CLAS = Cholesterol-Lowering Atherosclerosis Study; FATS = Familial Atherosclerosis Treatment Study; LCAS = Lipoprotein and Coronary Atherosclerosis Study; LOCAT = Lopid Coronary Angiographic Trial; MAAS = Multicenter Anti-Atheroma Study; MARS = Monitored Atherosclerosis Regression Study; PLAC I = Pravastatin Limitation of Atherosclerosis in the Coronary Arteries; REGRESS = Regression Growth Evaluation Statin Study; SCRIP = Stanford Coronary Risk Intervention Project.

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Part Two. Medical Treatment

These data indicate that LDL-C lowering, regardless of the agent used, has a similar effect in reducing coronary artery atherosclerosis progression, but that LDL-C lowering itself may have a threshold or maximal effect on reducing progression of atherosclerosis. This point is demonstrated by the two exceptions to the narrow range of angiographic outcome to LDL-C lowering where colestipol/niacin lipidlowering intervention was used, CLAS and FATS. In addition to lowering LDL-C by 43% in CLAS and 32% in FATS, total triglyceride levels were reduced 27% in CLAS and 29% in FATS and HDL-C raised by 36% and 40%, respectively. These data indicate that further reduction of atherosclerosis progression may result from the lowering of total triglyceride levels and raising of HDL-C levels in addition to the lowering of LDL-C levels. This latter point is further demonstrated by the FATS trial where the angiographic outcome in the colestipol/lovastatin arm of the trial was half that of the colestipol/niacin arm. In the colestipol/lovastatin arm of the trial, LDL-C was reduced by 45%, whereas total triglyceride levels were reduced only 9% and HDL-C raised by 16%. Further, the angiographic outcome of BECAIT, where only the total triglyceride level was reduced, and LOCAT, where only the total triglyceride level was reduced and the HDL-C level raised, had similar angiographic outcomes as the trials in which LDL-C was reduced (Fig. 15-1). Lifestyle Modification. The Leiden Intervention Study,[59] discussed previously, was the earliest clinical trial to demonstrate that coronary artery disease progression in humans could be arrested with dietary modification alone. This study, however, did not have a control group. The STARS trial[74] design contained a dietary intervention treatment arm that demonstrated a reduction in the progression of coronary artery disease relative to a usualcare group. The Lifestyle Heart Trial was a randomized, controlled trial specifically designed to study lifestyle modification without lipid-lowering therapy on the progression of coronary artery disease.[77] Men and women (10%) between 35 and 75 years of age were recruited; 53 subjects were randomized to the risk-reduction group and 43 subjects to the usual-care control group with 28 and 20 subjects, respectively, taking part in the trial. The restrictive nature of the lifestyle intervention most likely accounted for the large drop-off in subject participation. Risk reduction included low-fat vegetarian diet, smoking cessation, stress management, and aerobic exercise. Treatment group dietary targets included cholesterol intake #5 mg/day, 10% of calories as fat, and allowed no animal products except egg white and 1 cup per day of nonfat milk or yogurt. Stress management included stretching exercises, breathing techniques, meditation, relaxation, and imagery. Dietary fat and cholesterol, which averaged 31% of calories and 213 mg/day on entry, were reduced to 7% of calories and 13 mg/day, respectively. Average weight on entry was reduced from 204 to 181 lb and average blood pressure reduced from 134/83 to 127/79 mmHg. At the end of the 1-year intervention, there were 22 treated and 19 control subjects with analyzable film pairs in which 105 coronary artery lesions in the treated group were compared with 90 lesions in the control group by QCA. Average % S was reduced from 40.0% S to 37.8% S in the

treated group and increased from 42.7% S to 46.1% S in the control group ðp ¼ 0:001Þ: Degree of adherence to lifestyle changes was directly correlated with extent of change in % S. The 5 women (all postmenopausal and not taking hormonereplacement therapy) in this study—1 in the intervention group and 4 in the control group—demonstrated regression with only moderate lifestyle changes. The Heidelberg Study was a randomized, controlled coronary angiographic trial designed to study the effects of dietary modification and exercise on the progression of coronary artery disease in subjects recruited after undergoing routine coronary angiography for angina pectoris.[86] A total of 113 patients 35 –68 years of age were randomized; 56 subjects were randomized to the intervention group which included a low-fat, low-cholesterol dietary intake and daily exercise at home on a cycle ergometer for a minimum of 30 minutes at 75% of the maximal heart rate. Daily total caloric intake included 15% protein, 65% carbohydrates, and , 20% fat; cholesterol , 200 mg daily with the polyunsaturated-tosaturated fatty acid ratio of , 1.57 subjects were randomized to the usual-care comparison group. Neither group received lipid-lowering medications. Coronary angiograms were obtained at baseline and repeated in 1 year in 40 patients in the intervention group and 52 patients in the usual-care control group. In the intervention group, body weight decreased by 5% from the baseline level of 176 pounds, total cholesterol decreased 10% from the baseline level of 234 mg/dL, LDL-C decreased 8% from the baseline level of 164 mg/dL, and triglycerides decreased 24% from the baseline level of 174 mg/dL (all p , 0:05). Based on MLD determined by QCA, coronary angiographic change between the usual-care control group versus the intervention group was significantly different; progression was seen in 48% of patients in the usual-care control group versus 23% in the intervention group; regression in 17% versus 32% of patients, respectively; and, stabilization in 35% versus 45% of patients, respectively. On a per-lesion basis, mean % S and MLD remained stable in the intervention group, 65 ^ 24% S at baseline to 64 ^ 23% S at 1 year; 0:92 ^ 72 mm at baseline to 0:91 ^ 0:67 mm at 1 year. In the usual-care control group, the per-lesion analysis showed significant progression of coronary artery lesions, 63 ^ 29% S at baseline at 66 ^ 28% S at 1 year and 1:00 ^ 0:87 mm at baseline to 0:87 ^ 0:79 mm at 1 year. The changes (progression) in the usualcare control group were significantly different from the intervention group ðp , 0:05Þ:

Calcium Channel Blockers In addition to lipid-lowering agents, other forms of medical therapy have been tested in coronary angiographic studies. Loaldi et al.[87] compared 2 years of therapy with nifedipine, a dihydropyridine calcium channel blocker (39 patients), propranolol (50 patients), and isosorbide dinitrate (38 patients). Baseline total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides averaged 5.17, 4.14, 0.90, and 1.58 mmol/L (200, 160, 35, and 140 mg/dL), respectively. The propranolol group showed a 28% increase in the level of triglycerides and a 25% decrease in the level of HDL cholesterol on trial, while the other two groups showed no lipid changes. The percentage of subjects with progression

Chapter 15. Regression and Stabilization of Atherosclerosis by Medical Treatment

was 31% in the nifedipine group compared to 53% in the propanolol group and 47% in the isosorbide dinitrate group ðp , 0:05Þ: Development of new lesions was also significantly lower in the nifedipine group, 10% of subjects, versus 34% and 29% of subjects in the propanolol and isosorbide groups, respectively ðp , 0:05Þ: The International Nifedipine Trial on Antiatherosclerotic Therapy (INTACT) was a randomized, double-blind, placebocontrolled, serial coronary angiographic trial of 425 patients 65 years old or less with coronary artery disease.[88] Patients were randomized to either placebo or nifedipine 80 mg per day. Coronary angiograms were done at baseline and repeated in 348 patients after 3 years; 282 patients (134 nifedipine and 148 placebo) received treatment throughout the study. At entry, 13% of the placebo-treated subjects and 6% of the nifedipine-treated subjects were taking lipid-lowering medications. These medications did not change throughout the study. There were no statistically significant differences in progression or regression of lesions between the placebotreated and the nifedipine-treated groups. However, 59% of nifedipine-treated subjects compared to 82% of placebotreated subjects developed new lesions over the 3-year treatment period ðp ¼ 0:034Þ: These data indicated that nifedipine had no effect on established lesions but significantly reduced the number of new lesions during treatment. The Montreal Study was a randomized, double-blind, placebo-controlled, serial coronary angiographic trial of 383 patients (17% women) 65 years old or less with coronary artery disease.[89] Patients were randomized to either placebo or nicardipine, a dihydropyridine calcium channel blocker, 30 mg three times per day. Coronary angiograms were done at baseline and repeated in 335 patients after 2 years. Patients did not receive lipid-lowering medication. Across all coronary artery lesions, there were no statistically significant differences in progression or regression of lesions between the placebo-treated and the nicardipine-treated groups. However, fewer nicardipine-treated subjects (12%) than placebo-treated subjects (24%) had progression of lesions #20% S at baseline ðp ¼ 0:035Þ: In general, the three coronary angiographic trials of calcium channel blockers[87 – 89] consistently indicated that these agents had no effect on the progression of established or advanced coronary artery lesions but that they significantly reduced development of new lesions and/or progression of mild lesions. LDL-Apheresis. LDL-apheresis entails simple venous access and selective extracorporeal removal of LDL-C by columns that selectively bind LDL particles based on the physical-chemical properties of the LDL particle. In general, HDL-C is conserved during LDL-apheresis. Except for the Familial Hypercholesterolemia Regression Study[90] and the LDL-Apheresis Atherosclerosis Regression Study (LAARS),[91] previous angiographic studies using LDLapheresis have been uncontrolled, as reviewed elsewhere.[92] The Familial Hypercholesterolemia Regression Study (FHRS) was a randomized, controlled, serial coronary angiographic trial of LDL-apheresis plus simvastatin versus simvastatin-plus-colestipol therapy in 49 patients with heterozygous familial hypercholesterolemia and baseline

259

LDL-C levels greater than 8.0 mmol/L (309 mg/dL).[90] Baseline and repeat coronary angiograms after 2 years of therapy were obtained in 20 patients randomizd to LDLapheresis once every 2 weeks plus simvastatin 40 mg every day and 19 patients randomized to combination drug therapy of simvastatin 40 mg plus colestipol 20 g daily. Changes in serum lipids were similar between the two treatment groups except for a greater reduction in LDL-C (124 mg/dL vs. 131 mg/dL; p ¼ 0:03) and Lp(a) (geometric means 14 mg/dL vs. 21 mg/dL; p ¼ 0:03) in the pheresis group. However, there were no significant differences between the apheresis and drug groups in the mean % S change either on a per-patient or per-lesion basis after 2 years of therapy. There were no significant differences between the two treatment groups in the number of patients who showed progression, regression, or stabilization. When analyzed on a per-segment or perlesion basis, mean MLD increased in the drug group (0.07 mm) and decreased in the pheresis group (2 0.004 mm) ðp , 0:046Þ: There was no angiographic benefit from lowering Lp(a) in patients whose LDL-C was concurrently lowered. The LDL-Apheresis Atherosclerosis Regression Study (LAARS) confirmed the results from FHRS. In LAARS, 42 men with baseline LDL-C of . 5.8 mmol/L (224 mg/dL) were randomized to LDL-apheresis once every 2 weeks plus simvastatin 40 mg every day (19 men) versus simvastatin 40 mg every day (19 men). Men in both groups received the highest tolerable dosage of a bile acid sequestrant if their total cholesterol level exceeded 8 mmol/L (309 mg/dL) for more than 2 consecutive months. The total cholesterol, LDL-C, and Lp(a) reductions were significantly greater in the drug/pheresis group than the drug only group ðp , 0:05Þ: On-trial plasma concentration of total cholesterol was 4.63 mmol/L (179 mg/dL) versus 5.95 mmol/L (230 mg/dL), and LDL-C levels were 2.95 mmol/L (114 mg/dL) versus 4.13 mmol/L (160 mg/dL) in the drug/pheresis group versus the drug-only group, respectively. The Lp(a) on-trial level was 45 mg/dL in both groups. Coronary angiography, repeated 2 years after the baseline angiogram, showed no treatment differences between the two interventions analyzed on either a perpatient or a per-segment basis. In the pheresis group, MLD on a per-patient and per-segment basis showed a change of 2 0.01 mm, whereas the drug-only group showed a change of 0.01 mm. Although LDL-apheresis can be used to effectively reduce LDL-C, it appears not to have any advantage over lipidlowering therapy in the routine management of atherosclerosis. However, LDL-apheresis provides a safe and effective alternative for reducing LDL-C in individuals with established atherosclerosis who cannot tolerate or do not respond to lipid-lowering medications.

Surgery Partial ileal bypass alone or in combination with lipidlowering drugs can be used to lower blood cholesterol. In 1953 Byers, Friedman, and Gunning[93] provided evidence that cholesterol absorption occurs in the small bowel of the rabbit and that the more distal the segment, the greater the absorption. Siperstien and coworkers[94] noted that the presence of bile was obligatory to the intestinal absorption

260

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of cholesterol. The first partial ileal bypass (PIB), specifically intended to manage hyperlipidemia in a human, was performed in May 1965.[95] The Program on Surgical Control of the Hyperlipidemias (POSCH), a multicenter trial initiated in 1975, randomized 421 postmyocardial infarction patients to PIB and 417 to diet control. Entry criteria required total cholesterol levels greater than 5.66 mmol/L (219 mg/dL) and LDL cholesterol greater than 6.18 mmol/L (239 mg/dL).[96] Compared to control patients, PIB produced a 30% reduction in total plasma cholesterol, 40% reduction in LDL cholesterol, and a slight increase in HDL cholesterol.[97] In July 1990, the mean trial follow-up interval was 9.7 years and PIB patients had a 23.3% lower total cholesterol ðp , 0:001Þ; 37.7% lower LDL cholesterol ðp , 0:0001Þ; and 4.3% higher HDL cholesterol ðp ¼ 0:02Þ compared to controls. Partial ileal bypass produced a 21.7% reduction in total mortality and a 28% reduction in coronary heart disease mortality; mortality was not statistically significantly different between treatment groups. However, total mortality in a subgroup of patients with a 50% or better ejection fraction was reduced 36.1% (39 of 292 control and 24 of 281 PIB patients; p ¼ 0:02). When atherosclerotic coronary heart disease mortality was combined with proven nonfatal myocardial infarction, there were 138 events in controls and 91 events in PIB patients ðp , 0:001Þ: For the combined end point of atherosclerotic coronary heart disease mortality, proven or suspected myocardial infarction, and unstable angina, there were 222 events in the control group and 160 events in the PIB group ðp , 0:0001Þ: The need for coronary artery bypass grafting, angioplasty, or heart transplantation was significantly reduced ðp , 0:0001Þ; and there was development of clinical peripheral vascular events ðp ¼ 0:038Þ in PIB versus control patients. At 5 years, 33.6% of control and 19% of PIB patients developed significant reductions in ankle brachial index by Doppler assessment ðp , 0:01Þ: Sequential coronary angiograms demonstrated continued progression of coronary artery disease at each follow-up interval in both treatment groups. However, the progression was consistently greater in control patients ðp , 0:001Þ: Progression occurred in 41.4% of control patients versus 28.1% of PIB patients at 3 years, 65.4% versus 37.5% of PIB patients at 5 years, 77.4% of control patients versus 46.5% of PIB patients at 7 years, and 85.7% PIB patients versus 53.8% PIB patients at 10 years.[98] A 5-year posttrial report of clinical events in the POSCH cohort was published in 1998.[99] Mean patient follow-up was 14.7 years (range, 12.2 –20 years) for this 5-year posttrial report. All POSCH patients were available for this follow-up. After a mean follow-up of 14.7 years, there was a 21% reduction in total mortality and 30% reduction in mortality from atherosclerotic coronary heart disease in the PIB patients compared to the control group ðp ¼ 0:049Þ: In the subgroup of patients with a 50% or better ejection fraction, there was a 37% reduction in total mortality ðp ¼ 0:01Þ and 38% reduction in mortality from atherosclerotic coronary heart disease ðp ¼ 0:05Þ in the PIB patients compared to the control group. In the PIB group versus the control group, there was a 33% reduction in mortality from atherosclerotic coronary heart disease and confirmed nonfatal myocardial infarction

ðp , 0:001Þ and an 18% reduction in mortality from atherosclerotic coronary heart disease, proven or suspected myocardial infarction, and unstable angina ðp , 0:001Þ: There was a 27% reduction in the onset of peripheral vascular disease ðp ¼ 0:02Þ and 47% reduction in coronary artery bypass surgery or angioplasty ðp ¼ 0:001Þ in the PIB patients compared to the control group. The results of POSCH offer strong long-term evidence that lipid lowering is effective in the management of atherosclerosis. Partial ileal bypass may prove to be a useful adjunct to cholesterol-lowering drugs in patients with extreme hypercholesterolemia and premature atherosclerotic coronary heart disease, especially in those who may require many years of expensive medication therapy. Additionally, partial ileal bypass could be considered for those patients who have failed various drug regimens or for those patients who cannot tolerate or have toxic effects from the various drugs. Clinical Outcome. Although not specifically designed to do so, the majority of the coronary angiographic trials have demonstrated a reduction in clinical coronary events in the lipid-lowering treatment groups relative to control groups. Long-term follow-up of the CLAS cohort indicated that measurement of progression of coronary artery disease at 2 years by both GCS and QCA was predictive of clinical coronary events over a subsequent 7-year period.[70] These data provide the mechanistic link between the reduction in progression of coronary artery disease and the reduction in clinical coronary events seen in morbidity/mortality studies designed to determine the effects of lipid lowering on clinical outcome.[100 – 106] Venous Bypasss Grafts. As discussed earlier, CLAS initially demonstrated that reduction of LDL-C to 97 mg/dL with colestipol-niacin reduced progression of atherosclerosis in coronary venous bypass grafts.[68] These initial results have now been confirmed in the Post Coronary Artery Bypass Graft Trial (Post CABG), which was specifically designed to address the question of whether aggressive lipid lowering or low-dose anticoagulation reduces progression of coronary venous bypass graft atherosclerosis.[107] A two-by-two factorial design was used to assign patients to aggressive treatment with lovastatin (LDL-C goal of 60–85 mg/dL) plus warfarin placebo or active warfarin (to maintain an international normalized ratio below 2) and to moderate treatment with lovastatin (LDL-C goal of 130 –140 mg/dL) plus warfarin placebo or active warfarin (to maintain an international normalized ratio below 2). Post CABG was conducted in 1351 patients (8% women), 21–74 years old (average age, 62 years), who had undergone saphenous-vein coronary artery bypass graft surgery 1 –11 years prior to the study entrance baseline coronary angiogram. Angiography was repeated an average of 4.3 years after the baseline coronary angiogram. Average baseline lipids were as follows: total cholesterol 226 mg/dL; triglycerides 160 mg/dL; LDL-C 155 mg/dL; and HDL-C 39 mg/dL. Ontrial, the mean LDL-C ranged from 93 to 97 mg/dL in the aggressive-treatment group versus 132 to 136 mg/dL in the moderate-treatment group ðp , 0:001Þ: The mean international normalized ratio was 1.4 in the active warfarin – treated group versus 1.1 in the warfarin placebo –treated

Chapter 15. Regression and Stabilization of Atherosclerosis by Medical Treatment

group ðp , 0:001Þ: The mean percentage of grafts that showed progression was 27% in the aggressive LDLtreatment group versus 39% in the moderate LDL-treatment group ðp , 0:001Þ: There was no significant difference in angiographic change between the active warfarin – and warfarin placebo –treated groups.

Carotid Artery Intima-Media Thickness Atherosclerosis research has moved from angiographic measurement of atherosclerosis progression and its response to therapy to noninvasive imaging assessment techniques. Because the earliest anatomic manifestations of atherosclerosis begin in the intimal layer of the arterial wall, noninvasive imaging by B-mode ultrasonography, particularly of the carotid artery wall, has become widely used in clinical trials of atherosclerosis intervention. This technique resulted from the observation that the two parallel echogenic lines seen on longitudinal view of the arterial wall represented the lumen intima and media adventitia interfaces, commonly referred to as the intima-media thickness (IMT) or complex.[108] It has become well established that carotid artery IMT represents the degree of subclinical or early preintrusive atherosclerosis.[109,110] As a measure of the degree of atherosclerosis, carotid artery IMT correlates with the standard cardiovascular risk factors seen with angiographic assessment of atherosclerosis.[111] In addition, carotid artery IMT correlates with extent, severity,[112] as well as progression of atherosclerosis.[113] Furthermore, progression of carotid artery IMT predicts future clinical coronary events as well as progression of coronary artery disease as assessed by coronary angiography.[114] In addition to demonstrating that lipid lowering reduced the progression of intrusive atherosclerotic lesions with coronary and femoral angiograms, CLAS was the first randomized, placebo-controlled, lipid-lowering trial to demonstrate a reduction in early preintrusive atherosclerosis using a noninvasive end point derived from B-mode images of the carotid artery wall.[115] Using automated computerized edge detection algorithms to measure average IMT in the distal centimeter of the common carotid artery,[116] 78 patients (39 placebo-treated, 39 colestipol-niacin treated) were studied over a 4-year period.[115] The placebo-treated group showed linear progression of carotid IMT over the 4year study period at a rate of IMT thickening of 0.018 mm/year. In contrast, the colestipol-niacin –treated group showed thinning of the common carotid IMT. The rate of IMT thinning was linear over the first 3.2 years of the study at a rate of 2 0.026 mm/y, which then plateaued during the remaining year of the study. In terms of absolute change in common carotid IMT from baseline, significant treatment group differences were seen as early as 1 year[117] and continued to be seen after 2 and 4 years of treatment.[115] MARS results confirmed CLAS results in a different cohort of 188 patients under different treatment conditions using the same IMT methodology;[116,118] 99 patients were randomized to lovastatin 80 mg per day and 89 patients were randomized to placebo. The patients underwent highresolution B-mode carotid ultrasonography for carotid wall thickness measurements every 6 months for 4 years. The annual rate of change in carotid IMT differed significantly

261

between the treatment groups at 2 and 4 years ðp , 0:001Þ: The placebo-treated group showed linear progression of carotid IMT over the 4-year study period at a rate of IMT thickening of 0.015 mm/y (0.019 mm/y at 2 years). The lovastatin-treated patients showed a consistent thinning in carotid IMT over the 4-year study period of 2 0.028 mm/y (2 0.038 mm/y at 2 years). Significant treatment group differences in absolute change in common carotid IMT was seen as early as 1 year. Several additional studies using carotid IMT as a primary end point have been published. These trials have taken advantage of the noninvasive nature of carotid ultrasonography to include both a direct measure of atherosclerosis (carotid IMT) as well as clinical coronary event end points in clinically asymptomatic[119] as well as symptomatic[120 – 123] individuals. Although several different image-acquisition methods and wall-measurement techniques were used in these trials, lipid-lowering therapy consistently reduced the rate of carotid IMT progression relative to the placebo treatment (Table 15-2). In addition, these trials have demonstrated a greater reduction in clinical coronary events in the lipidlowering treatment groups compared to the placebo-treated groups.

EVOLVING EVIDENCE FOR NEWER ANTIATHEROSCLEROSIS INTERVENTIONS AND FUTURE DIRECTIONS Triglyceride-Rich Lipoproteins and Atherosclerosis More than 3 decades of clinical research has suggested a relationship between triglycerides and coronary heart disease.[124] However, because of the complexity of what is truly measured by a plasma triglyceride determination, the relationship between triglycerides and coronary heart disease remains unsettled. Triglycerides are carried in all plasma lipoproteins, making triglyceride-rich lipoproteins highly heterogeneous. This heterogeneity is a major contributing factor to the complexity of the relationship between triglycerides and coronary heart disease. Accumulating evidence indicates that specific triglyceriderich lipoproteins such as very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), lipoprotein B –containing particles, chylomicron remnants, markers of triglyceride-rich lipoprotein metabolism such as apo C-III, as well as lipoprotein particles of differing size and composition, are more related to progression of atherosclerosis than triglycerides per se.[125] A few observational studies have shown that an association exists between plasma triglyceride levels and the extent and severity of angiographically determined coronary artery disease after adjustment for HDL-C.[124] These observational studies have provided useful and important information about the relationships between the cross-sectional measurements of triglycerides and the severity of coronary artery disease. Serial coronary angiography has

54 58

62 na 57 55 61

CLAS [115] MARS [118]

ACAPS [119] PLAC II [120] KAPS [121] CAIUS [122] LIPID [123]

Asymptomatic Symptomatic 90% asymptomatic Asymptomatic Symptomatic

Symptomatic Symptomatic

Clinical status

231/231 (52) 75/76 (na) 212/212 (100) 151/154 (53) 273/249 (82)

39/39 (100) 99/89 (92) Lovastatin Pravastatin Pravastatin Pravastatin Pravastatin

Colestipol-Niacin Lovastatin

Intervention

HDL-C +33% +8% +5% 2 4% 2 2% +4% +5%

LDL-C 2 42% 2 45% 2 25% 2 28% 2 27% 2 22% 2 27% na 2 4% 2 8% 0% 2 13%

2 29% 2 24%

TG

PLAC-II ACAPS KAPS CAIUS LIPID

CLAS MARS

Trial 4 2 4 3 3 3 3 2 4

Trial duration (y)

Single maximum IMT measurement. Common = Wall thickness measurement obtained from common carotid artery. Aggregate = Wall thickness measurement obtained from the maximal thickness averaged over multiple carotid artery sites. na = Data not available. CLAS = Cholesterol-Lowering Atherosclerosis Study. MARS = Monitored Atherosclerosis Regression Study. ACAPS = Asymptomatic Carotid Atherosclerosis Prevention Study. PLAC II = Pravastatin Limitation of Atherosclerosis in the Coronary Arteries. KAPS = Kupio Atherosclerosis Prevention Study. CAIUS = Carotid Atherosclerosis Italian Ultrasound Study. LIPID = Long-term Intervention with Pravastatin in Ischemic Disease.

a

Mean age(y)

Sample size treatment/placebo (% males)

Randomized Control Trials with a Carotid Artery Wall Thickness Measurement End Point

Trial [Ref.]

Table 15-2.

0.010a 2 0.003a 0 2 0.0035

2 0.026 2 0.038 2 0.028 0.030a

Common

0.059 2 0.009 0.017 2 0.004

Aggregate

Active treatment

0.029a 0.008a 0.020 0.012

0.018 0.019 0.015 0.046a

Common

0.068 0.006 0.031 0.009

Aggregate

Placebo treatment

Progression rate (mm/y)

0.019a 0.011a 0.020 0.016

0.044 0.058 0.043 0.016a

Common

0.009 0.015 0.014 0.013

Aggregate

Treatment difference

262 Part Two. Medical Treatment

Chapter 15. Regression and Stabilization of Atherosclerosis by Medical Treatment

provided an opportunity to extend these cross-sectional associations to studies that permit the examination of the relationships between levels of triglyceride-rich lipoproteins and the progression of coronary artery disease. In a subset analysis of the analytical ultracentrifugational data from the NHLBI Type II Study, the 2-year change in IDL mass concentration (Sf 12 to 20) was significantly predictive of coronary artery disease progression at 5 years.[126] The 2year changes in LDL (Sf 0 to 12), VLDL (Sf 20 to 400), HDL2 (F1.20 3.5 to 9), and HDL3 (F1.20 0 to 3.5) mass concentrations were unrelated to progression of coronary artery disease at 5 years. This early finding demonstrated the atherogenic potential of the triglyceride-rich lipoprotein IDL in the progression of coronary artery disease. An unexpected finding in CLAS was the importance of triglyceride-rich lipoproteins in atherogenesis. This was discovered by analysis of the interrelations between apolipoprotein levels and angiographic change.[127] CLAS patients who progressed in the placebo group had significantly higher apolipoprotein B levels as well as apolipoprotein C-III levels in the LDL, VLDL, and HDL lipoproteins compared to placebo patients who did not progress. In the drug-treated group, a lower apolipoprotein CIII found in the HDL was associated with lesion progression. Multivariate analysis indicated that on-trial non-HDL-C and apo C-III heparin supernate (HS) (apo C-III found in HDL) were the single independent predictors of coronary artery disease progression in the placebo- and drug-treated groups, respectively. These data illustrated that after LDL-C was lowered below 100 mg/dL (i.e., removal of LDL-C as a risk factor for CAD progression), apo C-III-HS became the most significant risk factor for lesion progression. The association of plasma triglyceride and apo C-III levels with progression of coronary artery disease in CLAS strongly indicated the importance of triglyceride-rich lipoproteins in atherogenesis. The relationship between triglyceride-rich lipoproteins and atherogenesis is further substantiated by the association of apo C-III-HS, apo C-III-whole serum (WS), and the apo C-III ratio [apo C-III-HS/apo C-III-heparin precipitate (HP)] with the progression of early preintrusive atherosclerosis, as determined by measuring carotid IMT in a subset of the CLAS cohort.[115] In the MARS trial, multivariate analysis indicated absolute change in TC/HDL-C as the best predictor of lesion change in the placebo group for mild-moderate lesions (, 50% S) and severe lesions ($ 50% S). With LDL-C reduction below 85 mg/dL in the lovastatin group, on-trial LDL-C/HDL-C was the best predictor of lesion change for severe lesions. For mild-moderate lesions, on-trial apolipoprotein C-III levels in LDL-VLDL (apo C-III-HP), a marker of triglyceride-rich lipoprotein metabolism,[128] was the best predictor of lesion change.[129] These data indicated that triglyceride-rich lipoproteins play an important role in coronary artery lesion progression, their importance unmasked once LDL-C is aggressively lowered. These results are the first to indicate that lipoproteins have an important differential effect on lesion progression according to lesion severity. The results from MARS confirm those from CLAS. Thus, triglyceride-rich lipoproteins play an important role in the progression of CAD, their importance unmasked once LDL-C is lowered (,100 mg/dL in CLAS and ,85 mg/dL in MARS). In

263

addition, the finding of a differential effect of triglyceride-rich lipoproteins (apo C-III-HP) and cholesterol ester–rich lipoproteins (LDL-C:HDL-C ratio) on the progression of both mildmoderate and severe lesions, respectively, suggests that certain risk factors may act early and others late in the atherosclerotic process. This latter point is further illustrated by the significant association of on-trial plasma triglyceride and apo C-III levels with the progression of early nonintrusive atherosclerosis, determined by measuring carotid IMT in the entire MARS cohort.[118] The association of triglyceride-rich lipoproteins with the progression of early nonintrusive atherosclerosis in MARS confirmed the associations observed in the CLAS subgroup with the same IMT measurement methodology.[115] Taken together, these findings suggest that triglyceride-rich lipoproteins play an important role in the progression of early atherosclerosis. Further investigation of the relationship between triglyceride-rich lipoproteins and the progression of CAD was performed by analyzing the QCA and extensive analytical ultracentrifugational data of the lipoprotein subclasses from the MARS study.[130] In the placebotreated group, univariate risk factors for progression of lesions ,50% S were increases in small VLDL (Sf 20 to 60), intermediate VLDL (Sf 60 to 100), large VLDL (Sf 60 to 400), total VLDL (Sf 20 to 400), large IDL (Sf 14 to 20), and total IDL (Sf 12 to 20) mass. Multivariate analysis indicated the increase in small VLDL mass to be the single risk factor independently associated with progression of lesions , 50% S in the placebo-treated group. No lipoprotein mass was significantly associated with progression of lesions $ 50% S in the placebo-treated group. In the drug-treated group, multivariate analysis indicated lower on-trial peak LDL flotation rate to be the single risk factor independently associated (inversely) with progression of lesions , 50% S in the drug-treated group. The association between peak LDL flotation rate and progression of lesions , 50% S is consistent with an association between VLDL mass and progression of these lesions since the LDL peak flotation rate is inversely correlated to VLDL levels.[131] No lipoprotein mass was significantly associated with progression of lesions $ 50% S in the drug-treated group. With both treatment groups combined, univariate risk factors for progression of lesions ,50% S were on-trial levels of small VLDL, intermediate VLDL, total VLDL, and IDL total mass as well as a lower on-trial peak LDL flotation rate. Multivariate analysis indicated on trial small VLDL mass to be the single risk factor independently associated with progression of lesions ,50% S in the combined treatment group. No lipoprotein mass was significantly associated with progression of lesions $50% S in the combined treatment group. Thus, in the same cohort of MARS subjects, both apo CIII-HP and VLDL mass were correlated with progression of lesions , 50% S.[129,130] Apo C-III in VLDL is associated with denser, smaller VLDL subclasses believed to be particularly atherogenic.[132,133] In MARS, small VLDL, large VLDL, and total VLDL mass as well as apo CIII-HP were associated with progression of lesions , 50% S. The correlation between apo CIII-HP and total, small, and large VLDL was 0.71, 0.67, and 0.69, respectively, at baseline in the MARS cohort. Therefore, by two completely independent methods of identifying triglyceride-rich lipoproteins on the

264

Part Two. Medical Treatment

basis of different physiochemical properties, one based upon protein composition (electroimmunoassay for apo C-III) and the other based upon lipoprotein mass (analytical ultracentrifugation), the relationship between progression of lesions ,50% S and triglyceride-rich lipoproteins is confirmed. In addition, apo C-III-HP and apo C-III-WS were significantly correlated with progression of common carotid IMT in the MARS cohort;[118] these findings were consistent with those from CLAS.[115] Further compelling evidence for the relationship between triglyceride-rich lipoproteins and atherogenesis derive from the analytical ultracentrifugational lipoprotein subclass and carotid IMT data from the MARS cohort.[134] When the major apo B –containing lipoproteins were measured independently, IDL (Sf 0 to 12) but not VLDL (Sf 20 to 400) or LDL (Sf 0 to 12) was associated with the progression of carotid IMT.[134] Therefore, by two independent methods for measuring atherosclerosis progression, QCA for coronary artery atherosclerosis[130] and IMT for early carotid atherosclerosis,[134] the relationship between IDL and progression of atherosclerosis has been demonstrated. The lack of significant relationships between VLDL and LDL with carotid IMT progression may be indicative of a role of these lipoproteins in the more advanced intrusive lesions detected by coronary angiography but not in the progression of early preintrusive atherosclerosis detected by carotid IMT. The accumulated evidence for the role of triglyceride-rich lipoproteins in the progression of coronary artery disease indicates that apo B –containing lipoproteins other than those associated with cholesterol ester –rich lipoproteins may be involved in the progression of CAD. Data from the MARS study illustrate this newer concept of triglyceride-rich apo B – containing lipoprotein particle families and atherosclerosis. In a subset of 56 patients from the MARS study, lovastatin therapy significantly reduced LDL-C, apo B, and cholesterol ester –rich lipoprotein B(LP-B) levels without significantly affecting the apo B –containing triglyceride-rich LP (LP-Bc) particles, LP-B:C, LP-B:C:E, and LP-A-II:B:C:D:E.[135] Lipoprotein particles were isolated by column immunoaffinity techniques described by Alaupovic et al.[135] The differential effects of drug therapy on apo B –containing lipoproteins has provided the opportunity to determine the independent relationship of LP-B and specific LP-Bc particles on the progression of CAD.[136] In the placebo-treated group, significantly greater plasma triglyceride, apo C-III, and apo B levels were found in progressors versus nonprogressors. In the drug-treated group, significantly greater levels of LP-A-II:B:C:D:E and significantly lower levels of apo A-I were seen in progressors versus nonprogressors, but the LP-B:C or LP-B:C:E levels did not differ significantly. These data demonstrated that after lowering LP-B particles below 75 mg/dL in the drug-treated group, LP-A-II:B:C:D:E particles appeared to play a role in the progression of coronary artery disease. An increased residence time and exposure of the arterial wall to LP-AII:B:C:D:E due to its lower reactivity toward lipoprotein lipase may account for its greater atherogenicity compared to the other LP-Bc particles.[137] Apo C-III-HP, which was a significant predictor of coronary artery disease progression in both MARS and CLAS, is a constituent of intact or partially delipidized triglyceride-rich lipoprotein particles, including

the apo B –containing triglyceride-rich lipoprotein particles LP-B:C, LP-B:C:E, and LP-A-II:B:C:D:E. In the Nicardipine Study, progression of coronary artery disease and the occurrence of clinical coronary events were associated with the sum of a calculated IDL fraction and an estimated level of remnant VLDL-C.[138] These findings were consistent with those from MARS and CLAS, which demonstrate a significant association between apo C-III, as a marker of triglyceride-rich lipoprotein metabolism, and progression of coronary artery disease. Data from the control group of POSCH showed that triglyceride-rich lipoproteins at baseline and after 3 and 5 years were associated with serial coronary angiographic evidence of progression of lesions to 100% occlusion.[139] In a subgroup analysis of 333 control patients using baseline and 3-year angiographic data, the baseline plasma triglyceride and VLDL-C levels, as well as 3-year levels of triglycerides and VLDL-C, were greater in those subjects who demonstrated progression to total occlusion at 3 years versus those patients who did not. The baseline and 3-year total cholesterol, LDLC, and HDL-C levels did not differ between those patients with and without progression to total occlusion. In a subgroup analysis of 301 control patients using baseline and 5-year angiographic data, the baseline total cholesterol level and the 5-year level of plasma triglycerides were significantly greater in those patients who demonstrated progression to total occlusion at 5 years versus those subjects who did not. Not only did this trial fail to demonstrate an association between LDL-C with progression to total occlusion, but triglyceride levels were associated with new 3-year occlusions, even in the group of patients with higher HDL-C:TC ratios. Although the serial coronary angiographic evidence that links triglyceride-rich lipoproteins to the progression of coronary artery disease is compelling, the hypothesis that reducing triglyceride-rich lipoproteins will result in a reduction in the progression of atherosclerosis has only just begun to be studied. Except for 2 published trials (reviewed below), serial coronary angiographic trials have been designed to test the hypothesis that reducing LDL-C will result in a reduction in coronary artery disease progression, a hypothesis now well proven.[109,110] The Bezafibrate Coronary Angiographic Intervention Trial (BECAIT) was a double-blind, placebo-controlled serial coronary angiographic trial conducted in 92 survivors of a myocardial infarction under 45 years of age.[140] This trial was unique in that the intervention used was bezafibrate, a lipid-lowering medication that preferentially lowers plasma triglyceride levels without affecting LDL-C levels. Coronary angiography was done at baseline and after 2 and 5 years in intervention in 42 bezafibrate-treated and 39 placebo-treated patients. The efficacy analysis included the 81 patients who had a baseline and at least one posttreatment angiogram. The primary end point was change in MLD. In the bezafibrate-treated group, total cholesterol decreased from 7.73 mmol/L (226 mg/dL) to 5.92 mmol/L (229 mg/dL) (2 14%), and VLDL-C decreased from 1.11 mmol/L (43 mg/dL) to 0.72 mmol/L (28 mg/dL) (2 36%). In the placebo-treated group, total cholesterol decreased from 6.90 mmol/L (267 mg/dL) to 6.49 mmol/L (251 mg/dL) (2 6%), and VLDL-C remained unchanged at 0.85 mmol/L (33 mg/dL) (p , 0:001 between treatment

Chapter 15. Regression and Stabilization of Atherosclerosis by Medical Treatment

groups). In the bezafibrate-treated group, total triglycerides decreased from 2.44 mmol/L (216 mg/dL) to 1.81 mmol/L (160 mg/dL) (2 26%), and VLDL triglycerides decreased from 1.85 mmol/L (164 mg/dL) to 1.37 mmol/L (121 mg/dL) (226%). In the placebo-treated group, total triglycerides increased from 1.98 mmol/L (175 mg/dL) to 2.03 mmol/L (180 mg/dL) (3%), and VLDL triglycerides increased from 1.43 mmol/L (127 mg/dL) to 1.55 mmol/L (137 mg/dL) (8%) (p , 0:001 between treatment groups). HDL-C increased in the bezafibrate-treated group from 0.88 mmol/L (34 mg/dL) to 0.96 mmol/L (37 mg/dL) (þ9%), whereas HDL-C remained unchanged in the placebo-treated group at 1.01 mmol/L (39 mg/dL) (p ¼ 0:02 between treatment groups). LDL-C did not significantly change in either treatment group—from 180 mg/dL to 173 mg/dL (2 4%) in the bezafibrate-treated group and from 179 mg/dL to 175 mg/dL (2 2%) in the placebo-treated group ðp ¼ 0:55Þ: Therefore, the greatest on-trial lipid differences between the placebo-treated and the bezafibrate-treated groups were in total cholesterol 6.49 mmol/L (251 mg/dL) versus 5.92 mmol/L (229 mg/dL), VLDL-C 0.85 mmol/L (33 mg/dL) versus 0.72 mmol/L (28 mg/dL), total triglycerides 2.03 mmol/L (180 mg/dL) versus 1.81 mmol/L (160 mg/dL), and in VLDL triglycerides 1.55 mmol/L (137 mg/dL) versus 1.37 mmol/L (121 mg/dL), respectively. The differences between the placebo-treated and the bezafibrate-treated groups in HDL-C, 1.01 mmol/L (39 mg/dL) versus 0.95 (37 mg/dL) and LDL-C, 4.53 mmol/L (175 mg/dL) versus 4.47 mmol/L (173 mg/dL) levels were trivial. These are the expected lipid-altering effects of bezafibrate, which predominantly reduces the synthesis of VLDL particles resulting in a reduction in particle-associated cholesterol and triglycerides, which in turn results in a reduction in total cholesterol and total triglyceride levels. In addition to the lipid effects, the bezafibrate-treated group had a significantly greater treatment effect on apo A-I (þ7%), apo B (2 4%), and fibrinogen (213%) than the placebo-treated group — þ2%, þ2%, and no change, respectively. The median change in MLD in the placebo-treated group was 2 0.17 mm versus 20.06 mm in the bezafibrate-treated group ðp ¼ 0:049Þ: Compared to patients in the placebotreated group, fewer patients in the bezafibrate-treated group had progression of CAD (85% placebo vs. 74% bezafibrate) and more had regression of CAD (13% placebo vs. 21% bezafibrate). Clinical coronary events were significantly ðp ¼ 0:019Þ reduced in the bezafibrate-treated group after the 5year treatment period. In the placebo-treated group, 11 of the 45 patients (24%) had a clinical coronary event (3 myocardial infarctions, 1 myocardial infarction plus CABG, 4 CABG, and 3 PTCA). In the bezafibrate-treated group, 3 of the 47 patients (6%) had a clinical coronary event (1 myocardial infarction then death, 1 sudden death, 1 myocardial infarction plus CABG). BECAIT was an important study providing the first randomized serial coronary angiographic trial evidence for the reduction of coronary artery atherosclerosis progression and clinical coronary events with reduction in triglyceriderich lipoproteins, independent of a significant reduction in LDL-C. It is important to note that the angiographic results of BECAIT were similar to those from the serial coronary

265

angiographic trials that have tested the LDL-C –lowering hypothesis (Fig. 15-1). The angiographic results of BECAIT occurred even though the on-trial LDL-C remained high at an average level of 4.47 mmol/L (173 mg/dL) with essentially no change from baseline. In the LDL-C –lowering angiographic trials, on-trial LDL-C levels ranged from 2.46 mmol/L (95 mg/dL) to 3.36 mmol/L (130 mg/dL) with 20% to 45% reductions from baseline (Table 15-1; Fig. 15-1). BECAIT results are consistent with the accumulating evidence that triglyceride-rich lipoproteins play an important role in the progression of CAD. In particular, these data are consistent with those from the MARS trial in which triglyceride-rich lipoproteins were most important in the progression of lesions # 50% S, [129] the very lesions responsible for clinical coronary events.[70] The majority of lesions at baseline in the BECAIT study were in the range of 29–43% S. The Lopid Coronary Angiographic Trial (LOCAT) was a double-blind, placebo-controlled serial coronary angiographic trial conducted in 395 post –coronary artery bypass men #70 years of age.[141] The intervention used in LOCAT was gemfibrozil (slow-release 1200 mg/day), a fibric acid derivative similar to bezafibrate used in BECAIT. Coronary angiography was obtained at baseline and after an average of 32 months of intervention in 185 gemfibrozil-treated and 187 placebo-treated patients. In the gemfibrozil-treated group, total cholesterol decreased from 5.14 mmol/L (197 mg/dL) to 4.83 mmol/L (186 mg/dL) (2 6%), total triglycerides decreased from 1.65 mmol/L (149 mg/dL) to 1.02 mmol/L (92 mg/dL) (36%), LDL-C decreased from 3.58 mmol/L (137 mg/dL) to 3.39 mmol/L (130 mg/dL) (5%), and HDL-C increased from 0.81 mmol/L (31 mg/dL) to 0.98 mmol/L (38 mg/dL) (21%). In the placebo-treated group, total cholesterol increased from 5.21 mmol/L (201 mg/dL) to 5.48 mmol/L (211 mg/dL) (5%), total triglycerides increased from 1.63 mmol/L (149 mg/dL) to 1.69 mmol/L (154 mg/dL) (5%), LDL-C increased form 3.65 mmol/L (141 mg/dL) to 3.84 mmol/L (148 mg/dL) (5%), and HDL-C increased from 0.82 mmol/L (32 mg/dL) to 0.88 mmol /L (34 mg/dL) (7%). All percentage changes from baseline as well as the on-trial lipid levels were significantly different between treatment groups ðp , 0:001Þ: Although the primary study end point—segment unaffected by grafts and those distal to graft insertion—was negative, segments unaffected by grafts, graft-affected segments, and all native segments demonstrated a significant reduction in progression in the gemfibrozil-treated patients versus the placebo-treated subjects ðp , 0:05Þ: In segments unaffected by grafts, graft-affected segments, and all native segments, the differences in mean change in MLD between treatment groups were 0.06, 0.07, and 0.05 mm, respectively. In the aortocoronary bypass grafts, 23 patients (14%) randomized to placebo had new lesions in the follow-up angiogram compared with 4 patients (2%) in the bezafibratetreated group ðp , 0:001Þ: Thus, the LOCAT results confirmed those from BECAIT and, in addition, demonstrated that the reduction in total triglyceride levels in subjects with relatively low on-trial LDL-C levels [3.39 mmol/L (130 mg/dL)], with essentially no change from baseline results in coronary angiographic improvement in both native as well as aortocoronary bypass

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grafts. The angiographic results of LOCAT were similar to those from the serial coronary angiographic trials that have tested the LDL-C –lowering hypothesis (Fig. 15-1).

Antioxidants Although there is a large body of experimental and epidemiologic data that indicate that supplementary antioxidant vitamins may reduce cardiovascular disease, there have been no double-blind, placebo-controlled arterial imaging studies published to date that have addressed the question of whether antioxidants affect progression of atherosclerosis. However, subgroup analyses from CLAS strongly indicate the potential of vitamin E for reducing the progression of atherosclerosis.[142,143] In the CLAS cohort of colestipol-niacin and placebotreated patients, men who had a supplementary vitamin E intake of 100 IU per day or more had significantly less coronary artery lesion progression than did men with a supplementary intake less than 100 IU per day ðp ¼ 0:04Þ:[142] When examined by treatment group, colestipol-niacin patients with high supplementary vitamin E intake had significantly less coronary artery lesion progression of all lesions ðp ¼ 0:02Þ and mild/moderate lesions ðp ¼ 0:01Þ: These data have important implications for the potential use of supplemental vitamin E as adjunctive antioxidant therapy with LDL-C reduction, especially in terms of slowing or halting the progression of mild/moderate lesions, which are the lesions predictive of clinical coronary events.[70] Further analysis of the CLAS cohort with IMT data indicated that men in the placebo-treated group with a supplementary vitamin E intake of $ 100 IU per day had less carotid IMT progression than those men with , 100 IU per day supplementary vitamin E intake (0.008 vs. 0.023 mm/year; p ¼ 0:03).[143] Although encouraging, these results must be cautiously interpreted, since patients in this study self-selected and self-reported their antioxidant vitamin intake. Consistent with the CLAS findings were two clinical trials that demonstrated that probucol, an antioxidant, slowed the rate of restenosis after coronary angioplasty. In the Multivitamins and Probucol (MVP ) trial, 317 subjects were randomized to placebo, probucol (500 mg), multivitamins (30,000 IU beta-carotene, 500 mg vitamin C, and 700 IU vitamin E), or probucol plus multivitamins, all given twice daily.[144] An extra 1000 mg of probucol, 2000 IU of vitamin E, both probucol and vitamin E, or placebo were administered to the subjects, according to their treatment assignment, 12 hours before they underwent angioplasty. All subjects were treated 4 weeks prior and 6 months after the angioplasty. The

baseline and follow-up angiographic changes at the angioplasty site were measured by QCA. Mean reduction in luminal diameter 6 months after angioplasty was 0.12 mm in the probucol group, 0.22 mm in the probucol-plus-multivitamin group, 0.33 mm in the multivitamin group, and 0.38 mm in the placebo group (p ¼ 0:006 for subjects receiving vs. those not receiving probucol). The Probucol Angioplasty Restenosis Trial (PART ) was a study of 101 subjects randomly assigned to probucol 1000 mg per day or to a control group of no lipid lowering 4 weeks prior to angioplasty.[145] Baseline and follow-up angiographic changes were measured by QCA 6 months after angioplasty. MLD at the angioplasty site was 1.49 mm in the probucol group and 1.13 mm in the control group ðp ¼ 0:02Þ: Restenosis occurred in 23% of the probucol-treated patients and in 58% of the control-treated patients ðp ¼ 0:001Þ: Double-blind, placebo-controlled studies with both QCA and carotid IMT imaging end points in individuals with and without cardiovascular symptoms are currently underway to study the question of whether antioxidants prevent the progression of atherosclerosis.

CONCLUSION Evidence for the achievement of lesion regression with LDLC reduction is derived from (1) observations in experimental animal models, including controlled, quantitative regression studies (nonhuman primate results have been reviewed in detail); (2) angiographic human case studies and noncontrolled trials; and (3) controlled clinical trials. Together, these reports provide evidence for the reversibility of atherosclerosis of sufficient strength that risk-factor control and LDL-C reduction should be an integral part of the long-term postsurgical management of the atherosclerotic patient. Growing evidence indicates that triglyceride-rich lipoproteins play an important role in atherosclerosis and need attention in the control of atherosclerosis progression. Another area of increasing interest is the role of antioxidants in the prevention of atherosclerosis progression. Rational decisions concerning the use of antioxidants for the control of atherosclerosis progression await results from ongoing trials. The role of the vascular surgeon, beyond that of providing the surgical care for patients with symptomatic atherosclerosis, is to ensure that patients receive optimal medical care. The rationale for this is to prevent potential problems from disease progression in vascular grafts and to reduce lesion progression in other vascular beds.

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Coronary Artery Disease in Hypercholesterolemic Men. Lancet 1987, 62. Blankenhorn, D.H.; Alaupovic, P.; Wickham, E. et al. Prediction of Angiographic Change in Native Human Coronary Arteries and Aortocoronary Bypass Grafts: Lipid and Nonlipid Factors. Circulation 1990, 81, 470. Alaupovic, P. David Rubinstein Memorial Lecture. The Biochemical and Clinical Significance of the Interrelationship Between Very Low Density and High Density Lipoproteins. Can. J. Biochem. 1981, 59, 565. Hodis, H.N.; Mack, W.J.; Azen, S.P.; Alaupovic, P.; Pogoda, J.M.; LaBree, L.; Hemphill, L.C.; Kramsch, D.M.; Blankenhorn, D.H. Triglyceride- and CholesterolRich Lipoproteins Have a Differential Effect on Mild/Moderate and Severe Lesion Progression as Assessed by Quantitative Coronary Angiography in a Controlled Trial of Lovastatin. Circulation 1994, 90, 42. Mack, W.J.; Krauss, R.M.; Hodis, H.N. Lipoprotein Subclasses in the Monitored Atherosclerosis Regression Study (MARS). Treatment Effects and Relation to Coronary Angiographic Progression. Arterioscler. Thromb. Vasc. Biol. 1996, 16, 697. Krauss, R.M.; Williams, P.T.; Lindgren, F.T.; Wood, P.D. Coordinate Changes in Levels of Human Serum Low and High-Density Lipoprotein Subclasses in Healthy Men. Arteriosclerosis 1988, 8, 155. Le, N.A.; Givson, J.C.; Ginsberg, H.N. Independent Regulation of Plasma Apolipoprotein C-II and C-III Concentrations in Very Low Density and High Density Lipoproteins. Implications for the Regulation of the Catabolism of These Lipoproteins. J. Lipid Res. 1988, 29, 669. Carlson, L.A.; Ballantyne, D. Changing Relative Proportions of Apolipoproteins C-II and C-III of Very Low Density Lipoproteins in Hypertriglyceridemia. Atherosclerosis 1976, 23, 563. Hodis, H.N.; Mack, W.J.; Dunn, M.; Liu, C.R.; Liu, C.H.; Selzer, R.H.; Krauss, R.M. Intermediate-Density Lipoproteins and Progression of Carotid Arterial Wall IntimaMedia Thickness. Circulation 1997, 95, 2022. Alaupovic, P.; Hodis, H.N.; Knight-Gibson, C.; Mack, W.J.; LaBree, L.; Cashin-Hemphill, L.; Corder, C.N.; Kramsch, D.M.; Blankenhorn, D.H. Effects of Lovastatin on ApoA- and ApoB-Containing Lipoproteins. Families in a Subpopulation of Patients Participating in the Monitored Atherosclerosis Regression Study (MARS). Arterioscler. Thromb. 1994, 14, 1906. Alaupovic, P.; Mack, W.J.; Knight-Gibson, C.; Hodis, H.N. The Role of Triglyceride-Rich Lipoprotein Families in the Progression of Atherosclerotic Lesions as Determined by Sequential Coronary Angiography from a Controlled Clinical Trial. Arterioscler. Thromb. Vasc. Biol. 1997, 17, 715. Alaupovic, P.; Knight-Gibson, C.; Wang, C.S.; Downs, D.; Koren, E.; Brewer, H.B.; Gregg, R.E. Isolation and Characterization of a Lipoprotein-Containing Lipoprotein (LP-A-II:B Complex) from Plasma Very Low Density Lipoproteins of Patients with Tangier Disease and Type V Hyperlipoproteinemia. J. Lipid Res. 1991, 32, 9.

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Phillips, N.R.; Waters, D.; Havel, R.J. Plasma Lipoproteins and Progression of Coronary Artery Disease Evaluated by Angiography and Clinical Events. Circulation 1993, 88, 2762. 139. POSCH Group; Bissett, J.K.; Wyeth, R.P.; Matts, J.P.; Johnson, J.W. Plasma Lipid Concentrations and Subsequent Coronary Occlusion After a First Myocardial Infarction. Am. J. Med. Sci. 1993, 305, 139. 140. Ericsson, C.G.; Hamsten, A.; Nilsson, J.; Grip, L.; Svane, B.; Faire, U. Angiographic Assessment of Effects of Bezafibrate on Progression of Coronary Artery Disease in Young Male Postinfarction Patients. Lancet 1996, 347, 849. 141. Lopid Coronary Angiography Trial (LOCAT) Study Group; Frick, M.H.; Syvanne, M.; Nieminen, M.S.; Kauma, H.; Majahalme, S.; Virtanen, V.; Kesaniemi, A.; Pasternack, A.; Taskinen, M.R. Prevention of the Angiographic Progression of Coronary and Veingraft Atherosclerosis by Gemfibrozil After Coronary Bypass Surgery in Men with Low Levels of HDL Cholesterol. Circulation 1997, 96, 2137. 142. Hodis, H.N.; Mack, W.J.; LaBree, L.; Cashin-Hemphill, L.; Sevanian, A.; Johnson, R.; Azen, S.P. Serial Coronary

Angiographic Evidence That Antioxidant Vitamin Intake Reduces Progression of Coronary Artery Atherosclerosis. J. Am. Med. Assoc. 1995, 273, 1849. 143. Azen, S.P.; Qian, D.; Mack, W.J.; Sevanian, A.; Selzer, R.H.; Liu, C.R.; Liu, C.H.; Hodis, H.N. Effect of Supplementary Antioxidant Vitamin Intake on Carotid Arterial Wall Intima-Media Thickness in a Controlled Clinical Trial of Cholesterol Lowering. Circulation 1996, 94, 2369. 144. Tardif, J.C.; Cote, G.; Lesperance, J.; Bourassa, M.; Lambert, J.; Doucet, S.; Bilodeau, L.; Nattel, S.; de Guise, P. Probucol and Multivitamins in the Prevention of Restenosis After Coronary Angioplasty. N. Engl. J. Med. 1997, 337, 365. 145. Yokoi, H.; Daida, H.; Kuwabara, Y.; Nishikawa, H.; Takatsu, F.; Tomihara, H.; Nakata, Y.; Kutsumi, Y.; Ohshima, S.; Nishiyama, S.; Seki, A.; Kato, K.; Nishimura, S.; Kanoh, T.; Yamaguchi, H. Effectiveness of an Antioxidant in Preventing Restenosis After Percutaneous Transluminal Coronary Angioplasty. The Probucol Angioplasty Restenosis Trial. J. Am. Coll. Cardiol. 1997, 30, 855.

CHAPTER 16

Hyperthrombotic States in Vascular Surgery Jonathan B. Towne

Hypercoagulable states as a cause of acute arterial or venous thrombosis pose a difficult clinical problem. There are essentially four clinical situations in which such states occur: three involving the arterial system and one the venous system. The first is a sudden unexplained thrombosis of medium- to large-size arteries of either the upper or the lower extremity, which on occasion can involve renal, mesenteric, and cerebral vessels. The second situation, which is of particular concern to vascular surgeons, is the acute thrombosis of an arterial repair in the perioperative period. These problems are usually evident in the operating room, and all occur in the first 12 hours following surgery. The third situation is thrombosis of arterial repair at a time remote from the vascular reconstruction, which is the most uncommon occurrence. Finally, there is the sudden, unexplained episode of venous thrombosis, which can affect any and all parts of the venous circulation but most typically involves the lower extremities and on occasion also the upper extremities and the mesenteric venous circulation. The ability of blood to remain fluid within the intravascular system and to form a thrombus when there is disruption or injury to the endothelial lining depends on complex interactions between the various components of the vascular system. These components include the endothelium, platelets, plasma, procoagulant factors, and fibrinolytic factors. Any abnormality of these factors can result in either hemorrhage or thrombosis. Since vascular surgeons deal primarily with ischemia, they generally have to deal with abnormalities on the thrombosis side of the blood coagulation equilibrium. Over the last several decades there has been an explosion of knowledge regarding the coagulation system, so that our understanding of its various components is much better. With this increased understanding, several clotting disorders have been identified that are secondary to either inherited or acquired deficiency of one of the components of the clotting cascade, resulting in unusual or previously unexplained thrombosis. Early on, the first hypercoagulable states identified were those that involved problems on the procoagulant side. However, within the last decade, problems involving the fibrinolytic systems or anticoagulant side of the clotting cascade have been identified. In order to treat these

unusual thrombotic episodes adequately, some knowledge of these thrombotic syndromes is necessary. Hypercoagulability as a cause of unexplained vascular thrombosis poses difficult clinical problems. Most graft failures in the perioperative period are presumed to result from technical errors in the construction of the anastomosis, problems with the conduit, or poor patient selection. The diagnosis of abnormal coagulability is often made only after all these other factors have been excluded. Although the failure of heparin to prevent clotting in the operative field or the immediate thrombosis of a vascular repair suggests abnormal coagulation, the diagnosis can only be confirmed by the blood coagulation laboratory. The clotting disorder must be detected early in the course of the disease if there is to be a favorable outcome. Abnormal thrombosis falls into five general categories: abnormalities in the antithrombin system, abnormalities of the fibrinolytic system, heparin-induced platelet aggregation, lupus anticoagulant, and a miscellaneous category consisting primarily of abnormal platelet aggregation deficiencies of protein C and protein S and activated protein C resistance.

GUIDELINES FOR IDENTIFYING HYPERCOAGULABILITY A good patient history remains the most important means of identifying patients with potential hypercoagulable disorders. Patients should be asked about previously unexplained thromboses in themselves or family members. Patients with hypercoagulability syndromes will often report episodes of thrombophlebitis that occurred in young adulthood. Of particular importance are those episodes of thrombophlebitis that do not have any contributing factors for their development—e.g., long leg fractures or prolonged immobilization or bed rest due to illness. Such a history becomes even more significant in patients with recurrent episodes of thrombophlebitis. Likewise, previous arterial thrombosis, especially if it occurred in early life, is an indicator of a coagulation disorder.[1] Eldrup-Jorgensen et al.[2] found a

Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024899 Copyright q 2004 by Marcel Dekker, Inc.

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30% incidence of coagulation abnormalities in patients younger than 51 years undergoing vascular reconstruction. The abnormal clotting factors noted consisted of protein S deficiency, protein C deficiency, presence of lupuslike anticoagulants, and plasminogen deficiency. The incidence of arterial graft thrombosis in this group of patients was 20% at 30 days, which is markedly higher than one would expect from this type of vascular reconstruction.

Clinical Presentation With experience, one develops a sense for which reconstructions are likely to succeed and has some idea of the types of problems that may occur. Likewise, one develops a feel for the typical presentations of atherosclerotic occlusive disease. When unusual or unexplained thrombosis is identified—for example, a thrombosed suprarenal aorta, upper extremity thrombosis, or total fibial artery occlusion in a patient who is neither diabetic nor has any evidence of any atherosclerotic occlusive disease elsewhere—the surgeon should look for hypercoagulable disorders as a possible cause. Unusual radiographic findings, particularly occlusions in young patients or in one extremity when the other extremity has no evidence of any disease, should trigger an investigation into the coagulation system. The role of screening vascular surgery patients for hypercoagulable states is difficult to assess. Donaldson et al.[3] found, overall, that 9.5% of patients scheduled for a variety of vascular surgery procedures had test results indicating potential hypercoagulability. The three most common entities these patients demonstrated were heparininduced platelet aggregation, lupus anticoagulants, and protein C deficiency. The incidence of infrainguinal graft occlusion within 30 days was 27% among patients who were in the hypercoagulable group compared with 1.6% in patients who were not in this group. At present, we do not screen routinely for the wide variety of coagulation disorders. We depend on the history and clinical evaluation to identify patients who may be hypercoagulable. This is probably the more cost-effective and efficient approach. The greatest difficulty for the vascular surgeon is dealing with unexplained thrombosis intraoperatively. Often such an emergency occurs during late evening or nighttime hours, when support from the coagulation laboratory is not available. The first step—if, indeed, heparin has been given—is to see if there is any clotting in the operative field, which would indicate an antithrombin III deficiency, since antithrombin III is essential for heparin’s anticoagulant effect. The anesthesiologist should then test the heparin effect, by either determining the partial thromboplastin time (PTT) or doing one of the other tests that measure heparin anticoagulation. The next step is to obtain a platelet count. If it is higher than 100,000 and the PTT is not prolonged, the problem is presumed to lie with the antithrombin system. The patient is then given two units of fresh frozen plasma and two units more every 12 hours for 5 days. The antithrombin III deficiency is then confirmed, usually the next day, on blood drawn prior to the administration of any fresh frozen plasma. Patients with antithrombin III deficiency are maintained on long-term warfarin therapy. If the platelet count is less than

100,000, we presume the patient has developed heparininduced platelet aggregation. Certainly the patient’s history should be examined carefully so as to try to document the administration of heparin at some time in the past. We then start dextran intravenously with a 50-mL bolus and continue at 25 mL/h. The heparin is reversed with protamine, and the platelet aggregation abnormality is confirmed in the morning. Warfarin treatment is continued for 3 weeks to 6 months. If the platelet count is greater than 100,000 and the activated clotting time (ACT) is prolonged, we presume that the patient has some other form of hypercoagulability, such as a fibrinolytic abnormality or a problem with protein C, protein S, or lupus-type anticoagulants. In these patients, we institute continuous heparin therapy both intraoperatively and postoperatively and administer two units of fresh frozen plasma. Fresh frozen plasma is shotgun therapy for a wide variety of coagulation abnormalities. In the operating room, prior to the institution of any therapy, blood should be drawn for coagulation tests. (Many of these tests are quite involved, such as plasminogen electrophoresis, protein C, protein S, and determinations of lupus anticogulants, sometimes taking from days to a week at some centers. However, if the blood is properly handled, spun down, and frozen, the tests can be done routinely.) Our policy is to repeat, in 5 days, all tests that are abnormal. One of the problems in diagnosing coagulation abnormalities is that in the process of clotting, clotting factors can be consumed and abnormalities may be the result of clotting and not the cause of it. All factors that remain abnormal in the 5- to 7-day period are retested at 1 month. Patients who then have persistently abnormal values are labeled as truly hypercoagulable. McDaniel et al.[4] have noted the change in coagulation factors with operation. They noted that antithrombin III levels fell on the third postoperative day and returned to normal after 1 week. Antithrombin III declined from a mean preoperative level of 110% to 71% on the third postoperative day. This value had returned to normal by postop day 7, when it reached 95%. All this demonstrates the dynamic aspect of the clotting system and points out the danger of attaching significance to one isolated laboratory finding. Most patients who sustain complications due to hypercoagulable states are placed on warfarin in the perioperative and postoperative period. In patients with heparin-induced platelet aggregation, this can usually be stopped in 3 months: however, we have recommended prolonged administration in patients with protein C and S deficiencies, antithrombin III deficiency, and plasminogen abnormalities because of the risk of recurrent thrombosis.

ANTITHROMBIN DEFICIENCY Antithrombin III is an alpha globulin manufactured in the liver and by vascular endothelium, with a molecular weight of approximately 60,000 and a half-life of 2.8 days.[5] It is a serine proteinase inhibitor that binds in equimolar ratios to several enzymes participating in the intrinsic pathway of blood coagulation, including thrombin and factors Xa, Ixa, and XIa.[5] Heparin significantly accelerates the rate at which antithrombin III neutralizes these enzymes, thus limiting

Chapter 16.

sequential clotting reactions and preventing fibrin formation. In 1965, Egeberg[6] described a family with an inborn defect of antithrombin III, and subsequent work has demonstrated the genetic transmission of this disease.[7 – 10] The frequency of this defect is approximately 1 in 2000 to 1 in 5000 in the general population.[11,12] There are probably at least two types of antithrombin III deficiency. In the classic form, both the level of antithrombin III (as determined by measuring its protein concentration) and its activity level are reduced in the patient’s plasma.[13] However, there are other patients in whom the concentration of antithrombin III is normal or even slightly elevated as measured by protein level, but the biologic function as measured by activity tests is abnormal.[14] This suggests that these patients are manufacturing a defective antithrombin molecule. Acquired antithrombin III deficiency can occur in severe liver disease, nephrotic syndrome, hypoalbuminemia, malnutrition, and disseminated intravascular coagulation; it can also sometimes occur in patients taking birth control pills. Antithrombin III deficiency may be an indicator of significant protein catabolism. Flinn et al.[15] noted low antithrombin III activity in 16% of patients undergoing vascular surgery. There was low serum albumin (less than 3.0 mg/dL) in 48% of these patients, which was associated with an increased incidence of early graft failure.

Clinical Presentation Although antithrombin III deficiency is inherited, it is rare for episodes of thrombosis to be clinically manifest before the second decade of life. Despite continuously depressed levels of antithrombin III in these patients, thrombotic episodes are often related to predisposing factors such as operations, childbirth, and infection; they rarely occur spontaneously. This deficiency can cause venous thrombosis with resulting pulmonary embolism, dialysis fistula failure, arterial graft occlusion, and spontaneous arterial occlusion. In our initial report, we identified 7 patients with antithrombin deficiencies as a cause of thrombosis.[16] These included patients with spontaneous arterial occlusion in both the upper and lower extremities as well as patients whose vascular reconstructions became occluded in the perioperative period. One unusual patient presented with ischemia of one arm and both legs secondary to extensive thromboses of the brachial artery and its branches in one arm and the femoral, popliteal, and tibial systems of both legs. Extensive angiography of the entire aorta and cardiac evaluation failed to reveal a proximal origin of embolic material. What distinguishes these patients from those with thrombotic occlusive disease secondary to atherosclerosis is the unique history, distribution of occluded vessels, unusual angiographic findings, and absence of any proximal source of embolic material. Often clot formation in the operative field—despite heparin sodium administration— is the first clue that the patient may have an antithrombin deficiency. The presence of multiple thrombi on operative angiograms is suggestive of a clotting abnormality.

Diagnosis Results of routine coagulation tests are normal in patients with antithrombin III deficiency. Generally, reductions in

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antithrombin are measured by both immunologic assays (tests that measure the total amount of the protein) and functional procedures (tests that measure the activity of the antithrombin III molecules). Initially, patients with repeated episodes of venous thrombosis were identified because their levels of antithrombin III were reduced to 50– 60% of normal. Subsequent work identified patients with arterial thrombosis secondary to low antithrombin III levels. Lynch et al.[17] demonstrated a correlation between low preoperative plasma functional antithrombin III levels and the occurrence of thrombotic complications following cardiac and vascular surgery. Thrombotic complications included arterial thrombosis, graft thrombosis, deep venous thrombosis, cerebral vascular thrombosis, spinal infarction, and embolic cortical blindness. A decrease in antithrombin III levels is the mechanism of the increased thrombotic tendency of patients on oral contraceptives. Sagar et al.[18] demonstrated that antithrombin III activity was significantly lower in patients taking oral contraceptives than in control patients. During surgery, the antithrombin III activity fell in both the contraceptive and the control groups, but the decline was greater in patients on oral contraceptives. The only patients who developed deep venous thrombosis postoperatively as determined by the I125 fibrinogen test were those on oral contraceptives. Of the 31 patients on oral contraceptives, 5 had an antithrombin III activity below 50%, and of these, 3 developed deep venous thrombosis. More recent work has demonstrated that the administration of heparin tends to lower the antithrombin level. Conrad et al.[19] demonstrated that it is the presence of heparin and not the rate of administration which is the determinant of the decrease in antithrombin III. They noted that both subcutaneous and intravenous heparin cause antithrombin III levels to drop by the same amount. Since heparin is dependent on antithrombin for its antithrombotic action, the antithrombin-lowering affect of heparin in patients with an already low antithrombin concentration probably indicates that patients are at risk of thrombosis for two reasons. First, heparin is relatively ineffective in patients with low levels of antithrombin III. Second, because heparin binds with antithrombin III, the already low level is decreased even further, possibly to dangerous levels. This is the theoretic basis of the paradoxical thrombotic episodes occasionally seen after heparin is stopped. Since heparin administration has decreased the level of antithrombin III, sometimes to significantly dangerous levels, cessation of heparin is followed by a period of hypercoagulability because the patient’s lower antithrombin III level is not counteracted by the heparin. This is why warfarin administration should be overlapped with heparin cessation when thrombotic problems are being treated. Patients with a congenital antithrombin III deficiency should be on chronic long-term warfarin therapy because of the risk of recurrent thrombotic episodes. In addition to its anticoagulant effect, warfarin increases the level of antithrombin III by an as yet undetermined mechanism. More recently, purified antithrombin III had been obtained by recombinant techniques; in the future, this advance will change the treatment of antithrombin III deficiency. Antithrombin III concentrate factor is now available as factor-specific replacement.[20]

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DEFECTS IN THE FIBRINOLYTIC SYSTEM The fibrinolytic system has become better understood in recent years and has been found to be the source of coagulation abnormalities. The components of the fibrinolytic system include plasminogen; plasminogen activators, including tissue plasminogen activator (TPA) and urokinase; inhibitors directed against plasminogen activators; plasmin inhibitors, the most important of which is alpha II antiplasmin; and cellular plasmin inhibitors, which have been identified in platelets and endothelial cells.[21,22] The degradation of fibrin is normally carried out by the proteolytic enzyme plasmin, which is formed from the proenzyme plasminogen by the action of plasminogen activators such as TPA or urokinase. The process is regulated at many different levels, resulting in localized plasmin formation at the fibrin surface. TPA is the most important activator and is produced and released from vascular endothelium.[23] Plasminogen is a normal plasma protein consisting of a single polypeptide chain with a molecular weight of 90,000 – 94,000.[24] Thin-layer gel electrofocusing, coupled with immunofixation, can demonstrate up to 10 different forms of plasminogen, with each variant having a glutamic acid as its terminal amino acid. Plasminogen is converted to plasmin by activators, many of which are released from endothelial cells. Plasmin is a serine protease and is an important member of the fibrinolytic systems that acts by cleaving fibrinogen and fibrin. The biosynthesis of plasminogen and fibrinolytic inhibitors is probably under genetic control. In 1978, Aoki et al.[25] reported a patient with recurrent thrombosis who had a hereditary molecular defect of plasminogen. This was followed by reports by Kazama et al.[26] in 1981 and Soria et al.[27] in 1983. These authors demonstrated that the abnormal plasminogen did not have the functional ability of normal plasminogen, resulting in a discrepancy between the biologic activity and the amount of plasminogen detected in the serum by radioimmunoassay. These patients had normal concentrations of plasminogen antigen, with approximately half of the activity of normal plasminogen. Using electrofocusing techniques coupled with immunofixation and zymograms, they were able to identify 10 additional bands, each of which was located on the basic side in close proximity to the corresponding normal band. Determination of amino acid sequence has demonstrated defects in the arginine 516 valine bond and the substitution of alanine 600 by threonine.[28] The major function of the fibrinolytic system in vivo is the limitation of fibrin deposition. A reduction of fibrinolytic activity may provoke a thrombotic tendency by allowing the growth and development of thrombi after the initiating thrombotic event. Most patients with abnormal plasminogen are characterized by a normal antigen concentration and by decreased functional activity. Liu et al.[29] reported a plasminogen which was characterized by both low functional activity and low antigen; they called it plasminogen San Antonio. Congenital plasminogen deficiency is now divided into two groups. In Type I plasminogen deficiency the

immunoreactive plasminogen is reduced in parallel with its functional activity. In Type II plasminogen deficiency the immunoreactive plasminogen is normal and the functional activity is reduced.[30] Type I represents a problem of plasminogen production, and Type II indicates the manufacture of a defective molecule. In a study of patients with unusual and unexplained thrombosis who had an abnormal plasminogen band detected on immunoelectrophoresis, we noted that only 1 of our initial 8 patients demonstrated a decreased functional level of plasminogen as compared with antigenic levels.[31] We felt that this might be related to the assay of functional activity used in the study, or it might represent a different form of abnormality than reported in the literature. One of our patients had a low functional plasminogen level at the time of thrombotic activity, but when he was studied 4 months after the institution of warfarin therapy, an increase in the level of functional plasminogen to 70% of normal was found. One year later, he had normal plasminogen activity. The patient continued to show an abnormal band of plasminogen in the electrophoretic pattern, demonstrating persistence of an abnormal plasminogen molecule in the plasma. This patient has had two episodes of pulmonary emboli. Ikemoto et al.[32] reported that the genetic characteristics of this disorder follow an autosomal codominant inheritance pattern with the alleles completely expressed. The results of the study of two families in our series are in agreement with this. The clinical history of recurrent phlebitis in one of our patients and his sister supports the genetic aspect of this disease. The immunoelectrophoresis technique used in our study is quicker, simpler, and less costly than isoelectric focusing, and it is more applicable to screening large groups of patients. The significance of the abnormal plasminogen is uncertain. It is present in 10% of the normal population, and its presence does not ensure that a patient is going to have thrombotic complications. More likely, this abnormal plasminogen results in the relative defect of the fibrinolytic system, which places the patient at increased risk should he or she be in a thrombosis-prone situation. Our data suggest, however, that once a thrombotic episode occurs, it is likely to recur, emphasizing the need to identify and treat these patients with long-term warfarin therapy.

Clinical Presentation We have noted that thrombosis occurs on both the arterial and the venous sides of the circulation in patients with abnormal plasminogen. In our initial report of 8 patients, the age of onset of the first thrombotic episode ranged from 21 to 57 years. Of these 8 patients, 3 had venous thrombosis, 2 had spontaneous arterial thrombosis, 2 had occlusion of an arterial reconstruction in the early postoperative period, and 1 had separate episodes of both arterial and venous occlusion. Thrombosis involving the venous systems occurred in 4 patients: 2 had complete obstruction of the iliofemoral venons segment and inferior vena cava, 1 had primarily popliteal vein thrombosis, and the remaining patient had axillary and subclavian vein thrombosis. In 2 of these patients, concomitant pulmonary emboli occurred—in one case after

Chapter 16.

an interval of 4 months. Arterial thrombosis occurred in 5 patients: 2 patients presented with spontaneous thrombosis of the iliofemoral segment. Following thrombectomy with Fogarty catheters, there was no evidence of inflow obstruction, and a complete evaluation for the proximal source of the emboli was negative. Postoperative occlusions of arterial reconstructions occurred in 2 patients. Of the 6 patients who had recurrent episodes of thrombosis, 2 had three recurrences and 4 had two recurrences. The interval between thrombotic episodes ranged from 4 to 36 months. Significantly, 5 of the patients who had recurrent thrombosis were treated with warfarin following the first episode. Recurrent episodes of thrombosis occurred 2 weeks to several months following cessation of warfarin therapy, and recurrent thrombosis did not develop in any patient while on anticoagulation therapy. We subsequently identified 4 patients with an abnormal plasminogen, as detected by an abnormal arc on immunoelectrophoresis, who developed severe thrombosis in the upper extremities.[33] The lack of atherosclerosis in the upper extremities as well as the absence in these patients of any proximal embolic source further demonstrates the sometimes catastrophic consequences that can occur in patients with abnormal plasminogen. In the more than 35 patients that we have diagnosed over the last 7 years, we have seen only 1 patient develop recurrent thrombosis while on warfarin therapy.

Methods of Testing A complete coagulation profile on each patient should be performed, including tests of platelet aggregation, prothrombin time, partial thromboplastin time, fibrinogen level, and platelet count. Functional assays of (1) antithrombin III and plasminogen alpha II antiplasmin, (2) antigenic activities of antithrombin III, plasminogen, and alpha I antitrypsin, and (3) alpha II macroglobulins should be obtained. With immunoelectrophoresis, the abnormal plasminogen present as a abnormal band that is separate on the electrophoretic pattern located nearer the anode and distinct from the normal band. We have also seen a patient with a plasminogen that was separate from the main band but not confined to a distinct band. Indeed, this may represent still another species. Work by several investigators is ongoing to further characterize the molecular defect in these abnormal plasminogens and to assess the functional impairment. This requires rather sophisticated techniques to determine amino acid sequencing and to test the functional ability of the various components of the plasminogen molecule.

TPA AND ANTI-TPA With the discovery of the ability to measure tissue plasminogen activator (TPA), investigators have found that the levels of TPA can vary and may be related to the occurrence of thrombotic disease.[34] Also, the presence of an anti-TPA, which counteracts the effects of TPA, has been discovered.[35,36] Several studies have identified patients who are thrombosis-prone because of increased levels of anti-

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TPA.[34 – 37] Both the mechanisms and the effect of alterations of these mechanisms are poorly understood at the present time. Wiman[37] first developed the test to measure TPA. In a study of patients with deep venous thrombosis, he noted that 40% of his patients had a reduced fibrinolytic potential, which was found to be due to a reduced capacity to release TPA, to an increased plasma level of an anti-TPA, or to a combination of these.[34] He also noted a significant correlation between the plasma anti-TPA and serum triglycerides among patients with myocardial infarction below the age of 45. Obviously these are preliminary data, but they emphasize the need for ongoing investigation to more precisely determine the role of the fibrinolytic system in the pathogenesis of thrombotic disorders.

PROTEIN C Protein C is a vitamin K– dependent proenzyme which is involved in the control of clotting and fibrinolysis. Protein C itself is activated by thrombin, but slowly. This activation is increased up to 20,000-fold when thrombin forms a complex with an endothelial cell membrane called thrombomodulin. Activated protein C, when combined with phospholipids, calcium, and protein S, inactivates the cofactors of the two rate-limiting steps of coagulation, factors Vx and VIIIa.[38 – 40] Protein S is likewise a vitamin K–dependent factor. It acts as a cofactor for the anticoagulant activity of activated protein C by promoting its binding to lipid and platelet surfaces and thus localizing protein C activity.[41,42] Protein C, in conjunction with protein S, also acts as a profibrinolytic agent by increasing plasmin activity through the inactivation of the major inhibitor of TPA.[38,39] Heterozygous protein C deficiency is inherited in an autosomal dominant fashion. In hereditary protein C deficiency, the homozygous state is associated with a very high risk of thrombosis.[43,44] It usually presents as massive venous thrombosis in the neonatal period, which is often fatal. The survival of affected infants in utero may reflect the protection afforded by maternal transfer of protein C or reduced synthesis of other procoagulants by the fetal liver, thus compensating for the deficiency of protein C. In the heterozygous form, a protein C level of 50% is sufficient to predispose individuals to venous thrombosis.[44] The occurrence of thrombophlebitis in patients who are heterozygous for this deficiency is uncertain. Some kindreds have been identified in whom there is a very high incidence of venous thrombosis (up to 80%) by the age of 40, and there are others in whom the occurrence of thrombosis is sporadic.[45,46] Acquired protein C deficiency can be observed in the acute phase of thrombosis, in patients with disseminated intravascular coagulation, in patients with liver disease, and in postoperative patients. Protein C deficiency generally manifests with venous thrombosis. This can be in the form of lower extremity venous thrombosis, often accompanied by pulmonary embolism, or it may present as mesenteric venous thrombosis. We recently reported 5 patients with protein C deficiency. Of these, 4 had deep venous thrombosis of the lower extremity as their initial thrombotic event and 1 had mesenteric venous thrombosis

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with small bowel necrosis.[47] Our patients’ age range was 28–41 years. Two patients had recurrent lower extremity thrombosis, which was bilateral in one. One patient had only one clinical episode of deep venous thrombosis but developed venous stasis ulceration, suggesting multiple episodes of subclinical phlebitis. One patient had a pulmonary embolus. Green et al.[48] evaluated 8 consecutive patients with splanchnic venous thrombosis and demonstrated decreases in the levels of antithrombin III and protein C in all. They were unable to document whether the low levels of protein C and anithrombin III were a result or cause of the thrombosis. Of these 8 patients, 2 had an antecedent history of venous thrombotic problems, and 6 of them, on being evaluated after a period of 1–6 months, were found to have a persistently low level of protein C, which would certainly suggest a congenital etiology. The only case of peripheral arterial thrombosis secondary to protein C deficiency was reported by Coller et al.[49] That patient developed arterial occlusions of both the superficial femoral artery and radial and ulnar arteries. Nelson et al.[50] reported a patient who had two episodes of branch retinal arteriolar occlusion secondary to protein C deficiency. There reports indicate that protein C can cause arterial thrombosis, although it is unusual.

Methods of Testing Standard testing includes a radiolabeled Laurell electroimmunoassay to determine human protein C antigen in plasma samples. Activity levels of 70–130% are considered to be normal. In our patients with venous thrombosis, the level of protein C ranged from 34 to 61%. As with the evaluation of all patients with unusual or unexplained thrombosis, there should be simultaneous measurement of antithrombin III and protein S and routine coagulation studies. We evaluated the family of our patient with mesenteric venous occlusion for protein C deficiency, and the results were compatible with an autosomal dominant type of transmission. There have not, however, been any reports of thrombotic episodes among other family members with low protein C levels. Since not all family members with low protein C develop thrombosis, asymptomatic patients with low levels of protein C should be followed closely and not prophylactically anticoagulated. However, they should be prophylactically anticoagulated preoperatively if major surgery or prolonged immobilization is required. In those who develop thrombotic events, the onset is typically between 15 and 30 years of age. This delay in onset of the first thrombotic episode is not well understood. The fact that protein C rarely causes arterial thrombosis, as contrasted with our experiences with either abnormal plasminogen or antithrombin III abnormalities, is not well understood. It may be that protein C deficiency requires slower-moving blood and increased endothelial surface area, as found in the venous system. However, when protein C deficiency is homozygous, thrombosis is widespread, resulting in death in infancy unless it is treated. Because of the risk of recurrent thrombotic events with the possible sequelae of pulmonary emboli and venous stasis disease, long-term therapy with warfarin is recommended. No loading dose should be administered, as this could precipitate warfarin-associated skin necrosis.[41,42] This can occur 2–5

days following the onset of warfarin therapy and presents as an erythematous patch on the skin that rapidly progresses to a hemorrhagic area, which can become gangrenous. There is a predilection for involvement of the breasts, abdomen, buttocks, and thighs. The proposed mechanism is one of a transient hypercoagulable state, which is created by bolus loading doses of warfarin given to initiate anticoagulation. Because of warfarin’s short half-life, protein C levels fall faster than factor X and prothrombin levels; thus the inhibitory effect of protein C on the coagulation cascade is further diminished. If these levels fall to a critical degree, the procoagulant effects of the coagulation cascade proceed unabated and thrombosis ensues. Warfarin 5.0 mg by mouth once a day should be started to gradually attain a prothrombin time (PT) of 1.5 –2.0 times control. Heparin and warfarin therapy should overlap by 4 – 5 days.

