Clinical Approach to Sudden Cardiac Death Syndromes

Clinical Approach to Sudden Cardiac Death Syndromes

Ramon Brugada (Ed.)

Clinical Approach to Sudden Cardiac Death Syndromes

Ramon Brugada Dean, School of Medicine Director, Cardiovascular Genetics Center UdG-IDIBGi Universitat de Girona Pic de Peguera 11 17003 Girona, Catalonia, Spain

Pedro Brugada Scientific Director, Cardiovascular Division Head, Heart Rhythm Management Centre Free University of Brussels (UZ Brussel) VUB Laarbeeklaan 101 1090 Brussels. Belgium

Josep Brugada Medical Director Hospital Clínic Universitat de Barcelona Villarroel 170 08036 Barcelona, Catalonia, Spain

ISBN: 978-1-84882-926-8     e-ISBN: 978-1-84882-927-5 DOI: 10.1007/978-1-84882-927-5 Springer London Dordrecht Heidelberg New York Library of Congress Control Number: 2009938027 © Springer-Verlag London Limited 2010 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is ­concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer. Violations are liable to prosecution under the German Copyright Law. The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant ­protective laws and regulations and therefore free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature. Cover design: eStudio Calamar, Figueres/Berlin Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)

Preface

Much has changed in the field of arrhythmias and sudden cardiac death in these last decades. Successful innovative catheter therapies and protective devices have been determinant in enhancing treatment and prevention strategies of individuals at risk. However, despite the advances, sudden cardiac death still remains a major contributor to mortality in our society. While most deaths occur in adult cases and are associated with ischemic heart disease, occasionally the youngest and the fittest, even those who have become our role models for their athletic abilities, may also die suddenly, usually from noncoronary cardiac causes. It has not been until the advent of molecular biology and genetics in cardiology when we have been able to further deepen in our knowledge of these dreadful events in the young. In the last 20 years, genetic research in subjects and families with sudden cardiac death syndromes has brought a vast amount of information on genetic defects responsible for arrhythmogenesis, improving our understanding on how the abnormally codified proteins are involved in the pathogenesis of a disease and how this protein disrupts the myocyte electrical activity, generates a chaotic rhythm, and predisposes to ventricular fibrillation. Inherited sudden cardiac death syndromes are indeed rare diseases, much rarer than hypertension or coronary artery disease. However, it is highly likely that as physicians we will at some point encounter a patient with one of these genetic diseases, and we have to be aware of at least two clinical implications. First, the field of cardiac genetics has brought a new tool, genetic screening, which is presently standing out as a key diagnostic test, complementing the highly sophisticated, but often inaccurate, clinical instruments. With the use of genetic information in our practice, we have moved the information from the bench to the bedside, from research to clinical care, translational medicine at its best. Second, cardiac genetics is also bringing a fundamental change for our clinical practice, which is not to be taken lightly. With the care for patients with inherited arrhythmias, we have gone from facing the single patient to facing the family, from one individual with signs and symptoms of a disease to several family members with a genetic defect. Familial global care is a tremendous and complex new task that includes genetic screening, treatment decisions especially difficult in children, childbearing choices, disease expression, and genetic penetrance. The family, with all its complexity, cannot be assumed by the lone physician but only by a multidisciplinary team of geneticists, cardiologists, psychologists, and genetic counselors. Most cardiologists already appreciate that there is more to the sudden death of a young individual than just “natural” causes. Genetic information is changing the way we approach medical care in this genomic era. With this book, our goal is to provide v

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Preface

the latest information on sudden cardiac death and genetic syndromes, with the aim to guide the physician in this complex field.

Ramon, Josep and Pedro Brugada

Acknowledgments

A la nostra germana A la nostra família A totes les famílies

To our sister, to our family, to all families.

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Contents

Part I  Sudden Unexplained Death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1

  1 Sudden Unexplained Death in the Community . . . . . . . . . . . . . . . . . . . Sumeet S. Chugh, Carmen Teodorescu, Audrey Evanado, and Kyndaron Reinier

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  2 Sudden Infant Death Syndrome: Gene–Environment Interactions . . . . Carl E. Hunt, and Fern R. Hauck

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Part II  Arrhythmias and sudden cardiac death.     The initial investigation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   3 Unexplained Syncope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Carlos A. Morillo and Víctor Expósito-García   4 Arrhythmias and Sudden Cardiac Death in Adult Congenital Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Paul Khairy

23 25

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  5 Endurance Sport Practice and Arrhythmias . . . . . . . . . . . . . . . . . . . . . Eduard Guasch and Lluís Mont

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  6 Electrocardiograms Not to Miss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Andres Perez-Riera

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  7 Sudden Cardiac Death in Forensic Pathology . . . . . . . . . . . . . . . . . . . . Antonio Oliva and Vincenzo L. Pascali

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Part III  Cardiac genetic syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111   8 Genetic Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 Marie-Pierre Dubé and John Rioux   9 The Long QT Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 Ramon Brugada and Oscar Campuzano 10 Brugada Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131 Begoña Benito, Ramon Brugada, Josep Brugada, and Pedro Brugada ix

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11 Short QT Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 Christian Wolpert, Christian Veltmann, Rainer Schimpf, and Martin Borggrefe 12 Catecholaminergic Polymorphic Ventricular Tachycardia . . . . . . . . . . 157 M. Juhani Junttila, Olli Anttonen, and Heikki V. Huikuri 13 Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia . . . . . 163 Michela Bevilacqua, Federico Migliore, Cristina Basso, Gaetano Thiene, and Domenico Corrado, 14 Atrial Fibrillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 Oscar Campuzano and Ramon Brugada 15 Dilated Cardiomyopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179 Michelle S. C. Khoo, Luisa Mestroni, and Matthew R. G. Taylor 16 Hypertrophic Cardiomyopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191 A. J. Marian 17 Genetic Lipoprotein Disorders and Cardiovascular Disease . . . . . . . . 203 Khalid Alwaili, Khalid Alrasadi, Zari Dastani, Iulia Iatan, Zuhier Awan, and Jacques Genest 18 A Systematic Approach to Marfan Syndrome and Hereditary Forms of Aortic Dilatation and Dissection . . . . . . . . . . . . . . . . . . . . . . . 223 Peter N. Robinson and Yskert von Kodolitsch 19 Inherited Metabolic Diseases: Emphasis on Myocardial Disease and Arrhythmogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 Eduardo Back Sternick 20 Clinical Genetics in Congenital Heart Disease . . . . . . . . . . . . . . . . . . . . 259 Georgia Sarquella Brugada and Gregor Andelfinger Part IV  Polygenic cardiovascular genetics . . . . . . . . . . . . . . . . . . . . . . . . . 271 21 Pharmacogenomics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273 Simon de Denus, Michael Phillips, and Jean-Claude Tardif 22 Polygenic Studies in the Risk of Arrhythmias . . . . . . . . . . . . . . . . . . . . 289 Moritz F. Sinner and Stefan Kääb 23 The Genetic Challenge of Coronary Artery Disease . . . . . . . . . . . . . . . 297 Robert Roberts, George Wells, and Li Chen

Contents

Contents

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Part V  Ethical, legal and Social implications . . . . . . . . . . . . . . . . . . . . . . . 309 24 Psychological Implications of Genetic Investigations . . . . . . . . . . . . . . 311 April Manuel, Fern Brunger, and Kathy Hodgkinson 25 Participation in Recreational Sports for Young Patients with Genetic Cardiovascular Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . 317 Barry J. Maron 26 Genetic Counseling in Cardiovascular Conditions . . . . . . . . . . . . . . . . 327 Laura Robb Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337