PROTEIN S DEFICIENCY Protein S is also a vitamin K–dependent protein; it functions as a cofactor of anticoagulant activity of activated protein C. The liver is the major source of synthesis, although more recently the endothelial cells and megakaryocytes were identified as other sites of synthesis. Protein S functions by expediting the binding of activated protein C to lipid and platelet surfaces. To date, only heterozygous patients with protein S have been reported.[44] Symptomatic patients often have protein S levels 50% of normal, and, as in protein C deficiency, protein S likewise causes primarily venous thrombosis.[51 – 53] It has been estimated by some to be the cause of approximately 10% of spontaneous venous thrombosis. Coller et al.[49] also reported the only known case of a protein S –deficient patient who had arterial occlusive problems. As with patients with protein C problems, the clotting abnormalities tend to be recurrent; therefore it is essential that these patients remain on long-term warfarin therapy. Clark et al.[54] emphasized the importance of measuring both free protein S as well as the total, which is composed of both the free and bound factors. His patient with mesenteric venous thrombosis had a normal total protein S but a markedly decreased level of the free compound. The association of deficiencies in protein C and its cofactor protein S with hypercoagulable states has only recently been appreciated. Data now suggest that the incidence of protein C and protein S deficiencies is greater than that of either antithrombin III or plasminogen abnormalities. In a recent report evaluating 139 individuals who had at least one major venous thrombotic event, 7% were deficient in protein C, 5% were deficient in protein S, only 2% were deficient in plasminogen, and only 3% were deficient an antithrombin III[39] A majority (79%), however, had no coagulopathy detectable with current testing methods.

HEPARIN-INDUCED THROMBOSIS Paradoxical thrombotic complications of heparin sodium therapy are an uncommon but potentially limb-threatening

Chapter 16.

and occasionally fatal complication of heparin anticoagulant therapy. Several investigators[55 – 59] have identified a chemically induced, immune thrombocytopenia as the cause of the intravascular thrombosis initiated by heparin. When this complication occurs, it usually appears after 4 – 10 days of continued exposure to the drug. The implicated immune factor has been identified as an IgG antibody, which produces agglutination of normal platelets when heparin is added and is seen with both porcine gut as well as beef lung heparin. The thrombi of patients with heparin-induced thrombosis have an unusual grayish-white appearance, in distinction to the red color of most thrombi. The white color is secondary to fibrin platelet aggregates, which can be clearly identified on electron microscopy. Recent studies have demonstrated that heparin-induced thrombosis can be caused by IgA antibodies or antibodies directed against platelet Factor 4 –related chemokines.[60] Rhodes et al.[61] demonstrated an IgG-heparin –dependent antibody in the serum of several of their patients by means of the complement lysis inhibitions test. They also demonstrated a residual heparin platelet aggregating effect 12 days to 2 months after the patients’ recovery from the initial exposure to heparin. In these patients, a 24-hour infusion of heparin caused a mean reduction of platelet count of 197,000/mm3. Since heparin preparations are not pure substances, it is also possible that a high molecular weight contaminant not eliminated by the extraction procedure could be the cause of the antiplatelet effect.

Clinical Presentation We have seen heparin-induced intravascular thrombosis following a wide variety of indications for heparin administration, including thrombophlebitis with and without pulmonary embolus, perioperative heparin prophylaxis in patients prone to develop thrombophlebitis, cardiac surgery, and vascular reconstruction. Platelet aggregation induced by heparin can result from both porcine gut as well as bovine lung heparin. Heparin-induced intravascular thrombosis can affect either arterial or venous circulation. Both subcutaneous and intravenous heparin administration can produce this phenomenon.[62] Even heparin-coated catheters can cause heparin-induced thrombocytopenia. Laster and Silver[63] reported 10 patients who had heparin-coated pulmonary artery catheters inserted and developed heparin-induced thrombocytopenia, which persisted despite discontinuation of all other sources of heparin. Although all of their patients had also received intravenous heparin, it is theoretically possible that the heparin-bonded catheters alone caused the abnormal platelet aggregation. This same group has demonstrated that heparin-induced platelet aggregation can occur in neonates and is a common cause of aortic thrombosis in neonatal intensive care units.[64] Heparin-induced thrombosis can also be caused by low molecular weight heparin and other highsulfated polysaccharides, although the incidence is lower than with unfractionated heparin.[60] The clinical features of this syndrome are often dramatic. Heparin-induced platelet aggregation should be considered in any patient who develops thrombotic complications while receiving heparin therapy. This is especially important in

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patients with arterial occlusions who do not have any other evidence of atherosclerotic vascular disease. At operation, the finding of a white clot at thrombectomy should alert the surgeon to the possibility of a heparin-induced thrombosis. In contrast to several reports in the literature, increased heparin sensitivity rather than increased heparin resistance was seen in several of our patients.[62] We are uncertain as to the cause of this, but presently believe that it is unrelated to the heparininduced aggregative immune globulin.

Diagnosis The definitive diagnosis of heparin-induced intravascular thrombosis is obtained by performing platelet aggregation tests. We have noted two patterns of response. The more common is for the patient’s platelet-poor plasma to aggregate donor platelets upon the addition of heparin, indicating the presence of a relatively nonspecific platelet aggregating factor in the patient’s plasma. The less common pattern, as seen in one of our patients, is for the patient’s plasma to be active only against the patient’s platelets and to have no effect on donor platelets. A 14C-serotonin is also available. Antigen assays have been developed which should be used when functional tests are negative but there is a high clinical suspicion of heparin-induced thrombosis.[60] Other clotting factors are usually normal. The fibrinogen is normal, fibrin split products can be mildly elevated but not in the range seen with intravascular coagulation, and the prothrombin time is normal or slightly prolonged. All patients have a marked reduction in platelet count of less than 100,000/mm3 or a 50% decrease from admission level. In our series, the platelet count averaged 37,500 with a range of 6000–73,000. Patients with arterial thromboses often present with unique angiographic findings. These lesions consist of broad-based, isolated, lobulated excrescences that produce a variable amount of narrowing of the arterial lumen. Usually these signs appear abruptly, along with prominent luminal contour deformities in arterial segments that are otherwise normal. This distribution of disease is unusual and distinct from that commonly seen with atherosclerosis. These changes occur in both the suprarenal and the infrarenal portions of the abdominal aorta and represent adherent mural thrombi composed of aggregates of platelets and fibrin incorporating varying amounts of leukocytes and erythrocytes. Also, platelet aggregating tests should be performed on any patient in whom recurrent pulmonary embolism has developed in the course of adequate heparin therapy.

Treatment When heparin-induced thrombocytopenia is diagnosed, the heparin treatment should be reversed immediately with protamine, and dextran 40 should be administered for its antiaggregating and rheologic effects. We also begin warfarin therapy and continue it for several months. In patients with arterial occlusive manifestations of heparin-induced thrombosis, we recommend long-term warfarin therapy because of the possibility of coexisting latent venous occlusive disease. The response of the platelet count to discontinuation of heparin therapy is usually prompt, often rising to level of

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500,000–600,000/mm3 within several days. In our experience, the use of dextran 40 has facilitated the rebound in the platelet count, most likely because of its antiaggregating effect on the platelets.[65] Coagulation tests distinguish heparin-induced platelet aggregation from other clotting disorders. The fibrinogen level and prothrombin time are usually normal. The levels of fibrin split products and prothrombin time are normal or slightly elevated. The sole patient in our series with a noticeably elevated level of fibrin split products was the initial patient, in whom the diagnosis was not made antemortem. The heparin therapy was not stopped, and prior to her death, caused by an intracerebral hemorrhage, she had massive venous thrombosis involving both upper and lower extremities that resulted in the elevated level of fibrin split products. Early identification of the complication is necessary to minimize the catastrophic complications of major limb amputation and death. This experience suggests that it is imperative that all patients who are receiving heparin therapy have serial platelet counts done from the fourth day onward. It is our policy to perform platelet counts every other day, starting on the fourth day of heparin therapy. If a thrombocytopenia develops, platelet aggregation studies should be performed immediately. With early recognition, the mortality and morbidity of this syndrome can be minimized. Morbidity rates reported in the literature vary from 22 to 61% and mortality rates from 12 to 33%.[66,67]

Strategies for the Management of Patients with Heparin-Induced Platelet Aggregation Patients who require reexposure to heparin for other vascular or cardiac procedures require special management. Patients who develop heparin-induced platelet aggregation usually have their aggregation tests revert to normal within a 6-week to 3-month period. It is preferable to delay the vascular or cardiac procedure until these tests revert to normal. We test the patient at 6 weeks and then every 2 weeks to determine when the platelet-aggregation tests are negative. When they are negative, the patient is brought into the hospital. Cardiac catheterization or angiography is done as required without the use of heparin flush solutions. This is extremely important, since even small amounts of heparin in the flush solutions can stimulate the development of the heparin-induced antiplatelet antibodies. The patient then has the vascular or cardiac procedure done with the usual administration of heparin. At the conclusion of the procedure, all heparin is reversed with protamine and care is taken during the postoperative period to ensure that the patient does not receive heparin inadvertently, through the flushing central venous catheters or arterial lines. By using this procedure, we have not had any difficulty with reexposure to heparin. However, for those patients who require an additional vascular or cardiac procedure and cannot wait until the heparin-induced platelet aggregation tests are negative, a different strategy is necessary. When patients require procedures that can be done without the use of heparin, such as resection of abdominal aortic aneurysms, heparin is not used. However, when a complex lower extremity revascularization or cardiopulmonary bypass is required, some sort of

anticoagulation is necessary. There are basically two approaches to this. The approach favored by Silver and his group[68] consists of giving the patients aspirin and dipyridamole (Persantine) and using heparin for the operative procedure, as is customary. In addition to the aspirin and dipyridamole, we prefer also to use low molecular weight dextran, which, in addition to its rheologic properties, coats the platelets and interferes with platelet adhesion. In some patients, however, as noted by Kappa and his group,[69] the administration of aspirin had no effect on the tests of heparininduced platelet aggregation. Makhoul et al.[70] noted that aspirin abolished the aggregation in 9 of 16 patients with heparin-induced platelet aggregation and only decreased the aggregation in the remaining 7, suggesting that aspirin is not able to reverse the abnormal aggregation in all patients. Because of these reports, our procedure is to place patients who require reexposure to heparin on aspirin and dipyridamole for several days prior to the operative procedure.[1] On the day of operation, the platelet aggregation tests are performed with the addition of heparin. If the addition of heparin causes abnormal platelet aggregation, we use Iloprost to prevent heparininduced platelet aggregation during the procedure. The use of Iloprost can be complicated, particularly since it is a very potent vasodilator, and it must often be accompanied by rather large doses of alpha-adrenergic agents to support the blood pressure. Danaparoid sodium, a mixture of anticoagulant glycosaminoglycans (predominantly low-sulfated heparin sulfate and dermatan sulfate), can be used. There is an approximately 10% cross-reactivity with heparin. Prior to use, in vitro testing must be done to assure that danaparoid will aggregate a patient’s platelets.[60] Newer agents such as recombinant hirudin can be used. The advantage of hirudin is the lack of cross-reactivity with heparin-induced thrombosis antibodies. Sobel et al.[71] reported an alternate technique of placing patients on coumadin anticoagulation combined with dextran as a means of preventing intraoperative thrombosis during reconstruction. This is a reasonable alternative for peripheral vascular reconstruction but is not possible for cardiopulmonary bypass. In the future, different substances may be available to allow for adequate anticoagulation. Makhoul et al.[70] noted that, in vitro, heparinoids did not cause platelet aggregation in blood from patients with heparin-induced platelet aggregation. These new anticoagulant agents are being developed in Europe and, one hopes, may become available in this country. Cole et al.[72] have reported the use of ancrod, which is made from the venom of the Malaysian pit viper, as an anticoagulant in patients who have heparin-induced platelet aggregation. Ancrod acts enzymatically on the fibrinogen molecule to form a product that cannot be clotted by physiologic thrombin. At the present time this medication is in the investigational phase, and, like heparinoids, it may become commercially available fairly soon.

LUPUS ANTICOAGULANT Lupus anticoagulants are IgG or IgM antibodies which are directed against phospholipids that participate in coagulation disorders; they are found in 16 – 33% of the

Chapter 16.

patients who have lupus erythematosus. However, they are also found in a variety of other disorders as well as in normal individuals.[73 – 75] These antibodies belong to a family of antiphospholipid autibodies which were initially detected by their effect in vitro on the prolongation of plasma coagulation times. Most commonly, there is a prolongation of activated partial thromboplastin time; in some patients there is also a prolongation of prothrombin time. There have been only rare reports of bleeding tendencies related to the demonstration of a lupus anticoagulant; however, in the last decade there have been increasing reports of abnormal thrombosis in both the arterial and venous systems, spontaneous abortion secondary to placental thrombosis, cerebrovascular accidents, and thrombocytopenia. Lupus anticoagulants also cause falsepositive tests for syphilis. On occasion, lupus anticoagulant can occur after administration of phenothiazines, procainamide, and penicillin, following viral infections in children, and in patients with acquired immunodeficiency syndrome suffering from Pneumocystis carinii pneumonia.

Clinical Syndrome Recurrent thromboses have been reported in about one third of patients with lupus anticoagulant.[76] These consist of both venous thromboses, most commonly involving the lower extremities, and they are the most common manifestation. Patients may develop evidence of pulmonary hypertension due to recurrent pulmonary emboli or intrapulmonary thrombosis. Repeated strokes have been reported in 15 – 55% of these patients. Obstetric complications have been reported in 25–35% of women with lupus anticoagulant; they consist of spontaneous abortions, intrauterine growth retardation, and fetal death, all occurring in the second and third trimesters.[73 – 75] Ahn et al.,[77] in a study of patients undergoing surgery who had a lupus anticoagulant, noted that 9 of 18 vascular procedures were complicated by thrombosis. Seven of these patients suffered multiple postoperative thrombotic complications, resulting in amputations in three. The mechanism of action of lupus anticoagulants is not known. Several theories have been suggested, including an inhibitory activity on prostacyclin (PGI2), which is a potent in vivo inhibitor of platelet aggregation. IgG fractions with lupus anticoagulant activity have been shown experimentally to block the production of PGI2 in rat aortic endothelial cells.[78] Other investigators suggest that the lupus anticoagulant inhibits protein C activation, which is important in preventing thrombosis. Tsakiris et al.[79] feel that the inhibition of the catalytic activity of thrombomodulin might be explained by the direct attachment of lupus anticoagulant to thrombomodulin or to adjacent phospholipids of the cell membrane, preventing thrombin and/or protein C from binding to thrombomodulin.

Diagnosis Often the only indication that a patient has lupus anticoagulant is an abnormally prolonged activated partial thromboplastin time. On occasion, patients can also have a prolonged prothrombin time. An abnormal rabbit brain

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neutralization procedure and an enzyme-linked immunosorbent assay for the presence of anticardiolipin antibodies can more precisely identify the lupus anticoagulant.[77]

Treatment Because the precise mechanism whereby lupus anticoagulant causes intravascular thrombosis is not known, treatment has varied and has included antiplatelet medication with aspirin and dipyridamole, anticoagulation with warfarin and heparin, and the administration of steroids. The reason for the antiplatelet medication is that some authors feel that the lupus anticoagulant causes a decrease in the availability of arachidonic acid, which is necessary for the synthesis of prostacyclin inhibitor and platelet aggregation in vessel walls. In obstetric patients, it has been reported that steroids and aspirin are effective in preventing spontaneous abortion. Prednisone has been shown to suppress the production and/or activity of lupus anticoagulant as measured by lessened prolongation of the activated partial thromboplastin time. Until more information is available, we prefer to have patients on antiplatelet medications prior to procedures, using both aspirin and presantine. We use dextran routinely in all vascular reconstructions and have the patients on perioperative heparin. Postoperatively, the heparin is replaced by warfarin.

ACTIVATED PROTEIN C RESISTANCE The thrombomodulin/protein C anticoagulant pathway is an essential anticoagulant system. As thrombin is generated at sites of vascular injury, it activates and aggregates platelets and clots fibrinogen. It also binds to the endothelial membrane protein thrombomodulin. Upon binding to thrombomodulin, thrombin takes on anticoagulant properties by activating protein C. The activated protein C (APC) cleaves and inactivates factors Va and VIIIa in the presence of protein S. This endothelial base anticoagulant system allows blood to clot while maintaining intravascular fluidity. Defects in this anticoagulant pathway can provoke thrombosis, and indeed protein C and protein S deficiencies, discussed previously, are associated with an increased risk of thrombosis. To date, prothrombotic mutations have not been found in thrombomodulin or thrombin. A family history of thrombotic events is frequently obtained in young adults with venous thrombosis, but the inherited deficiencies in the anticoagulant protein such as protein C and protein S are found in only a small proportion of patients, approximately 5%.[80] This suggests the presence of another genetic defect that predisposes these patients to thrombosis. Work done by Svensson and Dahlba¨ck revealed a high prevalence of activated protein C resistance among young persons with a history of venous thrombosis.[80] Dahlba¨ck originally postulated that a defect in the protein C pathway interferes with the anticoagulant action of APC. He devised an assay to test this possibility in which the clotting time of blood measures the presence and absence of exogenous APC. In the normal response the clotting time is prolonged in the presence of APC because of the inactivation

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of factors Va and VIIIa. A defect is detected as a failure of prolongation of the clotting time resulting from resistance to added APC. Dahlba¨ck showed that this test detects an autosomal dominant trait associated with thrombosis. Further work done by Bertina and his group have demonstrated that the phenotype of APC resistance is associated with a heterozygosis of homozygous single-point mutation in the factor V gene, which predicts the synthesis of a factor V molecule that is not properly inactivated by APC (factor V Leiden).[81] Other data confirming these results were published by Zoller et al., who studied 50 Swedish families with inherited APC resistance.[82] They found that the specific point mutation in the factor V gene was present in 47 of 50 families. In their study, by age 33 years, 20% of the heterozygous and 40% of the homozygous patients had manifestations of venous thrombosis. The laboratory diagnosis is made by measuring the responsiveness of plasma to APC as the ratio of two activated

partial thromboplastin times: one in the presence of APC and one in its absence. The APC sensitivity ratio is normalized to the ratio obtained with a reference plasma. Resistance to APC is defined by an APC sensitivity ratio of ,0.84. A more recent way of identifying this factor V resistance to activated protein C is by direct assay for the factor V molecule, which is resistant to inactivation by APC (factor V Leiden). The question arises as to what can be done about these point mutations, which cause factor V to be resistant to activated protein C. It is clear that this is a major risk factor for thromboembolic disease, but the majority of patients with these mutant proteins will not suffer thrombosis. The risks of lifelong anticoagulation therapy in an asymptomatic patient must be weighed against the benefit of preventing infrequent yet devastating thrombotic attacks. At this point it would be a logical course of action to treat those patients who have already suffered thrombotic attacks with long-term warfarin therapy.

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Salem, H.H.; Mitchell, C.H.; Firkin, G.B. Current Views on the Pathophysiology and Investigations of Thrombotic Disorders. Am. J. Hematol. 1987, 25, 463. Broekmans, A.W.; Veltkamp, J.J.; Bertina, R.M. Congenital Protein C Deficiency and Venous Thromboembolism: A Study of Three Dutch Families. N. Engl. J. Med. 1983, 390, 340. Griffen, J.G.; Evatt, B.; Zimmerman, T.S. et al. Deficiency of Protein C in Congenital Thrombotic Disease. J. Clin. Investig. 1981, 68, 1370. Tollefson, D.F.J.; Friedman, K.D.; Marlar, R.A. et al. Protein C Deficiency: A Cause of Unusual or Unexplained Thrombosis. Arch. Surg. 1988, 123, 881. Green, D.; Ganger, D.R.; Blei, A.T. Protein C Deficiency in Splanchnic Venous Thrombosis. Am. J. Med. 1987, 82, 1171. Coller, B.S.; Owen, J.; Jesty, J. et al. Deficiency of Plasma Protein S, Protein C, or Antithrombin III and Arterial Thrombosis. Atherosclerosis 1987, 7, 456. Nelson, M.E.; Talbot, J.F.; Preston, F.E. Recurrent Multiple-Branch Retinal Arteriolar Occlusions in a Patient with Protein C Deficiency. Graefe’s Arch. Ophthalmol. 1989, 227, 443. Comp, P.C.; Esmon, C.T. Recurrent Venous Thromboembolism in Patients with a Partial Deficiency of Protein S. N. Engl. J. Med. 1984, 311, 1526. Schwarz, H.P.; Fischer, M.; Hopmeier, P. et al. Plasma Protein S Deficiency in Familial Thrombotic Disease. Blood 1984, 64, 1297. Rodgers, G.M.; Shuman, M.A. Congenital Thrombotic Disorders. Am. J. Hematol. 1986, 21, 419. Clark, D.A.; Williams, W.L.; Marlar, R.A. Mesenteric Vein Thrombosis Associated with a Familial Deficiency of Free Protein S. Arch. Pathol. Lab. Med. 1991, 115, 617. Babcock, R.B.; Dumper, C.W.; Scharfman, W.B. HeparinInduced Immune Thrombocytopenia. N. Engl. J. Med. 1976, 295, 237. Baird, R.A.; Convery, R.F. Arterial Thromboembolism in Patients Receiving Systemic Heparin Therapy. J. Bone Joint Surg. 1977, 59, 1061. Belt, W.R.; Romasulo, P.A.; Alving, B.M. et al. Thrombocytopenia Occurring During the Administration of Heparin. Ann. Intern. Med. 1976, 87, 155. Fratantomi, J.C.; Pollet, R.; Gralnick, H.R. HeparinInduced Thrombocytopenia: Confirmation of Diagnosis with In Vitro Methods. Blood 1975, 45, 395. Nelson, J.C.; Lemer, R.G.; Goldstein, R. et al. HeparinInduced Thrombocytopenia. Arch. Intern. Med. 1978, 138, 548. Warkentin, T.E.; Chang, B.H.; Greinacher, A. Heparin Induced Thrombocytopenia: Towards Consensus. Thromb. Haemostasis 1998, 79, 1. Rhodes, G.R.; Dixon, R.H.; Silver, D. Heparin-Induced Thrombocytopenia. Ann. Surg. 1977, 186, 752. Kapsch, D.N.; Adelstein, E.H.; Rhodes, G.R. et al. HeparinInduced Thrombocytopenia, Thrombosis, and Hemorrhage. Surgery 1979, 86, 148. Laster, J.; Silver, D. Heparin Coated Catheters and Heparin-Induced Thrombocytopenia. J. Vasc. Surg. 1988, 7, 667.

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64. Spadeon, D.; Clark, F.; James, E.; Laster, J.; Silver, D. Heparin-Induced Thrombocytopenia in the Newborn. J. Vasc. Surg. 1992, 15, 306. 65. Towne, J.B.; Bernhard, V.M.; Hussey, C. et al. White Clot Syndrome. Arch. Surg. 1979, 114, 372. 66. Silver, D.; Kapsch, D.N.; Tsoi, E.K.M. Heparin-Induced Thrombocytopenia, Thrombosis, and Hemorrhage. Ann. Surg. 1983, 198, 301. 67. Laster, J.; Cikrit, D.; Walker, N. et al. The Heparin-Induced Thrombocytopenia Syndrome: An Update. Surgery 1987, 102, 763. 68. Laster, J.; Elfrink, R.; Silver, D. Re-exposure to Heparin of Patients with Heparin-Associated Antibodies. J. Vasc. Surg. 1989, 9, 677. 69. Kappa, J.R.; Fisher, C.A.; Berkowitz, H.D. et al. Heparin-Induced Platelet Activation in Sixteen Surgical Patients: Diagnosis and Management. J. Vasc. Surg. 1987, 5, 101. 70. Makhoul, R.G.; Greenberg, C.S.; McCann, R.L. HeparinAssociated Thrombocytopenia and Thrombosis: A Serious Clinical Problem and Potential Solution. J. Vasc. Surg. 1986, 4, 522. 71. Sobel, M.; Adelman, B.; Szaboles, S. et al. Surgical Management of Heparin-Associated Thrombocytopenia. J. Vasc. Surg. 1988, 8, 395. 72. Cole, C.W.; Fournier, L.M.; Bormanis, J. HeparinAssociated Thrombocytopenia and Thrombosis: Optimal Therapy with Anerod. Can. J. Surg. 1990, 33, 207. 73. Espinoza, L.R.; Hartman, R.C. Significance of the Lupus Anticoagulant. Am. J. Hematol. 1986, 22, 331.

74. Tabechnik-Schor, N.F.; Lipton, S.A. Association of Lupuslike Anticoagulant and Nonvasculitic Cerebral Infarction. Arch. Neurol. 1986, 43, 851. 75. Shi, W.; Krills, S.A.; Chong, B.H. et al. Prevalence of Lupus Anticoagulant and Anticardiolipin Antibodies in a Healthy Population. Aust. NZ J. Med. 1990, 20, 231. 76. Du¨hrsen, U.; Brittinger, G. Lupus Anticoagulant Associated Syndrome in Benign and Malignant Systemic Disease. Klin. Wochenschr. 1987, 65, 818. 77. Ahn, S.S.; Kalunian, K.; Rosove, M.; Moore, W.S. Postoperative Thrombotic Complications in Patients with the Lupus Anticoagulant: Increased Risk After Vascular Procedure. J. Vasc. Surg. 1988, 7, 749. 78. Greenfield, L.J. Lupus-like Anticoagulants and Thrombosis. J. Vasc. Surg. 1988, 7, 818. 79. Tsakiris, D.A.; Settas, L.; Makris, P.E.; Marbet, G.A. Lupus Anticoagulant – Antiphospholipid Antibodies and Thrombophilia: Relation to Protein C – Protein S– Thrombomodulin. J. Rheumatol. 1990, 17, 785. 80. Svensson, P.J.; Dahlba¨ck, B. Resistance to Activated Protein C as a Basis for Venous Thrombosis. N. Engl. J. Med. 1994, 330 (8), 517. 81. Bertina, R.M.; Koeleman, B.P.; Kosta et al. Mutation in Blood Coagulation Factor V Associated with Resistance to Activated Protein C. Nature 1994, 369, 64. 82. Zoller, B.; Svensson, P.J.; Xuhaua, H.; Dahlba¨ck, B. Identification of the Same Factor V Gene Mutation in 47 Out of 50 Thrombosis-Prone Families with Inherited Resistance to Activated Protein C. J. Clin. Investig. 1994, 94, 2521.

CHAPTER 17

Anticoagulants Timothy K. Liem Donald Silver

4 are cofactors responsible for the regulation of the reactions catalyzed by the enzymatic factors, and one factor, fibrinogen, is converted to the fibrin monomer. The soluble fibrin monomer undergoes spontaneous polymerization and becomes cross-linked and stabilized by factor XIIIa. All clotting factors with the exception of factor VIII are produced by the liver. Factors II, VII, IX, and X and proteins C and S require the presence of vitamin K for their synthesis. The plasma half-lives of the coagulation factors vary from 5 to 6 hours for factor VII to 120 hours for factor XIII. All coagulation factors are found in fresh-frozen plasma. The labile factors, V and VIII, are rapidly depleted in stored plasma. Activation of the coagulation cascade may occur via the intrinsic and/or extrinsic pathway(s). Both pathways produce activated factor X and share a terminal pathway for the conversion of fibrinogen to fibrin (Fig. 17-1). Once thought to act independently, the extrinsic and intrinsic pathways are now known to have complex interactions. The integrity of the extrinsic and intrinsic pathways may be assayed by the measurement of the prothrombin time (PT) and activation partial thromboplastin time (aPTT), respectively. Excessive or continued activation of the coagulation mechanism is normally prevented by three mechanisms: blood flow reduces the local accumulation of activated clotting factors; the reticuloendothelial cells rapidly remove activated clotting factors; and natural anticoagulants [including antithrombin III (AT III), tissue factor pathway inhibitor (TFPI), protein C, and heparin cofactor II] block the action of activated coagulation factors. Antithrombin III inactivates thrombin (factor IIa), factor Xa, and the other serine proteases of the coagulation cascade. Tissue factor pathway inhibitor blocks the activity of factor VIIa, inhibiting the further activation of factor X to Xa. Protein C, a vitamin K – dependent proenzyme activated by thrombin, cleaves activated factors V and VIII and potentiates fibrinolytic activity by decreasing the activity of plasminogen activator inhibitor (PAI). Heparin cofactor II binds to and inhibits thrombin.

INTRODUCTION Antithrombotic agents are among the most frequently prescribed medications, with over a trillion units of heparin and 974 million milligrams of sodium warfarin (Coumadinw) utilized annually in the United States.[1] These agents enable vascular surgeons to alter the coagulation mechanism according to the needs of their patients. The vitamin K antagonists, unfractionated heparins (UH), and low molecular weight heparins (LMWH) are the mainstays of deep venous thrombosis (DVT) prophylaxis and have reduced the incidence of DVT and pulmonary embolism in postoperative and other at-risk patients. Intravenous or subcutaneous heparin followed by warfarin remains the primary therapy for venous thromboembolism. However, the low molecular weight heparins have been found to be as effective as UH. Heparinoids and recombinant hirudin (r-hirudin) recently have been approved for use by the U.S. Food and Drug Administration. These agents are gaining increased acceptance for patients who are otherwise unable to tolerate UH or LMWH. Various platelet function inhibitors including aspirin, ticlopidine, clopidogrel, and glycoprotein IIb/IIIa inhibitors also are being utilized with increased frequency. To optimize the benefits of anticoagulant therapy, the clinician must have a thorough knowledge of the pharmacology of each agent, the indications for their usage, and the potential complications associated with each agent.

COAGULATION MECHANISM The coagulation mechanism is composed of a series of interrelated enzymatic reactions, with feedback amplification, that result in the production of the stable hemostatic clot. Of the 12 clotting factors, 7 are proteolytic enzymes,

Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024900 Copyright q 2004 by Marcel Dekker, Inc.

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Figure 17-1. The intrinsic and extrinsic pathways of coagulation. HMWK, high molecular weight kallikrein; PL, phospholipid from activated platelets or endothelial membranes. [From Hoch, J.R.; Silver, D.: Hemostasis and Thrombosis. In Moore, W.S. (Ed): Vascular Surgery: A Comprehensive Review, 3rd Ed. Philadelphia, Pennsylvania, Saunders, 1990. Reproduced by permission.]

HEPARIN AND HEPARIN-LIKE AGENTS Physical Properties and Mode of Action Unfractionated Heparins and Low Molecular Weight Heparins Heparin molecules are a heterogeneous mixture of straight-chain glycosaminoglycuronan sulfate esters. The molecular weights range from 4000 to 40,000 for UH, and 3000 to 15,000 for the LMWH preparations. The glycosaminoglycuronan chains are composed of alternating uronic acids and glycosamines with a high degree of sulfation. The sulfation imparts a negative charge to the mucopolysaccharide and is in part responsible for its anticoagulant activity when compared with other glycosaminoglycuronans. The primary commercial sources for UH are bovine lung and porcine intestinal mucosa. Most LMWH preparations are derived from the chemical depolymerization and fractionation of porcine intestinal heparin. Heparin exerts its anticoagulant effect through an interaction with the naturally circulating anticoagulants AT

III and TFPI. Heparin combines with AT III in a 1:1 stoichiometric ratio. It induces a conformational change in AT III, which makes its active centers more available for binding to thrombin and the other serine proteases of the coagulation cascade. It does not alter the ratio of binding of AT III to thrombin; however, it does increase the rate at which the complex is formed. After the AT III has neutralized the activated factor, heparin may dissociate from the complex and catalyze other AT III –protease interactions.[1,2] The ability of heparin and LMWH to bind to AT III is determined by the presence of a specific pentasaccharide unit, present in only 30% of standard UH and LMWH molecules. Thrombin (factor IIa) inactivation requires the formation of a ternary complex in which thrombin and AT III bind simultaneously to heparin molecules with at least 18 –20 saccharide units. Only 25 –50% of the heparin molecules in the various LMWH preparations contain this critical length. Thus, UH in the presence of AT III can inactivate both factors Xa and IIa (Xa:IIa ratio approximately 1:1). LMWH preparations have reduced anti-IIa activity while maintaining anti-Xa activity (Xa:IIa ratio of 3 – 5:1), (Table 17-1). The sensitivity of factor Xa to inhibition by the heparin –AT III complex is in part responsible for the effectiveness of the lowdose UH and LMWH regimens in the prophylaxis of DVT.

Chapter 17. Table 17-1. Comparison of Number of Heparin Saccharide Moieties and Specific Anticoagulant Activity Anticoagulant activity Heparin oligosaccharide 08 12 16 18 20

Molecular weight

Anti-Xa

Anti-Ha

2,400 3,600 4,800 5,400 7,200

1.30 1.58 1.60 0.95 1.30

nil nil nil 0.51 1.21

Source: Pharmacol. Rev. 1994, 46, 89–109.

The inhibition of one unit of factor Xa prevents the generation of more than 50 units of thrombin. Another important antithrombotic mechanism is the heparin-induced mobilization of TFPI into the circulation. Tissue factor pathway inhibitor is a serine protease inhibitor produced by endothelial cells and hepatocytes. Although TFPI is present in minute amounts during baseline conditions, UH and LMWH cause a two- to sixfold increase in TFPI via release from the endothelial surface. Tissue factor pathway inhibitor forms a complex with factor Xa, factor VIIa, and tissue thromboplastin and prevents the conversion of factor X to Xa. The anticoagulant effect of UH varies from subject to subject and may be a function of circulating AT III concentrations and antiheparin agents such as platelet factor 4 (PF4). Unfractionated heparin has limited anticoagulant activity in patients with congenital or acquired AT III deficiencies. Circulating AT III concentrations may fall up to 12% within 4 hours of the initiation of heparin therapy and may be decreased by as much as 33% with continued therapy. Patients with preexisting AT III deficiencies may experience an even greater decrease in circulating AT III concentrations with prolonged heparin therapy.[2] Recent studies demonstrate that LMWH administration causes less of a decrease in circulating AT III.

Low Molecular Weight Heparinoids Heparinoids are low molecular weight heparin-like glycosaminoglycuronans (molecular weight , 5000 –6000) and are derived from porcine intestinal mucosa. Numerous heparinoid agents have been developed (e.g., synthetic pentasaccharide sequences, aprosulate, pentosyn polysulfate). Danaparoid is the most widely available heparinoid, with active components including heparan sulfate (, 84%), dermatan sulfate (, 12%), and chondroitin sulfate (,4%).[3] The mechanism of action is similar to that of LMWH; danaparoid increases the activity of antithrombin III, accelerating the inactivation of factor IIa. The anti-Xa:anti-IIa ratio of danaparoid (, 22:1) is even greater than that of most LMWHs. Heparinoid administration may cause minor derangements in PT, aPTT, fibrinolysis, bleeding time, and platelet aggregation.

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Pharmacokinetics Unfractionated and Low Molecular Weight Heparins Unfractionated heparin binds rapidly to plasma proteins, and its early distribution approximates that of plasma. The half-life of circulating UH is dose-dependent, ranging from approximately 45 to 90 minutes. The most likely mechanism for its clearance is the binding of heparin by the reticuloendothelial system, where it may be concentrated up to 7500 times its concentration in plasma.[2,4] The plasma clearance of UH is reduced with increasing doses. When the amount administered exceeds the endothelial binding capacity, heparin is excreted by the kidneys in a nonsaturable fashion. The pharmacokinetic properties of the various LMWH preparations are significantly different from that of UH. Low molecular weight heparins exhibit less binding to plasma proteins (histidine-rich glycoprotein, PF4, vitronectin, fibronectin, von Willebrand factor), resulting in an increased bioavailability and predictibility of response.[5] Unlike UH, LMWH/AT-III complex inactivates free factor Xa and factor Xa bound within the prothrombinase complex. The maximum anti-Xa activity is attained 3 –5 hours after subcutaneous LMWH administration. The half-life of LMWH is approximately two- to fourfold longer than that of UH, and the elimination approximates that of first-order kinetics.[6] The half-life varies depending upon the preparation, dosage, and route of administration (2 – 3 hours after intravenous administration; 3–5 hours if given subcutaneously).

Low Molecular Weight Heparinoids Treatment with danaparoid cannot be monitored with the thrombin time or the aPTT. The maximum anti-Xa activity achieved after subcutaneous or intravenous administration of danaparoid occurs in 2–5 hours. The half-life of danaparoid is approximately 24 hours. Elimination is primarily via the kidneys; thus dosage adjustment is recommended in patients with renal impairment or failure.

THE VITAMIN K ANTAGONISTS Physical Properties The vitamin K antagonists fall into two groups: the substituted 4-hydroxycoumarins, of which sodium warfarin is the most commonly used member, and the indanediones. The indanediones are rarely used in clinical practice today because of their frequent association with toxic cutaneous and hepatic side effects. The 4-hydroxycoumarins are minimally soluble in plasma at pH 7.4; this necessitates protein binding, principally to albumin, of the drugs following absorption and intravenous administration. The metabolites of the 4hydroxycoumarins have better solubilities in plasma and less binding to albumin. The high degree of protein binding of sodium warfarin is responsible for its long half-life, volume of distribution, and mode of metabolism and elimination.

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Mode of Action Vitamin K is a coenzyme for the g-carboxylation of the 10 – 13 glutamine (glu) residues on coagulation factors II, VII, IX, and X and on proteins C and S. The liver processes vitamin K according to the cycle shown in Fig. 17-2. Vitamin K is first reduced to its hydroquinone form (KH2) via an NAD(P)Hdependent reaction. The KH2 is oxidized during gcarboxylation and must be regenerated via a dithioldependent reaction. Each molecule of vitamin K is recycled several hundred to several thousand times before it is degraded into inactive metabolites.[7] Coumarin derivatives block the regeneration of KH2, resulting in the production of vitamin K–dependent proteins with a decreased number of gcarboxyglutamate (gla) residues. These altered coagulation factors have a decreased affinity for calcium (an obligatory cofactor) and significantly decreased biologic activity (less than 5%). The activity of coumarin derivatives depends upon the natural degradation of functional coagulation factors present in the circulation and their replacement by the inactive form. The half-lives of the affected clotting factors range from 6 hours for factor VII to 72 hours for prothrombin; therefore, a therapeutic reduction of the concentrations of all the affected factors (II, VII, IX, X) may take 3 –4 days. The vitamin K antagonists also decrease the concentrations of protein C and its cofactor protein S. Because of a short half-life of 4–6 hours, levels of protein C are reduced quickly with the initiation of warfarin therapy. This creates a potential hypercoagulable state until levels of the vitamin K – dependent coagulation factors are also reduced. Consequently, anticoagulation with UH or LMWH is begun prior to the administration of warfarin and continued for the first 3 days of warfarin therapy. During long-term anticoagulant therapy, factor X activity is usually depressed to the greatest degree and factor IX activity the least. Factor X deficiency is the most common cause of bleeding due to an overdosage of the vitamin K antagonists.[8] When the maintenance dose of warfarin is changed, a new steady-state concentration of each affected factor is achieved. The time required to achieve 90% of the total change is 20 hours for factor VII, 65 hours for factor IX, 130 hours for factor X, and 8 days for factor II. The rate of recovery to normal factor concentrations after the discontinuation of anticoagulant therapy follows a similar time course.[8] The turnover of the clotting factors may be

increased in hypermetabolic states such as hyperthyroidism, sepsis, or fever and reduced in hypometabolic states such as hypothyroidism.

Pharmacokinetics of Warfarin Orally ingested warfarin is rapidly absorbed and reaches a maximum plasma concentration within 2 –12 hours. There is considerable variation in the plasma half-life of warfarin, but in most patients it averages 36 –40 hours. At therapeutic plasma levels, at least 97% of warfarin is bound to albumin. The metabolism of vitamin K antagonists occurs primarily in the microsomal fraction of the hepatocytes, although soluble enzymes in the hepatic and renal cytosol also contribute. The coumarin metabolites are water-soluble and are primarily excreted in the urine. The unchanged parent drugs are not water-soluble and are therefore not significantly excreted by the kidney. There is some evidence for an enterohepatic circulation of coumarin metabolites, but this appears to be of minimal clinical significance.[8] A few patients have a genetically determined resistance to the coumarin anticoagulants. One autosomal dominant trait produces an abnormal vitamin K sensitivity, and another leads to an enhanced metabolism of the drug. Some patients may be overly responsive to the coumarin anticoagulants during the first few days following an acute thromboembolic episode and subsequently develop a relative resistance to the anticoagulant effect. For this reason, dosage adjustment is frequently necessary to avoid too much or too little anticoagulation in the early stages of therapy.[8] The anticoagulant effect of warfarin does not correlate with free drug concentrations or plasma albumin levels. Prolongation of the PT depends on the amount of dietary vitamin K, the age of the patient, and comorbid conditions. Foods high in vitamin K derivatives (spinach, broccoli, cabbage, cow’s milk, yogurt, etc.) may make patients more resistant to the action of warfarin. Certain diseases or deficiency states (hepatic insufficiency, obstructive jaundice, starvation, long-term parenteral nutrition without vitamin K supplementation) depress the synthesis of vitamin K – dependent and non – vitamin K – dependent coagulation factors, resulting in a marked potentiation of warfarininduced anticoagulation. Uremia does not significantly affect the response to oral anticoagulant.

Drug Interactions

Figure 17-2. Warfarin and other coumarin derivatives block the dithiol-dependent reactions decreasing the amount of KH2 available for the carboxylation of glutamine (glu) to gcarboxyglutamate (gla). K, vitamin K; KH2, hydroquinone form of vitamin K; KO, vitamin K epoxide.

Several common therapeutic agents (aspirin, phenobarbital, various antibiotics) alter the response of the coagulation system to regularly administered doses of coumarin derivatives. This alteration may occur through a decreased absorption from the gastrointestinal tract, a displacement of the drug from its binding site on albumin, an increase in the rate at which it is metabolized by the hepatic microsomes, a decrease in vitamin K availability, or an increase or decrease in the plasma half-life of the affected clotting factors. Table 17-2 lists some known drug interactions with coumarin derivatives. In addition, drugs that affect platelet function, such as aspirin and indomethacin, may increase the risk of hemorrhage by impairing platelet function. Patients

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289

Table 17-2. Mechanisms of Drug Interactions with Oral Anticoagulants (Partial List) Drugs Agonists Chloramphenicol Ethanol Diazoxide Ethacrynic acid Indomethacin Mefenamic acid Nalidixic acid Oxyphenbutazone Phenylbutazone Sulfonamides Tolbutamides Clofibrate D -Thyroxines Oral antibioticsa Anabolic steroids Quinidine Salicylates Antagonists Barbiturates Meprobamate Griseofulvin Cholestyramine Oral contraceptives Vitamin K Pregnancy a

Mechanisms Enzyme inhibition Displacement of bound oral anticoagulant from protein

Reduced availability of vitamin K

Reduced synthesis of clotting factors

Enzyme induction

Reduced absorption Increased synthesis of clotting factors

Especially moxalactam and other second- and third-generation cephalosporines.

who receive additional medications while taking warfarin should have more frequent laboratory testing to ensure that the anticoagulant effect is maintained.

Monitoring Warfarin Therapy Prothrombin time is most commonly used to monitor warfarin therapy. This test is sensitive to changes in activity of factors II, VII, IX, and X. PT is determined by adding thromboplastin (tissue factor and phospholipid derivative from lung, heart, or brain tissue) and calcium to citrated plasma. Thromboplastins vary according to their ability to activate the external coagulation cascade and are graded by the International Sensitivity Index (ISI). The International Normalized Ratio (INR) attempts to standardize PT assays that use different thromboplastins according to the following equation: INR ¼ ½patient PT ðsÞ=laboratory PT ðsÞISI The PT should be monitored on a daily basis for the first 4– 5 days of warfarin therapy. The INR usually achieves the desired range during this period. A longer period of daily monitoring will be required in patients resistant to warfarin. Once the therapeutic range is attained, the PT can be monitored two to three times per week and, when stable, every 4–6 weeks.

Many patients are receiving heparin when warfarin therapy is initiated. Concomitant administration of heparin may prolong PT because of the increased inactivation of factors IIa, IXa, and Xa by AT III. It should be expected that PT will decrease when heparin treatment is discontinued. The effect of heparin on PT can be reduced by removing heparin from the test plasma or by stopping the heparin infusion 6 or more hours before obtaining blood for the PT.

DIRECT THROMBIN INHIBITORS Physical Properties Direct thrombin inhibitors inactivate factor IIa via mechanisms that do not involve antithrombin III. These agents include hirudin, hirugen, hirulog, hirunorms, PPACK (D-PhePro-ArgCH2Cl), argatroban, and inogatran. Hirudin and its recombinant form (r-hirudin) are 65amino-acid polypeptides which bind to the catalytic site and exosite (an additional substrate-binding site) of thrombin, preventing the further conversion of fibrinogen to fibrin. The native form is derived from the salivary gland of the medicinal leech (Hirudo medicinalis ). r-Hirudin is derived from yeast cells and varies by a single amino acid substitution at its N-terminus (leucine for isoleucine) and lacks a sulfate group on tyr-63. This alteration results in a significantly

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decreased affinity for thrombin when compared with the native form. PPACK, argatroban, and inogatran block the catalytic site of thrombin either reversibly or irreversibly. Hirugen is an 11-amino-acid fragment derived from the C-terminus region of hirudin. It blocks the substrate recognition site of thrombin, preventing the binding to fibrinogen and to the thrombin receptor on the platelet surface. Hirulog was created by combining hirugen (specific for the substrate recognition site) with a PPACK derivative [D-Phe-Pro-Arg-Pro-(Gly)4] (specific for the active site).

Pharmacokinetics of Hirudin Hirudin may be administered via an intravenous or subcutaneous route. After an initial distribution phase, hirudin follows first-order elimination kinetics. It is excreted via glomerular filtration in its active form. The renal clearances of hirudin and r-hirudin in female and elderly patients are decreased when compared with young males. The elimination T1/2 is approximately 1.3 hours in healthy subjects, but increases significantly in patients with renal insufficiency or renal failure (elimination T1/2 up to 2 days). The aPTT, PT, and thrombin time (TT) are prolonged by the administration of hirudin or r-hirudin. However, the PT and aPTT dose-response curves obtained are either not sensitive enough (PT) or too sensitive (TT) for clinical use. Hirudininduced prolongation of the aPTT is fairly linear, thus allowing this test to be used for anticoagulation monitoring.

than 80% after oral administration, and 98% is bound to plasma proteins (albumin and lipoproteins). Maximum inhibition of ADP-dependent platelet aggregation is achieved after 8–11 days. Clopidogrel is readily absorbed and is metabolized in the liver to a carboxylic acid derivative; both are highly bound to plasma proteins (.90%). Neither the clopidogrel parent compound nor its primary derivative has platelet inhibitory effects. Most likely, the active platelet inhibitory compound is a metabolite of the carboxylic acid derivative. Clopidogrel induces a dose-dependent inhibition of platelet aggregation, which is more rapid (within 2 hours after oral ingestion) than that of ticlopidine. Approximately 50% of clopidogrel is excreted in the urine, and another 46% via the fecal route.

Glycoprotein IIb/IIIa Inhibitors Fibrinogen, fibrin, von Willebrand factor, and fibronectin have recognition specificity for the platelet glycoprotein IIb/IIIa (GP IIb/IIIa) receptor via the amino acid sequence Arg-Gly-Asp (RGD). Glycoprotein IIb/IIIa inhibitors block the binding of fibrinogen to the platelet membrane, the final common pathway for platelet aggregation regardless of the agonist. The first inhibitor to be developed was c7E3, the Fab fragment of a monoclonal anti-GP IIb/IIIa antibody. Subsequently, naturally occurring proteins (trigramin) containing the RGD sequence have been isolated from the venom of several species of vipers. Synthetic RGD-containing proteins and the more potent KGD analogs recently have been manufactured and have undergone clinical trials.[10]

PLATELET FUNCTION INHIBITORS Aspirin Aspirin is the most widely used platelet function inhibitor. It acetylates platelet cyclooxygenase (prostaglandin H synthase), inhibiting the conversion of platelet and endothelial arachidonic acid to thromboxane A2 and prostacyclin, respectively. This effect lasts for the life of the platelet, whereas the endothelium may generate new cyclooxygenase. Noncoated aspirin is rapidly disintegrated and absorbed in the stomach, whereas, enteric-coated aspirin dissolves in the more neutral to alkaline pH within the duodenum. Enteric coating does not significantly delay the bioavailability when compared to noncoated aspirin.

Ticlopidine and Clopidogrel Ticlopidine and clopidogrel are thienopyridine derivatives that irreversibly inhibit ADP-mediated platelet activation and the binding of fibrinogen to the platelet membrane. These agents also may have a vasomodulatory effect on serotonin-, endothelin-, and arachidonic acid –induced vascular smooth muscle contraction.[9] Intact ticlopidine has no effect on platelets in vitro; in addition, the in vivo platelet inhibitory effects are not observed for 24 –48 hours after administration, suggesting that a ticlopidine metabolite may be a more potent platelet function inhibitor. Ticlopidine absorption is greater

THERAPY FOR VENOUS THROMBOEMBOLISM The purpose of anticoagulant therapy in deep venous thrombosis (DVT) is to halt propagation of thrombus and to decrease the risk of pulmonary embolism. Untreated isolated calf vein thrombosis propagates into proximal veins in approximately 20% of patients.[11,12] Additionally, 50% of patients with untreated proximal (popliteal and/or femoral) venous thrombosis will develop pulmonary embolism.[11,13] All patients with DVT are treated with heparin and warfarin antithrombotic therapy, unless contraindicated. Urokinase or tissue plasminogen activator are used selectively, and the criteria for their use will not be discussed in this chapter. Patients with proximal DVT are given an intravenous bolus of unfractionated heparin (100 –200 USP units/kg of heparin). This is followed by a heparin infusion, usually beginning at 1000 USP units per hour (or 15 units/kg/h). Unfractionated heparin concentrations in the range of 0.2–0.4 U/mL (measured via protamine titration) have been shown to inhibit propagation of venous thrombi.[14,15] In most laboratories, this heparin concentration correlates with an aPTT in the range of 1.5–2.5 times the normal reference range. The aPTT is monitored every 6 hours for the first 24 hours; the frequency of testing is decreased once the aPTT is

Chapter 17.

stable. Most patients who are treated with warfarin will require approximately 3 – 4 days of overlap anticoagulation with heparin to ensure that the functional vitamin K – dependent coagulation factors with longer half-lives have become depleted. In addition, daily platelet counts are performed to allow early detection of heparin-induced thrombocytopenia (HIT). Most patients who develop HIT will demonstrate a decrease in the platelet count after the fourth or fifth day of heparin therapy. If the patient has been previously exposed to heparin, the thrombocytopenia may begin within hours of the administration of heparin. Some patients will test positive for the presence of heparin-associated antibodies and develop recurrent thromboses without developing thrombocytopenia or a decrease in the platelet count.[16] Subcutaneous LMWH has been used successfully as initial therapy for patients with proximal (popliteal and/or femoral) DVT. Several large studies have demonstrated that the efficacy and safety of selected LMWH regimens are equal or superior to intravenous unfractionated heparin. Patients treated with weight-adjusted or fixed-dose LMWH (subcutaneously) followed by warfarin appear to have a similar incidence of symptomatic recurrent thromboembolism (2.8 –7.1%) when compared to patients treated with intravenous unfractionated heparin, followed by oral warfarin therapy (7.0 –12.9%).[17,18] Subsequent studies also have demonstrated the efficacy of outpatient initial therapy with LMWH when compared with inpatient intravenous standard heparin.[19,20] The rate of recurrent thromboembolism in patients treated with primarily outpatient LMWH and warfarin (5.3 –6.9%) was not significantly different than in patients treated with unfractionated heparin and warfarin in an inpatient setting (6.7–8.6%). A pooled analysis of several studies indicates that the incidence of major bleeding complications was decreased with LMWH therapy when compared to UH (3.2% versus 0.9%).[21] However, several large prospective trials have not found any significant decrease in major bleeding complications.[17,22 – 24] Regardless of the route and type of heparin administered, warfarin administration is begun simultaneously. Five to 7.5 mg of warfarin is given every evening, and the dosage is adjusted to achieve a therapeutic prothrombin time (PT), with the INR ranging from 2 to 3. Some patients may develop a prolongation of the INR within 1 –2 days, due to the rapid depletion of factor VII (half-life of approximately 6 hours). However, a truly antithrombotic state is not achieved until factors II and X are functionally depleted (approximately 3 – 4 days). Patients with iliac, femoral, and/or popliteal DVT are treated with warfarin for approximately 6 months. Warfarin is continued indefinitely if risk factors for DVT continue to be present (congenital thrombophilic disorders, patient immobility, malignancy, etc.). Some testing for thrombophilic conditions can be performed after the acute thromboembolic event has subsided and while the patient is receiving warfarin (e.g., assays for Leiden factor, homocystinemia, antithrombin III deficiency, prothrombin 20210 mutation, antiphospholipid antibodies, and dysfibrinogenemias). Other tests should be performed when there is no active DVT and after the warfarin has been discontinued for at least 3 –4 weeks. These include tests for

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protein C, protein S, and other vitamin K – dependent coagulation factors. Patients who have a history of recurrent thromboembolic events may be at risk for the development of additional thromboses during this “unprotected” time. We treat these patients with outpatient subcutaneous unfractionated or low molecular weight heparin until the testing for thrombophilic conditions has been completed. The heparin is discontinued at least 6, preferably 24, hours before the testing is done. Those patients with a congenital hypercoagulable condition and a proven thrombotic event are placed on long-term or, preferably, life-long warfarin. Patients with antiphospholipid antibodies should receive warfarin until the antibodies are no longer detectable.[25]

THERAPY FOR ARTERIAL THROMBOEMBOLISM Intravenous heparin is an important therapeutic adjunct for patients with arterial thromboembolism. Patients with acute ischemia syndromes (limb and visceral ischemia, unstable angina, anterior Q-wave myocardial infarction, transient ischemic attack, acute ischemic stroke, etc.) are commonly treated with heparin. However, convincing evidence supporting the use of heparin therapy is lacking except in patients with unstable angina and anterior Q-wave infarction.[26] In patients with native arterial thrombosis or embolic occlusion, heparin probably decreases the propagation of thrombus, thereby preserving the existing collateral arterial beds. Once blood flow is restored, anticoagulation (using heparin with or without warfarin) may also decrease the rate of recurrent embolism. Evidence for the use of anticoagulants in acute limb ischemia is conflicting (and is based on retrospective and nonrandomized studies).[27] However, most authors continue to recommend heparin and/or warfarin anticoagulation prior to and after revascularization procedures.[28 – 30]

PROPHYLAXIS AGAINST ARTERIAL THROMBOEMBOLISM Aspirin and other platelet function inhibitors decrease the risk of myocardial infarction, stroke, and vascular death in patients who develop complications related to atherosclerosis. The Antiplatelet Trialists’ Collaboration reviewed 145 randomized trials involving approximately 70,000 “highrisk” patients and 28,000 “low-risk” patients (Antiplatelet 1). Subsequent vascular events were significantly reduced in patients with (1) acute myocardial infarction, (2) a past history of myocardial infarction, (3) a past history of stroke or transient ischemic attack, and (4) a history of other vascular events including unstable angina, stable angina, vascular surgery, angioplasty, atrial fibrillation, valvular disease, and peripheral vascular disease. Taken together, those high-risk patients who were treated with antiplatelet therapy had a onethird reduction in the rate of nonfatal myocardial infarction, a one-third reduction in nonfatal strokes, and a one-sixth

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reduction in vascular death. The most widely tested antiplatelet agent was aspirin (75 –325 mg/day). The Antiplatelet Trialists’ Collaboration and other studies demonstrated that lower dosages of aspirin (75 mg/day) are also effective in reducing the risks of myocardial infarction and stroke in high-risk patients.[31 – 34] Alternative antiplatelet regimens, including aspirin plus dipyridamole, sulfinpyrazone alone, and ticlopidine alone, were also found to provide similar protection against vascular events. Among patients at low risk (no prior history of a vascular event), antiplatelet therapy decreased the rate of nonfatal myocardial infarction by approximately one third.[31] Obviously, the number of infarctions prevented in the low-risk patients (5 per 1000 subjects) were less than in the high-risk group (13.3 per 1000 subjects). Taken together, the rate of vascular events (including nonfatal myocardial infarction, nonfatal stroke, and vascular death) in low-risk patients was not significantly altered by long-term antiplatelet therapy. Ticlopidine and clopidogrel have been compared directly with aspirin in a few randomized trials involving high-risk patients.[35,36] In patients with a prior history of stroke, long-term ticlopidine therapy was associated with a significant reduction in the rate of subsequent strokes when compared with aspirin (10% versus 13%).[35] Clopidogrel, recently approved by the Food and Drug Administration for clinical use, has been advocated as an antiplatelet agent with an efficacy superior to aspirin. However, the CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events) study demonstrated that the advantages of clopidogrel are marginal at best. More than 19,000 patients with a history of (1) recent ischemic stroke, (2) recent myocardial infarction, or (3) symptomatic atherosclerotic peripheral vascular disease were treated with either clopidogrel or aspirin. The risks of subsequent ischemic stroke, myocardial infarction, or vascular death were 5.32% in the clopidogrel group and 5.83% in the aspirin group. Although there was a

statistically significant relative risk reduction of 8.7% ð p ¼ 0:04Þ; the absolute reduction in the number of vascular events was quite small. Clopidogrel may be more beneficial as a combination therapy agent since aspirin and clopidogrel inhibit platelet function via different signal transduction pathways (thromboxane A2 and ADP inhibition). Long-term warfarin administration is recommended for the prevention of systemic thromboembolism in patients with tissue heart valves, mechanical heart valves, valvular heart disease, in selected patients with atrial fibrillation (AF), and in selected patients with acute myocardial infarction.[37] Patients older than 65 years with AF and younger patients with AF and additional risk factors (prior transient ischemic attack or stroke, hypertension, heart failure, diabetes, coronary artery disease, mitral stenosis, prosthetic heart valve, thyrotoxicosis) are candidates for long-term warfarin prophylaxis.[38] Patients with anterior Q-wave myocardial infarction, severe LV dysfunction, and echocardiographic evidence for mural thrombus also should be considered for warfarin anticoagulation. Recommended INR ranges from the American College of Chest Physicians (ACCP) Fourth Consensus Conference on Antithrombotic Therapy are included in Table 17-3.

PROPHYLAXIS AGAINST VENOUS THROMBOEMBOLISM The incidence of perioperative DVT depends on the number of risk factors (e:g:; . 40 years, obesity, malignancy, immobility, prior venous thromboembolism, varicose veins, low cardiac output, major trauma, oral contraceptive use) and the type of surgical procedure performed. The incidence ranges from 25 to 33% in patients undergoing general surgical procedures and 45 to 70% in patients having total hip replacement.[39] Fixed low-dose UH prophylaxis (5000 units SC every 8–12 hours) reduces the incidence of DVT in

Table 17-3. ACCP Consensus Conference on Antithrombotic Therapy Recommended INR Range for Various Indications Indication DVTa prophylaxis (high risk) Treatment of venous thrombosis Treatment of pulmonary embolism Bioprosthetic heart valve Mechanical heart valves (high risk) Myocardial infarctionb Valvular heart disease Atrial fibrillation a

INR 2.0 –3.0 3.0 –3.0 3.0 –3.0 2.0 – 3.0 (for the first 3 months) 2.5 –3.5 2.0 –3.0 2.0 –3.0 2.0 –3.0

Deep vein thrombosis. For the prevention of systemic embolism. If warfarin is being used to decrease the risk of recurrent myocardial infarction, an INR of 2.5–3.5 is recommended. Source: Modified and Reprinted with Permission (Hirsh, J.; Dalen, J.E.; Deykin, D.; Poller, L.; Bussey, H. Oral Anticoagulants: Mechanisms of Action, Clinical Effectiveness, and Optimal Therapeutic Range. Chest 1995, 108 (Suppl. 4), 231S–246S). b

Chapter 17.

moderate- and high-risk general surgery patients from approximately 25% to 8%.[40] The incidence of pulmonary embolism is reduced as well. However, fixed low-dose UH prophylaxis is not as effective in patients with hip fractures or in patients undergoing total hip or knee replacement. Orthopedic and very high-risk general surgical patients should receive more effective DVT prophylaxis (oral anticoagulants, adjusted-dose UH, LMWH, or combination prophylaxis with intermittent pneumatic compression). When using an adjusted-dose UH regimen, the aPTT should be monitored 2–6 hours after heparin administration, with a target range of 2–212 times the control. Adding pneumatic compression to fixed-dosage UH prophylaxis further decreases the incidence of perioperative DVT. The prophylactic effect of vitamin K antagonists in DVT was first demonstrated by Sevitt and Gallagher in 300 patients with hip fractures.[41] The treated group, which received phenindione, had a 3% incidence of clinically diagnosed venous thromboembolism, while the control group had a 29% incidence of venous thromboembolism. At autopsy, venous thrombosis was found in 83% of the control patients, with 10% having pulmonary emboli. Only 14% of the treated patients who died had evidence of DVT; no patient died from pulmonary embolism while receiving phenindione.[41] More recent studies have confirmed that warfarin (INR 2.0–3.0) is effective prophylaxis against DVT in patients undergoing orthopedic surgical procedures.[42,43] The administration and monitoring of warfarin prophylaxis in the perioperative period are more cumbersome than with other regimens (LMWH), limiting its widespread use.

COMPLICATIONS OF ANTICOAGULATION Heparin Heparin-induced thrombocytopenia from the development of heparin-associated antibodies is the most common nonhemorrhagic complication of heparin therapy. Depending on the type of heparin used, the definition of thrombocytopenia, and the tests used to detect the presence of HAAb, the incidence of HIT varies from 2.4 to 9.6%.[44] Heparinassociated antibody formation may occur in up to 21% of vascular surgery patients who are subjected to repeated exposures with heparin.[16] Low molecular weight heparin preparations also cause HAAb.[45] Patients who are HAAbpositive from prior exposures to UH have a variable rate of cross-reactivity (19.6– 60.8%) with various LMW heparin and heparinoid preparations.[46] The first step in the treatment of patients with suspected HAAb/HIT is the prompt discontinuation of heparin administration. The presence of HAAb may be confirmed with two-point platelet aggregation assays, 14C-serotonin release assays, and newly developed enzyme-linked immunosorbent assays (ELISA). Most patients can expect a gradual return to normal platelet counts within 4 –5 days after all forms of heparin have been discontinued. If patients require continued anticoagulation, several options arc available. Low molecular weight heparinoids

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(e.g., danaparoid) may be used only if cross-reactivity tests are negative. The low rate of cross-reactivity (10 –19.6%) indicates that most, but not all, HAAb-positive patients may safely receive LMW heparinoids.[46,47] The dosage and route of danaparoid administration depend on the indications for use. As prophylaxis against thromboembolism, danaparoid is administered at 750 –1250 units twice a day, subcutaneously. For rapid anticoagulation, it is administered as an IV bolus 2500 – 3750 units with subsequent continuous infusion. If cross-reactivity testing is not available, patients should be treated with recombinant hirudin. Rapid anticoagulation may be achieved with an IV bolus (0.4 mg/kg body weight, 44 mg maximum) followed by a continuous infusion (0.15 mg/kg body weight/h, 16.5 mg/h maximum). The aPTT should be monitored frequently, with a therapeutic range of 1.5–2.5 times control.

Warfarin The primary complication of warfarin therapy is hemorrhage. The true incidence of bleeding is probably more accurately reflected in observational and population-based studies (2.7 – 12% per year) than in well-monitored clinical trials.[48 – 51] The usual sites of major hemorrhage include the gastrointestinal tract, retroperitoneum, extremities, pelvic organ, and central nervous system. The risk factors for bleeding complications associated with oral anticoagulation include the intensity of warfarin therapy, the age of the patient, the presence of malignancy or peptic ulcer disease, and the type of coumarin derivative used.[48,49] More intense anticoagulation (INR . 3.0) is associated with a greater incidence of bleeding than less intense warfarin therapy (INR 2.0–3.0). Minor hemorrhagic events are not reliable indicators that major bleeding is likely to occur.[49] The greatest likelihood of bleeding occurs during the first months of therapy.[49,50] Increased bleeding events may occur when warfarin dosages are adjusted (e.g., in the perioperative period) or when vitamin K intake changes significantly (dietary modifications, critical illness). Bleeding, which occurs in the presence of an INR of 5.0 or less, may have other associated causes (e.g., peptic ulcer disease, malignancy). Other less common complications of warfarin include alopecia, urticaria, dermatitis, fever, nausea, diarrhea, abdominal cramping, and hypersensitivity reactions. Warfarin-induced skin necrosis is a rare complication occurring in 0.01– 0.1% of patients receiving warfarin;[52] individuals with protein C deficiency may be more susceptible.[53] The mechanism of warfarin-induced skin necrosis may involve the depletion of protein C prior to reductions of the other vitamin K– dependent proteins. This causes a temporary thrombophilic state, which may lead to dermal venous thrombosis. The most likely sites of dermal venous thrombosis are the breast, thigh, or buttocks, although other areas with increased subcutaneous fat also may be involved. This complication may occur more often with larger loading doses of warfarin, although this is not clearly established. In patients who do not require rapid anticoagulation, we recommend that subcutaneous UH or LMWH be administered concurrent with the

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first 3–5 days of warfarin to decrease the likelihood of skin necrosis.

Reversal of Warfarin Anticoagulation Patients may require reversal of anticoagulation due to an excessive warfarin effect. Another common indication for anticoagulation reversal is the need for diagnostic, surgical, or dental procedures. The method by which warfarin anticoagulation is reversed depends on the amount of INR prolongation and whether or not the patient is bleeding. Hirsh and Levine[6] have formulated recommendations as follows: if the INR is less than 6.0 and the patient is not bleeding, omit the next few doses and restart warfarin at a lower dose. If the INR is between 6.0 and 10.0 and the patient is not bleeding, vitamin K (1 –2 mg, subcutaneous injection) can be administered. If the INR is greater than 10.0 and the patient is not bleeding, higher doses of vitamin K (3–10 mg, subcutaneous injection) can be given. Additional doses of vitamin K are indicated if the INR is still significantly prolonged in 6–12 hours. If the INR is greater than 20.0 or if the patient has significant bleeding, vitamin K (10 mg subcutaneously or IV) should be administered in combination with fresh frozen plasma or prothrombin complex concentrate. Elective surgery and invasive diagnostic procedures in patients receiving warfarin should be delayed, if possible,

until the oral anticoagulation can be discontinued safely. If the patient is on lifelong warfarin therapy or if the surgical/diagnostic procedure cannot be delayed, the options for the management of these patients are as follows. The first choice is to discontinue warfarin 4 –5 days prior to surgery. Therapeutic LMWH (enoxaparin 1 mg/kg, subcutaneously twice a day) is administered during this time, discontinued 6–12 hours prior to surgery, and reinstituted several hours after surgery. Alternatively, the warfarin dosage is reduced to allow the INR to reach low therapeutic or subtherapeutic levels. The choice depends upon the original indication for anticoagulation and the type of surgical procedure being performed. Patients receiving warfarin who require emergent surgery can have the anticoagulation reversed with vitamin K (10 mg IV) and/or fresh frozen plasma (if fluid volume is not a problem). Patients with mitral or combined mechanical valve replacements have a significant incidence of perioperative thromboembolic complications that warfarin is discontinued in the perioperative period.[54] A protocol that replaces warfarin with UH or LMWH may be most appropriate in these patients.[55] Discontinuation of warfarin 3–5 days prior to noncardiac surgery (without heparin replacement) in patients with aortic valve prostheses appears to be associated with a low incidence of thromboembolism.[54,55] Patients who are to undergo relatively minor procedures, where mechanical hemostasis can be achieved without difficulty, probably do not need full reversal of warfarin anticoagulation.

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45. Warkentin, T.E.; Levine, M.N.; Hirsh, J.; Horsewood, P.; Roberts, R.S.; Kelton, J.G. Heparin-Induced Thrombocytopenia in Patients Treated with Low-Molecular-Weight Heparin or Unfractionated Heparin. [See Comments]. N. Engl. J. Med. 1995, 332 (20), 1330– 1335. 46. Kikta, M.J.; Keller, M.P.; Humphrey, P.W.; Silver, D. Can Low Molecular Weight Heparins and Heparinoids Be Safely Given to Patients with Heparin-Induced Thrombocytopenia Syndrome? Surgery 1993, 114 (4), 705– 710. 47. Greinacher, A.; Admiral, J.; Dummel, V.; Vissac, A.; Kiefel, V.; Mueller-Eckhardt, C. Laboratory Diagnosis of Heparin-Associated Thrombocytopenia and Comparison of Platelet Aggregation Test, Heparin-Induced Platelet Activation Test, and Platelet Factor 4/Heparin Enzyme-Linked Immunosorbent Assay. Transfusion 1994, 34 (5), 381– 385. 48. van der Meer, F.J.; Rosendaal, F.R.; Vandenbroucke, J.P.; Briet, E. Bleeding Complications in Oral Anticoagulation Therapy. An Analysis of Risk Factors. Arch. Intern. Med. 1993, 153 (13), 1557– 1562. 49. Gitter, M.J.; Jaeger, T.M.; Petterson, T.M.; Gersh, B.J.; Silverstein, M.D. Bleeding and Thromboembolism During Anticoagulant Therapy: A Population-Based Study in Rochester, Minnesota. [See Comments]. Mayo Clin. Proc. 1995, 70 (8), 725– 733.

50. Landefeld, C.S.; Goldman, L. Major Bleeding in Outpatients Treated with Warfarin: Incidence and Prediction by Factors Known at the Start of Outpatient Therapy. Am. J. Med. 1989, 87 (2), 144– 152. 51. Gurwitz, J.H.; Goldberg, R.J.; Holden, A.; Knapic, N.; Ansell, J. Age-Related Risks of Long-Term Oral Anticoagulant Therapy. Arch. Intern. Med. 1988, 148 (8), 1733– 1736. 52. Cole, M.S.; Minifee, P.K.; Wolma, F.J. Coumarin Necrosis—A Review of the Literature. Surgery 1988, 103 (3), 271– 277. 53. Pescatore, P.; Horellou, H.M.; Conard, J.; Piffoux, M.; Van Dreden, P.; Ruskone-Fourmestraux, A.; Samama, M. Problems of Oral Anticoagulation in an Adult with Homozygous Protein C Deficiency and Late Onset of Thrombosis. [See Comments]. Thromb. Haemostasis 1993, 69 (4), 311– 315. 54. Katholi, R.E.; Nolan, S.P.; McGuire, L.B. Living with Prosthetic Heart Valves: Subsequent Noncardiac Operations and the Risk of Thromboembolism or Hemorrhage. Am. Heart J. 1976, 92 (2), 162–167. 55. Katholi, R.E.; Nolan, S.P.; McGuire, L.B. The Management of Anticoagulation During Noncardiac Operations in Patients with Prosthetic Heart Valves. A Prospective Study. Am. Heart J. 1978, 96 (2), 163–165.

CHAPTER 18

Thrombolytic Therapy Sunita Srivastava Kenneth Ouriel

disulfide-linked heavy and light chains. The light chain of plasmin is capable of proteolytic activity and enables it to degrade active plasma proteins such as coagulation factors, complement, glucagon, ACTH growth hormone, fibrin, and fibrinogen.[5] Fibrin-bound plasminogen is more susceptible to activation than free plasma plasminogen. The fibrinolytic system in humans can be activated by two mechanisms. The first is the extrinsic pathway where plasmin activation is mediated by the presence of plasminogen activators released from endothelial cells. The physiologic plasminogen activators include direct agents such as urokinase plasminogen activator (u-PA) and tissue plasminogen activator (t-PA), while streptokinase and acetylated plasma streptokinase activator complex (APSAC) bind to plasminogen in equimolar complexes that subsequently become activators. The second mechanism of activation occurs when factor XIIa converts prekallikrein to kallikrein, a plasminogen activator. The process of fibrinolysis is self-perpetuating through a plasmin-mediated positive feedback loop. Plasmin is also capable of accelerating further plasmin formation by cleaving an activation peptide on plasminogen. This peptide converts Glu-plasminogen into a smaller Lys plasminogen, which has an increased fibrin affinity and activity.[6] Plasmin is rapidly inactivated in the free circulation by antiplasmin but is protected from it within the thrombus, where concentration of antiplasmin is low. The primary inhibitor is a2-antiplasmin, which is present in both plasma and platelets.[7] Its ability to rapidly complex with plasmin results in the very short half-life of circulating plasmin. Plasmin bound to fibrin is resistant to antiplasmin inhibition. The lysine binding sites on plasmin are bound to fibrin within a clot and therefore protect it from inactivation by antiplasmin, which also requires free lysine sites for attachment and subsequent inhibition. This allows fibrin degradation to occur with minimal systemic effects. Alpha macroglobulin may also act as a plasmin inhibitor when excess plasmin is present. Plasminogen inactivator inhibitor I, a glycoprotein present in endothelial cells, plasma, and platelets, is the primary

Thrombolytic agents are a group of proteins that dissolve intravascular thrombi. The discovery and use of these agents have transformed therapeutic options offered to patients with arterial and venous occlusions. Limb salvage, decreased morbidity and mortality, alleviation of postthrombotic symptoms, and the requirement for less invasive procedures are the potential benefits of therapy. The purpose of this chapter is to review the mechanisms of fibrinolysis and examine the various thrombolytic agents and their applications.

FIBRINOLYSIS Fibrinolysis refers to the dissolution of the fibrin network that forms the framework and supporting structure of thrombus. The process of fibrinolysis consists of a complex interaction of enzymes, which culminates in the breakdown of fibrin. Plasminogen is an inactive proteolytic enzyme and a precursor to plasmin. It is synthesized in the liver and is a constituent of plasma, although it is present in extracellular fluid as well.[1,2] Infancy, cirrhosis, and disseminated intravascular coagulation are associated with low levels of plasminogen, while conditions resulting in an increase in acute phase reactants such as trauma, surgery, and infectious processes are associated with an increase in circulating plasminogen.[3] All presently available fibrinolytic agents act indirectly through plasminogen. Human plasminogen is a single-chain glycoprotein with a five triple loop—three disulfide bridge regions of sequence homology called kringles, which function as independent domains. They are located on the heavy chain or NH2 terminal and exhibit homology with domains in lipoprotein a, tissue plasminogen activator and prothrombin.[4] The kringles have lysine-binding sites that bind to fibrin, plasminogen activators, and plasminogen inhibitors such as a2-plasmin inhibitor. The catalytic site is located at the COOH terminus and contains the amino acid triad of His 603, Asp 646, and Ser 740. Plasminogen is converted into plasmin, an active serine protease, by the cleavage of the Arg 560–Val 561 bond. This action converts the plasminogen into

Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024901 Copyright q 2004 by Marcel Dekker, Inc.

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inhibitor of plasminogen activators. It inhibits single- and double-chain t-PA and double-chain u-PA. It binds to fibrin and inhibits plasminogen activation. Plasminogen inactivator inhibitor II is found during the third trimester of pregnancy, and its role in fibrinolysis is uncertain. Fibrinolysis has several mediators, including fibrin itself. Fibrin formation is a stimulus for activation of the fibrinolytic cascade. The binding of plasminogen to fibrin at the kringle sites incorporates plasminogen molecules into clot formation and allows for its availability for activation by various agents. Degradation of fibrin creates additional lysine sites for plasminogen binding and activation. Non-cross-linked fibrin and fibrinogen are degraded by plasmin in the same manner and result in the same degradation products. These include fragments A, B, D, and E. Degradation of cross-linked fibrin is slower because of increased enzymatic resistance secondary to the presence of the cross-links. This results in several noncovalently bond fragments, including DD/E (ddimer),[8] which when present, are markers of true fibrin degradation.

THROMBOLYTIC AGENTS Thrombolytic agents can be classified by mechanism of action, mode of production, and fibrin specificity. Pharmacologic actions include agents that directly convert plasminogen to plasmin versus agents that are inactive zymogens and require change to an active form before they can cleave plasminogen. In addition, agents can be classified by mode of production—either bacterial or recombinant techniques. These agents can also be divided into fibrin specific (bind to fibrin but not fibrinogen) and nonspecific, as well as their ability to bind avidly to fibrin (fibrin affinity). Discussion of the agents is most efficient based on the origin of the parent compound. These four groups include streptokinase, urokinase, tissue plasminogen activators, and a miscellaneous group of novel agents.

Streptokinase Streptokinase (SK) is isolated from b-hemolytic streptococci and is a single-chain molecule weighing 48 kDa. Streptokinase has no enzymatic activity by itself but forms an equimolar complex with plasminogen. In this state it can function as a plasminogen activator and serine protease. The complex then converts plasminogen to plasmin and also gradually transforms into the streptokinase –plasmin complex, which also activates plasminogen. Streptokinase is antigenic and antibodies to streptococci are present in individuals with previous exposure. It forms a complex with these preformed antibodies, and its activity is neutralized. The half-life of streptokinase is reduced to 18 minutes from its biologic half-life of 90 minutes with the presence of antibodies. Drug dosage must be adjusted to neutralize circulating antibodies and establish therapeutic lysis. The neutralizing antibodies inactivate exogenously administered streptokinase and thus require a large initial bolus as a loading dose. This finding has led some investigators to recommend measurement of antibody titers before initiation of streptokinase therapy.[9]

Complications of streptokinase therapy have been reported, including pyrexia and allergic reactions. The allergic reactions range from cases of skin rashes (6 –9% reported)[1,2] to anaphylaxis and angioedema (incidence of 0.9–2%).[2,9] Antihistamines, antipyretics and steroids have been used to treat adverse reactions during drug administration. The major untoward effect associated with streptokinase therapy is systemic bleeding. Streptokinase has several mechanisms of promoting systemic lysis. It causes the proteolytic depletion of coagulation factors such as fibrinogen, factor V, and factor VIII. In vitro clotting parameters such as the prothrombin time (PT), partial thromboplastin time (PTT), and thrombin time (TT) are prolonged. The streptokinase-induced hyperplasminemia results in digestion of fibrin thrombi nonspecifically. The release of fibrin(ogen)degradation products that are also potent anticoagulants worsens the coagulopathy. The streptokinase derivative APSAC was developed as the limitations of SK became apparent. APSAC is an equimolar complex of streptokinase and human Lys-plasminogen that has been acylated at its catalytic serine site, rendering the complex inactive. In plasma and in fibrin, deacylation occurs by hydrolysis, resulting in free and active agent. The greater fibrinolytic potential of APSAC is a result of its longer halflife, enhanced affinity of the Lys-plasminogen for fibrin, and protection from plasma inhibitors due to the acylated site. The agent can be given as a single bolus with a half-life of 90–105 min and therapeutic effect up to 6 h. Therapy can be associated with adverse reactions similar to streptokinase. The longer half-life of APSAC (due to its acylation) was thought at first to offer a reduced risk of rethrombosis. The agent was studied in the setting of coronary occlusion and did not offer any clinical benefit over SK or rt-PA. It is currently not employed in the setting of peripheral thrombolytic therapy.

Urokinase Urokinase (UK), originally isolated from human urine by MacFarlane and Pilling in 1946,[10] is a serine protease composed of two polypeptide chains. It exists in two forms, which have similar activity. The first is a high molecular weight entity (54 kDa), and the second is a degradation product of the former called low molecular weight (32 kDa), urokinase. The high molecular weight form predominates in UK isolated form urine, while the low molecular weight form is found in UK of kidney cell culture origin. Unlike SK, urokinase activates plasminogen directly without forming an activator complex, is nonantigenic, and exposure resulting in preformed antibodies has not been observed. Urokinase is degraded by the liver and has a half-life of approximately 15 min, which allows for rapid reversal after discontinuation of the agent. The most commonly used form of UK is of tissue culture origin and manufactured from human neonatal kidney cells (Abbokinase, Abbott Laboratories, North Chicago, IL). In addition, a recombinant form, r-UK, has been developed from a murine hybridoma cell line. r-UK is a fully glycosylated agent, has a higher molecular weight than Abbokinase and a shorter half-life. The clinical effects of the two agents are similar.

Chapter 18.

A UK precursor was characterized and manufactured by recombinant technology using Escherichia coli (nonglycosylated) or mammalian cells (fully glycoslyated). Prourokinase is an inert zymogen that becomes activated in the presence of fibrin clot and activates plasminogen. The single-chain ProUk is also activated by plasmin or kallikrein to the two-chain form of urokinase, and this results in an increase in plasminogenactivating capacity. This property results in an amplification of the fibrinolytic process so that as plasmin is generated, more prourokinase is converted to active urokinase. Prourokinase is not affected by inhibitors circulating in plasma and is therefore able to reach the clot intact, unlike urokinase. It also preferentially activates fibrin-bound plasminogen found in thrombus over free plasminogen and is thus fibrin specific. Nonselective activators such as SK and UK activate both free and bound plasminogen equally, resulting in a systemic plasminemia, fibrinogenolysis, and degradation of factors V and VII. A recombinant form of prourokinase (r-ProUK) called Prolyse (Abbott Laboratories) was produced from a murine hybridoma cell line and has been studied in multiple clinical settings including acute myocardial infarction, stroke, and peripheral arterial occlusion.

Tissue Plasminogen Activator Tissue plasminogen activator is a naturally occurring fibrinolytic agent synthesized by endothelial cells. The agent is a serine protease composed of a single polypeptide chain (527 amino acids) with a molecular weight of 65 kDa and is converted into a two-chain molecule by plasmin. While the single chain form has greater intrinsic plasminolytic activity than the double chain form, activity of both forms is enhanced by the presence of fibrin and in this setting have no appreciable difference in activity. Unlike other agents, t-PA is both fibrin specific and has high fibrin affinity. The binding of t-PA and plasminogen complex to the fibrin surface causes a change in both molecules and enhances the conversion of plasminogen to plasmin and clot dissolution. t-PA has a plasma half-life of about 4 min and is degraded by the liver. Plasminogen activator inhibitor I rapidly complexes with t-PA in plasma. Other inhibitors of less importance include a2-antiplasmin and a2-macroglobulin. t-PA has been isolated from cadaver perfusate, uterine tissue, and human melanoma cells[15] but is currently used as a recombinant preparation (rt-PA). Activase (Genetech), a single-chain form of rt-PA, was approved for use in the clinical setting of acute myocardial infarction and pulmonary embolism. The agent has been extensively studied in the setting of coronary occlusion. The GUSTO-I study of 41,000 patients with acute myocardial infarction demonstrated better vascular patency with rt-PA compared to SK.[16] Overall mortality was reduced with rt-PA despite a slightly greater risk of intracranial hemorrhage.[17] Efforts to increase the bioavailabilty of t-PA have resulted in a newer agent, TNK-tPA, with greater half-life and fibrin specificity. As a result of this improved bioavailability, the drug can be administered as a single bolus as opposed to infusion. Its greater fibrin specificity than rt-PA also renders it less likely to cause fibrinogen depletion. In acute coronary

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occlusion studies, TNK-tPA demonstrated equal efficacy and greater ease of administration than rt-PA.[18,19] As in the case of TNK-tPA, the goal of reducing therapy duration and continuous infusion led to the development of reteplase. This novel recombinant plasminogen activator comprises the kringle 2 and protease domains of t-PA and is produced in Escherichia coli cells. Reteplase (Centocor Malvern, PA) is a nonglycosylated agent that demonstrates a lower fibrin-binding activity and diminished affinity to hepatocytes, which accounts for a longer half-life than rt-PA. Like TNK-tPA, it can be administered in bolus injection. The fibrin affinity of reteplase is only 30% of that seen with tPA and thus reduces the incidence of distant bleeding complications. The agent has been studied in the coronary setting and has shown some benefit over rt-PA in the RAPID 1 and RAPID 2 studies as well as in GUSTO III.[20,21]

Miscellaneous Agents A number of novel agents have been studied but not fully evaluated in patients. Fibrolase is a metalloproteinase derived from the venom of the Southern copperhead snake. It is a direct fibrinolytic agent that does not require plasminogen or any other blood component for activation. Staphylokinase, a byproduct of the Staphylococcus aureus bacterium, has been developed in recombinant form and studied in myocardial infarction,[22] peripheral arterial occlusion,[23] and deep venous thrombosis. Like SK, it is antigenic and requires plasminogen binding for activation. Despite this similarity to SK, it is also fibrin specific and thus spares circulating fibrinogen and plasminogen. Vampire bat plasminogen activator has been cloned and derived from the saliva of the vampire bat Desmodus rotundus (DSPA a-1).[24,25] It is extremely fibrin specific and has a plasminogenolytic activity 100,000 times greater in the presence of fibrin.[26 – 28] DSPA has a longer half-life than rtPA and thus offers greater ease of administration. So far, phase 1 studies have been performed in healthy volunteers.[29]

CLINICAL APPLICATION OF THROMBOLYTIC AGENTS Arterial Thrombolysis Although thrombolytic agents have been experimentally used since the 1950s, intervention for ischemic limbs consisted primarily of amputation, surgical revascularization, or balloon catheter embolectomy.[30] Surgical intervention in acute ischemia, however, has been identified associated with a high rate of amputation and patient demise. This was first examined by Blaisdell et al.[31] and later confirmed by Jivegard et al.[32] and Yeager et al.[33] The development of thrombolytic techniques provides the potential to restore arterial patency and limb viability with less invasive procedures and resultant lower morbidity. Thrombolytic dissolution of thrombus provides several potential advantages over standard surgical measures. First, the obstructing thrombus can be ameliorated using less invasive techniques. The patency of the native artery or

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interposed graft can be restored and thus obviate the need for harvesting of alternative conduit. A primary aim of thrombolytic therapy is to identify the anatomic lesion responsible for the occlusive event. Subsequent operative intervention or an endovascular procedure can then be employed to directly address the causative lesion. Studies examining outcomes and effectiveness of thrombolytic therapy should not be based on avoidance of surgical intervention. The goal of arterial thrombolysis is the discovery and definition of the etiologic mechanism of the occlusive event, limiting the magnitude and morbidity of the subsequent intervention. Regardless of the agent, peripheral arterial thrombolysis is most effective by a catheter-directed approach, resulting in the delivery of the agent directly into the thrombus. Charles Dotter popularized the use of catheter-directed streptokinase therapy and reported success rates greater than those achieved with systemic therapy.[34] Catheters can be inserted in both an antegrade (ipsilateral) and contralateral approach fashion. The antegrade approach can be hampered by an inability to pass the catheter through the occluded graft or thrombus due to the proximity of the occlusion to the site of vascular access. This proximity also increases the risk of bleeding from the site of catheter insertion. For these reasons, an antegrade approach is only appropriate when the level of occlusion occurs distally—e.g., at the distal superficial femoral artery or popliteal level. A contralateral approach may be the safest and allow access to the occlusion. Multiple sticks can cause bleeding during thrombolytic therapy and are best avoided if possible. Small-bore catheters (5 French) and low-dose heparin therapy are employed to prevent pericatheter thrombus with possible embolization during prolonged therapy. The method of thrombolytic administration is based on the experience of the clinical team and specific patient situation. Complications are associated with duration of infusion of thrombolytic agent, and therefore the recommended duration of drug administration is limited to 48 h. In addition, it is unlikely that successful lysis will be accomplished after 48 h if it has not already been achieved. Continuous infusions are started after a bolus dose and tapered as necessary. Techniques such as “lacing,” or bolusing, entail the infusion along the length of the thrombus to achieve even and complete distribution of high concentrations of agent. Pulse spray techniques involve the administration of multiple small boluses, forced under pressure through a multisided holed catheter to increase rate of dissolution, and are also used. Despite theoretical advantages, studies examining continuous versus periodic spray infusions have not shown statistically significant difference in treatment times.[35,36] The progression of thrombolysis is followed by serial arteriograms and catheter manipulation as necessary to reposition the infusion holes within the substance of the thrombus. Distal embolization is a recognized complication of therapy, and treatment with continued infusion of lytic agent is usually successful. Distal embolization occurs as a thrombus is lysed and macroscopic particles of clot travel distally at the time arterial flow are reestablished. Bolus and lacing techniques may increase the risk of distal embolization. Coagulation parameters (e.g., fibrinogen level) can be monitored, but their use remains controversial, as such measures do not necessarily predict the risk of distant bleeding

complications.[37] The STILE trial (discussed below), however, documented an association between the fibrinogen concentration and partial thromboplastin time and the incidence of hemorrhagic complications with thrombolytic procedure.[38]

Results of Thrombolysis in Acute Peripheral Arterial Occlusion Early studies of patients treated with thrombolytic therapy were retrospective and did not examine limb salvage or morbidity.[39 – 41] Investigators such as McNamara and Graor[40,41] reported successful experiences with thrombolytic therapy in large numbers of patients. Other reports[42,43] found disfavor with thrombolytic therapy because it did not eliminate the need for surgical intervention and documented poor patency with the sole use of thrombolytic agents as definitive therapy (i.e., without adjuvant surgery to correct causative lesions). Prior to the 1990s there existed no randomized comparison of thrombolysis with standard surgical intervention. A randomized trial appeared in the European literature comparing rt-PA versus surgical thrombectomy, but it was limited by its small size of 20 patients.[44] The first randomized trial in the United States comparing intraarterial urokinase versus surgical intervention was reported in 1994 by the Rochester group.[45] They studied 114 patients with acute (less than 7 days duration with a mean of approximately 1 day) and severe limb-threatening ischemia (mean ankle brachial index of , 0.04). The urokinase group demonstrated decreased cardiopulmonary complications and improvement in patient survival. These results were achieved with a limb salvage rate identical to that observed in the operative group. The Surgery or Thrombolysis for Ischemia of the Lower Extremity (STILE) trial was published shortly after the Rochester report.[46] It was a multicenter randomized comparison of rt-PA, urokinase, and surgical intervention in patients with ischemia of less than 6 months’ duration and thus included both chronic and acute ischemia subgroups. No differences in mortality or amputation rate were noted. The endpoint of the study was not limb salvage or survival but, rather, a composite endpoint that contained subjective outcomes including renal failure, wound complications, and “ongoing ischemia.” The trial was prematurely terminated because of a higher rate of ongoing ischemia in the thrombolysis group, 54%, versus 26% in the surgical group. A post hoc analysis of STILE demonstrated that patients with symptoms of less than 2 weeks’ duration appeared to do better with thrombolysis while those with more chronic occlusions benefited more from surgery than thrombolysis, with respect to the rate of amputation. A multicenter trial evaluating thrombolytic agents, the Thrombolysis or Peripheral Arterial Surgery (TOPAS) study,[47] was a two-part study designed to compare recombinant urokinase with operative intervention in the treatment of peripheral arterial occlusions # 14 days in duration. Part I was a dose-ranging study designed to evaluate the safety and efficacy of 2000, 4000, or 6000 IU/min r-UK administration with approximately 50 patients in each group. The different initial doses were followed by 2000 IU/min for up to 48 hours of total therapy. Although 50 patients were included in a surgical group, it was not adequately empowered to critically

Chapter 18.

evaluate r-UK versus surgery. This was the goal of the Part II study, which randomized 544 patients to r-UK or surgery. Part I identified 4000 IU/min dose as the safest and most effective dose. The data from Part II demonstrated that the efficacy of r-UK was the same as surgery with respect as amputation and

Table 1.

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survival.[48] Patients were followed for one year following therapy, and the rate and magnitude of subsequent interventions were monitored. The thrombolysis group was noted to have a lower rate of invasive interventions (operative or endovascular) than the surgical group (Table 1).

Contraindications to Thrombolytic Therapy

Absolute 1. Active internal bleeding 2. Recent cerebrovascular accident, trauma, or intracranial pathology ,12 months Relative Major 1. Recent surgery or trauma ,10 days 2. Gastrointestinal or genitourinary bleeding 3. Uncontrolled hypertension (.200 systolic or . 110 diastolic) Minor 4. 5. 6. 7. 8. 9.

Pregnancy Diabetic retinopathy with hemorrhage Bleeding disorders Left-sided cardiac thrombus Bacterial endocarditis Minor trauma or surgery

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32. Jivegard, L.; Holm, H.; Schersten, T. Acute Limb Ischemia Due to Arterial Embolism or Thrombosis: Influence of Limb Ischemia Versus Pre-Existing Cardiac Disease on Post Operative Mortality Rate. J. Cardiovasc. Surg. 1988, 29, 32– 36. 33. Yeager, R.A. Basic Data Related to Cardiac Testing and Cardiac Risk Associated with Vascular Surgery. Ann. Vasc. Surg. 1990, 4, 193. 34. Dotter, C.T.; Rosch, J.; Seaman, A.J. Selective Clot Lysis with Low Dose Streptokinase. Radiology 1974, 111, 31– 37. 35. Kandarpa, K.; Chopra, P.S.; Aruny, J.E.; et al. Prospective, Randomized Comparison of Forced Periodic Infusion and Conventional Slow Continuous Infusion. Radiology 1993, 188, 1 – 7. 36. Kandarpa, K. Technical Determinants of Success in Catheter Directed Thrombolysis for Peripheral Arterial Occlusions. J. Vasc. Interventional Radiol. 1995, 6, 55– 61. 37. Marder, V.J. The Use of Thrombolytic Agents: Choice of Patient, Drug Administration and Laboratory Monitoring. Ann. Intern. Med. 1979, 90, 802– 808. 38. Graor, R.A.; Risius, B.; Young, J.R. Low Dose Streptokinase for Selective Thrombolysis: Sytemic Effects and Complications. Radiology 1984, 152, 35– 39. 39. Krings, W.; Roth, F.J.; Cappius, G. Catheter Lysis: Indications and Primary Results. Int. Angiol. 1985, 4, 117–123. 40. Graor, R.A.; Risius, B.; Lucas, F.V. Thrombolysis with Recombinant Human Tissue Type Plasminogen Activator in Patients with Peripheral Artery and Bypass Occlusions. Circulation 1986, 74, 15– 20. 41. McNamara, T.O.; Fischer, J.R. Thrombolysis of Peripheral Arterial and Graft Occlusions: Improved Results Using High Dose Urokinase. Am. J. Roentgenol. 1985, 144, 769– 775. 42. Sicard, G.A.; Schier, J.J.; Totty, W.G. Thrombolytic Therapy for Acute Arterial Occlusion. J. Vasc. Surg. 1985, 2, 65– 78. 43. Ricotta, J. Intraarterial Thrombolysis: A Surgical View. Circulation 1991, 83, 120– 121. 44. Nilsson, L.; Albrechtsson, U.; Jonung, T. Surgical Treatment Versus Thrombolysis in Acute Arterial Occlusion: A Randomised Controlled Study. Eur. J. Vasc. Surg. 1992, 6, 189–193. 45. Ouriel, K.; Shortell, C.K.; DeWeese, J.A. A Comparison of Thrombolytic Therapy with Operative Revascularization in the Treatment of Acute Peripheral Arterial Ischemia. J. Vasc. Surg. 1994, 19, 1021– 1030. 46. Weaver, F.; Comerota, A.; Youngblood, M.; Foehlich, J.; et al. Surgical Revascularization Versus Thrombolysis for Nonembolic Lower Extremity Native Artery Occlusions: Results of a Prospective Randomized Trial. J. Vasc. Surg. 1996, 24, 513– 521. 47. TOPAS Investigators; Ouriel, K.; Veith, F.; Sasahara, A. Thrombolysis or Peripheral Arterial Surgery: Phase I Results. J. Vasc. Surg. 1996, 23, 64– 75. 48. Ouriel, K.; Veith, F.; Sasahara, A. A Comparison of Recombinant Urokinase with Vascular Surgery as Initial Treatment for Acute Arterial Occlusion of the Legs. N. Engl. J. Med. 1998, 338, 1105– 1111.

CHAPTER 19

Antiplatelet Agents Richard M. Green James A. DeWeese Platelets and antiplatelet agents play an increasing role in the clinical practice and research efforts of vascular surgeons. The role of antiplatelet agents has been investigated in arterial thrombosis and embolism, occlusive and hemorrhagic strokes, angina and myocardial infarctions, venous thromboprophylaxis and pulmonary embolism, and recurrent stenoses in endarterectomized arteries and in arterial graft occlusions. Antiplatelet agents have been studied in the laboratory as a deterrent to thrombus formation, atherosclerotic plaque formation, and development of anastomotic hyperplasia in vascular grafts. It is now clear that the platelet plays a pivotal role in all of the above named processes. Our understanding of platelet function and ways to alter its activity therefore become important concerns for the vascular surgeon.

Platelet aggregation can occur via three different pathways. The first occurs after vascular injury and is due to extrinsic activators such as thrombin and collagen. This results in the release of adenosine diphosphate (ADP) and serotonin (5-HT) and the synthesis of thromboxane A2 (TXA2). Thrombin and collagen are strong platelet agonists that do not require TXA2 to produce aggregation and are therefore effective even in the presence of aspirin. The second method of aggregation is mediated by ADP and 5-HT, which are released from the dense granules of the platelet. These substances are weak agonists and cause aggregation only in the presence of TXA2. The third pathway is mediated through arachidonic acid released from the platelet membrane and then converted to prostaglandins A2 and G2.[6] The final common pathway by which all platelet agonists ultimately effect platelet aggregation is the transformation of the GPIIb/IIIa receptor on the platelet membrane to its active (high-affinity) state. This glycoprotein receptor has been the subject of much investigation, including efforts to develop potent antiplatelet agents through inhibition of the receptor.

PLATELET FUNCTION Platelets are derived from the bone marrow megakaryocytes and have a life span of approximately 10 days.[1] The intact endothelium is nonreactive to platelets. Interruption of a blood vessel or intravascular stimuli such as endotoxins or immune complexes activate the platelet.[2] The activated platelet undergoes a morphological change from a disk to a spiny sphere, and the surface membrane develops the capacity to catalyze interactions between activated coagulation proteins, resulting in thrombin formation and fibrinogen polymerization. The exposure of specific surface receptors which bind fibrinogen is inhibited when platelet (cyclic adenosine monophosphate) cAMP levels are elevated by agents such as prostacyclin (PGI2).[3] The activated platelet adheres to exposed subendothelial collagen. The most avid bond forms to the fibrillar collagen within ruptured atherosclerotic plaques or within the arterial media rather than to fibrils immediately beneath the endothelium.[4] Shear forces affect the mechanism of platelet adherence. At low shear rates, platelet adherence to collagen occurs via glycoprotein la. At high shear rates, glycoprotein 1b binds to the damaged artery via von Willebrand factor.[5] Adhesion is accompanied by the recruitment of additional platelets (aggregation) and the formation of a hemostatic plug.

Interaction with Coagulation Cascade In the early stages of thrombus formation, platelets interact with the cascade of coagulation proteins to form thrombin, which generates the fibrin necessary to stabilize the hemostatic plug. The activated platelet provides membrane receptors for formation of coagulation complexes. Factor V, released from platelets, is essential for the formation of the prothrombinase complex to act on prothrombin. This accelerates the generation of thrombin by a factor of 278,000 compared with factor Xa alone.[7] The prothrombinase complex on the surface of the platelets provides resistance to heparin via three mechanisms. First, heparin, acting on antithrombin III, is unable to inhibit factor Xa when it is bound to platelets. Second, the large amounts of thrombin generated by this complex activate more platelets, which secrete platelet factor 4; this, in turn, blocks the action of heparin. Third, thrombin generates fibrin II monomer, which also inhibits the action of heparin.[8] Components of coagulation are constantly delivered to the enlarging thrombus, where they are concentrated. Systemic

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coagulation is avoided and the response is localized, partly because of the concentration of coagulation proteins on the activated platelet membrane and partly because of endogenous inhibitors of thrombosis such as antithrombin III, proteins C and S, elevated cAMP (via prostacyclin), and the fibrinolytic system. The role of the platelet in fibrinolysis is becoming more evident. Resting platelets have a high concentration of plasminogen membrane receptors. Activated platelets secrete plasminogen activator inhibitor I. High concentrations of this at the site of thrombosis may inhibit fibrinolysis and promote clot stability. The result of this is a thrombus resistant to thrombolytic agents.[9]

Interaction with the Arterial Wall To understand the interaction of the platelet and the vessel wall, some knowledge of the field of prostaglandins is needed. These compounds interact to regulate platelet aggregability in physiological and pathological conditions. Thromboxane A2 and prostacyclin represent opposite ends of the homeostatic regulation of platelet aggregability, since TXA2 is a potent vasoconstrictor and prostacyclin induces vasodilation and is an extremely potent inhibitor of platelet aggregation. Endothelial cells are the most active producers of prostacyclin, which works by stimulating adenylate cyclase, leading to an increase in cyclic AMP levels in the platelets. Prostacyclin generation may be responsible for some of the thromboresistant properties of vascular endothelium. Prostacyclin I2 can inhibit platelet aggregation (platelet-platelet interaction) at lower concentrations than those needed to inhibit adhesion (platelet-collagen interaction), which means that platelets can stick to vascular tissue and interact with it without necessarily initiating thrombus production.[10] In humans, there is no difference between prostacyclin production in arteries and veins.[11] If antiplatelet agents have a role to play in the prevention of atherosclerosis (as opposed to the prevention of thromboembolic disease associated with existing atherosclerosis), it will probably be in the modification of the prostaglandin system and modulation of cell proliferation. Platelets from patients with arterial thrombosis and deep venous thrombosis produce more TXA2 than normal and have a shortened survival time.[12] Prostacyclin generation from atherosclerotic arterial tissue has been shown to be significantly lower than from normal arterial tissue.[13] Furthermore, the accumulation of cholesterol esters in areas of damage has been related to a decrease in prostacyclin synthesis. Prostacyclin enhances the activity of cholesterol ester hydrolase, suggesting a positive feedback between the prostacyclin system and lipid accumulation in the vessel wall.[14] Low-density lipoprotein (LDL) has been shown to reduce the release of a prostacyclin-like substance from human endothelial cells, and high-density lipoprotein (HDL) stimulates prostacyclin production.[15] Prostacyclin also plays a role in modulating cell proliferation. Smooth muscle proliferation in atherosclerotic plaques may be a consequence of inhibition of prostacyclin generation by lipid peroxidases. High concentrations of these peroxidases have been demonstrated in advanced atherosclerotic lesions.[16] Cell proliferation in vitro is inhibited by

substances such as PGI2 which stimulated cyclic AMP formation.[17,18]

ANTIPLATELET DRUGS Aspirin Mechanism of Action Aspirin exerts its antiplatelet effect through the cyclooxygenase system, by irreversibly acetylating cyclooxygenase. This prevents the first step of prostaglandin synthesis, the conversion of arachadonic acid to prostaglandin H2. The subsequent steps of conversion of prostaglandin H2 (to thromboxane A2 by platelets and to prostacyclin by endothelial cells) are thus also inhibited.[19 – 21] In theory, therefore, aspirin has prothrombotic effects via the inhibition of both prostacyclin and thromboxane A2, respectively. In reality, however, the antiplatelet effects predominate to a very high degree.

Dosage, Administration, and Efficacy The usual method of administration of aspirin is by mouth. Regular aspirin is rapidly absorbed in the stomach, with peak plasma levels occurring in 30 minutes, and inhibition of platelet function occurring in approximately one hour. Enteric coated aspirin is absorbed more slowly,[22] and shows evidence of platelet inhibition in 3 –4 hours, therefore enteric coated aspirin should not be used in situations where a rapid effect is desired, such as postoperatively. Because aspirin irreversibly inhibits cyclooxygenase, the antiplatelet effect of both regular and enteric coated aspirin persists for the life of the platelet (7 –10 days). The optimal dosage of aspirin remains somewhat uncertain. Efforts to utilize the lowest effective dose of aspirin are centered on two issues: first, the higher the dose of aspirin, the greater the chance of gastric side effects, and second, aspirin is known to inhibit platelet function at a lower dose than that at which it inhibits endothelial cell function.[23] The relative effects of different doses of aspirin on thromboxane and prostacyclin metabolism have been studied. Aspirin at all doses suppressed collagen-induced platelet aggregation by at least 80%, while suppression of prostacyclin secretion was seen only at the higher dose (324 mg).[24] The clinical implications of this finding are less clear, however. A comparison of outcome in three studies of patients treated with different doses of aspirin (75 mg/d, 325 mg/d, 1300 mg/d) shows similar results at all doses with regard to myocardial infarction and vascular death.[25 – 27] The effect on stroke reduction appears to be similar between different doses of aspirin, as well. In two separate studies, different doses of aspirin (30 mg vs. 300 mg, and 300 mg vs. 1300 mg) were compared and found to have the same efficacy in preventing stroke in patients with transient ischemic attacks.[28,29] While there is no good evidence that aspirin at higher doses is clinically superior to low-dose aspirin, based on the same studies, there is also a lack of convincing

Chapter 19.

evidence that there is a detrimental effect of administering aspirin at doses which inhibit prostacyclin.[25 – 29]

Treatment and Prevention of Thromboembolic Complications of Atherosclerotic Cardiovascular Disease The efficacy of aspirin in the prevention of thromboembolic complications in patients with cardiovascular disease has been extensively examined in a large number of individual trials. Aspirin has been shown to be effective in reducing the incidence of myocardial infarction in males 50– 65 years of age;[30] in the treatment of acute myocardial infarction;[31,32] in the treatment of patients with unstable angina and non–Q-wave myocardial infarction;[25] in the treatment of stable angina; [33] and in patients with cerebrovascular disease.[29,31,34] In addition to information available from individual randomized studies, the Antiplatelet Trialists’ Collaboration provides an analysis and compilation of the results of 145 trials of antiplatelet agents in the treatment of thromboembolic disease. In most cases, the agent used was aspirin. The meta-analysis of 145 trials included 70,000 high-risk and 30,000 low-risk patients. Aspirin was found to reduce the risk of vascular complications as follows: from 14% to 10% in patients with acute myocardial infarction at one month, from 17% to 13% in patients with a history of myocardial infarction after 2 years, from 22% to 18% in patients with a history of stroke or transient ischemic attack after 3 years, and from 14% to 9% in patients with unstable angina after 6 months. With regard to all high-risk patients, there was a 30% reduction in the incidence of nonfatal myocardial infarction and stroke, and a 17% reduction in the incidence of vascular death.[23,34]

Use with Oral Anticoagulants The use of aspirin with oral anticoagulation (warfarin therapy) is warranted under certain circumstances. The primary indications for this combination of therapy are arterial embolization from prosthetic heart valves despite adequate anticoagulation with warfarin, and arterial embolization in patients with atrial fibrillation who have been adequately anticoagulated with warfarin.[23] Other potential indications include the prevention of thromboembolic complications in men at very high risk of cardiovascular death, and selected vascular patients who experience recurrent episodes of neointimal hyperplasia and/or graft occlusion. When aspirin and warfarin are administered together, the risk of major and minor bleeding is significantly higher than that associated with warfarin alone if both highdose aspirin (500 –1000 mg/d) and high-dose warfarin (INR 3.0–4.5) are used.[35] The use of low-dose aspirin (75 mg/d) and high-dose warfarin is associated with an increase in minor bleeding but only a trend toward a higher incidence of major bleeding when compared with warfarin alone.[36] The incidence of major bleeding is not increased, however, when low-dose aspirin and low-dose warfarin (INR 1.5 –2.0) are used.[37 – 40] In many circumstances, however, such as in patients with prosthetic heart valves, it is not feasible to reduce the dose of warfarin to this degree.

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Use in Venous Disease Aspirin has not been shown to be as effective as heparin in the prevention or treatment of acute deep venous thrombosis, although it probably has some benefit over no treatment at all.[23,41] Aspirin has been used successfully in the treatment of calf vein thrombosis in low-risk patients.

Complications and Side Effects By far the most common side effects of aspirin therapy are gastrointestinal. Aspirin-related complications range from mild erosions to frank ulceration, gastritis, and massive hemorrhage. Statistically, gastric complications are less severe with low-dose (325 mg/d or less) aspirin and shortterm use of aspirin. The proposed mechanism by which gastric injury occurs is by inhibition of prostaglandin production by gastric mucosa.[23] Two studies in which aspirin was used in the primary prevention of stroke and myocardial infarction (i.e., low-risk patients) have demonstrated a small but definite increase in the risk of intracranial hemorrhage in healthy men treated with aspirin as compared with no aspirin.[42,43] Studies in which aspirin was used in the secondary prevention of these events (i.e., higher-risk patients) failed to demonstrate this increased risk, probably because of the relatively greater benefit in reducing adverse events resulting from complications of atherosclerosis.[25,44] These findings raise the issue, therefore, as to whether or not aspirin should be used prophylactically in low-risk patients.[23]

Other Agents While aspirin remains the most widely used and most extensively studied antiplatelet agent, there are a number of alternative antiplatelet agents currently under investigation for the treatment of cardiac disease, stroke, and peripheral vascular disease. In most instances, the mechanism of action of these agents differs substantially from that of aspirin. Specifically, alternatives to the standard agents aspirin and heparin have been developed because platelet activation and thrombosis occurs at the site of exposed endothelium (i.e., ruptured atherosclerotic plaque) by mechanisms that are in large part resistant to these agents. For instance, platelet activation in this setting is mediated primarily via thrombin rather than thromboxane A2. Similarly, the heparin – antithrombin III complex is inactive against bound thrombin, thus rendering heparin ineffective in preventing thrombosis and platelet activation at the site of injured endothelium, although it is effective in preventing clot propagation.[45 – 48]

Glycoprotein IIb/IIIa Inhibitors The final common pathway for all mechanisms of platelet aggregation is glycoprotein IIb/IIIa (GPIIb/IIIa), the fibrinogen receptor on the platelet membrane. Several agents have been developed that inhibit this receptor, and they are extremely potent antiplatelet agents, generally associated with relatively more frequent and severe bleeding complications than other antiplatelet agents. Glycoprotein IIb/IIIa inhibitors have been investigated primarily for their efficacy

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in treating coronary thrombosis. They include monoclonal antibodies against the receptor and other agents such as RGDcontaining isolates from snake venom or synthetic compounds of similar structure. All of these agents act by competing with fibrinogen for occupation of the GPIIb/IIIa site.[49] The most intensely studied of the GPIIb/IIIa antagonists is the monoclonal antibody c7E3. It has been shown to improve early patency following tPA coronary thrombolysis,[50] to improve the results of coronary angioplasty (EPIC trial),[51] and to be effective in the treatment of unstable angina.[52] Similar results have been reported for Integrelin, another of the GPIIb/IIIa antagonists.[53,54]

Thienopyridines This class of antiplatelet drugs includes the oral agents ticlopidine and clopidogrel. Both agents prevent binding of ADP to the platelet receptor, thus inhibiting ADP-mediated platelet aggregation.[55] In the Canadian American Ticlopidine Study, ticlopidine was shown to be more effective than aspirin in the prevention of serious ischemic events (myocardial infarction, stroke, death) in patients who have experienced a prior ischemic neurologic event.[56] Similar reductions were demonstrated in the rates of ischemic stroke and death in the Ticlopidine Aspirin Stroke Study.[57] In the CAPRIE study, a comparison of clopidogrel and aspirin in the treatment of 19,000 patients at risk of ischemic stroke, there was a significant reduction (8.7%) in the combined risk of death, myocardial infarction, and ischemic stroke with clopidogrel as compared with aspirin.[58] Ticlopidine achieves 50% of maximal activity within 4 days of the initiation of therapy, and full activity within 7 days. Clopidogrel achieves initial inhibition of platelet activity within 2 hours of administration, and maximal platelet inhibition within 3 days. The incidence of significant gastrointestinal hemorrhage in the thienopyridines is comparable to that of aspirin (approximately 0.5%). The most important side effects of ticlopidine are reversible

neutropenia in 1.6% of patients and agranulocytosis in 0.8% of patients; therefore, regular monitoring for these events, which usually occur within the first 3 months of therapy, is required in patients receiving this medication. The major side effect of clopidogrel is a rash (0.3%); the incidence of neutropenia of even moderate severity is very low (0.1%).[58]

SUMMARY Platelets play an important role in both the progression of atherosclerosis and the occurrence of thrombotic complications of atherosclerosis. Antiplatelet agents, therefore, have been developed and studied with regard to treatment and prevention of these problems, and exert their effects through a variety of different mechanisms. Aspirin is the most widely used and most thoroughly investigated antiplatelet agent. It works by irreversibly inhibiting platelet cyclooxygenase. Aspirin has been shown to be effective in the prevention and treatment of coronary artery disease, stroke, peripheral vascular disease, and other related disorders. It appears to achieve a maximum effective at a relatively low dose (75 mg/d), which is also associated with the lowest level of gastrointestinal side effects. It is definitely indicated in highrisk patients, but may not be indicated in lower-risk patients because of a possible small increase in the risk of intracranial hemorrhage. Agents that inhibit the glycoprotein IIb/IIIa fibrinogen receptor are potent antiplatelet agents. They are primarily intravenous in nature, and are used in the treatment of coronary occlusion. Thienopyridines are a newer class of oral antiplatelet agents that inhibit ADP-mediated platelet aggregation. They have been approved for the prevention and treatment of myocardial infarction, stroke, and peripheral vascular disease. They appear to have comparable efficacy, but clopidogrel lacks the neutropenic complications associated with ticlopidine.

REFERENCES 1. Radley, J.M.; Haller, C.J. The Demarcation Membrane System of the Megakaryocyte: A Misnomer? Blood 1982, 60, 213. 2. Marcus, A.J. Recent Progress in the Role of Platelets in Occlusive Vascular Disease. Stroke 1983, 14, 475. 3. Graber, S.E.; Hawiger, J. Evidence that Changes in Platelet Cyclic AMP Levels Regulate the Fibrinogen Receptor on Human Platelets. J. Biol. Chem. 1982, 257, 14606. 4. Fuster, V.; Badimon, L.; Cohen, M. et al. Insights into the Pathogenesis of Acute Ischemic Syndromes. Circulation 1988, 77, 1213. 5. Baumgartner, H.R.; Sakariassen, K.S. Factors Controlling Thrombus Formation on Arterial Lesions. Ann. NY Acad. Sci. 1985, 454, 162. 6. Needleman, P.; Turk, J.; Jakschik, B.A. et al. Arachadonic Acid Metabolism. Ann. Rev. Biochem. 1986, 55, 69.

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Manson, J.E.; Stampfer, M.J.; Colditz, G.A. et al. A Prospective Study of Aspirin Use and Primary Prevention of Cardiovascular Disease in Women. J. Am. Med. Assoc. 1991, 266, 521. Antiplatelet Trialists’ Collaboration; Secondary Prevention of Vascular Disease by Prolonged Antiplatelet Treatment. Br. Med. J. 1988, 296, 320. ISIS-2 Collaborative Group; Randomised Trial of Intravenous Streptokinase, Oral Aspirin, Both or Neither Among 17,187 Cases of Suspected Acute Myocardial Infarction: ISIS-2. Lancet 1988, 2, 349. Juul-Moller, S.; Edvardsson, N.; Jahnmatz, B. et al. Double-Blind Trial of Aspirin in Primary Prevention of Myocardial Infarction in Patients with Stable Chronic Angina Pectoris. Lancet 1992, 340, 1421. Antiplatelet Trialists’ Collaboration; Collaborative Overview of Randomized Trials of Antiplatelet Therapy: I. Prevention of Death, Myocardial Infarction, and Stroke by Prolonged Antiplatelet Therapy in Various Categories of Patients. Br. Med. J. 1994, 308, 81. Cheesbro, J.H.; Fuster, V.; Elveback, L.R. et al. Trial of Combined Warfarin Plus Dipyridamole or Aspirin Therapy in Prosthetic Heart Valve Replacement: Danger of Aspirin Compared with Dipyridamole. Am. J. Cardiol. 1983, 51, 1537. Turpie, A.G.G.; Gent, G.; Laupacis, A. et al. A Comparison of Aspirin with Placebo in Patients Treated with Warfarin After Heart-Valve Replacement. N. Engl. J. Med. 1993, 329, 524. Altman, R.; Rouvier, J.; Curfinkel, E. et al. Comparison of Two Levels of Anticoagulant Therapy in Patients with Substitute Heart Valves. J. Thorac. Cardiovasc. Surg. 1991, 101, 427. Mead, T.W.; Roderick, P.J.; Brennan, P.J. et al. ExtraCranial Bleeding and Other Symptoms Due to Low Dose Aspirin and Low Intensity Oral Anticoagulation. Thromb. Haemostasis 1992, 68, 1. Cohen, M.; Adams, P.C.; Hawkins, L. et al. Usefulness of Antithrombotic Therapy in Resting Angina Pectoris or Non-Q Wave Myocardial Infarction in Preventing Death and Myocardial Infarction (a Pilot Study from the Antithrombotic Therapy in Acute Coronary Syndromes Study Group). Am. J. Cardiol. 1990, 66, 1287. Meade, T.W.; Wikes, H.C.; Stirling, Y. et al. Randomised Controlled Trial of Low Dose Warfarin in the Primary Prevention of Ischaemic Heart Disease in Men at High Risk: Design and Pilot Study. Eur. Heart. J. 1988, 9, 836. Antiplatelet Trialists’ Collaboration; Collaborative Overview of Randomised Trials of Antiplatelet Therapy: III. Reduction in Venous Thrombosis and Pulmonary Embolism by Antiplatelet Prophylaxis Among Surgical and Medical Patients. Br. Med. J. 1994, 308, 235. Steering Committee of the Physicians’ Health Study Research Group; Final Report on the Aspirin Component of the Ongoing Physician’s Health Study. N. Engl. J. Med. 1989, 321, 129. Peto, R.; Gray, R.; Collins, R. et al. Randomised Trial of Prophylactic Daily Aspirin in British Male Doctors. Br. Med. J. 1988, 296, 313.

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44. The SALT Collaborative Group; Swedish Aspirin LowDose Trial (SALT) of 75 mg Aspirin as Secondary Prophylaxis After Cerebrovascular Ischaemic Events. Lancet 1991, 338, 1345. 45. Fuster, V.; Badimon, L.; Badimon, J.J. et al. The Pathogenesis of Coronary Artery Disease and the Acute Coronary Syndromes. N. Engl. J. Med. 1992, 326, 242. 46. Hogg, P.J.; Jackson, C.M. Fibrin Monomer Protects Thrombin from Inactivation by Heparin-Antithrombin III: Implications for Heparin Efficacy. Proc. Natl Acad. Sci. USA 1989, 86, 3619. 47. Weitz, J.I.; Hudoba, M.; Massel, D. et al. Clot-Bound Thrombin Is Protected from Inhibition by HeparinAntithrombin III but Is Susceptible to Inactivation by Antithrombin III-Independent Inhibitors. J. Clin. Investig. 1990, 86, 385. 48. Bar-Shavit, R.; Benezra, M.; Eldor, A. et al. Thrombin Immobilized to Extracellular Matrix Is a Potent Mitogen for Vascular Smooth Muscle Cells: Nonenzymatic Mode of Action. Cell Regul. 1990, 1, 453. 49. Weitz, J.I.; Califf, R.M.; Ginsberg, J.S. et al. New Antithrombotics. Chest 1995, 108, 471s. 50. Kleinman, N.S.; Ohman, M.E.; Califf, R.M. et al. Profound Inhibition of Platelet Aggregation with Monoclonal Antibody 7E3 Fab Following Thrombolytic Therapy: Results of the TAMI 8 Pilot Study. J. Am. Cardiol. 1993, 22, 381.

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CHAPTER 20

Pentoxifylline, Vasodilators, and Metabolic Agents Samuel R. Money W. Charles Sternbergh III Far East have gained this drug marketing approval there.[6,7] However, these studies were small and had only short-term follow-up. Numerous large clinical studies on the efficacy of Cilostazol have been carried out in the United States.[8 – 11] Some of these studies will be reviewed in this section.

Over 5 million Americans suffer with peripheral arterial occlusive disease of the lower extremities. The prevalence of this disease increases with age, therefore as the population ages, there will be an increasing number of patients to treat. Intermittent claudication is the most common symptom. Some patients with intermittent claudication are so impaired that either surgical or endovascular intervention is warranted. However, for the vast majority of patients, intervention is not indicated as claudication is more of an annoyance than a disability. In the United States, pharmacologic therapy has been limited to only one approved agent. Presently, a second medication has received FDA approval, and more are under scrutiny. This chapter will evaluate some of the more promising and potentially available metabolic, hemorrheologic and vasodilating agents for the treatment of intermittent claudication secondary to peripheral arterial occlusive disease. Antiplatelet agents may also have salutary effects on claudication; these are discussed in Chapter 19.

Clinical Use In the first American study published, 239 patients were randomized to receive either Cilostazol (100 mg PO b.i.d.) or placebo for 16 weeks.[8] Patients underwent routine treadmill and ankle-brachial index (ABI) testing. The end points of the study were initial claudication time (distance-ICD) or absolute or maximal claudication distance (ACD) on the treadmill testing, which was performed at weeks 8, 12, and 16. The results of this study demonstrated significant increases in walking ability for both initial and absolute claudication time (distance) at all time points. In addition, the patients subjectively felt improvement in the physical function score of the short form-36 (medical outcomes) questionnaire at the completion of the study. In a separate study authored by Dawson et al., patients were treated with either Cilostazol or placebo for a total of 12 weeks.[10] In this study, the increase in initial claudication time (distance) in the group receiving Cilostazol improved by 58%, compared with an 8.9% increase in the placebo group. The absolute or maximal claudication time (distance) increased by 63% in those receiving drug versus 9.8% in the placebo group, a highly significant difference. Subjectively, the majority of patients felt that their walking performance was much better or better in the Cilostazol group, whereas the majority of patients in the placebo group felt that their symptoms were unchanged or worsening. The largest clinical study of Cilostazol randomly assigned 419 patients to either high-dose (100 mg PO b.i.d.) or lowdose (50 mg PO b.i.d.) Cilostazol or to placebo.[9] Patients underwent treadmill testing at baseline, and then at weeks 4, 8, 16, 20, and 24. At the completion of the study (week 24), pain-free walking distance (initial claudication distance and

CILOSTAZOL Mechanism Recently, Cilostazol has received FDA approval for the treatment of mild to moderate claudication secondary to peripheral vascular disease. Cilostazol is modified quinolinone, which exerts its action via type III phophodiesterase inhibition.[1,2] By blocking adenosine-3,5-cyclic phosphodiesterase, it serves to increase cAMP in the vessel walls and also in platelets. The principal mechanisms of action include vasodilitation and inhibition of platelet aggregation.[3 – 5] In addition to these, vascular smooth muscle relaxation will occur and platelet aggregation will be reduced due to increased prostagladin I2. Via the mechanisms described here, Cilostazol serves as both an antithrombotic agent and a vasodilator. Numerous animal studies using Cilostazol have confirmed both effects, which resulted in increases in muscle and dermal blood flow. Small preliminary studies done in the

Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024903 Copyright q 2004 by Marcel Dekker, Inc.

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absolute claudication distance) were statistically increased in the Cilostazol groups compared to the placebo group. The high-dose Cilostazol group demonstrated an increase in initial claudication distance by 59% versus a 20% increase in the placebo group. The low-dose Cilostazol group demonstrated an increase of 48%. Both of these changes were highly significant. Significant improvements in both initial claudication distance and absolute claudication distance were demonstrated at week 4 and were maintained throughout the subsequent time points of testing. Overall, in the high-dose group the ACD increased from a mean baseline of 130 meters to 259 meters by week 24. In another study, patients were randomly assigned to receive Cilostazol 100 mg PO b.i.d., pentoxifylline 400 mg PO t.i.d., or placebo for a total of 24 weeks.[12] There were a total of 699 patients randomized. Patients were evaluated using standard treadmill testing, and subjective data were obtained using the short form-36 (SF-36) and the walking impairment questionnaire. The results of this study were quite interesting. Cilostazol demonstrated a significant improvement over both placebo and pentoxifylline. There was no significant difference between pentoxifylline and placebo ðp ¼ 0:82Þ in distance walked. The subjective evaluation by the patients showed that more patients in the Cilostazol group judged their outcome to be significantly better than patients who received either placebo or pentoxifylline. In addition to the mechanisms outlined above, this compound has been found to have a beneficial effect on lipids. Elam and others have demonstrated that Cilostazol has positive effects on triglycerides and high-density lipoprotein (HDL).[11] Following chronic administration of Cilostazol for 12 weeks, serum triglycerides dropped by a mean of 15%. HDL cholesterol was shown to increase by 10% and apoA1 demonstrated a 5.7% increase. The actual mechanism of this effect is presently unknown, but the beneficial affect on lipids is a welcome side effect. Cilostazol is strictly contraindicated in patients with advanced heart failure (N-Y HA III and IV). Phosphodiesterase inhibitors cause increased mortality in this group. While most other side effects of this medication were minor, they were fairly common.[9 – 11] The majority of side effects reported were described by the patients as mild to moderate and usually responsive to over-the-counter medication. The most common side effect of Cilostazol treatment was headache. This complication was reported in approximately one third of the patients who received test drugs. It is interesting to note that this occurred in approximately 15% of the patients who received placebo. Most of these headaches responded to acetaminophen, and very few patients were eliminated from the studies due to inability to tolerate the medication secondary to headache. Approximately 15% of the patients reported soft or bulky stools. This was also minor and did not cause patients to exit the study. However, approximately 10% of the patients reported significant diarrhea, and this did cause some patients to exit the study. The most common causes of withdrawal from studies were either dizziness or palpitations. Both of these occurred approximately 10% of the time. The chronic use of Cilostazol in four separate clinical studies performed in the United States demonstrated a superiority over placebo on symptoms of claudication.[9 – 11]

Overall, the drug was fairly well tolerated, with patients subjectively reporting improvement in physical function. In addition, Cilostazol was found to be significantly more effective than pentoxifylline in a comparative study. Cilostazol is a new and effective drug which may aid in the nonoperative treatment of patients with claudication.

PENTOXIFYLLINE Hemorrheologic agents such as pentoxifylline (Trental) are those which can produce increased tissue perfusion by means of decreasing blood viscosity. Factors influencing blood viscosity include erythrocyte flexibility, leukocyte adhesion and activation, platelet aggregation, and plasma fibrinogen levels. Patients with peripheral occlusive arterial disease (POAD) are known to have an elevation in blood viscosity, fibrinogen level, and leukocyte activation, the extent of which appears to correlate with the severity of the POAD.[13]

Mechanism The primary mechanism of action of pentoxifylline was initially thought to be from an increase in erythrocyte deformability. In studies from the mid-1970s, patients with POAD were found to have elevated blood viscosity, which was later found to be decreased with pentoxifylline.[14,15] However, subsequent studies using washed erythrocytes devoid of other plasma constituents failed to show any impairment in erythrocyte deformability in those patients with POAD.[16] Furthermore, pentoxyfylline did not increase erythrocyte deformability in vitro with washed cells.[17] However, pentoxifylline does have beneficial hemorrheologic effects on other plasma constituents, including a decreased fibrinogen level,[18] decreased leukocyte activation and adhesion,[16,19] and decreased platelet activation.[20] Pentoxifylline’s salutary effects on these plasma constituents are the most likely mechanism(s) for its hemorrheologic activity. Further corollary support for a non –erythrocyte-mediated mechanism of action is provided in experimental studies of damage to the microcirculation during septic shock and ischemia/reperfusion injury. Leukocyte activation, adhesion and plugging of capillaries during reperfusion after significant acute ischemia has been conclusively demonstrated to play a significant role in end-organ injury.[21,22] Likewise, septic shock can produce similar microvascular injury.[23] Pentoxifylline has demonstrated beneficial effects in models of both ischemia/reperfusion injury[24,25] and septic shock.[26] While certainly not conclusive, these data lend further credence to the theory that modulation of leukocyte activation and adhesion by pentoxifylline may be an important component of its salutary effects.

Clinical Use Since its approval by the U.S. Food and Drug Administration in 1984, pentoxifylline has become a widely prescribed medication for claudication. It has been examined extensively in multiple well-designed prospective randomized placebo-

Chapter 20.

controlled clinical trials and does have a beneficial effect, albeit modest, in increasing walking distance.[27,28] In a metaanalysis of trials published between 1976 and 1994, Hood et al. found patients treated with pentoxifylline had a 24.9 m increase (,20% vs. control) in pain-free walking and a 48.4 m increase in the absolute claudication distance.[29] Close scrutiny of these and other trials suggest that particular subgroups, those with moderately severe claudication, may have substantially greater benefit from the drug. AbuRahma and Woodruff found that those patients with an ABI of $ 0:5 fared better than those with an ABI , 0:5.[30] Lindgarde and coworkers found those patients who had an ABI of #0.8 and had symptoms for greater than 1 year had a 52% and 33% improvement over placebo controls in initial and absolute claudication distance, respectively.[28] Those patients with ABI . 0:8 and/or with more acute symptoms did not have as great a benefit. While not conclusive, these trials suggest that patients with moderate POAD as defined by a ABI of 0.5–0.8 may receive more benefit from the pentoxifylline than those with either mild ðABI . 0:8Þ or severe ðABI , 0:5Þ POAD. Pentoxyifylline is typically prescribed 400 mg three times daily. Side effects are chiefly gastrointestinal, including nausea and bloating, and should require discontinuation of therapy in less than 5% of cases.

CARNITINE While hemorrheologic agents appear to be beneficial due to their augmentation of microvascular perfusion, metabolic agents such as carnitine may improve claudication by enhancing ischemic muscle metabolism. Carnitine, an important cofactor for skeletal muscle metabolism, augments entry of pyruvate into the citric acid cycle, hypothetically increasing the production of adenosine triphosphate (ATP).[31] It also enhances oxidation of long-chain fatty acids and decreases lactate levels. Many, but not all, patients with PAOD have increased levels of acetylcarnitine, an intermediate of oxidative metabolism which correlates with impaired exercise performance.[32] Exogenously supplied carnitine may facilitate a more efficient degradation of this metabolic intermediate, improving ischemic muscle metabolism and thus exercise performance. Several studies have shown beneficial effects of carnitine and propionyl-L -carnitine on walking distance in patients with POAD. Preliminary results of a multicenter phase III trial involving 155 patients randomized to propionyl-L -carnitine or placebo have recently been reported.[33] After 6 months of treatment, there was a 26% increase in absolute claudication distance in the treated group over the placebo group. Functional status, using the medical outcomes form SF-36, was also improved.[33] Similar improvements in walking distance have been noted by other investigators.[34 – 36] Propionyl-L -carnitine may have a greater effect than carnitine.[37] Because carnitine and its analogs are naturally occuring substances which appear to be free of toxic effects, there is considerable interest in their use for patients with claudication. While not approved for such use by the FDA, the average dose used in these studies has been 2 g/day.

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NAFTIDROFURYL Naftidrofuryl (Praxilene) is another metabolic agent felt to enhance skeletal muscle ATP production. Unlike carnitine, its metabolic actions appear to stimulate the tricarboxylic acid cycle. As a serotonin receptor antagonist, it may also have salutary vasoactive properties.[38] In a meta-analysis of five European studies pooling 888 patients, those receiving the drug had a significant improvement in initial claudication distance when compared to controls.[39] A reduced need for subsequent lower extremity bypass procedures was also noted in the treatment group. Naftidrofuryl is not available in the United States but is widely prescribed in Europe at a dose of 600 mg/day in 2 –3 divided doses. It is well tolerated, with mild gastrointestinal effects requiring withdrawal of the drug in less than 2% of patients.

PROSTAGLANDINS Prostaglandins have significant vasodilator properties and are also potent inhibitors of platelet aggregation. While vasodilator drugs have generally proven ineffective in treatment of POAD symptoms,[40] there continues to be clinical interest in prostaglandins and its analogs. Most studies with these drugs have been in patients with limbthreatening ischemia, with mixed results.[41 – 43] However, there are an increasing number of studies using these agents for the treatment of claudication. Beraprost, an orally active PGI2 analog, has been evaluated in a phase II dose-ranging study.[44] While walking distance increased by as much as 50%, these differences were not statistically significant, perhaps because of scatter in the data and/or a type II error. Significant side effects including flushing, and headaches were seen in a large percentage of the patients. Further studies of this drug will be required. Intravenous PGE1 has also been evaluated in the treatment of claudication. In these studies, absolute walking distances have been increased by 20 –40% when compared with placebo controls.[45,46] These studies typically gave 1- to 2-hour infusions 5 days a week for the duration of the study. Practical use for such a drug requiring frequent intravenous delivery in the treatment of claudication is likely to be limited.

VERAPAMIL Verapamil is a well-known calcium channel blocker presently in clinical use due to its antihypertensive actions. It has been suggested by some authors that verapamil may have a positive effect in the treatment of intermittent claudication.[47,48] Other studies have demonstrated no significant effect of verapamil on claudication. However, in a study by Bagger et al.,[49] they demonstrated that verapamil can increase absolute walking distances significantly. Patients were not given a standardized dose of verapamil. In a pretrial pilot study, patients were treated to determine individual dose-

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response curves and then experimentally studied following a washout period. Patients demonstrated significant improvement in walking ability after 2 weeks of treatment. Verapamil was not studied solely because of its vasodilating effect, but because it reportedly raises the oxygen-extracting capacity of

the ischemic lower extremity. It is obvious that more work on the effects of verapamil are needed, and presently despite the availability of verapamil in the United States, its use in treating intermittent claudication has yet to be completely elucidated.

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Lehert, P.; Comte, S.; Gamand, S.; Brown, T.M. Naftidrofuryl in Intermittent Claudication: A Retrospective Analysis. J. Cardiovasc. Pharm. 1994, 23 (Suppl. 3), S48 –S52. Coffman, J.D. Vasodilator Drugs in Peripheral Vascular Disease. N. Engl. J. Med. 1979, 300L713. Norgren, L.; Alwmark, A.; Angqvist, K.A. et al. A Stable Prostacyclin Analog (Iloprost) in the Treatment of Ischaemic Ulcers of the Lower Limb: A ScandinavianPolish Placebo-Controlled, Randomized Multicenter Study. Eur. J. Vasc. Surg. 1990, 4, 463. Trubestein, G.; von Bary, S.; Breddin, K. et al. Intravenous Prostaglandin E1 Versus Pentoxifylline Therapy in Chronic Arterial Occlusive Disease—a Controlled Randomized Multicenter Study. Vasa 1989, 28, 44. Nizandowski, R.; Krolikowski, W.; Beilatowicz, J.; Szczeklik, A. Prostacyclin for Ischemic Ulcers in Peripheral Arterial Disease: A Random Assignment, Placebo-Controlled Study. Thromb. Res. 1985, 37, 21. Lievre, M.; Azoulay, S.; Lion, L.; Mornd, S.; Girre, J.P.; Boissel, J.P. A Dose-Effect Study of Beraprost Sodium in Intermittent Claudication. J. Cardiovasc. Pharmacol. 1996, 27, 788– 793. Belch, J.J.F.; Bell, P.R.F.; Creissen, D. et al. Randomized, Double Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of AS-013, a Prostaglandin E1 Prodrug, in Patients with Intermittent Claudication. Circulation 1997, 95, 2298– 2302. Diehm, C.; Balzer, K.; Bisler, H.; et al. Efficacy of a New Prostaglandin E1 Regimen in Outpatients with Severe Intermittent Claudication: Results of a Multicenter Placebo-Controlled Double-Blind Trial. J. Vasc. Surg. 1997, 25, 537– 544. Bagger, J.; Mathar, R.; Paulsen, P.; Gormsen, J.; Olsen, K. Verapamil Induced Increment of Oxygen Extraction in the Arteriosclerotic Limb. Cardiovasc. Res. 1985, 19, 567–569. Kimose, H.; Bagger, J.; Aagaard, M.; Paulsen, P. PlaceboControlled Double-Blind Study of the Effect of Verapamil in Intermittent Claudication. Angiology 1990, 41, 595–598. Bagger, J.; Helligsoe, P.; Randsbaek, F.; Kimose, H.; Jensen, B. Effect of Verapamil in Intermittent Claudication. Circulation 1997, 95, 411– 414.

CHAPTER 21

Perioperative Evaluation and Management of Cardiac Risk in Vascular Surgery Piotr Sobieszczyk Joshua A. Beckman Michael Belkin

revascularization versus medical therapy. Preoperative testing should therefore be undertaken only if the information obtained will change medical management or the type of planned surgery. Selection of patients for investigation and the appropriate studies to be performed requires understanding the risks of vascular surgery and the purpose of cardiac evaluation. While the most obvious goal of preoperative assessment is reduction of surgical risk, the combined morbidity of invasive cardiac investigation, coronary revascularization, and subsequent peripheral vascular surgery must be weighed against the risk of the latter procedure alone. Since the overall mortality for most elective vascular procedures remains well under 5%, preoperative testing should be performed selectively. Cardiovascular assessment may also help determine the propriety of surgery in some patients. Small aortic aneurysms, asymptomatic carotid stenosis, or calf claudication, for example, are only relative indications for operation. An evaluation of cardiac function or coronary anatomy may influence the decision to proceed with surgical versus conservative management. For example, it is unlikely that a patient with a life expectancy of less than 2 years will benefit from a carotid endarterectomy of an asymptomatic lesion. Finally, since cardiac disease is so prevalent in patients with peripheral vascular disease, a thorough cardiac evaluation may be justified in some patients simply to address the longterm consequences of their cardiac disorder, regardless of the need for reconstruction of the peripheral lesion. Evaluation by vascular surgical and medical specialists offers an opportunity for implementing a preventive therapy to halt disease progression and ensure longevity of surgical reconstruction.

INTRODUCTION The prevalence of heart disease in the general population and the increasingly aggressive surgery performed in the elderly make perioperative risk of cardiovascular complications a major concern for all surgeons. As the population ages, the prevalence of atherosclerotic risk factors increases commensurately, increasing the risk of the typical surgical patient.[1] The systemic nature of atherosclerosis imposes a particular challenge on the successful perioperative cardiac management of patients with peripheral arterial disease. Studies on the prevalence of coronary artery disease (CAD) in patients with intermittent claudications show that history, clinical examination, and electrocardiography typically indicate the presence of coronary artery disease in 40 –60% of such patients.[2 – 6] In patients requiring arterial reconstructive surgery, clinically evident cardiac dysfunction has been noted in 50% of the patients, while an additional 18% have highly significant but clinically silent coronary artery disease.[2 – 4] In a study of routine coronary angiography at the Cleveland Clinic, surgically correctable coronary disease was found in 31% of patients with aortic aneurysms, 26% of those with cerebrovascular disease, and 21% of patients with peripheral arterial ischemia.[3] Routine coronary angiography and revascularization is neither necessary nor desirable in all patients with peripheral vascular disease. There are no controlled trials comparing perioperative outcomes after noncardiac surgery for patients treated with surgical or percutaneous coronary

Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024904 Copyright q 2004 by Marcel Dekker, Inc.

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PREOPERATIVE CARDIOVASCULAR ASSESSMENT Coronary Artery Disease Risk factors leading to peripheral arterial disease also cause atherosclerosis of the coronary vessels. A large fraction of patients undergoing vascular surgery will thus have CAD of varying severity. Many of these patients have major or intermediate predictors of perioperative risk (Table 21-1) but do not necessarily have clinically manifest CAD. The immediate goal of evaluation is to identify patients who are at an increased risk of perioperative complications: patients presenting with progressive symptoms of CAD and those with severe but clinically silent CAD. This small subgroup of patients may require preoperative coronary revascularization. The indications for percutaneous or surgical coronary revascularization in patients undergoing vascular surgery are the same as those for general population.[7,8] Patients with mild to moderate CAD, on the other hand, can usually safely undergo vascular surgery with optimal medical management. Currently available tools for cardiovascular risk assessment include careful history taking with attention to functional status and symptoms of ischemic heart disease, physical examination, resting ECG and, in selected patients, noninvasive evaluation of the severity of CAD. Patients presenting with new or escalating symptoms and signs of CAD warrant aggressive evaluation, including stress testing and coronary angiography. The decision to proceed with percutaneous or surgical revascularization should be based on the guidelines established for general population, taking the urgency of vascular reconstruction under consideration.[7,8] The optimal timing of elective vascular

surgery after catheter-based coronary intervention is controversial. There is ample evidence that PTCA and stenting induces systemic autoimmune and inflammatory responses,[9,10] which persist up to 3 weeks after percutaneous transluminal coronary angioplast (PTCA).[10] This prothrombotic state can increase perioperative cardiovascular complications. The majority of coronary interventions today involve implantation of coronary stents. In a small study of 40 patients, most of whom were asymptomatic or had stable CAD, Kaluza et al.[11] found that surgery (72% of patients had vascular surgery) within 14 days of coronary stenting was associated with a 17.5% rate of MI, a 20% rate of death, and a 20% rate of significant bleeding. Whenever possible, elective surgery should be postponed for 4–6 weeks after coronary stenting. Evaluation of patients with a recent coronary event (defined as more than 7 but fewer than 30 days) has evolved considerably over the last decade. An antecedent myocardial infarction (MI) is one of the most significant risk factors associated with subsequent surgical morbidity. Furthermore, the mortality from a postoperative reinfarction has been shown to be considerably higher than the mortality from an initial infarction, ranging from 50 to 83%.[12 – 16] The large series have indicated that the surgical risk was greatest immediately after the infarction, in the range of 30 –50%, then dropped exponentially over the next 6 months to a stable reinfarction rate of 5% with subsequent surgical procedures.[13,17] Subsequent studies, however, indicated that improved surgical and anesthetic techniques have reduced the risk of reinfarction to 8% within the first 3 months after MI and 3.5% in the subsequent 3 months.[18,19] These reports involved a variety of surgical procedures, which did not necessarily reflect the risk of specific vascular operations. Modern guidelines for management of acute MI[20,21] require

Table 21-1. Clinical Predictors of Increased Perioperative Cardiovascular Risk Major

Intermediate

Minor

Unstable coronary syndromes Acute or recent MI with evidence of important ischemic risk Unstable or severe angina (Canadian Class III-IV) Decompensated heart failure Significant arrhythmia High-degree AV block Symptomatic ventricular arrhythmia in the presence of underlying heart disease Supraventricular arrhythmia with uncontrollable ventricular rate Severe valvular disease Mild angina (Canadian Class I-II) Previous MI by history or pathological Q waves Compensated or prior heart failure Diabetes mellitus Renal insufficiency Advanced age Abnormal ECG Rhythm other than sinus Low functional capacity History of a cerebral vascular event Uncontrollable systemic hypertension

Source: Adapted from Ref. [22].

Chapter 21.

Perioperative Evaluation and Management of Cardiac Risk in Vascular Surgery

evaluation and aggressive treatment of coronary pathology at the time of the acute presentation and risk stratification during recovery. Although there are no clinical trials to evaluate the optimal time interval before an elective surgery, most recent guidelines recommend waiting 4–6 weeks after MI before performing an elective surgery.[22] However, urgent revascularization, especially for limb salvage, should not be avoided solely on the basis of a recent infarction. Patients with established but stable coronary artery disease require a different approach. Those who underwent coronary artery bypass grafting (CABG) within 5 years or percutaneous revascularization within 2 years and have not experienced deterioration in functional capacity or recurrent symptoms of CAD usually do not require further preoperative testing.[22] Many patients will present with a diagnosis of CAD but no history of revascularization. Patients with noncritical CAD on invasive or noninvasive testing within 2 years are at an acceptable risk provided that they had no change in symptoms. This approach includes patients with stable angina. These patients do not require further testing. Noninvasive testing should be performed in patients with CAD who experienced a change in their functional status or whose functional status cannot be assessed due to immobility. A large proportion of patients undergoing preoperative evaluation will be asymptomatic and not carry a diagnosis of coronary artery disease but will have an increased probability of CAD by virtue of their risk factors. Many will have intermediate clinical predictors of perioperative risk (Table 21-1). In this group, the immediate aim of preoperative risk assessment should focus on determination of functional capacity and, if CAD is detected, the degree of the ischemic burden. Their management should be guided by the established guidelines irrespective of the planned surgery. Those whose functional capacity can be reliably established to be above 4 MET (Table 21-2) have a good long-term prognosis[24] and can generally undergo surgery under appropriate medical management without further testing. Sedentary patients who have a normal resting ECG and who are able to exercise should undergo exercise stress testing. The onset of myocardial ischemia response at a low workload is associated with increased risk of perioperative and longterm cardiac events[22,24] and warrants a more invasive evaluation. On the other hand, the onset of ischemic response at high exercise workloads is associated with significantly lower risk.[22] The utility of this test in vascular patients, however, is limited due to their inability to exercise. In a series of 100 patients scheduled for vascular surgery who could exercise, 70% could not reach the required heart rate or had an abnormal resting ECG.[25] Nonexercise stress testing should be used in patients unable to exercise. Two commonly used techniques rely on either increase in myocardial oxygen consumption (intravenous dobutamine) or induction of hyperemic response by pharmacological agents such as intravenous dipyridamole or adenosine. Dobutamine stress echocardiography and intravenous dipyridamole/adenosine myocardial perfusion imaging using thallium-201 or technetium-99m are commonly used today. The choice of diagnostic modality should be guided by local expertise and patient characteristics. Although adenosine-technetium imaging is most commonly used today, more data exist for the older

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Table 21-2. Average Metabolic Equivalent (METs) Levels for Common Activities Activity Getting dressed Walking indoors Walking at 2.0 mph Walking at 3.0 mph Golf (with cart) Golf (without cart) Light work around the house Calisthenics (no weights) Climbing a flight of stairs Gardening Cycling (leisurely) Cycling (moderately) Swimming (slowly) Swimming (fast) Climbing hills No load With 5 kg load Tennis (doubles) Tennis (singles) Running (10 min/mile) Running (7.5 min/mile)

METsa 1.0 1.5 2.5 3.5 2.5 4.9 3.9 4.0 4.0 4.4 4.0 5.7 4.5 7.0 6.9 7.5 6.0 7.5 10.2 13.2

a

Functional capacity can be expressed in metabolic equivalent (MET) levels; the oxygen consumption (VO2) of a 70 kg, 40-year-old man in a resting state is 3.5 mL/kg/min, or 1 MET, i.e., 3 MET represents an exercise intensity three times the metabolic rate at rest. Source: From Refs. [22,23].

dipyridamole/thallium imaging. A reversible perfusion defect has a positive predictive value for a perioperative cardiac event among vascular patients ranging from 5 to 20%. The negative predictive value is consistently high at 95 to 100%.[22] Patients with fixed perfusion defects have a higher risk of perioperative cardiac complications compared with those whose scan is normal, but this risk is significantly lower than in patients with reversible perfusion defects. A meta-analysis of dipyridamole thallium imaging for perioperative risk stratification prior to vascular surgery in 1994 patients confirmed the significant prognostic utility of this technique.[26] Overall, reversible myocardial perfusion defects predicted perioperative events, while fixed thallium defects predicted long-term cardiovascular events. In contradistinction to these retrospective studies and meta-analysis documenting the predictive value of nuclear stress imaging are prospective trials in which the studies were not predictive of perioperative cardiac risk. Mangano and associates studied a group of 60 patients who underwent blinded dipyridamole-thallium imaging proir to major vascular surgery.[27] In that study there was no association between redistribution defects and adverse cardiac events. Fifty-four percent (7 of 13) of adverse events occurred in patients without redistribution defects, while the relative risk

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for patients with redistribution defects to have an adverse event was only 1.5 ð p ¼ 0:43Þ: In another prospective blinded trial of 457 patients undergoing abdominal aortic surgery after blinded dipyridamole-thallium imaging, Baron and associates found no predictive value to the test.[28] The relative risk for adverse cardiac events was 1.1 for patients with redistribution defects and 1.5 for patients with fixed perfusion defects. Several studies have investigated the safety and accuracy of dobutamine stress echocardiography in patients undergoing vascular surgery.[22,29 – 33] The definition of positive and negative results varied among these studies. On the whole, however, these studies indicate that dobutamine stress echocardiography can be performed safely. The predictive value of a positive test for perioperative cardiac events (death or MI) ranged from 7 to 25%, while the negative predictive value ranged from 93 to 100%.[22] The presence of new wall motion abnormalities[29] and the extent of wall motion abnormality at a low level of pharmacological stress are particularly important and predict short- and long-term outcomes.[32,34] Current guidelines support the use of this technique in properly selected patients undergoing vascular surgery.[22] In patients in whom the presence of coronary artery disease has been established by noninvasive testing, management decisions should be based on their functional capacity and the severity of CAD. Coronary angiography and revascularization should not be undertaken just to “get the patient through surgery.” There have been no randomized trials examining the role of prophylactic coronary artery bypass graft surgery prior to noncardiac surgery. Preoperative coronary arteriography with prophylactic percutaneous revascularization has not been rigorously studied. Elmore et al.[35] and Huber et al.[36] have retrospectively examined small numbers of patients who underwent coronary balloon angioplasty before elective vascular surgery (median 10 and 9 days, respectively). The risk of MI was 0% and 5.6% and the risk of death was 0% and 1.9%, respectively. Both studies argued that percutaneous intervention prior to surgery is safe. A larger series, however, showed that patients who underwent percutaneous transluminal coronary angioplasty fewer than 90 days before the surgery had a twofold increase in the rate of perioperative MI compared with patients with uncorrected CAD.[37,38] Mason et al.[39] and Fleisher et al.[40] found that patients with CAD undergoing vascular surgery without coronary interventions had better outcomes than patients who were revascularized. Furthermore, as we have already suggested, the added risk of cardiac catheterization and coronary intervention or bypass surgery may negate the protection derived from future noncardiac surgery. In the absence of randomized, controlled trials comparing preoperative prophylactic revascularization versus medical therapy, coronary angiography and revascularization should be reserved for patients who would qualify for such treatment irrespective of planned surgery.[7,8] This would include patients with low ischemic threshold or evidence of multivessel disease. Medical therapy should be optimized in the remaining patients. Patients with no historical or ECG evidence of ischemic heart disease and excellent functional status determined by history do not require any further investigation. The surgical experience at our center demonstrates that a postoperative

cardiac morbidity and mortality of less than 0.5% can be achieved in this group, including patients undergoing aortic reconstruction.[41] Despite attempts to refine and improve the predictive value of the clinical scoring system, stress testing, and myocardial scintigraphy, these methods of evaluation all have their limitations. Recognition of these limitations, along with the gradual but steady decrease in cardiac morbidity and mortality after vascular surgery procedures, have led some authors to question the utility of preoperative attempts at cardiac risk evaluation. Taylor and associates reported only a 3.9% myocardial infarction rate (, 1% cardiac mortality) after 534 vascular operations with no routine cardiac evaluation other than history, physical exam, and ECG.[42] Only 5.8% of patients who were felt to have severe symptomatic coronary artery disease had further cardiac evaluation, and only 3 patients underwent prophylactic coronary bypass surgery prior to the planned vascular surgery operation. These authors argued that cardiac screening is unnecessary and cost ineffective when applied to the general vascular surgery population. While it has been clearly shown that the great majority of patients can be “gotten through” vascular surgical procedures with acceptably low morbidity and mortality, few would argue the merits of identifying the presence and significance of coronary artery disease in preoperative patients. While few patients will require coronary arteriography and even fewer any form of coronary revascularization, the recognition of coronary artery disease allows optimal short- and long-term care. Optimization of perioperative medical management, perioperative monitoring, and long-term risk factor modification are all facilitated by an accurate cardiac evaluation. A recent study by McDermott et al.[43] demonstrated the advantage of such multidisciplinary approach in management of patients with peripheral arterial disease.

Congestive Heart Failure Clinically evident heart failure at the time of operation is one of the most serious risk factors for postoperative cardiac morbidity.[44,45] Patients with a third heart sound or jugular venous distention have a 25–30% risk of postoperative pulmonary edema as well as a higher operative mortality.[44] The surgical risk is primarily dependent on the degree of decompensation at the time of operation rather than the historical severity of the heart failure. Furthermore, the presence of active heart failure should not be confused with a less worrisome finding of low ejection fraction in patients without fluid overload. The etiology of heart failure should be identified as it may have significant prognostic implications. Congestive heart failure due to ischemic heart disease implies a poorer prognosis than that due to longstanding hypertension. Satisfactory preoperative control of congestive heart failure substantially reduces the cardiac risk[16] and is mandatory in all but the most urgent circumstances. Rapid control of heart failure may be associated with some degree of hypovolemia. Preoperative management must therefore include appropriate anesthetic techniques to minimize sudden vasodilation.

Chapter 21.

Perioperative Evaluation and Management of Cardiac Risk in Vascular Surgery

Arrhythmias and Conduction Disturbances The presence of an arrhythmia or conduction system abnormality should prompt an evaluation of the underlying cardiopulmonary disease, drug toxicity, or metabolic abnormality. Symptomatic or hemodynamically significant arrhythmias should be treated. The indications for pacing or antiarrhythmic therapy should be the same as in the nonoperative setting.[46] Frequent premature ventricular contractions and asymptomatic nonsustained ventricular tachycardia have not been associated with an increased risk of nonfatal MI or cardiac death in the perioperative setting.[47,48] The presence of nonsustained ventricular tachycardia may, however, be a marker of underlying left ventricular dysfunction and carry an increased long-term risk of sudden cardiac death. An implantable cardiac defibrillator may be warranted in selected patients. Patients with complete heart block are at considerable risk for postoperative complications, not only because of the underlying myocardial disease but also due to their inability to augment cardiac output in response to stress.[49] This impairment is exacerbated by anesthetic agents, which further depress myocardial contractility or cause peripheral vasodilatation. These patients should be provided with a temporary pacemaker perioperatively. Management of patients with chronic bifascicular block is more controversial. Although 5% of such patients will develop complete heart block each year,[50] anesthesia and surgery do not usually precipitate this conversion. Patients with an associate history of syncope or those deemed at high risk of postoperative MI (which may lead to severe hemodynamic decompensation in the presence of heart block) may be considered for temporary pacing. Otherwise, management should be directed toward the underlying cardiac disease rather than the conduction defect itself.

Valvular Heart Disease Although there is a slight increase in the incidence of embolization and endocarditis, the cardiac mortality and morbidity of valvular disease are predominantly associated with the degree of underlying myocardial decompensation. Patients who are either asymptomatic or have only a mild degree of functional limitation (NYHA class II) do not appear to be at a higher risk. These patients do not require additional preoperative therapy with the exception of prophylactic antibiotics for endocarditis. Patients with critical valvular stenosis and significant physical limitations characteristic of NYHA class III or IV are clearly at higher risk for perioperative sudden death or pulmonary edema.[51,52] Every effort must be made to identify these high-risk individuals and to institute appropriate perioperative therapy. Severe and symptomatic aortic stenosis poses the greatest risk for noncardiac surgery. Patients with symptoms of angina, syncope, or congestive heart failure should be evaluated for aortic valve surgery prior to an elective noncardiac surgery. In patients who refuse or are not candidates for valve replacement, the noncardiac surgery is associated with a 10% mortality risk.[53,54] Percutaneous

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balloon aortic valvuloplasty may be considered in special situations as a short-term solution to lower operative mortality and morbidity. These patients will be very sensitive to perioperative fluid shifts and may benefit from perioperative pulmonary artery catheter monitoring. Mitral stenosis is decreasing in frequency but, when significant, carries an increased risk of perioperative congestive heart failure. Mild to moderate mitral valve stenosis mandates careful heart rate control to maintain the diastolic filling period and careful attention to volume status. Severe mitral vale stenosis may require preoperative balloon mitral valvuloplasty or surgical replacement. Regurgitant valvular lesions are easier to manage in the perioperative setting. Patients in congestive heart failure due to aortic or mitral regurgitation should be medically optimized but do not require valve surgery preoperatively. Aortic regurgitation requires careful perioperative attention to volume status and afterload. Low heart rate increases the regurgitant volume and, unless CAD is present, should be avoided. Patients with prosthetic valves are often maintained on chronic anticoagulation with sodium warfarin, depending upon the type of the valve. Chronic anticoagulation should be withheld during the perioperative period to avoid an increased incidence of hemorrhagic complications. Since most bleeding can be controlled, while the sequelae of a single thromboembolic event may well be irreversible, short-term anticoagulation should be provided during the perioperative period. Perioperative heparin therapy is particularly important for patients in whom the risk of thromboembolism without anticoagulation is high: patients with a mechanical valve in the mitral position, a Bjork-Shiley valve, recent (i.e., less than one year) thrombosis or embolus, or three or more of the following risk factors: atrial fibrillation, previous embolus at any time, hypercoagulable condition, or mechanical prosthesis and LVEF less than 30%.[55] Chronic warfarin therapy should be discontinued 2–3 days before the surgery. Low molecular weight heparin can be used to facilitate the transition from chronic coumadin therapy in the perioperative setting. Alternatively, intravenous heparin can be instituted until 4 –6 hours before the surgery and started again postoperatively until coumadin reaches therapeutic level.

Hypertension Several investigations[56 – 60] have demonstrated that stage 1 or stage 2 hypertension (systolic blood pressure , 180 mmHg and diastolic blood pressure , 110 mmHg) does not pose an increased risk for perioperative cardiac complications. On the other hand, stage 3 hypertension (systolic blood pressure $ 180 mmHg and diastolic blood pressure $ 110 mmHg) should be controlled before surgery even if it requires a brief postponement. An effective regimen can be achieved over several days to weeks of preoperative outpatient treatment. Based on the available evidence, beta-blockers,[61] ACE inhibitors,[62] and thiazides[63] are particularly attractive in this patient population. If surgery is more urgent, rapid-acting agents can be administered that allow effective control in a matter of minutes or hours.

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Hypertension is quite common, and treatment has been shown to decrease death rates from stroke and CHD in the nonsurgical setting. Unfortunately, few patients with hypertension are treated effectively or treated at all. Accordingly, the perioperative evaluation offers an opportunity to identify patients with hypertension and initiate appropriate therapy. Patients who are on antihypertensive therapy should continue their regimen during the perioperative period. Particular care should be taken to avoid withdrawal of beta-blockers and clonidine because of potential heart rate or blood pressure rebound. In patients unable to take oral medications, parenteral beta-blockers and transdermal clonidine may be used.

PERIOPERATIVE MANAGEMENT Surgical Procedure The type of operative procedure itself plays a major role in the risk of a cardiac complication. Aortic surgery is more stressful than infrainguinal arterial reconstruction. Nonetheless, the incidence of significant coronary artery disease and cardiac morbidity and mortality is generally higher after infrainguinal surgery. Emergency surgery is generally more dangerous than elective surgery for most procedures. The morbidity and mortality of emergent repair of symptomatic but unruptured aneurysms, for example, has been reported as much higher in some series than that associated with elective repair.[64,65] The overall mortality rate, 1.6% in our experience, applies equally to all intact aneurysms, symptomatic or not.[41,66,67] However, this low mortality rate has not been equaled in most other hospitals. Somewhat surprisingly, the duration of surgery has not proven to correlate with cardiac risk, at least for noncavitary operations. We believe that the increased complication rate sometimes noted for very long operations is related to the nature of the surgery rather than its duration.

Medical Management Several trials in the last decade have demonstrated the beneficial effect of perioperative administration of betablockers in reducing cardiac events. Mangano et al.[68] studied 200 patients with or at risk for CAD who were scheduled to undergo noncardiac surgery (40% of patients had vascular surgery). They were randomized to atenolol, administered immediately before surgery and for up to 7 days thereafter, or placebo. This randomized, double-blind, placebo-controlled trial did not show any effect on immediate postoperative mortality, but the 6-month mortality was significantly lower in the atenolol arm (0% vs. 8%). This benefit persisted for 2 years of follow-up. Moreover, there was a significant reduction in postoperative ischemia on continuous Holter monitoring.[69] Poldermans et al.[61] investigated the effect of bisoprolol in high-risk patients undergoing vascular surgery. In a randomized, multicenter trial, 112 patients with CAD documented by a positive dobutamine echocardiogram were randomized to bisoprolol, started an average 37 days before surgery, or placebo. After 30 days of follow-up,

bisoprolol significantly reduced the risk of myocardial infarction (0% vs. 17%) and death (3.4% vs. 17%) compared to placebo. Boersma et al.[70] subsequently reanalyzed the total cohort of 1351 consecutive patients enrolled in this randomized trial of bisoprolol and showed that the benefit of therapy extended to all subsets of patients except those with most extensive ischemia on dobutamine stress echocardiogram. These two trials have confirmed the finding of several smaller and older studies[71 – 74] and thus have firmly established the benefit of perioperative beta-blockers. We routinely use beta-blockers in patients with or at risk for CAD, preferably started in the outpatient setting, with target heart rate in the range of 50–70 beats per minute. Patients undergoing vascular surgery remain at an increased risk of future cardiovascular events. Perioperative medical and surgical attention offers a great opportunity for aggressive modification of risk factors and reduction of future morbidity and mortality. Several recent large trials have shown the efficacy of specific medical interventions in reaching these goals. The HOPE trial randomized 9297 patients with vascular disease or diabetes and one additional cardiovascular risk factor to treatment with the ACE inhibitor ramipril or placebo.[62] Ramipril significantly reduced the rate of death from cardiovascular cause (6.1% vs. 8.1%), rate of MI (9.9% vs. 12.3%), and rate of CVA (3.2% vs. 4.9%) when compared to placebo. The role of cholesterol-lowering therapy with statins in reducing future cardiovascular events has been well established. The recently completed Heart Protection Study confirmed this benefit across all strata of LDL levels.[75] In 20,536 patients with CAD, peripheral arterial disease or diabetes who were randomized to simvastatin or placebo, active arm treatment significantly lowered rates of all-cause mortality (12.9% vs. 14.7%), coronary death (18% relative reduction) and reduced by nearly 25% the event rate for first MI and CVA. Antiplatelet therapy continues to be the most cost-effective intervention in vascular patients. A recent update from the Antithrombotic Trialists’ Collaboration Group reviewed all randomized trials of antiplatelet therapy. In 135,000 patients studied, antiplatelet therapy (aspirin was studied most widely) significantly reduced the combined outcome of any serious vascular event by nearly 25%, nonfatal myocardial infarction by 33%, nonfatal stroke by 25%, and vascular mortality by one sixth.[76] Clopidogrel, a thienopyridine derivative platelet antagonist, is slightly superior to aspirin in reducing the combined risk of ischemic stroke, myocardial infarction, or vascular death in patients with atherosclerotic vascular disease.[77] It is an effective, though more costly, alternative to aspirin in this group of patients. Its use is increasing in patients with coronary artery disease and percutaneous coronary interventions.[78,79] The recently published ALLHAT trial[63] has shown that thiazide diuretics, when compared with a calcium channel blocker or ACE inhibitor, are equally effective in reducing coronary heart disease events and allcause mortality. In this trial of 33,357 patients, diuretic therapy was more effective in reducing blood pressure. In the absence of strong contraindications, all patients with established vascular disease should be on longterm antiplatelet therapy, cholesterol-lowering therapy,

Chapter 21.

Perioperative Evaluation and Management of Cardiac Risk in Vascular Surgery

beta-blockers, and ACE inhibitors. Thiazide diuretics should be chosen for control of hypertension.

Perioperative Hemodynamic Monitoring Intraoperative and postoperative hemodynamic monitoring with the aid of a pulmonary artery (PA) catheter can provide significant information critical to the care of the cardiac patient. Its use, however, must be balanced against the cost and risk of complications from insertion and use of the catheter, as well as variable physician understanding of data provided by the PA catheter. There are relatively few controlled studies examining clinical outcomes in patients managed perioperatively with the guidance of PA catheters. Several trials in vascular surgical patients did not find any differences in cardiac morbidity.[80 – 84] Patients undergoing infrainguinal arterial reconstruction did not have any difference in cardiac morbidity whether monitored by a pulmonary artery catheter from the evening before surgery, 3 hours before surgery, or only if clinically indicated. Pulmonary artery catheter monitoring, however, led to fewer intraoperative hemodynamic disorders.[85] Polanczyk et al. conducted a prospective cohort study of 4059 patients aged 50 years or older who underwent major elective noncardiac surgery.[86]

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Perioperative pulmonary artery catheterization was associated with a threefold increase in the incidence of major postoperative cardiac events [34 (15.4%) vs. 137 (3.6%); p , 0.001]. More recently, Sandham et al.[87] investigated the use of PA catheters in high-risk patients (ASA class III-IV) undergoing high-risk surgery (55% underwent vascular surgery). This randomized, multicenter trial showed no difference in perioperative or long-term mortality between the two treatment groups. There was no difference in postoperative MI, CHF, or arrhythmia. The group with PA catheters suffered a higher incidence of pulmonary embolism. Current evidence does not support routine use of pulmonary artery catheters perioperatively. They may, however, be beneficial in specific clinical situations where the extent of intraoperative and postoperative fluid shifts must be closely monitored. Patients with severe aortic stenosis may fit in this category. The decision to use PA catheter monitoring should be individualized and based on patient disease, surgical procedure, and practice setting. Practice parameters for the intraoperative use of a pulmonary artery catheter have been established by the American Society of Anesthesiologists.[88] More recently, transesophageal echocardiography has been employed as an intraoperative adjunct for monitoring cardiac function and filling during aortic cross clamping.

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Eagle, K.A.; Guyton, R.A.; Davidoff, R.; Ewy, G.A.; Fonger, J.; Gardner, T.J.; Gott, J.P.; Herrmann, H.C.; Marlow, R.A.; Nugent, W.C.; O’Connor, G.T.; Orszulak, T.A.; Rieselbach, R.E.; Winters, W.L.; Yusuf, S. ACC/AHA Guidelines for Coronary Artery Bypass Graft Surgery: A Report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1991 Guidelines for Coronary Artery Bypass Graft Surgery). J. Am. Coll. Cardiol. 1999, 34, 1262– 1346. Serrano, C.V.; Ramires, J.A.; Venturinelli, M.; et al. Coronary Angioplasty Results in Leukocyte and Platelet Activation with Adhesion Molecule Expression: Evidence of Inflammatory Response in Coronary Angioplasty. J. Am. Coll. Cardiol. 1997, 29, 1276– 1283. Azar, R.R.; McKay, R.G.; Kirnan, F.J.; et al. Coronary Angioplasty Induces a Systemic Inflammatory Response. Am. J. Cardiol. 1997, 80, 1476– 1489. Kaluza, G.; Joseph, J.; Raizner, M. Catastrophic Outcomes of Noncardiac Surgery Soon After Coronary Stenting. J. Am. Coll. Cardiol. 2000, 35, 1288– 1294. Plumlee, J.E.; Boettner, R.B. Myocardial Infarction During and Following Anesthesia and Operation. South Med. J. 1972, 65, 886. Tarhan, S.; Moffin, E.A.; Taylor, W.F.; et al. Myocardial Infarction After General Anesthesia. J. Am. Med. Assoc. 1972, 220, 1451. Rose, S.D.; Corman, L.C.; Mason, D.T. Cardiac Risk Factors in Patients Undergoing Noncardiac Surgery. Med. Clin. N. Am. 1979, 63, 1271.

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15. Portal, R.W. Elective Surgery After Myocardial Infarction. Br. Med. J. 1982, 284, 843. 16. Goldman, L.; Caldera, D.L.; Southwick, F.S.; et al. Cardiac Risk Factors and Complications in Noncardiac Surgery. Medicine 1978, 57, 357. 17. Steen, P.A.; Tinker, J.H.; Tarhan, S. Myocardial Reinfarction After Anesthesia and Surgery. J. Am. Med. Assoc. 1978, 239, 2566. 18. Wells, P.H.; Kaplan, J.A. Optimal Management of Patients with Ischemic Heart Disease for Noncardiac Surgery by Complementary Anesthesiologist and Cariologist Interaction. Am. Heart J. 1981, 102, 1029. 19. Rao, T.L.K.; El-Etr, A.A. Myocardial Reinfarction Following Anesthesia in Patients with Recent Infarction. Anesth. Analg. 1981, 60, 271. 20. Braunwald, E.; Antman, E.M.; Beasley, J.W.; Califf, R.M.; Cheitlin, M.D.; Hochman, J.S.; Jones, R.H.; Kereiakes, D.; Kupersmith, J.; Levin, T.N.; Pepine, C.J.; Schaeffer, J.W.; Smith, E.E. III, Steward, D.E.; Theroux, P. ACC/AHA 2002 Guideline Update for the Management of Patients with Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). J. Am. Coll. Cardiol. 2002, 40, 1366– 1377. 21. Ryan, T.J.; Antman, E.M.; Brooks, N.H.; et al. ACC/AHA Guidelines for the Management of Patients with Acute Myocardial Infarction: 1999 Update: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). Available at http:/www.acc.org/clinical/guidelines. 22. Eagle, K.A.; Berger, P.B.; Calkins, H.; et al. ACC/AHA Guideline Update for Perioperative Cardiovascular Evaluation for Noncardiac Surgery: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1996 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery). Available at www.acc.orp/clinical/guidelines. 23. Myers, J. Exercise and Cardiovascular Health. Circulation 2003, 107 (1), e2 –e5. 24. Weiner, D.A.; Ryan, T.J.; McCabe, C.H.; et al. Prognostic Importance of a Clinical Profile and Exercise Test in Medically Treated Patients with Coronary Artery Disease. J. Am. Coll. Cardiol. 1984, 3, 772– 779. 25. McPhail, N.; Calvin, J.E.; Shariatmadar, A.; Barber, G.G.; Scobie, T.K. The Use of Preoperative Exercise Testing to Predict Cardiac Complications After Arterial Reconstruction. J. Vasc. Surg. 1988, 7, 60– 68. 26. Shaw, L.J.; Eagle, K.A.; Gersh, B.J.; Miller, D.D. MetaAnalysis of Intravenous Dipyridamole-Thallium-201 Imaging (1985 to 1994) and Dobutamine Echocardiography (1991 to 1994) for Risk Stratification Before Vascular Surgery. J. Am. Coll. Cardiol. 1996, 27, 787– 798. 27. Mangano, D.T.; London, M.J.; Tubau, J.F.; et al. Dipyridamole Thallium-201 Scintigraphy as a Preoperative Screening Test. A Reexamination of Its Predictive Potential. Circulation 1991, 84, 493– 502.