Contributors

Khalid Alrasadi  Medical Biochemistry, McGill University, Royal Victoria Hospital, Montreal, QC, Canada H3A 1A1 Khalid Alwaili  Medical Biochemistry, McGill University, Royal Victoria Hospital, Montreal, QC, Canada H3A 1A1 G. Andelfinger  Department of Pediatrics, CHU Sainte Justine, University of Montreal, Montreal, QC, Canada H3A 1A1 Olli Anttonen  Department of Cardiology, Päijät Häme Central Hospital, Lahli, Finland Zuhier Awan  Medical Biochemistry, McGill University, Royal Victoria Hospital, Montreal, QC, Canada H3A 1A1 Eduardo Back Sternick  Arrhythmia and Electrophysiology Unit, Biocor Instituto, Nova Lima, Minas Gerais, Brazil [email protected] Cristina Basso  Department of Cardiac, Division of Cardiology, Thoracic and Vascular Sciences and Cardiovascular Pathology, University of Padua, Padova, Italy Begoña Benito  Research Center, Montreal Heart Institute, 5000 Rue Belanger Montreal, H1T 1C8 Canada Michela Bevilacqua  Department of Cardiac, Division of Cardiology, Thoracic and Vascular Sciences and Cardiovascular Pathology, University of Padua, Padova, Italy Martin Borggrefe  Department of Medicine – Cardiology, University Hospital Mannheim, Mannheim 68167, Germany Josep Brugada  Department of Cardiology, The Thorax Institute, Hospital Clinic of Barcelona, Barcelona, Spain Pedro Brugada  Heart Rhythm Management Centre, Cardiovascular Institute, UZ Brussel, VUB Brussels, Belgium Ramon Brugada  Cardiovascular Genetics Center UdG-IDIBGi, School of Medicine, University of Girona, Girona, Spain [email protected] Fern Brunger  Memorial University of Newfoundland, St. John’s, Newfoundland, Canada A1B 3V6

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Oscar Campuzano  Cardiovascular Genetics Center, UdG-IDIBGI, Girona, Spain [email protected] Li Chen  Cardiovascular Research Methods Centre, University of Ottawa Heart Institute, Ottawa, ON, Canada K1Y 4W7 Sumeet S. Chugh  Associate Director, the Heart Institute, Cedars-Sinai Medical Center, Los Angeles CA, USA 90048. [email protected] Francis Collins  National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20894, USA Domenico Corrado  Professor of Cardiovascular Medicine, Department of Cardiac, Thoracic and Vascular Sciences, University of Padua Medical School, Via Giustiniani, 2 35121Padua, Italy [email protected] Zari Dastani  Human Genetics, McGill University, Montreal, QC, Canada H3A 1A1 Simon de Denus  Université de Montréal, Montreal Heart Institute, Montreal, QC, Canada H3A 1A1 [email protected] Marie-Pierre Dubé  Department of medicine, Montreal Heart Institute Research Center, and Université de Montréal, 5000, Bélanger, Montreal, QC, Canada H1T1C8 [email protected] Víctor Expósito-García  Universitary Hospital “Marqués de Valdecilla,” Santander – Cantabria, Spain Audrey Evanado  Cardiac Arrhythmia Center, Division of Cardiovascular Medicine, Oregon Health Sciences University, Portland, OR 97239, USA Jacques Genest  Division of Cardiology, McGill University, Royal Victoria Hospital, 687 Pine Avenue West, Montreal, QC, Canada H3A 1A1 [email protected] Eduard Guasch  Department of Cardiology, Thorax Institute, Hospital Clinic, University of Barcelona, Barcelona, Spain Fern R. Hauck  University of Virginia, Charlottesville, VA 22903, USA Kathy Hodgkinson  Clinical Epidemiology Unit, Memorial University, St. John’s, Newfoundland, Canada A1B 3V6 Heikki V. Huikuri  Department of Medicine, Institute of Clinical Medicine, University of Oulu, Oulu, Finland [email protected] Carl E. Hunt  Uniformed University of the Health Sciences, 4550 North Park Avenue, Suite 405, Chevy Chase, MD 20815, USA [email protected] [email protected] Lulia Latan  Biochemistry, McGill University, Montreal, QC, Canada H3A 1A1

Contributors

Contributors

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Juhani M. Junttila  Department of Medicine, Institute of Clinical Medicine, University of Oulu, PO Box 5000, Oulu 90014, Finland [email protected] Stefan Kääb  Ludwig-Maximilians University Klinikum Grosshadern, Medizinische Klinik und Poliklinik I, Marchioninistrasse 15, Munich 81377, Germany [email protected] Paul Khairy  Montreal Heart Institute, University of Montreal, Montreal, QC, Canada H3A 1A1 [email protected] Michelle S. C. Khoo  University of Colorado Denver, 12401 East 17th. Avenue, Leprino Building, Room 559, Aurora, CO 80045, USA [email protected] Yskert von Kodolitsch  Abteilung Kardiologie, Universitaires Herzzentrum, UKE, Martinistrasse 52, 20246 Hamburg, Germany April Manuel  Memorail University of Newfoundland and Labrador, St. John’s, Newfoundland, Canada A1B 3V6 [email protected] A. J. Marian  Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, 6770 Bertner Street, Texas Heart Institute at St. Luke’s Episcopal Hospital, DAC 900A, Houston, TX 77030, USA [email protected] Barry J. Maron  The Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, 920 E. 28th Street, Suite 620, Minneapolis, MN 55407, USA [email protected] Luisa Mestroni  Electrophysiology Division, Medicine/Cardiology, University of Colorado Denver, Aurora, CO 80909, USA Federico Migliore  Department of Cardiac, Division of Cardiology, Thoracic and Vascular Sciences and Cardiovascular Pathology, University of Padua, Padova, Italy Lluís Mont  Thorax Institute, Department of Cardiology, Hospital Clinic, University of Barcelona, Villarroel 170, Barcelona 08036, Spain [email protected] Carlos A. Morillo  Department of Internal Medicine, Cardiology Division, McMaster University, Hamilton Health Sciences, HGH-McMaster Clinic 5th Floor, 237 Barton Street East, Hamilton, ON, Canada L8L2X2 [email protected] Antonio Oliva  Institute of Forensic Medicine, Catholic University, School of Medicine, Rome, Italy [email protected] Vincenzo L. Pascali  Institute of Forensic Medicine, Catholic University, School of Medicine, Rome, Italy

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Andres Perez Riera  Electro-Vectocardiography, ABC Foundation, São Paulo, Brazil [email protected] Michael Phillips  The Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA Kyndaron Reinier  Cardiac Arrhythmia Center, Division of Cardiovascular Medicine, Oregon Health Sciences University, Portland, OR 97239, USA John Rioux  Department of medicine, University of Montreal, Montreal Heart Institute, 5000 Bélanger, Montreal, QC, Canada H1T1C8 Laura Robb  Cardiovascular Genetic Centre, Montreal Heart Institute, Montreal, QC, Canada H3A 1A1 [email protected] Robert Roberts  Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON, Canada K1Y 4W7 [email protected] Peter N. Robinson  Institut für Medizinische Genetik, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany [email protected] Georgia Sarquella-Brugada  Department of Pediatrics, CHU Sainte Justine, University of Montreal, Montreal, QC, Canada H3A 1A1 Rainer Schimpf  Department of Medicine – Cardiology, University Hospital Mannheim, Mannheim 68167, Germany Moritz F. Sinner  Ludwig-Maximilians University Klinikum Grosshadern, Medizinische Klinik und Poliklinik I, Marchioninistrasse 15, Munich 81377, Germany [email protected] Jean-Claude Tardif  University of Montreal/Montreal Heart Institute, Montreal, QC, Canada H3A 1A1 Matthew R.G. Taylor  Electrophysiology Division, Medicine/Cardiology, University of Colorado Denver, Aurora, CO 80909, USA Carmen Teodorescu  Cardiac Arrhythmia Center, Division of Cardiovascular Medicine, Oregon Health Sciences University, Portland, OR 97239, USA Gaetano Thiene  Division of Cardiology, Department of Cardiac, Thoracic and Vascular Sciences and Cardiovascular Pathology, University of Padua, Padova, Italy Christian Veltmann  Department of Medicine – Cardiology, University Hospital Mannheim, Mannheim 68167, Germany George Wells  Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, ON, Canada K1Y 4W7 Christian Wolpert  Department of Medicine-Cardiology, Klinikum Ludwigsburg, Ludwigsburg, Germany [email protected]

Contributors

Part Sudden Unexplained Death

I

1

Sudden Unexplained Death in the Community Sumeet S. Chugh, Carmen Teodorescu, Audrey Evanado, and Kyndaron Reinier

With approximately 250,000 US lives lost to this condition on a yearly basis, sudden cardiac death (SCD) is a public health problem of significant magnitude.1,2 In most cases, an associated cardiac disease condition leading to the fatal event can be identified, but for a distinct subgroup of cases, SCD can remain completely unexplained.3 The postmortem examination is negative, with a structurally normal heart and no other identifiable etiologies of sudden death. Most commonly, this form of SCD is referred to as sudden unexplained death syndrome (SUDS), but other terms such as sudden arrhythmic death syndrome and idiopathic ventricular fibrillation have also been used.3-5 The vast majority of cases have some form of primary electrical disorder of the heart leading to a fatal cardiac arrhythmia. Since this syndrome mostly afflicts younger adults and there are significant limitations for predicting risk in family members who are left behind, SUDS is a devastating manifestation of heart disease.6 The goal of this review is to discuss the magnitude of the problem, age-and gender-related prevalence, diagnostic considerations, and clinical/research implications of these observations.

1.1 Magnitude of the Problem While these subjects constitute a small subgroup of overall SCD cases, SUDS is recognized as a distinct phenotype, frequent enough, and with implications

S. S. Chugh () Associate Director, the Heart Institute, Cedars-Sinai Medical Center, Los Angeles CA, USA, 90048 e-mail: [email protected]

significant enough, to merit serious ongoing clinical as well as investigational attention. By definition, the diagnosis of sudden cardiac arrest or death in a structurally normal heart requires detailed imaging of the heart in the survivor, or detailed postmortem examination in the nonsurvivor. With the US national percentage of survival from cardiac arrest estimated at 5%, survivors are by far in the minority. For a variety of reasons, autopsy examination rates have decreased significantly, and even among sudden death victims, these are usually performed in 5–15%. As a consequence, an accurate estimate of the community-wide magnitude of SUDS is difficult to obtain, and we have to rely on studies of cardiac arrest survivors, or autopsy series of SCD. Studies of cardiac arrest survivors have reported a »5% prevalence of SUDS.7-11 Similar observations regarding SUDS have been made from autopsy series of SCD. A 270-patient autopsy series of SCD cases from the Jesse Edwards Registry of Cardiovascular Disease reported that 256 patients (95%) had evidence of structural abnormalities, but 14 patients (5%) had structurally normal hearts.3 The mean age was 35 ± 9 years (median age, 33 years), and the majority (10 of 14) were females. Seven patients had a history of syncope, palpitations, or chest pain prior to SCD. In the remaining seven cases, sudden death was the first presentation of an illness. A detailed review of other published autopsy series identifies interesting trends related to age and gender. In general, the younger the age group, the higher the prevalence of SUDS. In two separate postmortem studies of subjects less than 35 years of age, prevalence of SUDS was 18%12 and 28%.13 The National Swedish Rattsbase study (age 15–35 years) has reported SUDS prevalence rates of 21%.14 In a retrospective study of military recruits aged 18–35 years, prevalence of SUDS was as high as 35%.15 A 30-year population-based postmortem study in Olmsted County,

R. Brugada et al. (eds.), Clinical Approach to Sudden Cardiac Death Syndromes, DOI: 10.1007/978-1-84882-927-5_1, © Springer-Verlag London Limited 2010

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Minnesota observed a 13% prevalence of SUDS among 54 young adults aged 20–40 years.16 Among age groups older than 50 years, though detailed studies have not been performed, chances are that the prevalence of SUDS will be well below 5% of overall SCD cases. Therefore, depending on the age group, SUDS prevalence can range between <5 and 35% of overall SCD cases. Bowker and colleagues performed a nationwide prospective epidemiological survey of SUDS in England (residents under the age of 65 years) using a stratified random sample of 83 of the 132 coroner’s jurisdictions in England and found that 4.1% of all ­sudden deaths were unexplained.17 This study did not evaluate all cases of SCD in the general population. Analysis was limited to cases of presumed SCD that underwent postmortem evaluation by a sampling of coroners in the UK. Acknowledging the difficulty of obtaining an accurate estimate using this methodology, Behr and coworkers used death certificate codes to estimate the annual incidence of SUDS in the UK. Among healthy individuals aged 16–64 years,4 they found the annual incidence to be 1.38/100,000 residents and postulated that this figure is likely to be an underestimate. In the ongoing, prospective Oregon Sudden Unexpected Death Study, the annual incidence of overall SCD in this population is consistently in the range of 60/100,000 residents per year.1 On the basis of these numbers, we estimate the annual incidence of SUDS in the general population to be in the range of 3/100,000 residents per year.

1.2 Relationship with Gender In the general population, males are more likely to have SCD compared to females (60% males in the Oregon Sudden Unexpected Death Study1). Similar to overall SCD, SUDS seems to have a predilection for males (mean age range 24–32 years), with the largest autopsy series reporting 63–68% of affected subjects as males.6,14 However, given the lower overall SCD rates in females, SUDS cases make up a higher proportion of SCD cases in women compared to men, particularly in younger adults. From the Edwards Registry 270-patient autopsy series of SCD, the age-group of 35–44 years consisted of 72 patients, of which 27 were women (32% of total women) and 45, men (24% of total men).18 Detailed cardiac pathologic examinations revealed

S. S. Chugh et al.

significant gender-related differences. As expected, the prevalence of associated significant coronary artery disease was lower in women vs. men (22 vs. 40%) in this age group. However, there was a significantly high rate of SUDS in these younger women. Following detailed autopsy, cardiac pathologic examination, and analysis of available clinical findings, 50% of women had SCD of undetermined etiology compared to 24% of men.18 In a separate study of even younger women, clinical information was reviewed for 852,300 female army recruits, who entered basic military training from 1977 to 2001.19 During this period, there were 13 SCD cases (median age 19 years, 73% African-American), occurring at a median of 25 days after arrival for training. Of these, eight recruits (53%) suffered SUDS, and anomalous coronary origins were found in two recruits (13%). Therefore, SUDS was the leading cause of nontraumatic sudden death in young female recruits during military training. These findings suggest that the overall burden of SUDS in younger women could be higher than anticipated.

1.3 Diagnostic Considerations and Role of the Molecular Autopsy There are important reasons why all patients who succumb to presumed SUDS should undergo a full, detailed postmortem examination including histologic evaluation of the myocardium. From the Edwards Registry 270-patient series of SCD, a special subgroup of six patients was identified. Initially, both gross and histologic examination of the heart were reported as normal, but due to qualitative findings of what appeared to be increased interstitial fibrosis, a more detailed and quantitative histologic examination was performed that included calculation of the collagen volume fraction.20 There was a diffuse but heterogeneous increase in myocardial collagen content that was exclusively interstitial, without evidence of myocyte necrosis or stigmata of myocarditis. Transforming growth factor-beta 1 was implicated as a mediator of idiopathic myocardial fibrosis but specific triggers as well as subcellular signaling pathways have not been determined.20 With the discovery of genetic causes of sudden death and the technological ability to identify culprit gene defects, the definition of SUDS is evolving. A diagnosis of SUDS now requires both a “structurally