28. Baron, J.F.; Mundler, O.; Bertrand, M.; et al. Dipyridamole-Thallium Scintigraphy and Gated Radionuclide Angiography to Assess Cardiac Risk Before Abdominal Aortic Surgery. N. Engl. J. Med. 1994, 330, 663– 669. 29. Poldermans, D.; Fioretti, P.M.; Forster, T.; et al. Dobutamine Stress Echocardiography for Assessment of Perioperative Cardiac Risk in Patients Undergoing Major Vascular Surgery. Circulation 1993, 87, 1506 –1512. 30. Lane, R.T.; Sawada, S.G.; Segar, D.S.; et al. Dobutamine Stress Echocardiography for Assessment of Cardiac Risk Before Noncardiac Surgery. Am. J. Cardiol. 1991, 68, 976– 977. 31. Eichelberger, J.P.; Schwarz, K.Q.; Black, E.R.; Green, R.M.; Ouriel, K. Predictive Value of Dobutamine Echocardiography Just Before Noncardiac Vascular Surgery. Am. J. Cardiol. 1993, 72, 602– 607. 32. Da´vila-Roma´n, V.G.; Waggoner, A.D.; Sicard, G.A.; Geltman, E.M.; Schechtman, K.B.; Perez, J.E. Dobutamine Stress Echocardiography Predicts Surgical Outcome in Patients With an Aortic Aneurysm and Peripheral Vascular Disease. J. Am. Coll. Cardiol. 1993, 21, 957– 963. 33. Poldermans, D.; Arnese, M.; Fioretti, P.M.; et al. Sustained Prognostic Value of Dobutamine Stress Echocardiography for Late Cardiac Events After Major Noncardiac Vascular Surgery. Circulation 1997, 95, 53–58. 34. Poldermans, D.; Amese, M.; Fioretti, P.M.; et al. Improved Cardiac Risk Stratification in Major Vascular Surgery With Dobutamine-Atropine Stress Echocardiography. J. Am. Coll. Cardiol. 1995, 26, 648– 653. 35. Elmore, J.R.; Hallett, J.W.; Gibbons, R.; et al. Myocardial Revascularization Before Abdominal Aortic Aneurysmorrhaphy: Effect of Coronary Angioplasty. Mayo Clin. Proc. 1991, 68, 713– 715. 36. Huber, K.; Evans, M.A.; Bresnahan, J.; et al. Outcome of Noncardiac Operations in Patients with Severe Coronary Artery Disease Successfully Treated Preoperatively with Coronary Angiography. Mayo Clin. Proc. 1992, 67, 15– 21. 37. Posner, K.; van Morman, G. Adverse Cardiac Outcomes After Noncardiac Surgery in Patients with Prior Percutaneous Transluminal Coronary Angioplasty. Anesth Analog. 1999, 89, 553– 560. 38. van Norman, G.; Posner, K. Coronary Stenting or Percutaneous Transluminal Coronary Angioplasty Prior to Noncardiac Surgery Increases Adverse Perioperative Cardiac Events: The Evidence Is Mounting. J. Am. Coll. Cardiol. 2000, 36, 2351– 2352. 39. Mason, J.J.; Owens, D.K.; Harris, R.A.; et al. The Role of Coronary Angiography and Coronary Revascularization Before Noncardiac Vascular Surgery. J. Am. Med. Assoc. 1995, 273, 1919– 1925. 40. Fleisher, L.A.; Eagle, K.A.; Shaffer, T.; et al. Mortality After Major Vascular Surgery: Analysis of the Medicare Database (Abstr). Anesth Anal. 1997, 84, SC43. 41. Golden MA, Whittemore AD, Donaldson MC, Mannick JA: Selective evaluation and management of coronary artery disease in patients undergoing repair of abdominal aortic aneurysms: A 16 year experience. Ann Surg 1990, 212, 415. 42. Wolf MA, Braunwald E: General anesthesia and noncardiac surgery in patients with heart disease. In Braunwald E (ed): Heart Disease. Philadelphia, Saunders, 1980.

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McDermott, M.M.; Hahn, E.A.; Greenland, P.; et al. Atherosclerotic Risk Factor Reduction in Peripheral Arterial Disease. Results of a National Physician Survey. J. Gen. Intern. Med. 2002, 17, 895– 904. Goldman, L.; Caldera, D.L.; Nussbaum, S.R.; et al. Multifactorial Index of Cardiac Risk in Noncardiac Surgical Procedures. N. Engl. J. Med. 1977, 297, 845. Goldman, L. Cardiac Risks and Complications of Noncardiac Surgery. Ann. Int. Med. 1983, 98, 504. Gregoratos, G.; Abrams, J.; Epstein, A.E.; et al. ACC/ AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/ AHA/NASPE Committee on Pacemaker Implantation. 2002). Available at http:/www.acc.org/clinical/ guidelines. O’Kelly, B.; Browner, W.S.; Massie, B.; Tubau, J.; Ngo, L.; Mangano, D.T. Ventricular Arrhythmia in Patients Undergoing Noncardiac Surgery. The Study of Perioperative Ischemia Research Group. J. Am. Med. Assoc. 1992, 268, 217– 221. Mahla, E.; Rotman, B.; Rehak, P.; et al. Perioperative Dyrrhythmias in Patients with Structural Heart Disease Undergoing Noncardiac Surgery. Anesth Analg. 1998, 86, 16– 21. Lyons, C. Cardiac Arrhythmias as a Predictable Surgical Risk. Surgery 1954, 35, 292. Wolf, M.A.; Braunwald, E. General Anesthesia and NonCardiac Surgery in Patients with Heart Disease. In Heart Disease; Braunwald, E., Ed.; Saunders: Philadelphia, 1980. Skinner, J.F.; Pearce, M.L. Surgical Risk in the Cardiac Patient. J. Chronic. Dis. 1964, 17, 57. Chambers, D.A. Anesthesia for the Patient with Acquired Valvular Heart Disease. In Cardiac Anesthesia; Kaplan, J.A., Ed.; Grune and Stratton: New York, 1979; 197. Raymer, K.; Yang, H. Patients with Aortic Stenosis: Cardiac Complications in Non-Cardiac Surgery. Can. J. Anaesth. 1998, 45, 855– 859. Torsher, L.C.; Shub, C.; Rettke, S.R.; Brown, D.L. Risk of Patients with Severe Aortic Stenosis Undergoing NonCardiac Surgery. Am. J. Cardiol. 1998, 81, 448– 452. ACC/AHA Guidelines for the Management of Patients with Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association. Task Force on Practice Guidelines (Committee on Management of Patients with Valvular Heart Disease). J. Am. Coll. Cardiol. 1998, 32, 1486– 1588. Goldman, L.; Caldera, D.L.; Nussbaum, S.R.; et al. Multifactorial Index of Cardiac Risk in Noncardiac Surgical Procedures. N. Engl. J. Med. 1977, 297, 845– 850. Ashton, C.M.; Petersen, N.J.; Wray, N.P.; et al. The Incidence of Perioperative Myocardial Infarction in Men Undergoing Noncardiac Surgery. Ann. Intern. Med. 1993, 118, 504– 510. Lette, J.; Waters, D.; Bernier, H.; et al. Preoperative and Long-Term Cardiac Risk Assessment: Predictive Value of 23 Clinical Descriptors, 7 Multivariate Scoring Systems, and Quantitative Dipyridamole Imaging in 360 Patients. Ann. Surg. 1992, 216, 192– 204.

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72. Pasternack, P.F.; Imparato, A.M.; Baumann, F.G.; et al. The Hemodynamics of Beta-Blockade in Patients Undergoing Abdominal Aortic Aneurysm Repair. Circulation 1987, 76 (Suppl 3, Pt 2), III-1-7. 73. Yeager, R.A.; Moneta, G.L.; Edwards, J.M.; Taylor, L.M., Jr. McConnell, D.B.; Porter, J.M. Reducing Perioperative Myocardial Infarction Following Vascular Surgery: The Potential Role of Beta-Blockade. Arch. Surg. 1995, 130, 869– 872. 74. Raby, K.E.; Brull, S.J.; Timimi, F.; et al. The Effect of Heart Rate Control on Myocardial Ischemia Among HighRisk Patients After Vascular Surgery. Anesth. Analg. 1999, 88, 477–482. 75. Heart Protection Study Collaborative Group; MRC/BHF Heart Protection Study of Cholesterol Lowering in 20,536 High-Risk Patients: A Randomized, Placebo-Controlled Trial. Lancet 2002, 360 (9326), 23– 33. 76. Antithrombotic Trialists’ Collaboration. Collaborative Meta-Analysis of Randomised Trials of Antiplatelet Therapy for Prevention of Death, Myocardial Infarction, and Stroke in High Risk Patients. BMJ 2002, 321, 71– 86. 77. CAPRIE Steering Committee. A Randomized, Blinded, Trial of Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE). Lancet 1996, 348, 1329 –1339. 78. Yusuf, S.; Zhao, F.; Mehta, S.R.; Chrolavicius, S.; Tognoni, G.; Fox, K.K. The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of Clopidogrel in Addition to Aspirin in Patients with Acute Coronary Syndromes Without ST-Segment Elevation. N. Engl. J. Med. 2001, 345 (7), 494– 502. 79. Steinhubl, S.R.; Berger, P.B.; Mann, J.T., 3rd.; Fry, E.T.; DeLago, A.; Wilmer, C.; Topo1, E.J. CREDO Investigators. Clopidogrel for the Reduction of Events During Observation. Early and Sustained Dual Oral Antiplatelet Therapy Following Percutaneous Coronary Intervention: A Randomized Controlled Trial. J. Am. Med. Assoc. 2002, 288, 2411– 2420.

80. Isaacson, I.J.; Lowdon, J.D.; Berry, A.J.; et al. The Value of Pulmonary Artery and Central Venous Monitoring in Patients Undergoing Abdominal Aortic Reconstructive Surgery: A Comparative Study of Two Selected, Randomized Groups. J. Vasc. Surg. 1990, 12, 754– 760. 81. Joyce, W.P.; Provan, J.L.; Ameli, F.M.; McEwan, M.M.; Jelenich, S.; Jones, D.P. The Role of Central Haemodynamic Monitoring in Abdominal Aortic Surgery: A Prospective Randomised Study. Eur. J. Vasc. Surg. 1990, 4, 633– 636. 82. Ziegler, D.W.; Wright, J.G.; Choban, P.S.; Flancbaum, L. A Prospective Randomized Trial of Preoperative “Optimization” of Cardiac Function in Patients Undergoing Elective Peripheral Vascular Surgery. Surgery 1997, 122, 584– 592. 83. Bender, J.S.; Smith-Meek, M.A.; Jones, C.E. Routine Pulmonary Artery Catheterization Does Not Reduce Morbidity and Mortality of Elective Vascular Surgery: Results of a Prospective, Randomized Trial. Ann. Surg. 1997, 226, 229– 236. 84. Valentine, R.J.; Duke, M.L.; Inman, M.H.; et al. Effectiveness of Pulmonary Artery Catheters in Aortic Surgery: A Randomized Trial. J. Vasc. Surg. 1998, 27, 203– 211. 85. Berlauk, J.F.; Abrams, J.H.; Gilmour, I.J.; O’Connor, S.R.; Knighton, D.R.; Cerra, F.B. Preoperative Optimization of Cardiovascular Hemodynamics Improves Outcome in Peripheral Vascular Surgery: A Prospective, Randomized Clinical Trial. Ann. Surg. 1991, 214, 289– 297. 86. Polanczyk, C.A.; Marcantonio, E.; Goldman, L.; et al. Impact of Age on Perioperative Complications and Length of Stay in Patients Undergoing Noncardiac Surgery. Ann. Intern. Med. 2001, 134, 637– 643. 87. Sandham, J.D.; Hull, R.D.; Brant, R.F.; et al. A Randomized, Controlled Trial of the Use of PulmonaryArtery Catheter in High-Risk Surgical Patients. N. Engl. J. Med. 2003, 348, 5 – 14. 88. Practice Guidelines for Pulmonary Artery Catheterization: A Report by the American Society of Anesthesiologists Task Force on Pulmonary Artery Catheterization. Anesthesiology 1993; 78, 380– 394.

CHAPTER 22

The Biology of Restenosis and Neointimal Hyperplasia Robert A. Larson Michael A. Golden disease. Balloon angioplasty is a common procedure used to treat the stenoses caused by atherosclerotic lesions in both the heart and periphery. Unfortunately, approximately 30 –60% of patients undergoing coronary angioplasty will develop restenosis due in large part to neointimal encroachment on the luminal area (Fig. 22-1).[4,5] Neointimal hyperplasia is also the leading cause of vein graft failure 3 months to 2 years after bypass surgery.[6 – 8] The failure rate for lower extremity vein grafts averages 20–30% in long-term follow-up.[9] The problem of neointimal hyperplasia is even worse with prosthetic grafts. Restenosis is also seen after surgical endarterectomy. As many as 20% of patients undergoing carotid endarterectomy will develop a hemodynamically significant neointimal lesion.[10] Fortunately, few of these become symptomatic. The impact of restenosis on society is significant in terms of the associated morbidity, mortality, and cost to the health care system. It is not surprising, therefore, that a great deal of research effort has been directed towards understanding and controlling this process.

INTRODUCTION Definition Since the first vascular anastamoses were constructed by Carrel,[1] it has been known that injured arteries respond with a pathologic healing process that can lead to luminal narrowing. The advances in vascular surgery and endovascular techniques over the past half century have greatly expanded the number of arterial lesions that can be treated. Unfortunately, the occurrence of restenosis is still one of the most important factors preventing acceptable long-term patency. The term neointima is used to describe the pathologic intima that forms in response to vessel wall injury.[2] The physiologic response to injury, which produces the neointima, is loosely called neointimal hyperplasia. This process is not a hyperplasia in the strict sense since it is comprised of varying degrees of cellular proliferation, cellular hypertrophy, and extracellular matrix deposition. Neointimal hyperplasia presumably represents an attempt to heal the injured arterial wall and is analogous to wound-healing responses in other areas of the body. Restenosis is the narrowing or occlusion of a vessel that was previously stenotic and has undergone a therapeutic procedure to open it. This term is often inappropriately used when a stenosis develops after the injury of a normal artery in an animal model. The mechanisms that control neointimal hyperplasia are redundant and involve the participation of multiple players, including numerous cell types, growth factors, and hormones. This complexity has likely contributed to the generally poor results in human clinical trials based on data derived from successful animal experiments.[3]

EMBRYOLOGY/HISTOLOGY The arterial wall is comprised of three concentric layers of cells and connective tissue (Fig. 22-2). The innermost layer is the intima, which is formed by a thin layer of endothelial cells on the basement membrane, a variable amount of subendothelial connective tissue, and the internal elastic lamina. There can be smooth muscle cells in the intima in humans and primates, but they are generally not present in rats and mice. The neointima that forms after injury is found inside the internal elastic lamina. Between the internal and external elastic laminae is the arterial media. This layer is made up of smooth-muscle cells (SMCs) and extracellular matrix made up of primarily elastin and collagen. The exact composition of the media depends on the size and location of the artery. Arterioles responsible for

Clinical Significance Atherosclerosis is the leading cause of morbidity and mortality in the western world. Consequently, a large number of procedures have been devised to treat the effects of this

Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024905 Copyright q 2004 by Marcel Dekker, Inc.

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Figure 22-1. Thrombosed coronary artery with IH after PTCA. N ¼ Neointima; T ¼ Thrombus; IH ¼ Intimal Hyperplasia; PTCA ¼ Percutaneous Transluminal Coronary Angioplasty. Figure 22-2. Arterial wall histology. (From David Low, M.D.)

the control of systemic vascular resistance have relatively more SMCs than larger arteries like the aorta. The outer layer of the arterial wall is the adventitia. This layer is primarily made up of loose connective tissue, some SMCs, and fibroblasts. The adventitia is supplied with tiny blood vessels of its own, vasa vasorum, which also nourish the outer layers of the media. At birth, the intima of human arteries consists solely of endothelial cells lining the internal elastic lamina.[11] Two notable exceptions include the ductus arteriosus and the origin of the left main coronary artery, which have SMCs in the intima at this time.[12] In the first few years of life, however, SMCs begin to appear in the space between the endothelial cells and the internal elastic lamina in the aorta and other large muscular arteries. The areas of SMC accumulation are called intimal cushions; these represent areas prone to future development of atherosclerotic plaques.

INJURY RESPONSE Models In order to study the underlying mechanisms of neointimal hyperplasia, models of arterial injury have been developed in animals that allow for controlled environments and less complex injury responses. The rat has been the most widely used model of arterial injury and has provided many insights into the pathophysiology of neointimal hyperplasia. The rat carotid artery is a relatively simple artery, comprised of a single layer of endothelium lining the internal elastic lamina.[13] For experimental purposes, it has fairly easy access via the external carotid artery, and the common carotid artery is devoid of branches, limiting the origin of reendothelialization to the proximal and distal artery. The response of the rat carotid to injury has been studied closely and occurs without an inflammatory response or fibrin deposition (Fig. 22-3).[14,15] The simplicity of this model allows for a close examination of the basic mechanisms of the response to injury, but it may not be directly applicable

to the much more complex environment of an injured atherosclerotic human artery. Mouse models have been very useful in helping to determine the roles played by several mediators of the neointimal response. The use of transgenic and knockout mice has been helpful in determining the roles that specific mediators play in the injury response, including basic fibroblast growth factor (bFGF, or FGF-2)[16] and plasminogen activators.[17] It is, however, technically more challenging to use a mouse model due to the size of the arteries. Several methods, such as external electrocautery,[18] have been devised to provide an easier and more reproducible method of arterial injury. The degree to which these methods of injury model a physiologically relevant response, however, is debatable. Rabbits reliably develop hypercholesterolemia when fed a diet high in cholesterol. These animals provide a way to study the arterial response to injury in a physiologic milieu more complex than the rat and more closely approximating human disease. Pig models of balloon angioplasty are widely used to study the effects of coronary angioplasty and stenting. The pig responds to arterial injury with a thrombotic process similar to that seen in humans. They also develop arterial wall calcifications akin to those in human disease. This model is frequently used to study new endovascular techniques and devices. Primate models provide the model closest to human atherosclerosis and arterial response to injury. They have been used extensively to study the natural history of prosthetic grafts in vivo because both the size of the arteries and hemodynamic parameters are comparable to those in humans.[19] A neointimal injury response can be induced by a number of methods. The most commonly used method is the balloon catheter technique: the catheter is inserted into the artery, the balloon inflated, and the catheter withdrawn, with or without twisting. Other methods of injury include using a small guide wire to denude the artery, electrocoagulating the exterior of

Chapter 22. The Biology of Restenosis and Neointimal Hyperplasia

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Figure 22-3. Photomicrograph of rat carotid before and 2 weeks after balloon injury. M ¼ Media; A ¼ Adventitia; N ¼ Neointima; IEL ¼ Internal Elastic Lamina; EEL ¼ External Elastic Lamina.

the artery, distal ligation of the artery, placement of periadventitial bands, and local application of noxious chemicals. There are also vein graft models in mice, rats, and rabbits. Each method has strengths and weaknesses as a model of the neointimal response in humans. Each of the injury methods produces a different set of responses, including varying degrees of endothelial damage, medial damage, thrombosis, and flow modification. By carefully choosing the animal model (with specific genetic and metabolic characteristics, such as hyperlipidemia) and the method of injury, one can focus the experiment on a specific vascular wall process or a particular aspect of the injury response.

Cellular Response to Injury Endothelium The endothelium is an important regulator of many vessel activities, including vasomotor tone and thrombosis. It also plays a central role in the regulation of smooth-muscle cell function.[20] A baseline antiproliferative effect is exerted on the SMCs by secreted prostacyclin,[20] heparan sulfate,[21] and nitric oxide.[22] The endothelium is also a natural barrier to platelet adherence, thus preventing platelet activation, a process that results in the release of several growth factors important in the neointimal response. After experimental vascular injury, reendothelialization begins within 24 hours, starting from the leading edge of the denuded area and the ostea of branch arteries.[23] It has been shown that after mild injury, consisting of a gentle endothelial denudation, complete reendothelialization can occur.[24] However, after more severe injury involving disruption of the basement membrane and the deeper layers of the media, endothelial dysfunction persists even if the regrowth is complete.[24,25] After vascular injury and endothelial regrowth, vasodilators which work via an endotheliumdependent mechanism show a decreased effect, while the ability of the underlying SMCs to relax or contract is unchanged. This may be due to decreased levels of nitric oxide (NO) synthesis in the endothelial cells.[26] As mentioned above, the endothelium exerts an antiproliferative effect on the underlying SMCs. In fact, areas of injured artery that are covered by endothelial regrowth exhibit

less neointimal hyperplasia than areas that remain bare. Animal studies using vascular endothelial growth factor (VEGF) to stimulate endothelial regrowth have shown accelerated re-endothelialization and reduced neointimal thickening in injured arteries.[27,28]

Platelets Vascular injury and endothelial cell loss exposes the underlying basement membrane and arterial media. Without the inhibitory effect of the endothelium, platelets adhere to the denuded vascular wall and become activated. Stimulated platelets degranulate, releasing several factors, including platelet-derived growth factor (PDGF) and transforming growth factor-b (TGF-b),[29] as well as thromboxane A2, a potent platelet chemoattractant. As mentioned below, PDGF is an important factor in initiating migration of SMCs from the media to the intima.

Smooth-Muscle Cells The mass of a vessel wall is comprised largely of SMCs and the associated matrix. The luminal narrowing associated with neointimal hyperplasia is primarily due to the overabundance of SMCs and their secreted matrix. Consequently, a great deal of attention has been focused on the role of the SMC in the arterial response to injury. One of the key events in the development of a neointima is the activation of normally quiescent medial SMCs. The activation of medial SMCs occurs soon after injury and is mediated by hormones, growth factors, and mechanical factors (see Fig. 22-4). One of

Figure 22-4.

Mediators and sequence of SMC activation.

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the earliest indicators of SMC activation is the expression of proto-oncogenes (e.g., c-myc, c-myb, c-jun, and c-fos) which are associated with the events proceeding DNA replication. These have been detected as early as 30 minutes after injury.[30] Indeed, prevention of proto-oncogene expression using antisense oligonucleotides has reduced the neointimal response in animal models.[31] The first consequence of SMC activation is proliferation. Under normal circumstances, there is very little turnover in the SMC population, only 0.06% per day in the adult rat.[15] In response to hypertension[32] or direct injury,[15] however, there is a dramatic increase in the proliferation rate of medial SMCs. This is followed by the migration of SMCs to the intima and the deposition of extracellular matrix. Studies of the response of the rat carotid artery to balloon injury have lead to the division of the SMC response into three phases. This response is characterized by the reactions of the medial smooth-muscle cells.

Medial SMC Proliferation The first wave consists of a burst of medial smooth-muscle cell proliferation that is evident 24 hours after injury, peaks within 4 days, and subsides by 10–14 days.[15] At the peak, between 20 and 40% of the SMC population can become activated.[33] The primary mitogen during this phase is bFGF, which is released by dead and injured SMCs.[34] The loss of endothelial nitric oxide synthesis also plays a role in the initial wave of SMC proliferation. This phase is not dependent on the presence of platelets, as shown in experiments using thrombocytopenic animals.[35] Consequently, PDGF does not seem to play a major role in the initiation of proliferation after injury.

SMC Migration The second wave involves migration of the medial SMCs to the intima. This process, unlike the first phase, is strongly affected by platelets[35] and PDGF.[36,37] The SMCs can be seen on the luminal side of the internal elastic lamina by 4 days after injury.

Proliferation of SMCs in Intima The third wave consists of the continuing proliferation of the intimal smooth-muscle cells, which can persist for several weeks after injury. This continued proliferation is highest at the luminal surface of the lesion.[38] The control of this process is poorly understood, but it is important due to the intimal mass added to the lesion during this time.[13] The deposition of extracellular matrix (ECM) is also important during this phase and adds to the bulk of the neointima.

Inflammation Inflammatory cells are important contributors to the development of atherosclerotic lesions, but their function in the arterial response to injury is less clear. Leukocytes adhere to the denuded arterial wall after balloon injury. Indeed, several inflammatory cell chemoattractants are released by injured SMCs and activated platelets.

Mediators Growth Factors The importance of growth factors to the arterial response to injury cannot be understated. One of the most closely studied of these is basic fibroblast growth factor (bFGF).[34,39] This 18 kDa protein is a member of the heparin-binding growth factor family and is a potent SMC and endothelial cell mitogen. It is located within preformed granules in the quiescent medial smooth-muscle cell and does not contain a secretory domain. Its action, therefore, depends on its release from injured or dead SMCs into the extracellular matrix. At the time of SMC injury, bFGF is released and stimulates the initial phase of SMC proliferation. If antibodies to bFGF are given at the time of injury, the initial wave of SMC proliferation is reduced by 80%, but the final degree of neointimal thickening is not affected.[34] This is due in part to the ongoing production of bFGF in the activated SMCs and to the presence of other mediators that stimulate neointimal thickening. Platelet-derived growth factor is another important regulator of the arterial response to injury. It is a basic dimeric protein with a molecular weight of about 30 kDa, with the two isoforms of the monomers being PDGF-A and PDGF-B. It is present in the a-granules of platelets, primarily as PDGF-AB, and is released during degranulation. PDGF can also be expressed by several other cell types, including endothelium, SMCs,[40] and leukocytes. As mentioned before, PDGF does not significantly induce replication among medial SMCs in vivo, but is a potent factor in stimulating their migration to the intima.[36] In vitro, however, it does have some mitogenic effect. TGF-b is a potent stimulator of SMC collagen production and matrix deposition. In vitro, TGF has antiproliferative effects on SMCs that vary with the growth rate.[41] In rat carotid injury models, however, antibodies to TGF-b given at the time of injury reduce neointimal formation.[42] Nitric oxide, a molecule central to the regulation of vascular tone, is also an important regulator of medial SMC activation and neointimal formation after injury. NO has been found to be a potent inhibitor of SMC proliferation and migration.[43] In animal studies, adenoviral gene transfer of nitric oxide synthase (NOS) to injured arteries reduced the subsequent neointimal hyperplasia.[44,45]

Increased Response of SMCs to Mitogens Some investigators have proposed the addition of a fourth phase in SMC response. It has been shown that proliferating intimal SMCs in a previously injured artery have an increased responsiveness to restimulation with mitogens. Again, the mediation of this response is poorly understood.

Hormonal Factors The renin-angiotensin system, long known to be important in the pathogenesis of hypertension, has also been found to play a role in the neointimal response.[46] In the classic description of this system, the juxtaglomerular apparatus in

Chapter 22. The Biology of Restenosis and Neointimal Hyperplasia

the kidney produces renin in response to hemodynamic and electrolyte stimuli. Circulating renin then cleaves angiotensinogen (produced by the liver) to produce angiotensin I, which is physiologically inactive. Circulating angiotensin I is then cleaved to produce angiotensin II by the angiotensinconverting enzyme (ACE), which is expressed on endothelial cells throughout the body, especially in the lungs. Angiotensin II is a potent vasoconstrictor and is the mediator of the neointimal response. This classic description has been expanded by the observation that rennin[47] and angiotensinogen[48] are produced in vascular endothelial and smoothmuscle cells. Thus, with the ACE present, the complete system is contained within the vascular wall. The significance of this tissue renin-angiotensin system is still unclear. The exact mechanism underlying the effect of angiotensin II on neointimal hyperplasia is not known, but it is believed to stimulate the production of other growth factors, such as PDGF, and mitogens, including the proto-oncogenes c-fos, cjun, and c-myc. Angiotensin II has been shown to be a potent mitogen of SMCs in vitro[49] and in vivo.[46] Additionally, angiotensinogen gene expression is increased in arterial wall after injury, providing a higher concentration of substrate for local ACE.[50] ACE inhibitors such as captopril and enalapril block the conversion of angiotensin I to angiotensin II. The use of ACE inhibitors has been shown to reduce the amount of neointimal hyperplasia in a dose-dependent fashion in the rat model of arterial injury.[51] This response has also been shown in the rabbit model.[52] In addition, treatment with ACE inhibitors was shown to reduce the biosynthesis of PDGF-AB[53] and bFGF[54] in the arterial wall after injury. These results were promising and led to the study of the effects of ACE inhibitors in higher animals. Unfortunately, experiments using baboons were not able to replicate the beneficial effects seen in rodents.[55] Likewise, clinical trials in humans have failed to show any ability to prevent restenosis,[3] although medication doses for humans were less aggressive than those for the experimental animals. In addition to blocking the production of angiotensin II, investigators have studied the effects of blocking the angiotensin receptor. Angiotensin II receptors have been classified into two types, AT1 and AT2. The AT1 receptor mediates vasoconstriction and is the predominant type on SMCs. It has been shown that neointimal tissue possesses up to four times the number of AT1 receptors compared to the normal arterial wall, perhaps augmenting the responsiveness of the neointima to angiotensin II stimulation.[56] In the rat model, blockade of the AT1 receptor was shown to reduce neointima formation after balloon arterial injury. The receptor blockade was also shown to suppress several cell-proliferation proto-oncogenes, which likely contributed to the histologic effect.[57,58]

Mechanical Factors The pressure and high-flow environment of the arterial system produces stresses that the normal arterial wall must support. These forces can influence the development of a pathologic neointima after arterial injury and play an especially important role in vein and prosthetic grafts (see below).

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As discussed in detail below, subjecting a vein graft to arterial pressures results in repetitive stretch injuries that can lead to wall thickening. Also, grafts with lower blood velocities, and subsequently lower shear stress, have a more pronounced neointimal response.[59] Both endothelial cells and smooth-muscle cells have been shown to respond to changes in shear forces. Changes in the shear force can also affect an existing neointima. Experiments in baboons using PTFE grafts have shown that the thick neointima that forms in a low shear stress graft can be reduced by converting it to a high flow/shear stress fistula.[19] The loss in neointimal mass is represented by both decreased SMC and matrix content. The converse is also observed in the laboratory.

Extracellular Matrix In the injured rat artery, up to 80% of the intimal mass consists of matrix,[60] which is produced for up to 3 months after injury.[15] The matrix is a complex set of proteins secreted by activated SMCs and includes collagen type I, elastin, osteopontin, and proteoglycans.[61,62] Not only does the matrix provide a scaffold for the SMCs of the neointima, it also helps to facilitate the migration of activated SMCs by interacting with specific integrin receptors expressed by these cells.[63] In order for the medial SMCs to migrate to the neointima, they must be able to digest the surrounding matrix. Several proteases are activated by arterial injury and are important to neointimal formation. Both plasminogen activators[64] and matrix metalloproteinases (MMP)[65] have been shown to increase after injury in animal models. Both urokinase and tissue type plasminogen activators are stimulated by arterial injury and remain activated for about 2 weeks. The proteolytic enzymes MMP2 and MMP9 have been shown to be important in the SMC migration process after arterial injury.[65] In fact, the use of an MMP inhibitor prevents SMC migration.[66] It has also been shown that knockout mice deficient in the urokinase plasminogen activator (uPA) show a delayed and reduced neointimal response after arterial injury.[67] In addition to the structural importance of the matrix, it also functions as a repository for growth factors, especially bFGF. As SMCs die, they release bFGF into the surrounding matrix, where it adheres to the heparan sulfate proteoglycans.[68] As the matrix is degraded by proteases, the bound bFGF is released and can stimulate adjacent SMCs.

Thrombosis In animal models more complex than the rat, thrombosis appears to play a key role in the restenosis process. This is well established in porcine stent models.[69] Thrombin stimulates SMC proliferation in vitro,[70] and antibodies against the thrombin receptor reduce injury-induced neointimal thickening in vivo.[71]

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ATHEROSCLEROSIS AND HUMAN ANGIOPLASTY The pathophysiology of restenosis in a human atherosclerotic artery is probably more complex than the arterial response to injury in animal models, and may in fact represent a different process. Three mechanisms are known to be responsible for the failure of angioplasties in humans. First, there is elastic recoil of the artery, which occurs shortly after the procedure. Second, there is remodeling of the artery, which results in the change of the total vessel area. Third, there is intimal thickening. The relative contribution of these three processes determines the degree of restenosis that occurs.[72] Elastic recoil has been dealt with recently by the use of endovascular stents, thus leaving remodeling and neointimal hyperplasia as the main areas of interest. Human vessels can compensate for increased luminal mass by dilation and remodeling.[73] Vessels can maintain constant levels of blood flow until the lesion mass exceeds about 40% of the area encompassed by the internal elastic lamina. Indeed, in the hypercholesterolemic rabbit model it has been shown that compensatory enlargement occurs after experimental angioplasty, compensating for about 60% of the luminal area lost to neointimal hyperplasia. [74] The mechanisms underlying the remodeling process are not well understood, but possibly include responses to increased flow and wall stress resulting in altered extracellular matrix metabolism.[73] It appears that the endothelium plays a role in the remodeling process, likely regulated by the response to changes in shear stress.[75] In the absence of functional endothelium, or with dysfunctional regenerated endothelium, the compensatory enlargement is prevented. Constriction of the artery after injury also occurs and can greatly increase the restenotic process. Chronic inflammation has been found to occur in injured arteries.[76] Increased expression of TGF-b and tissue inhibitors of metalloproteinases (TIMP) may cause an increase in matrix deposition and a decrease in matrix digestion, resulting in the inability to remodel outwardly. The process of intimal thickening in human lesions differs from that in animal models. Human atherosclerotic lesions, unlike the uninjured rat carotid artery, are already populated with SMCs.[2] In addition, there is some evidence to suggest that smooth-muscle replication may not be as important a factor in human restenosis as in experimental models.[77] Since most of the experimental models use initially normal vessels, the process of stenosis that occurs after injury may be vastly different from that of an initially atherosclerotic and stenotic artery.

The development of neointimal hyperplasia in the vein graft is similar to that which develops after angioplasty; it is an injury response consisting of SMC proliferation and matrix deposition that is modulated by several growth factors. The difference, however, is that the injury response in vein grafts is initially one of healthy adaptation, which in some grafts progresses to a pathologic state (Fig. 22-5). The insertion of a vein into the high-pressure, high-flow environment of the arterial system subjects the vein to stresses to which it is not accustomed. The adaptation of a vein to the arterial system involves the thickening of its wall. This process is driven by the repetitive injury caused by the arterial pressures. Other factors also contribute to graft injury early on, including rough handling during harvest, hypotonic irrigation fluids, and overzealous distention.[78] The thickening of the vein wall serves to reduce the tangential stress applied to it by arterial pressures. According to LaPlace’s law, the tangential stress (t) in the wall of a sphere is proportional to the pressure (P) and the radius (r), and inversely proportional to the wall thickness (d): t ¼ Pr=d Thus, by increasing the wall thickness the stress in the wall is reduced. In an experimental rabbit model, reducing the stress exerted on a vein graft by placing a rigid cuff around the graft was shown to decrease the intimal thickening.[79] The shear stress (s), exerted longitudinally on the vessel wall, is a function of the blood flow (Q), vessel radius (r), and blood viscosity (h). Assuming laminar flow: s ¼ 4hQ=pr3

NEOINTIMAL HYPERPLASIA IN VEIN BYPASS GRAFTS The use of autologous vein for the bypass of arterial lesions is a staple of cardiac and peripheral vascular surgery. One of the main factors contributing to the failure of these grafts after one year is stenosis due to neointimal thickening.

Figure 22-5. anastamosis.

Angiogram of stenosis at SFA-RSVG

Chapter 22. The Biology of Restenosis and Neointimal Hyperplasia

With the high flow rate of the arterial system, the shear stress is increased in vein grafts and is important in the regulation of neointimal hyperplasia. It is well known that high flow grafts develop less intimal thickening than low-flow systems.[80] One hypothesis for this phenomenon is that in high-flow systems it is more difficult for bloodborne elements to adhere to the vessel wall. Adherent platelets and leukocytes secrete growth factors that can stimulate SMC proliferation and matrix deposition. It has also been shown that increased shear stress induces endothelial cells to produce nitric oxide,[81] a potent inhibitor of SMC proliferation. Shear stress is probably more important in the development of neointimal thickening in prosthetic grafts, as described below. The kinetics of the adaptation of a vein graft to the arterial environment has been studied in the rabbit model.[82] Early events include platelet aggregation and microthrombi at areas of endothelial denudation around the anastamoses. By two weeks, the denuded areas have been reendothelialized and the vein wall starts to thicken. For the first 4 weeks, proliferating SMCs provide the bulk of the neointima, followed by the progressive deposition of ECM. This process reaches a maximum at 12 weeks, by which time the ratio of wall thickness to vessel diameter is the same in the vein graft as in the artery. At this point, the wall tension in the vein graft is equal to that of the artery. Unlike neointimal hyperplasia that occurs after the angioplasty of an atherosclerotic lesion, the SMC proliferation that occurs in the vein graft takes place under an intact endothelium. Clearly, the normally antiproliferative influences of the endothelium seen in the arterial system are not present in the vein graft. It has been shown that vein graft endothelium produces less nitric oxide,[83] a potent SMC proliferation inhibitor. Restoration of nitric oxide to the vein graft reduces neointimal hyperplasia.[84,85] Stenoses are frequently seen at the anastamoses of vein grafts. The turbulent flow and compliance mismatch between the vein and artery produce additional stresses that cause local endothelial disruption and persistent intimal proliferation.[80,86] In fact, the geometry of the anastamosis may contribute to the development of neointimal hyperplasia. Biomechanical analyses have shown that the suture line stress generated by compliance mismatch is greater in end-to-side anastamoses compared to end-to-end.[87] It has also been shown that the shear stress at an anastamosis is dependent on the angle of the anastamosis, with larger angles producing more shear stress.[88,89]

NEOINTIMAL HYPERPLASIA IN PROSTHETIC BYPASS GRAFTS Prosthetic grafts are used frequently for the replacement of large arteries and when autogenous vein is not available for arterial reconstruction. Neointimal hyperplasia also develops in these grafts and is a significant contributor to their decreased long-term patency. In experimental animal models, porous grafts, such as ePTFE, become lined with a neointima made of smoothmuscle and endothelial cells. The cells populate the graft from

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capillary ingrowth through the 60 mm pores in the graft and from the arterial anastamoses.[90] Endothelialization is complete by 3 weeks, but the SMCs continue to proliferate and deposit matrix for several months.[91,92] The neointima in the prosthetic graft is quite active biologically and produces several growth factors that stimulate SMC proliferation,[93,94] including PDGF[95] and TGF-b.[94] As in vein grafts, the stresses induced by the arterial system play a central role in the development of prosthetic graft neointimal thickening. Unlike vein grafts, however, the prosthetic grafts are rigid and can support the tangential stress easily. The neointima responds primarily to the shear stress caused by the flowing arterial blood. This has been studied extensively in baboon models, where high-flow grafts were found to have less neointimal hyperplasia than normal-flow grafts.[96] It has also been shown that exposing a graft with a mature neointima to high-flow conditions (by creating a distal arterio-venous fistula) can cause the regression of the neointima.[19] Closure of the AV fistula results in an increase in neointimal thickness. As in vein grafts, it has been postulated that shear stress induces the production of nitric oxide, which has a static effect on SMCs. Indeed, nitric oxide synthase was shown to be induced in the neointima of highflow grafts.[19] Compliance mismatch between graft and artery is a greater concern when a stiff prosthetic graft is used. A Dacron graft in the end-to-side configuration was shown to have a 40% greater suture line strain than an autologous graft.[87] The geometry of the anastamosis also plays an important role. In the end-to-end position the Dacron graft was associated with only a 5% increase in suture line stress compared to an arterial graft.[87] The combination of decreased flow velocities (and thus shear force) and increased suture line stress of prosthetic grafts likely contributes to the poor performance of belowknee prosthetic bypass grafts compared to autologous vein grafts. A great deal of effort is being directed towards finding ways to increase the long-term patency of these grafts as more patients present for distal bypass without adequate autologous conduit.

RESTENOSIS AFTER ENDARTERECTOMY Since its introduction by Dos Santos[97] in 1947, the technique of endarterectomy has been an important part of vascular surgery. A natural cleavage plane tends to develop in the outer region of the media in older, atherosclerotic arteries. The careful dissection of this cleavage plane allows for the removal of the diseased intima and inner media. The result is a relatively clean surface comprised of SMCs and extracellular matrix. Endarterectomy has been used in almost every part of the vascular system with variable success. The limiting factor is generally restenosis due to neointimal hyperplasia. Results for long-term patency of endarterectomized arteries varies by location (see Table 22-1), with more proximal arteries having better results. The carotid artery system is a special case.

332 Table 22-1.

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Patency (%) After Endarterectomy 1 year

Aorto-lliac[138] CFA[139] SFA[140] CCAa

2 years 94

95 78

73 89– 93[141]

3 years 5 years 7 years 90 85 70

90 82 35 – 71 79[10]

CFA, common femoral artery; SFA, superficial femoral artery; CCA, common carotid artery. a For carotid artery, data represent patients with ,50% stenosis.

Recurrent restenosis to greater than 50% of luminal diameter develops in 16 –22% of patients.[10] It generally develops within the first year and becomes stable thereafter; about 10% of lesions will eventually regress.[10] These lesions are quite different from the atherosclerotic lesions seen in primary operations. The neointima is smooth, white, and rarely ulcerates. In addition, they do not frequently produce symptoms, with only 3–4% of patients suffering recurrent transient ischemic events or strokes.[10] Recurrent atherosclerotic stenosis usually takes many years to develop, making control of atherosclerosis risk factors critically important. The etiology of neointimal hyperplasia after endarterectomy is similar to that seen in other forms of arterial injury. Smooth-muscle cells become activated, proliferate, and produce extracellular matrix. The basic mechanisms have not been as clearly defined as in the angioplasty model, but strong parallels are evident. The endothelium is removed by the procedure, and the loss of the endothelial inhibition on Table 22-2.

SMCs likely contributes to the process. The endarterectomized artery is quite thrombogenic, and the exposed media provides a rich scaffold for platelet adhesion and activation. Growth factors are also important in the development of the neointima. Infusing bFGF locally to endarterectomized carotid arteries in a canine model has been shown to increase the degree of neointimal thickening by 72% and increase the SMC proliferation rate by 73%.[98] The inflammatory response likely also plays a role. Administration of an antibody to block very late antigen-4 (VLA-4), which is important to monocyte adhesion and migration, has been shown to reduce neointimal hyperplasia in a primate carotid endarterectomy model.[99] Mechanical stresses have also been implicated in the development of neointimal hyperplasia. Patients who were found to have residual flow disturbances by duplex scanning after carotid endarterectomy were found to have a 22% incidence restenosis compared to 9% in patients without residual flow defects.[100]

PREVENTIVE STRATEGIES Numerous attempts have been made to use the results of animal experiments to help reduce restenosis in humans. Unfortunately, these trials have been largely unsuccessful. Most of the studies have attempted to limit restenosis by controlling thrombosis, SMC proliferation, inflammatory reactions, and lipid regulation in the setting of Percutaneous Transluminal Coronary Angioplasty (PTCA). Table 22-2 lists the results of trials that have attempted to reduce restenosis pharmacologically. Selected examples are discussed in detail.

Prospective Agents to Inhibit the Formation of Neointimal Hyperplasia Animal models

Class Platelet inhibitors Anticoagulants

PGDF receptor antagonist Thromboxane A2 antagonist Calcium channel blocker ACE inhibitora

HMA CoA reductase inhibitor Corticosteroid

Drug Aspirin Dipyridamole LMWH Heparin Hirudin Warfarin Trapidil Vapiprost Diltiazem Nifedipine Cilazapril Enalapril Lovastatin Dexamethasone Predinisolone

Species

Artery

Injury

Result

Rat[142] Rabbit[144] Rabbit[127] Rat[33] Pig[146] Rabbit (HL)[147] Rabbit[149] Rat[151] Rat[153] Rabbit[155] Rat[157] Rat[159] Primate[55] Rabbit[52] Pig[160] Rabbit (NL)[114] Pig[161] Rabbit[163]

Carotid Ear Illiac Carotid Coronary Femoral Carotid Aorta Aorta Carotid Aorta Carotid Carotid Carotid Coronary Carotid Carotid Ear

Balloon denudation Crush Balloon angioplasty Balloon angioplasty Angioplasty/stent Balloon angioplasty Air desiccation Balloon angioplasty Balloon denudation Collar Balloon denudation Balloon denudation Endarterectomy Balloon denudation Angioplasty/stent Collar Angioplasty/stent Crush

# # # # N/E # # # # # # # N/E # # # N/E #

N/E = no effect; +/ 2 = limited effect; # = decreased restenosis; NL = normolipidemic; HL = hyperlipidemic. a Despite the efficacy of ACE inhibitors in lower animals, no effect was seen in the primate model. Source: De Meyer.[164]

Human PTCA restenosis N/E[143] N/E[145] N/E[107,109] N/E[105] +/ 2 [148] N/E[150] # [152] N/E[154] N/E[156] N/E[158] N/E[3,110]

N/E[116] N/E[162]

Chapter 22. The Biology of Restenosis and Neointimal Hyperplasia

Heparin Heparin has long been known to reduce the amount of neointimal hyperplasia in animals.[101] Thrombosis is an important event in the development of restenosis in humans and in larger animal models, but not in the rat model. Heparin is a potent anticoagulant, but its ability to reduce neointimal hyperplasia is not due entirely to its anticoagulant properties. Heparin reduces the intensity of the first phase of SMC activation, i.e., proliferation and the start of SMC migration to the intima. If heparin therapy is initiated more than 4 days after the experimental injury, there is no effect on neointimal hyperplasia. The inhibition of SMC activation is due, at least partly, to the ability of heparin to bind a range of growth factors, collectively called the heparin-binding growth factors. The most important of these growth factors is bFGF, which has already been shown to be a key regulator of early SMC activation. This ability of heparin to bind certain growth factors is not related to its antithrombotic effects. In fact, several heparin analogs have been developed which also bind growth factors avidly,[102] yet have no antithrombotic effects. These compounds have also been shown to reduce neointimal hyperplasia.[103] Heparin also has been shown to prevent SMC activation by other pathways, such as inhibition of mitogen-activated protein kinase (MAPK) activation,[104] which is important in the cell response to thrombin and angiotensin II stimulation. The usefulness of heparin in reducing restenosis in humans is unproven.[105] The anticoagulant effects of heparin limit the dosage and duration of therapy that can be used in human trials; bleeding is a significant concern. The doses of heparin and length of therapy that successfully reduce neointimal hyperplasia in animal models are generally not safe to use in humans. Low molecular weight heparin (LMWH) has also been used to try to prevent neointimal hyperplasia. Because of easier dosing and administration and a lower risk of severe bleeding complications compared to unfractionated heparin, LMWH would be a better choice in human trials. Indeed, studies have shown a reduction in neointimal hyperplasia in rabbits treated with LMWH.[106] Unfortunately, human trials have not been able to match these results, even when therapy is started before treatment and continued for several weeks afterwards.[107 – 109]

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degradation by ACE inhibitors may contribute to the effect on neointimal hyperplasia.[112] Differences between human and rodent metabolism of bradykinin may contribute to the different outcomes of ACE inhibitor treatment.

Lipid-Lowering Agents Lipids play a central role in atherogenesis and are important in the development of restenosis after angioplasty. Patients who have low high-density lipoprotein (HDL) levels have been shown to have a higher risk for restenosis.[113] Lovastatin, an HMG–CoA reductase inhibitor, has been shown to reduce neointimal hyperplasia in both normocholesterolemic[114] and hypercholesterolemic[115] rabbit arterial injury models. In humans, however, the results have been less than impressive in trials with lovastatin,[116] fluvastatin,[117] and pravastatin.[118]

Photodynamic Therapy Photodynamic therapy (PDT) has been used for many years in experimental cancer therapy. It involves the administration of a non-toxic photosensitizing dye, which is taken up preferentially by proliferating cells. The area of interest is then exposed to a specific wavelength and intensity of laser light, which causes the dye to produce highly reactive oxygen radicals. These radicals denature cellular proteins and lipids, resulting in cell death. The preferential uptake of the photosensitizers by proliferating cells spurred interest in its ability to prevent neointimal hyperplasia. It has been shown that intimal hyperplastic tissue accumulates photosensitizing dye more avidly than normal arterial tissue and retains it longer.[119] Consequently, PDT has been shown to prevent neointimal hyperplasia in rat[120] and rabbit[121] models of arterial injury. Histologically, the treated artery is found to contain an acellular media with little signs of inflammation. The endothelium was shown to regenerate by 4 weeks in the rat model, but the media remained barren.[122] The long-term implications of this phenotype are unclear. A great deal of research still needs to be done before PDT can be applied to human restenosis, but experience from clinical trials for cancer therapy and the development of endovascular lasers will encourage these efforts.

ACE Inhibitors The success of ACE inhibitors in the prevention of neointimal hyperplasia in animal models spurred the organization of several large clinical trials of human restenosis. Unfortunately, the human trials testing the effects of ACE inhibitors on post-PTCA restenosis have been disappointing.[3,110] Several explanations for the inability of ACE inhibitors to prevent restenosis have been postulated. One difference is that the doses used to treat experimental animals greatly exceed the doses used to treat hypertension in humans. In addition, several other vasoactive peptides are inactivated by the angiotensin-converting enzyme, including bradykinin and the enkephalins.[111] Bradykinin is a potent vasodilator and stimulator of constitutive NOS. The prevention of bradykinin

Radiation Radiation therapy plays a central role in oncology because of its ability to kill proliferating cells. Due to the importance of cellular proliferation in the development of neointimal hyperplasia, investigators have been studying the ability of locally delivered radiation to prevent restenosis. Several animal models have been used to study the effects of radiation on neointimal hyperplasia. In a porcine balloon injury model, the use of intravascular beta irradiation (14 – 56 Gy) was shown to inhibit neointimal thickening in a dosedependent manner.[123] Similarly, in a rat carotid injury model of intravascular 192Ir radiation, doses as low as 5 Gy were found to significantly inhibit neointimal hyperplasia.[124]

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Part Two. Medical Treatment

Due to the success in animal models, several clinical trials have been organized to see if radiation therapy can reduce neointimal hyperplasia in humans. The Scripps Coronary Radiation to Inhibit Proliferation Post Stenting (SCRIPPS)[125] trial used a gamma-emitting 192Ir ribbon compared to placebo in 55 patients undergoing angioplasty and stenting. At 6 months, the mean stenosis in the radiated group was 17% compared to 37% in controls. Additionally, only 11.5% of patients in the treated group required revascularization of the target lesion by 12 months, compared to 44.8% of patients in the control group. A 2-year follow-up of these patients showed that the reduced need for revascularization of the target lesion remained reduced in the radiated group (15.4%) compared to controls (44.8%).[126] The results of radiation therapy for prevention of restenosis are promising, but the long-term consequences of this technique are still to be determined. Arteries exposed to radiation for the treatment of cancer are found to undergo several pathologic changes, including aneurysm formation, occlusion, intimal and medial fibrosis, stenosis, occlusion of the vasa vasora, plaque formation, and periarterial fibrosis causing extrinsic arterial constriction. These changes can take many years to become clinically apparent.

Drug Delivery Methods In addition to oral and intravenous routes of administration of drugs for the prevention of neointimal hyperplasia, multiple catheter-based mechanisms have been devised to allow for the delivery of the test drug directly to the treated segment of artery. For example, the Dispatch[127] catheter has a central flow channel to keep the artery patent while specially designed drug compartments allow for passive diffusion of drugs to arterial wall. Iontophoresis, the movement of selectively charged drugs across a membrane by the application of an electric field, has also been used to deliver drugs via catheter.[128] Several methods have been developed for the long-term time-release delivery of substances to the arterial wall. Biodegradable microspheres containing the drug of interest have been injected into the arterial walls of rabbits.[129] Coated stents have also been used as a method of drug delivery.[130] Recently, bioresorbable microporous polymer stents have used to deliver adenoviral vectors to the vessel wall in rabbits.[131] The local sustained-release delivery of DNA plasmids has also been demonstrated using polymer matrices.[132] These new delivery technologies will play increasingly important roles in clinical trials of human restenosis. The

ability to achieve a high local concentration of a drug or biologic agent while limiting the systemic effects is crucial for the success of many emerging therapies, including future applications of gene therapy.

FUTURE DIRECTIONS We have learned much about the biology of the vessel wall and restenosis, but we are currently unable to reliably prevent clinical restenosis in humans. With continuing advances in molecular biology and gene therapy, however, several new tools are being applied in this endeavor. Adenoviral vectors have been used to transfer many different potentially beneficial genes to arterial walls. Many of these experiments have been successful in reducing neointimal hyperplasia in animal models. Examples include the transfer of nitric oxide synthase[44,45] and wild-type p53 gene.[133] Several new genes and delivery vectors are tested in experiments each year, but no large-scale human trials have been carried out. The use of antisense technology has also been successfully used to modulate the arterial response to injury. Although the mechanism of action of antisense oligonucleotides is not completely understood, they have been shown to inhibit the translation of targeted mRNA. Several cell cycle –related proteins have been targeted, such as c-myc,[31] as well as growth factors important in the injury response, including bFGF.[134,135] These methods have been successful in reducing neointimal hyperplasia in animal models. The transcription factor E2F plays an important role in the coordination of cell cycle activation and thus cellular proliferation. Adenovirally delivered double-stranded DNA with a high affinity for E2F has been used as a “decoy” and has successfully blocked cell cycle activation and reduced neointimal hyperplasia in rat models.[136] A similar technique, using liposomes instead of viruses to deliver the E2F decoy DNA, is currently being used to treat vein grafts in humans in an attempt to prevent stenosis and graft failure.[137] These new techniques not only provide potential treatments for neointimal hyperplasia, they also provide important insights into the genetic and molecular control of this complex pathologic process. Due to the multifaceted nature of the arterial response to injury, it is likely that successful control of neointimal hyperplasia will require a combination of several strategies, possibly with each working on a different pathway.

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stenosis After Percutaneous Transluminal Coronary Angioplasty. The EMPAR Study. Circulation 1996, 94, 1553– 1560. Karsch, K.R.; Preisack, M.B.; Baildon, R.; et al. Low Molecular Weight Heparin (Reviparin) in Percutaneous Transluminal Coronary Angioplasty. Results of a Randomized, Double-Blind, Unfractionated Heparin and Placebo-Controlled, Multicenter Trial (REDUCE Trial). Reduction of Restenosis After PTCA, Early Administration of Reviparin in a Double-Blind Unfractionated Heparin and Placebo-Controlled Evaluation. J. Am. Coll. Cardiol. 1996, 28, 1437– 1443. Faxon, D.P. Effect of High Dose Angiotensin-Converting Enzyme Inhibition on Restenosis: Final Results of the MARCATOR Study, a Multicenter, Double-Blind, Placebo-Controlled Trial of Cilazapril. The Multicenter American Research Trial With Cilazapril After Angioplasty to Prevent Transluminal Coronary Obstruction and Restenosis (MARCATOR) Study Group. J. Am. Coll. Cardiol. 1995, 25, 362– 369. Campbell, D.J. Circulating and Tissue Angiotensin Systems. J. Clin. Investig. 1987, 79, 1 – 6. Farhy, R.D.; Carretero, O.A.; Ho, K.L.; Scicli, A.G. Role of Kinins and Nitric Oxide in the Effects of Angiotensin Converting Enzyme Inhibitors on Neointima Formation. Circ. Res. 1993, 72, 1202– 1210. Shah, P.K.; Amin, J. Low High Density Lipoprotein Level Is Associated with Increased Restenosis Rate After Coronary Angioplasty. Circulation 1992, 85, 1279– 1285. Soma, M.R.; Donetti, E.; Parolini, C.; et al. HMG CoA Reductase Inhibitors. In Vivo Effects on Carotid Intimal Thickening in Normocholesterolemic Rabbits. Arterioscler. Thromb. 1993, 13, 571– 578. Gellman, J.; Ezekowitz, M.D.; Sarembock, J.J.; et al. Effect of Lovastatin on Intimal Hyperplasia After Balloon Angioplasty: A Study in Atherosclerotic Hypercholesterolemic Rabbits. J. Am. Coll. Cardiol. 1991, 17, 251– 259. Weintraub, W.S.; Bocuzzi, S.J.; Klein, J.L.; et al. Lack of Effect of Lovastatin on Restenosis After Coronary Angioplasty. N. Engl. J. Med. 1994, 331, 1331– 1337. Serruys, P.W.; Foley, D.P.; Jackson, G.; et al. A Randomized Placebo-Controlled Trial of Fluvastatin for Prevention of Restenosis After Successful Coronary Balloon Angioplasty; Final Results of the Fluvastatin Angiographic Restenosis (FLARE) Trial. Eur. Heart J. 1999, 20, 58– 69. Bertrand, M.E.; McFadden, E.P.; Fruchart, J.C.; et al. Effect of Pravastatin on Angiographic Restenosis After Coronary Balloon Angioplasty. The PREDICT Trial Investigators. Prevention of Restenosis by Elisor After Transluminal Coronary Angioplasty. J. Am. Coll. Cardiol. 1997, 30, 863– 869. LaMuraglia, G.M.; Ortu, P.; Flotte, T.J.; et al. Chloroaluminum Sulfonated Phthalocyanine Partitioning in Normal and Intimal Hyperplastic Artery in the Rat. Implications for Photodynamic Therapy. Am. J. Pathol. 1993, 142, 1898– 1905. Ortu, P.; LaMuraglia, G.M.; Roberts, W.G.; Flotte, T.J.; Hasan, T. Photodynamic Therapy of Arteries. A Novel Approach for Treatment of Experimental Intimal Hyperplasia. Circulation 1992, 85, 1189– 1196.

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158. Whitworth, H.B.; Roubin, G.S.; Hollman, J.; et al. Effect of Nifedipine on Recurrent Stenosis After Percutaneous Transluminal Coronary Angioplasty. J. Am. Coll. Cardiol. 1986, 8, 1271– 1276. 159. Powell, J.S.; Clozel, J.P.; Mu¨ller, R.K.M.; et al. Inhibitors of Angiotensin-Converting Enzyme Prevent Myointimal Proliferation After Vascular Injury. Science 1989, 245, 186– 188. 160. Veinot, J.P.; Edwards, W.D.; Camrud, A.R.; Jorgenson, M.A.; Holmes, D.R., Jr.; Schwartz, R.S. The Effects of Lovastatin on Neointimal Hyperplasia Following Injury in a Porcine Coronary Artery Model. Can. J. Cardiol. 1996, 12, 65– 70. 161. Muller, D.W.; Golomb, G.; Gordon, D.; Levy, R.J. SiteSpecific Dexamethasone Delivery for the Prevention of Neointimal Thickening After Vascular Stent Implantation. Coron. Artery Dis. 1994, 5, 435– 442. 162. Stone, G.W.; Rutherford, B.D.; McConahay, D.R.; et al. A Randomized Trial of Corticosteroids for the Prevention of Restenosis in 102 Patients Undergoing Repeat Coronary Angioplasty. Catheter. Cardiovasc. Diagn. 1989, 18, 227– 231. 163. Voss, R.; Mueller, I.R.; Matthias, F.R. Effect of Monocytopenia on Trauma-Induced Atherosclerotic Lesions in the Rabbit Ear Artery. Exp. Mol. Pathol. 1988, 49, 75– 86. 164. De Meyer, G.R.; Bult, H. Mechanisms of Neointima Formation—Lessons from Experimental Models. Vasc. Med. 1997, 2, 179–189.

CHAPTER 23

Basic Nomenclature Edward B. Diethrich peripheral interventions is distinctly different, and recommendations regarding minimal requirements for credentialing in percutaneous endovascular therapy vary from organization to organization. There are currently no formal requirements for training in endovascular surgery as part of the standard one-year instruction in general vascular surgery. According to the Accreditation Council for Graduate Medical Education, “residents [should] have an acquaintance with the methods and techniques of angiography,” while guidelines for radiologists require a minimum of a year’s training and 500 cases that include arteriography, venography, angioplasty, related percutaneous vascularization procedures, and placement of stents and filters. Despite considerable interest in training for peripheral endovascular intervention in the United States and abroad, there are relatively few opportunities available. The majority of the approved vascular surgery fellowship programs in the United States provide very limited exposure to endovascular techniques and tend to emphasize the classic vascular procedures instead. Surgeons may participate in endovascular fellowships to become thoroughly proficient in endovascular surgery techniques, and intensive training is also available through clinical “hands-on” courses or through association with a professional endovascular specialist in a private or teaching hospital setting. Approximately 90% of transluminal peripheral vascular interventions are performed percutaneously, and interventionists should be familiar with a variety of access approaches. Decisions about access should be based on the patient, target lesion, and intended procedure—there is no realistic justification for inadequate percutaneous access skills. A surgical approach is an important alternative in some situations (e.g., cutdown for direct vessel needle puncture or combined endoluminal/reconstructive procedures). All interventionists should develop proficiency in wire manipulation and fluoroscopically guided intraluminal navigation. Coordination of fluoroscopic imaging and hand guidance has become an important component of endoscopic training and should provide the vascular trainee with an added advantage when performing endoluminal procedures. Prior experience with catheter techniques in an angiography suite or cath lab is very helpful for the aspiring endovascular surgeon. A competent radiological technologist who possesses adequate knowledge of the procedure maximizes the

INTRODUCTION Endovascular surgery is relatively new, but the techniques it encompasses have already made a substantial impact on the treatment of vascular disease. The profusion of new devices available for percutaneous intervention is staggering, and specialized training is a necessity for those clinicians interested in performing these procedures. Advancements in endovascular device design have yielded low-profile catheters, hydrophilic catheter coatings, and significant improvements in catheter flexibility and in balloon materials. The introduction of stents has taken percutaneous intervention to a whole new level of efficacy; these devices demonstrate an ability to restore patency and flow in occluded vessels and limit restenosis. Both the Palmaz stent (Cordis, Warren, NJ), and the Schneider Wallstent (Schneider, Minneapolis, MN) have FDA approval for the iliac arterial location. When applied in the larger-sized vessels with diameters of .6 mm, the results of stenting in these locations have been excellent.[1 – 4] Successful use of these new endovascular techniques relies on adequate imaging capability. Knowledge of sophisticated imaging techniques, such as angioscopy and intravascular ultrasound (IVUS), and experience with radiologic and monitoring equipment are extremely important in achieving optimal results during complex endovascular procedures. The future of endovascular intervention is very bright, and the introduction of new technologies, such as endoluminal grafts (ELGs), is certain to ensure additional success in endovascular intervention. In this chapter, a basic introduction to clinical training requirements, vascular access, equipment, and imaging techniques is provided. A discussion of the future of endovascular intervention is also presented.

ENDOVASCULAR SURGICAL TRAINING Adequate training in the field of endovascular intervention is vital to a successful practice, and a certain degree of technical proficiency is required to obtain hospital privileges. The training of a vascular surgeon, an interventional radiologist, and a cardiologist performing

Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024906 Copyright q 2004 by Marcel Dekker, Inc.

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ACCESS There are a number of different access approaches; some techniques are used periprocedurally as well as preprocedurally (Fig. 23-1). In general, the closer the puncture site is to the area of therapy, the easier it is to maneuver and access the area of interest. The retrograde femoral approach is the most familiar to many interventionists and can be used for visualization of any portion of the arterial tree. The antegrade femoral route limits the operator to lower extremity visualization. Retrograde brachial, like the retrograde femoral, may also be used for visualization of any portion of the arterial tree. The transaortic approach is useful for contralateral techniques—especially when there is occlusive disease in the lower iliac and femoral regions (Fig. 23-2).

Anesthesia Most endovascular procedures do not require the use of a general anesthetic. At the Arizona Heart Institute and Arizona Heart Hospital, we prefer a local anesthesia with mild sedation for percutaneous retrograde femoral interventions. It is possible to use agents that allow the patient to be completely comfortable and conversant during the procedure so that immediate assessment of any neurologic change may be made.[5] This is particularly important when aortic arch and carotid lesions are being treated during the endovascular procedure. In the rare case in which a neurologic deficit arises from ischemia caused by balloon inflation, rapid deflation quickly reverses the symptoms. Balloon inflation at the carotid bifurcation more commonly yields baroreceptor stimulation, causing bradycardia. Cardiac standstill may result, and momentary sternal compression may be required. One milligram of atropine sulfate administered 60 seconds before balloon expansion usually prevents this complication but does not guarantee against it. Thus, careful attention should be paid to the EKG monitor during ballooning.

Figure 23-1. Diagram illustrating the various access sites for arterial visualization and intervention. The site selected depends on several factors, including the device the operator intends to use. (A) The retrograde brachial, (B) the retrograde femoral, and (C) the antegrade femoral are the most commonly used approaches and are sometimes used simultaneously.

endovascular surgeon’s potential for success; the importance of optimal image acquisition in endovascular procedures cannot be underestimated.

Figure 23-2. The transaortic approach is often used when there is occlusive disease in the iliac and femoral regions. When the iliac artery is occluded, this approach may be used to instill thrombolytics such as urokinase.

Chapter 23. Basic Nomenclature

In the carotid region, direct or open access techniques may be required, and the positioning of the patient and need for immobilization during the procedure may dictate a preference for general anesthesia. Short-acting, rapidly reversible drugs should be used so that the patient may be awake and extubated in the endovascular suite immediately following the procedure.[5] Although cervical block and local anesthesia have been used successfully in carotid interventions,[6,7] immobilizing the head and neck during the procedure is difficult, particularly if the patient is not intubated and the anesthesiologist must support a mask over the patient’s face. For most noncervical procedures, a local anesthesia is very effective; the exception is in cases where an entirely motionless field is essential for exact deployment of a stent or an ELG. Heavy sedation requiring respiratory assistance may be required in these settings.

EQUIPMENT The rapid advancement in angioplasty and stenting techniques has placed a demand on equipment manufacturers to supply sheaths, catheters, wires, balloons, and stents in a greater variety of dimensions and to incorporate design features that address specific pathologies.

Sheaths Sheaths come in a number of lengths and diameters with assorted sideports for infusion. The “profile” of the equipment continues to be reduced, and it is now possible to perform most standard angioplasty procedures through 6F and 7F sheaths. Some sheaths (e.g., Super Flex Introducer, Arrow International, Reading, PA) are particularly useful in obese patients and those with heavy scarring from previous interventions. For angioplasty techniques using the brachial approach (aortic arch vessel origins and aorta), a 7F sheath is generally used. Long sheaths, such as the 7.5F and 8F, 70 cm made by Daig Corporation (Minnetonka, MN) are also useful. In some situations, using a sheath to cross the lesion where a stent is to be deployed is effective in preventing any movement of the device. This is certainly more important when balloon-expandable devices such as the Palmaz stent are being used; self-expanding stents such as the Wallstent and Symphony stent (Boston Scientific/Meadox, Watertown, MA) are deployed without mounting on the sheath. When the retrograde or antegrade femoral approaches are used for the deployment of an ELG in the superficial femoral artery or the iliac vessels, we have typically used a 7–9F, 30–45 cm Cordis sheath. The radiopaque tip marker is particularly helpful in defining the tip of the catheter, which may be placed precisely at the desired location of stent or ELG deployment and then retracted. A similar technique can be employed for stent deployment in the renal artery. A Cobra (Fig. 23-3) or similar catheter can be guided across the renal lesion, the stent positioned, and the sheath withdrawn; this technique is extremely safe and may

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be an ideal method for use by the relatively inexperienced interventionist. We have found the Flexor sheath (Cook, Bloomington, IN) (Fig. 23-4) to be advantageous when it is necessary to perform a high-volume contrast injection in an over-the-wire configuration. The nonkinking sheath of this catheter has a 0.073 in. internal diameter that permits ample space for fluid injection even when a 0.035 in. wire is used. Devices like this allow efficacy and safety in complex endovascular procedures such as angioplasty and stenting of the carotid or in ELG exclusion of aneurysmal disease.

Guidewires Hydrophilic-coated guidewires (Glidewire, Boston Scientific/Meditech) (Fig. 23-5) have greatly increased the ease and safety of lesion traversal, and high-resolution fluoroscopic equipment ensures more accurate positioning of all wires. Steerable guidewires add another measure of control and cost, but in our experience, the nitinol alloy core of the Glidewire resists bending and kinking, making it functionally identical to the steerable wires in all but the most circuitous vessels. At times, the lubricity of a wire may not be as important as its relative rigidity. The Glidewire is available in an extra stiff version, but when an artery has to be “straightened out” in order to deliver a stent or an ELG, the Amplatz Superstiff wire (Cook) is probably the one most commonly used. It comes in both flexible and “J”-tip versions and offers the operator maximum leverage in working through difficult arterial lesions.

Balloons Advances in balloon technology have been considerable, and manufacturers have succeeded in lowering the profile of their products and improving performance capabilities with new materials. Indeed, a number of designs have successfully overcome the traumatic aspects of the traditional overflagged balloon design. For peripheral interventions, catheter lengths

Figure 23-3. Photograph of a Cobra angiographic catheter, which is particularly useful for renal angiograms and angioplasty with stent deployment.

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Figure 23-5. Hydrophilic-coated wires like the Glidewire (Meditech/Boston Scientific) have greatly increased the success rate of angioplasty in tortuous vessels and occlusive lesions.

Stents

Figure 23-4. (A) Photograph of the Flexor sheath (Cook), which is relatively kink resistant and constructed with a 0.073 in. internal diameter that permits high-volume injections for good opacification. The 0.073 in. size requires an internal adapter such as the Tuohy-Borst (Cook) to prevent excessive bleeding (B).

Stents represent an extremely important technological advance in endovascular surgery. The Palmaz stent and the Wallstent were the first two stents to be approved by the FDA for use in the iliac artery system. These devices were introduced to treat abnormal dilation characteristics (e.g., resistance, recoil and dilation failure, persistent filling defects, dissection, intimal flaps).[8,9] The results of stenting in the iliac region have been excellent and equally as good in the abdominal aorta.[10,11] Stenting has also been used successfully to treat lesions in the brachiocephalic arteries arising from the aortic arch.[12 – 16] Large series now document the use of stents in ostial renal artery stenosis for treatment of hypertension and preservation of renal function.[17,18] More recently, stenting technology has been applied to lesions in the extracranial carotid arteries.[19,20]

from 65 cm to 150 cm are commonly inventoried for a variety of balloon dimensions. Balloons of all diameters and shaft lengths are now being made by a number of different manufacturers. While there are some specific features noted among these products, the most important common characteristics are the lower profile shafts and better quality balloons, which help reduce both the incidence of breakage or leakage. As an example, when iliac artery stenting was initiated, the deployment of the Palmaz stent was performed through a 9F sheath long enough to cross the lesion. The technology has now advanced to the point that the same stent can be delivered and deployed in the iliac arterial system using a 6F sheath placed retrograde in the common femoral artery (Fig. 23-6). The major impact of these techniques is in reduction of access complications. The small puncture site lessens the potential for bleeding and hematoma formation and also diminishes patient discomfort.

Figure 23-6. sheaths.

Low profile systems permit stenting through 6F

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There are several models of stents now being used in the peripheral vessels from the carotids to the popliteals, and there are many more under study. All have certain advantages and varying degrees of radiopacity that make high-resolution fluoroscopy mandatory. The Palmaz balloon-expandable stent is a stainless steel tube designed with multiple rows of staggered rectangular slots that assume a diamond shape when expanded, reducing the amount of metal in contact with the luminal surface to just 10%. The Palmaz design is available in varying lengths from 10 to 39 mm with expansion ranges of 4–18 mm; newer models will permit expansion to even longer lengths (42– 78 mm) (Fig. 23-7). Despite their length, these stents are considerably more flexible than the standard Palmaz design (e.g., P308) because the components are connected with bridging members to permit some bending. This feature allows enough flexibility that the stent can be deployed in tortuous arteries but does not compromise the device’s radial strength. The Wallstent is a cylindrical device constructed by braiding multiple stainless steel monofilaments. Because of its spring-like structure, the Wallstent is flexible, compliant, and self-expanding, making it useful for delivery through curved arteries, implantation overlying the graft-artery junction in end-to-side anastomoses, and in vessels subject to flexion from adjacent joints or structures, such as in the common femoral and popliteal arteries. The Wallstent comes in a variety of lengths ranging from 50 to 150 mm and in diameters from 5 to 10 mm. Larger sizes have been approved for nonarterial applications but are available for “off-label” uses. A new generation of flexible stents has been introduced; these are very useful at sites of articulation, where flexion and extension of the artery is common. The Symphony stent (Fig. 23-8) and others like it may provide answers to the challenges faced near or across joint spaces. The Symphony stent permits transaortic deployment, a highly useful technique in settings of diffuse disease. The major disadvantage of this stent, however, is its low radiopacity.

IMAGING

Figure 23-7. Longer stents have become available for treatment of diffuse lesions. The medium-long Palmaz stent (Cordis) shown here is more flexible than the shorter versions but retains its radial strength.

Figure 23-8. New stent designs like the Symphony (Boston Scientific/Meadox) are particularly useful in situations where there is flexion and extension of the vessel. The Symphony resists deformity under these conditions.

Angiography Despite the development of many new imaging modalities to assess arterial pathologies, arteriography continues to be the gold standard. All arterial systems can be visualized using one of several access options; the choice of an access method depends on the particular location of the pathology being studied. There is a trend, however, away from the use of classic arteriography in favor of less invasive imaging techniques. Digital subtraction angiography (DSA) has become a favorite tool of radiologists and allows visualization of wide areas of the arterial tree using minimal amounts of contrast. The main problem with DSA is the appearance of artifacts, which are also present in magnetic resonance angiography (MRA) and may obscure accurate diagnosis. Choosing the appropriate contrast material, injection rate, and volume is extremely important in minimizing the risk associated with imaging. Types of contrast agents include high-osmolality ionic, low-osmolality ionic, and lowosmolality nonionic preparations. In general, the highosmolality preparations are more toxic and cause more pain during administration, but they are considerably less expensive than low-osmolality formulations. Low-osmolality ionic and nonionic preparations, such as Isovue, Omnipaque, Optiray, and Hexabrix, are associated with far fewer side effects than their high-osmolality counterparts. Injection rates and volumes should provide complete opacification of the vessel over the entire field of view and satisfactory density of the contrast/blood admixture to allow uniform opacity; the use of automated injectors should be considered. Reactions to contrast are relatively infrequent and generally occur within the first 5 minutes of administration; delayed reactions may be seen in a small number of patients. Most mild reactions may be treated by administering an antihistamine (e.g., diphenhydramine 25 –50 mg IV or IM) and reassuring the patient. When a reaction is more severe, 0.1–0.2 mL of a 1:1000 solution of epinephrine may be administered IV at 1- to 3-minute intervals until the reaction

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dissipates. Severe reactions may necessitate steroid administration or even cardiopulmonary resuscitation. Many centers have now eliminated any type of preoperative arteriographic studies for carotid artery bifurcation disease by substituting duplex scanning. The procedure of endarterectomy is carried out based on the findings of this single noninvasive study. Certainly, there is some controversy regarding this approach since both proximal arch vessel and intracranial pathology may be completely overlooked. At the opposite extreme, all protocols under study for deployment of ELGs in abdominal aortic, thoracic, and peripheral aneurysm exclusion demand high-resolution arteriography for preoperative evaluation. This has, indeed, proved to be extremely important in assessing visceral artery location, patency, and the size and condition of the iliac arteries (through which the relatively large device must pass). Computed tomography (CT) and now spiral CT are also used for preoperative evaluation of vessels in which ELGs will be used. These techniques are important in measuring the sites for ELG deployment and may help the interventionist minimize the potential for complications such as endoleaks, migration, and other procedural difficulties.

Angioscopy Complex percutaneous and open interventions often require imaging techniques that are complementary to angiography. Angioscopy provides direct visualization and is particularly useful in viewing the suture lines and lumens of grafts, evaluating hemorrhagic plaques, determining the flowinhibiting potential of flaps, assessing intimal hyperplasia in stents, and in estimating thrombosis volume and marking the progress of its removal. Angioscopic imaging is also valuable in assessing the etiology of restenosis after interventional therapy. Poststent dissection, bulging of tissue into the lumen at the stent articulation site, gaps between stents, and thrombus are easily visualized. Angioscopic data may motivate changes in therapy or guide the selection of treatment before and after stent deployment.[21 – 23] Angioscopic equipment is available from a variety of manufacturers. We use a 2.3F disposable angioscope (Baxter Healthcare Corp., Irvine, CA) connected to high-quality medical video color monitors with video recorders for hard copy documentation. Irrigating systems provide computerassisted pulsed irrigation and image storage for maximum visibility with minimal flush volume. On-demand delivery of heparinized saline under pressure at preset pulse durations via a foot pedal is extremely convenient. Both freeze-frame and real-time imaging are possible when flushing is synchronized with image capture for digitized output.

plasty (intraluminal cross sections and arterial circumferences) along with precise determination of arterial architecture and lesion pathology. In most cases, the IVUS examination following balloon dilation plays a significant role in both determining the need for stenting and in assessing adequate deployment of the devices. It is also invaluable in studying stents over the long term, allowing detection and definition of the extent of intimal hyperplasia (Fig. 23-9). IVUS has become a standard tool in the ELG program for exclusion of abdominal aortic aneurysms. Exact measurements can be acquired to facilitate selection of the proper device size, and IVUS also allows for assessment of the device after it has been deployed. Both have proven to be important uses of this imaging technique.

The Imaging “Workshop” Regardless of the multiple interventional tools and the imaging modalities available today, the end result of endovascular intervention depends heavily on the quality and flexibility of equipment in the operating suite at the time of the procedure. Unfortunately, many surgeons do not have the proper “workshop” and are forced to perform endovascular procedures using standard operating tables and mobile fluoroscopic equipment. Under some circumstances, satisfactory results can be obtained using these tools. As procedures become more complex, however, surgeons who do not have access to the most sophisticated imaging tools will be at a distinct disadvantage. Endoluminal grafting, which is proliferating at a rapid rate, is a prime example of the kind of procedure that demands advanced imaging capabilities. Over the last 25 years, clinicians at the Arizona Heart Institute have advocated the use of ceiling-mounted C-arm image intensifiers and carbon fiber operating tables that are completely free of metallic obstructions. Innovation in equipment and in suite design has been extremely important

Intravascular Ultrasound Other imaging techniques used in interventional procedures include duplex scanning and intravascular ultrasound. At the Arizona Heart Institute and Heart Hospital, we incorporate IVUS as an adjunct to angiography and angioscopy. IVUS provides baseline luminal dimensions pre- and postangio-

Figure 23-9. Intravascular ultrasound study showing intimal hyperplasia on a stent deployed 12 months earlier. This imaging modality is useful for periprocedural control images and for longterm surveillance.

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347

Figure 23-10. Photograph of an ideal “workshop” that incorporates a completely sterile environment for sophisticated endovascular procedures. The new Arizona Heart Hospital has three endovascular suites like this to permit maximum efficiency and flexibility during complex procedures.

to us during the planning and construction of our new facility at the Arizona Heart Hospital. The fixed, ceiling-mounted fluoroscopy system [Institutional Surgical Systems (ISS), Phoenix, AZ] shown in Fig. 23-10 is ideal for the operating environment. Among the most important of its many advantages is that the unit allows the operator to pan a long area or distance quickly and without image distortion.

THE FUTURE OF ENDOVASCULAR TECHNOLOGY Although angioplasty has been used with some excellent results, long-term efficacy in small-diameter vessels has been elusive. Even catheter-based recanalization tools and

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endovascular stents have not provided the solutions we had hoped for in some anatomic locations. A number of investigators now believe one way to discourage cellular growth in the intima is to provide a new, artificial intraluminal surface that resists the proliferation of cells. This idea has prompted the development of ELGs and covered stents. Lining the diseased arterial wall with biomaterials that exclude contact with blood may protect the lumen from the cellular overgrowth that results in constriction and restenosis. In addition, placement of the device effectively eliminates the conventional anastomotic junction—a site of inherent flow disturbances. The incidence of graft thrombosis may also be decreased. The use of ELGs has proven valuable in the exclusion of abdominal aortic, thoracic, or peripheral aneurysms. Although the procedure was initially designed for use in patients with cardiac pathologies, pulmonary insufficiency, a hostile abdomen, or other conditions that heighten the risk of classical surgical intervention,[24] it is now used even in patients with small, asymptomatic aneurysms.[25] The beauty of the endoluminal procedure cannot be challenged; a minimal incision, limited potential for complications, short hospitalization and rapid recovery are obvious advantages. Improvements in device design and deployment techniques have brought us closer to routine success with this new procedure. Review of clinical results with the various devices indicates a reduction in endoleaks and distal embolization (the major disadvantages of the procedure) with second- and thirdgeneration devices. Still, it is clear that we have yet to achieve a perfect device, and we continue to see shifts in research efforts to clinical arenas outside the United States, where more lenient regulatory climates encourage a rapid and, perhaps, less costly development effort to bring the product to market. At present, it is impossible to draw any firm conclusions about whether or not the covered stent-graft or ELG may increase long-term patency as compared to the classic uncovered stent. However, if intimal hyperplasia on the stent

can be reduced by covering the stent on one or both sides with a fabric such as polytetrafluoroethylene,[26] some of the newer stent-grafts under development may have significant promise for increasing long-term patency. Questions remain about the potential for occlusion of collateral vessels with a covered stent and the ultimate effect on distal perfusion.

CONCLUSIONS The field of endovascular surgery is constantly changing as new techniques and devices are adopted. The introduction of stent technology has been a very important breakthrough in the treatment of coronary and peripheral lesions, and the use of modern endovascular and imaging equipment requires specialized training. Indeed, innovations in imaging techniques such as angioscopy and IVUS have helped to provide the interventionist with indispensable information about lesion morphology and appropriate stent placement. The future for surgeons to expand their roles in these new and exciting developments will depend to a great extent on whether or not they are able to establish proper “workshops” for endovascular procedures. ELG technology is proliferating at an unprecedented rate, and clinical trials are in progress at institutions throughout the world. A great deal of progress has been made in ELG design, and advancements in deployment technique have also been realized. ELG technology has already changed the indications for treatment in many centers, and we can anticipate numerous opportunities for additional investigation with this exciting treatment modality. It is certainly clear that successful endovascular procedures depend on knowing how to properly access the lesion, choosing the correct device for treatment, and using imaging and monitoring equipment to maximize device placement and ensure the patient’s well-being.

REFERENCES 1. No¨ldge, G.; Richter, G.M.; Ro¨ren, T.; et al. A Randomized Trial of Iliac Stenting Versus PTA in Iliac Artery Stenoses and Occlusions: Updated 6-Year Results. (Abstract). J. Endovasc. Surg. 1996, 3, 99– 100. 2. Murphy, K.D.; Encarnacion, C.E.; Le, V.A.; Palmaz, J.C. Iliac Artery Stent Placement with the Palmaz Stent: Follow-Up Study. J. Vasc. Intervent. Radiol. 1995, 6 (3), 321– 329. 3. Murphy, T.P.; Webb, M.S.; Lambiase, R.E.; et al. Percutaneous Revascularization of Complex Iliac Artery Stenoses and Occlusions with Use of Wallstents: ThreeYear Experience. Vasc. Intervent. Radiol. 1996, 7 (1), 21–27. 4. Vorwerk, D.; Guenther, R.W.; Schu¨rmann, K.; et al. Primary Stent Placement for Chronic Iliac Artery Occlusions: Follow-Up Results in 103 Patients. Radiology 1995, 194, 745– 749.

5. Kharrazi, M.R. Anesthesia for Carotid Stent Procedures. J. Endovasc. Surg. 1996, 3, 211– 216. 6. Bergeron, P.; Chamabran, P.; Benichou, H.; et al. Recurrent Carotid Disease: Will Stents Be an Alternative to Surgery? J. Endovasc. Surg. 1996, 3, 76–79. 7. Alessandri, C.; Bergeron, P. Local Anesthesia in Carotid Angioplasty. J. Endovasc. Surg. 1996, 3, 31– 34. 8. Palmaz, J.C.; Garcia, O.J.; Schatz, R.A.; et al. Placement of Balloon-Expandable Intraluminal Stents in Iliac Arteries: First 171 Procedures. Radiology 1990, 174, 969– 975. 9. Becker, G.J. Intravascular Stents. General Principles and Status of Lower Extremity Arterial Applications. Circulation 1991, 83 (Suppl 11), 1122– 1136. 10. Diethrich, E.B.; Santiago, O.; Heuser, R.R.; Gustafson, G. Preliminary Observations of the Use of the Palmaz Stent in the Distal Portion of the Abdominal Aorta. Am. Heart J. 1993, 125, 490– 501.

Chapter 23. Basic Nomenclature 11.

12.

13.

14.

15.

16.

17.

18.

Diethrich, E.B. Endovascular Treatment of Abdominal Aortic Occlusive Disease: The Impact of Stents and Intravascular Ultrasound Imaging. Eur. J. Vasc. Surg. 1993, 7, 228–236. Diethrich, E.B. Initial Experience with Stenting in the Innominate, Subclavian, and Carotid Arteries. J. Endovasc. Surg. 1995, 2, 196– 221. Diethrich, E.B.; Cozacov, J.C. Subclavian Stent Implantation to Alleviate Coronary Steal Through a Patent Internal Mammary Artery Graft. J. Endovasc. Surg. 1995, 2, 77– 80. Kumar, K.; Dorros, G.; Bates, M.; Palmer, L.; Mathiak, L.; Dufek, C.; et al. Primary Stent Deployment in Occlusive Subclavian Artery Disease. Catheter. Cardiovasc. Diagn. 1995, 34, 281– 285. Sullivan, T.M.; Bacharach, M.; Childs, M.B. PTA and Primary Stenting of the Subclavian and Innominate Arteries. (Abstract). Circulation 1995, 92, 1 – 383. Martinez, R.; Rodriguez-Lopez, J.; Torruella, L.; Ray, L.; Lopez-Galarza, L.; Diethrich, E. Stenting for Occlusion of Subclavian Arteries: Technical Aspects and Follow-Up Results. Tex. Heart Inst. J. 1997, 24, 23– 27. Dorros, G.; Jaff, M.R.; Mathiak, L.; Dorros, I.I.; Lowe, A.; Murphy, K.; He, T. Stent Revascularization for Atherosclerotic Renal Artery Stenosis. One-Year Clinical FollowUp. Tex. Heart Inst. J. 1998, 25, 40– 43. Fiala, L.A.; Jackson, M.R.; Gillespie, D.L.; O’Donnell, S.D.; Lukens, M.; Gorman, P. Primary Stenting of Atherosclerotic Renal Artery Stenosis. Ann. Vasc. Surg. 1998, 12, 128– 133.