1  Sudden Unexplained Death in the Community

normal” as well as “genetically nondiagnostic” heart. In the happy circumstance that a patient survives cardiac arrest, candidate gene-based screening can be performed. Unfortunately, since most SUDS patients will not survive, genetic testing is usually done from myocardial tissue obtained during postmortem examination, also called as a molecular autopsy.21 Given the critical need to assess SUDS risk among living family members of the deceased, studies have evaluated the potential role of molecular autopsies in identifying a diagnosis. From the Edwards Registry series, postmortem genetic analysis was performed to investigate the frequency of long QT and Brugada syndrome gene defects in the subgroup of 12 adult subjects with SCD and structurally normal heart (mean age 32 years). Only two of these 12 patients (17%) were found to have a defect in KCNH2 among all five candidate genes tested.21 In a 49-patient group of younger patients (mean age 14 years) studied by Ackerman and colleagues,22 the yield of molecular autopsy was higher (35%). Ten patients had mutations in any of several long QT syndrome genes and 7 in the Ryanodinereceptor 2 gene. However, the vast majority still did not have an etiology identified. In another study, where Behr et al performed clinical evaluations in surviving relatives (without molecular autopsy), the yield was equally poor, with etiologies identified in only 19%.6 Wilde and co-workers were able to enhance the yield of identified etiologies to 40% by combining clinical evaluation with molecular autopsy, but again with no answers in the majority of SUDS cases.23 From these studies, it would seem that the single largest gap in identifying the molecular etiologies of SUDS is the current limited repertoire of candidate genes that we associate with mechanisms of fatal arrhythmogenesis. It is possible that extracardiac conditions and factors may also function as substrates or triggers for SUDS.3 There is increasing evidence of a potential role for seizure disorder in at least a subgroup of SUDS patients. Sudden unexplained death is a relatively common cause of mortality in the epilepsy population with an estimated incidence of 0.7–1.3 per 1,000 patientyears in large cohorts of patients.24-27 A populationbased study documented a sudden death incidence of 0.35/1,000 patient-years, a 24-fold increase over the general population. In a recent prospective cohort study of 4,578 patients with epilepsy, ten deaths qualified as definite sudden unexpected death.28 All cases underwent detailed clinical evaluation and autopsy, with

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gross examination of organs. There were no extracardiac abnormalities and nine of these ten patients had no cardiac abnormality attributable to SCD. Risk factors for sudden death were tonic-clonic seizures, mental retardation, and number of anticonvulsant drugs used. In another study, a careful pathologic examination was conducted at autopsy in seven patients with epilepsy who suffered sudden death.29 Abnormalities were limited to the heart and included nonspecific myocardial findings such as interstitial fibrosis and myocyte vacuolization with absence of specific cardiac conditions. Mechanisms remain unresolved, but precipitation of fatal arrhythmia due to autonomic storm has also been postulated as a cause of sudden unexplained death in epilepsy.30,31

1.4 Conclusions Approximately 5% of patients who suffer SCD will have the SUDS. The overall annual incidence of this condition in the general population is likely to be in the range of 3/100,000. These individuals succumb to a fatal arrhythmia, but have a structurally normal heart and genetically nondiagnostic molecular autopsy. SUDS is a devastating manifestation of heart disease affecting the young and with significant implications for surviving family members. As a result, this entity continues to pose a difficult diagnostic and therapeutic challenge to health care providers and investigators alike. There is likely to be a significant genetic component in the pathogenesis of SUDS, but enhancements in screening, risk stratification, and prevention await the elucidation of a more complete understanding of genetic targets.

References   1. Chugh SS, Jui J, Gunson K, et al. Current burden of sudden cardiac death: multiple source surveillance versus retrospective death certificate-based review in a large U.S. community. J Am Coll Cardiol. 2004;44:1268–1275   2. Myerburg RJ. Scientific gaps in the prediction and prevention of sudden cardiac death. J Cardiovasc Electrophysiol. 2002;13:709–723   3. Chugh SS, Kelly KL, Titus JL. Sudden cardiac death with apparently normal heart. Circulation. 2000;102:649–654

6   4. Behr ER, Casey A, Sheppard M, et al. Sudden arrhythmic death syndrome: a national survey of sudden unexplained cardiac death. Heart. 2007;93:601–605   5. Chugh SS. Sudden cardiac death with apparently normal heart: clinical implications of progress in pathophysiology. Cardiac Electrophysiol Rev. 2001;5:394–402   6. Behr E, Wood DA, Wright M, et  al. Cardiological assessment of first-degree relatives in sudden arrhythmic death syndrome. Lancet. 2003;362:1457–1459   7. Graboys TB, Lown B, Podrid PJ, DeSilva R. Long-term survival of patients with malignant ventricular arrhythmia treated with antiarrhythmic drugs. Am J Cardiol. 1982;50:437–443   8. Myerburg RJ, Conde CA, Sung RJ, et al. Clinical, electrophysiologic and hemodynamic profile of patients resuscitated from prehospital cardiac arrest. Am J Med. 1980;68: 568–576   9. Poole JE, Mathisen TL, Kudenchuk PJ, et al. Long-term outcome in patients who survive out of hospital ventricular fibrillation and undergo electrophysiologic studies: evaluation by electrophysiologic subgroups. J Am Coll Cardiol. 1990;16:657–665 10. Swerdlow CD, Bardy GH, McAnulty J, et al. Determinants of induced sustained arrhythmias in survivors of out-of-hospital ventricular fibrillation. Circulation. 1987;76:1053–1060 11. Trappe HJ, Brugada P, Talajic M, et al. Prognosis of patients with ventricular tachycardia and ventricular fibrillation: role of the underlying etiology. J Am Coll Cardiol. 1988;12: 166–174 12. Morentin B, Suarez-Mier MP, Aguilera B. Sudden unexplained death among persons 1–35 years old. Forensic Sci Int. 2003;135:213–217 13. Corrado D, Basso C, Thiene G. Sudden cardiac death in young people with apparently normal heart. Cardiovasc Res. 2001;50:399–408 14. Wisten A, Forsberg H, Krantz P, Messner T. Sudden cardiac death in 15–35-year olds in Sweden during 1992–99. J Intern Med. 2002;252:529–536 15. Eckart RE, Scoville SL, Campbell CL, et al. Sudden death in young adults: a 25-year review of autopsies in military recruits. Ann Intern Med. 2004;141:829–834 16. Shen WK, Edwards WD, Hammill SC, Bailey KR, Ballard DJ, Gersh BJ. Sudden unexpected nontraumatic death in 54 young adults: a 30-year population-based study. Am J Cardiol. 1995; 76:148–152 17. Bowker TJ, Wood DA, Davies MJ, et al. Sudden, unexpected cardiac or unexplained death in England: a national survey. QJM. 2003;96:269–279

S. S. Chugh et al. 18. Chugh SS, Chung K, Zheng ZJ, John B, Titus JL. Cardiac pathologic findings reveal a high rate of sudden cardiac death of undetermined etiology in younger women. Am Heart J. 2003;146:635–639 19. Eckart RE, Scoville SL, Shry EA, Potter RN, Tedrow U. Causes of sudden death in young female military recruits. Am J Cardiol. 2006;97:1756–1758 20. John BT, Titus JL, Edwards WD, Shen W-K, Chugh SS. Global remodeling of the ventricular interstitium in idiopathic myocardial fibrosis and sudden cardiac death. Heart Rhythm. 2004;1:141–149 21. Chugh SS, Senashova O, Watts A, et al. Postmortem molecular screening in unexplained sudden death. J Am Coll Cardiol. 2004;43:1625–1629 22. Tester DJ, Ackerman MJ. Postmortem long QT syndrome genetic testing for sudden unexplained death in the young. J Am Coll Cardiol. 2007;49:240–246 23. Tan HL, Hofman N, van Langen IM, van der Wal AC, Wilde AA. Sudden unexplained death: heritability and diagnostic yield of cardiological and genetic examination in surviving relatives. Circulation. 2005;112:207–213 24. Hauser WA, Hesdorffer DC. Epilepsy: frequency, causes and consequences. New York, NY: Demos; 1990 25. Nilsson L, Farahmand BY, Persson PG, Thiblin I, Tomson T. Risk factors for sudden unexpected death in epilepsy: a casecontrol study. Lancet. 1999;353:888–893 26. Nilsson L, Tomson T, Farahmand BY, Diwan V, Persson PG. Cause-specific mortality in epilepsy: a cohort study of more than 9, 000 patients once hospitalized for epilepsy. Epilepsia. 1997;38:1062–1068 27. Tennis P, Cole TB, Annegers JF, Leestma JE, McNutt M, Rajput A. Cohort study of incidence of sudden unexplained death in persons with seizure disorder treated with antiepileptic drugs in Saskatchewan, Canada. Epilepsia. 1995;36:29–36 28. Walczak TS, Leppik IE, D’Amelio M, et al. Incidence and risk factors in sudden unexpected death in epilepsy: a prospective cohort study. Neurology. 2001;56:519–525 29. Natelson BH, Suarez RV, Terrence CF, Turizo R. Patients with epilepsy who die suddenly have cardiac disease. Arch Neurol. 1998;55:857–860 30. Lathers CM, Schraeder PL. Autonomic dysfunction in epilepsy: characterization of autonomic cardiac neural discharge associated with pentylenetetrazol-induced epileptogenic activity. Epilepsia. 1982;23:633–647 31. Lathers CM, Schraeder PL. Review of autonomic dysfunction, cardiac arrhythmias, and epileptogenic activity. J Clin Pharmacol. 1987;27:346–356

2

Sudden Infant Death Syndrome: Gene–Environment Interactions Carl E. Hunt and Fern R. Hauck

“All illnesses have some hereditary contribution. Genetics loads the gun and environment pulls the trigger”

2.1 Introduction Sequencing of the human genome has resulted in a rapidly expanding understanding of the molecular basis of many human diseases and the incredible complexity of genotype–phenotype relationships.1-5 Some genes are expressed only in healthy individuals or in disease conditions, only at specified ages, or in response to specific perturbations or states (e.g., sleep). Some genes, thus contribute to susceptibility to disease, but other genes and their polymorphisms contribute to protection against illness. Knowing the genotype even in single-gene disorders does not necessarily identify the phenotype. Phenotype is also influenced by gene–gene and gene– environment interactions. Most human disorders are not single-gene disorders, but rather are polygenic ­disorders associated with complex and quite variable phenotypes.6 Multiple genes interact with multiple environments to both increase and decrease the risk of clinical disease, and epigenetic processes resulting from environmental factors can lead to altered gene expression.7 Common examples of major disorders

C. E. Hunt (*) Uniformed Services University of the Health Sciences, 4550 North Park Avenue, Suite 405, Chevy Chase, Bethesda, MD 20815, USA e-mail: [email protected]

with polygenic inheritance, genetic heterogeneity, and multiple environmental exposures determining phenotypic expression include atherosclerosis and cardiovascular disease, asthma, diabetes, and cancer.4,6 For such complex disorders, the whole is not only greater but may be different than the sum of its parts. Sudden Infant Death Syndrome (SIDS) is defined as the sudden death of an infant less than 1 year of age that is unexpected by history and unexplained after a thorough postmortem examination, including a complete autopsy, investigation of the scene of death, and review of the medical history.8 There were 2230 SIDS deaths in the U.S. in 2005, equaling a rate of 0.54 per 1,000 live births.9 SIDS rates have declined over 50% since the introduction of national Back to Sleep campaigns in the past decade, which encouraged parents to place infants on their back for sleep. However, SIDS remains the leading cause of postneonatal infant mortality, accounting for approximately a quarter of all deaths between 1 month and 1 year of age.10,11 Additionally, there is evidence that the declining SIDS rate has reached a plateau. Changes in the classification of sudden unexpected deaths in infants by medical examiners, coroners, and other certifiers from SIDS to the categories of “asphyxia” or “unascertained” may be falsely lowering the rate of SIDS, while the overall rate of sudden, unexpected deaths in infancy (SUDI) remains the same.11,12 As prone sleeping among infants has become less common, other risk factors have emerged as being important in the causal pathway of SIDS (see later sections). This chapter reviews the evidence indicating that SIDS, like other clinical disorders, has important genetic and environmental risk factors, that in complex and not yet well-defined ways interact to yield phenotypes susceptible to SUDI.

R. Brugada et al. (eds.), Clinical Approach to Sudden Cardiac Death Syndromes, DOI: 10.1007/978-1-84882-927-5_2, © Springer-Verlag London Limited 2010

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2.2 Genetic Risk Factors Recent genetic studies have identified multiple ways in which SIDS victims differ significantly from ­control groups of infants.4,13 In addition to poly­morphisms in sodium and potassium channel genes, SIDS  infants, as a group, differ from control infants with regard to ­documented polymorphisms in genes related to the serotonin transporter (5-HTT), early embryology of autonomic nervous system (ANS) development, energy production, and regulation of inflammation/ infection. This latter group includes polymorphisms in complement C4, interleukin (IL)-6 and IL-10, and vascular endothelial growth factor (VEGF) (Table 2.1).

Table 2.1  Twenty-one genes have been identified for which the distribution of polymorphisms differs in SIDS compared to control infants Cardiac channelopathies(6)   Sodium channel (SCN5A)   Potassium channel (KCNQ1, KCNH2, KCNE2)   RyR2-encoded cardiac ryanodine receptor   CAV3-encoded caveolin-3   Sodium channel beta-4 subunit (SCN4B)   Glycerol-3-phosphate dehydrogenase 1-like gene (GPD1-L) Serotonin (5-hydroxytryptamine, 5-HT)(3)   5-HT transporter protein (5-HTT)   Intron 2 VNTR, copy number   5-HT FEV Gene Autonomic nervous system (ANS) development(6)   Paired-like homeobox 2A (PHOX2A)   PHOX2B   Rearranged during transfection factor (RET)   Endothelin converting enzyme-1 (ECE 1)   T-cell leukemia homeobox (TLX 3)   Engrailed-1 (EN 1) Infection and inflammation(5)   Complement C4A   Complement C4B   Interleukin (IL)-6   IL-10   Vascular endothelial growth factor (VEGF) Energy production(1)   Mitochondrial DNA (mtDNA) polymorphisms Phenotypes can be inferred for the cardiac channelopathies and the infection/inflammation-related genotypes. Very little is known about phenotypes resulting from polymorphisms in ANS, 5-HT, or energy-production-related genes. See text for individual references. Source: adapted from Hunt CE4

C. E. Hunt and F. R. Hauck

2.2.1 Sodium and Potassium Cardiac Channelopathies As detailed in other chapters, sodium and potassium channelopathies causing abnormalities in QT interval can result not only in arrhythmias or sudden cardiac death in children and adults, but also in SUDI and SIDS.13-16 Long QT syndrome (LQTS) is now associated with >10 distinct LQTS-susceptibility genes that encode critical channel pore-forming alpha subunits or essential channel interacting proteins.17,18 On the basis of the molecular analysis of 93 SIDS cases, 2% had a distinct sodium channel gene (SCN5A) channel defect, one related to exon 17 and one related to exon 28. The high prevalence of SCN5A mutations in SIDS is consistent with their established role in causing arrhythmia during sleep, when most sudden and unexpected deaths occur. LQTS can also be caused by potassium channel polymorphisms. To date, polymorphisms have been observed in increased frequency in SIDS vs. controls for KCNQ1, KCNH2, and KCNE2. The mechanism by which potassium channel variants can contribute to SIDS is thought to be mediated at least in part through increased sympathetic activity during sleep, including REM sleep, and associated sleep-related hypoxemia and chemoreceptive reflexes.19 A recent molecular study in a large number of SIDS infants and controls from Norway further substantiates the importance of LQTS variants in SUDI.20 Polymor­ phisms in 5 genes [KCNQ1, KCNH2, SCN5A, Caveolin-3 (CAV3), and KCNE2] associated with LQTS were observed in 9.5% of 201 SIDS infants (CI. 5.8–14.4%). On the basis of functional analyses, a total of eight mutations and seven rare variants found in 19 cases were considered to be likely contributors to sudden and unexpected death. Since disease-causing mutations have been identified only in about 70% of clinically diagnosed LQTS, the true prevalence of LQTS associated with SUDI or SIDS may be underestimated in this study. Functional characterization of multiple SCN5A polymorphisms revealed a spectrum of sodium channel dysfunction ranging from overt to latent or concealed pathological phenotypes. In variants with latent dysfunction, persistent current was evident only under conditions of internal acidosis, or when expressed in the context of a common SCN5A splice variant.21 In a separate study of 224 U.S. cases of SIDS, an increased frequency of a SCN5A polymorphism