19.

20.

21.

22.

23.

24.

25.

26.

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Diethrich, E.B.; Ndiaye, M.; Reid, D.B. Stenting in the Carotid Artery: Initial Experience in 110 Patients. J. Endovasc. Surg. 1996, 3, 42– 62. Diethrich, E.B.; Rodriguez-Lopez, J.A.; Lopez-Galarza, L.A. Stents for Vascular Reconstruction in the Carotid Arteries. (Abstract). Circulation 1995, 92, 1 – 383. Tierstein, P.S.; Schatz, R.A.; Rocha-Singh, K.J. Coronary Stenting with Angioscopic Guidance. (Abstract). J. Am. Coll. Cardiol. 1992, 19, 223A. Strumpf, R.K.; Heuser, R.R.; Eagan, J.T. Angioscopy: A Valuable Tool in the Deployment and Evaluation of Intracoronary Stents. Am. Heart J. 1993, 126, 1204– 1210. Senneff, M.J.; Schatz, R.A.; Tierstein, P.S. The Clinical Utility of Angioscopy During Intracoronary Stent Implantation. J. Intervent. Cardiol. 1994, 7, 181– 186. Parodi, J.C.; Palmaz, J.C.; Barone, H.D. Transfemoral Intraluminal Graft Implantation for Abdominal Aortic Aneurysms. Ann. Vasc. Surg. 1991, 5, 491– 499. May, J.; White, G.; Yu, W.; Waugh, R.; Stephen, M.S.; Harris, J. Concurrent Comparison of Endoluminal Repair Versus No Treatment for Small Abdominal Aortic Aneurysms. Eur. J. Vasc. Endovasc. Surg. 1997, 13, 472–476. Diethrich, E.B. Polymeric Covers and Coats for Metallic Stents: Microporous PTFE and the Inhibition of Intimal Hyperplasia. J. Endovasc. Surg. 1995, 2, 266– 271.

CHAPTER 24

Peripheral Atherectomy Samuel S. Ahn Kyung M. Ro INTRODUCTION

INDICATIONS

Recent advances in endovascular technology have generated numerous alternative procedures in the treatment of peripheral arterial occlusive disease. The application of catheter-based endovascular systems has provided a less invasive method to enhance or replace standard revascularization procedures. Mechanical atherectomy, which is based on the concept of “debulking” plaque, has been developed as an alternative to conventional percutaneous balloon angioplasty due to the limitations of PTA. Unlike PTA, which is not ideally suited for use in complex lesions (i.e., heavily calcified or intimal hyperplastic lesions), diffusely diseased vessels, and eccentric stenosis, atherectomy has a wider application to lesions not amenable to percutaneous balloon angioplasty. Atherectomy has proven to have a greater immediate success rate with less intimal dissection and occlusion; however, the long-term results are less promising. Atherectomy selectively removes atheromatous materials from diseased arteries by cutting, pulverizing, or shaving it using a mechanical catheter-deliverable endarterectomy device. Atherectomy is performed either percutaneously or through a small arteriotomy located romote from the diseased site. More than a dozen atherectomy devices have been developed over the years to meet the current challenges, each offering its own unique advantages and disadvantages. Of these atherectomy devices, four have undergone critical evaluation with extensive preclinical or clinical investigation: Simpson AtheroTrak (Mallinckrodt Medical Inc., St Louis, MO), the Transluminal Extraction Catheter (TEC) (Interventional Technologies, San Diego, CA), the OmniCath (American Biomed, Inc., The Woodlands, Texas), and the Auth Rotablator (Boston Scientific Corp., Natick, MA). Atherectomy devices are either extirplative (directional atherectomy) or ablative (rotational atherectomy). Of the four catheters mentioned above, only the Rotablator is an ablative device. Extirplative catheters shave or slice the atheroma and directly remove the excised plaque from vessels with a collection chamber, while ablative catheters use a highspeed rotary device that pulverizes atheroma into microparticles small enough to be aspirated or removed through the reticuloendothelial system.

Indications for atherectomy vary with each catheter (Table 24-1). Atherectomy may be a suitable option for high-risk patients with severe disabling claudication or limb-threatening ischemia and short stenotic lesions less than 5 cm. In addition, atherectomy can be performed as an adjunct to standard revascularization in high-risk patients. In the iliac artery, atherectomy can be used as an adjunct to standard open revascularization in heavily calcified eccentric plaques; however, the use of atherectomy in the femoropoliteal artery should be determined by the type of plaque in the region as well as the length of the lesion. Lesions in the tibioperoneal artery are generally diffused, calcified and not suitable for PTA; therefore, atherectomy using the Auth Rotablator is recommended. It has been suggested that patients with failing lower extremity bypass grafts should be treated with atherectomy, rather than PTA, because graft failure is often caused by intimal hyperplastic tissue not readily amenable to balloon angioplasty. Atherectomy has been shown to be successful in the treatment of recurrent stenoses resulting from intimal hyperplasia.

TYPES OF ATHERECTOMY DEVICES Simpson AtheroTrak Device Description The Simpson AtheroTrak is the modified version of the AtheroCath. The AtheroTrak catheter is available in 7, 8, 9, 10, and 11 French sizes. The improved AtheroTrak offers both an over-the-wire and fixed wire shaft design that enhances the steering maneuverability for easier introduction into complex or simple stenotic lesions. The housing unit, which contains a cutter within a longitudinal opening on one side and a balloon attached to the other side, is located at the distal end of the catheter (Fig. 24-1). Once inflated, the balloon engages the atheroma against a 20 mm cutter window.

Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024907 Copyright q 2004 by Marcel Dekker, Inc.

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352 Table 24-1.

Indications for Use by Atherectomy Device

Device Simpson AtheroCath

TEC

OmniCath

Auth Rotablator

Amenable lesions

Arterial site

Stenoses Short (,5 cm) Eccentric atheroma Intimal hyperplasia Ulcerative plaques Stenoses Short (,5 cm) Eccentric atheroma Stenoses Short (,5 cm) Eccentric atheroma Stenoses Eccentric atheroma Hard calcified plaques Recurrent vein graft stenoses

Iliac Superficial femoral Popliteal

Bulky/stiff catheter Lengthy procedure Hematoma Restenosis

Superficial femoral Popliteal

Small lumen Restenosis Reocclusion Hematoma Restenosis

The cutter then slices the plaque at 2000 rpm while simultaneously pushing the excised particles into a collection chamber. The wire tip of the catheter is protected with a tip guard containing a hemostasis valve. The proximal assembly consists of a balloon inflation port, a flush port and an adaptor spline for the drive cable connector. To lock the cutter in place before advancing it manually, a small lever is attached to the cable.

Iliac Superficial femoral Popliteal Superficial femoral Popliteal Tibial

Complications/limitations

Dissection Restenosis Reocclusion Thrombosis

Indications The AtheroTrak is ideally suited to treat short, discrete, eccentrically located atheroma. Unless occlusions can be crossed with a guidewire, they are not amenable to this device. Heavily calcified lesions, although not contraindicated, can create difficulties for the cutter. Similar to balloon angioplasty, the AtheroTrak, with its own balloon,

Figure 24-1. Simpson AtheroTrak catheter system. 1, cylindrical housing; 2, longitudinal opening; 3, cutter; 4, cutter drive cable (to motor); 5, specimen collection area; 6, balloon support mechanism; 7, fixed guidewire; 8, motor; 9, cutter advance lever; 10, balloon inflation port; 11, flush port; 12, Touhy – Borst opening for cable connector. (From Simpson J. B., Selmon M. R., Robertson G. C., et al.: Transluminal atherectomy for peripheral vascular disease. Am. J. Cardiol. 61: 96G – 101G, 1988.[5])

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can create an arterial lumen larger than the catheter used. As indicated in Table 24-1, this catheter can be used to treat ulcerative lesion, concentric stenoses and intimal hyperplasia located in the iliac, superficial femoral, and popliteal arteries. Recent studies have indicated that Simpson atherectomy provides more durable results when compared to balloon angioplasty in treating recurrent infrainguinal bypass graft stenoses.[1,2] In addition, the Simpson atherectomy has been indicated for use in the treatment of failing hemodialysis access fistulas with promising results.[3,4]

Technique The choice of catheter size should be based on the size of the adjacent normal artery; the catheter should be the same size or slightly larger. A 9 Fr catheter is most commonly used. Figure 24-2 illustrates the Simpson catheter procedure. Diluted contrast solution should be injected into the balloon port and aspirated until all air is evaporated and the balloon filled with solution. The inflation device is then attached to the balloon port and the removable collection chamber and nose cone secured by turning the proximal and distal thread joints clockwise with an Atherowrench. The motordrive can then be turned on to test the advancement and retraction capabilities of the cutter. With the cutter fully advanced, the AtheroTrak catheter is inserted through the introducer sheath and advanced past the stenotic lesion. Under fluoroscopic guidance, the cutter window is positioned against the stenotic lesion. The opposing balloon is inflated to 20–40 psi to push the window open and to press the plaque into it. The motor drive of the cutter is activated, the balloon completely deflated, and the plaque sliced off and pushed into the distal collecting chamber. To obtain full atherectomy, the collecting chamber can be rotated; multiple cuts and passes are usually required to achieve a final lumen of less than 25% residual stenosis. Before retracting the cutter, the balloon should be reinflated to 10 psi to prevent embolization; after the cutter is retracted, the balloon pressure should be increased to 20– 40 psi. The catheter must be withdrawn to remove the excised particles from the collecting chamber. Perform a completion angiogram to assess patency and to determine if residual stenosis is less than 25%. Repeat atherectomy should be performed until recanalization is complete. Throughout the procedure, contrast should be periodically injected via the sidearm of the introducer to facilitate positioning of the cutter window for subsequent passes. Before the catheter is removed, the cutter is advanced completely within the housing unit and the tip guard passed through the hemostasis valve.

Results In 1988, Simpson et al.[5] first reported their use of atherectomy for peripheral arterial occlusive disease on 130 lesions in 61 patients with a 6-month patency rate of 64%. Since then, several clinical studies using the Simpson atherectomy device to treat peripheral arterial occlusive disease have been reported, promising initial success rates ranging from 80% to 100%.[1 – 4,6 – 8] Graor and Whitlow[6] reported a less than 20% residual stenosis in 100% of lesions less than or equal to 5 cm and 93% of lesions greater than 5 cm. Other investigators, however, reported less enthusiastic

Figure 24-2. Simpson atherectomy procedure. (A) The lesion before atherectomy. (B) Atherectomy catheter in position across the lesion. (C) The balloon support is inflated. (D) The cutter is advanced. (E) The specimen is trapped in the housing. (F) The balloon is deflated and the catheter removed. (From Hinohara T., Robertson G. C., Selmon M. R., Simpson J. B.: Transluminal atherectomy. The Simpson atherectomy catheter. In Moore W. S., Ahn S. S. (eds): Endovascular Surgery. Philadelphia, WB Saunders Company, 1989, pp 310 – 322.)

intermediate patency rates at 6 –24 months (Table 24-2). Vroegindewij and colleagues[7] and Lugmayr et al.[8] reported discouraging 2-year patency rates of 35% and 42%, respectively. Adjunctive use of balloon angioplasty with atherectomy appears to provide more durable results. Kim and associates[12] used balloon angioplasty to either facilitate the passage of the atherectomy catheter or further improve the final lumen. In this study, the investigators attempted to assess the results of the Simpson device with those of balloon angioplasty. They compared lesions treated with atherectomy alone ðn ¼ 68Þ with lesions treated with both atherectomy and supplemental balloon angioplasty ðn ¼ 17Þ: Lesions treated with the Simpson device alone had patencies of 92%, 84%, and 84% at 1, 2, and 3 years, respectively, and reduced patencies of 78%, 67%, and 57% at 1, 2, and 3 years, respectively, were obtained with the combined treatment modality. In this study, however, it was difficult to delineate the respective roles of atherectomy and balloon angioplasty or to make a comparison between the groups. In another prospective randomized study conducted by Vroegindewij and colleagues,[7] 2-year cumulative patency rates of 35% ðn ¼ 38Þ in lesions treated with Simpson atherectomy alone versus 56% ðn ¼ 35Þ in patients treated with balloon angioplasty alone were found. The results of this study indicated that atherectomy with the Simpson catheter did not result in an improved clinical or hemodynamic outcome and was associated with a notably worse patency rate than balloon angioplasty for patients with lesions of 2 cm or greater. In a recent study conducted by Osborn and associates,[15] combination therapy involving Simpson atherectomy, balloon angioplasty, and video angioscopy was used to treat focal stenotic lesions ðn ¼

354 Table 24-2.

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Results Reported Using the Simpson Atherectomy Device Primary patency (%)

Authors

Patient (no.)

Lesion (no.)

Technical success (%)

6 months

12 months

24 months

Simpson et al.[5] Graor and Whitlow[6]

61 106

136 106

Vroegindewij et al.[7] Lugmayr et al.[8] Polnitz et al.[9] Hinohara et al.[10] Dorros et al.[11] Kim et al.[12] Savader et al.[13] Widenhain et al.[14]

38 94 60 100 126 77 61 75

38 132 94 195 213 85 136 84

87 100 (lesions #5 cm) 93 (lesions . 5 cm) 92 95 82 90 99 92 80 92

69 NA NA 84 NA 99 83 45 94 NA NA

NA 93 86 42 69 72 NA NA 86 76 78

NA 88 73 35 42 NA NA NA 86 58 57

NA = not available.

96Þ in the superficial femoral and popliteal arteries with greater than 80% stenoses. The investigators reported a promising 94% technical success rate and 1- and 2-year patency rates of 78% and 71%, respectively. Although longterm studies are warranted, this study combining atherectomy and balloon angioplasty may prove to be more durable than any one treatment modality alone. A number of recent studies have shown much improved mid-term and long-term results from Simpson atherectomy in the treatment of vein graft stenoses, with sustained patency rates better than that historically reported for balloon angioplasty. Dolmatch et al.[1] reported a 92% technical success rate in treating 18 lower extremity bypass grafts (11 PTFE, 7 autologous saphenous veins) with 23 areas of anastomotic stenoses. The authors reported a 92% technical success rate in 19 lower extremity bypass grafts with a mean 14-month patency of 88%. In addition, Porter et al.,[2] in an attempt to evaluate the long-term results of Simpson atherectomy, performed 52 procedures (atherectomy alone = 42, atherectomy plus PTA = 10) to treat 67 stenoses (28 anastomotic, 39 intragraft) in 44 infrainguinal grafts. The technical success rate was an impressive 96%, with a mean diameter reduction from 81% to 11% stenosis after treatment. In addition, the sustained patency rates were 83%, 80%, and 80% at 1, 2, and 3 years, respectively. These results clearly

Table 24-3.

surpass those previously reported for balloon angioplasty and rival those of standard surgical revision in the treatment of recurrent stenosis in infrainguinal bypass graft. The Simpson atherectomy device has also been indicated for use in the treatment of failing hemodialysis access fistulas. Zemel et al.[3] reported a 77% technical success rate in treating stenotic hemodialysis fistulas in 13 patients. Gray and colleagues[4] reported an 83% technical success rate and a 50% patency rate a 6 months in treating hemodialysis access with 12 intragraft stenoses. Although the data are preliminary and further clinical trials are warranted, the use of atherectomy in the treatment of recurrent stenotic hemodialysis access fistulas appears to be a safe and durable alternative.

Complications and Limitations Although there have been reported complications of hematomas caused by bleeding at the atherectomy entry site, pseudoaneurysm, and distal embolization, the Simpson atherectomy catheter is a relatively safe catheter. Table 24-3 outlines the complications associated with the Simpson device. Savader and colleagues[13] stated that Simpson atherectomy has similar patency compared with that reported for balloon angioplasty in the treatment of femoral and

Complications Associated with the Simpson Catheter

Complications

Simpson et al.[5]

Graor and Whitlow[6]

Vroegindewij et al.[7]

Polnitz et al.[9]

Hinohara et al.[10]

Kim et al.[12]

Dissection Embolization Hematoma Pseudoaneurysm Retroperitoneal bleeding Thrombosis

3/61 (5%) 1/61 (2%) — — — 1/61 (2%)

— — 7/106 (7%) 1/106 (1%) — —

2/38 (5%) — — — — 1/38 (3%)

— 1/60 (2%) 2/60 (3%) — — —

— 2/100 (2%) 1/100 (1%) — — 1/100 (1%)

— 3/77 (4%) 11/77 (14%) 3/77 (4%) 1/77 (1%) —

Chapter 24.

popliteal artery lesions but also a high complication rate of 42.8%, equally divided into major and minor complications. The major complications included 4 puncture-site hematomas, which were attributed to the use of sheaths 9 Fr or larger and subsequently required vessel repair or an extended hospital stay; 7 embolizations treated with aspiration embolectomy and/or urokinase therapy; 2 contrast-induced renal failures that required rehydration or dialysis; a pseudoaneurysm that required surgical repair; a thrombosed arterial lesion within 24 hours. All minor complications were related to puncture-site hematomas and required no additional treatment. Other complications reported by Kim et al.[12] were primarily related to the bulky sheaths, which caused 11 cases of hematomas; less prevalent complications included problems related to distal emboli and 3 cases of pseudoaneurysms that required surgical repair. One of the primary limitations of the Simpson atherectomy device for widespread use in the treatment of peripheral arterial occlusive disease is its failure to reduce restenosis. Generally, short-terms results are disappointing; at 6 months, Simpson and his colleagues[5] reported a restenosis rate of 36%; Polnitz and others[9] reported restenosis rates of 24% and 11% for concentric and eccentric lesions, respectively; and Dorros and associates[11] reported a significant 55% recurrence rate. In the treatment of recurrent infrainguinal bypass graft stenosis, Dolmatch et al.[1] reported a 26% restenosis and reocclusion rate while Porter and his colleagues[2] found a low 12% restenosis rate in treating vein graft stenosis. Another significant limitation of the Simpson atherectomy device is its inability to treat long, diffusely diseased segments and long, completely occluded lesions. The reported restenosis rates in these long lesions are higher; Polnitz et al.[9] found restenosis rates of 14% in lesions with complex occlusions 5 cm or greater as compared to 7% in simple stenosis less than 5 cm. Vroegindewij and others[7] found that their treated lesions of 2 cm or greater had notably worse patency rates (14%) at one year as compared to lesions smaller than 2 cm (50%).

Transluminal Extraction Catheter Device Description The Transluminal Extraction Catheter (TEC, Inventional Technologies, Inc., San Diego, CA) is a semi-flexible, torquecontrolled catheter with a rotating, cone-shaped cutter that is placed through an introducer sheath over a central guidewire (Fig. 24-3). The catheter itself is hollow, so that the particles resulting from atherectomy can be suctioned out of the vessel and collected in a separate collecting chamber. The coneshaped cutter itself rotates at approximately 700 rpm and leaves relatively large-sized (1 mm) particles; the cone also has openings on its distal tip. Suction is applied from the proximal port to suction the particles into a separate collecting chamber (125 mL), thereby minimizing embolic complications. Continuous heparin irrigation is required through the introducer sheath’s sidearm to maintain efficiency in the aspiration of the excised particles. The catheter is currently available in 6, 7, 8, 9, 10, 12, and 14 Fr sizes.

Figure 24-3.

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355

The TEC device. See text for description.

Indication The current indications for the TEC device are the same as those previously described for the Simpson AtheroTrak. The TEC device is currently recommended for short stenotic lesions with eccentrically placed atheroma. The use of this atherectomy device in treating total occlusions and long stenotic lesions has produced suboptimal results.[16,17] Adjunctive use of balloon angioplasty to facilitate the recanalization of such lesions is recommended.

Technique Atherectomy with the TEC device is usually performed percutaneously but can be done intraoperatively. Due to the limited size of the TEC catheter, standard balloon angioplasty is often required to achieve a channel that is of adequate size. Under fluoroscopic guidance, an appropriately sized introducer sheath is placed into the artery in antegrade fashion for the superficial, popliteal, and tibial arteries. A guidewire is then passed through the introducer sheath and the obstructing lesion. Once the guidewire is in place, a 4- or 5-Fr polyethylene exchange catheter is inserted. The existing guidewire is then replaced with a TEC 0.014-in. guidewire. The exchange catheter is then removed, followed by the passing of the TEC over the TEC guidewire until the catheter meets resistance at the obstructive lesion. The motor drive unit, which rotates the cutter, is turned on and the suction is applied. The rotating cutter is advanced freely but gently over the guidewire until the obstructing lesion is traversed. The shaved particles are then aspirated through the hollow catheter into the collecting bottle. Fluoroscopy is used to document the progress of the atherectomy and the final lumen. Continuous heparin irrigation is administered via the sidearm of the introducer sheath to minimize embolic complications. If there is significant residual stenosis (. 25%), adjunctive balloon angioplasty can be used to dilate the artery to its final lumen.

Results Very few results using the TEC device in the treatment of peripheral arterial occlusive disease have been reported.

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Wholey and Jarmolowski[16] reported promising initial technical success rates of 92% and an immediate clinical success rate of 90%. However, only 50 of 95 patients (53%) underwent follow-up at 6 months; furthermore, 16 had undergone repeat angiography, 4 of whom had angiographic evidence of reocclusion. Myers and associates[17] achieved a 6-month patency rate of 80% for lesions 5 cm or smaller and 64% for lesions greater than 5 cm. In addition, adjunctive balloon angioplasty was performed in 76% of patients.

Complications/Limitations Complications associated with the TEC device have not been reported in full detail. Table 24-4 outlines the complications associated with this device. Wholey and Jarmolowski[16] reported only 2 of 126 (2%) thrombotic complications, both of which were treated with urokinase infusion. Myers and associates[17] reported a 6% complication rate in treating long, complex lesions including 2 deaths, 2 catheter fractures requiring removal and replacement, 2 cases of thromboembolism, and 3 patients with puncturesite bleeding. Restenosis and reocclusion are the primary limitation of the TEC device. Of the 16 patients who underwent repeat angiography during follow-up, Wholey and Jarmolowski[16] found restenosis in 4 patients at 3-month follow-up and reocclusion in 4 whose lesions were longer than 8 cm. Myers and associates[17] found restenosis in 26 lesions (18%) and reocclusion in 51 lesions (35%) at 6 months.

OmniCath Device Description The OmniCath is a new atherectomy device currently approved by the U.S. Food and Drug Administration (FDA) for investigational use only (Fig. 24-4). It is a radiopaque, torqueable, braided catheter with a hollow cylindrical housing at the distal end. The housing unit contains the cutter within a longitudinal window on one side and a unibody tripod extendible deflector wire configuration on the opposite side, which serves as an anchoring pad. The internal beveled cutter spins at 11,000 rpm and is stabilized by an axial guide or track when making a cut. The cutter is activated by a batterypowered motor via a hollow drive shaft. An idler shaft covers a 2-cm section of the drive shaft at the distal end to minimize or eliminate the potential of tissue wrapping or binding onto

Figure 24-4. The OmniCath atherectomy device tip.

the shaft. The catheter is then advanced transluminally over a 0.014 or 0.018 in. guidewire. Once the cutter window is positioned over the stenotic lesion, the cutter is activated and passed back and forth across the lesion, shaving off thin segments of the atheroma with each pass. The atheromatous debris is then collected in the housing unit and continuously aspirated through a removable port at the proximal end of the catheter. A radiopaque gold dot just beyond the distal end of the window enhances operative visualization of the device. The atraumatic deflector wire is designed to anchor the cutter assembly securely against the obstructing lesion and allow for continuous distal perfusion during atherectomy. The anchoring system can be adjusted to regulate the depth of cut by its degree of extension; it can withhold a maximum pressure of 27 psi, which is designed to prevent injury to the vessel wall (i.e., perforation) and reduce the occurrence of acute closure and restenosis.

Indications The OmniCath is designed to treat short stenotic lesions with concentrically or eccentrically placed atheroma. From animal as well as preliminary clinical data, it can be used in the iliac, superficial femoral, and popliteal arteries. The OmniCath is currently under investigative trial for peripheral atherectomy. The OmniCath may potentially have application in the treatment of arteriovenous dialysis fistulas. Clinical trials are currently in progress as of this writing.

Techniques Complications Associated Transluminal Extraction Catheter

Table

24-4.

Complication Bleeding Catheter fracture Death Embolization Thrombosis

with

the

Wholey and Jarmolowski[16]

Myers et al.[17]

— — — — 2/126 (2%)

3/144 (2%) 2/144 (1%) 2/144 (1%) — 2/144 (1%)

Atherectomy with the OmniCath device is generally performed percutaneously. The OmniCath is prepared by flushing the injection port through the guidewire lumen with heparinized saline. All the air should be evacuated from the device. Using fluoroscopic guidance, the catheter can be introduced to the obstructive lesion by either placing the OmniCath over a 0.014 in. exchange guidewire or by placing the catheter onto the exchange guidewire and then inserting this unit into an introducer sheath. The OmniCath is then advanced slowly until the cutting window is positioned against the stenotic lesion. The radiopaque gold dot at the

Chapter 24.

distal end helps confirm the proper positioning of the cutter window, which is opened by moving the cutter actuation slide to its “advanced” or closed position. The anchoring deflector wire pad is extended by advancing the wire actuation ring to stabilize the catheter and brace the cutter window against the plaque site. Before atherectomy is initiated, the guidewire is withdrawn from the catheter tip and the aspiration tubing clamp opened to provide suction to the aspiration port. The motor drive of the cutter is then activated and the cutter advanced slowly across the obstructing lesion until it has traversed the full length of the window. Aspiration should only be done during the cutting process to limit blood loss and should be performed gently. The deflector wire pad may need to be adjusted to maintain a portion of the lesion within the window. Multiple passes across the lesion may be made with the cutter window in the same location until completion angiography confirms a residual stenosis of less than 25%. If residual stenosis persists, reposition the catheter and repeat the above cutting and removal process. If the catheter is removed before completion of the procedure, aspirate heparinized saline through the catheter lumen to remove all atheromatous debris and blood remaining within the lumen.

Results Animal data using the OmniCath device for peripheral atherectomy have been published by Mazur and coworkers.[18] Concentric and eccentric lesions were induced in the bilateral external iliac arteries of 10 miniature swine and subsequently underwent atherectomy with the OmniCath device. Five swine were sacrificed 3 days after the atherectomy procedure and the other five at 6 weeks. Histologic sections of the 6-week atherectomized lesions revealed minimal healing response. No evidence of vessel wall injury or significant neointimal proliferation at the anchoring wire deployment sites was found. Angiography revealed 20% luminal narrowing in one lesion at 6 weeks. In evaluating a prototype of the device in microswine, Sapoval and colleagues[19] determined the maneuverability to be satisfactory but its aspiration apparatus inefficient. The OmniCath device underwent several modifications before it was used in humans. In an ongoing clinical trial comparing atherectomy with the OmniCath device versus balloon angioplasty in the treatment of peripheral arterial occlusive disease, Ahn et al.[20] recently reported their preliminary results on 13 patients. They concluded that in this group of high-risk, comorbid patients, atherectomy or balloon angioplasty alone demonstrated high technical failure rates, 71% and 33% for atherectomy and balloon angioplasty, respectively. However, patients who failed their initial randomization treatment were immediately crossed over to the alternate treatment modality (i.e., atherectomy ! PTA, PTA ! atherectomy) to achieve a 100% initial technical success rate and future clinical success. The primary, primary-assisted, and secondary patency rates at a mean follow-up of 9 months using the life tables method were 57%, 91%, and 100%, respectively. These results suggested that a combined therapy of atherectomy plus balloon angioplasty will increase the immediate technical success rate and may increase the long-term patency rates with additional follow-up.

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Complications/Limitations Mazur and coworkers[18] reported spasm at the atherectomy site in most animals, and Sapoval et al.[19] reported arterial rupture in 3 out of 4 animals. In the preliminary clinical data reported by Ahn et al.,[20] there were no perioperative mortalities; however, 2 of 13 patients developed hematomas at the puncture site, one requiring surgical drainage. Long-term clinical trials are currently warranted to determine the clinical safety and efficacy of the OmniCath device in the treatment of peripheral arterial occlusive disease.

Auth Rotablator Device Description The Auth Rotablator (Biophysics International, Bellevue, WA) is a flexible, ablative catheter-deliverable atherectomy device with a variable-sized, football-shaped metal burr on the distal tip (Fig. 24-5). A 0.009 in. guidewire must first traverse the lesion before rotational atherectomy can be provided. The burr is studded with multiple diamond chips (22–45 mm in size) that function as multiple microknives. The burr is available in various sizes, ranging from 1.25 to 6.0 mm in diameter. Burrs of different sizes are used during the recanalization process until a satisfactory lumen is achieved. The metal burr is welded onto a flexible drive shaft that is encased within a protective plastic sheath to form a flexible catheter-deliverable system. A control knob on top of the plastic casing allows the operator to deliberately advance or retract the burr over the guidewire. The burr rotates at 100,000–200,000 rpm and tracks along a central guidwire. The guidewire must first traverse the lesion before rotational atherectomy can proceed. The high-speed rotation allows the diamond microchips to preferentially attack hard, calcified

Figure 24-5. The Rotablator atherectomy burr and guidewire. Burrs 1.25 and 4.5 mm in diameter, respectively, are shown. Note the diamond microchips are embedded in the distal half of the burr. Also note coaxial spring tip (top) and semirigid guidewires (bottom). (From Ahn S. S.: The Rotablator-high speed rotary atherectomy: Indications, techniques, results and complications. In Moore W. S., Ahn S. S. (eds): Endovascular Surgery. Philadelphia, WB Saunders Co, 1989, pp 327 – 335.)

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atheroma while leaving the surrounding elastic soft tissue of normal arterial wall intact. The device leaves a smooth, polished intraluminal surfaces and no intimal flaps. The pulverized particles are generally smaller than red blood cells and have been shown to pass harmlessly through the circulation in previous canine studies.[21]

Indications The Auth Rotablator is ideally suited for hard calcified lesions, especially in diabetic patients who have disabling claudication or limb-threatening ischemia. Recanalization can be achieved expeditiously in short as well as long lesions. Superficial femoral, popliteal, and tibial artery lesions can be treated. Stenotic lesions are better suited for this device because a central guidewire must first traverse the lesion. Total occlusions can be treated if the guidewire can be passed. Eccentric plaques can be treated adequately since the atherectomy device preferentially attacks hard, calcified plaque.

Technique Atherectomy with the Auth Rotablator is performed preferentially through an open arteriotomy, although the percutaneous method can be used. The open cutdown approach is generally preferred because the percutaneous technique limits the burr size to 3.0 mm and ultimately required subsequent balloon angioplasty. When performing atherectomy alone, an open arteriotomy using a larger-sized burr is preferred. A 9- or 12-Fr introducer sheath is inserted into the artery through the arteriotomy. An angioscope may be inserted to document the lesion and to help with proper placement of the guidewire. Alternatively, conventional fluoroscopy can be used and is more readily available. A small atraumatic guidewire is placed through the sheath and advanced using fluoroscopic guidance through the obstructing lesion, after which an exchange guide catheter is inserted. A 0.014 in. high-torque floppy coronary guidewire is recommended. The initial guidewire is removed and replaced with a more rigid 0.009 in. atherectomy guidewire. The exchanged guide catheter is then removed while the atherectomy guidewire is left in place. The burr is backloaded onto the atherectomy guidewire followed by the drive shaft Table 24-5.

and advanced to the site of the obstructing lesion. The burr is advanced slowly in a vibratolike to-and-fro manner over the guidewire, recanalizing the artery; residual stenosis is , 25%. Initially, the burr size is half the diameter of the native artery; the size of the burr is increased incrementally until a large enough lumen is obtained. Following this initial atherectomy, the burr is removed, leaving the guidewire in place. The burr is advanced using fluoroscopic guidance. Nitrogen pressure should be set at 40 –45 psi; this will cause the surrounding tissue to snag onto the burr, and as rotation quickens, excessive heat may be produced and quickly dissipated due to the fluid around the burr. The control knob is used to slowly and gently advance the burr back and forth. Once the burr traverses the obstructive lesion it is removed; fluoroscopy is used to confirm and maintain the guidewire’s position across the lesion. Angiography is performed through the sidearm of the introducer sheath; if residual stenosis persists, a slightly larger burr is loaded onto the guidewire and the procedure is repeated until the stenosis is less than 25%. The patient is placed on anticoagulation therapy for the first 24 hours postoperatively to prevent early thrombosis. Long-term aspirin is maintained postoperatively.

Results Clinical studies reported promising and immediate clinical success rates with the Auth Rotablator (Table 24-5). However, half of these series reported only a short followup of 6 months, and patencies obtained at time interval were suboptimal, ranging from 47 to 82%. Furthermore, patencies obtained at 1 year were worse.[23,25,27] Ahn et al.[23] performed atherectomy with the Auth Rotablator in 20 patients with claudication, ulcer or gangrene, rest pain, and asymptomatic failing graft. A total of 25 lesions were treated; 20 lesions had 50–95% stenosis, and 5 lesions were occluded. Although the initial success rate was an impressive 93%, the in-hospital success rate dropped to 72% as a result of complications that developed in 17 of 25 (68%) of the cases. The 2-year cumulative patency rate was only 12%. The Collaborative Rotablator Atherectomy Group (CRAG)[25] reported their experience with the Auth Rotablator from a multicenter trial. Technical angiographic success (,25% residual stenosis) was achieved in 70 of 79

Results Reported Using the Auth Rotablator Clinical patency (%)

Authors [22]

Dorros et al. Ahn et al.[23] White et al.[24] CRAG[25] Henry et al.[26] Myers et al.[27] a

Patency at 4 months.

Patients (no.)

Lesions (no.)

Technical success (%)

Immediate clinical success (%)

6 months

12 months

24 months

43 20 17 72 150 34

82 42 18 107 212 36

95 93 94 89 97 94

88 72 94 77 85 92

— 66 82 47 58a 68

— 47 — 31 — 61

— 12 — 19 — —

Chapter 24.

limbs (89%) and in 82 of 107 arteries (77%). In addition to the 9 technical failures, in-hospital thrombosis occurred in nine limbs, resulting in an in-hospital success rate of 77% (61 of 79 limbs). Furthermore, complications occurred in approximately half of the patients, and half of them subsequently underwent an urgent or emergent surgical procedure within 30 days. Of these patients, 6 underwent an amputation, 2 of which were associated with this device. Late failure was observed in 32 limbs within a period of 15–41 months; 4 of the 32 failures also resulted in an amputation. The cumulative patency rate at 2 years was a dismal 18.6%.

Complications/Limitations As a result of the poor intermediate and long-term results discussed above, coupled with the complications associated with this device, peripheral atherectomy with the Auth Rotablator currently has limited application. Table 24-6 outlines the complications associated with device. Ahn et al.,[23] the CRAG,[25] and Henry and associates[26] all reported significant early thrombosis; Ahn et al.[23] reported 5 in-hospital cases of thrombosis, 4 of which were related to the hypercoagulable states. The CRAG[25] reported 9 cases of early thromboses (11%), 2 of which subsequently led to amputation. Henry and colleagues[26] associated the 12 thromboses (8%) in their series with a number of factors, including dissection, elastic recoil, intimal flaps, lengthy lesion, residual stenosis, and vasospasm. In addition, arterial spasm was found in 23% of cases by Dorros et al.[22] and 11% by Henry and associates,[26] most often in small distal arteries. These spasms were largely attributed to the use of large burrs, long rotational sequences, and/or rotational speed. Gross hemoglobinuria without any clinical sequalae was found in 63% of cases by Dorros and others,[22] in 20% by Ahn et al.,[23] and in 13% by the CRAG.[25] These cases were transient and developed in lesions that required larger burrs and prolonged rotational sequences. Contrary to previously reported studies, the atherectomized particles are not always small enough to pass through the reticuloendothelial system safely.[21] Indeed, embolic complications developed in 20% of cases described by Ahn et al.,[23] 10% by the CRAG,[25] and 1% by Henry and associates.[26] Three of the 8 embolic events reported by the CRAG[25] resulted in cutaneous necrosis, and one resulted in toe amputation. Similar to the other atherectomy devices, the Auth Rotablator was also reported to cause dissections, perforations, and puncture-site hematomas.[22 – 26] Also, late restenosis and reocclusions are the significant limiting factor Table 24-6.

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of the Auth Rotablator. Although most of the residual lumens achieved were less than 20%, Ahn et al.[23] reported restenosis in 45% (9 of 20) of their patients and reocclusion (4 of 5) within 18 months. Intimal hyperplasia was believed to be the causative factor in these cases. The CRAG[25] reported late restenoses and reocclusion in 40% of their patients (32 of 79 limbs) during a long-term follow-up of 15 –41 months. Henry and associates[26] reported a 24% restenosis rate, primarily in lesions 7 cm or longer. The inability to ablate and pulverize chronic thrombus and/or rubbery plaque limits the Auth Rotablator.[28] These lesions preferentially deflect away from the rotating burr, leading to suboptimal recanalization. The need for multiple burrs and the exchange of burrs over the guidewire lengthens the procedure. Although particles are generally small, a large particle burden could create a potential problem. Thus, in dealing with long, completely occluded lesions, an atherectomy-induced large-particle burden could lead to problems that have yet to be identified or defined. The device should not be used for carotid lesions, since the microemboli could lead to focal neurological deficits and perhaps even frank global cerebral dysfunction.

COMMENTS All atherectomy devices that have undergone extensive clinical investigation have failed to improve the restenosis rate of standard balloon angioplasty in the treatment of peripheral arterial occlusive disease. Despite actual removal, debulking, and polishing of the plaque, the invariable arterial wall trauma still induces intimal hyperplasia, which subsequently results in restenosis. Initial studies of atherectomy reported promising results, but subsequent follow-up has demonstrated poor intermediate and long-term patency rates. Moreover, follow-up illustrated that the intermediate and long-term patencies were less than satisfactory when compared with standard balloon angioplasty. These results contradicted the postulate that physical removal of arterial plaque using atherectomy would lower the rate of restenoses compared to the mechanical reorganization seen in PTA. Until the problem of restenosis can be resolved, atherectomy will be limited to those instances when balloon angioplasty may be ineffective or contraindicated. Such instances might include the presence of hard, calcified lesions that are difficult to dilate, the presence of intimal flaps or dissections

Complications Associated with the Auth Rotablator

Complications Bleeding Dissection Embolization Hematoma Hemoglobinuria Thrombosis

Dorros et al.[22]

Ahn et al.[23]

White et al.[24]

CRAG study[25]

Henry et al.[26]

Myers et al.[27]

— — — 10/43 (23%) 27/43 (63%) 1/43 (2%)

— 1/20 (5%) 4/20 (20%) 1/20 (5%) 4/20 (20%) 5/20 (25%)

— — — 1/17 (6%) — 1/17 (6%)

10/79 (13%) 5/79 (6%) 8/79 (10%) 4/79 (5%) 10/79 (13%) 9/79 (11%)

— — 2/150 (1%) — — 12/150 (8%)

1/34 (3%) — — — — —

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secondary to the balloon angioplasty itself, or ulcerative lesions that have lead to thromboembolic complications. Furthermore, Porter et al.’s[2] report of their 6-year experience using directional atherectomy for vein graft stenoses is encouraging. They showed that the technique has a high technical and clinical success rate and approached patency rates seen in surgical vein patch angioplasty. Recently, atherectomy has been indicated for the treatment of failing hemodialysis fistulas; although the data are not definitive, the initial results are encouraging. Also, the

preliminary data on the combined use of atherectomy and balloon angioplasty appear promising. The results reported by Ahn et al.[20] suggest that combined therapy will increase the intermediate success rate and may increase the long-term patency rates with additional follow-up, further validating the study conducted by Osborn and associates.[15] Continued long-term follow-up and further investigation of combined therapy, as well as the use of atherectomy in the treatment of vein graft stenoses and failing hemodialysis fistulas, is clearly warranted.

REFERENCES 1. Dolmatch, B.L.; Gray, R.J.; Horton, K.M.; Rundback, J.H.; Kline, M.E. Treatment of Anastomotic Bypass Graft Stenosis with Directional Atherectomy: Short-Term and Intermediate-Term Results. J. Vasc. Intervent. Radiol. 1995, 6, 105– 113. 2. Porter, D.H.; Rosen, M.P.; Skillman, J.J.; Kent, K.C.; Kim, D. Long-Term Results with Directional Atherectomy of Vein Graft Stenoses. J. Vasc. Surg. 1996, 23, 554– 567. 3. Zemel, G.; Katzen, T.; Dake, M.D.; Benenati, J.F.; Lempert, T.E.; Moskowitz, L. Directional Atherectomy in the Treatment of Stenotic Dialysis Access Fistulas. J. Vasc. Intervent. Radiol. 1990, 1, 35– 38. 4. Gray, R.J.; Dolmatch, B.L.; Buick, M.K. Directional Atherectomy Treatment for Hemodialysis Access: Early Results. J. Vasc. Intervent. Radiol. 1992, 3, 497 –503. 5. Simpson, J.B.; Selmon, M.R.; Robertson, G.C.; et al. Transluminal Atherectomy for Occlusive Peripheral Vascular Disease. Am. J. Cardiol. 1988, 61, 96G – 101G. 6. Graor, R.A.; Whitlow, P.L. Transluminal Atherectomy for Occlusive Peripheral Vascular Disease. J. Am. Coll. Cardiol. 1990, 15, 1551– 1558. 7. Vroegindewij, D.; Tielbeek, A.V.; Buth, J.; Schol, F.P.G.; Hop, W.C.J.; Landman, G.H. Directional Atherectomy Versus Balloon Angioplasty in Segmental Femoropopliteal Artery Disease: 2-Year Follow-Up with Color Flow Duplex Scanning. J. Vasc. Surg. 1995, 21, 255– 269. 8. Lugmayr, H.; Pachinger, O.; Deutsch, M. Long-Term Results of Percutaneous Atherectomy in Peripheral Arterial Occlusive Disease. Rofo. Fortschr. Geb. Ro¨ntgenstr. Bildgeb. Verfahr. 1993, 158, 532– 535. 9. Polnitz, A.; Nerlich, A.; Berger, H.; Hofling, B. Percutaneous Peripheral Atherectomy. J. Am. Coll. Cardiol. 1990, 15, 628– 688. 10. Hinohara, T.; Selmon, M.R.; Robertson, G.C.; Braden, L.; Simpson, J.S. Directional Atherectomy: New Approach for Treatment of Obstructive Coronary and Peripheral Vascular Disease. Circulation 1990, 81 (Suppl. IV), IV79– IV-91. 11. Dorros, G.; Iyer, S.; Lewin, R.; Zaitoun, R.; Mathiak, L.; Olson, K. Angiographic Follow-Up and Clinical Outcome of 126 Patients After Percutaneous Directional Atherectomy (Simpson AtheroCath) for Occlusive Peripheral Vascular Disease. Catheter. Cardiovasc. Diagn. 1991, 22, 79–84. 12. Kim, D.; Gianturco, L.E.; Porter, D.H.; Orron, D.E.; Kuntz, R.E.; Kent, K.C.; Siegel, J.B.; Schlam, B.W.; Skillman, J.J.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

Peripheral Directional Atherectomy: 4-Year Experience. Radiology 1992, 183, 773– 778. Savader, S.J.; Venbrux, A.C.; Mitchell, S.E.; Trerotola, S.O.; Wang, M.C.; Sneed, T.A.; Tudder, G.B.; Rosenblatt, M.; Lund, G.B.; Osterman, F.A. Percutaneous Transluminal Atherectomy of the Superficial Femoral and Popliteal Arteries: Long-Term Results in 48 Patients. Cardiovasc. Intervent. Radiol. 1994, 17, 312– 318. Widenhain, P.M.; Wholey, M.H.; Jarmolowski, C.R.; Hill, K.L. Infrainguinal Directional Atherectomy: Long-Term Follow-Up and Comparison with Percutaneous Transluminal Angioplasty. Cardiovasc. Intervent. Radiol. 1994, 17, 305– 311. Osborn, J.J.; Pfeiffer, R.B.; String, T. Directional Atherectomy and Balloon Angioplasty for Lower Extremity Arterial Disease. Ann. Vasc. Surg. 1997, 11, 278–283. Wholey, M.H.; Jarmolowski, C.R. New Reperfusion Devices: The Kensey Catheter, the Atherolytic Reperfusion Wire Device, and the Transluminal Extraction Catheter. Radiology 1989, 172, 947– 952. Myers, K.A.; Denton, M.J.; Devine, T.J. Infrainguinal Atherectomy Using the Transluminal Endarterectomy Catheter: Patency Rates and Clinical Success for 144 Procedures. J. Endovasc. Surg. 1994, 1, 61– 70. Mazur, W.; Ali, M.N.; Rodgers, G.P.; Schulz, D.G.; French, B.A.; Raizner, A.E. Directional Atherectomy with the Omnicath: A Unique New Catheter System. Catheter. Cardiovasc. Diagn. 1994, 33, 79. Sapoval, M.R.; Gaux, J.C.; Bruneval, P.; Peronneau, P. Animal Evaluation of the Prototype OmniCath Catheter. Cardiovasc. Intervent. Radiol. 1994, 17, 226. Ahn, S.S.; Daniel, E.J.; Ro, K.M. Personal Communication. Presented at the XI Annual International Congress Endovascular Interventions, Scottsdale, Arizona, February 1998. Ahn, S.S.; Arca, M.; Brauel, G.; Marcus, D.L.; Auth, D.C.; Moore, W.S. Histological and Morphological Effects of Rotary Atherectomy on Human Cadaver Arteries. Ann. Vasc. Surg. 1990, 4, 563– 569. Dorros, G.; lyer, S.; Zaitoun, R.; Lewin, R.; Cooley, R.; Olson, K. Acute Angiographic and Clinical Outcome of High Speed Percutaneous Rotational Atherectomy (Rotablator). Catheter. Cardiovasc. Diagn. 1991, 22, 157– 166. Ahn, S.S.; Eton, D.; Yeatman, L.R.; Deutsch, L.S.; Moore, W.S. Intraoperative Peripheral Rotary Atherectomy: Early

Chapter 24. and Late Clinical Results. Ann. Vasc. Surg. 1992, 6, 272– 280. 24. White, C.J.; Ramee, S.R.; Escobar, A.; Jain, S.; Collins, T.J. High Speed Rotational Ablation (Rotablator) for Unfavorable Lesions in Peripheral Arteries. Catheter. Cardiovasc. Diagn. 1993, 30, 115– 119. 25. The Collaborative Rotablator Atherectomy Group (CRAG); Peripheral Atherectomy with the Rotablator: A Multi-Center Report. J. Vasc. Surg. 1994, 19, 509 – 515.

26.

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Henry, M.; Amor, M.; Ethevenot, G.; Henry, I.; Allaoui, M. Percutaneous Peripheral Atherectomy Using the Rotablator: A Single Experience. J. Endovasc. Surg. 1995, 2, 51– 66. 27. Myers, K.A.; Denton, M.J. Infrainguinal Atherectomy Using the Auth Rotablator: Patency Rates and Clinical Success for 36 Procedures. J. Endovasc. Surg. 1995, 2, 67– 73. 28. Ahn, S.S. Peripheral Atherectomy. Semin. Vasc. Surg. 1989, 2, 143– 154.

CHAPTER 25

Endovascular Grafts for Aneurysms, Occlusive Disease, and Vascular Injuries Takao Ohki Evan C. Lipsitz Frank J. Veith direct exposure of the diseased artery through extensive incisions and/or dissection. This chapter reviews the design and use of endovascular grafts in the treatment of various vascular pathologies including aortoiliac aneurysms, aortoiliac occlusive disease and traumatic vascular lesions. In addition, it will explore the future potential of this technology.

INTRODUCTION The past several decades have witnessed a marked improvement in the treatment results for a variety of vascular lesions. The operative mortality for elective repair of aortic aneurysms has decreased from 21% in early surgical series to less than 5% in recent studies.[1 – 5] Lower extremity occlusive disease with ischemic tissue loss which at one time mandated major amputation can now be treated by either interventional techniques, bypass surgery, or a combination of the two with favorable limb salvage rates.[6] Finally, despite advances in the delivery of emergency medical services and in critical care medicine, major arterial injury secondary to penetrating or blunt trauma has remained a challenging problem, especially when central arteries such as the aorta, the iliacs, or the subclavian arteries are involved.[7 – 9] Despite these improvements in the management of vascular lesions, significant perioperative morbidity and mortality still occur, particularly in cases associated with severe comorbid medical illness, scarring from previous operations, or multiorgan trauma.[10 – 13] Even in good-risk patients, standard vascular repairs have associated morbidity. Additionally, standard surgical treatment adversely impacts quality-of-life measures such as incisional pain and paresthesias, sexual dysfunction, and other problems. Finally, lengthy hospital stays are a major contributing factor to rising health care costs. These problems are at least in part related to the large incisions and extensive tissue dissection required for surgical access to major arterial lesions. Endovascular grafting is a blend of intravascular stent and prosthetic graft technologies, which offers an alternative to standard open treatment of vascular pathology. Endovascular grafts are inserted through remote arterial access sites to treat vascular lesions at a distance, thus eliminating the need for

HISTORY OF ENDOVASCULAR GRAFTS Attempted repair of aortic aneurysms using an intraluminal approach has a long history, which predates both early and modern open surgical techniques. In 1813 an Italian surgeon, Giovanni Monteggia, unsuccessfully attempted to “harden” the wall of an aneurysm by injecting a sclerosing agent into the lumen.[14] In 1864 Charles Moore attempted to promote thrombosis of a thoracic aneurysm by injecting 75 feet of silver wire into the sac.[15] This latter technique was expanded in 1879 by Corradi, who passed an electrical current through intraluminally placed wires to increase thrombosis.[16] Blakemore and King further refined this technique in 1938 when they described electrothermic methods for inducing thrombosis of aneurysms by heating intraluminal wires with an electric current.[17] The beginning of the modern era of endovascular grafting can be traced back to 1969, when Dotter placed plastic tubular endovascular prostheses into canine femoral and popliteal arteries.[18,19] The problem of thrombosis in these grafts was addressed by replacing them with a stainless steel wire made into a coilspring configuration. Although acceptable longterm patency was obtained, significant intimal hyperplasia

Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024908 Copyright q 2004 by Marcel Dekker, Inc.

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developed within the grafts. Due to size constraints and the lack of compressibility of these devices, only small-bore grafts could be placed. The use of nitinol, a nickel –titanium alloy that possesses temperature-dependent memory, in these stents allowed for larger devices to be placed. The experimental work of Balko, Mirich, and their colleagues[20,21] with exclusion of experimental aneurysms and Lazarus’s patent for an endovascular graft appeared in the late 1980s.[22] The first endovascular graft placed in a patient was reported by Volodos et al. in 1986,[23] but this Russian report received little attention. However, the report of Parodi and his colleagues in 1991 of five cases of abdominal aortic aneurysms treated with endovascular grafts stimulated a great deal of interest in this approach.[24] These authors described a Dacron graft sutured to balloonexpandable slotted stainless steel Palmaz stent to treat a large abdominal aortic aneurysm using epidural anesthesia in a 70-year-old symptomatic patient who was felt not to be a candidate for conventional open repair. A total of five cases were reported in this preliminary series, and, although one patient required conversion to open repair after accidental stent deployment within the iliac artery, subsequent follow-up showed patent grafts without aneurysm related complications in the remaining patients. The first endovascular repair of an abdominal aortic aneurysm (AAA) in North America was performed by the Montefiore Hospital group in 1992.[25]

ENDOVASCULAR GRAFTS FOR ABDOMINAL AORTIC ANEURYSMS Almost a decade has passed since Parodi’s group first reported the use of endovascular stented grafts to treat abdominal aortic aneurysms.[24] During this early experience, we and others utilized largely physician-made devices constructed

from either Palmaz or Gianturco (self-expanding) stents.[26] Each of these physician-made devices consists of a single unit, and although there are several different configurations, the majority consist of a tubular aortoaortic or an aortouniiliac configuration. It was several years after Parodi’s report before the first industry-made stent-grafts appeared. Recently, a number of these industry-made devices have become available for clinical trials in the United States, including Vanguard (Boston Scientific Corp.), Talent (World Medical), Ancure (Guidant-EVT), AneuRx (Medtronic), Corvita (Schneider), Excluder (W.L. Gore), Zenith (Cook), and Baxter grafts (Baxter) (Fig. 25-1). These industry-made devices are mostly bifurcated grafts, the majority of which consist of two or more components (modular grafts), although they are also made in tubular versions. Endovascular graft devices can be categorized into a few distinct types based on device design and the anatomic variations of the aneurysm they can treat.

Construction and Design Self-Expanding vs. Balloon-Expandable Stents Endovascular grafts are a combination of vascular stents and prosthetic grafts where the stents serve as fixation devices and sometimes as support skeletons. Depending on the type of stent that is used, endovascular grafts can be categorized into two distinct types, self-expanding or balloon-expandable. The advantages of self-expanding devices include ease of deployment and the ability to accommodate some degree of subsequent aortic neck enlargement. All manufactured grafts except the LifePath (Baxter) employ self-expanding stents. An example of a “surgeon-made” device with a selfexpanding stent is the Chuter graft. The balloon-expandable stent that has been used for endovascular grafts has predominantly been the large Palmaz stent (P5014)(Cordis, Johnson and Johnson, Warren, NJ).

Figure 25-1. Various types of endovascular grafts used for the treatment of AAA. From left: Montefiore endovascular graft, Ancure graft, Vanguard graft, Corvita endoluminal graft, Talent graft, AneuRx graft, Excluder graft, Zenith graft.

Chapter 25.

Endovascular Grafts for Aneurysms, Occlusive Disease, and Vascular Injuries

Although this stent may be technically more demanding to deploy accurately at the desired location, it has stronger radial (hoop) strength than self-expanding stents. This may be important in preventing graft migration if one considers the high aortic flow and pressures that these endovascular grafts must withstand. The Palmaz stent has been used for many surgeon-made devices, including the Parodi graft, the Montefiore endovascular graft (Fig. 25-1), and the Leicester graft. The LifePath has a specially made, balloon-expandable stent that is called a graft attachment device (GAD).

Fully Supported vs. Partially Supported Grafts Most manufactured grafts are “fully supported” or have a stent that supports the entire length of the graft. This feature has several advantages. First, when endovascular grafts are deployed in tortuous arteries, this fully supported framework will help to prevent compression or kinking of the graft, a phenomenon that has been encountered more frequently in grafts that lack this support.[27] Second, this full support adds additional column or longitudinal strength to withstand distortion or displacement by the aortic flow. This strength is essential to keep the graft in position during deployment. In addition, this feature may help prevent distal migration of the graft even if the proximal stent lacks secure fixation.

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Examples of Individual Devices for Endovascular AAA Repair Ancure (Guidant EVT, Menlo Park, CA) Unlike other devices, the Ancure device secures the graft to the proximal and distal aneurysm necks with stents that have hooks. A balloon is used to ensure seating of the stent hooks into the aortic wall. In addition to the tubular version of this graft, second-generation models consist of bifurcated and aortouniiliac versions, which lack hooks on the distal stents. The latter version of this graft resembles that originally used by Parodi and requires the placement of a femorofemoral bypass graft and an occluder in the contralateral iliac artery. Regardless of the configuration, all Ancure grafts consist of a

Single Component vs. Multiple Component (Modular) Since the anatomy, length, and diameter of aortic and aortoiliac aneurysms vary significantly from patient to patient, it is advantageous for an endovascular graft to have a certain dimensional adaptability to accommodate this variability. Variability in length between the proximal and the distal ends or termination points can be managed by changing the amount of overlap between each of two modular components. This concept was first described by the Sydney group and was called the “trombone” graft.[28] In the bifurcated grafts the additional limb of a modular bifurcated graft as well as extenders will serve to achieve this form of lengthwise dimensional adaptability.[29] The distal landing zone of the limb can be adjusted by changing the amount of overlap between the main body and the limb. In addition, the length of the main limb can be extended distally with an extender stent-graft. All industry-made devices except for the Ancure graft utilize such a system. Another approach to achieve length adaptability is demonstrated by the Montefiore endovascular graft system (MEGS) (Fig. 25-2), and the Leicester graft.[26] These grafts have enough length so that the distal end of the graft emerges from the insertion femoral arteriotomy site, thereby allowing the surgeon to customize the length of the graft during the procedure. The distal end of the graft is cut to the appropriate length and a sutured endoluminal anastomosis is performed within the femoral artery. Endovascular grafts that lack such length versatility include the Chuter and the Ancure grafts. Precise preoperative measurement of the length of the graft is therefore crucial when using these grafts.[26]

Figure 25-2. A schematic drawing of the Montefiore endovascular graft. The bare portion of the proximal stent is placed above the renal arteries in order to maximize the fixation within the aorta. The graft covered portion of the stent marked by the radiopaque bead is placed just below the renal arteries (m). The distal end of the graft is brought out of the insertion arteriotomy site where it is cut to the appropriate length and fixed with a hand-sewn endoluminal anastomosis (e). (c: embolization coils, o: occluder device). (From Ref. [26].)

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single component. This means that the graft lacks the ability for intraoperative customization, and therefore, precise preoperative length measurement is essential when using this device. Since the size of the introducer sheath is 24 Fr in outer diameter, difficulties inserting the device through the femoral and iliac arteries as well as injuries to these vessels have been encountered. The Ancure graft is the only industrymade device that lacks a stent in the midportion of the graft. This has led to compression or kinking of the graft limb, which has resulted in graft occlusion.[27] In such cases, placement of an additional intragraft stent, either a Wallstent (Schneider, Minneapolis, MN) or a Smart stent (Johnson & Johnson, Warren, NJ), has been required.

Vanguard Endovascular Aortic Graft (Meadox, Oakland, NJ) and AneuRx Graft (Medtronic, Eden Prairie, MN) The Vanguard device employs a temperature-dependent Nitinol stent for fixation and structural support of the graft body, which is made of Dacron fibers. The stent is placed inside the graft to which it is held by sutures. This device is modular and is composed of a main graft and a separate contralateral limb component.[30] The main graft is loaded into a 20.5 Fr outer-diameter introducer sheath and delivered through a femoral arteriotomy site. The proximal stent is deployed just below the lowest renal artery. An extender graft may be added to the iliac limb of the main graft if required. Following deployment of the main graft, a contralateral limb is inserted via the contralateral femoral artery and deployed. This graft is currently undergoing Phase II FDA trials in the United States for good-risk patients. The AneuRx graft (Medtronic, Eden Prairie, MN) resembles the Vanguard graft, except for the fact that the entire supporting Nitinol stent is located outside the graft material.

Talent Endovascular Bifurcated Spring Graft (World Medical Manufacturing Corporation, Sunrise, FL) The Talent graft is similar to the Vanguard in regard to its modular configuration and its utilization of a Nitinol stent skeleton. Since the proximal stent has wide interstices, one can place the uncovered portion of the stent above and across the renal artery orifices. This feature along with the high hoop strength of the stent allows this device to treat some abdominal aortic aneurysms with a short proximal neck (# l.5 cm). In addition, this graft is supported with longitudinal Nitinol wire throughout its entire length. This gives the graft additional column strength, which prevents downward displacement of the graft by aortic flow during deployment as well as helping to prevent distal migration in cases where the proximal stent lacks secure fixation. In addition to the standard sizes, this graft can be custom-made to fit those patients that cannot be treated with standard-sized grafts. This customization includes graft diameter (up to 36 mm) as well as length and configuration.

The Zenith (Cook, Inc., Indianapolis, IN) The Zenith is a derivative of surgeon-made graft. It initially was used by Chuter et al. and subsequently by many others around the world. It is a combination of a large Gianturuco stent and Dacron fabric. The Zenith is unique in several aspects of its design. First, it has a long uncovered stent at its proximal end. This stent also has multiple long barbs that assures secure fixation of the stent into the suprarenal aortic neck. Second, although it is a modular bifurcated design, it is composed of three components: the main body and the two limbs. This allows for intraoperative customization of both length and diameter of each attachment site. Finally, it can treat aneurysms with proximal neck diameter up to 30 mm and distal neck diameter up to 22 mm, which is the widest range among all industry-made bifurcated grafts. It also can be custom-made.

The Excluder (W.L. Gore and Associates, Flagstaff, AZ) The Excluder is composed of an external Nitinol framework and an ultrathin polytetrafluoroethylene (PTFE). This is the only endovascular graft that does not utilize an outer introducer sheath as a deployment mechanism. Instead, the selfexpanding graft is encased in a thin membrane, which is connected to a strip cord. Once the graft is in place, the operator will pull the strip cord, releasing the thin membrane and thereby deploying the graft. Because of this unique deploying system that does not require a rigid sheath, the introducer system is extremely flexible. In addition, the fact that each Nitinol stent is independent and is not attached to another contributes to the flexibility of the system. The ease of use and the flexibility of the graft are the strengths of this graft.

The Montefiore Endovascular Graft System (MEGS) The MEGS device is a derivative of the original Parodi graft, which was fabricated from a Palmaz stent and a Dacron graft. [24] The current MEGS has undergone several modifications and has several improvements, which have increased its versatility and its ease of use (Fig. 25-2).[26] It utilizes a tulip-shaped PTFE graft instead of a Dacron graft. Originally, the length of the graft needed to be measured precisely preoperatively so that the distal end could be fixed in the common or the external iliac artery by a second stent. This precise measurement was difficult, and placement of the second stent added complexity to the procedure. The current MEGS endovascular graft is made long enough so that in each case, the distal end of the graft will emerge from the insertion site in the femoral artery. The graft is then cut to the appropriate length as it emerges from the artery and is sutured to the inside of the femoral artery to fashion an endoluminal anastomosis. This has enhanced the ease of the procedure by eliminating difficult preoperative length measurements and a potential endoleak site (distal attachment site leak). Another beneficial modification has been the placement of the proximal uncovered portion of the stent above the orifice of the renal arteries. This provides more secure fixation of the proximal stent even in cases with necks shorter than 1.5 cm.

Chapter 25.

Endovascular Grafts for Aneurysms, Occlusive Disease, and Vascular Injuries

Furthermore, contralateral iliac outflow obstruction during stent-graft deployment allows for more precise control and has increased the accuracy of stent placement, which is of paramount importance in cases where the proximal neck is short.[31] For the delivery system, we have been able to decrease the outer diameter of the introducer sheath from 24 Fr to 16 Fr. These modifications, along with some technical improvements such as the occasional use of a brachial wire and snare (which adds tension to the guidewire and helps to straighten tortuous iliac arteries and aneurysm necks), have facilitated device insertion. This has expanded the anatomic variations that can be treated with this type of endovascular graft. There is little question that the industry-made modular devices have made the insertion of these grafts easier and less complicated than was the case with the surgeon-made grafts. This relative ease of device delivery led many to believe that surgeon-made devices might become obsolete. However, as experience with endovascular grafting has increased, it has become apparent that the modular devices are largely applicable only in selected cases with favorable anatomy, as already discussed (Fig. 25-3). On the other hand, surgeonmade devices, especially the MEGS, have become far more versatile in their ability to treat a wide range of patients, including many who were excluded from industry-made protocols (Figs. 25-4 and 25-5). This is attributable to the versatility of the MEGS device itself and to the strong radical force generated by the Palmaz stent. At our institution, we have shown that 80% of consecutive AAA cases can be treated with an endovascular graft, while only 20% required open repair (Fig. 25-6).[32] Of the endovascular grafts used in this series, various industry-made devices accounted for approximately 50% of grafts placed while the MEGS accounted for the remaining 50%. The ability to treat such a high proportion of patients by endovascular methods depends on having access to a wide variety of grafts, each of which expands the inclusion criteria for and/or the advantages of endovascular repair.

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Basic Setup of the Operating Room The operator and first assistant usually stand on the right side of the patient and the screen of the fluoroscope is placed so that it faces the operator (Fig. 25-7). The operating table must be radiolucent and is controlled (height, oblique, and longitudinal adjustments) by the surgeon using a foot pedal. An extension table is attached to the caudal end of the operating table so that the lengthy guidewires and catheters are supported and do not become contaminated. This extension table has wheels so that it simultaneously moves with the operating table.

Basic Technical Considerations Unlike open repair, endovascular repair is performed from remote access sites. Therefore, the surgeon does not have direct control of the devices employed for repair such as

Required Equipment for Endovascular Grafting The vast majority of endovascular grafts are currently performed in an operating room using a portable C-arm digital fluoroscope with road-mapping capabilities (Philips Models BV-212, BV-312 Philips Medical systems, Bridgeport, CT; OEC Diasonics, Model 9600, OEC Medical Systems, Inc., Salt Lake City, UT). The rationale for performing procedures in an operating room environment includes: (1) the potential need for rapid conversion to an open major surgical procedure without delay when necessary; (2) an optimally sterile environment, which is mandatory since all the devices currently leave prosthetic material within the body and require surgical exposure of the femoral artery (although infection has not been a major problem, the risk of graft infection must be minimized); and (3) the ability to perform open procedures simultaneously, such as femorofemoral bypass or repair of a damaged iliac or femoral artery.

Figure 25-3. (A) Preoperative angiogram of an aneurysm suitable for industry made devices. The aneurysm is characterized by (1) long straight proximal neck, (2) good quality common iliac artery, (3) minimal tortuosity. (B) Completion angiogram. This particular case was treated using the Vanguard bifurcated graft. Complete exclusion of the aneurysm as well as preservation of renal and hypogastric arteries are demonstrated. (From Ref. [129].)

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Figure 25-4. (A) Preoperative angiogram of an aneurysm with short proximal neck and bilateral iliac artery occlusive disease. In addition there is a large left internal iliac artery aneurysm that precludes the use of current bifurcated grafts. (B) Completion angiogram following deployment of an aortounifemoral graft, femorofemoral bypass (f) and an occluder device (o). Note that the bare portion of the proximal stent (s) is placed across the renal arteries. (c: embolization coils.)

catheters, guidewires, and the graft itself. In addition, all endovascular manipulation is performed under fluoroscopic guidance, which gives the surgeon only a two-dimensional image. Moreover, the information provided by these fluoroscopic images is quite limited. Radiolucent structures including thrombus, plaque, arterial wall, radiolucent catheters, and graft material are not visualized. Therefore, throughout the procedure the operator must conceptualize all events that may be occurring, including those not revealed on fluoroscopic imaging. These events include arterial dissection, rupture, embolization, and kinking or tearing of the graft. Another limiting factor is the size of the field fluoroscopy provides compared to open repair in which the surgeon can obtain a great deal more information visually by simply adjusting his/her field of view or by tactile sensation. Therefore, when performing an endovascular repair, the operator must constantly be cognizant of those elements that are both outside the fluoroscopic field or not visualized fluoroscopically. The operative technique required for endovascular AAA repair is not simply a blend of surgical and interventional

techniques, but rather involves many techniques that are unique to this procedure. These techniques are constantly evolving and are yet to be standardized. Although the basic principles are consistent among various devices, it is likely that some new and different techniques will be required for each new device that is developed.

Techniques to Obtain Vascular Access All currently available devices require surgical exposure and an arteriotomy in the femoral artery due to the large profiles of the introducer systems. The incision is placed higher (close to the inguinal ligament) than for a standard femoropopliteal bypass, and retraction of/or partial division of the inguinal ligament may be necessary in order to dissect the external iliac artery. This technique is helpful in straightening a tortuous external iliac artery, which is not an uncommon finding in complex AAA cases. Following arterial exposure, vessel loops are placed around the artery proximal and distal to the puncture site. It is usually not

Chapter 25.

Endovascular Grafts for Aneurysms, Occlusive Disease, and Vascular Injuries

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Figure 25-5. (A) Intraoperative angiogram of a 7 cm aneurysm with (1) severely angulated proximal neck and (2) aortoiliac occlusive disease which precluded the use of industry-made endovascular grafts (EVGs). The patient had oxygen-dependent chronic obstructive pulmonary disease (COPD) and severe coronary artery disease (CAD) and was not a good candidate for open repair. (B) Endovascular repair was successfully performed under epidural anesthesia utilizing the Montefiore endovascular graft. Completion angiogram reveals complete exclusion of the aneurysm and absence of an endoleak.

necessary to dissect the origin of the deep femoral artery unless the common femoral artery is heavily calcified and unclampable. An 18-gauge, one-wall needle is used to puncture the artery, and a 0.035 inch guidewire is inserted through the needle. The needle is then removed and an introducer sheath (7–9 Fr. 10–25 cm long) is inserted over the guidewire.

Deployment Technique of a Bifurcated Modular Graft The previously placed guidewire is then exchanged for a superstiff wire to help to straighten any tortuosity in the access vessel and to improve trackability of the device. A

marker pigtail catheter is inserted in the proximal neck through a sheath inserted in the contralateral femoral artery. The ipsilateral femoral artery is clamped proximally and distally to the sheath insertion site with a hydrogrip clamp and the sheath is then removed. A vertical artcriotomy is made with a knife for the insertion of the large sheath containing the main graft. Once the introducer sheath is advanced to the proximal neck of the AAA, an angiogram is performed via the pigtail catheter to identify the location of the lowest renal artery. The position of the sheath containing the stented graft is adjusted based on this angiogram. In general, since it is possible to pull the stent graft caudally, but difficult to push it cranially, when it is partially deployed it is recommended to begin the deployment at a point higher than the desired site. After partial deployment, the stent-graft is pulled caudally to

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Figure 25-6. Breakdown of how AAAs were treated at Montefiore Medical Center during 1997 –1998. MEGS: Montefiore endovascular grafting system.

the target site and the deployment completed. Deployment is performed by maintaining the pusher rod stationary and retracting the outer sheath. Following complete deployment, a balloon is inflated within the entire length of the graft to ensure full expansion and anchoring (Fig. 25-8). The pigtail catheter that was inserted from the contralateral side is retracted into the aneurysm prior to final deployment and exchanged to a directional catheter after deployment. This is then used to cannulate the short limb of the graft (Fig. 25-8). Since the short limb orifice is located within the aneurysm, difficulties in cannulating it may be encountered. An alternative means to cannulate the short limb is to pass a guidewire either from within the contralateral (main graft) side (over the top of the bifurcation) or from the brachial artery. This wire can then be introduced down to the femoral

Figure 25-7. Basic setup of the operating room. The operator stands on the right side of the patient and the screen of the fluoroscope (S) is placed so that it faces the operator. A foot switch (F) for the fluoroscope and the table are placed in front of the operator (O). An extension table (E) is attached caudal to the operating table. The cranial end of the operating table is placed towards the caudal end of the patient and the post of the table (P) is under the patient’s lower extremity. The left arm is also prepped in case a brachial access is required. A, assistants; N, nurse; C, fluoroscope; AN, anesthesiologist; T, table for endovascular equipment. (From Ref. [130].)

Figure 25-8. Implantation sequence of a modular graft. (A) The delivery system containing the main body is advanced in to the aorta over a superstiff guidewire. (B) Deployment is performed by maintaining the pusher rod stationary and retracting the outer sheath. Following complete deployment, a balloon is inflated within the entire length of the graft to ensure full expansion and anchoring. (C) Once the short limb is cannulated with a guidewire, a sheath containing the contralateral limb is passed over the wire. (D) Retraction of the outer sheath will expose the graft and deployment will be completed. (From Ref. [131].)

Chapter 25.

Endovascular Grafts for Aneurysms, Occlusive Disease, and Vascular Injuries

artery or can be captured with a snare inserted from the ipsilateral (short limb side) femoral artery. Once the short limb is cannulated with a guidewire, an angiogram is taken through the side port of the sheath to localize the orifice of the hypogastric artery. The marker pigtail can be used to measure the distance between the short limb and the hypogastric artery. Based on this measurement, the appropriately sized contralateral limb is chosen and inserted over the wire into the short limb. At this point, the operator should focus on the distal end of the extension limb so that it does not cover the orifice of the hypogastric artery (Fig. 25-8) while assuring that there is sufficient overlap between the stent limb and the extension. Retraction of the outer sheath will expose the graft and deployment will be completed. An angioplasty balloon is used to ensure full expansion and fixation. Following a completion angiogram, all the sheaths and wires are removed and the arteriotomics arc closed. At this point, the abdomen should be palpated to confirm resolution of the pulsatility of the AAA. If an endoleak is identified on angiogram, the source should be identified and corrected. If the endoleak is due to too low a deployment of the proximal stent, a covered stent may be deployed proximal to the stent graft. For distal attachment site leaks, an extra limb may be used. Those endoleaks that originate from the junction site between the main body and the limb may be corrected by deployment of a Palmaz stent or an additional covered stent. Stenosis due to buckling, twist, or kink of the limb is more often found in grafts that lack stent support, and these stenoses are best treated with a Wallstent (Schneider). A pull through pressure gradient study is then performed, which can sometimes detect an abnormality even in those cases without angiographic findings. Although we do not routinely use intravascular ultrasound, in this circumstance it may be a very useful tool to clarify the cause of unexpected pressure gradients. In cases where the femoral artery is small or diseased, a patch closure of the arteriotomy may be performed. Before completing the procedure, pulse examination or angiography should document adequacy of the distal circulation or restoration of the preoperative status.

Patient Selection for Endovascular Graft Repair of AAA Three basic graft configurations are utilized for the endovascular repair of abdominal aortic aneurysms: aortic tube, bifurcated modular aortobiiliac, and aortouniiliac or aortounifemoral with placement of a contralateral common iliac occlusion device and femorofemoral bypass graft. Only a certain proportion of abdominal aortic aneurysms are anatomically suitable for endoluminal repair with each of these devices. It has been estimated that 4 –14% of aneurysms are suitable for aortic tube stent-grafts,[33 – 36] 30–50% for aortobiiliac stent-grafts,[30,37] and 55% for aortouniiliac stentgrafts.[38] The exact selection criteria and contraindications for these procedures have yet to be precisely defined, but are evolving rapidly. Suitability for endovascular repair varies depending on which endovascular graft system is chosen and its suitability for a given patient’s anatomy. Moreover, the selection criteria utilized for each of the endovascular grafting

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systems are completely different from those traditionally used for open repair. This section reviews the unique selection criteria for endovascular AAA repair with reference to the different endovascular grafting systems currently available.

PREOPERATIVE IMAGING The evaluation of patients for endovascular AAA repair includes a screening abdominopelvic computed tomography (CT) scan. This study should be performed with intravenous contrast on a spiral scanner using 3 –6 mm cuts. Aneurysm length, diameter, and the quality and dimensions of the proximal and distal necks are evaluated along with the characteristics and diameter of the access vessels. The presence or absence of mural thrombus at the necks, which is of paramount importance, can only be ascertained on CT scan. If it appears that the patient may be a candidate for endovascular grafting based on the CT findings, then a contrast aortogram is performed. This permits assessment of the renal, inferior mesenteric, and iliac arteries. The mesenteric circulation as a whole, lumbar arteries, and any other aberrant vessels are evaluated. Tortuosity, kinking, size (diameter), and calcification of the iliac vessels, which have implications for device insertion and deployment, are noted. The study is performed with a calibrating catheter, which contains radiopaque markers at 1 cm intervals allowing for precise measurement of the vessels by minimizing the effects of parallax and magnification. However, since preoperative arteriography has some morbidity (0.5 – 1%) and cost ($2000–$3500), a magnetic resonance angiogram (MRA) or an intraoperative angiogram at the time of endovascular graft insertion may be used in place of preoperative arteriography.[39,40]

ANATOMIC SELECTION CRITERIA Regardless of the type of endovascular graft used, there are several anatomic criteria that must be fulfilled prior to attempting endovascular repair. If these criteria are not fulfilled, the procedure is generally contraindicated. These criteria will vary somewhat depending on the graft used, the risk status of the patient, and the experience of the operator.[26,27,30,41 – 44] The basic criteria that render an AAA suitable for endovascular repair include: 1. Quality and dimensions of the proximal aortic neck. In our experience, this is the most important factor determining suitability and outcome. (a) Optimally, the proximal neck should consist of a normal caliber, cylindrical aortic segment at least 1.5–2 cm in length (Fig. 25-9A, length a) and not more than 25 –30 mm in diameter (Fig. 25-9A, diameter b), distal to the renal ostia and proximal to the aneurysm to afford adequate proximal fixation of the graft. This area should be free of thrombus and not conical or flaring in shape, i.e., no more than 3–4 mm widening from

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Figure 25-9. (A) Measurements used in determining suitability for endovascular AAA repair. Lines a, d, and f represent the lengths of the proximal neck, distal neck, and common iliac artery, respectively. Line c represents the length of aorta from the renal arteries to the bifurcation. Lines b, e, g, and h represent the diameters of the proximal neck, the distal neck, the common iliac artery, and the external iliac and/or femoral arteries, respectively. (Adapted from Ref. [132].) (B) Angles essential for determining suitability for endovascular AAA repair and device selection. The dashed lines represent the angle (1) created by the neck of the aneurysm and the aneurysm itself. The dotted lines represent an angle (2) created by tortuosity of the iliac artery. (From Ref. [133].)

the proximal to distal ends of the neck. One exception to these guidelines involves the Talent graft, which can be customized to accommodate proximal aortic neck diameters up to 40 mm. This ability clearly enables surgeons to treat a wider range of patients. However, since larger aortic necks tend to dilate more than smaller necks, the long-term durability of endovascular repair in these circumstances remains questionable.[45] In addition, larger grafts require larger sheaths making access more difficult. Certain endovascular grafts with an uncovered portion of the stent at the proximal end permit transrenal

deployment of the stent. This has allowed the treatment of some abdominal aortic aneurysms with proximal necks , 15 mm. Grafts with this property include those which utilize a large proximal Palmaz stent (including the MEGS), the Talent graft, the Zenith graft, and to some extent the Vanguard graft. The patency of the renal arteries and maintenance of renal function following such transrenal stent deployment has been documented in most cases in both animal studies and human experience, although there have been occasional problems in humans and animals.[46,47] (b) Another important factor is the angle between the proximal neck and the suprarenal aorta or the proximal neck and the aneurysm. If this angle is quite large, it may preclude endovascular repair, especially if one is using an endovascular graft with a self- expanding stent or framework (Fig. 25-9B, angle 1). The Vanguard and Talent devices, for example, require that these angles not be greater than 60 degrees, and the Corvita graft requires that it not be greater than 30 degrees. As the aorta enlarges in diameter, it often elongates. This elongation results in angulation of the proximal neck. and accordingly larger aneurysms tend to have more angulated necks. In our experience, this angulation has been a leading factor which precludes endovascular repair.[32] Parodi-type grafts and their derivatives including the MEGS and the Leicester graft are unique in that they utilize a Palmaz stent, which generates the strongest radial force.[26,47] This has enabled successful treatment of abdominal aortic aneurysms with severe proximal angulation. 2. Quality of the distal landing zone. (a) If a straight or tubular graft is to be employed, the presence of a normal distal aortic segment approximately 2 cm in length (Fig. 25-9A, length d) and not greater than 25 mm in diameter (Fig. 25-9A, diameter e) without thrombus proximal to the aortic bifurcation (distal neck) is a requirement. Since tube grafts have tended to fail at the distal attachment site, some researchers have advocated that minimal distal neck length for tube grafts should be . 25 mm.[48] We believe very few abdominal aortic aneurysms need such treatment. (b) Quality of the iliac arteries. If the site selected for distal implantation is the common or external iliac artery, its morphology must be adequate for obtaining an adequate seal with the attachment system. Patients with tortuosity of . 90 degrees at any point (Fig. 25-9B, angle 2), significant dilatation to 16–20 mm bilaterally (Fig. 25-9A, diameter g), or severe circumferential iliac artery calcification are generally poor candidates. The presence of a short (, 30 mm) common iliac (Fig. 25-9A, length f) or the use of the external iliac as the target vessel requires

Chapter 25.

Endovascular Grafts for Aneurysms, Occlusive Disease, and Vascular Injuries

embolization of the internal iliac artery, if patent, to prevent back filling of the aneurysm. Unfavorable characteristics of the iliac arteries are other reasons that preclude the use of most industry-made bifurcated grafts. In fact, it has been shown that up to 16% of patients with abdominal aortic aneurysms have at least one iliac artery aneurysm, and 12% have them bilaterally.[49] The aortounifemoral or aortouniiliac type of endovascular graft such as the MEGS device is very useful in dealing with patients with large diameter iliac arteries, (Fig. 25-5). 3. Quality of the access arteries. (a) The common iliac, external iliac, and femoral arteries must be of sufficient caliber to allow passage of the introducer sheath or must be amenable to balloon dilatation to facilitate passage (Fig. 25-9A, diameter h). The size of the access vessels determines not only whether or not the patient is a candidate for endovascular repair but also which devices may be used. The outer diameter of the delivery sheath for each device varies. The outer diameters of the introducer systems are as follows: Talent (20 – 24 Fr), Vanguard (20.5 Fr), Ancure (24 Fr), AneuRx (24 Fr), Corvita (21 Fr), Excluder (20 Fr), Zenith (20 Fr), and MEGS (18 Fr)(3 Fr is equivalent to 1 mm). Future miniaturization of delivery systems will make endovascular graft introduction easier, safer, and feasible in more patients. However, due to the large introducer sizes of currently available devices as listed above, the size and quality of the access vessels remain important factors in selecting patients for endovascular repair. (b) The femoral and iliac vessels must demonstrate limited tortuosity after arterial straightening maneuvers, e.g., use of superstiff guidewires or dissection and caudal traction on the external iliac artery, use of through-and-through (brachial-to-femoral) wire traction, are employed.

Figure 25-10.

373

Tortuosity of the access vessels is seldom a factor that precludes endovascular graft repair, since it usually responds to straightening maneuvers. However, tortuosity plus heavy calcification may prevent device passage and obviate endovascular repair. 4. Presence of indispensable branches. (a) Aberrant vessels, particularly an indispensable accessory renal artery, must not arise from the segment of aorta to be excluded from the circulation by the graft. (b) The patient cannot be dependent on the inferior mesenteric artery for perfusion of the intestine, since this artery will be excluded from the circulation. This is especially true in cases with an occluded superior mesenteric artery and/or in which an aortounifemoral system is used, since coil embolization of the ipsilateral hypogastric artery will be required. 5. The patient must be both willing and able to comply with the appropriate follow-up regimen.

Summary of Selection Criteria for Endovascular Grafts Based on Anatomical AAA Classification Abdominal aortic aneurysms have been classified into five distinct groups according to their morphology and the extent of the aneurysm (Fig. 25-10).[50] The feasibility and the selection of an appropriate endograft for the treatment of a given aneurysm may be summarized on the basis of this classification. Type I: Abdominal aortic aneurysm with sufficient proximal (. 15 mm) and distal (. 15 mm) aortic necks (tube graft). Type IIA: Proximal neck . 15 mm, absence of distal aortic involvement (bifurcated graft) Type IIB: Proximal neck . 15 mm with proximal common iliac artery involvement. (bifurcated graft)

Classification of abdominal aortic aneurysms. (From Ref. [37].)

374

Part Three. Endovascular Intervention

Type IIC1: Proximal neck .15 mm with iliac artery involvement to the iliac bifurcation on one side (aortouniiliac graft with contralateral iliac occlusion, femorofemoral bypass, and coil embolization of one hypogastric artery) Type IIC2: Both iliacs involved needing sacrifice of both internal iliac arteries or replant of one internal iliac artery Type III: Proximal neck , 15 mm (requires grafts that permit suprarenal stent placement). In cases where there is no proximal neck and the aneurysm involves one of two renal arteries arising at different levels of the aorta, one option is to use a graft that covers one renal artery, but leaves the opposite one patent. This is especially true if the patient is a prohibitive risk for open repair.

PATIENT SELECTION BASED ON RISK STATUS Good-Risk Patients Some endovascular graft protocols select patients whose general health is good and who have favorable anatomy for endovascular repair. The rationale in these protocols is that if the endovascular procedure fails, the patients are likely to tolerate conversion to an open procedure. However, emergent conversions have been shown to be associated with a high morbidity and mortality.[51] Although a reduction in the already low mortality rates of standard AAA repair would be a welcome result of any new procedure, the primary goal of endovascular repair in these good-risk patients is to improve quality of life by reducing postoperative pain, sexual dysfunclion, and complications resulting from an extensive intraabdominal operation. An additional goal is to reduce costs by decreasing both the need for ICU care and the postoperative length of stay. Most of the manufactured devices, including the Ancure, Vanguard, AneuRx, Corvita, Excluder, and Talent grafts are currently being evaluated in the United States in good-risk patients.