2  Sudden Infant Death Syndrome: Gene–Environment Interactions

was also observed, and African Americans homozygous for the S1103Y mutation had a 24-fold increased risk for SIDS compared with controls.22 Of particular note, acidosis was again shown to be an important perturbation in that the molecular phenotype of increased late sodium current and hence prolonged QT interval was expressed only when the mutant channels were exposed to acidosis. Sodium channel-interacting proteins are also implicated in SIDS.23 Caveolin-3 (CAV3) and sodium channel beta-4 subunit (SCH4B), for example, are two mutations in SCN5-A associated channel-interacting proteins that are novel LQTS-susceptibility genes.24,25 CAV3 mutations have been reported in black SIDS infants.24 Most recently, three novel SIDS-associated mutations have been reported in a novel sodium channel-interacting protein, glycerol-3-phosphate dehydrogenase 1-like gene (GPD1-L).23 Mutations in the RyR2-encoded cardiac ryanodine receptor cause the highly lethal catecholaminergic polymorphic ventricular tachycardia (CPVT1).26 It closely mimics LQTS, but is not associated with an abnormal resting electrocardiogram. It typically manifests in response to stress and may lead to sudden arrest during sleep, in which instances the causal stress could be hypoxia or other sleep-related increases in sympathetic activity. Two distinct and novel RyR2 gain-offunction mutations have been documented in SIDS infants, and neither mutation was observed in 400 reference alleles from 100 African American and 100 Caucasian healthy control subjects.26 A short QT interval (SQTS) has also been associated with familial sudden death and may be a cause of arrhythmogenic sudden death in early infancy.27 Gainof-function mutations in at least three potassium channel genes have been reported, resulting in enhanced repolarization, and hence a shortened QT interval and increased risk of atrial and ventricular arrhythmias and cardiac arrest. Although the extent to which SQTS may contribute to risk for SIDS is unknown, a gain-offunction KCNQ1 mutation has been identified postmortem in one Norwegian SIDS infant, and three children later diagnosed with SQTS had a history of an apparent life-threatening event (ALTE) or syncope in infancy.27,28 No antemortem analyses of QT intervals are available in infants who were found to have a sodium/potassium cardiac channel gene polymorphism postmortem. However, one infant with an ALTE has been reported,

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in whom LQTS was subsequently diagnosed and was associated with a spontaneous mutation on the SCN5A gene.14 On the basis of the aggregate of all the genetic studies, it is presently estimated that 10%, and perhaps as many as 15% of SUDI are associated with a primary cardiac channelopathy, causing a sudden, unexpected lethal arrhythmia.13

2.2.2 Serotonin Transporter (5-HTT) Several polymorphisms have been identified in the promoter region of the serotonin (5-HT) transporter protein (5-HTT) gene which is located on chromosome 17.4,13 Variations in the promoter region of 5-HTT affect 5-HT membrane uptake and regulation. The long “L” allele increases effectiveness of the promoter and hence would lead to reduced extracellular 5-HT concentrations at nerve endings compared to the short “S” allele.29,30 The L/L genotype is associated with increased 5-HTT binding on postmortem neuroimaging and binding studies.29 Caucasian, African American, and Japanese SIDS victims are more likely than matched controls to have the “L” allele.29,30 Among 27 Japanese SIDS victims and 115 controls, for example, there are differences in genotype distribution (p<0.01) and allele frequency (p<0.01), and frequency of the L allele is higher in SIDS victims vs. controls (22.2 vs. 13.5%, p < 0.003).31,32 Among 44 Caucasian and 43 African American SIDS victims and matched controls, there is an association between SIDS and the 5-HTT genotype distribution (p < 0.022), specifically with the L/L genotype (p < 0.048), and between SIDS and the 5-HTT L allele (p < 0.005). There is also a negative association between SIDS and the S/S genotype (p < 0.011). An association has also been observed between SIDS and a 5-HTT intron 2 polymorphism which differentially regulates 5-HTT expression.32 There are positive associations between SIDS and the intron 2 genotype distributions (p < 0.041) in African American (AA) SIDS vs. AA controls, specifically with the 12/12 genotype (p < 0.03) and with the 12 repeat allele (p < 0.018). The promoter and intron 2 loci are in linkage disequilibrium, and the L-12 haplotype is associated with SIDS in the AA (p < 0.002) but not Caucasian (p < 0.117) subgroups. These results indicate a relationship between SIDS and the 12-repeat allele of the

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intron 2 variable number tandem repeat of the 5-HTT gene in AA, and a role of the haplotype containing the 12-repeat allele and the promoter L-allele in defining SIDS risk in AA infants. The human fifth Ewing variant (FEV) gene is specifically expressed in central 5-HT neurons in the brain, with a predicted role in specification and maintenance of the serotonergic neuronal phenotype.33 A new insertion mutation has been identified in intron 2 of the FEV gene, and the genotype distribution of this mutation differs significantly in SIDS compared to control infants, 6.2 and 0.0%, respectively (p < 0.01). This mutation was present in 6/98 African American vs. 0/0 Caucasian infants (p < 0.03). Identification of this mutation expressed exclusively in SIDS infants in a transcriptional regulator responsible for terminal 5-HT differentiation may be causally related to the observed abnormalities in the 5-HT system in some SIDS infants.29

2.2.3 Autonomic Nervous System (ANS) Molecular genetic studies in SIDS victims have also identified mutations pertinent to early embryologic development of the ANS.34 The relevant genes include mammalian achaete-scute homolog-1 (MASH 1), bone morphogenic protein-2 (BMP 2), paired-like homeobox 2a (PHOX2a), PHOX 2b, rearranged during transfection factor (RET), endothelin converting enzyme-1 (ECE 1), endothelin-1 (EDN 1), T-cell leukemia homeobox (TLX3), and engrailed-1 (EN 1) (Table  2.1). Eleven protein-changing rare mutations have been identified in 14/92 SIDS cases among the PHOX 2a, RET, ECE 1, TLX3, and EN 1 genes. Only one of these mutations (TLX 3) was found in 2/92 controls. Each of these mutations occurred in a single SIDS case, except for the TLX3 base change that occurred in 4 SIDS and the two control infants. African American infants accounted for 10/11 mutations in SIDS cases and in both affected controls with proteinchanging mutations. Eight polymorphisms in the third exon of the PHOX2B gene occur significantly more frequently in SIDS compared to control infants.13,34 Two of the eight polymorphisms identified were protein-altering missense mutations occurring in nine SIDS (10%) and four controls (4%).

C. E. Hunt and F. R. Hauck

2.2.4 Infection and Inflammation Genetic differences in unexplained SUDI victims compared to control infants have been reported for two complement C4 genes.35 Among 104 SIDS victims, 19 infection-related infant deaths, and 84 healthy infant controls, SIDS victims with mild upper respiratory infection prior to death were more likely to have deletion of either the C4A or the C4B gene compared to SIDS victims without infection, or living controls (p < 0.039). Among living infants, there were no differences in the C4 gene in those with vs. without an upper respiratory infection. These data suggest that partial deletions of C4 in combination with a mild upper respiratory infection place these relatively hypoimmune infants at increased risk for sudden unexpected death. Inflammation has been postulated to have a significant role in triggering the terminal events in SIDS. SIDS victims have been reported to have loss-of-function polymorphisms in the gene promoter region for IL-10, an antiinflammatory cytokine.36 Among 46 SIDS victims compared to 660 living controls, sudden infant death was strongly associated with IL-10 genotype, both with the ATA haplotype (p < 0.003) and with the presence of −592*A allele (p < 0.0014). Presence of the −592*C allele was associated with an odds ratio of 3.3 (p < 0.007) for SIDS. These IL-10 polymorphisms are associated with decreased IL-10 levels and hence could contribute to SIDS by delaying initiation of protective antibody production or reducing the capacity to inhibit inflammatory cytokine production. A larger study did not find differences in IL-10 genes in SIDS compared to control infants, but did identify an association with the ATA haplotype in 29 sudden and unexpected infant deaths thought to be due to infectious diseases.37 There are no differences in SIDS victims for other IL-10 gene polymorphisms, IL-4, interferon, or transforming growth factor.38 Significant associations with SIDS have been observed for a VEGF polymorphism (−1154*G/A) and for two IL-6 polymorphisms.38,39 Both are proinflammatory cytokines and these gain-of-function polymorphisms would result in increased inflammatory response to infectious or inflammatory stimuli, and would contribute to an imbalance between proinflammatory and antiinflammatory cytokines. As apparent proof-of-principle, elevated levels of IL-6 and VEGF have been reported from CSF in SIDS infants.40,41 In a study of 175 Norwegian SIDS and 71 control

2  Sudden Infant Death Syndrome: Gene–Environment Interactions

infants, however, there were no group differences in the IL6 – 174G/C polymorphism.42 Nevertheless, the aggregate evidence suggests an activated immune system in SIDS, thus implicating genes involved in the immune system. This may involve other IL-6 polymorphisms, or other genes expressing proteins important in acute phase responses such as IL-1 and TNF-alpha.

2.2.5 Energy Production Mitochondria are cytoplasmic organelles that provide most of cell energy. Mitochondria contain their own DNA, mitochondrial DNA (mtDNA), which has a high rate of disease-causing mutations.43 Several studies of mtDNA have been performed in SIDS and control infants, some of which have demonstrated significant differences in mutations in SIDS compared to control infants, including a high substitution rate in the HVR-1 region of the D-loop and an association between a high number of these substitutions and mutations in coding areas of mtDNA. Most recently, however, a study of mitochondrial tRNA genes and flanking regions did not demonstrate an association between a specific mitochondrial tRNA gene mutation and SIDS, nor a higher mtDNA mutation frequency in SIDS vs. control infants.43 Cardiac arrhythmias, including prolonged QT intervals, have been observed in families with mitochondrial disease.44 Study of the mtDNA polymorphism T3394C that is associated with cardiac arrhythmia, however, did not indicate a frequency difference in SIDS vs. control infants. Such apparently negative studies, however, do not rule out the possibility that mtDNA mutations such as T3394C may be genetic variants that when combined with environmental factors not present in controls could predispose to sudden death.44 Other genetic studies of disordered energy production in SIDS have focused on several other relevant genes. Gene polymorphisms involved with glucose metabolism, including glucokinase and glucose-6phosphatase (G6PC), have not demonstrated differences in SIDS vs. control infants.45 However, a novel variant found in the G6PC promoter that reduces basal promoter activity, though not present in SIDS infants, was found in a significantly higher frequency (6.3%) in nonSIDS sudden and unexpected infant deaths vs.control infants (only 2.9%) .

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2.3 Environmental Risk Factors 2.3.1 Sociodemographic Factors A large number of modifiable and nonmodifiable factors has been found to have significant associations with SIDS (Table 2.2). Infants are at a greatest risk of SIDS at 2–4 months of age, with about 90% of deaths having occurred by 6 months. Males are 30–50% more likely to be affected than females.46-48 In some countries, as the SIDS incidence has declined, deaths have occurred at earlier ages and the  peak incidence has been less pronounced.49,50 Similarly, the winter seasonal predominance of SIDS has declined or disappeared in some countries as the prevalence of infants sleeping in the prone position has decreased, supporting prior findings of an interaction between sleep position and factors more

Table 2.2  Environmental factors associated with increased risk for SIDS. Source: adapted from Hunt CE and Hauck FR5 Maternal and antenatal risk factors                        

Smoking Alcohol use Illegal drug use (especially opiates) Inadequate prenatal care Low socioeconomic status Younger age Lower education Single marital status Increased parity Shorter inter-pregnancy interval Intrauterine hypoxia Fetal growth retardation

Infant risk factors   Age (peak 2–4 months, but peak is decreasing as rates are declining)   Male gender   Race/ethnicity (i.e., AfricanAmerican, and American Indian and other indigenous peoples)   No pacifier used at bed time   Prematurity   Prone and side sleep position   Recent minor infectious illness   Smoking exposure   Soft sleeping surface, soft bedding, pillows   Thermal stress/overheating   Face covered by bedding   Bed sharing between infant and mother, both parents, and/ or others   Sleeping in own room rather than in parents’ room   Colder season, no central heating

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common in colder months, i.e., overheating and infection.51,52 Although SIDS affects infants from all social levels, lower socioeconomic status, younger maternal age, lower maternal education, and single marital status are consistently associated with higher risk. African American, American Indian, and Alaskan Native infants are 2–3 times more likely than white infants to die of SIDS, whereas Asian, Pacific Islander, and Hispanic infants have the lowest incidence of SIDS.10 Five to seven times higher rates of  SIDS among indigenous peoples have been reported in other countries.53 While biological differences (such as racial differences in tobacco meta­ bolism) may partially explain this disparity, it is also likely related to the higher concentration of poverty and other adverse environmental factors found within these communities.54 Although SIDS rates have declined across all social and racial groups following back to sleep campaigns, recent trends indicate that these social and racial disparities have worsened.55-57

2.3.2 Pregnancy-Related Factors Mothers of SIDS infants generally receive less prenatal care and initiate care later in pregnancy.47,58 Addi­ tionally, low birth weight, preterm birth, intrauterine growth retardation, and shorter inter-pregnancy interval are risk factors.47,48,59 SIDS infants are often the second or higher-order birth child. This suggests that a suboptimal in utero environment may cause biological changes in the infant leading to greater susceptibility to SIDS. Maternal depression in the year before the infant’s birth was found to be a risk factor for SIDS in a study  conducted in the U.K. (OR 4.21, 95% CI ­1.18–14.98).60 Depression after birth (a new episode) was not significantly associated with SIDS, nor was schizophrenia or bipolar disorder, before or after birth. Similarly, a Danish cohort study reported that psychiatric admission of mothers for schizophrenia or affective disorders (i.e., bipolar disorder or other affective disorders) was not associated with a significant increased risk of SIDS in their offspring.61 This study found a small but statistically significant increased risk of SIDS if the father had a history of a psychiatric

C. E. Hunt and F. R. Hauck

admission for an affective disorder (OR 2.1, 95% CI 1.1–4.3).

2.3.3 Tobacco, Illicit Drug, and Alcohol Use Maternal smoking during pregnancy consistently has been found to be a strong risk factor for SIDS. The risk of SIDS increased from about 3 times greater among infants of mothers who smoked in studies conducted before SIDS risk reduction campaigns to reduce prone sleeping among infants, to 5 times higher after implementation of these campaigns.62 Most studies have shown that the risk of death is progressively greater as daily cigarette use increases, but the accuracy of self-reported cigarette use data is uncertain.48, 59, 63 There may be a small independent effect of paternal smoking.62 It is very difficult to assess the independent effect from postnatal exposure to environmental tobacco smoke (ETS), because parental smoking behaviors during and after pregnancy are highly correlated.62 An independent effect of postnatal ETS has been found by a small number of studies as well as a dose response for the number of household smokers, people smoking in the same room as the infant, cigarettes smoked, and time the infant was exposed.64-68 These data suggest that keeping the infant free of ETS may further reduce an infant’s risk of SIDS. Use of illicit drugs by mothers during pregnancy,  especially opiates, is associated with an increased risk of SIDS, ranging from 2 to 15-fold increased risk.53,56,69-72 The majority of studies have not found an association between SIDS and maternal  alcohol use prenatally or postnatally. In one study  of Northern Plains Indians, however, peri-­ conceptional alcohol use and binge drinking in the first trimester were associated with a sixfold and an eightfold increased risk of SIDS, respectively.73 In  a recent Danish cohort study, mothers who were admitted to the hospital at any time before their infants  were born or after their birth for an alcoholor  drug-related disorder had a 3 times higher risk of  an  infant dying from SIDS.61 In a Dutch study, maternal alcohol consumption in the 24 h before the infant  died carried a two to eightfold increased risk.74 Siblings of infants with fetal alcohol syndrome