High-Risk Patients Although the morbidity and mortality rates of standard open abdominal aortic aneurysm repair have proven to be excellent in good-risk patients, these rates increase with the presence of associated diseases. Mortality rates as high as 60% have been reported in very high-risk patients.[52] Furthermore, standard repair may be difficult or impossible in patients with severe cardiopulmonary disease or a “hostile” abdomen secondary to such factors as multiple previous abdominal operations that produce extensive scarring, hernias, or infection. Selection of these high-risk patients for endovascular repair is justified on a “compassionate need” basis.[24] The goal of the endovascular repair in this group of patients is not only to reduce costs and improve the postoperative quality of life, but also to broaden the indications for AAA repair by providing

treatment for those patients who might otherwise be deemed untreatable. The devices that are presently available in such a high-risk group are primarily “surgeon-made” devices, which include the Parodi graft, the Leicester graft, the MEGS and the Nottingham graft.[43,53,54] In the United States, the Talent and to some extent the Excluder graft also have an FDA investigational device exemption that permits some usage in high-risk cases.

PATIENT SELECTION BASED ON ANEURYSM SIZE As previously discussed, in contrast to open repair where patient selection is not strictly dependent on the anatomical characteristics of the abdominal aortic aneurysm, both the feasibility and technical success of endovascular repair depend heavily on these anatomical features. Although Armon et al. have postulated that abdominal aortic aneurysm size does not influence the feasibility of endovascular repair, it is generally believed that smaller abdominal aortic aneurysms have better quality proximal and distal landing zones and straighter access vessels compared to those of larger AAAs.[55 – 57] Therefore, endovascular repair applied to abdominal aortic aneurysms at earlier stages of growth is expected to be both more feasible and possibly safer than if applied at later stages. In this way a higher proportion of patients with abdominal aortic aneurysms could benefit from endovascular repair. Based on this notion, some authors have advocated early endovascular intervention for small abdominal aortic aneurysms.[57] Despite these recommendations, the benefit of such early intervention has yet to be proven, and several issues suggest it may be unwise. First, patients with smaller aneurysms are generally younger and healthier. Therefore the endovascular graft must be more durable than when used for sicker patients. It is also known that with current stent-graft technology, the failure rate increases with time.[48] On the other hand, the failure of an endovascular graft does not always lead to death, and more often than not an endovascular solution is possible.[58,59] However, if surgical conversion is required, it has been shown that such secondary open repairs carry a higher mortality rate than a primary operation.[51] Second is the mortality that endovascular graft repair carries. May et al.[51] performed endovascular graft repair in 43 small aneurysms with a mortality rate of 14%. This rate is clearly higher than that of untreated small abdominal aortic aneurysms. However, some recent results from prospective trials using the Ancure and AneuRx grafts had impressively low mortality rates of 1% to 2%, respectively.[60,61] The third reason for questioning the use of stented grafts in patients with small abdominal aortic aneurysms is the risk of immediate open conversion. Such conversions may result from renal artery occlusions, obstruction of flow to the lower extremities, or the presence of a proximal attachment site endoleak. Although conversion rates are declining rapidly with increasing operator expertise and technological advancements, they are still in the range of 2 –8%. Therefore, we believe that at present endovascular grafts should only be

Chapter 25.

Endovascular Grafts for Aneurysms, Occlusive Disease, and Vascular Injuries

used to treat abdominal aortic aneurysms of a size that justifies open repair. The recent U.K. randomized trial showed no benefit of open repair over ultrasound surveillance in abdominal aortic aneurysms ranging between 4 and 5.5 cm in diameter.[62] The end point was survival rate at 6 years. This study concluded that there is no justification for early surgical intervention on abdominal aortic aneurysms that are smaller than 5.5 cm. The surgical mortality rate in this study was 5.8%. However, it is noteworthy that 60% of the patients assigned to the surveillance group ultimately underwent surgery during the study period, mainly due to the enlargement of the aneurysm beyond 5.5 cm. In addition, 7% of those in the surveillance group with aneurysm size of 5–5.5 cm died from aneurysmal rupture during surveillance period. Only when endovascular graft repair demonstrates further reduction in mortality rate and conversion rate and when these grafts are proven to have long-term durability can this form of treatment be advocated for patients with smaller abdominal aortic aneurysms (, 5 cm). It is apparent that endovascular repair is far less invasive than open repair. However, it should be remembered that endovascular repair is still far more invasive and carries a higher mortality than no repair, Thus, we currently believe that the indications for endovascular repair of abdominal aortic aneurysms based on their size should be equal to those of open repair. As advocated by May et al., when further improvements in endovascular repair occur, a randomized prospective trial comparing endovascular repair and ultrasound surveillance may be warranted.[60] Isolated iliac artery aneurysms may also be amenable to endovascular graft repair depending on their anatomic characteristics. A variety of MEGS configurations has been used to treat these aneurysms (Fig. 25-11).

SUMMARY OF RESULTS OF ENDOVASCULAR GRAFT REPAIR OF ABDOMINAL AORTIC ANEURYSMS At least 10 endovascular devices have been employed clinically for the treatment of abdominal aortic aneurysms. These devices are highly variable with significant differences in configuration, attachment mechanism and graft composition. Whether any single device will prove more effective in the treatment of aneurysmal disease cannot be determined at present. The feasibility of endovascular abdominal aortic aneurysm repair has been established, and both the safety and technical success of endovascular repair have improved substantially over the past several years. These improvements are attributable to refinements in device manufacturing and operative technique as well as in patient selection. However, complications including deaths and technical difficulties specific to endovascular repair of abdominal aortic aneurysms have been encountered. Just as the deployment of these stent-grafts have their inherent techniques, a number of early and late complications inherent to the endovascular method of repair have been identified (Tables 25-1 and 25-2; Fig. 25-12). Early

375

Figure 25-11. Techniques for the endoluminal repair of aortoiliac aneurysms: (A) A localized common iliac artery aneurysm treated with stents anchoring the endovascular graft proximal and distal to the aneurysm. (B, C) If the aneurysm of the common iliac artery extends to the hypogastric vessel, either placement of occlusion coils in the internal iliac artery or deployment of an additional stent within the endovascular graft is performed to prevent retrograde flow from the hypogastric artery into the common iliac artery aneurysm. In cases in which there is no proximal neck of the iliac aneurysm (D) or in cases with common iliac artery aneurysms with aortic aneurysms (F), a large aortic stent will be placed in the distal aorta. Prior to graft insertion, an occlusion coil will be placed in the hypogastric artery or its branches. In order to perfuse the contralateral limb, a standard femorofemoral bypass will be performed. (E) If a wide mouth opening to a internal iliac artery aneurysm is present, the anterior and posterior divisions of the hypogastric artery are individually coil embolized and the endovascular graft is secured with a stent above and below the origin of the aneurysmal artery, functionally excluding it from the circulation. In any of these reconstruction techniques, the second (distal) stent which is responsible for fixing the distal portion of the graft to the arterial wall may be eliminated by extending the endovascular graft to the common femoral artery (site of device insertion) and performing an endoluminal anastomosis. (From Ref. [102].)

complications of endovascular procedures include arterial dissections and ruptures, endoleaks, renal dysfunction from contrast agents, inaccurate deployment requiring device retrieval or removal, neurologic deficits, buttock claudication, groin wound infections, and early graft thromboses. The majority of graft failures tend to occur within the first month after operation (Fig. 25-13).[63] After that time there

1996

1996

1997

Moore and Rutherford[67] Balm et al.[70]

Yusuf et al.[38]

29 (81) 19 (95) 15 (75)

36 20 20

16 (89) 20 (80)

18 25

106 (88) 106 (88) 106 (88)

17 (81)

21

54 26 41

25 (83)

24 (77)

22 (48)

43 (80)

81 (74) 81 (74)

81 (74)

18 (86) 116 (87)

Primary technical success

30

31

46

54

46 12

51

21 133

n

n.a.

n.a.

5

n.a.

15 15 15

2 1 5b

32 (89) [1]a 19 (95) 15 (75) n.a. n.a. n.a.

0

n.a.

5

1

27 (87) [3]a 25 (83)

7

32 (70) [9]a

4 4

93 (85) [2]a 93 (85) [2]a 3

4

93 (85) [2]a

n.a.

0 3

Conversion to open repair

21 (100) 128 (96) [3]a

Success after additional endoluminal procedure

n.a.

0 (0)

n.a. n.a. n.a.

6 (8) 0 (8) 0 (8)

7 (33)

3 (10)

3 (10)

7 (15)

14 (26)

16 (15) 16 (15)

16 (15)

(6) (6)

Persisting endoleak or other late failure

3 (6)

5 (5) 5 (5)

5 (5)

1 (1) 1 (1)

30-day mortality

6 (24)

8 (44)

(15) (15) (15)

(33) (33) (33)

11 (52)

2 (8)

5 (28)

6 (5) 6 (5) 6 (5)

3 (4) 3 (4) 3 (4)

1 (5)

27 complications (rate 0 (0) not stated) 34 complications in 1 (3) 23 patients 6 (20) 2 (7), 3 (10) in hospital

n.a.

8 (7) 8 (7)

8 (7)

15 (10) 15 (10)

Other postoperative complications

Values in parentheses are percentages. Primary success refers to primary technical success rate as defined in the SVS/ISCVS (Society for Vascular Surgery/International Society for Cardiovascular Surgery) reporting standards. a Totals include cases in which spontaneous thrombosis of endoleaks occurred (number is square brackets) within 6 months of surgery (primary clinical success[23]). b Includes one failed deployment treated by axillofemoral grafting. n.a., Data not available; GAD, graft attachment device. Source: Ref. [138].

Thompson et al.[68]

Marin et al.[53]

May et al.[56][60]

Aortoaortic (EVT)

Aortouniiliac Aortobiiliac (Parodi device) Aortobiiliac (Chuter-Gianturco) Aortoaortic (EVT)

Aortouniiliac (Ivancev-Malmo) 1996 Aortobiiliac (Perth device) 1997 Aortoaortic Aortouniiliac Aortobiiliac (White-Yu GAD) 1996, 1997 Aortoaortic Aortouniiliac Aortobiiliac (GAD[41] and others) 1995 All types (EVTand Parodi) 1997 Aortouniiliac (Leicester device)

1997

LawrenceBrown et al.[44] White et al.[28]

Device

Aortoaortic Aortobiiliac (Vanguard or Passager) 1995, 1997 Aortoaortic

1997

Year

Chuter et al.[64]

Parodi et al.[69][65]

Blum et al.[30]

Reference

Table 25-1. Reported Results of Endoluminal Repair of Abdominal Aortic Aneurysm

376 Part Three. Endovascular Intervention

1 10 6 — — 3 — 4 — — — — — — — — — — — —

3 2 7 — 4 1 — — 2 1 1 — — 87 2 — — — — 1

Parodi[65] ðn ¼ 109Þ

— — — —

9 — —

2 — — 1 — — — —

8 1 7 6 —

Moore[67] ðn ¼ 46Þ

1 1 2 1

5 2 2

2 6 — 1 — — — —

6 2 — 1 1

Blam[70] ðn ¼ 31Þ

1 2 — —

— — 1

1 — — — — — 1 —

— 3 — — —

Yusuf[38] ðn ¼ 30Þ

1 1 — —

— — 1

— — — — — — — —

— 4 — 1 3

Lawrence-Brown[44] ðn ¼ 21Þ

3 — — —

— 7 8

— 1 — — 1 — — —

9 3 5 6 4

May[60] ðn ¼ 121Þ

— — 1 —

— 1 —

— — 1 — — — — 1

— — — 2 1

Thompson[68] ðn ¼ 25Þ

6 (1) 4 (1) 3 (1) 2

101 (19) 12 (2) 12 (2)

9 (2) 7 (1) 5 (1) 4 (1) 2 1 1 1

27 (5) 25 (5) 25 (5) 16 (3) 13 (2)

Total ðn ¼ 537Þ

Values in parentheses are percentages. Only series in which individual complications are specified have been included. Complications are categorized according to the SVS/ISCVS (Society for Vascular Surgery/International Society for Cardiovascular Surgery) reporting standards for infrarenal aortic aneurysm repair. Source: Ref. [138].

Local vascular complications Arterial access injury requiring surgery Persisting endoleaks Late-onset endoleaks Wound or minor graft infection Thromboembolic events leading to surgery Minor embolic events Blood loss requiring . 2 units transfusion Fatal embolic events Lymph leak Hematoma requiring surgical treatment Arteriovenous fistula Colonic ischaemia Bowel perforation Remote systemic complications Pyrexia Renal failure Myocardial infarct, cardiac failure, or arrhythmia Cerebrovascular event Pneumonia Respiratory failure Hepatic or multiorgan failure

Complication

Blum[30] ðn ¼ 154Þ

Table 25-2. Complications Reported Following Endoluminal Repair of Abdominal Aortic Aneurysm Chapter 25. Endovascular Grafts for Aneurysms, Occlusive Disease, and Vascular Injuries 377

378

Part Three. Endovascular Intervention

Figure 25-12. Classification of endoleaks. Type I: endoleak occurs at the proximal and/or distal attachment zones. Type II: endoleak is caused by retrograde flow from patent lumbar or inferior mesenteric arteries. Type III: endoleak arises from a defect in the graft fabric, inadequate seal, or disconnection of modular graft components. Type IV: endoleak is due to graft fabric porosity, often resulting in a generalized mild blush of contrast within aneurysm sac. (From Ref. [134].)

is a slow, steady rate of failure. Late complications include persistent endoleaks or de novo endoleaks. Both can cause ongoing pressurization and enlargement of the aneurysm leading to potential rupture. Other late complications are graft disruption secondary to suture or graft material fatigue and late graft thrombosis. The majority (. 55%) of late failures are due to problems at the fixation sites of the endovascular graft (Table 25-3).[28,30,44,64 – 67] However, device migration, fabric and/or suture fatigue, retrograde flow into the aneurysm sac from lumbar vessels or the inferior mesenteric artery, and graft distortion leading to occlusion all contribute significantly to the late failure rate. The initial technical success rate of endoluminal repair ranges from 48 to 95%, but when additional endoluminal interventions performed at the time of graft placement are included these figures jump to 70 –100%.[28,30,44,53,54,64 – 72] The overall reported incidence of reported postoperative complications ranges from 7 to 52%, with the incidence of persistent endoleaks and other late failures being 6 –33%. Recently, a number of investigators have reported their midterm results with mixed conclusions. One favorable

Figure 25-13. Durability of endovascular grafts according to the configuration of grafts shown by Kaplan– Meier curves. The curve is adjusted for death without prior procedure failure. (From Ref. [135].)

article was published by May et al.[73] In their analysis, they showed that the long-term patient survival was better during a follow-up period up to 5 years following EVG repair than it was after open surgical repair in a control group of patients. Zarins et al. reported an encouraging rupture-free rate of 99.5% at 3 years using the AneuRx graft.[74] There have been similar encouraging reports on the outcome of the Ancure graft as well.[75,76] However, a number of others have raised concerns regarding the midterm durability of EVG repair. Zarins himself and his colleagues reported 7 unexpected AAA ruptures after EVG repair with 5 deaths.[77] Furthermore, the European collaborators reported their experience with 2464 EVGs over a 4-year period. Of these, 14 patients presented with aneurysm rupture 0–24 months following EVG repair with 9 deaths.[78] Ho¨lzenbein et al. reported that 26% of their patients needed to undergo a secondary procedure to treat EVG-related complications during a follow-up period of 18 months.[79] Others reported similar results and raised similar concerns.[78,80 – 84] We have also reported our midterm results which expand on these findings and concerns.[85] Two hundred and thirty-nine patients who were treated endovascularly were followed over a 6-year period (mean 16 months). During this period, 2 AAAs ruptured and were surgically repaired with one death. Other late complications included: type I endoleak (7), aortoduodenal fistula (2), graft thrombosis/stenosis (7), limb separation or fabric tear with a subsequent type III endoleak (1), and a persistent type II endoleak (13). Secondary intervention or surgery was required in 23 cases (10%). These included: deployment of a second EVG (4), open AAA repair (5), coil embolization (6), extraanatomic bypass (4) and stent placement (3). At 3 years, the primary clinical success, secondary clinical success, and freedom from aneurysm-related death were 86%, 92%, and 84% respectively. The increasing occurrence of late failure with time in patients whose treatment was originally successful for more than one year is alarming.[73,74,77 – 93] From our and others’ experience, it is clear that EVG repair is not as durable as open surgical repair. EVGs can fail in a greater number of ways and with greater frequency than standard AAA grafts

Chapter 25. Table 25-3.

379

Endovascular Grafts for Aneurysms, Occlusive Disease, and Vascular Injuries

Causes of Late Failure Reported Following Endoluminal Repair of Abdominal Aortic Aneurysm Endoleak

Fabric failure

Lumbar or mesenteric backbleed

Further endoluminal treatment successful

0 0 4 0

6 0 0 0

3 0 2 2

7 2 2 0

4

0

0

0

0

6

0

0

0

2

Fixation Graft Graft site Device thrombosis infection failure migration

Reference

Year

Total no. of late failures

Blum et al.[30] Parodi et al.[65] Chuter et al.[64] Moore and Rutherford[67] LawrenceBrown et al.[44] White et al.[28]

1997 1997 1997 1996

9 16 14 7

0 0 5 0

0 0 1 0

0 16 2 5

1996

7

3

0

1997

6

0

0

Endoleak refers to clinical failure of endoluminal surgery because of leaks persisting or arising de novo more than 6 months after graft implantation. Source: Ref. [138].

placed at an open operation. These modes of endovascular graft failure included occurrence of late endoleaks, graft thrombosis, aortoenteric fistula, and ultimately rupture of the aneurysm with and sometimes without a known endoleak. Such disadvantages of EVG repair must be weighed against several positive attributes. These include the low mortality rate, even in patients at high risk for open surgery, and the short length of hospital stay. Also, the fact that most late failures can be detected prior to causing a catastrophic event or death is a positive finding. This allows one to perform secondary salvage procedures in a timely fashion to prevent aneurysm rupture or limb loss. Moreover, the secondary procedures, when required, are mostly minimally invasive and the technical success rate is high. Most of the late problems that have been encountered have been treated with percutaneous procedures, and many were done transfemorally.[79,80,85,89,92,94] Therefore, late failure in itself does not necessarily produce a bad overall outcome. On the other hand, failure to detect late failure can lead to aneurysm rupture and death.[77,78] Therefore, diligent postoperative surveillance is critically important after an EVG repair.

inducing thrombosis in this circumstance may lead to a successful outcome.[80,91,94,97,98] In contrast, short endoleak channels with a wide diameter will require covering of the feeding orifice with graft material in order to obliterate pressure transmission. Thus, although the type of endoleak will influence the method of treatment, we believe that the treatment method should also be determined by the length and diameter of the endoleak channel, and we have applied this concept in the treatment of endoleaks (Fig. 25-14).[85,91] For endoleaks with short, large-diameter channels (most type I and III endoleaks), deployment of a second EVG or an extension cuff is needed as opposed to inducing thrombosis. Placement of such a second graft is often possible. However, when it is not, surgical conversion should be performed if the patient was deemed an acceptable risk. For those patients with long, narrow endoleak channels (most type II endoleaks and some type I), inducing thrombosis can be performed by either temporarily terminating chronic anticoagulation therapy or by percutaneous coil embolization or injection of a biological glue. For methods of access, we have utilized both trans-

TREATMENT OF VARIOUS TYPES OF ENDOLEAKS Various methods of endoleak treatment have been attempted and reported. Options for treating endoleaks include coil embolization by transarterial or translumbar access routes, addition of stent-graft cuffs and extensions, endoscopic ligation of inferior mesenteric and lumbar arteries, redo endovascular stent-graft repair, and open surgical repair.[79,80,84,89,91 – 95] The method of treatment for a given endoleak is the subject of considerable controversy and debate. Based on the findings of various experimental models, we believe that when an endoleak has a long and narrow channel, pressure transmission across thrombus induced in this channel may be significantly reduced.[91,96] Thus,

Figure 25-14. Treatment strategy for various types of endoleaks. (From Ref. [85].)

380

Part Three. Endovascular Intervention

arterial and translumbar approaches.[80] Since most type II endoleaks have more than one inflow and/or outflow, it may be difficult to coil embolize all the endoleak channels via a transarterial approach. Thus, we currently recommend the translumbar approach for all type II endoleaks.[80,85,91]

ENDOVASCULAR GRAFT REPAIR OF AORTOILIAC OCCLUSIVE DISEASE Endovascular Grafts For aortoiliac occlusive disease we have used exclusively a modification of the Montefiore endovascular graft system. For this indication the graft is composed of a Palmaz balloonexpandable stent (P-294, Cordis, Johnson & Johnson Interventional Systems, Warren, NJ) and a 5 or 6 mm thinwalled (PTFE) graft (W.L. Gore and Associates, Flagstaff, AZ; or IMPRA, Inc., Tempe, AZ) (Fig. 25-15). The stent is attached to the proximal end of the PTFE graft by four interrupted CV-6 PTFE sutures (W.L. Gore and Associates) such that one-half of the stent protrudes beyond the end of the graft. After suturing the graft to the stent, the stent-graft complex is mounted onto an angioplasty balloon by manually crimping the stent over the 6–8 mm £ 4 cm angioplasty balloon (OPTA, Cordis, Johnson & Johnson Interventional Systems, Warren, NJ). The entire stent-graft and balloon complex is then inserted into a delivery sheath. A smooth transition zone at the end of the sheath is created by using a

6 mm £ 4 cm tip balloon. The tip balloon is adjusted so that one-half of the tapered portion of the balloon protrudes from the distal portion of the delivery sheath. A modified form of this delivery system consists of a dual balloon catheter (tip balloon and stent-deploying balloon) on a single shaft (Fig. 25-15). In both delivery system configurations, the tip balloon functions to create a smooth transition zone at the distal end of the delivery sheath as well as to occlude the sheath, which permits pressurization of the sheath with saline is injection from the flush port. This pressurization provides variable pushability and flexibility of the sheath, depending on the amount of pressure applied. This feature facilitates the insertion of the delivery sheath through diseased and tortuous iliac arteries. More recently, a single balloon system with a tapered introducer tip has been used. This modification permits the sheath size of the entire system be 16 French outer diameter.

Endovascular Graft Insertion and Location of Stent Deployment in Bilateral Iliac Disease In cases in which both iliac arteries are occluded or diffusely stenotic, a bilateral stent-graft aortobifemoral repair can be performed (Fig. 25-16A). We performed this procedure early in our experience. However, since bilateral reconstructions were technically more difficult and resulted in some suboptimal outcomes, we now prefer to perform a unilateral repair followed by a femorofemoral bypass (Figs. 25-16B and

Figure 25-15. Schematic drawings of an endovascular graft and the delivery systems for occlusive disease. (A) An endovascular thinwalled PTFE graft. A Palmaz balloon expandable stent (S) is sutured to the graft using four diametrically opposed “U” sutures (two on each side), which permit one-half of the stent to protrude from the graft. (B) Double balloon catheter introducer/delivery system used for the delivery and deployment of endovascular stented grafts. In this system the introducer catheter is equipped with two separate balloon catheters. Balloon “A” functions as a mechanism to form a tapered tip to the catheter system and also allows pressurization of the flexible sheath (C) after saline is injected from port D. The second balloon (B) functions to deploy the overlying Palmaz stent (S). With expansion of balloon B, the endovascular graft (G) becomes firmly fixed to the underlying arterial wall. (V = hemostatic valve.) (C) An alternative delivery system consisting of a single balloon catheter which has two balloons on a single shaft. The first balloon serves as a tip balloon (A), while the stent graft complex is mounted onto the independent deploying balloon (B). (V = hemostatic valve.) (From Ref. [99].)

Chapter 25.

Endovascular Grafts for Aneurysms, Occlusive Disease, and Vascular Injuries

381

Figure 25-16. (A) Drawing of bilateral endovascular aortofemoral graft insertion. Two stents are squeezed into a small, diseased distal aorta. (From Ref. [90].) (B) Drawing depicting the completion of an endovascular aortoiliac bypass and a standard femorofemoral bypass. (From Ref. [99].)

25-17A and B).[100] The iliac artery in which the endovascular graft is to be deployed and the positioning of the proximal stent are determined by preoperative angiographic findings. Deployment of the endovascular graft across the origin of the common iliac artery will certainly result in occlusion of the internal iliac artery and all the small branches along the vessel that are covered by the graft. The presence of a patent internal iliac artery(ies) will therefore influence the side of endovascular graft access and deployment. Every effort should be made to preserve a patent internal iliac artery in cases of occlusive disease. In addition, the length and degree of disease within the common or external iliac artery will often determine the technical difficulty associated with vessel recanalization. Generally, it is easier and safer to recanalize through a stenotic rather than an occluded lesion. Shorter lesions are also easier to recanalize. The classification of disease patterns, the choice of side for endovascular graft insertion, and the location of the proximal stent can be determined using the algorithm outlined in Fig. 25-18.

Operative Technique Following sheath placement in the femoral artery, either a Benson wire (Cook, Inc., Bloomington, IN) or a Glidewire

(Terumo, Tokyo, Japan) is used to recanalize the occluded iliac artery. Under fluoroscopic control, a directional catheter is used to direct and control the guidewire through the occluded or stenosed iliac artery (Fig. 25-19).[91] It is of paramount importance to return to the true lumen at the proximal end of the occluded segment, since the guidewire has a tendency to traverse the dissection plane (between the adventitia and the media) through the occluded segment. In cases where the contralateral iliac artery is patent, recanalization of the occluded iliac artery may be performed in a prograde fashion with a catheter placed through a percutaneous puncture of the contralateral femoral artery (Fig. 25-19). This technique has the advantage of assuring that the recanalized lumen will always join the true lumen at the proximal end of the occlusion. After successful wire passage, a 6 – 8 mm diameter angioplasty balloon is passed over the wire and the iliac artery is fully dilated along its entire length. The previously prepared endovascular graft device is then inserted into the newly created tract within the arterial wall over the same guidewire. Once the fixation stent is fluoroscopically located at the appropriate predetermined site, the sheath is partially retracted while holding the balloon catheter in place. If a tip balloon is used, it is deflated before sheath retraction. The exposed proximal stent can now be deployed The introducer

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Figure 25-17. (A) Preoperative arteriogram of patient with critical bilateral aortoiliac occlusive disease. This patient had received axillobifemoral bypass twice, both of which had failed. Angiogram demonstrates diffusely stenosed right iliac artery system and total occlusion of the left side. Since the right internal iliac artery is negligible, the right side was chosen for recanalization and graft insertion. The pelvic circulation is maintained by the inferior mesenteric artery (open arrow). (B) Completion arteriogram. By placing the stent (S) above the lesion (within the distal aorta), a good angiographic result was obtained. (C) Arch arteriogram of same patient reveals a 90% stenosis at the origin of the innominate artery and occluded left common carotid and subclavian arteries. Unrecognized inflow disease may have contributed to the failure of the two previous axillofemoral bypasses. (From Ref. [99].)

Figure 25-18. Algorithm and classification of endovascular grafting for bilateral aortoiliac occlusive disease. The classification of the distribution of disease, the determination of the appropriate side for graft insertion, and the identification of the location for proximal stent deployment may be approached using this algorithmic outline. (From Ref. [99].)

Chapter 25.

Endovascular Grafts for Aneurysms, Occlusive Disease, and Vascular Injuries

383

Figure 25-19. (A) Intraoperative angiogram of an iliac artery with occlusive disease demonstrating complete occlusion of the left external iliac artery. The left internal iliac artery is patent. (B) The “up and over” technique for recanalization. Recanalization is performed from the contralateral side in order to assure that the recanalized tract joins the true lumen at the proximal end of the occlusion. (C) Endoluminal anastomosis. Following proximal stent deployment, the distal end of the endovascular graft emerges from the arteriotomy site at which point it is cut to an appropriate length. An endoluminal anastomosis (EA) is then carried out. (D) Completion angiogram. The external iliac artery is recanalized with the endovascular graft. The proximal stent is placed at the orifice of the internal iliac artery, thus preserving this artery. (C reprinted from Ref. [130].)

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sheath is then completely withdrawn, permitting the redundant portion of the distal end of the endovascular graft to emerge from the arteriotomy in the access vessel. The distal, redundant portion of the graft is then cut to an appropriate length and endoluminally hand-sewn into a patent, distal runoff vessel (Fig. 25-19). For bilateral occlusions, a 6 mm, externally supported, thin-walled PTFE graft is used to create a femorofemoral bypass. The arteriotomy site used for insertion of the endovascular graft serves as the proximal anastomotic site of the femorofemoral bypass (Fig. 25-20). The graft is then subcutaneously tunneled to the contralateral side and the recipient anastomosis is performed in a standard fashion to the patent distal runoff vessel.

Results of Endovascular Grafting for Aortoiliac Occlusive Disease We have performed endovascular graft repair for aortoiliac disease in 55 patients over a 5-year period. The vast majority of these patients had major contraindications to standard treatment (Fig. 25-17). The mean age of the patients was 67, and there were 28 males and 27 females. Forty-six percent of the patients had diabetes, 81% had coronary artery disease, and 19% had COPD. Of note is

Figure 25-20. The distal end of the endovascular graft is endoluminally hand-anastomosed in a customized fashion to the patent runoff vessel. The proximal anastomosis of a femorofemoral bypass is then performed over the arteriotomy site.

that 60% of the patients had a history of myocardial infarction. Technical success was achieved in 94% of the patients. Cases that failed were due to inability to recanalize the occluded segment. The mean graft length was 23 cm, and a simultaneous infrainguinal bypass was performed in 47% of the cases. The complication rate was 10%, and 30-day mortality was 4%. Using life table analysis employing the intention-to-treat principle, primary (78 ^ 7%) and secondary (86 ^ 6%) rates were achieved at 3 years. Graft failures were attributed to the endograft in 2 patients (4%), progression of inflow or outflow disease in 2 patients (4%) and 6 patients (12%), or an undefined cause in 1 patient (2%), respectively. Limb salvage and patient survival rates at 3 years were 93 ^ 4% and 71 ^ 7%, respectively.

Endovascular Grafts for the Treatment of Vascular Trauma Following the first report of endovascular grafting for the treatment of abdominal aortic aneurysms by Parodi in 1991,[24] the indications for endovascular grafting have expanded to include arterial occlusive disease,[99,100] occluded grafts,[101] peripheral aneurysms,[102,103] and traumatic arterial lesions (pseudoaneurysms, arteriovenous fistula, etc.). Although the treatment of abdominal aortic aneurysms with endovascular grafts seems to hold the major interest for both physicians and manufacturers, the longterm effectiveness of this treatment for this indication remains to be proven. This is due to a continuing significant rate of complications including “endoleaks,” some of which occur long after the graft is placed, as well as to the availability of standard aneurysm repair, which has been proven to be both safe and durable. On the other hand, based on reported results from our group and others,[104 – 118] the use of endovascular grafts already seems to be justified for the treatment of some traumatic arterial injuries, especially those involving large central vessels. This is particularly true in patients who are critically ill from other injuries or medical comorbidities. The surgical repair of vascular injuries may be complicated by the inaccessibility of the vascular lesion when trauma occurs to a vessel within the thorax or abdomen, by distorted anatomy due to a large hematoma or a false aneurysm, and by venous hypertension when an arteriovenous fistula is present. These conditions make the use of endovascular techniques appealing, since repair can be performed from a remote access site obviating the need for direct surgical exposure of the injury site, thus reducing the morbidity and mortality rates of the repair. Endovascular techniques for the treatment of vascular trauma includes the use of coil embolization, intravascular stents, and more recently the use of stented grafts or covered stents. Furthermore, when endovascular grafts are used for traumatic lesions, there are usually normal, healthy proximal and distal arterial segments available for use as graft fixation zones, which is not always the case with aortic aneurysms. This contributes to the high technical success rate and a low rate of endovascular graft migration or leakage in this setting.

Chapter 25.

Endovascular Grafts for Aneurysms, Occlusive Disease, and Vascular Injuries

Review of Endovascular Stented Grafts for Arterial Trauma Endovascular grafts have significantly extended the potential of endovascular therapy for vascular trauma. These grafts have been used to treat almost every kind of injury at various locations in the body, as well as in circumstances in which coil embolization or stent placement was deemed inappropriate.[104 – 118] In some instances, endovascular grafts have been used to treat life-threatening acute hemorrhage.[118] The types of devices that have been reported are predominantly a combination of Palmaz stents and expanded polytetrafluoroethylene (ePTFE) grafts. Since the traumatized field is often contaminated, the use of a vein graft in combination with a Palmaz stent has also been reported.[105,110] The different types of stented grafts that have been reported are shown in Fig. 25-21.

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Characteristics of the lesions, site of arterial access, technical success rate, and outcome of endovascular graft treatment of vascular trauma are summarized in Table 25-4. The results reported included a high technical success rate (94– 100%) and a complication rate of 0 –7%. These results are encouraging, especially when one considers the difficulties that could be encountered in treating these lesions by a direct surgical repair. In addition, the minimal access required and the potential for cost-effectiveness of these endovascular techniques is apparent from the short length of stay (3.3 –5.3 days) in patients so treated. Since these endovascular grafts are inserted into nonatherosclerotic central vessels of a large caliber, it is not surprising that they have proven to be more durable than grafts used to treat other arterial lesions. With a mean follow-up of 16 months, excellent midterm patency rates ranging from 85 to 100% have been

Figure 25-21. Endovascular stented grafts. (A) Palmaz stent covered with PTFE. (B) Autologous vein can be used to cover the stents. creating biological stented grafts. The collapsed stent-graft assumes a small profile, which effectively covers the struts of the stent following deployment (inset). (C) Dacron graft material may be used to cover the balloon-expandable stents. (D) Corvita endovascular graft used for arterial trauma. This polycarbonate clastima covered stent structurally resembles the Wallstent. Corvita graft is manually crimped into a 9 or 10 Fr delivery sheath.

386 Table 25-4.

Part Three. Endovascular Intervention

Endovascular Grafts for Arterial Trauma: Lesion Characteristics and Outcome by Arterial Site

Location of trauma Number of cases Cause of injury

Axillary-subclavian artery 15 Bullet: 57% Catheterization: 29% Others: 14%

Presence of pseudoaneurysm Presence of AV fistula Arterial access

60% 47% Brachial arteriotomy: 27% Brachial percutaneous: 47% Femoral percutaneous: 27% 100%

Technical success rate Complication: Minor Major Mean length of stay Mean follow-up Primary patency

0% 7%a 3.6 days 18 months 81%c

Aortoiliac artery 15 Surgical: 36% Catheterization: 18% Bullet: 9% Others: 36% 67% 73% Femoral arteriotomy: 64% Femoral percutaneous: 36%

Superficial femoral artery 5 Bullet: 60% Catheterization: 40%

80% 40% Femoral arteriotomy: 80% Femoral percutaneous: 20%

100%

100%

7% 7%b 4 days 10.5 months 100%

0% 0% 5.3 days 17.4 months 100%

a

Brachial artery injury during device insertion. Distal embolization requiring thrombectomy. c Two failures due to stent deformity. Source: Ref. [116]. b

achieved, depending on the location in which they were inserted.

graft in position while the outer sheath is retracted allowing the covered graft to expand and be deployed.

MONTEFIORE EXPERIENCE WITH ENDOVASCULAR GRAFTS FOR ARTERIAL TRAUMA

Results

Technique and Devices We have predominantly used the Palmaz stent (Cordis, Johnson and Johnson Company, Warren, NJ) in combination with a thin-walled ePTFE graft (W.L. Gore and Associates, Flagstaff, AZ; or IMPRA, Inc., Tempe, AZ) covering to perform arterial repairs of pseudoaneurysms and arteriovenous fistulas. Depending on the length of the lesion, either a singly stented or a doubly stented device was used. The stents varied between 2 and 3 cm in length (Palmaz P-204, 294, 308) and were fixed inside 6 mm ePTFE (W.L. Gore and Associates, Flagstaff, AZ) by two “U” stitches (Fig. 25-21A). The stented graft was then mounted on a balloon angioplasty catheter which had a tapered dilator tip firmly attached to its end. The entire device was placed within a 12 Fr delivery system for over-the-wire insertion either percutaneously or through an open arteriotomy. Another device used by our group was the Corvita stentgraft (Corvita Corporation, Miami, FL), which is fabricated from a self-expanding stent of braided wire. The stent is covered with polycarbonate –urethane elastomer fibers (Fig. 25-21D). This stent-graft may be cut to the desired length in the operating room using a wire-cutting scissors and then loaded into a specially designed delivery sheath. This sheath has a central “pusher” catheter, which is used for maintaining the

All procedures but one were performed in the operating room under fluoroscopic and intravascular ultrasonographic control (Hewlett-Packard Company, Paramus, NJ). A total of 17 stented grafts or covered stents have been used to treat 17 patients with traumatic arterial lesions. Seven injuries resulted from gunshot wounds, one from a knife wound, four from iatrogenic catheterization injuries, two from iatrogenic arterial trauma (gynecological surgery or lumbar disk surgery) (Fig. 25-22), and three from arterial graft disruptions possibly associated with infection. All injuries except one were associated with an adjacent pseudoaneurysm. In 5 instances the arterial injury formed a fistula to an injured adjacent vein. Associated injuries were present in 8 patients with arterial trauma. The majority of the cases were performed under local or epidural anesthesia. One patient who had an axillary pseudoaneurysm repaired with a stented graft required a vein patch to close the insertion site in a small brachial artery. Procedural complications were limited to one distal embolus treated with suction embolectomy and one wound hematoma, which resolved without further intervention. Graft patency was 100%, and there were no early or late graft occlusions with a mean follow-up of 30 months (range 6 – 46 months). One patient with a left axillary-subclavian stentgraft developed compression of the stent after 12 months, which was treated with balloon angioplasty. The problem recurred 3 months later, but no intervention was required. This device remains patent with normal circulation to the extremity now with an additional 312 years of follow-up.

Chapter 25.

Endovascular Grafts for Aneurysms, Occlusive Disease, and Vascular Injuries

387

Figure 25-22. (A) Preinterventional angiogram of an iatrogenic arteriovenous fistula (F) involving the right common iliac artery due to lumbar disc surgery. The left common iliac vein and the inferior vena cava (V) is visualized by the contrast flowing through the fistula. (B) Intravascular ultrasound (IVUS) image taken at the time of angiography. The amount of substance loss and the location (by identifying the location of the probe (P) of the IVUS under fluoroscopy) are well demonstrated (arrows denote the extent of the fistula). (C) Coil embolization of the right internal iliac artery. Since the location of the fistula was close to the origin of the internal iliac artery, the internal iliac artery was embolized with multiple coils (C) at the time of angiogram. (D) Completion angiogram. A Corvita graft (10 mm £ 6 cm) was used to repair the arteriovenous fistula. Note the preservation of iliac flow and the obliteration of the arteriovenous fistula. (From Ref. [136].)

CONCLUSIONS Endovascular grafts have greatly extended the potential of endovascular therapy for vascular trauma. These grafts have been used to treat almost every kind of injury at various locations in the body. Intravascular ultrasound as an adjunct can provide certain details that are otherwise difficult to obtain, including the exact location and size of the injury or fistula. These details are especially important when a coexisting arteriovenous fistula makes the angiographic interpretation difficult and may be essential when performing an endovascular repair. Regardless of the type of the device used, stented grafts appear to be associated with a low morbidity rate, high success rate, a less invasive surgical procedure, reduced requirements for anesthesia, and a limited need for extensive dissection in the traumatized field. These advantages are especially important in patients with central arteriovenous fistulas or false aneurysms, particularly those who are critically

ill from other coexisting injuries or medical comorbidities. In such instances, the use of endovascular grafts may already be justified. Endovascular grafts are important tools for the treatment of vascular trauma and should be included in the armamentarium of the vascular surgeon.

FUTURE DIRECTIONS There has been tremendous growth in the endovascular treatment of vascular lesions as evidenced by the increasing number of procedures performed throughout the world and the variety of commercial grafts becoming available. This increased graft availability has expanded the potential indications for endovascular repair in a number of patients while simplifying the approach. With further improvements in the materials and designs of these grafts, more complex

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Figure 25-23. CT scan images of a ruptured AAA treated endovasacularly. This 71-year-old man was admitted to another hospital for medical treatment of his pneumonia secondary to chemotherapy for leukemia. Other comorbid disease includes severe COPD requiring home oxygen and congestive heart failure with ejection fraction of 25%. The patient experienced sudden onset of severe abdominal pain, which was confirmed by CT scan to be ruptured AAA. Due to his coexisting disease, standard repair was deemed prohibited and was transferred to our institution. On arrival, his systolic blood pressure was 75 mmHg and hematocrit was 18%. (A) Preoperative CT scan reveals possible rupture site (arrow) in the AAA. (B) Preoperative CT scan showing more distal portion of the AAA. The AAA measures 7.5 cm. In addition, a large hematoma (H) can be seen in the right retroperitoneal space, which is displacing the duodenum (D). (C) Postoperative enhanced CT scan. Contrast is confined within the EVG (E) with evidence of complete aneurysmal exclusion. The ureter, which is displaced by the large hematoma, is visualized. Despite his comorbid condition, he was extubated 6 hours following the procedure and was on diet on the second postoperative day. (C reprinted from Ref. [137].)

lesions may be amenable to endovascular repair. Despite this progress, the long-term durability of these grafts, for both aneurysmal and occlusive disease, has yet to proven. One emerging area of great promise is the endovascular graft treatment of ruptured aortoiliac aneurysms (Fig. 25-23). There are some significant theoretical advantages to this

approach, especially in patients who have undergone previous abdominal surgery. Over a 7-year period we have treated 20 patients with ruptured aortoiliac aneurysms.[119] All patients were felt to be a prohibitive surgical risk. The MEGS system was used in most cases. Both of these systems allow for intraoperative length customization of the graft. Stent-graft deployment was successful in all cases, with a perioperative mortality of 10%. Among the potential advantages of this approach are the following. First, endovascular grafts can be inserted and deployed through a remote access site, thereby obviating the need for laparotomy and, more importantly, eliminating the technical difficulties that one encounters when performing a standard repair in this setting. The anatomy of the retroperitoneal structures are often distorted and obscured because of the large hematoma. This may lead not only to technical difficulties but also to inadvertent injury of the inferior vena cava, the left renal vein, or genital branches. The iliac veins, inferior mesenteric vein, ureters, or the duodenum can also be injured. These iatrogenic injuries are the cause of significant operative mortality and morbidity following standard surgery for ruptured aneurysms.[120 – 125] In contrast, endovascular repair is performed from within the arterial tree, and as such is unaffected by the extravasated blood or by scarring from previous operations. In fact, from a technical standpoint the endovascular treatment of a ruptured aneurysm does not differ significantly from that performed electively. These advantages are magnified in patients with a “hostile” abdomen. Indeed, in such cases we believe that proximal arterial control may be obtained not only more safely but also more rapidly than in a standard repair. Second, the blood loss associated with endovascular graft repair may be reduced compared to standard repair. We found that the average blood loss was much less (mean 715 mL) than that reported in the literature for standard repair (range 2600– 8000 mL).[125 – 128] This reduction in blood loss is largely due to the fact that the tamponade effect within the retroperitoneum and surrounding structures is not released during endovascular repair. Coagulopathy and poor organ perfusion, which generally follow a large blood loss, are major problems associated with standard repair. Additional blood loss associated with free bleeding as the retroperitoneum is opened and decompressed can lead to complete cardiovascular collapse. This may be exacerbated by hypothermia, which is promoted by having an open abdomen. The endovascular approach greatly reduces this problem. Other major sources of blood loss during standard repair include backbleeding from the iliac and lumbar arteries, bleeding from the anastomotic suture lines, and iatrogenic venous injuries. Each of these can be largely eliminated by endovascular repair and offer a major advantage over standard repair. There are, however, some inherent limitations to the endovascular graft repair of ruptured aneurysms. These include the lack of preoperative aneurysmal and arterial length and diameter measurements, the time required to fabricate the graft, and the time needed to accurately deploy the graft. However, these problems may not be insurmountable. Having a stock of appropriately sized grafts or one or two sizes of graft that will fit most patients (as with the MEGS devices) should overcome measurement and fabrication problems. Obtaining proximal control with a balloon catheter

Chapter 25.

Endovascular Grafts for Aneurysms, Occlusive Disease, and Vascular Injuries

introduced through the brachial artery and guided fluoroscopically into the para-renal aorta should prevent exsanguination and allow adequate time for graft deployment. Even without the latter maneuvers we have found that many patients with ruptured aneurysms, if allowed to remain hypotensive, will remain stable with intact organ function long enough for the endograft to be deployed. In light of the results presented in this chapter, and the fact that endovascular grafting is still a young field with

389

technological improvements occurring at a rapid rate, we believe that endovascular graft treatment of patients with aneurysms and occlusive and traumatic arterial lesions will have improved success rates in the future. As long-term durability of these endovascular grafts are proven and they become applicable to a larger proportion of patients with vascular lesions, we believe their role will increase and they will become a major tool that will become integrated into vascular surgical practice.

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Adjunctive Endovascular Procedures: Techniques to Facilitate Operative Vascular Surgery Reese A. Wain Frank J. Veith necessary to begin the imaging process. After the radiation passes through the patient, it is collected by an image intensifier which forms an optical representation of the relevant anatomy. Next, a video system turns the optical representation into an electronic image consisting of shades of black and white. Finally, a computer converts the video image into a digital image by assigning numeric values to the shades of black and white. The entire process occurs in real time, and the resulting image can be viewed on a video display monitor or sent to a storage disk or printer.

INTRODUCTION Endovascular procedures require an imaging modality that provides real-time image acquisition. Although some investigators have reported success using intravascular or conventional ultrasound to guide endovascular procedures, the vast majority of these procedures are performed using digital fluoroscopy. In the past, digital fluoroscopes were only available in the radiology department. However, digital imaging equipment is becoming increasingly available to vascular surgeons in the operating room. Armed with a portable digital fluoroscope or a specially constructed interventional suite, vascular surgeons can use digital imaging and endovascular techniques as adjuncts to standard vascular procedures. This chapter will describe digital imaging and show how this modality can be used in conjunction with endovascular procedures to improve and simplify conventional vascular operations.

Subtraction Current digital imaging systems can process an image to enhance its quality or to add subtraction, roadmapping, and magnification effects. Subtraction is a process whereby radiopaque structures are electronically removed from an image so that contrast within the vasculature can be viewed in an unobstructed fashion. To accomplish this, the computer stores a noncontrast view of an imaged structure in its memory. A second contrast-enhanced image of the vasculature is then obtained. Finally, the computer “subtracts” the digitized information in the first image from that in the second image. The resulting “subtracted” image therefore contains only the contrast-filled vasculature and not over- or underlying radiodense structures. In theory, by removing the effect of soft tissue and bone, the quality of the resulting image can be better than that produced by conventional unsubtracted techniques. In addition, smaller amounts of contrast are usually required for a satisfactory subtracted arteriogram when compared to that required for a standard arteriogram. Therefore, patients with crural and pedal disease, especially in the presence of proximal lesions, may be better imaged using this technique. Also, patients with renal

DIGITAL FLUOROSCOPY Basic Principles Conventional film-based arteriography uses x-rays to precipitate silver crystals on a photographic plate. A picture of the imaged vasculature is produced when shades of black and white appear on the developed film according to the density of x-rays passing through the radiated object. Rather than relying on a chemical reaction to produce an image of the relevant anatomy, digital arteriography relies on a computer to assess the density of x-rays traversing the patient.[1,2] First, conventional x-ray tubes and generators produce the radiation

Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024909 Copyright q 2004 by Marcel Dekker, Inc.

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insufficiency or an allergy to contrast dye may benefit from a digital arteriogram obtained with less of a contrast load than would have otherwise been possible[3 – 8] (Fig. 26-1).

Roadmapping Roadmapping is another feature of digital fluoroscopes that can facilitate endovascular procedures. This feature causes a contrast-enhanced “map” of the vasculature to remain on the video screen to guide real-time interventions such as selective arterial cannulations. As an example of this technique, a contrast-enhanced image of the common femoral artery bifurcation can remain on the monitor while a guidewire and catheter are selectively positioned within the superficial femoral artery. Without roadmapping, it might be difficult to ascertain whether the guidewire and catheter have been correctly positioned without repeating a contrast study.[9]

Magnification Digitized images can be magnified to aid in their interpretation. Magnification can be performed by focusing the x-ray beam over a smaller area or by “zooming” in on a section of a previously stored image using computer software. Both types of magnification result in a smaller field of view, but the former approach produces an image with greater resolution while the latter sacrifices resolution to increase image size. The degree of magnification that can be obtained by focusing the x-ray beam is hardware limited, while the degree to which the image can be magnified by the computer is not.

images can also be viewed individually in sequence. Visualization of the cine loop of stored images at regular speed allows the interpreter to assess flow-dependent events while the playback of individual images is ideal for diagnosing native vessel or bypass graft lesions.

TECHNIQUES TO FACILATE STANDARD VASCULAR OPERATIONS The remainder of this chapter will describe how we use digital fluoroscopy-based techniques to enhance standard vascular procedures such as intraoperative preprocedure and completion arteriograms, thromboembolectomies, and the repair of traumatic arterial lesions. In addition, we will explain how this modality can be used in conjunction with other endovascular techniques to precisely localize hemodynamically significant, angiographically occult arterial lesions, facilitate balloon angioplasty and stent insertion, perform thrombolysis, and obtain proximal arterial control using a balloon catheter. All of our vascular operating rooms contain radiolucent tables as well as portable digital C-arm fluoroscopes with subtraction, magnification, and roadmapping features. (Figs. 26-2 and 26-3) The equipment is arranged so that all table movements and the most frequently used fluoroscopic settings can be controlled by the operating surgeon. Therefore, additional assistance from radiology technicians or other support personnel is not required.

Completion Arteriography Cine Loop Playback Another attraction of current digital fluoroscopes is cine loop playback. This feature enables a continuous sequence of stored fluoroscopic images to be played back and viewed at the same rate at which they were acquired. Alternatively, the

Figure 26-1. Example of the effect of subtraction on an intraoperative arteriogram of the pedal vasculature. (left) Photograph of an unsubtracted arteriogram. (right) The same vasculature imaged using a subtraction technique.

It is our practice to obtain completion angiograms in the majority of patients undergoing lower extremity reconstructions to discover native arterial or bypass graft lesions which could result in early procedural failure.[10,11] Therefore, all peripheral interventions are performed on fluoroscopy tables. After a reconstructive procedure has been completed, we insert a 21 gauge angiocatheter or butterfly needle into an exposed proximal vessel. If this vessel is circumferentially calcified or otherwise unsuitable, the catheter is introduced into the proximal hood of a prosthetic graft or a side branch of a vein graft. Next, the fluoroscope is brought into the operative field and appropriately positioned. Five to 10 cc of iodinated contrast is required to obtain one subtracted image. By moving the fluoroscope or changing the position of the table, both anastomoses, the entire bypass graft, and outflow vessels can all be imaged. In this fashion, potential problems such as technically imperfect anastomoses, tunnel defects, or distal emboli can be discovered. This examination can be performed within 5 minutes—less time than it used to take to develop a single arteriographic film which visualized only a small part of the relevant vasculature (Fig. 26-4). Arteriograms obtained with the digital fluoroscope can be considerably better than those obtained using conventional imaging techniques. In the past, errors due to incorrect timing of the contrast injection or improper positioning of the film cassette often resulted in a suboptimal image that had to be repeated. With digital fluoroscopy, the contrast bolus can be

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Figure 26-2.

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An adjustable fluoroscopic table, which is used to perform all of our endovascular procedures.

visualized in real time as it travels through the vessels and timing errors do not occur. For similar reasons, over- and underfilling of the vasculature with contrast also do not occur. Finally, a portable fluoroscope and a movable table help assure that the extremity being imaged is not subjected to excessive manipulation as occurs when photographic plates are used. Therefore, the potential to inadvertently displace an arterial cannula can be decreased. Once images of the desired vasculature have been obtained, suspicious lesions can be magnified to better evaluate their significance. Alternatively, the angiogram can be repeated after repositioning the fluoroscope at an

Figure 26-3.

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alternative oblique angle. Magnification cannot be performed using standard arteriographic techniques, and obtaining multiple oblique views with conventional equipment is time consuming and labor intensive. A real-time assessment of a fluoroscopic run can provide additional information that is unavailable on a single shot arteriogram. Namely, the time required for the contrast to travel the length of a bypass graft and reach the distal anastomosis may reflect resistance within the outflow vasculature. In our experience, longer transit times occur in patients with disadvantaged outflow. In addition, collateral vessels adjacent to the course of the bypass graft may opacify

Typical setup of a C-arm digital fluoroscope for an endovascular procedure in the operating room.

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the cine loop of the contrast run. After the fistula is repaired a repeat study can be performed to confirm the success of the procedure (Fig. 26-5). In our experience this technique has been most useful when fistulae originate from the deep femoral artery or one of its branches.

Catheter Pressure Localization of Arterial Stenoses

Figure 26-4. Completion arteriogram following a popliteal to anterior tibial artery bypass with a reversed greater saphenous vein. Using a subtraction technique the proximal anastomosis (left), the entire length of the vein graft (middle) and the distal anastomosis (right) can all be satisfactorily imaged.

before the graft itself in these patients. Conversely, bypass grafts with good outflow evidence faster contrast flow rates and a lag in collateral visualization. Intraoperative digital fluoroscopy can also be used to locate patent vein branches following in situ bypasses. After both anastomoses have been completed, contrast is injected and the site of the arterialized branches can be marked on the skin relative to radiopaque landmarks such as metallic staples. Next, the branches can be individually ligated through small precisely placed incisions. This technique is especially useful following procedures in which the vein has not been exposed throughout its entire length.

Most vascular surgeons obtain preoperative arteriograms to document the pattern of disease and to help plan an appropriate bypass. In the majority of cases, these studies will provide the requisite information. However, the hemodynamic significance of lesions in the inflow vasculature may be underestimated if these vessels are diffusely diseased or have serial stenoses. In addition, borderline lesions which may not cause pressure gradients on preoperative imaging studies could become flow limiting following insertion of a bypass graft. Digital fluoroscopy and endovascular techniques are ideally suited to discover and treat these lesions in the intraoperative setting. If the pulse in a bypass graft is weak or there is a significant pressure gradient within the graft, we perform catheter-based pullback pressure measurements to localize the offending lesion. To accomplish this, a hemostatic sheath is first inserted over a guidewire into the relevant inflow vessel. Under fluoroscopic guidance, the guidewire is advanced atraumatically into the abdominal aorta using a guiding catheter when necessary. Next, an endhole catheter is inserted and attached to a calibrated pressure transducer. As the catheter is pulled back its position is followed fluoroscopically. If the pressure at the leading edge of the catheter is noted to decrease acutely relative to systemic pressure, the site of the lesion has been identified. Further arteriographic studies may then be required to decide

Preprocedure Arteriography Intraoperative preprocedure digital fluoroscopy can result in the discovery of suitable outflow vessels in patients not felt to be bypass candidates based on preoperative imaging studies. When preoperative contrast studies are suboptimal, we frequently directly infuse contrast into a crural or pedal vessel to assess its patency. This approach can save patients an attempt at a bypass that is doomed to fail or discover that a bypass is a feasible option whereas an amputation would otherwise have been indicated.[12 – 15] For the reasons discussed above, digital imaging is better suited in this role than conventional techniques. Intraoperative preprocedure digital imaging can also be used to precisely localize hard-to-find arteriovenous fistulae. When the origin of a fistula is readily apparent, intraoperative imaging is usually unnecessary. However, if the fistula involves a small arterial branch, radiographic localization may be preferable to an extensive and potentially dangerous dissection. To localize such fistulae, we first dissect the anterior surface of a proximal uninvolved vessel and perform a contrast examination through a small angiocatheter. The origin of the fistula can usually be identified after reviewing

Figure 26-5. Intraoperative arteriogram used to identify a traumatic arteriovenous fistula. (left) Contrast injected through a catheter in the common femoral artery reveals early filling of the femoral vein (arrow). On cine loop playback, the fistula is noted to arise from the superficial femoral artery. (right) After the fistula has been ligated, a completion arteriogram confirms its disappearance.

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whether the lesion should be treated by balloon angioplasty or whether a direct operative approach is preferable. If the source of the pressure gradient cannot be localized to the inflow vasculature, then the tunnel or the bypass graft itself is further scrutinized.[16]

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and requires setting up, exposing and developing multiple photographic plates. Perhaps even more importantly, if residual clot remains despite multiple passages of a balloon

Proximal Arterial Control Using a Balloon Catheter Obtaining proximal aortic control with a vascular clamp in the setting of acute traumatic hemorrhage or a ruptured aneurysm may be problematic. It may also be difficult to achieve conventional control of a vessel when it lies within an infected or scarred field, is circumferentially calcified, or harbors an intravascular stent or graft. In these situations, we have found it useful to obtain proximal arterial control in an endovascular fashion using an occlusion balloon technique. This technique requires open or percutaneous exposure of an access vessel proximal or distal to the artery requiring control. Under fluoroscopic guidance a guidewire is advanced through an 18 gauge needle previously placed within the access vessel. After the needle has been retrieved, a hemostatic sheath is situated within the vessel and a guiding catheter is used to direct the wire to the site requiring occlusion. Finally, an angioplasty balloon of the appropriate size is brought to this site and inflated enough to occlude prograde arterial flow. When the reconstruction is finished, the balloon is deflated and flow is restored. When control immediately proximal to the arterial site is needed, a simple balloon catheter can be inserted under direct vision and guidewires and fluoroscopic control are not necessary[17] (Fig. 26-6).

Fluoroscopically Assisted Thromboembolectomy In the past, most patients with acute embolic disease did not have underlying atherosclerotic disease and the success of an embolectomy could be assured by retrieving an embolic “bullet” and visualizing backbleeding. However, now that patients with embolic disease also tend to have underlying arterial lesions, these findings are no longer the sine quo non of success. Instead, we believe that arteriographic confirmation of restored luminal patency should accompany all but the most straightforward thromboembolectomies. Prior to surgery, we routinely obtain preoperative imaging studies to ascertain the patient’s pattern of disease and the extent of the thromboembolic process. In addition, we perform routine intraoperative completion studies to confirm the success of our thromboembolectomies. These studies not only confirm that the clot burden has been removed and that straight-line flow has been restored but may diagnose hemodynamically significant lesions which could compromise an otherwise successful procedure.[18 – 22] Digital fluoroscopy has distinct advantages over conventional arteriography in these cases. First, it is easy to obtain images following retrieval of the balloon catheter using the digital fluoroscope so that the need for further intervention can be assessed. Contrarily, the same approach using conventional techniques is cumbersome, time consuming,

Figure 26-6. A patient underwent three failed peripheral bypasses, all of which originated from the right common femoral artery. Ultimately, an external iliac to anterior tibial artery bypass was successful in restoring distal perfusion. However, the patient experienced massive hemorrhage from the hood of a prosthetic graft that had been incompletely excised during a debridement of the right groin. Emergency local control of the bleeding site by conventional measures was deemed impossible, and proximal control of the common femoral artery was achieved with a balloon catheter. (A) Access to the relevant vasculature was achieved percutaneously through the left femoral artery. (left) A preprocedure arteriogram demonstrating (a) the external iliac artery, (b) the bypass graft to the anterior tibial artery, (c) the common femoral artery and (arrow) the location of the bleeding hood of the prosthetic graft. (right) A guiding catheter has been used to advance a wire over the aortic bifurcation and into the right external iliac artery. Note the presence of a previously placed stent (arrow) within the proximal external iliac artery. (B) (left) An angioplasty balloon was advanced into the right common femoral artery and inflated to occlude prograde flow. (right) A repeat arteriogram demonstrates flow in the bypass graft (arrow) and the lack of flow in the common, superficial, and deep femoral arteries. Following successful balloon occlusion, the disrupted prosthetic graft was removed and the femoral artery was repaired in a conventional fashion.

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catheter or if additional lesions are unmasked, digital fluoroscopy can guide intraoperative balloon angioplasty or the infusion of thrombolytic agents. In our practice, patients with emboli at or below the level of the knee were formerly subjected to a medial belowknee incision after which each of the three crural arteries was individually mobilized and thrombectomized.[23] We currently perform fluoroscopically assisted thromboembolectomies to avoid the lengthy and potentially difficult dissection needed to expose and control the origin of each crural vessel. To carry out this procedure, we dissect and mobilize only the proximal below-knee popliteal artery. After confirming that the patient is fully anticoagulated, proximal and distal arterial control are achieved and a small longitudinal arteriotomy is made. Next, a local thrombectomy is performed to facilitate insertion of a hemostatic sheath within the distal popliteal artery. A contrast injection is performed through the sheath and the status of the distal vasculature is assessed. If any of the crural or pedal vessels harbor thrombus, roadmapping techniques are used to selectively catheterize the involved vessels(s) with a guidewire. Finally, an over-the-wire embolectomy catheter is used to clear the vasculature. A similar technique can also be used to treat thromboemboli within bypass grafts or the aortoiliac vessels.[24] Conventional equipment may be used to perform thromboembolectomies if dual lumen embolectomy catheters and fluoroscopes with roadmapping capabilities are not available. In these circumstances, standard embolectomy catheters can be guided into one crural or pedal vessel at a time using a conventional fluoroscope. To accomplish this, a small amount of dilute contrast can be injected into the balloon catheter to confirm its position fluoroscopically relative to the known course of a vessel- or bone-based landmark. Blind balloon insertion is still avoided and the potential for intimal injury or perforation is therefore minimized (Figs. 26-7 and 26-8). Vascular injury secondary to balloon overinflation can also be limited when thromboembolectomies are performed under fluoroscopic control. If a balloon containing contrast is noted to inflate in an asymmetric fashion or if a significant deformity in its shape is noted, the balloon can be partially deflated and the procedure resumed. Using this technique, intimal injury leading to an exuberant hyperplastic response and diffuse arterial narrowing can be avoided.[25 – 30] In addition, significant balloon deformation might highlight the site of a stenotic lesion which could be treated by intraoperative balloon angioplasty. Finally, fluoroscopic guidance during balloon inflation can help prevent balloon underdistention, inadequate balloon-arterial wall apposition, and an imperfect procedure.

Intraoperative Thrombolysis Following a thrombectomy of the distal vasculature, it is not uncommon for clot to remain within a diseased crural of pedal vessel. In these cases, multiple attempts to remove the clot with a balloon catheter may not only prove ineffective but may cause the vessel to become occluded. One option for eliminating the thrombus is to infuse thrombolytic agents

Figure 26-7. Fluoroscopically assisted thrombectomy of a femoropopliteal bypass graft. An attempt at thrombolysis of a recently occluded femoropopliteal bypass graft resulted in restoration of flow through the graft however, residual thrombus within the graft and distal anastomosis could not be lysed. (A) (left) Filling defects within the graft (arrows) on a pre-procedure intraoperative contrast study represent residual thrombus. (right) A balloon catheter has been advanced and inflated (arrow) in the native popliteal artery under fluoroscopic guidance prior to thromboembolectomy. (B) (left) A filling defect noted in the balloon (arrow) during its retrieval indicates the location of adherent thrombus. (right) Completion arteriogram demonstrating complete removal of all residual thrombus and a widely patent distal anastomosis (arrow).

through an infusion catheter placed proximal to or within the affected artery. A pulse-spray technique is used to inject 50,000 IU of urokinase over a 10-minute interval. If the clot has not entirely lysed, the catheter can be repositioned if necessary and additional urokinase can be infused up to doses of 250,000 IU or more. After successful lysis, unsuspected lesions which are amenable to balloon angioplasty may be revealed. Despite partial or unsuccessful clot lysis, thrombolytic therapy may make the residual clot more susceptible to balloon thromboembolectomy. In addition, the lytic treatment may open important collaterals which might otherwise have remained occluded.[31 – 34]

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Intraoperative Balloon Angioplasty and Stenting Digital fluoroscopy has also made it feasible to perform balloon angioplasty and stent insertions during standard vascular procedures. [35 – 38] We have employed these techniques intraoperatively when hemodynamically significant lesions are found during native arterial of bypass graft thromboembolectomies. In addition, balloon angioplasty and stenting have a well-documented role in treating inflow lesions during infrainguinal bypass procedures. The ability to perform these techniques intraoperatively can save the patient from an extended unanticipated operation or an

Figure 26-8. Fluoroscopically assisted thrombectomy of an occluded prosthetic bypass graft. (A) (left) After thrombectomy of the body of a prosthetic femoral – distal bypass graft an arteriogram demonstrates residual flow limiting thrombus within the proximal anastomosis (arrow). Conventional embolectomy catheters could not be advanced through the anastomosis so an endovascular approach was undertaken. (right) Under fluoroscopic control, a guidewire (arrow) was advanced atraumatically through the anastomotic site. (B) (left) An over-the-wire embolectomy catheter (arrow) was then inserted and the thromboembolectomy was performed. (right) In addition, thrombectomy of the outflow vasculature was performed under fluoroscopic guidance to avoid balloon overinflation (arrow). (C) Completion arteriograms demonstrating a thrombus free proximal anastomosis (left) and patent runoff vasculature (right).

Figure 26-9. (A) (left) A patient with toe gangrene underwent a preoperative angiogram demonstrating a high grade, focal, right common iliac artery stenosis and a long segment superficial femoral artery occlusion (not shown). The patient was brought to the operating room for simultaneous femoropopliteal bypass grafting and balloon angioplasty and stenting of his iliac lesion. (right) An intraoperative pre-procedure arteriogram obtained through the right femoral artery demonstrates minimal reflux of contrast into the aorta confirming the pre-occlusive nature of the iliac lesion (arrow). (B) (left) After pre-dilating the stenotic segment, an appropriately sized balloon inflatable stent was deployed. (right) A completion arteriogram demonstrates that the iliac lesion has been adequately treated. The patient then underwent an uneventful femoropopliteal bypass.

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additional interventional procedure in the pre- or postoperative period. When a hemodynamically significant lesion is discovered, a guidewire is advanced through an introducer sheath and across the stenotic lesion. An appropriately sized angioplasty balloon is used to perform the dilatation, and the results can be readily visualized with a repeat angiogram. In the presence of a residual stenosis, repeated attempts at balloon dilatation can be performed or a stent can be inserted (Fig. 26-9).

CONCLUSIONS Digital fluoroscopy and endovascular skills must be considered indispensable tools for surgeons performing vascular procedures. In addition to improving and simplifying standard vascular operations, they allow surgeons to undertake a host of therapeutic interventions previously impossible to perform in the operating room.

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15. Patel, K.R.; Semel, L.; Clauss, R.H. Extended Reconstruction Rate for Limb Salvage with Intraoperative Prereconstruction Angiography. J. Vasc. Surg. 1988, 7, 531– 537. 16. Kinney, T.B.; Rose, S.C. Intraarterial Pressure Measurements During Angiographic Evaluation of Peripheral Vascular Disease: Techniques, Interpretation, Applications and Limitations. Am. J. Roentgenol. 1996, 166, 277– 284. 17. Veith, F.J.; Sanchez, L.J.; Ohki, T. Technique for Obtaining Proximal Intraluminal Control When Arteries Are Inaccessible or Unclampable Because of Disease or Calcification. J. Vasc. Surg. 1998, 27, 582– 586. 18. Bosma, H.W.; Jorning, P.J.G. Intra-Operative Arteriography in Arterial Embolectomy. Eur. J. Vasc. Surg. 1990, 4, 469– 472. 19. Crolla, R.; van de Pavoordt, E.; Moll, F.L. Intraoperative Digital Subtraction Angiography After Thromboembolectomy: Preliminary Experience. J. Endovasc. Surg. 1995, 2, 168– 171. 20. Giordano, J.M.; Trout, H. The Use of Fluoroscopy with the C-Arm for Femoral Arterial Embolectomy and Cannulation of the Popliteal Trifurcation Vessels. Surg. Gynecol. Obstet. 1984, 158, 503– 505. 21. Hill, S.L.; Donato, A.T. The Simple Fogarty Embolectomy: An Operation of the Past. Am. Surg. 1994, 60, 907– 911. 22. Robicsek, F. Dye-Enhanced Fluoroscopy-Directed Catheter Embolectomy. Surgery 1984, 95 (5), 622– 624. 23. Gupta, S.K.; Samson, R.H.; Veith, F.J. Embolectomy of the Distal Part of the Popliteal Artery. Surg. Gynecol. Obstet. 1981, 153, 255– 256. 24. Parsons, R.E.; Marin, M.L.; Veith, F.J.; et al. Fluoroscopically Assisted Thromboembolectomy: An Improved Method for Treating Acute Arterial Occlusions. Ann. Vasc. Surg. 1996, 10 (3), 201– 210. 25. Bowles, C.R.; Olcott, C.; Pakter, R.; et al. Diffuse Arterial Narrowing as a Result of Intimal Proliferation: A Delayed Complication of Embolectomy with the Fogarty Balloon Catheter. J. Vasc. Surg. 1988, 7, 487– 494. 26. Cronenwett, J.L.; Walsh, D.B.; Garrett, H.E. Tibial Artery Pseudoaneurysms: Delayed Complication of Balloon Catheter Embolectomy. J. Vasc. Surg. 1988, 8, 483– 488. 27. Dobrin, P.B. Mechanisms and Prevention of Arterial Injuries Caused by Balloon Embolectomy. Surgery 1989, 106 (3), 457– 466. 28. Dobrin, P.B.; Jorgensen, R.A. Balloon Embolectomy Catheters in Small Arteries: A Technique to Prevent Excessive Shear Forces. J. Vasc. Surg. 1985, 2, 692– 696.

Chapter 26. 29.

Masuoka, S.; Shimomura, T.; Ando, T.; et al. Complications Associated with the Use of the Fogarty Balloon Catheter. Cardiovasc. Surg. 1980, 21, 67– 74. 30. Schwarcz, T.H.; Dobrin, P.B.; Mrkvicka, R.; Skowron, L.; Cole, M.B. Early Myointimal Hyperplasia After Balloon Catheter Embolectomy: Effect of Shear Forces and Multiple Withdrawals. J. Vasc. Surg. 1988, 7, 495– 499. 31. Beard, J.D.; Nyamekye, I.; Earnshaw, J.J.; et al. Intraoperative Streptokinase: A Useful Adjunct to BalloonCatheter Embolectomy. Br. J. Surg. 1993, 80, 21– 24. 32. Knaus, J.; Ris, D.; Stirnemann, D. Intraoperative Catheter Thrombolysis as an Adjunct to Surgical Revascularization for Infrainguinal Limb-Threatening Ischaemia. Eur. J. Vasc. Surg. 1993, 7, 507– 512. 33. Quinones-Baldrich, W.; Baker, J.D.; Busuttil, R.W.; et al. Intraoperative Infusion of Lytic Drugs for Thrombotic

34. 35. 36.

37.

38.

Adjunctive Endovascular Procedures

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Complications of Revascularization. J. Vasc. Surg. 1989, 10, 408– 417. Wasselle, J.; Bandyk, D.F. Intraoperative Thrombolysis in Peripheral Arterial Occlusion. JCC 1993, 36 (4), 354– 335. Al-Salman, M.M. Intraoperative Balloon Angioplasty: A Useful Adjunct. Int. Surg. 1998, 83, 79– 83. Ammar, A.D.; Hutchinson, S.A. Management of Acute Infrainguinal Arterial Thrombosis: Combined Intraoperative Balloon Thrombectomy with Balloon Angioplasty: A Preliminary Report. Surgery 1987, 101 (2), 176–180. Demasi, R.J.; Snyder, S.O.; Wheeler, J.R.; et al. Intraoperative Iliac Artery Stents: Combination with Infrainguinal Revascularization Procedures. Am. Surg. 1994, 60, 854– 859. Pfeiffer, R.B.; String, S.T. Adjunctive Use of the Balloon Dilatation Catheter During Vascular Reconstructive Procedures. J. Vasc. Surg. 1986, 3, 841– 845.

CHAPTER 27

Acute Arterial Insufficiency F. William Blaisdell James W. Holcroft now is more commonly caused by coronary artery disease. A less common cardiac source of emboli is a left ventricle that is damaged by myocardial infarction; ventricular aneurysms can harbor a mural thrombus, and an infarcted endocardium can predispose to clot formation. The most common extracardiac sources of arterial emboli include ulcerating atheromatous lesions in the abdominal aorta and common iliac arteries. The lesions may be associated with aneurysmal disease of these vessels as well as more distal vessels. Other sources or causes of emboli are listed in Table 27-1 and include atrial myxoma, endocarditis, prosthetic heart valves, complications of arterial catheterization, and paradoxical embolization. In approximately 25% of cases of acute ischemia caused by embolism, no source for the embolus can be identified. These cases may be due to small ulcerative lesions not demonstrated angiographically or may be caused by paradoxical emboli in which a septal defect cannot be demonstrated. Thrombus is the second major cause of acute arterial ischemia, and in one recent review it accounts for 50% of all acute ischemic episodes reported.[5] Thrombosis usually occurs at a point of narrowing in an atherosclerotic vessel, particularly in association with a flow-related disorder such as congestive heart failure, shock, dehydration, or polycythemia. Additionally, hemorrhage within an atherosclerotic plaque can result in sudden occlusion.[6] Traumatically induced ischemia is covered in Chaps. 74 through 77.

Whenever the motion of the blood in the arteries is impeded, by compression, by infarction, or by interception, there is less pulsation distally, since the beat of the arteries is nothing else than the impulse of blood in these vessels. William Harvey The concept of occlusion or “interception” of arterial flow was introduced by William Harvey[1] in 1628. John Hunter[2] has been credited with proposing embolectomy in 1768 as a procedure for restoring flow. One hundred and forty years later, Labey[3] performed the first successful embolectomy. The twentieth century has witnessed rapid progress in salvaging limbs that are threatened by acute arterial ischemia, primarily because of two developments. First, heparin anticoagulation has made it possible to limit the propagation of clot distal to the point of occlusion and to reduce the incidence of recurrent embolus and thrombosis. Second, the Fogarty balloon catheter, introduced in 1963, has made it possible to extract emboli and thrombi from arteries, the Fogarty catheter being far better suited for this purpose than the devices used in the past such as corkscrew wires or suction catheters.[4] This chapter describes current procedures for dealing with acute arterial insufficiency. The chapter describes the etiology, pathophysiology, diagnosis, and treatment of acute arterial insufficiency.

ETIOLOGY

PATHOPHYSIOLOGY

Acute arterial ischemia is caused by emboli or by acute thrombosis superimposed on a chronic underlying partial obstruction (Table 27-1). Emboli can be of cardiac or noncardiac origin. In the past, 80% of all emboli originated from the heart, the majority of these being of left atrial origin in patients with rheumatic heart disease and atrial fibrillation. With the recent decreased incidence of rheumatic heart disease, other embolic sources of acute arterial ischemia are becoming more prevalent. The most common cardiac source of an embolus remains a fibrillating atrium, but the fibrillation

Emboli of cardiac origin tend to obstruct at bifurcations of large arteries where the luminal diameter suddenly decreases. These arteries are usually more than 5 mm in diameter. Atheroemboli, consisting of debris from atheromatous lesions of the proximal arterial system, are smaller and occlude vessels less than 5 mm in diameter. The size of the obstructed vessel then can help in differentiating between emboli that originate from the heart and emboli that originate from the aorta or common iliac arteries. For example, an embolus that lodges in the common femoral artery is usually of cardiac

Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024910 Copyright q 2004 by Marcel Dekker, Inc.

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406 Table 27-1.

Part Four. Peripheral Occlusive Disease

Etiology of Acute Arterial Occlusion

Embolic Cardiac Atrial fibrillation Valvular heart disease (rheumatic heart endocarditis) Myocardial infarction (with or without aneurysm) Prosthetic heart valves Left atrial myxoma Paradoxical embolus Congestive cardiomyopathy Hypertrophic cardiomyopathy Mitral annulus calcification Mitral valve prolapse Peripheral Ulcerating atherosclerotic lesions Aneurysms (aortic, iliac, femoral, popliteal, axillary) Arterial catheterization complications Thrombotic Narrowed atherosclerotic segment (with or flow-related disorder) Intraplaque hemorrhage Drugs of abuse

disease or ventricular

subclavian,

without a

origin; an embolus that leads to infarction of an isolated toe usually arises from the distal aorta or common iliac arteries. Once an embolus lodges in an artery, or once a thrombus occludes a previously diseased artery, the vasculature distal to the obstruction goes into spasm. Clot then forms proximal to the site of the obstruction, back to the point of adequate collateralization. The distal spasm lasts for approximately 8 hours and then subsides. At this point clot forms in the arterial system distal to the site of obstruction and propagates downward, obstructing any residual collateral flow, resulting in worsening of the ischemia. As a result the skin usually becomes patchy, blue, and mottled. Skeletal muscle and peripheral nerves withstand acute ischemia for some 8 hours without permanent damage; skin can withstand severe ischemia for as long as 24 hours. The extent of the ischemic necrosis depends on the adequacy of collateral circulation, the patient’s underlying cardiovascular function, viscosity of the blood, oxygen-carrying capacity of the blood, propagation of clot into the microvasculature, and effectiveness and promptness of treatment. If muscle ischemia progresses to necrosis, the muscle becomes paralyzed and acquires a firm, spastic consistency. When peripheral nerves become ischemic, they cease to function, and the affected parts become anesthetic. As the skin undergoes profound ischemia, maximum oxygen extraction results in a cyanotic, blotchy appearance. When these blotchy, cyanotic areas no longer blanch with pressure, the skin is gangrenous and the ischemia is no longer reversible.[7] The reperfusion of an ischemic extremity poses a threat to the rest of the body.[8,9] Anaerobic metabolism produces

unbuffered acid, dead cells release potassium and myoglobin, microthrombi form in the areas of stasis and acidosis, and procoagulants and inflammatory products accumulate. With reperfusion, oxygen radicals, leukotrienes, and many other inflammatory mediators are generated, and all of these products are released into the systemic circulation. Here they produce systemic vascular permeability, extravasation of plasma into the interstitium, and damage to remote organs. The lungs receive the first onslaught, but damage to the heart and kidneys also occurs.[10] We have documented a mortality rate of 85% when a limb with advanced ischemia is revascularized. The degree of insult to the body as a whole depends upon the mass of ischemic tissue, the duration of the ischemia, and the underlying condition of the remote organs.

DIAGNOSIS In most cases a history and physical examination allow identification of the level of obstruction, the probable cause, and the degree of ischemia (Tables 27-2 and 27-3). This information is usually all that is needed to direct the therapy. The history should review the duration and progression of the symptoms and should document prior cardiac or vascular disease that might complicate the treatment. A history of claudication indicates prior atherosclerotic occlusive disease. In a nonsmoker, aortoiliac occlusive disease is unlikely. A history of heart disease, particularly one associated with arrhythmias, makes the possibility of embolization from the heart likely. The physical examination gives information about the heart and the likelihood that the heart is the source of an embolus. Signs of chronic ischemia in the lower extremities—

Table 27-2. Signs of Ischemia Acute ischemia Pale extremity at resting position Temperature change, with sharp line of demarcation Pain and paresthesias Decreased sensation Mottled cyanotic color that blanches with pressure Mottled cyanotic color that does not blanch Paresis progressing to paralysis Firm, spastic musculature Chronic ischemia Atrophic musculature Decreased hair Hypertrophic nails Pulse deficits Temperature Venous troughinga Slow capillary refill Prolonged pallor with elevation Dependent rubor a

Collapse of the superficial veins of the foot.

Chapter 27. Table 27-3.

Patient Evaluation

Cardiac evaluation

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Table 27-4. Laboratory Assessment Vascular evaluation

History Myocardial infarction Transient ischemic attack Arrhythmias—syncope Amaurosis fugax Angina Claudication Palpitations Impotence Medications Intestinal angina Congestive heart failure Prior surgery Physical examination Rate and rhythm Absent pulses Murmurs and gallops Aneurysmal vessels Blood pressure Bruits Cardiomegaly Acute ischemia Peripheral edema Chronic ischemia Jugular venous distension Dehydration

hypertrophic nails, atrophic skin, and hair loss on the feet— indicate previously existing obstructive disease. The presence of an acute arterial insufficiency is usually manifest by an abrupt temperature change in an extremity distal to the level of the obstruction (Fig. 27-1). The ability to dorsiflex and plantarflex the toes indicates the viability of the musculature in the calves; the inability to move the toes indicates impending necrosis of at least some of those muscles. Development of firm, spastic musculature, especially if the contralateral side is normal, indicates extensive necrosis or impending necrosis of the musculature. Paresthesias and anesthesia indicate the status of the nerves in the ischemic extremity. Waxy, white skin is characteristic of active spasm and indicates that there are viable arterioles supplying blood to the skin; blotchy cyanosis that does not blanch with pressure indicates thrombosed capillaries in the subcuticular areas and skin necrosis.

Hematocrit, PT/PTT, platelets Electrolytes, BUN, creatinine, glucose Urinalysis—test for myoglobinuria CPK with isoenzymes Chest radiograph Electrocardiogram Two-dimensional echocardiogram Arteriogram

Laboratory tests are aimed at evaluating hydration, oxygen-carrying capacity of the blood, renal function, cardiac function, and muscular damage (Table 27-4). A chest x-ray shows the size of the heart and may identify thoracic aortic disease. A hematocrit can make a diagnosis of polycythemia. A urinalysis that shows protein and pigment suggests the presence of myoglobin in the urine. The determination of creatinine phosphokinase with isoenzymes can give information about muscle necrosis. An electrocardiogram defines arrhythmias and gives information about the status of the heart. Two-dimensional echocardiography identifies the cardiac chamber size, estimates the ejection fraction, studies the valvular pathology, evaluates the wall motion, and sometimes identifies intracardiac thrombus or tumor.[11,12] Echocardiography may also detect a potentially patent atrial septal defect. Echocardiography is not helpful acutely in deciding whether to operate, anticoagulate, or amputate.[13] It is of value in discovering underlying cardiac disease that requires attention after successful management of the acute ischemic event. An ultrasound examination of the abdomen may reveal an abdominal aortic aneurysm. Ultrasonography of the popliteal fossa may demonstrate a nonpalpable thrombosed popliteal aneurysm. Unless a therapeutic decision hangs in the balance, we do not obtain arteriograms initially. When an arteriogram is

Figure 27-1. Level of temperature and color change with occlusion of different arteries.

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obtained later, however, it can give useful information. An arteriogram sometimes shows a sharp cutoff of a proximally normal artery, indicating an embolus. It may also show preexisting underlying atherosclerotic occlusive disease. Abdominal aortic aneurysms or atheromatous disease involving the distal aorta and common iliac arteries may be demonstrated.

TREATMENT All patients with limb-threatening acute arterial insufficiency should be anticoagulated with heparin to prevent distal clot propagation. Heparin is the drug of choice because it is fastacting, rapidly metabolized, and reversible by protamine sulfate. Many surgeons use conventional dosages of heparin (100–200 USP units/kg by bolus, followed by 15 –30 USP units/kg/h by constant infusion). We strongly advise higher dosages and prefer a bolus of 300 USP units/kg, followed by 60–70 USP units/kg/h.[14] An activated clotting time, partial thromboplastin time, or Lee-White clotting time should be obtained to ascertain that the patient is responding to the anticoagulants, preferably maximizing at our upper limit of laboratory assessment ðPTT . 15000 Þ: We do not use these tests, however, to gauge the adequacy of our heparin dose. The degree of anticoagulation distal to an obstruction is not the same as the anticoagulation of blood taken from an antecubital vein. We use the higher doses of heparin because we want the anticoagulation to be adequate in the ischemic areas; we judge the amount of anticoagulation by the patient’s clinical response rather than by a laboratory test.[15] Regardless of the dosage, if the limb fails to improve following anticoagulation, the dosage is not adequate. Active clotting results in the downstream release of inflammatory factors that produce vascular “spasm.” This results in narrowed vessels and is protective in that it tends to prevent propagating clot from filling the vascular lumen. However, this spasm interferes with collateral flow. When full anticoagulation is obtained in the ischemic limb, spasm reverses and collateral flow improves. This is followed by a decrease in pain and a drop in the level of ischemic demarcation. Inevitably the viability of the limb will improve. If the limb is viable at initiation of anticoagulation, viability will improve with adequate anticoagulation, and revascularization, if necessary, can be carried out electively. If the patient is seen within 4 –6 hours of onset of ischemia and viability of the limb is in question—as manifest by pain, paralysis, or paresthesia—immediate operative intervention is indicated. Meticulous surgical technique is necessary to ensure wound hemostasis so that the patient can remain fully anticoagulated postoperatively. In the patient with probable thrombosis superimposed on preexisting vascular disease who has an ischemic but viable limb, revascularization is delayed until anticoagulation has resulted in improved collateralization and stabilization of the level of ischemia. An extensive early reconstructive procedure compromises the ability to administer full heparin therapy postoperatively because of a prohibitively high rate of hemorrhage.

We do not operate as an emergency on patients who present with ischemia of longer than 8 hours duration. If the ischemic insult is severe enough to result in muscle necrosis, the necrosis will already be established within 8 hours. Revascularization after this period of time salvages no more muscle beyond that salvaged by anticoagulation, a treatment associated with a lower mortality. We do not attempt immediate revascularization in patients with serious underlying medical problems. Revascularization of ischemic tissue washes products of ischemia into the central circulation, where those products damage the lungs, heart, kidneys, liver, and perhaps other organs. The patient’s medical condition should be considered with respect to the amount of ischemic tissue that would be revascularized. Only a fairly strong patient can tolerate revascularization of an extremely ischemic entire lower extremity, whereas a patient with a modest degree of cardiopulmonary disease will tolerate the establishment of flow into a moderately ischemic foot. No arteriogram is obtained initially because arterial punctures are likely to bleed with full anticoagulation. The heparin anticoagulation is given to achieve clinical improvement. The improvement can be gauged by the patient’s symptoms, by progression of the line of temperature demarcation distally along the leg, by recovery of sensation in the extremity, by maintenance or recovery of skeletal muscle function in the extremity, and by the appearance of the skin. As long as the skin blanches with pressure, it is potentially salvageable; when the skin develops blotchy, cyanotic areas that do not blanch with pressure, the tissue involved is beyond salvage. Hemorrhage is the major complication of anticoagulation with heparin.[16] Patients without surgical wounds and without underlying bleeding dyscrasias seldom bleed on heparin, even high-dose heparin, for the first several days of therapy. Bleeding becomes more common on about the fifth day, when heparin-induced thrombocytopenia can contribute to the anticoagulant effect of the heparin itself. Fortunately, most patients receive most of the benefit form heparin anticoagulation within the first few days of treatment. This permits a gradual reduction of heparin dosage, over the next 3–4 days, to more conventional levels. Failure to maintain therapeutic benefit on these lower doses, however, requires raising the level of anticoagulation. If bleeding should develop on the fifth day or later, the heparin can usually be stopped at that time, and in most instances therapeutic benefit will be maintained. The heparin should be given for 48 –72 hours at the high recommended doses. It should then be decreased and the patient’s clinical condition assessed. If the patient’s status remains unchanged with lower doses of heparin, the heparin can be decreased approximately 1000 USP units/h every 24 hours until the heparin is stopped about 7 days after the initiation of therapy or the patient is transferred to oral anticoagulation or low-dose subcutaneous heparin. At that time the extremity will be viable or partially necrotic. Amputation, revascularization, or chronic anticoagulation are treatment options in this situation. Revascularization is performed 7 days or more after the acute ischemic insult to maximize the chance of healing of an amputation or to alleviate residual ischemic symptoms.

Chapter 27.

We have found that this treatment, a plan that emphasizes the importance of anticoagulation, results in low mortality and salvages extremities as well as those treatment regimens that emphasize immediate revascularization in all patients, both low risk and high risk.[14] We do advocate thromboembolectomy in patients who are seen shortly after the onset of symptoms. In the remaining patients who present with ischemic but viable limbs, revascularization can be performed at a time of election if anticoagulation is given in adequate dosages to prevent thrombus propagation. In these patients with ischemic skin necrosis or dead muscle, initial anticoagulation followed later by amputation is the treatment of choice. Patients presenting with a viable extremity more than 48 hours after the onset of symptoms can be managed like patients with chronic severe obstructive disease. High-dose heparin therapy is of limited value, as these extremities have already survived the initial ischemic insult by developing collateral flow. An angiogram to evaluate the vasculature should be obtained. Many of these patients will require revascularization. Some have benefited from embolectomy as a form of revascularization up to 7 weeks after the onset of symptoms.[17] Chronic anticoagulant therapy with warfarin (Coumadin) or subcutaneous heparin is subsequently indicated in many of these patients.

Embolectomy Technique Low-risk patients who present with ischemia of less than 8hour duration should have an embolectomy performed if it is likely that the acute ischemia is caused by an embolus. With the patient under local or regional anesthesia, thrombus or embolus can frequently be easily removed via a peripheral incision.[18] A Fogarty balloon catheter is passed through the clot or embolus, the balloon inflated gently, and the catheter withdrawn. There are several important aspects to the application of this technique. Proximal and distal control of the vessel should be ensured before arteriotomy. The common femoral, popliteal, and brachial arteries allow access to most vessels with extractable material. Catheter-related complications can be kept to a minimum by continually modifying the amount of fluid in the balloon while the catheter is being withdrawn to prevent overinflation at plaque sites and consequent vessel damage. Backbleeding as well as distal pulsation do not guarantee adequate clot extraction. Therefore, an angiogram should be obtained after the removal of the embolus to confirm an adequate clot extraction. The nature of the operation is subsequently dictated by the arteriographic and operative findings. Most acute thromboemboli can be removed completely through the groin. However, if the occlusion is atherosclerotic or is distal to the distal superficial femoral artery, clearing the occlusion may be difficult or impossible. In such cases the arteriotomy is better performed in the distal popliteal artery or in the tibioperoneal trunk opposite the origin of the anterior tibial artery. Balloon catheter embolectomy of the tibial arteries can then be performed gently and accurately. In some cases, with arteriosclerotic or aneurysmal changes, a bypass operation must be performed with or without extraction of the proximal thrombus or embolus.

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There are four primary complications associated with the use of the balloon catheter: rupture, perforation, intimal injury, and fragmentation of clot resulting in inadequate removal and distal embolization. These complications serve to emphasize another reason for obtaining an angiogram after an embolus extraction. If the angiogram demonstrates an intimal injury compromising circulation, repair is necessary. If there is extravasation of contrast material but good distal perfusion without signs of ongoing hemorrhage, repair may or may not be necessary. These patients can often be followed clinically and studied later with arteriograms to confirm the resolution of the problem. For at least 24 hours after surgery, the patient should be placed in an intensive care unit so that the distal circulation can be monitored. If evidence of rethrombosis or recurrent embolus is identified, the patient should be returned to the operating room immediately. Pulmonary, cardiac, and renal complications should be treated in standard fashion as they present. Common complications of revascularization are noted in Table 27-5.

Postoperative Anticoagulation All patients should be maintained on heparin anticoagulation postoperatively for at least 72 hours, and warfarin (Coumadin) should be started in those patients presumed to have had embolic occlusions. Hemorrhage is a frequent postoperative complication in patients receiving heparin. Postoperative bleeding can be minor, as indicated by melena, hematuria, ecchymosis, or small wound hematomas, in which case the heparin therapy can be continued with monitoring of the hematocrit, platelet count, and partial thromboplastin time. The conversion to oral anticoagulation therapy should be accomplished as soon as possible. If the bleeding is major, the heparin effect should be reversed with protamine. Major bleeding can be defined as that requiring transfusion for stabilization, cerebrovascular accidents, pulmonary infarction, and large wound hematomas. Further anticoagulation therapy should then await the stabilization of the patient and reevaluation. Acutely, heparin is used in the postoperative period to prevent recurrent embolus or thrombosis. In our experience and that of others, mortality is decreased with postoperative anticoagulation.[19] The trade-off is a 20% incidence of wound complications, including an 8% incidence of hematomas requiring drainage.[20] Table 27-5. Complications of Revascularization Hemorrhage Thrombosis Recurrent emboli Pulmonary embolus Microembolic acute respiratory distress syndrome Extremity edema Acute renal failure Cardiac dysfunction—myocardial infarction, arrhythmias Mesenteric infarction

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Fasciotomy Following revascularization of an ischemic limb, some degree of muscle edema is the rule. The amount of edema parallels the severity and duration of the ischemia. When the subfascial compartments become tense, and in particular when compartment pressures exceed 40 mmHg, many surgeons feel that four-compartment fasciotomy is indicated to preserve circulation and enhance muscle viability.[21] When the increased compartment pressure is due to direct tissue injury, hemorrhage, or venous obstruction, fasciotomy is noncontroversial. However, when increased compartment pressure is due to swelling of ischemic muscle, fasciotomy that exposes this muscle will not necessarily reverse the damage, which is often irreversible necrosis. Exposed ischemic or dead muscle is vulnerable to infection, and when infection occurs above knee, amputation is usually the result. Limbs are lost only when the covering (skin) is lost. Necrotic muscle, protected from infection, atrophies and resorbs. Lower leg muscles, which are the ones most commonly involved, affect ankle function, but a partially paralyzed limb is still functional. Moreover, a below-knee amputation, should this be required, is associated with much less disability than is amputation above the knee. Finally, the decision for or against fasciotomy is a judgment decision in which the risk/benefit ratio must be weighed. Fasciotomy is rarely necessary when the ischemic limb is revascularized within the period of muscle tolerance (6–8 hours of profound ischemia) or when the muscle is still functional.[21]

be caused by the antigen–antibody interaction of streptokinase with preformed streptococcal antibodies. Urokinase is harvested from human renal cells in tissue culture and is not antigenic. It is a trypsinlike protease that directly converts plasminogen to plasmin. Low-dose urokinase at 20,000 IU/h, selectively infused, has been effective in restoring vessel patency. Its primary disadvantage is that it is six times more expensive than streptokinase. Ideally, fibrinolytic therapy would be most useful for fresh thrombosis prior to clot organization, propagation, or vessel wall damage. In contrast to heparin, the streptokinase actively lyses clot and therefore might accelerate the return of circulation to normal. Heparin prevents the formation of new clot, allowing fibrinolysis to predominate over clotting. Heparin can be given systemically and, by preventing clot formation, allows collateral circulation to develop while the patient’s fibrinolytic system slowly lyses clot. Lytic therapy has been combined with percutaneous transluminal angioplasty. It has also been successful in restoring patency in vessels occluded for several weeks. The appropriateness of chronic anticoagulation in both of these groups of patients should be determined on an individual basis. Even with low-dose selective treatment, systemic fibrinolysis can be documented, and complications have been identified. Thrombin time, fibrinogen levels, prothrombin times, partial thromboplastin time, platelet counts, hematocrit, and fibrin split products should be monitored to prevent complications associated with fibrinolytic therapy (Table 27-6). Posttreatment anticoagulation should be monitored because patients have an increased susceptibility to bleeding complications.

Fibrinolytic Therapy We do not use fibrinolytic therapy as primary treatment in limbs with advanced ischemia because therapy requires 12 – 24 hours to become effective and permanent muscle death follows 6–8 hours of ischemia. For limbs with subacute ischemia, which often is associated with thrombotic rather than embolic occlusion, lytic therapy will often unmask the underlying lesion and permit many conservative and operative alternatives. Initially, systemic thrombolytic agents, administered intravenously, were evaluated in acute arterial ischemia, and they effectively restored patency in occluded vessels at the expense of hemorrhagic complications. More recently, lowdose plasminogen activators have been selectively infused through a percutaneous arterial catheter placed in the occluding thrombus.[22 – 24] In theory, the hemorrhagic complications of systemic fibrinolytic therapy are avoided by low-dose local infusion; however, the dosages currently advocated for local therapy are similar to those recommended for systemic treatment. Streptokinase is a nonenzymatic protein product of group C b-hemolytic streptococci that combines with plasminogen to form an active enzymatic complex capable of converting plasminogen to plasmin. The low-dose intraarterial regimen provides for 5000–10,000 IU/h to be selectively infused for 12–48 hours with the therapeutic effect monitored by physical examination or by serial arteriography. The lowgrade fever at times accompanying the treatment is thought to

EVOLUTION OF ISCHEMIC MANIFESTATIONS The nature of ischemic manifestations has slowly changed such that the incidence of embolic occlusion has dropped dramatically in recent decades in favor of thrombotic occlusion. Although thrombotic occlusion may produce severe ischemia, more often the lesion responsible for the occlusion has, through gradual build-up, stimulated collateral development. Under these circumstances limb ischemia is less severe and more therapeutic options are available. If limb sensation and muscle function are present, initiation of anticoagulation may be deferred in favor of

Table 27-6.

Complications of Fibrinolytic Therapy

Intracranial hemorrhage Arterial site hematomas Distal embolization Extravasation of blood through graft interstices—lysis of pseudointima of Dacron prosthesis Retroperitoneal hemorrhage Mild allergic reaction

Chapter 27.

urgent arteriographic evaluation. Arteriography offers many potential advantages, including detection of other unsuspected emboli and atypical localization of thromboembolic occlusions—a very common condition in the elderly atherosclerotic patients that currently comprise the bulk of those presenting with acute limb ischemia. Moreover, arteriography defines the patency and degree of atherosclerotic involvement of the inflow and outflow arteries available for a bypass procedure. Such a bypass is often required for the definitive treatment of acute ischemia, whether it be due to thrombosis or embolism. In this group of patients, the arteriogram may also reveal an unexpected popliteal or aortic aneurysm, or, in the occasional patient, nonocclusive unilateral ischemia due to a low flow state. Immediate arteriography followed by lytic therapy to unmask the lesion responsible for the ischemia is a popular option. Once uncovered, the lesion may lend itself to stenting or bypass depending on its location and extent. In summary, there are multiple options for treatment of the acutely ischemic limb. The limb that has been cold, paralyzed, and insensate for more than 8 hours is best treated with high-dose anticoagulation initially since revascularization attempts will be associated with high morbidity and mortality. If sensation and motor function in the foot are abnormal and the limb can be revascularized within 8 hours, attempt to restore blood flow to the limb is appropriate. In the viable but ischemic limb, emergent arteriography may be optimal. Armed with the findings obtained by performing urgent or emergency arteriography in the marginally viable limb, aggressive management is possible. Options include lytic therapy, stenting of stenotic lesions, or surgical bypass. The decision as to when and when not to attempt revascularization is often difficult and must be based on a surgeon’s experience and ongoing evaluation of results in order to optimize the chances for saving a given patient’s life and limb in this high-risk setting. Many variables influence the choice of treatment for acute ischemia of the lower extremity. The severity of the ischemia, the condition of the patient, and—to some extent—the surgeon’s preference and experience will determine whether treatment with surgery, heparin, or lytic agents should be the preferred therapeutic option. Finally, it should be recognized that revascularization for arterial ischemia carries with it considerable risk. The current mortality for restoration of flow to severely ischemic extremities remains anywhere from 8 to 50%, depending upon the location of the arterial lesion and the duration of the ischemia. Mortality rates were reported as follows: 8%,[25] 22%,[26] 50%,[27] 12%,[28] 17.8%,[29] 19%,[30] and 9.7%.[31]

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UPPER EXTREMITY ISCHEMIA In contrast to lower extremity ischemia, cardiac embolization accounts for the vast majority of cases of upper extremity ischemia.[32] Thoracic outlet obstructions at the third portion of the subclavian artery can result in intimal damage, aneurysmal or poststenotic dilation, and subsequent atheroemboli or thrombosis[33] (see Chap. 62). The principles of management of upper extremity ischemia are similar to those of lower extremity ischemia. Because collateral flow to the upper extremity is extensive, conservative treatment with high-dose heparin is often effective. Embolectomy is more dangerous in the upper extremity because of the smaller size of the vessels and because of the danger of dislodging thrombus into the carotid or vertebral arteries. The mortality is lower and the limb salvage rate is higher for upper extremity ischemia compared with lower extremity ischemia, presumably because the amount of tissue necrosis is less and collateral circulation is better.

CEREBRAL ISCHEMIA Embolism has been estimated to cause 20 –30% of all cerebral infarctions, and the incidence of stroke is five times greater in patients with atrial fibrillation than in the general population.[34] Because the risk of recurrent stroke in these patients is approximately 20% per year, the treatment is directed at controlling cardiac arrhythmias and at preventing further cerebral infarctions with oral anticoagulants.[35]

VISCERAL ISCHEMIA Most visceral ischemia of sudden onset occurs when the superior mesenteric artery is occluded acutely by an embolus or by thrombosis (see Chap. 59). Abdominal catastrophe associated with cardiac disease is the classic setting. Traditionally, mortality has been 80% and treatment has focused on resection of necrotic bowel rather than revascularization. However, revascularization by aortomesenteric bypass, transaortic endarterectomy, or embolectomy may rarely be successful in the acute case. More recently a combination of revascularization followed by resection of necrotic bowel has been advocated to improve mortality.[36] A second-look procedure is always indicated and is of particular value when marginal bowel has been left behind at the initial operation.

REFERENCES 1.

Harvey, W. Exercitatio Anatomica de Motu Cordis et Sanguinis in Anjmalibus; English Translation by Leake, C.D. Charles C Thomas: Springfield, IL, 1931; 37. 2. Shor, P.M.; Fogarty, T.J. Acute Arterial Insufficiency. In Diagnosis and Management of Peripheral Vascular

Disease; Miller, D.C., Avon, A.J., Eds.; Addison-Wesley: Menlo Park, CA, 1982. 3. Mosney, M.; Dumont, N.J. Embolie Fe´morale Aucours d’un Re´tre´cissement Mitral pur. Arte´riotomie. Guerison Bull. Acad. Med. 1911, 66, 358.

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4. Abbott, W.M.; Maloney, R.D.; McCabe, C.C.; et al. Arterial Embolism: A 44 Year Perspective. Am. J. Surg. 1982, 143, 460. 5. Dale, W.A. Differential Management of Acute Peripheral Arterial Ischemia. J. Vasc. Surg. 1984, 1, 269. 6. Lusby, R.J.; Wylie, E.J. Acute Lower Limb Ischemia: Pathogenesis and Management. World J. Surg. 1983, 7, 340. 7. Jivegard, L.; Holm, J.; Schersten, T. Acute Limb Ischemia Due to Arterial Embolism or Thrombosis: Influence of Limb Ischemia Versus Pre-existing Cardiac Disease on Postoperative Mortality Rate. J. Cardiovasc. Surg. 1988, 29, 32. 8. Blaisdell, F.W.; Lim, R.G.; Amberg, J.R.; et al. Pulmonary Microembolism: A Cause of Morbidity and Death After Vascular Surgery. Arch. Surg. 1966, 93, 776. 9. Stallone, R.J.; Blaisdell, F.W.; Cafferata, H.T.; Levin, S.M. Analysis of Morbidity and Mortality from Arterial Embolectomy. Surgery 1969, 65, 207. 10. Haimovici, H. Metabolic Complications of Acute Arterial Occlusions. J. Cardiovasc. Surg. 1979, 20, 349. 11. Nishide, M.; Irino, T.; Gotoh, M.; et al. Cardiac Abnormalities in Ischemic Cerebrovascular Disease Studied by Two-Dimensional Echocardiography. Stroke 1983, 14, 541. 12. Caplan, L.R.; Hier, D.B.; D’Cruz, I. Cerebral Embolism in the Michael Reese Stroke Registry. Stroke 1983, 14, 530. 13. Robbins, J.A.; Sagar, K.B.; French, M.; Smith, P.J. Influence of Echocardiography on Management of Patients with Systemic Emboli. Stroke 1983, 14, 546. 14. Blaisdell, F.W.; Steele, M.; Allen, R.E. Management of Acute Lower Extremity Arterial Ischemia Due to Embolism and Thrombosis. Surgery 1978, 84, 822. 15. Blaisdell, F.W. Use of Anticoagulants in the Ischemic Lower Extremity. In Management of Lower Extremity Ischemia; Kempczinski, R.F., Ed.; Year Book: Chicago, 1989. 16. Walker, A.M.; Jick, H. Predictors of Bleeding During Heparin Therapy. J. Am. Med. Assoc. 1980, 244, 1209. 17. Jarrett, F.; Dacumos, G.C.; Crummy, A.B.; et al. Late Appearance of Arterial Emboli: Diagnosis and Management. Surgery 1979, 86, 898. 18. Fogarty, T.J.; Cranley, J.J.; Krause, R.J.; et al. A Method for Extraction of Arterial Emboli and Thrombi. Surg. Gynecol. Obstet. 1963, 116, 241. 19. Holm, J.; Schersten, T. Anticoagulant Treatment During and After Embolectomy. Acta Chir. Scand. 1972, 138, 683.

20. Tawes, R.L.; Beare, J.P.; Scribner, R.G.; et al. Value of Postoperative Heparin Therapy in Peripheral Arterial Thromboembolism. Am. J. Surg. 1983, 146, 213. 21. Patman, R.D.; Thompson, J.E. Fasciotomy in Peripheral Vascular Surgery. Arch. Surg. 1970, 101, 663. 22. Hallett, J.W.; Yrizarry, J.M.; Greenwood, L.H. Regional Low Dosage Thrombolytic Therapy for Peripheral Arterial Occlusions. Surg. Gynecol. Obstet. 1983, 156, 148. 23. Hargrove, W.C.; Barker, C.F.; Berkowitz, H.D.; et al. Treatment of Acute Peripheral Arterial and Graft Thrombosis with Low-Dose Streptokinase. Surgery 1982, 92, 981. 24. Marder, V.J.; Sherry, S. Thrombolytic Therapy: Current Status. N. Engl. J. Med. 1988, 318, 1585. 25. Cambria, R.P.; Abbott, W.M. Acute Arterial Thrombosis of the Lower Extremity: Its Natural History Contrasted with Arterial Embolism. Arch. Surg. 1984, 119, 784. 26. Balas, P.; Bonatsos, G.; Xeromeritis, N. Early Surgical Results on Acute Arterial Occlusion of the Extremities. J. Cardiovasc. Surg. 1985, 26, 262. 27. Litooy, F.; Baker, W.H. Acute Aortic Occlusion: A Multifaceted Catastrophe. J. Vasc. Surg. 1986, 4, 211. 28. Tawes, R.L., Jr.; Harris, E.J.; Brown, W.H. Acute Limb Ischemia: Thromboembolism. J. Vasc. Surg. 1987, 5, 901. 29. Stryga, O.; Myracha, P.; Zmijewski, M. Acute Limb Ischemia After Arterial Surgery. Wiad. Lek. 1993, 46, 420. 30. Harward, T.R.; Ingegno, M.D.; Carlton, L.; Flynn, T.C.; Seeger, J.M. Limb-Threatening Ischemia Due to Multilevel Arterial Occlusive Disease. Ann. Surg. 1995, 221, 498. 31. Neuzil, D.F.; Edwards, W.H., Jr.; Mulherin, J.L. Limb Ischemia: Surgical Therapy in Acute Arterial Occlusion. Am. Surg. 1997, 270, 63. 32. Haimovici, H. Cardiogenic Embolism of the Upper Extremity. J. Cardiovasc. Surg. 1982, 23, 209. 33. Haimovici, H. Arterial Thromboembolism of the Upper Extremity Associated with the Thoracic Outlet Syndrome. J. Cardiovasc. Surg. 1982, 23, 214. 34. Sage, J.I.; Van Uitert, R.L. Risk of Recurrent Stroke in Patients with Atrial Fibrillation and Non-Valvular Heart Disease. Stroke 1983, 14, 537. 35. Easton, J.D.; Sherman, D.G. Management of Cerebral Embolism of Cardiac Origin. Stroke 1980, 11, 433. 36. Bergan, J.J.; Dean, R.H.; Conn, J.; Yao, J.S.T. Revascularization in Treatment of Mesenteric Infarction. Ann. Surg. 1975, 182, 430.

CHAPTER 28

Microcirculatory Dysfunction in the Pathophysiology of Skeletal Muscle Ischemia Walter N. Dura´n Mauricio P. Boric´ Peter J. Pappas Robert W. Hobson II

molecular oxygen occurs after ischemia has depleted or reduced cellular energy stores. Under these conditions it appears that cellular oxygen sensors adjust themselves to an apparently lower pO2, so that reintroduction of normoxic blood constitutes a hyperoxic and toxic insult to the ischemic tissues. The microcirculation represents the first barrier in ischemia-reperfusion injury in all tissues, and thus may serve as a useful target for therapeutic interventions. Increased permeability to macromolecules, stimulated adhesion and emigration of leukocytes, and the no-reflow phenomenon are characteristic responses of ischemic microvessels. However, the relationship between microvascular dysfunction and tissue damage in the ischemiareperfusion (I/R) injury has not been fully investigated, even though they are intimately related. Increased microvascular permeability to macromolecules is one of the earliest signs of microvascular dysfunction in skeletal muscle. It is difficult to assess to what extent ischemia and reperfusion contribute differentially to microvascular dysfunction. Changes in permeability occur during ischemia and a large increase in macromolecular transport can be measured immediately upon reperfusion.[10,11] Application of clearance and intravital microscopy techniques indicate that a significant increase in macromolecular transport is observed in the reperfusion phase (Fig. 28-1).[12] Some studies have examined the reperfusion period exclusively due to methodological reasons.[13,14] It is important to evaluate carefully the limitations imposed by the experimental design in the assessment of the differential contributions of ischemia and of reperfusion to microvascular dysfunction. It is safe to state that, inasmuch as functional hyperemia does not cause

INTRODUCTION The basis for tissue injury during ischemia depends on depletion of tissue oxygen and energy substrates with predominance of anaerobic metabolism. Decreasing cellular energy stores and accumulation of toxic metabolic byproducts[1,2] alter cellular membrane integrity leading to fluid and electrolyte movement, release of intracellular components, cell injury, and ultimately cell death.[3] Cell injury appears to begin after only 30 minutes of ischemia, as is evidenced by progressive cellular edema[4] and lysosomal degranulation.[5] Irreversible changes in skeletal muscle occur after 4 – 6 hours of warm ischemia.[4] The injury associated with acute arterial occlusion is not limited to the period of ischemia alone. Revascularization and restoration of blood flow initiates a series of complex events that lead to the reperfusion syndrome. Light microscopic studies have documented that cell injury following an ischemic period occurs after blood flow has been reestablished.[4] This injury also has been found to be maximal in areas with the greatest degree of blood flow during reperfusion.[5] The reintroduction of molecular oxygen appears to be an important and critical event in the genesis of reperfusion injury in postischemic muscle. Damage occurs in part as the result of the formation of oxygen-derived free radicals leading to lipid peroxidation.[6,7] Reperfusion with hypoxic blood decreases the incidence of injury while reperfusion with normoxic blood leads to postischemic damage.[8] Similar results are obtained by limiting the rate of blood flow during the first hour of reperfusion.[9] The reintroduction of

Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024911 Copyright q 2004 by Marcel Dekker, Inc.

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MICROVASCULAR PERMEABILITY Structural and Biochemical Bases for Microvascular Permeability

Figure 28-1. Microvascular permeability alterations in ischemia-reperfusion injury in striated muscle. The rat cremaster muscle was prepared for intravital microscopy as described in Ref. [10]. The animal received FITC-dextran-150, a fluorescent macromolecular tracer. (A) The control observation. Note that the fluorescent macromolecule is confined to the vascular compartment. (B) Observations made within 10 minutes after onset of reperfusion. Note that the fluorescent macromolecular tracer has extravasated into the interstitial space, and there are a few microvessels showing signs of the no-reperfusion phenomenon (dark vessels on right-hand side).

either microvascular or tissue damage, reperfusion exaggerates cellular alterations produced by ischemia and, in addition, causes new injury due to complex interactions between newly reintroduced molecular oxygen and the cellular metabolic state set up by ischemia. Regardless of whether it is an ischemic- or a reperfusiondriven event, the reproducibility of alterations in microvascular permeability in I/R injury has led to its wide utilization as an index for microvascular dysfunction[13 – 16] and as an endpoint to test the mechanisms of damage and to assess the efficacy of potential therapies. In this chapter, which builds on the previous edition, we will review the fundamental basis of the regulation of microvascular permeability by biochemical signaling as well as its impact on ischemia-reperfusion injury.

An early and productive interpretation of the morphological basis of increased microvascular permeability is the concept that endothelial cell contraction widens the intercellular gap and allows passage of macromolecules.[11] Electron and fluorescence microscopy identified postcapillary venules as the morphologic main site of action of modulation of permeability by inflammatory mediators.[17 – 19] These microvessels are also responsible for the permeability alterations in I/R injury (Fig. 28-1). Several observations have led to the consideration of an alternative hypothesis of the structural and biochemical basis of microvascular permeability. Experiments in single microvessels demonstrated that transport of protein remains elevated even though the intercellular gap has returned to normal dimensions.[20] Increased transport of macromolecules also occurs in I/R injury despite the normal appearance of microvascular ultrastructure in striated muscle.[10,11] Based on the properties and biochemical structure of the glycocalyx, the alternative hypothesis proposes that the endothelial cell regulates the composition of its glycocalyx in response to environmental physical and chemical stimuli. This capacity of the endothelium has been demonstrated both in tissue culture[21] and in vivo.[22] Changes in the order or structure of the molecules that make up the glycocalyx can determine the rate of transport of solutes from blood to tissue. This latter concept, based broadly on the physicochemical behavior of chromatographic columns, is termed the fiber matrix theory of capillary transport.[23] If indeed changes in the order of fiber matrix glycoproteins are responsible for the observed increased permeability, then it is plausible that therapies based on the administration of macromolecules may work by sealing the larger gap interstices developed by I/R[24 – 26] or by interacting with endothelial integrins and adhesion molecules.

Mechanisms of Signal Transduction in Hyperpermeability Biochemical signaling determines the action of vasomediators in the control of microvascular permeability and flow. Signaling interactions between vascular wall and blood cells provide a unique way of communicating, coordinating, and integrating an appropriate physiologic response to the changing tissue environment in vivo. This brief review of cell signaling in the microcirculation focuses preferentially on in vivo studies of increased permeability (hyperpermeability) in health and in inflammatory microvascular permeability dysfunction. Intravital microscopy has been applied to study microvascular permeability in health and disease using physiologic and pharmacologic approaches to gain insights into regulatory mechanisms. The intravital microscopy approach is greatly enhanced by the utilization of computerassisted digital image analysis (Fig. 28-2).[27 – 29] An example of the application of intravital microscopy is the in vivo investigation of the biochemical signaling pathways in our

Chapter 28.

Figure 28-2. Diagram of video-microscopy computer-assisted image analysis. The fluorescent intensity of a macromolecular tracer is measured at a window adjacent to a postcapillary venule. The measuring window is usually 100 £ 120 pixels (a TV image has 512 £ 512 pixels). The fluorescent intensity is measured according to a computer grayscale (0 – 255) in which 0 = black and 255 = white. The integrated optical intensity of the fluorescent tracer reflects its permeation through the microvascular wall.

laboratory. The basic working scheme, derived from the in vitro literature and our own experimental results, is shown on Fig. 28-3. The signaling pathways for inflammatory agents that cause hyperpermeability [e.g., platelet-activating factor (PAF), bradykinin (BK), histamine, leukotriene C4 (LTC4), and vascular endothelial growth factor (VEGF)] involve the activation of protein kinase C (PKC), activation of nitric oxide synthase (NOS), and synthesis of nitric oxide (NO).[30 – 41] Because of the short duration of the stimulus and the brief delay between stimulus and permeability response (seconds to minutes), endothelial constitutive nitric oxide synthase (eNOS) is the most likely candidate for the generation of NO under these experimental conditions. These reactions are followed by the synthesis of cyclic guanylate monophosphate (cGMP)[42] and are independent of changes in calcium influx.[43] In isolated coronary venules, blood flow modulates permeability also via a mechanism mediated by the synthesis of NO.[44] Flow may possibly induce NO production in endothelial cells due to changes in shear stress.[45] Our own work and the reports of others are consistent with the hypothesis that eNOS activity and release of NO serve to increase microvascular permeability. The issue of whether NO is a universal signaling mechanism remains, however, unresolved. There is persuasive evidence that endogenous NO serves to maintain a tight microvascular barrier. This view is supported by studies showing that inhibition of NOS with L -arginine analogs increases extravasation of macromolecules in the intestine.[46] The action of the NOS inhibitor could be reversed by administration of an NO donor. In the mesentery, the maintenance of a tight microvascular barrier characteristic is thought to involve the participation of cGMP.[47] In either view, the compelling evidence for endogenous NO involvement as a modulator of permeability is based mainly on either the specificity of L -arginine analogs to block NOS or the ability of NO donors to mimic NO actions. The studies cited have not measured NO production under the experimental conditions. In order to fill this gap in

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Figure 28-3. Biochemical signaling pathways in the control of microvascular permeability. The diagram indicates possible molecular interactions leading to hyperpermeability. Because eNOS plays a pivotal role in signal transduction, several upstream pathways converge on eNOS. Among the upstream elements, PKB is being recognized as an important regulator that may directly phosphorylate eNOS and increase NO production (see Refs. [63] and [64]). Nitric oxide stimulates soluble guanylate cyclase to produce cGMP, which in turn activates PKG and leads to the activation of MAP kinases. It is plausible that MAP kinases lead to conformational changes of skeletal and junctional proteins to achieve an increase in microvascular permeability. Abbreviations: PLD, PLC, PLA2 = phospholipases; PKB, PKC, PKG = protein kinases B, C, and G, respectively; PA = phosphatidic acid; DG = diacyl glycerol; Ca2+-CAM = calcium-calmodulin; IP3 = inositol triphosphate; eNOS = endothelial constitutive nitric oxide synthase; cGMP = cyclic guanylate monophosphate; MAP kinase = mitogen-activated protein kinases.

knowledge, we have measured NO in preliminary experiments—using a chemiluminescence method recently validated for its application in the hamster cheek pouch[48]—and determined that PAF increases NO synthesis, causes vasoconstriction, and increases macromolecular transport.

Regulation of Nitric Oxide Synthase by Phosphorylation The genes encoding for human and bovine endothelium eNOS have been characterized and their cDNA have been cloned.[49 – 55] It is important to recognize that while the gene sequence is highly conserved among species, the regulatory modalities may vary in different species.[56] The possibility of eNOS regulation by phosphorylation is supported by its deduced amino acid sequence, which contains phosphorylation sites (largely serine/threonine phosphorylation consensus, even though tyrosine phosphorylation consensus sites also have been identified). However, whether phosphorylation leads to activation or inactivation of eNOS and/or nNOs activity is controversial. PKC and calmodulin kinase II have been reported to phosphorylate

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nNOS by one group,[57] while another group failed to induce phosphorylation of nNOS through these kinases.[58] Activation of PKC (30 minutes exposure to tetradecanoyl phorbol acetate, TPA) leads to nNOS phosphorylation.[57,59] Bradykinin leads to phosphorylation of eNOS and to an increase in the activity of eNOS[60] in bovine aortic endothelial cells (BAEC). However, and in contrast to nNOS, pharmacologic inhibition of PKC as well as PKC depletion by prolonged exposure to TPA elevates the production of NO-related nitrites in BAEC.[61] Tyrosine phosphorylation may play a role in the regulation of eNOS, particularly in its interactions with cavcolin-l.[62] Two recent reports have established that protein kinase B (PKB; a serine/threonine kinase) phosphorylates eNOS directly and leads to an increase in NO production.[63,64] It is tempting to postulate that this direct phosphorylation of eNOS by PKB plays a role in the regulation of microvascular permeability. Dr. Haruo Aramoto, in our laboratory, has shown that wortmannin (a blocker of phosphatidylinositol-3kinase and, thus, an indirect inhibitor of PKB) inhibits in vivo the elevation in microvascular transport of macromolecules caused by VEGF. In reference to the pathway depicted in Fig. 28-3, it is plausible that PAF and other agonists stimulate PKB in its modulation of microvascular permeability. In fact, a recent study suggests that VEGF-induced hyperpermeability is mediated in vivo by PAF.[65] The full functional significance of PKB-induced phosphorylation and its enhanced NO production remains to be elucidated. The impact of the available data on eNOS phosphorylation on our knowledge of microvascular transport is difficult to evaluate. It is important to recognize that the main focus of the molecular biology studies of eNOS has been the role of NO in control of blood flow and blood pressure.[45,66,67] These studies have been conducted in endothelial cells (EC) derived from large vessels. Because of an interest in long-term regulation, these studies have also exposed endothelial cells to agonists for several hours.[61] Under these experimental conditions, in addition to the uncertainty of translating in vitro to in vivo experiments, investigators of the microcirculation are forced to extrapolate data from large vessel endothelium, not normally involved in blood-tissue transport processes, to postcapillary venular endothelium, where the majority of the transport of macromolecules occurs. Moreover, the uncertainty of the extrapolation may be compounded by the possible phenotypical changes undergone by EC grown in specifically designed and controlled culture media. The tissue culture situation is, by necessity, at variance with the dynamic environment of EC in the microcirculation. These considerations underscore the importance and the need to investigate the influence of eNOS phosphorylation on the regulation of permeability under conditions that closely resemble its microvascular environment.

Molecular Movement of eNOS Changes in eNOS activity may be associated with its translocation from the membrane to the cytosolic compartment.[60] However, the location of eNOS to the Golgi complex seems to enhance the efficiency of NO synthesis.[56] Both membrane-bound and cytosolic eNOS are able to release

NO, but the relative importance of each pool for basal or stimulated release of NO has not been fully determined.[68] It has been suggested, however, that “biologically active eNOS resides in different subcellular compartments and that each pool can be differentially regulated and responsive to different forms of stimulation.”[68] Translocation of eNOS to the nuclear environment has been reported under hormonal stimulation.[69,70] In preliminary experiments conducted by Dr. Koichi Yoshimura in our laboratory, we find evidence for eNOS movement from membrane to cytosol after prolonged ischemia. Thus, it is plausible that the cellular location of eNOS may represent a mechanism that determines the rate of NO production under different experimental (physiologic or pathophysiologic) conditions.

Microvascular Permeability, eNOS, and Junctional Proteins The cellular events that are necessary to account for the translation of agonist stimulation to the final microvascular permeability response are the subject of active investigation. The final step in the sequence of molecular modifications appears to involve proteins located at the cell junctionalcytoskeletal complex. Studies performed mainly in tissue culture have identified VE-cadherin and b-catenins as possibly key molecules. VE-cadherin is unique in that it is distributed specifically in the vascular endothelial intercellular junction (zonula adherens), as opposed to other cadherins that are present nonspecifically along the cell membrane in most cell types.[71 – 75] As a transmembrane glycoprotein. VE-cadherin forms a complex with b-catenins. The presence and distribution of VE-cadherin at junctions is modulated by Ca2+.[71] However, it is not known whether eNOS activity influences this apparently key permeabilityrelated protein. Evidence for the role of VE-cadherins in permeability has been obtained in HUVEC and in mesenteric venules. In both tissues, the organization of VE-cadherins is altered at the endothelial cell junction by agents that cause hyperpermeability.[76,77]

Nitric Oxide Synthase and Permeability Changes in Ischemia-Reperfusion The role of eNOS in I/R injury is still unresolved. There is compelling evidence that inhibition of eNOS ameliorates the impact of I/R on hyperpermeability, and also compelling evidence that inhibition of eNOS leads to enhanced leukocyte adhesion and exaggerated macromolecular leakage. We have demonstrated that the increased permeability associated with I/R injury is, at least partially, mediated by PAF and NOS.[78,79] Importantly, inhibition of PAF with a specific receptor antagonist or inhibition of NOS with L-NMMA are efficacious when applied either before the onset of ischemia or at the time of reperfusion.[78,79] Evidence obtained by other investigators indicates that inhibition of NOS leads to an indirect increase in permeability due to enhanced leukocyte adhesion.[80] The difference in results may be due in part to

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the specific model of ischemia applied to the tissue under examination. We have investigated models of global ischemia in the hamster cheek pouch[79,81] and in rat striated muscle,[10,11,78,82] while other investigators have studied partial ischemia in the rat and cat mesentery.[80,83] The differences in degree of ischemia and oxygen availability may lead to variations in the biochemical and physiologic mechanisms of the signaling sequence that stimulates NOS under specific experimental conditions.

FACTORS AND MECHANISMS OF MICROVASCULAR DYSFUNCTION Endothelial and Vascular Wall Cells The pathophysiology of ischemia-reperfusion injury involves a sequence of events that lead to inadequate oxygen delivery, reduction in cellular energy stores, accumulation of noxious metabolites, and reperfusion injury mediated by oxygenderived free radicals.[13] The formation of reactive oxygen metabolites is pivotal to the biochemical basis of injury. There are many potential biologic sources of oxygen free radicals. The microvascular endothelial cell containing xanthine oxidase and the neutrophil with its membranebound NADPH oxidase have been subject to the closest scrutiny. Ischemia activates a calcium-dependent protease that catalyzes the conversion of xanthine dehydrogenase to its oxidase form (Fig. 28-4). As ischemia continues, ATP is degraded to hypoxanthine which is then converted to uric acid by xanthine oxidase with the production of superoxide anion. Superoxide dismutase converts superoxide anion to hydrogen peroxide, which in the presence of ferric ion, produces the hydroxyl radical. The hydroxyl radical is capable of reacting with proteins, lipids and nucleic acids making it a highly toxic oxidant.[84] The ability of the hydroxyl anion to promote lipid peroxidation of cell membranes may be a major contributor to the mechanisms by which microvascular permeability is increased following reperfusion of ischemic tissues. Oxygen-derived free radicals play an important role in the genesis of reperfusion damage.[85] The formation of oxygenderived free radicals depends on the generation of O2 2 through endothelium– and leukocyte-stimulated biochemical reactions. A major contribution comes from the conversion of xanthine dehydrogenase (XDH) to xanthine oxidase (XO). Endothelial cells have been identified as a major site of localization of xanthine oxidase,[86] while parenchymal cells appear to have a low concentration of XDH.[87] However, based on measurements of XDH activity in isolated endothelial cells, it is estimated that skeletal muscle cells contain a significant amount of XDH.[6] Xanthine oxidase activity increase in postischemic skeletal muscle from a baseline of 3:6 ^ 0:3 to 5:2 ^ 0:4 mU=g wet tissue;[88] a measurement that includes both endothelial and muscle XDH. In favor of the importance of the role of endothelial cells and of microvascular dysfunction in skeletal muscle I/R injury is the report that the conversion of XDH to XO proceeds at a slow rate in skeletal myocytes.[89] Support for the role of oxygen-derived free radicals in the microvascular dysfunction associated with I/R comes from

Figure 28-4. Interactions between endothelium and leukocytes in ischemia-reperfusion injury. During ischemia parenchymal cell energy is depleted. Macrophages may influence the process by production and release of cytokines (e.g., interleukin-1, or IL-1). The endothelium appears to be the site capable of significantly converting xanthine dehydrogenase (XDH) to xanthine oxidase (XO) during ischemia and responsible for the formation of oxygen-derived free radicals (superoxide anion ¼ O2 2 ; OH = hydroxyl radical). The endothelium also releases PAF. The adherent leukocyte also forms oxygen-derived free radicals and through its myeloperoxidase (MPO) generates hypochlorous acid (HClO). Weak adhesion (rolling) is the result of interactions between P-selectin (P-Sel; endothelium) and L-selectin (L-sel; leukocyte). Upon stimulation by PAF, the CD11/CD18 adhesion complex interacts with the endothelial ICAM-1, leading to firm adhesion.

experiments using free radical scavengers. Compounds such as superoxide dismutase (SOD), catalase, mannitol, allopurinol, deferoxamine, and apotransferrin have proven to be efficacious in reducing changes in capillary solvent drag reflection coefficient[13] and in salvaging skeletal muscle.[15] The efficacy of SOD, catalase, and mannitol is predicated on the basis of their ability to scavenge either superoxide anions or hydroxyl radicals. Conversely, the efficacy of deferoxamine and apotransferrin, two chemically different ironbinding compounds, indicates an important role for iron in the genesis of postischemic damage, particularly as a catalyst for the Haber-Weiss reaction between superoxide and hydrogen peroxide. Free radical scavengers, as a group, are able to reduce the indices of I/R-induced microvascular dysfunction to about half of their unopposed values (Fig. 28-4). Nitric oxide has been implicated among the substances produced by vascular and perivascular cells that may play a role in I/R-induced microvascular dysfunction. Nitric oxide is a product of the metabolism of L -arginine and can be produced by most cells. In the case of I/R injury the more

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likely vascular and perivascular sources of NO include endothelial cells, mast cells, resident macrophages and leukocytes. Under normal conditions, NO is a strong vasodilator,[90 – 93] it may enhance the transport of macromolecules across postcapillary venules,[37,38] and it may serve as an antiadhesive substance to protect the endothelium against leukocyte adherence.[94] With the onset of ischemia, the levels of NO seem to decrease. It is possible that the reduced levels of NO result in enhanced leukocyte adhesion and increased microvascular permeability.[6,94] In addition, NO reacts with superoxide to form peroxynitrite, a powerful reactive oxygen metabolite, and leads also to further formation of hydroxyl radicals.[95] Experimental evidence for the involvement of the L -arginine –nitric oxide pathway in myocardial reoxygenation injury has been reported in the piglet heart in which NO synthase inhibitors afford adequate protection during cardiopulmonary bypass reoxygenation.[96] In this framework, the L -arginine –NO pathway represents an alternative or additional mechanism to produce hydroxyl radical. It must be kept in mind that peroxynitrite (ONOO2), the reaction product of superoxide and NO, is potentially more harmful and more toxic than either superoxide or hydroxyl radical due to its longer half-life.

leukopenia that reaches a nadir in 3 days. Leukopenia decreases the impact of I/R on changes in microvascular permeability and solvent drag reflection coefficient.[100,102] The impact of leukocytes is exemplified by the observation that leukopenia reduces the increase in transport of macromolecules to a 2-fold increase, down from a 7-fold increase obtained in the untreated ischemic muscle.[100] The extent of skeletal muscle I/R injury, as measured by the infarct size demarcated by triphenyl-tetrazolium chloride reduction, is significantly decreased by leukopenia.[99] Circulating leukocytes do not appear to become activated by traversing the circulation of postischemic muscle.[103] Leukocyte adhesion to microvascular endothelium and emigration to tissue are fundamental required steps for PMN-associated damage in I/R.[104]

Leukocytes Leukocytes, and in particular polymorphonuclear leukocytes (PMNs), have been the subject of much investigation recently in regard to their contributions to injury in ischemiareperfusion (Figs. 28-4, 28-5). Leukocytes produce superoxide anion by the activity of their membrane-bound NADPH oxidase, which converts cytoplasmic NADPH to NADP+. The Haber-Weiss (Fenton) reaction then proceeds to form superoxide anion and hydrogen peroxide, with subsequent release of hydroxyl radicals. Leukocytes possess myeloperoxidase, an enzyme that further catalyzes a reaction between hydrogen peroxide and chloride to form hypochlorous acid, a powerful oxidant agent. In addition, activated PMNs release elastase, collagenase, and cathepsin G, substances that are able to degrade microvascular basement membrane and lead to increases in permeability and cellular dysfunction. Much attention has been directed at understanding the mechanisms that activate leukocytes and contribute to their adherence to and emigration across microvascular endothelium. The levels of myeloperoxidase (MPO, an index of PMN) have been found to remain constant during ischemia and to increase at 15 minutes and 1 hour of reperfusion.[97] These data are interpreted as an indication of influx of leukocytes into the tissue upon reperfusion. Other investigators have failed to find significant increases in MPO in postischemic canine gracilis muscle until 24 hours of reperfusion.[98] Further support for the involvement of leukocytes in I/R comes from experiments in which either the animal or the experimental muscle have been rendered leukopenic by radiation or chemical or physical means. Chemotherapeutic agents such as hydroxyurea, nitrogen mustard,[99] and vinblastine[100] may be administered prior to the onset of ischemia to render the animal leukopenic. Similarly, animals may be subjected to whole-body irradiation,[101] resulting in

Figure 28-5. Illustration of leukocyte adhesion to postcapillary venular endothelium in the rat cremaster muscle. (A) Adhering and rolling leukocytes can be visualized by brightfield transillumination. The leukocytes can be identified as the cells palisading along the venular wall near the vessel bifurcation. (B) The animal was injected with acridine orange, a fluorescent dye, prior to the microscopic observation. Leukocytes are the first cells to take up the dye. The leukocytes are the bright white dots decorating the faintly stained postcapillary venular wall.

Chapter 28.

Endothelium-Leukocyte Interactions The actions of the endothelial cell (EC) and the PMNs are not independent of one another (Figs. 28-4, 28-5). Xanthine oxidase –derived free radicals may influence the interaction between the leukocyte and the endothelial cell. These reactive oxygen metabolites may attract PMNs to the site of injury or they may initiate the release of other chemoattractants [platelet-activating factor, (PAF); leukotriene B4, (LTB4)]. The oxidants produced may serve to alter the adhesion properties of the EC surface by allowing the expression of intercellular adhesion molecules (ICAM-1, ICAM-2). These molecules are inducible proteins on the EC surface which modulate neutrophil adhesiveness in areas of inflammation. The PMN also has a membrane glycoprotein, designated CD11/CD18 complex—a b2-integrin, which is involved in regulating PMN-EC adhesion. The mechanisms that link xanthine oxidase –mediated oxygen free radical production to reperfusion-induced leukocyte activation, adhesion, and extravasation form the foundation for all the events that are described as ischemia-reperfusion (I/R) injury. Adhesion molecules, such as b2-integrins and L-selectin, are constitutively expressed on the PMN surface. The stimuli produced by I/R are able to induce upregulation of the number and/or functional state of these proadhesive molecules. Monoclonal antibodies (MAbs) directed against these molecules specifically and efficaciously block the adhesion of PMNs to EC. The endothelium also expresses adhesion molecules. Normally, ICAM-1 is weakly expressed, while P-selectin is stored presumably in Weibel-Palade bodies. Appropriate stimuli cause upregulation of ICAM-1 and translocation of Pselectin to the membrane. Conversely, E-selectin is induced very effectively by activation with interleukin 1 (IL-1). As with leukocyte adhesion molecules, the development of specific monoclonal antibodies has become a most useful tool in demonstrating the critical role of EC adhesion molecules in I/R injury. Firm adhesion of leukocytes to endothelium is preceded by a weak adhesion, also termed “rolling” by intravital microscopists. This weak adhesion occurs under rheological conditions of relatively high shear rate. Nonetheless, leukocytes roll along venular walls at rates about 100-fold slower than the rate of local flow.[105] The use of MAbs to Lselectin has demonstrated the importance of L-selectin for leukocyte rolling[105] and by inference for the initiation of the PMN-EC adhesion process. Evidence obtained in vitro in laminar flow chambers under conditions mimicking venular shear rates shows that endothelial P-selectin modulates leukocyte rolling.[106] Strong PMN-EC adhesion requires the involvement of integrins and ICAM-1 and possibly Eselectin. Much knowledge has been derived in vivo from the administration of MAbs prior to the induction of the ischemia-reperfusion protocol in animal models. Under baseline conditions only a few leukocytes adhere to venular endothelium (2 – 4 leukocytes per 100 mm vessel length).[81,104,107] Upon reperfusion of postischemic tissue the number of adherent leukocytes increases severalfold.[81,104,107] The monoclonal antibody 60.3, which is directed against the beta chain of the CD18 complex, inhibits

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neutrophil adherence and attenuates extravasation of plasma proteins in the intestinal mucosa.[108] Similarly, MAb IB4, also directed against the CD11/CD18 glycoprotein adhesive complex, successfully inhibits the adhesion of leukocytes to venular endothelium induced by PAF in the intestine.[109] In canine gracilis muscle, MAb IB4 administered prior to ischemia has the ability to diminish the I/R-induced increase in microvascular solvent drag reflection coefficient.[110] Similarly, using MAbs against CD11b/CD18 and against ICAM-1 in the rat cremaster muscle, we demonstrated that inhibiting leukocyte adhesion caused a reduction of the impact of I/R on microvascular transport and decreased infarct size[104] (Fig. 28-6). Taken together, these in vivo data demonstrate that EC-PMN adhesion and PMN emigration are a cause of I/R-induced microvascular dysfunction. The preceding observations suggest that xanthine oxidase– derived free radicals may be among the primary mediators of I/R injury and PMN infiltration and that subsequent release of other mediators may occur as a secondary event. Conversely, reactive oxygen metabolites produced by xanthine oxidase may act primarily to stimulate PMN infiltration and activation, and thus the leukocyte would be ultimately responsible for tissue damage. In addition, if the PMN represents the prime effector of cell injury, by what mechanisms does it actually perform this role? There is in vitro evidence that activated neutrophils cause endothelial

Figure 28-6. Evaluation of tissue damage in rat cremaster muscle by computer-assisted digital image analysis. Muscles were stained with nitroblue tetrazolium (NBT). Dye uptake is related to muscle viability: the greater the uptake, the more viable the muscle is and the darker the muscle becomes. The darker the muscle, the lower its optical density is, i.e., the lower values of optical density show greater viability, while the higher optical density values demonstrate greater muscle damage. Labels are: No Rx = group subjected to I/R without therapeutic treatment; IgG = group subjected to I/R and received IgG; 1B6 = group subjected to I/R and treated with monoclonal antibody 1B6 (directed against the CD11ba-subunit of the leukocyte’s CD11/CD18 adhesion glycoprotein); 1A29 = group subjected to I/R and treated with monoclonal antibody 1A29 (directed against the endothelial ICAM-1 adhesion molecule). Note that sham-operated muscle group shows the least tissue damage, while the No Rx muscle group displays the greater tissue damage. The monoclonal antibodies IB6 and 1A29, administered at the time of reperfusion, decreased leukocyte adhesion to endothelium and effectively reduced tissue damage. (From Ferrante et al. J. Vasc. Surg. 24: 187 – 193, 1996. Reprinted with permission.[104])

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cell detachment that is inhibited by neutral protease inhibitors, but not by catalase or superoxide dismutase.[111] These observations suggest that the I/R injury to the microvasculature and tissue is multifactorial and can be explained by the release of neutrophil-derived proteases as well as by leukocyte-endothelium– produced oxygen free radicals.

Other Chemical Mediators and Signaling Molecules Eicosanoids have been thought of as important chemical mediators in I/R injury for a long time. However, no clear picture is currently available regarding the involvement or importance of these arachidonic acid derivatives in either the genesis or the consequences of I/R. Thromboxane A2 (TXA2) has been implicated in causing microvascular alterations in the lung following reperfusion of ischemic canine hindleg.[99,112] Most of the evidence for this interpretation comes from transient elevations in TXA2 associated with a transient, self-resolved increase in lung water. These events are prevented by the use of TXA2 inhibitors prior to the onset of ischemia. In the specific instance of changes in microvascular permeability, no clear correlation appears to exist between eicosanoid levels and transport of macromolecules in postischemic striated muscle.[113] Prostaglandins have physiologic and pharmacologic properties that may be useful in attempts to ameliorate the consequences of I/R. In particular, prostacyclin is a vasodilator, but it also prevents platelet aggregation and may inhibit leukocyte adhesion to endothelium. Stable analogs of prostacyclin, such as Iloprost, have also shown some degree of protection against microvascular alterations in postischemic muscle[114] and adequate protection against platelet sequestration and infarct size.[115] Similar protection against I/R damage has been afforded by Iloprost in the myocardium.[116] Calcium, a universal signaling molecule, plays an important role in the pathophysiology of skeletal muscle I/R injury and associated microvascular injury. Both calcium entry and calcium mobilization are involved. In regard to muscle damage, muscle function is impaired in part due to a slower calcium uptake by the sarcoplasmic reticulum, which is partially prevented by pretreatment with scavengers of oxygen-derived free radicals.[117] In regard to microvascular dysfunction, calcium ions modulate the activity of leukocytes as well as the contractile properties of endothelial cells. The impact of calcium entry on microvascular dysfunction is supported by the prevention of changes in microvascular permeability to macromolecules afforded by verapamil, a calcium entry blocker.[113] One attractive putative mediator of ischemia-reperfusion is PAF. Even though not constitutively present in ECs, PAF can be quickly synthesized upon stimulation with thrombin, histamine, and other agonists, including PAF itself. This short-lived phospholipid (1-O-alky1-2-acetyl-sn-3-phosphocholine) is a vasoconstrictor,[118] a strong promoter of microvascular permeability,[119,120] and a powerful chemoattractant for PMNs at concentrations of l0211 M and 10 29 M.[120,121] It is worth noting that subthreshold

concentrations of PAF prime the microcirculation for strong responses to subthreshold doses of histamine, another important proinflammatory agent of potential importance in I/R.[122] Recent evidence, based on the use of chemically different inhibitors of PAF receptors, indicates that some of these microvascular functions of PAF are mediated by different receptors in the pre- and postcapillary segments.[123] Pharmacologic advances based on this finding may permit to differentially block the activity of PAF to prevent or counteract the damage of I/R. In vitro studies provide strong support for a role for PAF in ischemia-reperfusion. It is possible that the production of H2O2 serves as the stimulus for the synthesis of PAF. Primary cultures of bovine pulmonary artery endothelium and human umbilical vein endothelium synthesize PAF when stimulated with H2O2.[124] This PAF synthesis is associated with an increase in intracellular Ca2+, suggesting that a transmembrane Ca2+ flux may serve as a signal to initiate PAF production. Furthermore, H2O2 also induces endothelial cell – dependent adhesion of neutrophils to human umbilical vein endothelial cell monolayers. Current theories indicate that PAF synthesized by activated ECs is expressed on the cell surface and binds to a receptor on the PMNs.[125,126] This interaction causes upregulation of CD11a/CD18 and CD11b/CD18 leading to firm adhesion of PMNs to ECs. The role of PAF in mediating endothelial cell –leukocyte interaction in vivo has been studied in inflamed and in reperfused tissues. Exogenously administered PAF, an agonist for PAF synthesis by microvascular ECs, increases leukocyte adherence at concentrations of 1029 M[120] and enhances permeability at 1027 M[119] in the hamster cheek pouch. The possibility that H2O2 may be the stimulus for PAF synthesis in I/R is indirectly supported by experiments in which human recombinant superoxide dismutase, administered intravenously, caused a 30% decrease in PMN adherence.[107] In isolated autoperfused segments of feline intestine, reperfusion after 1 hour of ischemia increased the adhesion and extravasation of leukocytes, and pretreatment with intravenous doses of the PAF-receptor antagonists BN 52021 and WEB 2086 reduced the rates of leukocyte adhesion and extravasation during reperfusion.[127] These results suggest that PAF plays a role in mediating the adhesive interaction between the leukocyte and the endothelial cell during I/R and promotes extravasation. It is worth noting that administration of WEB 2086 (a PAF-receptor antagonist) just prior to reperfusion successfully protects against increased leukocyte adherence.[128] In addition to strengthening the viewpoint of PAF’s role in I/Rinduced leukocyte adhesion, this finding may provide a valuable basis for development of therapeutic approaches applicable to acutely ischemic patients at the critical step of starting reperfusion. PAF may also play a paracrine role in I/R-induced increased leukocyte adhesion. In models of focal I/R in which other areas of the tissue remain perfused at normal flowrates, the number of adherent leukocytes tends to increase in the nonischemic, normally perfused areas.[81,128] These observations have been tentatively interpreted to indicate the release of a soluble chemical mediator by the ischemic area, which in turn diffuses into the normal microcirculation and stimulates the increment in leukocyte adhesion. The

Chapter 28.

possibility that PAF is the paracrine chemical mediator derives (a) from in vitro data in which the supernatant of hypoxic-reoxygenated endothelial cells increased leukocyte adhesion in normoxic endothelial cells[129] and (b) from the in vivo demonstrated characteristic of soluble PAF of being a powerful chemoattractant for leukocytes.[120,121] Cytokines are also potentially important in the sequel of I/R, particularly when the ischemic period is prolonged enough to allow for protein synthesis. Among cytokines, tumor necrosis factor alpha (TNF-a) has been the subject of investigation because it may upregulate adhesion molecules in both leukocytes and endothelium. The leukocyteendothelium interactions initiated by TNF-a can serve as a positive feedback and lead to a cascade of stronger reactions. We tested the hypothesis that synthesis of TNF occurs during ischemia and is related to the observed microvascular hyperpermeability. We reasoned that inhibitors of protein synthesis (actinomycin D, an antibiotic that blocks transcription) would prevent synthesis of TNF-a and attenuate the increase in permeability to macromolecules. Our initial results showed that striated muscle I/R causes a significant and long-sustained elevation in plasma TNF-a.[82] Topical administration of actinomycin D, during ischemia and reperfusion, reduced synthesis of TNF-a and decreased the hyperpermeability response to I/R[82] (Fig. 28-7). Our results, in agreement with those of other investigators,[130 – 132] support an association between protein synthesis, TNF-a levels, and transport of macromolecules in postischemic muscle.

Figure 28-7. Statistical analysis of impact of inhibition of protein synthesis on microvascular transport in the rat cremaster muscle. Actinomycin D (AMD) did not change baseline microvascular transport (Control + AMD). Integrated optical intensity (IOI, an index of microvascular transport) values for control groups represent the final 120 minutes of a 6-h sham experimental preparation. The influence of ischemia-reperfusion (I/R) on transport of macromolecules is demonstrated by the I/R group. Topical superfusion with 1026 M AMD attenuated significantly the increase in postischemic microvascular transport (I/R + AMD). *p , 0:05, ***p , 0:001 compared with control group. ###p , 0:001 compared with I/R + AMD Group. +++ p , 0:001 compared with control + AMD group. (From Takenaka et al. Am J Physiol 274: H1914-H1919, 1998. Reprinted with permission.[82])

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Clinical Considerations Current management of acute limb ischemia is based on the restoration of blood flow to the ischemic extremity as rapidly as possible in order to reduce the degree of ischemic injury. However, reperfusion occurs in the setting of cellular damage secondary to ischemia, creating new significant injury. As discussed, interactions between endothelial cells and leukocytes with associated PMN activation and infiltration are largely responsible for microvascular dysfunction and also play a significant role in the onset and final outcome of parenchymal injury. The arsenal of pharmacological agents available to the vascular surgeon is limited. Administration of antioxidants directed against the hydroxyl radical (mannitol) or agents acting at various times along the path of hydroxyl radical formation (superoxide dismutase, or polyethyleneSOD) may have modest success when applied at the time of reperfusion. Heparin may also have a role, not only as an anticoagulant but possibly related to its nonanticoagulant properties. Heparinization is a preventive part of current clinical protocols, and its use may preserve skeletal muscle viability,[133,134] in addition to reducing intravascular propagation of thrombus. In addition, lytic therapy[135] may be useful to distal vasculatures and facilitate tissue salvage. However, there is a need to develop a variety of modern pharmacologic approaches to diminish the impact of ischemia-reperfusion on parenchymal structure, biochemistry, and function. Modulation and control of leukocyte –endothelial cell interaction may contribute to afford greater protection against the damage caused by I/R. The administration of PAFreceptor inhibitors at reperfusion offers promise in animal models.[128] Similarly, inhibition of leukotriene B2—another potent chemoattractant—may be useful in decreasing firm adhesion of leukocytes. The use of MAbs to block adhesion molecules also shows promise of contributing to ameliorate I/R injury.[104] Potential problems in their clinical application include half-life (if too long they may mimic the condition of leukocyte adhesion deficiency and render the patient susceptible to infectious diseases) and the possibility of further interactions with the patient’s immune system. On the other hand, investigators have suggested that molecules derived from the known structures of the selectin carbohydrate ligands may offer the greatest potential to inhibit leukocyte-endothelium adhesion.[136] This possibility is supported in part by the observation that dextrans attenuate leukocyte rolling and adhesion.[137] Gene therapy promises an attractive future to vascular surgeons as a possible treatment for I/R. Local administration of vascular endothelial growth factor (VEGF, also termed vascular permeability factor, VPF) appears to improve perfusion in ischemic limbs.[138 – 141] The mechanisms of action of VEGF, a powerful angiogenic and permeability factor, are not completely elucidated yet, but they involve the specific VEGF-R2 receptors (also known as flk-1/KDR) and stimulation of PKB, NOS, and MAP kinases.[142 – 144] The double jeopardy facing the vascular surgeon is that unattended ischemia leads to necrosis, making prompt restoration of blood flow a must; however, reperfusion compounds the problem, and its consequences may interfere

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significantly with survival of the organ and/or patient. Furthermore, any therapy to be instituted must be delivered effectively and quickly to the injured site. The best way to deliver substances to parenchymal cells is the microcirculatory system of convection and exchange vessels. When no reflow is present, the ability to deliver therapeutic agents via the bloodstream is greatly impaired. Therefore, in addition to developing more refined chemical therapeutic agents, it is important to develop ways of bypassing the obliterated vessels to access the compromised microcircula-

tion and contribute to salvaging viable tissue. Significant steps in this direction are being taken in the methodologies associated with intramuscular administration of VEGF. Advances in molecular biology, gene therapy, and catheterbased procedures have opened new horizons for comprehensive treatment of ischemia-reperfusion damage. These advances demonstrate how skilled vascular surgeons and physiologists are meeting the formidable task and exciting challenge of solving the intrinsic dilemma of ischemiareperfusion injury.

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CHAPTER 29

Arterioarterial Atherothrombotic Microemboli of the Lower Limb Dhiraj M. Shah R. Clement Darling III Benjamin B. Chang Philip S. K. Paty Paul B. Kreienberg Sean P. Roddy Robert P. Leather microemboli were dislodged from atheromatous aortoiliac lesions and were observed in the digital arteries of the toes. Although this possibility has also been mentioned by other authors,[2,5,7,8] little attention has, in general, been paid to its ultimate pathological implications. Moreover, the natural history of this syndrome was not clearly defined by these observers. The threatened survival of a single toe is not in itself of great clinical consequence, but continuing experience with this pathological entity indicates that when untreated, these episodes are such omens of disaster for the leg that subsequent diagnostic and therapeutic measures should promptly be concentrated on the location and eradication of the source of microemboli.

Although attention has recently been paid to atherothrombotic microembolism from atheromatous plaques or from adherent thrombotic material, such pathological occurrences were first mentioned in the German literature over a century ago.[1] However, within the last several decades, the pathological implications of this specific entity have come to our attention, showing it to be a mechanism of serious pathology of the brain, viscera, and both upper and lower limbs. The lodgment of atherothrombotic microemboli (defined as particles 1 mm in size or smaller) into end arteries has now been documented in virtually every part of the human body. The production of stroke or cerebral insufficiency by this mechanism is discussed in Chap. 48, but atherothrombotic emboli are also known to cause renal cortical ischemia,[2,3] left colonic gangrene,[4] and ischemia of the fingers (Chap. 63). This chapter deals specifically with such embolization in the lower limbs. The sudden appearance of a painful, discolored toe may be very baffling when the rest of the foot appears to be well perfused, particularly when the pedal pulses can be readily felt by digital examination. The confusion has been deepened by the application of a variety of misleading labels to this condition, including vasospasm, cold injury, localized Raynaud’s phenomenon, polymyositis, and idiopathic digital artery thrombosis.[5] However, in most of these patients the ischemia is due to microembolization to the digital arteries. Crane[6] reported on this entity in 3 patients in whom distal

INCIDENCE OF THIS CONDITION From the literature, it has been difficult to gain any idea of the incidence of this problem. However, examination of our own data tends to offer some perspective. In the 7-year period from 1978 to 1985, 4820 vascular consultations were held on the Vascular Service of Albany Medical Center; of these, 120 (2.5%) were for suspected microembolism to the lower limbs. Of this entire group, 4043 vascular reconstructions were carried out, and of these, 93 (2.3%) were done specifically for eradication of emboligenic sources of microemboli to the

Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024912 Copyright q 2004 by Marcel Dekker, Inc.

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Incidence of Microembolic Sources

Number of vascular consultations Number of consultations for atherothrombotic microemboli Number of vascular procedures Number of reconstructions for microembolizations

4820 120 (2.5%) 4043 93 (2.3%)

lower limb. In general, therefore, these data suggest that perhaps 1 in 50 of all vascular reconstructions will be carried out for these purposes in a general vascular service (Table 29-1).

SOURCES AND NATURE OF MICROEMBOLI A variety of lesions will act as sources of microemboli, and these range in location from the infrarenal aorta to the termination of the popliteal artery. Aneurysms of the popliteal artery have long been recognized for this predisposition and are discussed in Chap. 45. Iliac and common femoral aneurysms rarely produce distal embolization and are more prone to acute thrombotic occlusion. In marked contrast, however, atherosclerotic lesions of the iliac, common, and superficial femoral arteries are important sources of microemboli. While it may be instinctively surmised that pathological degeneration of the larger arteries would be the predominant origin of such arterioarterial emboli, Table 29-2 indicates the somewhat surprising finding that the femoral arteries are the most common emboligenic sources. Apart from popliteal aneurysms, which occupy a special category (as previously mentioned), stenotic, irregular, and ulcerated lesions of the iliac and femoropopliteal arteries are frequently microembolic sources, as shown by their relative incidence. However, when there is widespread atheromatous degeneration of the infradiaphragmatic arteries, it can be difficult to identify precisely the specific area that has been responsible for the clinically apparent downstream release of microemboli.[9]

Many authors have expressed the view that these microemboli result solely from fragmentation of atheromatous plaques and subsequent dislodgment of the debris.[2,3,5,8,10 – 12] Indeed, atheromatous plaques are known to undergo ulceration and fragmentation, and atheromatous or cholesterol-containing material has been identified in digital vessels and in the smaller arteries of the calf muscles.[10] However, many of the microemboli of the lower limb have been identified as being made up of fibrinoplatelet or thrombotic material. The microemboli released from aneurysmal sources (popliteal, aortic, etc.) are part of the flocculent laminated thrombus that lines the arterial flow path. A common surgical finding is that atheromatous plaques are very friable, but the shaggy, frondlike clumps of fibrinoplatelet debris which are invariably present on these lesions are not only impressive but also appear more likely to be dislodged. It has also been confirmed[4,6,7,13] that in addition to cholesterol fragments, fibrinoplatelet aggregates are loosely attached to ulcerated or stenotic atheromatous plaque and are easily swept off. Schechter[14] has recovered a shred of atheromatous plaque (gravel) from a tibial artery and has postulated that after these particles impact, surrounding fibrinoplatelet aggregates and propagated thrombus increase the degree of obstruction. Branowitz and Edwards[7] concluded that the clinical and pathological processes involve either distal embolization of atheromatous debris or fibrinoplatelet or thrombotic material. Kempezinski[13] has further clarified this by showing that cholesterol emboli tend to originate in the infrarenal aorta, to be diffuse, and to lodge in arteries 100 –200 mm in size (e.g., muscular arteries). By contrast, microemboli formed from hemocellular elements tend to be larger and occlude vessels up to 1 mm in size. Digital arteries are customarily involved, but emboli have been recovered that were large enough to occlude the tibial, popliteal, and superficial femoral arteries (Fig. 29-1).[3,7,15,16] Larger emboli of this type usually arise within the infrarenal aorta in an area of severe atheromatous degeneration, which has larger, loosely attached fibrinoplatelet clumps.[17] These larger emboli form far less often than do the microemboli. This clinical entity has been described in various ways in the literature. It has been called the blue-toe syndrome,[18] atheromatous embolization,[12,14] acute focal ischemia,[19] and peripheral atheroembolism.[16] From the

Table 29-2. Location of Embolic Sources Embolic sources Author Karmody et al.[4] Kwaan and Connolly[15] Schechter[14] Crane[6] Carvajal et al.[2] Branowitz and Edwards[7] Kempezinski[13] Mehigan and Stoney[19] Keen et al.[23]

No. of cases

AAA

Aortoiliac

Femoropopliteal

93 15 17 3 4 4 10 12 87

12

18 15 9 3

63

3

2

4 2 20

4 8 5 47

7 20

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in which there was repeated microembolization, and the report of Mehigan and Stoney[19] mentions 4 patients who also experienced this problem, each with threatened tissue loss. This tendency has also been confirmed by Branowitz and Edwards (Table 29-2).[7] Early diagnosis and treatment are, therefore, necessary if recurrence is to be prevented, and it is this aspect of microembolization that enhances its clinical importance and makes recognition and treatment mandatory. The natural history of atherothrombotic microembolization of the lower limb consists, therefore, of a repetition of embolic episodes. Each successive event causes progressive

Figure 29-1. Good example of emboligenic lesion in midsuperficial femoral from which a distal embolus has occluded the popliteal artery.

foregoing pathological description, the term arterioarterial atherothrombotic microembolism, although cumbersome, is preferred, since it most accurately describes all of the pathological events.[17]

NATURAL HISTORY OF ATHEROTHROMBOTIC MICROEMBOLIZATION Gore and Collins[20] have shown by autopsy examination that atherothrombotic microembolization is a more frequent clinical problem than has been generally recognized. This has been confirmed by Maurizi et al.,[11] who conclude that the microemboli usually lodge in the lower limbs and that recurrent microembolization, which finally leads to extensive tissue loss, is common (Fig. 29-2). In 12 of our patients, repeated microemboli to the foot were clinically recognized, and loss of one or more toes occurred in 5 of these patients. In another patient, the second embolic shower resulted in ischemic death of the forefoot. Schechter[14] reported 11 cases

Figure 29-2. Natural history of arterial microemboli. The great toe, which was ischemic from the first microembolus, has been hastily amputated, and the wound is healing poorly. In addition, another microembolus has lodged (arrow ) at the side of the foot. This process will continue until the emboligenic source is corrected.

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Figure 29-4. Most common appearance of microembolic disease, consisting of a deep-blue painful area of the great toe.

Figure 29-3. Occlusion of anterior tibial artery (arrow ) by microembolus, jeopardizing entire foot.

loss of collateral arteries until tissue necrosis finally occurs. Larger emboli, of course, are likely to occlude the popliteal or tibial arteries and cause acute, profound ischemia of the foot (Fig. 29-3). It has been well documented[7,11,13,14,18] that initially both the patient and the physician are frequently lulled into a false sense of security, since in most instances the signs are evanescent and recovery is prompt. Further embolization may occur in a few hours or even after many weeks, but the repetitive tendency remains pronounced in any event. Although this pattern of events is well recognized in the cerebral circulation, the probable reason that more emphasis has been placed on the carotid lesion relates to the relative ease of identifying serious pathological effects of cerebral microemboli (i.e., stroke potential, as compared to less clinical concern about small emboli to the digits or feet).

Figure 29-5. More diffuse involvement of the foot, with uniform discoloration and mottling resulting from embolization of the plantar arch.

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noticeable disability, but, more commonly, the initial insult will provide symptoms and signs for a few days, although gangrenous changes will rarely occur at this time (Fig. 29-6). The eventual outcome is obviously determined by the available collateral pathways, which are themselves determined both by the site of embolic impaction and the effects of previous or unrecognized embolic episodes. Even if the first or subsequent episodes are short-lived and cause little clinical difficulty, it should be recognized that further emboli are not only probable but also tend to “stream” to the identical area, thus increasing the risk of tissue loss because of progressive reduction of collateral capacity. In

Figure 29-6. Nonhealing wound caused by injudicious amputation of great toe without correction of proximal stenotic lesion (cf. Fig. 29-2).

Early and complete eradication of the embolic source has been well established as the definitive treatment in the cerebral arterial system, and these same principles also apply to the peripheral limb arteries, because microemboli cause comparable transient ischemic attacks of the foot and also carry a serious threat of tissue loss, which deserves attention similar to that of loss of brain tissue.

CLINICAL DIAGNOSIS The typical picture of patients suffering from this condition includes the sudden appearance of a painful digit or small area on the foot (Fig. 29-4), which is generally bluish in color (hence the name blue-toe syndrome ), has a sluggish capillary return, and is quite tender to the touch. The discoloration may be either uniform or mottled in character (Fig. 29-5). These symptoms may last only a few minutes and cause little

Figure 29-7. Typical popliteal aneurysm filled with large quantities of mural thrombus.

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DIAGNOSTIC INVESTIGATIONS When the emboligenic arterial lesion is also hemodynamically significant, the systolic pressures in the pedal arteries with the patient at rest may show such a small gradient that they may not be discernible on digital palpation of pulses. Repeated examination after exercise in most instances will produce a bruit with diminution of the ankle pulses and a measurable decrease in the arterial systolic pressure. Segmental plethysmographic tracings (waveforms) should be obtained at the thigh, calf, ankle, transmetatarsal, and digital levels. As mentioned above, although these may be normal at rest, exercise of the affected limb will commonly

Figure 29-8. Well-marked aortic stenosis, which was responsible for bilateral microemboli. Treated by endarterectomy.

many patients, a detailed history will reveal that sudden attacks of pain in the muscles of the lower limbs, particularly in the gastroenemius muscle complex, have been caused by unrecognized microembolization that preceded the most clinically obvious episodes of digital ischemia.[2,10] Physical examination should include the pulses from the aorta to the foot. As noted previously, the presence of palpable pedal pulses is the rule rather than the exception in these patients, but manual examination of the abdominal aorta and femoral and popliteal arteries may reveal clinically significant aneurysmal enlargement (Fig. 29-7). A bruit is frequently present over the affected artery, particularly in the common and superficial femoral vessels. The Doppler ultrasound signal over the distal arteries is usually normally pulsatile, as are the arterial plethysmographic tracings at rest. In many instances in which the toes are affected, ultrasound mapping of the course of the digital arteries with a 10 MHz Doppler probe will demonstrate abrupt occlusion of the digital arteries. This may be hard to accomplish in the smaller toes; for practical purposes, it is useful only in the transmetatarsal arteries and the great toe.

Figure 29-9. The other end of the scale (i.e., lesion in distal popliteal). These two figures (Figs. 29-8 and 29-9) stress the need for complete angiography.

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Figure 29-10. Lateral view of proximal popliteal showing emboligenic lesion, which was poorly identified in the anteroposterior projection.

Figure 29-11. Anteroposterior arteriogram of the pedal arch, in which the arrows demonstrate well-defined sites of microembolic impaction.

produce changes in the waveforms, which are clearly diagnostic of a hemodynamic lesion. The use of B-mode duplex ultrasound scanning in the investigation of abdominal aortic aneurysms, particularly in obese patients, and in the common femoral to distal popliteal arteries is especially useful. Computerized tomography body scan may also be helpful, particularly in the abdominal region. With continued development of these techniques and an increasing ability to obtain more accurate soft-tissue evaluation by newer methods (e.g., nuclear magnetic resonance), it is sometimes possible at present to actually demonstrate intraluminal debris in both the aorta and arteries of the limb. Muscle biopsies have been used[2,10] as a diagnostic tool in the evaluation of patients with microemboli. The biopsies were taken either surgically or by needle from the gastrocnemius muscles, and a high correlation with the clinical symptomatology has been reported. We have not found this diagnostic method to be very useful, although it may have a place in evaluating patients with atherosclerosis who have obscure symptoms of the calf and foot. Although, in the modern context, angiography should not be considered a diagnostic tool but rather a preoperative

Figure 29-12. Lateral view of foot is more easily obtained, and obstruction of the dorsalis pedis (arrow ) is easily seen.

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Figure 29-13. (A ) Typical emboligenic lesion in the superficial femoral artery. The stenosis is easily recognized, but immediately distal to it is the characteristic foamy appearance of fibrinoplatelet debris, which forms the basis of the emboli. (B ) Surgical exposure of this lesion. The arrow points to the dark gray fibrinoplatelet mass.

measure, biplane angiography in this particular context is the most accurate of all diagnostic methods. Ideally, this examination should define the arteries from the infrarenal aorta (Figs. 29-8 and 29-9) to the toes. Arterial irregularities may be present in many areas, and a complete angiographic examination is necessary if correct clinical decisions are to be made about the most probable source of emboli. The use of high-quality biplane angiograms obtained with a single arterial injection and radiological magnification has greatly improved these studies (Fig. 29-10). Although it is generally quite difficult to obtain anteroposterior angiograms of the pedal arches, these can be quite informative (Fig. 29-11). However, routine and satisfactory lateral views of the foot can readily be made, and when the obstructions occur within the plantar arch or dorsalis pedis artery, they are easily identified (Fig. 29-12). It should be stressed that one of the prerequisites for the diagnosis of microembolization is the identification of a

continuous anatomic arterial channel between the site of the emboligenic source and the point at which the embolic impaction has occurred. While it is also possible that extensive collaterals around an obstructive lesion may be large enough to carry emboli distally, such occurrences are rare in our experience. The ischemia of the toe or foot that has resulted from microembolic problems should, therefore, be clearly differentiated from the more common form of ischemia, which has been caused by extensive proximal obliterative arterial disease.

SURGICAL MANAGEMENT The foremost principle of treatment of this condition is the removal of the source of emboli. In addition, since many of these emboligenic lesions also cause acute hemodynamic flow

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not only tedious but is also less durable; the standard bypass procedure with distal interruption of the native artery is the preferable method of treatment.[21] When these lesions are identified angiographically, the physician should be alerted to the possibility of microembolic dislodgment, particularly following intraluminal catheter passage during subsequent attempts at intraluminal balloon dilation. In some instances, the exact identification of the emboligenic area can be quite difficult. Flynn et al.[22] have shown that intrainguinal bypasses can be threatened by dislodgment of sizable emboli from the infrarenal aorta and iliac arteries. We have seen this on two occasions, and its onset can be both frustrating and puzzling. Such experiences have led to the suggestion that a total arterial reconstruction may be needed to remove or bypass all the lesions from the infrarenal to the popliteal arterial system. However, this extensive surgical approach is generally not warranted in the management of most of these cases, because it is usually not difficult to identify precisely the responsible lesion and treat it by a relatively local procedure.

MEDICAL MANAGEMENT

Figure 29-14. Treatment of the lesion in Fig. 29-13A by thrombointimectomy and vein patch graft.

reduction, their repair also brings about reversal or improvement of ischemic changes in the foot. The operative procedures for the various aneurysms that are the source of emboli are described in Chapters 43 –47, and the principles of endarterectomy and/or bypass of arterial lesions are also well known. In highly localized stenotic lesions (1 –2 cm) of the femoral and popliteal arteries, operative removal of the fibrinoplatelet clumps together with adherent intima (thrombointimectomy) (Fig. 29-13) followed by vein patch angioplasty has produced very satisfactory long-term results (Fig. 29-14), although all of these arteries inevitably display various degrees of atheromatous degeneration both proximally and distally to their actual stenotic lesion. The great majority of patients treated by this method have maintained patency of these arteries up to 5 years (Figs. 29-15 and 29-16).[9] In patients with longer segments of significant atherosclerotic changes (. 5 cm), vein-patch angioplasty is

In the carotid distribution, nonsurgical therapy for what are undoubtedly atheroembolic events has become popular in some medical circles. The efficacy of such treatment remains controversial. In the case of peripheral atheroembolism, no controlled clinical trial to date has demonstrated any efficacy for nonsurgical therapy in the long-term treatment of these events. Nevertheless, there is some rationale for the use of antiplatelet medications to prevent mural thrombus formation in the case of a single atheroembolic event from a patent yet diseased artery. Typically, a combination of aspirin and dipyridamole is given in these instances, but other nonsteroidal anti-inflammatory agents may be used. It is unclear whether some of the perceived therapeutic benefit of these drugs is in their anti-inflammatory effect rather than in the prevention of further episodes. The use of full anticoagulation with warfarin has been reported in some cases to lead to paradoxical increases in the severity of embolic events (“purple-toe syndrome”), probably due to the increased severity of plaque hemorrhage associated with degenerating plaques. If nonsurgical treatment is to be selected for clinical phenomena typical of atheroembolism, angiographic confirmation of the arterial pathology should be entertained before initiation of therapy. This is particularly important in order to avoid missing an easily treatable preocclusive lesion.

SPECIAL NEW OR IATROGENIC MICROEMBOLIC CIRCUMSTANCES DURING FIBRINOLYTIC THERAPY Fibrinolytic enzymes (e.g., streptokinase, urokinase) are now in reasonably widespread use for the dissolution of thrombi that occur either in native arteries or in grafts. These enzymes

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Figure 29-15. (A ) Similar lesion to Fig. 29-13A treated in the same fashion. (B ) Five-year follow-up showing durability of reconstruction.

are used both as a primary means of treatment of acute occlusion and in an attempt to determine the nature of the precipitating pathological lesion by angiography after thrombolysis. It is now well documented that in some instances, after the majority of thrombus in the conduit has been dissolved, the final residual fragments of thrombus are now exposed to full arterial pressure and may suddenly be dislodged and swept into the distal arterial tree. There appears to be no way of preventing this event, which in some instances may prove to be a fatal blow to the foot.

Performance of Catheter Angiograms Through Diseased Arteries The passage of angiographic catheters, particularly of larger size (6 French or greater), and their subsequent manipulation

for selective catheterization may in fact cause the dislodgement of fibrinoplatelet clumps or the fragmentation of atheromatous plaques, which may embolize distally. This is not a common event but should be recognized by the angiographers and clinicians concerned.

Balloon Angioplasty Balloon widening of stenotic areas in arteries is also widely carried out, but in lesions that appear to be stenotic, as mentioned previously, fibrinoplatelet clumps may exist as part of the pathology of the lesion; when compressed or manipulated by the balloon, these may, in fact, be suddenly dislodged. Such lesions should be noted on the previous arteriograms wherever possible, since they contraindicate intraluminal instrumentation.

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Thrombotic Occlusion of Synthetic Grafts We have observed that one of the terminal events following sudden thrombotic occlusion of certain synthetic grafts may, in fact, be a dislodgment of small thrombi as microemboli distally, thus compromising the collateral circulation and the survival of the foot in addition to the jeopardy already caused by the occlusion of the graft. This unwelcome event usually necessitates even more difficult and more distal arterial reconstructions to provide limb salvage.

Suprarenal Atherosclerosis as a Source of Blue-Toe Syndrome Atherosclerotic disease from the suprarenal aorta such as arch and descending thoracic aortic and shaggy aorta syndrome may be the source of this syndrome in a certain number of cases. Actual incidence is unknown, but in larger series it may account for 2 – 13% of patients.[23 – 26] Diagnosis and treatment of this condition is somewhat challenging. There is no accurate diagnostic tool that offers uniform delineation of lesions of all segments of the suprarenal aorta. Transesophageal echo, magnetic resonance angiogram, enhanced computed-tomography angiogram, and aortogram all offer about equal specificity and sensitivity for making the diagnosis, depending on the location of the disease.[23] Still, contrast angiogram probably is the “gold standard.”[23,24] Ultrasonogram in the thoracic aorta was not found to be that accurate. Once diagnosis is made, the treatment options are very few. Direct repair by surgical treatment is most durable and effective,[26] but thoracotomy and replacement of the arch vessels have high complications, mortality, and morbidity.[23,25] Any medical treatment besides aspirin is not effective; anticoagulation has occasionally been used with conflicting results. Most mortality and morbidity from this disease are caused by embolization to the brain, visceral artery, or renal artery and not necessarily from the consequences of blue-toe syndrome. Thus, when the source of blue-toe syndrome is not found in conventional locations, one should keep in mind and explore the possibility of arterial atheroemboli arising from the suprarenal, supraceliac, and thoracic aorta.

Figure 29-16. An example of a longer patch that has lasted for over 7 years.

REFERENCES Paunam, P.L. Experimentalle Beitra¨ge zur Lehre von deren Embolie. Arch. Pathol. Anat. 1962, 25, 308. 2. Carvajal, J.A.; Anderson, W.R.; Weiss, L.; et al. Atheroembolisms: An Etiological Factor in Renal Insufficiency, Gastrointestinal Hemorrhages and Peripheral Vascular Disease. Arch. Intern. Med. 1977, 119, 593. 3. Kaplan, K.; Millar, I.D.; Canilla, P.A. “Spontaneous” Atheroembolic Renal Failure. Arch. Intern. Med. 1962, 110, 218. 4. Karmody, A.M.; Jordan, R.F.; Zaman, S.M. Left Colon Gangrene After Acute Interior Mesenteric Artery Occlusion. Arch. Surg. 1976, 111, 972.

1.

5.

Haygood, T.A.; Fessel, W.J.; Strange, D.A. Atheromatous Microembolism Simulating Polymyositis. J. Am. Med. Assoc. 1968, 203, 135. 6. Crane, C. Atherothrombotic Embolism to Lower Extremities in Arteriosclerosis. Arch. Surg. 1967, 94, 96. 7. Branowitz, J.B.; Edwards, W.S. The Management of Atheromatous Emboli to the Lower Extremities. Surg. Gynecol. Obstet. 1976, 143, 941. 8. Kazmie, F.J.; Sheps, S.G.; Bernatz, P.E.; Sayre, G.P. Livedo Reticularis and Digital Infarctions: A Syndrome Due to Cholesterol Emboli Arising from Atheromatous Abdominal Aortic Aneurysms. Vasc. Dis. 1966, 3, 12.

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9. Karmody, A.M.; Leather, R.P. Atherothrombotic Microemboli of the Lower Limb. In Vascular Surgery; Rutherford, R.B., Ed.; Saunders: Philadelphia, 1984;. 10. Anderson, W.R.; Richards, A.M. Evaluation of Lower Extremity Muscular Biopsies in the Diagnosis of Atheroembolism. Arch. Pathol. 1968, 86, 528. 11. Maurizi, C.P.; Barker, A.E.; Trueheart, R.E. Atheromatous Emboli: A Post-Mortem Study with Special Reference to the Lower Extremities. Arch. Pathol. 1968, 86, 528. 12. Wagner, R.B.; Martin, A.S. Peripheral Atheroembolism: Confirmation of a Clinical Concept with a Case Report and Review of the Literature. Surgery 1973, 73, 353. 13. Kempezinski, R.F. Lower Extremity Arterial Emboli from Ulcerating Atherosclerotic Plaques. J. Am. Med. Assoc. 1979, 214, 807. 14. Schechter, D.C. Atheromatous Embolization to Lower Limbs. N. Y. State J. Med. 1979, 79, 1180. 15. Kwaan, H.J.; Connolly, J.E. Peripheral Atheroembolism. Arch. Surg. 1977, 112, 987. 16. Williams, G.M.; Ricotta, J.J.; Zimmer, M. The Extended Retroperitoneal Approach for Treatment of Extensive Atherosclerosis in the Aorta and Renal Vessels. Surgery 1980, 88, 846. 17. Williams, G.M.; Harrington, D.; Burdick, J.; White, R.I. Mural Thrombosis of the Aorta: An Important, Frequently Neglected Cause of Large Peripheral Emboli. Ann. Surg. 1981, 194, 737.

18. Karmody, A.M.; Powers, S.R.; Monaco, V.J.; Leather, R.P. “Blue Toe Syndrome”: An Indication for Limb Salvage Surgery. Arch. Surg. 1976, 111, 1263. 19. Mehigan, J.T.; Stoney, R.J. Lower Extremity Atheromatous Emboli. Am. J. Surg. 1976, 132, 163. 20. Gore, I.; Collins, D.P. Spontaneous Atheromatous Embolization: Review of the Literature and a Report of 16 Additional Cases. Am. J. Clin. Pathol. 1960, 33, 416. 21. Corson, J.D.; Karmody, A.M.; Shah, D.M.; et al. In Situ Vein Bypasses to Distal Tibial and Limited Out-Flow Tracts for Limb Salvage. Surgery 1984, 96, 756. 22. Flynn, W.R.; Harris, J.P.; Rudo, M.D. Atheroembolism as a Cause of Graft Failure in Femoro-Distal Reconstruction. Surgery 1981, 90, 698. 23. Keen, R.R.; McCarthy, W.J.; Shireman, P.K.; Feinglass, J.; Pearce, W.H.; Durham, J.R.; Yao, J.S. Surgical Management of Atheroembolization. J. Vasc. Surg. 1995, 21 (5), 773. 24. Baumann, D.S.; McGraw, D.; Rubin, B.G.; Allen, B.T.; Anderson, C.B.; Sicard, G.A. An Institutional Experience with Arterial Atheroembolism. Ann. Vasc. Surg. 1994, 8 (3), 258. 25. Kvilekval, K.H.; Yunis, J.P.; Mason, R.A.; Giron, F. After the Blue Toe: Prognosis of Noncardiac Arterial Embolization in the Lower Extremities. J. Vasc. Surg. 1993, 17 (2), 328. 26. Bujar, R.M.; Payne, D.D.; Murphy, R.E.; Schwartz, S.L.; Belden, J.R.; Caplan, L.R.; Rastegar, H. Surgical Treatment of Systemic Atheroembolism from the Thoracic Aorta. Ann. Thorac. Surg. 1996, 61 (5), 1389.

CHAPTER 30

Aortoiliofemoral Occlusive Disease K. Wayne Johnston Peter G. Kalman Atherosclerotic occlusive disease commonly occurs in the aortoiliac segment. Two-thirds of these patients are male, and the vast majority have a history of prolonged cigarette smoking. Most often, they present in their mid-fifties 25–10 years earlier than patients with more distal occlusive disease.[1] The purpose of this chapter is to review the surgical therapy for aortoiliac occlusive disease, with attention to the historical aspects, pathology, diagnostic methods, conservative and operative management, and complications.

In the past decade, the most common operation for correction of aortoiliac occlusive disease, an aortobifemoral bypass, has been performed less commonly because of the impact of percutaneous transluminal balloon angioplasty and stenting, the increasing tendency to extra-anatomical bypass, and the recognition that claudication is generally a benign disease.[14]

PATHOPHYSIOLOGY HISTORICAL ASPECTS

Chronic Atherosclerosis

The possibility for surgical correction of aortoiliac obstruction was suggested by Leriche[2] in 1940, when he described the syndrome of bilateral claudication, sexual impotence, and absent common femoral pulses. Thromboendarterectomy was introduced by Dos Santos[3] in 1947 and first described for the aortoiliac segment by Wylie[4] in 1952 and later by Barker and Carmon[5] in 1953. Resection of the obstructed segment and replacement with an arterial allograft was described by Oudot[6] in 1951, Julian et al.[7] in 1952, and DeBakey et al.[8] in 1954. The allografts were cumbersome to obtain and were complicated by the development of late aneurysms. Following the description by Voorhees et al.[9] of a fabric arterial prosthesis in 1952, durable grafts made of Teflon or Dacron were introduced by Edwards[10] and DeBakey and Crawford[11] in 1957. Throughout the 1960s, bypass grafting from the aorta to the external iliac arteries increased in popularity. Moore et al.[12] in 1968 and Perdue et al.[13] in 1970 suggested that superior long-term results followed anastomoses to the common femoral rather than the external iliac level, and this was confirmed by Baird et al.[1] in 1977. At present, operations are selected that correct the entire aortobifemoral occlusive segment as well as the frequently associated disease involving the profunda femoris. The current focus is on the durability of the procedure and the prevention of complications.

Atherosclerosis may produce partial or complete occlusion of the distal aorta and one or both common iliac arteries, and it frequently extends into the proximal portion of the external and/or internal iliac arteries. Usually the plaque is more extensive on the posterior wall; thus the distal lumbar and median sacral arteries are occluded at an early stage. Immediately distal to the renal arteries, the aorta is usually free of disease or minimally involved, and the periarterial surgical planes are well preserved. These features are exploited in the surgical repair: the upper clamp is placed immediately below the renal arteries and the upper anastomosis is performed about 2 cm distally. In some cases, the disease process extends proximally and involves the orifices of the renal arteries. In these cases, clamps must be placed at a higher level and care taken to ensure that the arterial supply to the kidneys is not compromised by embolization of atherosclerotic debris or inadequate removal of the obstructive material. The origin of the inferior mesenteric artery may be occluded, and the status of this vessel influences the design of the operation. With chronic aortoiliac occlusive disease, collateral vessels enlarge and compensate to some degree. The potential for collateral flow is higher with aortoiliac than with femoral, popliteal, or tibial artery obstruction. Important collateral pathways include internal mammary to inferior epigastric; superior mesenteric to inferior mesenteric and internal iliac;

Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024913 Copyright q 2004 by Marcel Dekker, Inc.

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intercostals and lumbars to circumflex iliac and internal iliac; inferior mesenteric to internal iliac; and internal iliac to profunda femoris. Patients with isolated aortoiliac disease generally present with complaints of intermittent claudication and/or sexual impotence. By the time symptoms are noted, half the patients also have occlusive disease in the femoral popliteal and/or tibial arteries. By comparison to the patients with only aortoiliac involvement, those with multilevel disease present at an earlier age, and the viability of the leg may be threatened.[1,15,16]

Occlusive Mid-Aneurysmal Disease Although patients with abdominal aortic aneurysms rarely have claudication, symptoms from occlusive disease may be associated with aortoiliac aneurysms if there is significant coexisting atherosclerotic occlusive disease, embolic occlusion from the mural thrombus, or kinking of the arteries.

Hypoplastic Aorta The hypoplastic aortoiliac syndrome almost always occurs in women with a history of significant, long-standing cigarette smoking. Characteristic features include a high aortic bifurcation, acute angle of the aortic bifurcation, straight iliac arteries without the normal lateral bowing, an aortic diameter less than 14 mm (or less than one-quarter of the diameter of the lumbar vertebrae), and a common iliac diameter less than 7 mm.[17] Collaterals are poorly developed and the femoral and distal vessels are also small. Symptoms of claudication are more severe than expected from the angiographic pattern.[18] Recognition of this syndrome is important because the operative procedures are technically difficult and the longterm results of bypass surgery are often poor.[17,19] If conservative treatment fails, aortoiliac endarterectomy with patch grafting or percutaneous transluminal angioplasty is recommended for those with localized disease. For patients with extensive occlusive disease, an aortofemoral bypass graft is indicated, using a small prosthesis (12 £ 6 mm in diameter) with a proximal end-to-side anastomosis to minimize the size discrepancy.[17] Burke et al.[20] noted improved results with a PTFE prosthesis, although this has not been our experience. In a group of 24 women less than 50 years of age with aortoiliac occlusive disease, Gagne et al. found a high incidence of coagulation abnormalities, particularly antiphospholipid antibody, and encouraged further investigation and aggressive anticoagulant management of this group.[21]

Acute Obstruction Acute aortoiliac occlusion may result from an embolus originating in the heart or from an aortic aneurysm. Other causes include an aortic dissection, blunt or penetrating trauma, or iatrogenic injury (e.g., diagnostic catheters, intraaortic balloons, or percutaneous transluminal dilatation).

Since collateral channels are poorly developed in these cases, severe ischemia and the risk of tissue loss is usual.

CLINICAL DIAGNOSIS Typically, patients with isolated aortoiliac disease are male cigarette smokers who present with buttock, thigh, and calf claudication and often have some degree of sexual impotence. Complaints of rest pain or ischemic night pain are usually absent unless multilevel disease is present or the occlusion extends up to the renal arteries, thereby interfering with collateral pathways. On physical examination, one or both femoral pulses are reduced and iliac or femoral bruits are audible. The feet usually appear warm and well perfused, without nutritional changes. An accurate clinical diagnosis of aortoiliac occlusive disease is usually straightforward; however, one-quarter of the patients with isolated aortoiliac disease complain only of calf claudication rather than thigh or buttock pain. Conversely, one-quarter of the patients with normal aortoiliac segments and isolated femoral popliteal disease have low thigh as well as calf claudication.[22] Femoral bruits are present in only two-thirds of the patients with symptomatic isolated aortoiliac obstruction. The differential diagnosis must identify patients complaining of buttock and thigh pain of neurogenic or musculogenic origin. The symptoms from spinal stenosis may be difficult to distinguish; however, these patients usually complain of leg pain or “weakness” on standing or on walking very short or variable distances, and relief is achieved only by sitting or lying down for prolonged periods or after adequate analgesics. Numbness and tingling are common and are usually localized in the distribution of one or more nerve roots. An uncommon clinical presentation of aortoiliac disease is the blue-toe syndrome.[23] These patients present with an ischemic blue and tender toe and peripheral pulses are palpable. Arteriography may demonstrate an ulcerating plaque, but occasionally a high-resolution computed tomography (CT) scan is necessary to demonstrate the ulcerating atherosclerotic lesion.

OBJECTIVE DIAGNOSIS Noninvasive Assessment Noninvasive tests augment clinical and arteriographic assessment and in general have a role in determining the severity of arterial occlusive disease, localizing the site of involvement, and clarifying the differential diagnosis. The ankle-brachial systolic blood pressure ratio objectively determines the severity of the vascular insufficiency but can be artifactually high if the tibial arteries are calcified, e.g., in diabetics. Through the use of treadmill exercise testing, the physician can assess the extent of the patient’s disability and distinguish the symptoms of claudication from pain secondary to musculoskeletal or neurologic disease.

Chapter 30.

Several noninvasive methods are potentially useful for assessing the severity of aortoiliac disease.[22] Although the thigh systolic blood pressure can be measured, it is not sufficiently accurate for assessing the aortoiliac segment, particularly in patients with combined aortoiliac and femoral popliteal disease. It is not possible to place the pressure cuff high enough on the thigh to measure a pressure equivalent to that in the common femoral artery and thus accurately assess the severity of the iliac disease. Hemodynamically significant aortoiliac disease can be detected through analysis of Doppler recordings of bloodflow velocity from the common femoral artery using duplex Doppler equipment.[24] The Doppler waveform is normally triphasic, with a large initial forward component followed by a reverse and then a second smaller forward flow component. If the waveform is dampened (i.e., monophasic or a reverse flow lost), significant iliac disease is likely to be present. The waveforms are usually analyzed by subjective evaluation or quantified by the calculation of pulsatility index[25] or other measurements. Alternatively, peak velocity measurements can be made along the length of the aortoiliac segment. A stenosis .50% is diagnosed if the peak velocity is at least two times greater than the velocity in an adjacent normal arterial segment, the waveform becomes monophasic, and spectral broadening is present.[26]

Arteriography An arteriogram is obtained only when the history indicates that the symptoms are sufficiently disabling to warrant a consideration of percutaneous transluminal angioplasty or surgery. Although arteriography remains the most important method for evaluating the severity of aortoiliac disease, standard anterior –posterior views may underestimate the severity of the occlusive disease[27] in which case biplane views will be necessary. Even with digital subtraction techniques, the diagnostic accuracy of arteriography is better with the retrograde femoral than the translumbar approach, since it is easier to obtain biplane views and to achieve a more rapid injection of a larger bolus of dye. In most patients, it is optimum to obtain biplane aortoiliac views unless a severe lesion is demonstrated on the anterior –posterior arteriogram. The aortogram should be of sufficient quality to allow the surgeon to see adequate details from the renal arteries to at least the midcalf. Although magnetic resonance angiography (MRA) is a noninvasive and cost-effective method for imaging providing angiograms without the use of iodinated contrast agents, the visualization of the proximal aortoiliac segment is often not ideal in the authors’ experience, However, in a small series, Carpenter et al. have demonstrated that it provides adequate information to plan aortobifemoral bypasses, and that the results are comparable to those expected with standard arteriography.[28]

Direct Pressure Measurements When the severity of aortoiliac occlusive disease is difficult to determine from the arteriogram, the best method for assessing the hemodynamic significance of an aortoiliac lesion is to

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directly measure the aortofemoral pressure gradient at rest or after reactive hyperemia has been induced. The aortofemoral pressure difference is measured from pressure recordings which are made as the angiographic catheter is withdrawn from the aorta to the level of the external iliac or common femoral artery. A systolic pressure gradient of more than 10 mmHg at rest is considered to be hemodynamically significant. Alternatively, the difference between the femoral systolic pressure at rest and after intra-arterial injection of 30 mg of papaverine is obtained. Normally, the femoral artery systolic pressure does not fall significantly, but a fall of more than 15% is indicative of significant iliac disease.[24,29]

CONSERVATIVE TREATMENT Mild intermittent claudication from aortoiliac disease causes minimal disability and its natural history is usually favorable.[30] Although significant symptomatic improvement is unlikely, the symptoms usually remain stable for many years. Consequently, investigation and treatment of patients with claudication is indicated only for significant disability – that is, when their employment and enjoyment of life are threatened. After the discovery of significant atherosclerosis, steps should be taken to identify and control risk factors such as smoking, hypertension, hyperlipidemia, and diabetes. If the patient is obese, weight reduction will reduce the work load associated with walking and improve the claudication distance. The patient often believes that walking to the point of claudication is harmful to the leg. The patient should be informed, however, that exercise therapy is of proven value and frequently improves the claudication distance.[31,32] Vasodilators, megavitamins, and most pharmacologic products are unproved or of little benefit. Although studies have suggested that pentoxifylline (Trental) is useful in the treatment of claudication,[33,34] we have not found this drug to be particularly effective.

SUMMARY ALGORITHM FOR INTERVENTION For patients with significant vascular symptoms secondary to localized aortoilaic occlusive disease, the recommended approach is percutaneous transluminal angioplasty (PTA) if feasible. There is little evidence to support routine primary stenting after successful aortoiliac PTA other than for a few specific indications: recoil, eccentric lesion, and dissection after PTA. In general, the results with PTA are less satisfactory than surgical reconstruction, but considering the low morbidity and the option for the procedure, PTA is justified for localized aortic or iliac stenoses or short occlusions. The only lesions not amenable to PTA are the less common focal aortic or iliac “coral-reef” plaques that are best managed with endarterectomy. For diffuse aortioiliac occlusive disease, surgical revascularization can be achieved by anatomic or extraanatomic bypass. Aortobifemoral (ABF) bypass is the

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standard operation for treating good-risk patients with aortic and bilateral iliac disease. Although popular in the 1960s, the role of aortoiliac endarterectomy has decreased considerably. The long-term results of localized endarterectomy are excellent; however, the results for extensive endarterectomy are poor. Many patients with localized disease who were previosly treated by endarterectomy are now treated by PTA. Endarterectomy is tedious and time consuming and is associated with a greater blood loss than bypass grafting and a higher incidence of sexual dysfunction in males. In certain circumstances, ileofemoral, axillofemoral, and femorofemoral bypasses are acceptable alternatives to ABF. A unilateral ileofemoral bypass is preferred over femorofemoral bypass provided that the aorta and ipsilateral common iliac artery are normal or only minimally diseased. Ileofemoral has a small patency advantage compared to femorofemoral but the main advantage is avoidance of a second groin incision with the potential for lymphatic complications and infection. Axillofemoral bypass is indicated in patients with a high anesthetic risk or when a transabdominal approach is contraindicated (e.g., sepsis, dense adhesions, prior irradiation, malignancy). Femorofemoral bypass is indicated with extensive unilateral iliac disease in the presence of a normal donor iliac artery. A more durable long-term alternative to axillofemoral bypass is desirable for low-risk patients in whom a transabdominal approach is considered hazardous. In these cases, inflow from a more proximal aortic source such as the ascending or descending thoracic or supraceliac aorta is available. Both the ascending and descending thoracofemoral bypass provide excellent inflow and have comparable patency, and the choice depends upon individual preference. With the exception of concomitant aortocoronary surgery, most surgeons prefer the descending thoracic to femoral bypass.

PERCUTANEOUS TRANSLUMINAL ANGIOPLASTY In our experience with 667 iliac balloon angioplasties, the average success rates were 75 ^ 2% (mean ^ 1 standard error) at 1 year, 60 ^ 2% at 3 years, and 53 ^ 3% at 5 years. The results were better if the common iliac artery was dilated versus the external iliac artery, the indication for the procedure was claudication versus salvage, a stenosed versus an occluded artery was dilated, and the runoff was good versus poor.[35] Aortic angioplasty was carried out in 17 patients, 16 of whom were women. The success rates were 80 ^ 10%, 80 ^ 10%, and 70 ^ 10% at 1, 3, and 5 years, respectively. Although these results are less satisfactory than surgical repair, the low morbidity of the procedure when performed by an experienced radiologist justifies its use in treating localized iliac stenoses or occlusions. Thrombolytic therapy can be used to open chronically occluded aortoiliac segments and the underlying occlusive disease treated by percutaneous transluminal angioplasty. Although one series reported that lysis allowed subsequent

angioplasty in approximately 50% of cases, long-term results with this approach are not available.[36]

SURGICAL TREATMENT The surgical repair of atherosclerotic aortoiliac occlusive disease is achieved by aortoiliac endarterectomy, an anatomic bypass graft, or an extra-anatomical bypass graft.

Aortoiliac Endarterectomy Endarterectomy still has a role in the management of aortoiliac disease, but its place has diminished greatly since the 1960s. The procedure usually involves an open endarterectomy of the distal aorta and either an open or semiclosed endarterectomy of one or both common iliac segments down to the level of the external iliac arteries. Extensive aortoiliac femoral endarterectomy has been abandoned. Closed endarterectomy using the LeVeen “plaque cracker” was popularized in Europe and permits extensive retroperitoneal endarterectomy of the aorta, iliac, and femoral segments.[37,38] In general, the long-term results of endarterectomy for localized disease are excellent and are comparable to those of bypass grafting; however, the results of extensive endarterectomy are poor.[15] By comparison to bypass grafting, endarterectomy is more tedious, time-consuming, and technically demanding and is associated with a greater blood loss. The procedure should be considered in young patients with localized aortoiliac occlusive disease that does not involve the external iliac artery, since involvement of this site is often associated with recurrence of symptoms necessitating reoperation.[39] Many patients with this distribution of localized disease can now be treated quite satisfactorily by percutaneous transluminal angioplasty. If the risk of infection is high, endarterectomy is preferable to prosthetic bypass grafting. In selected cases, aortoiliac endarterectomy is useful as a salvage procedure for the treatment of an infected aortofemoral bypass graft. After removal of the infected prosthesis, the arterial channel to the leg can be reconstituted by endarterectomy of the native vessels and patching with autogenous material.[40] In spite of its limited application at the present time, every vascular surgeon should be aware of and competent in the techniques of aortoiliac endarterectomy.

Anatomical Bypass Grafts Over the past three decades, bypass grafting has become the standard method for aortoiliac repair. An iliofemoral bypass graft is a durable procedure for managing external iliac occlusive disease that is not amenable to percutaneous transluminal angioplasty, especially when it extends down to the level of the common femoral artery or is the result of iatrogenic occlusion following arterial catheterization.[41] A unilateral aortofemoral bypass graft is rarely indicated. The standard operation for aortoiliac disease is an aortobifemoral bypass and is discussed in detail in the following sections. This operation is indicated for good-risk

Chapter 30.

patients with bilateral aortoiliac occlusive disease. Although we advocate a unilateral reconstruction of iliac occlusive disease if feasible, others prefer an aortobifemoral bypass for the management of unilateral disease, especially if the superficial femoral artery is also occluded.[42]

General Principles of Aortobifemoral Bypass The aortic anastomosis can be made either end-to-side or end-to-end. End-to-side anastomosis is indicated in the following circumstances: if a large aberrant renal artery that supplies a significant amount of renal parenchyma is present; if a large inferior mesenteric artery is present, especially if pelvic flow is reduced because of associated severe iliac disease; if the patient is a male who is concerned about his sexual potency and there is a significant occlusive disease involving both external iliac arteries, therefore compromising retrograde flow to the internals after aortobifemoral bypass; or if the aorta is hypoplastic. End-to-end anastomosis is indicated in patients with coexisting aortic aneurysmal disease or a complete aortic occlusion extending up to the renal arteries. We prefer the end-to-end technique and argue that the long-term hemodynamic results may be better than with end-to-side. Furthermore, the incidence of intraoperative atheromatous embolization and the risk of subsequent aortoenteric fistulas may be lower.[43 – 49] Despite the fact that this preference has been supported by others,[14,35 – 40,49] the evidence does not strongly support either technique. Melliere et al.[50] could not find any difference between the results of end-to-end and end-to-side anastomoses and suggested choosing the simplest procedure that maintains adequate pelvic and colonic flow according to the angiographic findings. The distal anastomosis is usually made to the common femoral artery. If the distal anastomosis is made to the external iliac artery, there is an increased chance that a subsequent downstream repair will be required unless the external iliac artery is completely free of disease. lf the superficial femoral artery is occluded or severely stenosed and any narrowing of the profunda femoris artery is present, the toe of the graft should be extended onto the profunda as far as necessary beyond palpable disease.

The Technique of Aortobifemoral Bypass Preoperatively, bowel preparation is achieved by a fluid diet for 24 hours and administering enemas until clear the evening prior to surgery. Prophylactic antibiotics, usually a cephalosporin, are administered preoperatively and continued for 48 h. Important aspects of preoperative preparation and intraoperative management are described below, under “Myocardial Infarction.” The electrocardiogram (ECG), arterial blood pressure, and central venous pressures are monitored routinely, and a Swan –Ganz catheter is used in only selected cases. Routine use of a Swan– Ganz catheter does not reduce perioperative mortality.[51] The patient is positioned in the supine position and draped so that the groins and legs are exposed and the feet are visible in transparent plastic “bowel” bags.[1] Longitudinal groin incisions are made to expose the common femoral artery from the inguinal ligament to the bifurcation. If the superficial

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femoral artery is occluded, the first 1–2 cm of the profunda femoris artery is also exposed and is carefully palpated to confirm the absence of disease at its origin. The anterior 3 – 4 mm of the inguinal ligament is cut and the incision carried posteriorly to divide the posterior layer as well. Gentle blunt dissection is used to create a tunnel into the retroperitoneal space anterior to the iliac artery and the lateral circumflex iliac vein. The groin wounds are loosely packed with a moist sponge and the self-retaining retractors removed. The abdomen is opened through a midline incision from the xiphoid to midway between the umbilicus and pubis, using a blended cautery to reduce blood loss. Laparotomy is performed and a large fixed abdominal retractor is positioned. The transverse colon is elevated, and the small bowel is gathered to the right (either inside or outside the abdomen depending on body habitus) and protected by moist towels. A retroperitoneal incision to expose the aorta may be a good alternative to the standard transperitoneal incision.[52] It can be carried out without endotracheal intubation and general anesthetic and may be of advantage in high-risk patients. The surgeon identifies the duodenum on the right and the inferior mesenteric vein on the left and dissects between them directly down to the anterior wall of the aorta. The origin of the inferior mesenteric artery is noted but is not dissected. The anterior and lateral walls of the aorta are exposed up to the level of the renal vein. No attempt is made to divide lumbar arteries or to encircle the aorta. In the male, postoperative sexual dysfunction can be minimized by preserving the preaortic autonomic nerves and dissecting the preaortic tissue longitudinally and toward the right side and by not dividing the tissue in the region of the inferior mesenteric artery or near the aortic bifurcation.[53,54] Heparin (75–100 units per kilogram, usually approximately 5000 units) is administered by the anesthetist. Before the aorta is crossclamped, the anesthetist is given appropriate warning so that pharmacologic intervention is possible as required to reduce the cardiac afterload if necessary. We prefer knitted Dacron rather than woven because of its greater ease of handling, improved healing properties, and ease of appropriate fashioning for distal anastomoses without fraying of edges. However, the type of Dacron prosthesis implanted does not appear to be of great importance for outcome. There is no significant difference in early or late thrombogenicity between knitted and woven Dacron prostheses as assessed by 111In-labeled platelet deposition studies,[55] nor is there a difference in the early or late patency rotes.[56] Collagen- or gelatin-coated grafts are commonly used because they eliminate the necessity for preclotting and reduce blood loss. Since current Dacron grafts usually exhibit an initial dilatation upon exposure to arterial blood pressure and 10–25% diameter dilatation over the first year,[57] we prefer a 14 £ 7 mm graft rather than a larger prosthesis. When the graft was selected to match the size of the native arteries, there was no difference in long-term patency between small (12 or 14 mm) and large (16 or 18 mm) grafts.[58] For an end-to-end anastomosis, the proximal clamp is placed just below the renal arteries and the distal clamp approximately 3 cm distally. The clamps are placed from an anterior position and no attempt is made to dissect behind the aorta. The aorta is divided 1 cm, proximal the distal clamp,

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with great care being taken to avoid entering posterior lumbar veins. Removal of a small wedge of the anterior wall of the distal aorta often allows the surgeon to visualize the posterior aortic wall more clearly prior to dividing it. The distal stump of aorta is oversewn with a 2 –0 or 3–0 monofilament polypropylene suture, starting at the posterior wall and coming anteriorly with both needles in two layers so that only one knot is required. The lower clamp is removed as this suture is pulled tight and tied, so that the aortic tissue comes together snugly. Debris in the proximal aortic trunk is carefully removed. The graft is cut so that the aortic trunk is about 3 –3.5 cm long. It is sewn to the end of aorta with a double-ended 2 –0 or 3–0 monofilament polypropylene suture which is started on the left lateral wall and continued across the back wall to the right lateral wall with a “parachute” technique in which the end of the prosthesis is held about 4 –5 cm from the aorta. All tissue bites are taken in a forehand manner and great care is taken not to exert caudad traction on the aortic stump. The suture is moistened with saline, pulled down into place, and tightened. A nerve hook is used to tighten any loose strands and the final traction is exerted in the plane parallel to the posterior wall of the aorta. The left limb of the suture is then fixed in a taut position and held in place by a rubber-shod clamp. The right side is continued to the midline of the graft, where it is then held tautly while the left suture is continued to meet it. The clamp is temporarily released and hemostasis is confirmed by inspecting the circumference of the anastomosis. Any leaks are repaired with interrupted sutures. A long curved clamp is then passed from each groin to grasp the limbs of the prosthesis and draw them into the femoral incisions. Care is taken to make each tunnel behind the ureter if possible and, on the left, behind the sigmoid arterial and venous branches. In performing an end-to-side anastomosis, the proximal aorta is clamped just distal to the renal arteries and this distal clamp is positioned just above or below the inferior mesenteric artery and clamped in an oblique direction so that patent lumbar arteries are occluded. An arteriotomy 3.5 – 5 cm, in length is made. Atheromatous debris is removed, the arteriotomy is flushed with saline, and the clamps are released temporarily to expel loose debris. The graft is suitably beveled and anastomosed using a single running monofilament suture starting at the base. The design of each lower anastomosis is determined by the severity of disease in the infrainguinal arteries. If the superficial and profunda femoris arteries are normal, the anastomosis is made to the common femoral artery. Narrowing at the origin of the superficial or profunda femoris arteries is corrected by appropriate arterioplasties. Good-quality preoperative angiograms with oblique views are helpful in detecting stenosis at the origin of the profunda femoris artery, but the final decision about a stenosis involving this artery is made in the operating room. If there is any doubt, the common femoral arteriotomy is continued into the profunda. The profunda femoris artery is often quite fragile and thin-walled; great care is taken to avoid injury to it or its branches, and extensive endarterectomies are avoided.[59 – 66] The groin anastomoses can be performed simultaneously if two experienced surgeons are available. The anastomoses are made with 5 –0 or 6–0 monofilament

polypropylene sutures, starting and finishing on one side of the heel and using a one-knot technique. Before the anastomoses are completed, adequate flushing of all the vessels is necessary, including the native superficial femoral, profunda femoris, and common femoral arteries as well as the graft. The anesthetist is given 5–10 minutes warning before the graft is opened. The surgeon controls the flow through the new conduit until the blood pressure has stabilized. The heparin is then reversed with protamine. Hemostasis is checked, the color of the sigmoid colon is noted, and the retroperitoneal space is closed. All blood is removed from the abdomen, a careful sponge and instrument count is completed, and the abdominal incision is closed with a single-layer continuous 1 –0 monofilament polypropylene suture. Before the groin incisions are closed, the femoral pulses are checked and the feet inspected to ensure that the peripheral flow is adequate. If there is any concern, intraoperative angiograms should be obtained or the anastomoses reopened and a Fogarty catheter passed. Groin closure is important and should be done in two to three layers to minimize dead space and avoid a lymphatic leak. Skin closure is with metallic skin clips. Postoperatively, the patient is monitored for hemodynamic stability, respiratory function, renal function, and the status of the circulation to both legs. In most cases the patient can be extubated in the operating room or shortly after surgery. If the patient is hemodynamically stable, observation in a stepdown unit, rather than an intensive care unit, is adequate. Ambulation begins on the first or second day and most patients are ready for discharge between the fifth and seventh postoperative days. Before discharge, they are evaluated in the noninvasive vascular laboratory to provide an objective baseline for follow-up studies.

Multilevel Occlusive Disease The optimum management of patients with multilevel occlusive disease (i.e., combined aortoiliac and femoral popliteal disease) remains controversial. Our current practice is to perform the proximal reconstruction with a profundaplasty if necessary and to delay femoropopliteal bypass grafting until the results of the initial procedure are assessed. Even in patients with extensive profunda disease requiring an extended profundaplasty, the results are good. This approach provides adequate outflow to maintain graft limb patency, good distal perfusion with adequate relief of symptoms even if the popliteal artery is occluded, and durability.[67,68] Local wound complications and lymphoceles are frequent with extended profundaplasties.[48] However, with this approach, some patient will have persistent significant claudication and require a subsequent distal procedure; in others, a limb of the aortobifemoral bypass will thrombose as a result of poor outflow.[69 – 71] In our experience, it is uncommon to require distal reconstruction at the same time as a proximal repair; however, there are some situations in which synchronous aortobifemoral and femoropopliteal grafting should be considered.[64] If the iliac disease and profunda disease are not severe by comparison to the femoropopliteal disease as assessed by clinical evaluation, noninvasive vascular

Chapter 30.

laboratory studies, biplane angiography, and intraoperative findings, proximal repair alone will not produce a good hemodynamic result. In this case, PTA of the iliac arteries is attempted if feasible. If the profunda is extensively diseased and has a poor collateral supply to the distal vascular bed, many surgeons prefer to perform a distal reconstruction rather than an extended profundaplasty of a small artery. Patients with severe distal ischemia and ulceration or gangrene may have poor collateralization from the profunda bed to the distal circulation, and concomitant distal reconstruction should be considered.[1,62] Although some surgeons argue that synchronous procedures can be carried out without an increase in morbidity or mortality, yield better long-term patency rates, and eliminate the need for subsequent distal reconstruction,[65,66] this approach cannot be recommended as routine for the average vascular surgeon.

Juxtarenal Occlusion If the thrombotic material extends up to the level of the renal arteries, the proximal clamp should be placed on the suprarenal aorta. Exposure of this area is improved if the left renal vein is retracted by vessel loops. The aortic clamp is placed in the anterior posterior direction, and the aorta is divided about 2 –3 cm below the renal arteries. When thrombotic material in this area is removed, it is essential that the surgeon clearly see each renal artery orifice and be assured that they are absolutely clear of loose debris. If necessary, the aortotomy can be extended up the anterior wall of the aorta so that this inspection can be made carefully. The trunk of the graft is cut appropriately and sutured as described above. Alternatively, the anterior aortic incision can be closed and the clamp repositioned distal to the renal arteries, thus reestablishing the renal perfusion. With an ischemic time of less than 30 minutes, postoperative renal dysfunction is rarely a problem.

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Extra-Anatomical Bypass Grafts When indicated, femorofemoral and axillobifemoral bypasses are good alternatives to aortoiliac revascularization. Femorofemoral graft is the procedure of choice if a normal donor artery is available to bypass extensive unilateral iliac disease.[77,78] Axillobifemoral bypass is justified in high-risk patients, especially those in whom a transabdominal approach is contraindicated.[79] There are certain low-risk patients in whom a transabdominal approach is contraindicated but who should be considered for a more durable procedure than axillobifemoral bypass. Baird et al.[80] described the technique of using the ascending aorta as an inflow source for revascularization to the level of the femoral arteries and have reported excellent, durable results. Alternatively, the descending thoracic aorta can be used as the inflow site.[81 – 86] The choice between these two procedures is largely dependent on personal preference. The advantage of using the descending aorta is that it is a shorter bypass, is less susceptible to kinking, and does not interfere with future abdominal or coronary surgery. However, a lateral thoracotomy is more painful than a sternotomy.

Endovascular Bypass In patients with major comorbid conditions, an endovascular procedure may be possible. A unilateral endovascular aortofemoral bypass procedure is performed using a prosthesis which is held in place at the proximal end by a Palmaz stent and is sewn into the ipsilateral outflow vessel. The procedure is completed with a standard femorofemoral reconstruction.[87] The role of this approach remains to be established when long-term results are available.

RESULTS Transfusion Transfusion can usually be avoided by careful attention to hemostasis or if a significant blood loss is anticipated by using a cell saver or encouraging the patients to donate their own blood prior to the aortic procedure.[72] Although the hemoglobin on discharge may be low, there are usually no untoward consequences. In a study comparing the postoperative hemoglobin measurements, complications, and length of stay, Kelley-Patteson et al.[73] concluded that routine use of autotransfusion was not necessary when performing an aortobifemoral bypass but that it should be used selectively.

Laparoscopic Aortobifemoral Bypass Recent experimental and human studies have demonstrated the feasibility of performing an aortobifemoral bypass using laparoscopic methods.[74 – 76] With the further development of new instruments, the technique will be able to be applied in humans with good results; however, the advantage of a laparoscopic approach over an open technique will have to be demonstrated in a carefully controlled comparative study.

In a recent meta-analysis of 23 studies, de Vries and Hunink reported a mortality rate of 3.3% for studies that started after 1975.[88] In the hands of very experienced surgeons, the perioperative mortality for aortobifemoral reconstruction is now between 2 and 3%.[1,43,44] Perioperative myocardial infarction accounts for half the deaths, and stroke, respiratory failure, or renal failure for the remainder.[44] Five years postoperatively, 25% will be dead, and 10 years postoperatively, 50%.[44,89] There is general agreement that the expected long-term patency rates of aortofemoral bypasses are excellent. From their meta-analysis, de Vries and Hunink reported that limbbased patency rates for patients with claudication were 91.0% and 86.8% at 5 and 10 years, respectively, as compared with 87.5% and 81.8% for patients with severe ischemia.[88,90 – 95] Thus, patency rates are lower if the indication for the operation is ischemic rest pain or ulceration but also the results are less satisfactory if coexisting femoropopliteal occlusive disease is present.[41] Gender does not appear to play a major factor in determining the selection of the type of aortoiliac procedure or the results of intervention. Schneider reviewed his own

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experience and the reports by other investigators and concluded that gender did not have an effect on the indications for aortoiliac surgery as assessed by clinical and hemodynamic measures of severity or on the results of reconstruction. He concluded that concerns that results of aortoiliac reconstruction would be inferior in women due to small arteries or other differences appear unfounded.[58]

COMPLICATIONS AND THEIR PREVENTION Complications of vascular surgery can be classified as systemic, local vascular, local nonvascular, or remote. The most significant complications associated with an aortobifemoral bypass are discussed below.

Systemic Complications Myocardial Infarction Patients with significant coronary artery disease can frequently be identified prior to surgery, and cardiac complications can be avoided by careful preoperative preparation, the selection of appropriate operative procedures, and careful intraoperative monitoring and postoperative care. Patients without a history of coronary artery disease and with a normal ECG have a low risk of fatal myocardial infarction and can undergo surgery without further cardiac investigation.[96] On the other hand, for patients with symptomatic coronary disease, screening by radionuclide ventriculography, dipyridamole thallium scanning, or exercise stress testing may be necessary to identify those high-risk patients who will benefit from coronary revascularization. Dipyridamole thallium imaging is very specific[97] and is our preference. Unless an exercise ECG shows evidence of severe ischemia (i.e., ST segment depression greater than 2 mm), it is a poor screening test because of its low sensitivity.[97] Furthermore, it is rarely feasible in this group of patients with disabling claudication. In spite of previous reports[98,99] angiography is not likely to prove cost-effective for screening but is indicated if the noninvasive tests are strongly positive or severe crescendo angina is present and the patient is a potential candidate for coronary repair. Patients who are suitable for coronary revascularization should have balloon angioplasty or coronary surgery performed before their elective aortofemoral bypass. The protective effect of this approach has been demonstrated.[98 – 100] Selected patients with unstable coronary artery disease and severe peripheral arterial insufficiency can undergo simultaneous coronary artery bypass grafting and peripheral arterial bypass grafting with a low mortality.[100,101] Patients who are not candidates for myocardial revascularization represent the greatest risk. Although some will tolerate aortic surgery if extensive monitoring is used to minimize the cardiac stress, in general an extra-anatomic reconstruction is preferable.

The use of a Swan-Ganz catheter aids in optimal fluid management in the perioperative period; however, the measurements may be misleading in some patients with coronary disease.[102] Preoperatively, by fluid loading and assessment of myocardial performance, the optimum preload can be determined.[103]

Stroke Patients with symptomatic internal carotid artery stenosis should have carotid artery repair before their aortoiliac surgery. However, those with an asymptomatic lesion should receive their aortoiliac repair, and carotid repair is usually delayed until symptoms occur.[104]

Pulmonary Problems Poor pulmonary function is not a contraindication to abdominal aortic surgery; however, patients with significant pulmonary disease require specific management. Careful preoperative preparation includes abstinence from smoking, chest physiotherapy, a trial of bronchodilators, and antibiotics if there is evidence of pulmonary infection. In order to reduce the incidence of pulmonary damage caused by microaggregates in stored blood, it is ideal to minimize blood administration, use blood filters, and consider an autotransfusion device. lf postoperative mechanical ventilation is necessary, the patient should be extubated early. It is important to minimize narcotic administrations, and epidural morphine may be of benefit.

Renal Problems Renal failure is rare following an aortobifemoral bypass.[105] It is likely that the same three factors that predict the risk of renal damage associated with abdominal aortic aneurysm surgery are relevant to aortobifemoral bypass.[96] Deterioration of renal function is more likely if the preoperative serum creatinine is elevated, the aorta is clamped above the renal arteries, and/or the renal vein is ligated. Since these three factors are additive, it is important to consider the risk of renal damage due to their combined effects in planning the operative procedure. Additional disposing factors include toxicity from angiographic dye, reduced intravascular volume, and atheromatous embolization.

Coagulation Complications The most common coagulopathy is dilutional after multiple transfusions when appropriate blood components are not replaced by administering fresh frozen plasma and platelets. A preexisting familial or acquired coagulopathy can be diagnosed preoperatively by routine screening with a platelet count, prothrombin time, activated partial thromboplastin time, and bleeding time. In rare patients, heparinassociated antiplatelet antibodies are produced on exposure to heparin; on reexposure to the drug during angiography or vascular surgery, bleeding may occur due to thrombocytopenia or thrombosis secondary to platelet activation.[106] In patients with heparin-associated antibodies, thromboembolic complications can be prevented by the administration of

Chapter 30.

aspirin 325 mg bid and dipyridamole 75 mg tid.[107] In our experience, Malayan pit viper venom (Arvin) has been used successfully as an alternative to heparin for cardiopulmonary bypass and vascular reconstructive surgery.[108]

Local Vascular Complications Graft Infection Infection of a prosthetic aortofemoral bypass is a very serious complication. Since the most likely cause is graft contamination at the time of the original operation, prevention is directed toward the perioperative period. Prophylactic antibiotic coverage preoperatively, intraoperatively, and for 48 h postoperatively has reduced the incidence to about 1%.[24,27,35,36,43,44,63,89] Generally, a cephalosporin is prescribed, but if an open wound is present in the extremity, specific antibiotic coverage is indicated based on the results of appropriate cultures. Retrograde femoral angiography may be associated with an increased incidence of positive cultures from the ipsilateral groin puncture, but there is no apparent increased incidence of graft infection.[109] In the operating room, one study showed that contamination of the prosthesis can be reduced if the surgeon changes gloves prior to the preclotting process.[110] The management of an infected graft usually involves the administration of systemic antibiotics, removal of all infected prosthetic material, and arterial reconstruction if indicated. If the infection is limited to the graft in the area of the groin and there is no bleeding, a trial of nonoperative treatment is justified, especially if the organism is of low virulence.[111 – 113] If this approach is not successful, a retroperitoneal approach through clean tissue, division of the prosthetic limb near its origin, and extraction of the distal portion via the groin is required. The native groin arteries are closed with a monofilament suture or an autogenous patch, if necessary, and the wound is allowed to granulate. If the viability of the limb is threatened, an extra-anatomic bypass through clean tissue is indicated— from the axillary artery, the contralateral femoral artery, or the ipsilateral or contralateral limb of the bifurcation graft via the obturator foramen. When an infection involves the body of the graft and both limbs, complete removal of the prosthesis is necessary. Although aortoiliac endarterectomy and patch grafts may be possible, usually an axillary graft must be taken to the distal profunda, superficial femoral, or popliteal artery.[32,40] In situ replacement with autogenous superficial femoral veins is an important current approach for patients with extensive aortic prosthetic infection.[114] Isolated case reports suggest that cryopreserved arterial homografts constitute a good alternative to prosthetic grafts for in situ reconstruction.[115] Groin wound debridement and coverage with a muscle flap has produced clinical salvage in selected cases, but the role of this technique in long-term salvage remains to be established.

False Aneurysm Formation Van den Akker et al.[116] report that the chance of a patient developing a false aneurysm in late follow-up after an aortoiliac or aortobifemoral bypass graft is quite high. At

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15 years, the cumulative chance of a false aneurysm is 7.7% at an aortic anastomosis. 15.5% at an iliac anastomosis, and 23.8% at a femoral anastomosis. It is likely that the current incidence is lower as the result of improved techniques, grafts, and sutures. Since most false aneurysms were asymptomatic and detected by clinical examination, ultrasound, or angiography, lifelong follow-up of patients having aortobifemoral bypass grafts is recommended. Etiologic factors include excessive graft tension, graft dilatation or degeneration, suture disruption, degeneration of the host arterial wall or primary aneurysm formation, poor suture technique with inadequate bites, or infection. Host artery degeneration appears to be the most common cause,[117,118] but graft dilatation and secondary arterial dilatation was a major cause in the series reported by Carson et al.[88,118] The etiologic importance of a low-grade infection due to organisms such as Staphylococcus epidermidis remains to be defined; however, by disrupting the graft surface biofilm using ultrasound oscillation, Kaebnick et al.[119] demonstrated a very high incidence of growth of these bacteria on prostheses removed because of a false aneurysm. Based on this evidence, it is important to culture all explanted prostheses using a technique that increases the recovery of microorganisms and to consider long-term suppressive antibiotics. Clinical factors associated with an increased incidence of false aneurysms include hypertension and multilevel progressive atherosclerotic disease.[87,117] Carson et al.[118] reported that recurrent false aneurysms are most likely due to graft dilatation with secondary arterial degeneration of the host artery, but infection due to a lowvirulence organism may be important. The importance of this latter factor is supported by Ernst et al.,[120] who noted that recurrent false aneurysms were more common in patients with previous wound complications. Since false aneurysms slowly enlarge, may rupture, and may be associated with thrombosis or distal embolization, elective surgery is indicated. In repairing a false aneurysm of the femoral anastomosis, once the inflow limb of the prosthesis is clamped, control of the groin arteries is best accomplished by intraluminal occlusion with balloon catheters. The anastomosis is revised by extension or replacement of the distal portion of the graft. False aneurysms of an aortic anastomosis are rare, irrespective of whether the anastomosis is end-to-side or end-to-end. They are usually asymptomatic and are found during investigation of a concurrent groin aneurysm. Repair is by resuture or by the replacement of at least the upper end of the graft.

Hemorrhage Hemorrhage is a complication in 1 –2%[30] and may be due to a coagulopathy or venous or arterial bleeding. A preexisting coagulopathy is detected by preoperative screening. A dilutional coagulopathy due to the administration of a large volume of stored blood is prevented by the concomitant administration of appropriate blood components. Venous injuries are avoided by employing the technique of minimal dissection. Arterial bleeding from the proximal anastomosis

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requires the placement of additional sutures, often with a felt pledget.

Deterioration of the Prosthesis Sporadic cases of generalized dilatation of the prosthesis, elongation, kinking, or localized aneurysm formation have been reported. With current prostheses, these risks are rare. However, irrespective of the type of Dacron prosthesis employed, late graft degeneration and aneurysm formation can occur because of imperfections in the Dacron- or graftmanufacturing process or damage or fracture of the fibers by improper handling by the surgeon.[121,122]

Unilateral Limb Occlusion Diagnosis of graft limb occlusion in the immediate postoperative period can be difficult in a patient with multilevel occlusive disease, since peripheral perfusion may not begin to increase for 4– 6 h and consequently the limbs remain cool and pulses are poor.[123] Graft occlusion may result from inadequate inflow, kinking or twisting of the graft, a technical error in making the distal anastomosis, or inadequate outflow. Although early thrombosis is most often due to a technical defect at the distal anastomosis and can usually be corrected by thrombectomy with Fogarty catheters and appropriate refashioning of the distal anastomosis, it is often prudent to expose the entire aortobifemoral bypass and explore it for defects. The causes of late graft occlusions are anastomotic abnormalities in about 80% (i.e., neointimal hyperplasia, false aneurysm, progressive atherosclerosis), graft infection, reduced inflow, or hypercoagulability.[124] If the occlusion is recent, the inflow can usually be reestablished through the use of Fogarty catheters.[125] An endarterectomy curette or Fogarty thrombectomy catheter is useful in removing fibrocollagenous plugs at the prosthetic bifurcation.[126] In our view, fibrinolysis has little advantage over surgical treatment since invariably it demonstrates a distal anastomotic lesion which requires repair.[124] However, others have found that the underlying cause may be amenable to endovascular treatment in a significant number of cases.[127] lf prograde flow cannot be obtained, a cross-femoral bypass is employed or the limb of the prosthesis is replaced. Outflow stenosis can usually be corrected by graft extension onto the deep femoral artery. A femoropopliteal bypass graft is indicated if the profunda is small or extensively diseased. In our experience, a distal bypass is rarely necessary, but Brewster et al.[93,125] used this approach in 32% of their reoperative cases. Although the reoperative procedures are generally difficult, the results are usually good.[63,66,89,92]

Aortoenteric Fistula A communication between a portion of the gastrointestinal tract and the aortic prosthesis or periprosthetic space is a tragic complication of intra-abdominal vascular surgery. It is more common after emergency aneurysm repair than after bypass grafting for occlusive disease.[37,38,45,46] Of such communications, 75% communicate with the duodenum, 20% to the remaining small bowel or the colon, and 5% to the

stomach or a combination of sites.[37,45] Aortoenteric fistulas result from a sterile or infected perigraft collection that drains into adjacent bowel, erosion of the mobile viscera by the fixed and pulsatile prosthetic graft, or erosion by the suture. The diagnosis must be suspected whenever an episode of GI hemorrhage or septicemia occurs in a patient with an intra-abdominal prosthetic graft. An upper GI series may show distortion of the terminal portion of the duodenum. Endoscopy may visualize the prosthesis or the site of the hemorrhage. A computed tomography (CT) scan that demonstrates air or fluid collection around the prosthesis is considered positive. White blood cell –labeled nuclear scans may localize an area of infection. An aortogram may demonstrate a false aneurysm but will only rarely show dye passing into bowel; nonetheless, it is essential for planning vascular reconstruction. Sequential cultures along the graft may reveal one consistently positive site. The standard method of treatment is removal of all the prosthetic material, closure of the hole in the bowel, and an extra-anatomic reconstruction. The overall mortality is 50– 70%,[45] therefore, attention to prevention is important. We believe that our technique of using an end-to-end anastomosis with a short stump and a high bifurcation keeps the graft in the plane of the aorta and minimizes contact with the bowel.[1,43,48] To reattach the terminal portion of the duodenum to the right of the prosthesis and thus avoid contact is rational but risks causing bowel obstruction. Graft coverage with interposition of free or attached omentum between the duodenum and the graft may minimize the complication.

Local Nonvascular Complications Lymphatic Fistula or Lymphocele The division of lymphatics during femoral arterial exposure may result in a lymphatic fistula or a lymphocele. This complication is avoided by using an incision directly over the common femoral artery or somewhat laterally, cauterizing any divided lymph nodes or lymphatics, and carefully and completely closing the groin wound in layers. The management of this problem may be conservative or operative; both approaches are aimed at stopping the leak of lymphatic fluid and preventing graft contamination. With conservative treatment, the patient is confined to bed to reduce the lymphatic flow from the leg, appropriate antibiotics are given, and a pressure dressing is applied. Most fistulas close within 2–3 weeks; however, a more aggressive surgical approach may shorten the hospital stay and reduce the chances of a wound or graft infection.[128] At reoperation, the feeding lymphatic is sutured or cauterized if it can be identified, the cavity is obliterated, and the wound is drained with suction. Operative identification of the offending lymphatic may be facilitated by preoperative intradermal injection of Evans blue dye. In our series, delayed graft infection and false aneurysm were rare following both conservative and surgical treatment.[129] It is not proven if early surgical exploration leads to more prompt healing.[130]

Chapter 30.

Sexual Dysfunction Erection involves the complex interaction of vascular, neurologic, hormonal, and psychologic mechanisms. Aortobifemoral bypass grafting may affect male sexual function by dividing the preaortic fibers of the autonomic nervous system or by reducing pelvic blood flow. The preaortic sympathetic fibers control the closure of the bladder neck during ejaculation; if they are damaged, retrograde ejaculation may result. The surgical techniques described above minimize aortic dissection and reduce the risk of injuring these nerves. Specifically, the aorta is controlled just distal to the renal arteries, and the preaortic tissue is divided longitudinally more toward the right side and is reflected toward the left, particularly in the region of the inferior mesenteric artery.[53] In the presence of severe external iliac artery occlusive disease, an end-to-end aortic anastomosis will reduce the flow to the internal iliac arteries. In this situation, an end-to-side anastomosis is preferred. By following these principles of nerve sparing and preserving pelvic blood flow, Flanigan et al.[54] demonstrated that it was possible to maintain sexual function in most patients and sometimes to improve it. In selected cases, it is possible to improve the pelvic blood flow by an internal iliac endarterectomy or an appropriate bypass graft, although there is some risk of autonomic nerve damage during the dissection.[131]

Ureteric Obstruction Ureteric obstruction and hydronephrosis and consequent urinary sepsis and renal failure may follow an aortobifemoral bypass. Obstruction may be caused by direct operative trauma to the ureter, ischemic damage, inadvertently grasping the periureteric tissue during tunneling and kinking the ureter, or the dense fibrotic reaction surrounding the prosthesis which invades the muscular wall of the ureter.[132 – 134] Care in tunneling may reduce the risk of ureteric damage. Although the ureter may be trapped by a graft placed anterior to it, this mechanism does not appear to be a major factor. Ureteric abnormalities consist of three clinical types. Early transient hydronephrosis occurs in 10 –15% of aortic cases due to edema from the dissection and is of no clinical significance, since it usually resolves.[135] Early persistent hydronephrosis is uncommon, occurring in approximately 1–2% of aortic cases.[135] Operation is necessary only for those patients who develop further complications. Wright et al.[136] clarified the pathology associated with delayedonset hydronephrosis, which occurred in 1.2%. In half the cases, delayed ureteric obstruction was due to a dense local fibrotic reaction, the etiology of which is unknown. To detect this complication during late follow-up, patients should be studied by ultrasound, CT scan, or intravenous pyelogram (IVP). The other half of the cases were associated with graft complications including thrombosis, false aneurysm, graftenteric fistula, and infection.[136,137] Thus, patients who present with ureteric complications should be investigated for associated graft complications, and, conversely, patients who present with aortic graft complications should have a full urological workup, since 5% will have an abnormality. Ureteric obstruction is treated in conjunction with a urologist and involves renal decompression, lysis of

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periureteric fibrosis, and ureteric reimplantation or repositioning of the arterial graft.

Remote Ischemic Vascular Complications Sigmoid Colon Ischemia Clinically significant ischemic colitis is observed in 1 –2% of cases but is detected by colonoscopy in 6 –7%.[138] The sigmoid colon is perfused by the inferior mesenteric artery and collateral branches from the internal iliac and the superior mesenteric arteries. Measurements by Iliopoulos et al.[139] suggest that the branches of the superior mesenteric artery provide the major collateral pathways to the inferior mesenteric artery bed. Sigmoid ischemia may result if prograde flow through a large inferior mesenteric artery is diminished by the reconstructive procedure, collateral flow is poor because of superior mesenteric artery occlusive disease, or perfusion is reduced by inadvertent dissection in the sigmoid mesocolon, operative trauma to important collateral pathways, or atheromatous emboli. If a large inferior mesenteric artery is present and will not be perfused by retrograde flow up the native circulation from the femoral level, the surgeon should consider an end-to-side aortic anastomosis with preservation of the inferior mesenteric artery or reimplantation of the vessel. However, based on clinical observations, routine reimplantation is not justified. Further, in a study of a small group of patients, pH in the sigmoid mucosa was not improved in patients who underwent inferior mesenteric artery reimplantation in comparison to those who had ligation of the artery.[140] The sigmoid colon should always be inspected before the abdomen is closed. If it appears ischemic, the origin of a patent inferior mesenteric artery can be anastomosed to the prosthesis, a direct pass to an internal artery constructed,[138] or Fogarty catheters used to ensure that there is no thrombus in the iliac arteries. If a superior mesenteric artery stenosis is present, revascularization may improve collateral flow to the colon. In the early postoperative period, left lower quadrant abdominal pain, tenderness, or bloody diarrhea require prompt diagnosis by sigmoidoscopy and early decompression or sigmoid resection is indicated, since transmural infarction is associated with a 60% mortality rate.[138] Based on data from the Swedish Vascular Registry, the authors concluded that systemic hypotension, surgical skill and decision making (namely, operating time, cross-clamp time, ligation of one or both internal iliac arteries) and patient-related factors (namely, renal disease, age) were important predictors of intestinal ischemia.[141] The complications of chronic sigmoid ischemia include fibrosis or stenosis; they may appear months to years later and require resection.

Trash Foot Atheromatous debris or loose intraluminal debris or clot formed in areas of stasis may be washed downstream during the operation. The material may shower in such a way that distal gangrene may occur even with good ankle pulses. Prevention is important and is achieved by gentle

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manipulation of the aorta prior to cross clamping and adequate flushing of the graft via open arteriotomies.

Spinal Cord and Cauda Equina Ischemia Following an aortobifemoral bypass, spinal cord or more likely cauda equina or lumbosacral plexus injury is very rare.[142 – 146] Severe hypotension, reduction of pelvic flow by interruption of internal iliac flow, or atheromatous emboli are the major etiological factors.[147] Since the cauda equina begins at the level of the LI-L2 vertebrae, injury may involve spinal roots rather than the cord, thereby producing incomplete paralysis in the distribution of peripheral nerve roots with asymmetric reduction in tendon reflexes and flexor plantar responses as well as patchy sensory loss. Lumbosacral plexus damage may produce similar but unilateral clinical findings. Usually the level of injury can be distinguished on purely clinical grounds, but in difficult cases, spinal cord

lesions may be differentiated from those of the cauda equina or lumbosacral plexus by electrophysiologic evaluation. Treatment is supportive. Although spinal cord injury is usually permanent, some patients continued to show neurologic and functional improvement for years following their injury, particularly those with incomplete deficits. If the site of damage is the cauda equina or lumbosacral plexus, the prognosis for recovery is better since the lesion involves lower motor neurons with capacity for regeneration.

CONCLUSION With proper patient selection and operative technique, gratifying long-term results are achieved by the surgical repair of aortoiliac occlusive disease.

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Ehrenfeld, W.K.; Wieber, B.C.; Olcott, C.N.; Stoney, R.J. Autogenous Tissue Reconstruction in the Management of Infected Prosthetic Grafts. Surgery 1979, 85, 82. Kalman, P.G.; Hosang, M.; Johnston, K.W.; Walker, P.M. Unilateral Iliac Disease: The Role of Iliofemoral Bypass. J. Vasc. Surg. 1987, 6, 139. Piotrowski, J.J.; Pearce, W.H.; Jones, D.N. et al. Aortobifemoral Bypass: The Operation of Choice for Unilateral Iliac Occlusion? J. Vasc. Surg. 1988, 8, 211. Baird, R.J. Techniques and Results of Arterial Prosthetic Bypass for Aortoiliac Occlusive Disease. Can. J. Surg. 1982, 25, 476. Crawford, E.S.; Bomberger, R.A.; Glaeser, D.H. et al. Aortoiliac Occlusive Disease: Factors Influencing Survival and Function Following Reconstructive Operation Over a 25 Year Period. Surgery 1981, 90, 1055. Perdue, G.D., Jr.; Smith, R.B., III.; Ansky, J.D.; Costantino, M.J. Impending Aortoenteric Hemorrhage: The Effect of Early Recognition on Improved Outcome. Surgery 1980, 192, 237. Baird, R.J.; Garry, J.F.; Kellam, J.F.; Wilson, D.R. Abdominal Aortic Aneurysms: Recent Experience with 210 Patients. Can. Med. Assoc. J. 1978, 118, 1229. Pierce, G.E.; Turrentine, M.; Stringfield, S. et al. Evaluation of End-to-Side v End-to-End Proximal Anastomosis in Aortobifemoral Bypass. Arch. Surg. 1982, 117, 1580. Dunn, D.A.; Downs, A.R.; Lye, C. Aortoiliac Reconstruction for Occlusive Disease: Comparison of End-to-End and End-to-Side Proximal Anastomoses. Can. J. Surg. 1982, 25, 382. Madiba, T.E.; Mars, M.; Robbs, J.V. Choosing the Proximal Anastomosis in Aortobifemoral Bypass. Br. J. Surg. 1997, 84, 1416– 1418. Melliere, D.; Labastie, J.; Becquemin, J.P. et al. Proximal Anastomosis in Aortobifemoral Bypass: End-to-End or End-to-Side? J. Cardiovasc. Surg. 1990, 31, 77. Valentine, R.J.; Duke, M.L.; Inman, M.H.; Grayburn, P.A.; Hagino, R.T.; Kakish, H.B.; Clagett, G.P. Effectiveness of Pulmonary Artery Catheters in Aortic Surgery: A Randomized Trial, 1998. Rosenbaum, G.J.; Arroyo, P.J.; Sivina, M. Retroperitoneal Approach Used Exclusively with Epidural Anesthesia for Infrarenal Aortic Disease. Am. J. Surg. 1994, 168, 136– 139. DePalma, R.G.; Levine, S.B.; Feldman, S. Preservation of Erectile Function After Aortoiliac Reconstruction. Arch. Surg. 1978, 113, 958. Flanigan, D.P.; Schuler, J.J.; Keifer, T. et al. Elimination of Iatrogenic Impotence and Improvement of Sexual Junction After Aortoiliac Revascularization. Arch. Surg. 1982, 117, 544. Robicsek, F.; Duncan, G.D.; Anderson, C.E. et al. Indium III-Labeled Platelet Deposition in Woven and Knitted Dacron Bifurcated Aortic Grafts with the Same Patient as a Clinical Model. J. Vasc. Surg. 1987, 5, 833. Robicsek, F.; Daughtery, H.K.; Cook, J.C. et al. Patency Rate of Bifurcated Aortic Grafts: Comparative Analysis of Woven Versus 69, Knitted Prostheses in the Same Patient. Ann. Thorac. Surg. 1985, 40, 172.

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Part Four. Peripheral Occlusive Disease Optimal Methods and Long-Term Results. J. Vasc. Surg. 1987, 5, 363. Ernst, C.B.; Daughterly, M.E. Removal of a Thrombotic Plug from an Occluded Limb of an Aortofemoral Graft. Arch. Surg. 1978, 113, 301. Enon, B.; Reigner, B.; Lescalie, F.; Hoste, P.; Peret, M.; Chevalier, J.M. In Situ Thrombolysis for Late Occlusion of Suprafemoral Prosthetic Grafts. Ann. Vasc. Surg. 1993, 7, 270–274. Kwann, I.; Bernstein, J.; Connolly, J. Management of Lymph Fistula in the Groin After Arterial Reconstruction. Arch. Surg. 1979, 114, 1416. Kalman, P.G.; Walker, P.M.; Johnston, K.W. Consequences of Groin Lymphatic Fistulae After Vascular Reconstruction. Vasc. Surg. 1991, 25, 210. Tyndall, S.H.; Shepard, A.D.; Wilczewski, J.M.; Reddy, D.J.; Elliott, J.P.J.; Ernst, C.B. Groin Lymphatic Complications After Arterial Reconstruction. J. Vasc. Surg. 1994, 19, 858– 863. Flanigan, D.P.; Sobinsky, K.R.; Schuler, J.J. et al. Internal Iliac Artery Revascularization in the Treatment of Vasculogenic Impotence. Arch. Surg. 1985, 120, 271. Frusha, I.D.; Porter, J.A.; Batson, R.C. Hydronephrosis Following Aorto-Femoral Bypass Grafts. J. Cardiovasc. Surg. 1982, 23, 371. Barber, N.J.; Emberton, M.; Das, G.; Derodra, J. Symptomatic Unilateral Hydronephrosis: A Late Complication of Aortobifemoral Bypass Graft Surgery. Eur. J. Vasc. Endovasc. Surg. 1997, 13, 419– 420. Bastounis, E.; Papastamatiou, M.; Picoulis, E.; Balas, P. Obstructive Uropathy, Following Redo Aortobifemoral Bypass Surgery. Int. Angiol. 1994, 13, 343– 346. Goldenberg, S.L.; Gordon, P.B.; Cooperberg, P.L.; McLouglin, M.G. Early Hydronephrosis Following Aortic Bifurcation Graft Surgery: A Prospective Study. J. Urol. 1988, 140, 1367. Wright, D.J.; Ernst, C.B.; Evans, J.R. et al. Ureteral Complications and Aortoiliac Reconstruction. J. Vasc. Surg. 1990, 11, 29.

137. Schubart, P.; Fortner, G.; Cummings, D. et al. The Significance of Hydronephrosis After Aortofemoral Reconstruction. Arch. Surg. 1985, 120, 377. 138. Zelenock, G.B.; Strodel, W.E.; Knot, J.A. et al. A Prospective Study of Clinically and Endoscopically Documented Colonic Ischemia in 100 Patients Undergoing Aortic Reconstructive Surgery with Aggressive Colonic and Direct Pelvic Revascularization, Compared with Historic Controls. Surgery 1989, 106, 771. 139. Iliopoulos, J.I.; Pierce, G.E.; Hennreck, A.S. et al. Hemodynamics of the Inferior Mesenteric Arterial Circulation. J. Vasc. Surg. 1990, 11, 120. 140. Kuttila, K.; Perttila, J.; Vanttinen, E.; Niinikoski, J. Tonometric Assessment of Sigmoid Perfusion During Aortobifemoral Reconstruction for Arteriosclerosis. Eur. J. Surg. 1994, 160, 491– 495. 141. Bjorck, M.; Troeng, T.; Bergqvist, D. Risk Factors for Intestinal Ischaemia After Aortoiliac Surgery: A Combined Cohort and Case-Control Study of 2824 Operations. Eur. J. Vasc. Endovasc. Surg. 1997, 13, 531– 539. 142. Dunki, J.P.B.; Dicke, H.W. Ischemic Damage to the Spinal Cord Following Surgery of the Abdominal Aorta. Neth. J. Surg. 1984, 36, 1. 143. Paaschburg, N.B. Ischemic Injury to the Spinal Cord as a Complication to Abdominal Aortic Surgery. Acta Chir. Scand. 1985, 151, 433. 144. Friedman, S.G.; Moccio, C.G. Spinal Cord Ischemia Following Elective Aortoiliac Reconstruction. Ann. Vasc. Surg. 1988, 2, 295. 145. Sutton, J.; Nesbit, R.R., Jr. Spinal Cord Ischemia Following Surgery for Aortoiliac Occlusive Disease. J. Vasc. Surg. 1984, 1, 697. 146. Plecha, E.J.; Seabrook, G.R.; Freischlag, J.A.; Towne, J.B. Neurologic Complications of Reoperative and Emergent Abdominal Aortic Reconstruction. Ann. Vasc. Surg. 1995, 9, 95– 101. 147. Picone, A.L.; Green, R.M.; Ricotta, J.R. et al. Spinal Cord Ischemia Following Operations on the Abdominal Aorta. J. Vasc. Surg. 1986, 3, 94.

CHAPTER 31

Femoral-Popliteal-Tibial Occlusive Disease Frank J. Veith Evan C. Lipsitz or occlusion occurs in one or more of the arteries below the inguinal ligament. As the average age of our population increases, the number of individuals with this hemodynamically significant infrainguinal arteriosclerosis also increases. This chapter deals with the present status of treatment for arteriosclerotic occlusive disease of the femoral, popliteal, and tibial arterial systems. Obviously, this disease is associated in varying degrees with arteriosclerotic involvement elsewhere in the body, and this fact must constantly be considered when one is making therapeutic decisions in afflicted patients. Frequently, it is this consideration that guides those caring for the patient to correctly seek palliation rather than cure and to attempt a lesser intervention or operation that maintains function rather than one that will restore a normal circulation. The generalized and slowly progressive nature of the disease process and the imperfect results of all interventional treatments should also deter any who might be unwisely tempted to treat asymptomatic or minimally disabling arteriosclerotic occlusive lesions. In the management of the increasingly common entity of infrainguinal arteriosclerosis, diagnostic and therapeutic restraint and the desire to minimize risks and avoid doing harm must be paramount considerations if the disease is not producing major functional impairment or tissue necrosis. On the other hand, despite the advanced age and poor general condition of many afflicted patients, aggressive intervention for both diagnosis and treatment is justified if limb loss is truly threatened by the disease process.

The last three decades have witnessed enormous advances in the treatment of lower-limb ischemia from infrainguinal arteriosclerosis. In the late 1960s most patients with a threatened ischemic limb were subjected to a major amputation because they had infrainguinal arterial occlusive disease, which was deemed too difficult or risky to treat. This was particularly true of diabetic patients, who were often regarded as having such advanced distal or smallartery occlusive disease that they were categorically inoperable. Although some patients were undergoing successful aortofemoral or femoropopliteal bypasses for segmental occlusive disease of the iliac or superficial femoral arteries, many of them had only intermittent claudication. Most patients with rest pain or necrosis had complex, multilevel occlusive disease in patterns that were deemed unfavorable to treat surgically, and these patients were often subjected to primary amputation. This situation has changed dramatically in the last 20 –25 years as interventional management strategies have been developed to treat virtually all patterns of arteriosclerotic disease underlying severe limb ischemia.[1] Moreover, the resulting aggressive therapeutic approach to threatening ischemia of the lower limb has proven to be effective and worthwhile.[1,2] This form of treatment has gained increasing acceptance throughout the world, even though some still question its value and cost-effectiveness.[3] Despite this residual skepticism, most vascular surgeons, most physicians, and virtually all patients acknowledge the value of the aggressive surgical and radiological approach to patients with limb-threatening ischemia. Indeed, almost all these individuals regard the advances in this field, which will be summarized in this chapter, as one of the most important positive developments that has occurred in vascular surgery in the last quarter century. Arteriosclerosis may involve the common femoral artery and its branches; the above-knee and below-knee popliteal artery; any of the infrapopliteal arteries, including their terminal branches; or any combination of these arteries. This involvement generally begins early in adult life and progresses slowly to the point where a flow-reducing stenosis

CLINICAL PRESENTATION The reserve of the human arterial system is enormous. Hemodynamically significant stenoses or major artery occlusions can exist in the infrainguinal arterial tree in patients with minimal or no symptoms. This is particularly true if collateral pathways are normal or the patient’s activity level is limited by coronary anteriosclerosis or other disease processes. Accordingly, the most common manifestation of a

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short segmental occlusion of the superficial femoral artery— the most common site of major arteriosclerotic involvement below the inguinal ligament—will be mild intermittent claudication. Similarly, this lesion will often be totally asymptomatic, and this is usually the case if only one or two tibial arteries are occluded without other significant lesions. Thus the usual patient who presents with severe disabling intermittent claudication or tissue necrosis has multiple sequential occlusions or so-called combined segment disease. Hemodynamically significant lesions at the aortoilic level and the femoral/popliteal level can occur in any combination with severe infrapopliteal disease as well.[1]

Staging Patients with hemodynamically significant infrainguinal arteriosclerosis may be classified into one of five stages, depending on their presentation, as indicated in Table 31-1. Patients in stages III and IV are those whose limbs may be considered imminently threatened, although some patients with mild ischemic rest pain may remain stable for many years and an occasional patient with a small patch of gangrene or an ischemic ulcer will heal a lesion with conservative inhospital treatment.[4] With the exception of these few patients, invasive diagnostic procedures such as angiography are easily justified for those with stages III and IV disease, which is usually associated with disease at several levels. Rest pain as an isolated symptom in patients with infrainguinal arteriosclerosis can be difficult to evaluate unless it is accompanied by other findings. Many patients with significant arterial lesions have pain at rest from causes other than their arteriosclerosis, such as arthritis or neuritis. Such pain will not be relieved even by a successful revascularization. Significant ischemic rest pain is almost always associated not only with decreased pulses but also with other objective manifestations of ischemia, such as atrophy, decreased skin temperature when compared to the other extremity, and marked rubor and

relief of pain with dependency. In some patients whose rest pain has a complex etiology, it may be necessary to perform a noninvasive laboratory and angiographic evaluation before the predominant cause can be determined and appropriate treatment instituted. Every patient with pain at rest and decreased pulses is not a candidate for angiography and an interventional arterial procedure. Some of these patients will be relieved by appropriate treatment for gout or osteoarthritis. Others can be well managed with simple analgesics and reassurance that their limb is not in jeopardy. Such reassurance generally suffices for patients with stage I disease and those with stage II disease who are elderly (over age 80) or at high risk because of intercurrent disease or atherosclerotic involvement of other organs such as the heart, kidneys, or brain. This conservative approach to patients with stage I involvement from infrainguinal arteriosclerosis is becoming increasingly widespread, albeit not universally so.[5] Conservatism appears to be clearly justified by the numerous reports of the benignity and slow progression of stage I disease to more advanced stages.[6 – 8] Only 1% of claudicators per year will develop a threatened limb. Moreover, without treatment, 10–15% of patients in stage I will improve over 5 years, and 60–70% will not progress over the same period. The 10–15% who do worsen are, in our opinion, best treated with a primary operation or other therapeutic intervention after their disease progresses. We further believe that this conservative approach to stage I disease is justified by the greater surgical difficulty encountered when a procedure for claudication fails in the early or remote postoperative period and the patient then has a threatened limb, a situation that we have been presented with all too frequently. The fact that some patients in stage II and a few in stage III or IV may remain stable and easy to manage without operation for protracted periods of 1 or more years justifies a cautiously conservative nonoperative approach to selected patients in these stages.[4] This often requires a careful evaluation and frequent visits to the physician so that the patient and the progression of ischemia can be assessed.

Staging of Infrainguinal Arteriosclerosis with Hemodynamically Significant Stenosis or Occlusions

Table 31-1.

Stage 0 I

II

III

IV

Presentation No signs or symptoms Intermittent claudication (. 1 block) No physical changes Severe claudication (, 1/2 block) Dependent rubor Decreased temperature Rest pain Atrophy, cyanosis Dependent rubor Nonhealing ischemic ulcer or gangrene

Invasive diagnostic and therapeutic intervention Never justified Sometimes justified Not always necessary May be stable or improve Often justified Not always necessary May remain stable Usually indicated but may do well for long periods without revascularization Usually indicated

Chapter 31.

Moreover, this conservative nonoperative approach is particularly indicated if the patient is elderly and a poor surgical risk from a systemic or anatomical point of view. An example of this would be an octogenarian with intractable congestive heart failure in whom a difficult distal small-vessel bypass would be required to alleviate stage III signs and symptoms. Close observation can and often should be the preferred management for such a patient for several months or even years; however, we would not hesitate to revascularize such a patient when his rest pain became intolerable or he developed a small patch of gangrene.[1,2]

Impact of Newer Interventional Treatments on Threshold for Therapy The relative simplicity of percutaneous balloon angioplasty alone or in combination with other new endovascular treatments (atherectomy devices, stents, or endovascular grafts) to recanalize arteries with arteriosclerotic plaque has prompted some physicians to recommend lowering the therapeutic thresholds for treatment of infrainguinal arteriosclerosis. Some surgeons, radiologists, and particularly cardiologists new to the peripheral vascular field, armed with these new techniques and devices, have used them routinely to treat stage I and even stage 0 disease detected incidentally during physical examination or arteriography. This practice is to be condemned at this time for many reasons.[9] Most importantly, except for simple balloon angioplasty, the mid- and long-term results of these newer treatments remain largely unknown. Even if they are successful immediately, they can initiate a healing process in the artery that causes late failure or, worse, an acceleration of the occlusive process and ultimately net harm to the patient. Therefore, they subject patients to risks they may not fully appreciate. Although these newer high-tech treatments are exciting and interesting to patients and doctors alike and although they may prove to be safe and effective, this has not yet been shown. Accordingly, although balloon angioplasty may be used when an operation would not, there is otherwise little justification as yet to lower the threshold for intervening in patients with infrainguinal arteriosclerosis. This fact should be communicated freely to patients to offset the unjustified marketing efforts of uninformed practitioners.

Differential Diagnosis Intermittent claudication, or pain brought on by exertion and relieved by rest, is a fairly distinct symptom and usually a manifestation of arteriosclerotic occlusive disease, although mild calf claudication can be produced by a significant stenotic lesion in the iliac, superficial femoral, or popliteal artery. An occasional patient will describe claudication as a sense of heaviness, weakness, or fatigue in the limb without pain, and such patients may be mistakenly diagnosed as having neuromuscular disorders. Sometimes claudication-like symptoms can be produced by lesions compressing the lower spinal cord or cauda equina.[10,11] Such pseudoclaudication is most often produced by spinal stenosis and can easily be suspected when peripheral pulses are normal. Occasionally,

Femoral-Popliteal-Tibial Occlusive Disease

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neurologic problems will coexist with arterial occlusive disease, making an exact determination of the cause of the patient’s symptoms a difficult challenge for the neurologist and the vascular surgeon. In such circumstances, angiography, computed tomography (CT), or magnetic resonance imaging (MRI) of the lumbar spine may be necessary. Some of the difficulties that can be encountered in differentiating pain at rest from true ischemic rest pain have already been discussed. Again, these difficulties are greatest when arterial occlusive disease coexists with other pathology. Similar difficulties can be encountered in determining the primary cause of ulcerating lesions in the ankle region and on the foot. The typical venous ulcer is easy to recognize. It occurs in a setting of chronic venous disease, is associated with stasis changes and normal arterial pulses, is usually relatively painless, and heals with leg elevation and compressive measures. The typical arterial or ischemic ulcer is far more painful and is often associated with other manifestations of ischemia. It usually has a more necrotic base and is located at an area of chronic pressure or trauma, such as over the mallcoli or the bunion area. It can also occur between the toes. Both conditions may be improved by hospitalization, bed rest, and local care. Ulcer differentiation is usually only difficult when chronic venous and arterial disease coexist. Noninvasive arterial and venous evaluation with duplex scanning and even arteriography may be required. In some patients the primary cause of the ulcer can only be determined when arterial reconstruction produces healing after a period of intense conservative management has failed to do so. When a patient presents with a gangrenous (black) or pregangrenous (blue) toe, several etiologies other than progression of chronic arteriosclerotic occlusive disease must be considered. Local infection can be the sole or a contributing cause of the toe lesion. This is particularly common in diabetics. If foot pulses or noninvasive tests of arterial perfusion are normal, the gangrenous condition can be presumed to result from local thrombosis secondary to infection. Radical local excision and drainage of all involved tissue will usually result in a healed foot. Diagnosis is more difficult when infection coexists with arterial occlusive disease. Noninvasive studies and arteriography are usually required before it can be determined whether treatment should consist of excision and drainage alone or combined with an arterial reconstruction. The decisions to be made under these conditions can be very difficult. Black or blue toes may also develop as the result of embolic phenomenon. Such emboli may originate from the heart, a proximal aneurysm, or any proximal atherosclerotic lesion. In the latter circumstance, small cholesterol, platelet, or fibrin emboli may lodge in interosseous or digital arteries. Peripheral pedal pulses may be normal, and spontaneous improvement of the resulting blue toe often occurs. This sequence of events has been termed the “blue toe syndrome,” and its pathogenesis is thought to be analogous to that of transient ischemic attacks from atherosclerotic disease at the carotid bifurcation.[12] If a single dominant large-artery lesion can be identified by angiography, it should be treated by endarterectomy or more commonly by an appropriate bypass. However, in our experience it has been difficult to identify a single lesion in the arterial tree of many of these patients, and

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Part Four. Peripheral Occlusive Disease

we have usually operated on them only after they have had several embolic episodes. In any patient whose ischemia developed suddenly, the possibility of a major embolus from the heart or from a proximal aneurysm must be considered. In such circumstances, angiography is indicated even if limb viability is not in question, since major emboli should be removed or lysed as soon as they are identified. In the last several decades, with improvements in cardiac surgery for rheumatic heart disease, major arterial emboli and acute arterial occlusions in almost all such patients that we have seen have been superimposed on extensive arteriosclerosis. Even with arteriography, which we employ routinely in such cases, the diagnosis and treatment of embolic disease is difficult and the results are imperfect.[13] The only certain diagnostic feature of an embolus is multiplicity. Furthermore, the location of the embolus may be atypical, and the vascular surgeon treating a presumed embolus in the presence of extensive arteriosclerosis must be prepared to perform an extensive arterial reconstruction or bypass even if the operation is undertaken soon after the acute event.[13] Because of these facts and because acute thrombosis sometimes cannot be differentiated in any way from an embolus, complete preoperative arteriography should be mandatory in any suspected embolic occlusion of the lower extremity in a patient who could have arteriosclerosis. Exploration of the distal popliteal artery is usually the best surgical approach in patients with severe ischemia due to an acute occlusion of the popliteal or distal superficial femoral arteries.[14] The use of intraarterially administered lytic agents, particularly urokinase, may have significant therapeutic advantages in the management of acute thromboembolic occlusions of lower-extremity arteries, especially those with some underlying atherosclerosis.[15] Moreover, the care and surgical treatment of such cases should be undertaken only by an experienced vascular surgeon. A more complete discussion of the management of acute thromboembolic arterial occlusions appears in Chaps. 27 and 28.

PATIENT EVALUATION Local Factors and Physical Examination of the Extremity As already indicated, the findings on physical examination of the involved extremity contribute to the staging of the atherosclerotic process and provide a rough guide to whether or not diagnostic or therapeutic intervention is justified. Physical examination, by revealing discoloration and swelling, should also provide evidence of the presence and extent of infection in the involved foot. As a general rule, the extent of infection and necrosis deep to the skin is greater than one might expect from an examination of the skin. Reexamination after a short period of soaking to soften the epidermis and dried exudate may also be helpful in revealing purulent collections and subcutaneous necrosis. Exploration of suspicious areas can sometimes be carried out without anesthesia if the patient has diminished sensation from diabetic neuropathy. If not, such exploration and necessary

debridement should be performed in the operating room under anesthesia. In the initial examination of a patient with suspected infrainguinal arterial disease, careful inspection for previous operative scars is essential, since patients may be unaware of a prior sympathectomy or the nature and extent of previous arterial surgery. The site of scars can provide clues as to whether the arteries below the knee were used, whether the ipsilateral saphenous vein was utilized, and, if so, how much is left. Physical examination can also provide evidence of associated chronic disease. In evaluating an ischemic limb, particular attention must be given to careful inspection of the heel and the area between the toes, where unsuspected ischemic ulcers or infection may be present. A flashlight is extremely helpful in this regard. The uninvolved extremity must also be