2  Sudden Infant Death Syndrome: Gene–Environment Interactions

have  a  tenfold increased risk of SIDS compared to controls.75

2.3.4 Infant Sleep Practices and Environment Sleeping prone has consistently been shown to increase the risk of SIDS.76 As rates of prone positioning have decreased in the general population, the odds ratios for SIDS in infants still sleeping prone have increased. For example, in Norway, the precampaign odds ratio for prone sleeping was 2.0, while postcampaign, it was 11.3.77 The highest risk of SIDS occurs in infants who are usually placed nonprone but placed prone for last sleep (“unaccustomed prone”) or found prone (“secondary prone”).76 The unaccustomed prone position is more likely to occur when infants are cared for by ­secondary caregivers, such as grandparents, other relatives, babysitters, or child care providers. This highlights the need for the back to sleep message to reach all infant caregivers. The initial SIDS risk reduction campaigns considered side sleeping to be nearly equivalent to the supine position in reducing the risk of SIDS, but subsequent studies have indicated that side-sleeping infants are twice as likely to die of SIDS as infants sleeping supine.78 Thus, current recommendations call for placing all infants supine for sleep except those few with specific medical conditions for which a different position may be justified.76 Some newborn nursery staff still place infants on the side, which models inappropriate infant care practice to parents.79 Many parents and healthcare providers were initially concerned that supine sleeping would be associated with an increase in adverse consequences, such as difficulty in sleeping, vomiting, or aspiration. However, evidence suggests that the risk of regurgitation and choking are highest for prone-sleeping infants.80 Infants sleeping on their backs do not have more episodes of cyanosis or apnea, and reports of apparent life-threatening events (ALTEs) decreased in Scandinavia after increased use of the supine position.81 A US cohort study found that no clinical symptoms or reasons for  outpatient visits were more common among infants sleeping on their back or side, and some symptoms and visits were less common among supine sleepers.82

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Soft mattresses, older mattresses, and soft, fluffy bedding such as comforters, pillows, sheepskins, and polystyrene bean pillows are associated with a two to threefold increased risk of SIDS.48, 53, 83, 84 Combinations of risk factors result in even higher risk; for example, prone sleeping and soft bedding are associated with a 20-fold increased risk of SIDS.85 Head and face covering by loose bedding including heavy comforters is also associated with increased risk.77,86 Overheating has been associated with increased risk for SIDS based on indicators such as higher room temperature, high body temperature, sweating, and excessive clothing or bedding.53 Some studies have identified an interaction between overheating and prone sleeping, with overheating increasing the risk of SIDS six to tenfold only when infants were sleeping prone.87,88 High outside temperatures, however, have not been associated with increased SIDS incidence in the US.89 Several studies have implicated bed sharing as a risk factor for SIDS, defined as the infant sleeping with mother, both parents, and/or other individuals.90 Earlier case-controlled studies in England and New Zealand found a five to ninefold increased risk associated with bed sharing only among smoking mothers.91,92 More recent studies have found that bed sharing was associated with increased risk of SIDS even if mothers did not smoke or if they breastfeed.48,59,93 Bed sharing has been found to be particularly hazardous when other children are in the same bed, when the parent is sleeping with an infant on a couch or other soft or confining sleep surface, and for infants younger than 4 months of age.59,85,91,93-95 Risk is also increased with longer duration of bed sharing during the night, while returning the infant to his or her own crib was not associated with increased risk.91,94 Some authors have hypothesized potentially protective effects among infants who are bed sharing and breastfed based on observations from sleep laboratory studies, including improved maternal inspections, more infant arousals, and less deep sleep.96,97 However, no epidemiologic studies have reported a protective effect from bed sharing, and hence, bed sharing should not be encouraged as a method to reduce risk for SIDS. There is evidence that room sharing without bed sharing is associated with about a third the risk of SIDS compared to infants sleeping in a room separate from their parents.59,91,93,98 Thus, the safest place for an infant to sleep may be in the parental bedroom in a separate crib or bassinet.

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2.3.5 Infant Feeding Practices and Exposures The association between breastfeeding and SIDS is inconclusive, which may reflect the different ways in which breastfeeding is defined and measured.76 Several studies demonstrated a protective effect of breastfeeding that was not present after adjusting for confounding factors, suggesting that breastfeeding is a marker for lifestyle or socioeconomic status and not an independent factor.53 A few studies have shown a reduced risk even after adjustment for potential confounders or a dose-response, with longer breastfeeding duration associated with lower risk.48,49,99 A recent meta-analysis prepared for the Agency for Healthcare Research and Quality of selected studies found a reduced risk of SIDS with breastfeeding (summary adjusted odds ratio 0.64, 95% confidence interval 0.51–0.81).100 However, an analysis of national US data found that breastfeeding is associated with decreased postneonatal deaths overall, but not with decreased SIDS.101 Thus, at this time, the data are inadequate to conclusively recommend breastfeeding as a strategy to reduce the risk for SIDS, but it should be recommended on the basis of its many other benefits to infant health. Upper respiratory tract infections have generally not been found to be an independent risk factor for SIDS, although one recent study found an increased incidence of these infections among SIDS infants compared with control infants in the 4 weeks prior to death.102 These and other minor infections may play a role in the pathogenesis of SIDS. Risk for SIDS, for example, has been found to be increased after illness among prone sleepers, those who were heavily wrapped, and those whose heads were covered during sleep.53 SIDS infants are less likely to be immunized than control infants. However, in immunized infants, no temporal relationship between vaccine administration and death has been identified. Parents and healthcare providers should be reassured that immunizations do not present a risk for SIDS.76

2.3.6 Pacifier Use Pacifier use has been found to significantly lower SIDS risk in the majority of case-control studies when used

C. E. Hunt and F. R. Hauck

for last/reference sleep. A meta-analysis found this reduced risk to be equal to an adjusted summary odds ratio of 0.39 (95% confidence intervals 0.31–0.50).103 Two studies and another meta-analysis published, subsequently mirrored these results.48,104,105 The study from California found an even lower risk associated with pacifier use during last sleep (adjusted odds ratio 0.08 [95% CI 0.03–0.21]), and this reduced risk occurred for all sociodemographic and risk categories examined, including breastfed infants.104 It is not known if this apparent protection results from a direct effect of the pacifier itself or from associated infant or parental behaviors. There is increasing evidence, however, that pacifier use and dislodgment may enhance arousability of infants during sleep or help regulate autonomic control in a favorable way.106,107

2.3.7 Child Care Settings About 20% of SIDS deaths occur in child care settings (i.e., when under the care of a nonparental caregiver).108-110 Although it was found that the higher incidence of SIDS in child care facilities was due to infants being placed prone for sleep (unaccustomed prone),109 recent studies indicate that this is no longer a problem in licensed facilities.110 As many of the SIDS deaths occur in the first week of child care, it is possible that the higher incidence of SIDS in these settings is related to infant stress and sleep disruption during this transition period.111

2.3.8 Recurrence of SIDS in Siblings The next-born siblings of first-born infants dying of a natural cause are at significantly increased risk for infant death from the same cause, including SIDS.­112-115 The risk for recurrent infant mortality from the same cause as in the index sibling is increased to a similar degree in subsequent siblings for both explained causes and for SIDS, with relative risk ranges of 5–13 and 5–6 for recurrence, respectively. The extent to which risk for SIDS may be increased in subsequent siblings has been controversial, primarily due to absence of objective criteria for ruling out intentional suffocation and limited prior understanding of the role of genetic risk

2  Sudden Infant Death Syndrome: Gene–Environment Interactions

factors.112,117 Metabolic or genetic disorders, such as fatty acid oxidation disorders or prolonged QT syndrome, may go unrecognized and subsequent deaths may be attributed to SIDS.111 However, there are now substantial data in support of genetic risk factors for recurrent SIDS, and recent epidemiological data confirm that second infant deaths in families are not rare and that at least 80–90% are natural.115 While homicide should be considered as a possibility, a sudden infant death in a subsequent sibling is 6 times more likely to be SIDS than homicide.115

2.4 Phenotypes Associated with Increased Risk for SIDS The genetic polymorphisms documented in SIDS infants (Table 2.1) cannot yet be directly linked with any defined phenotype that has been ascertained antemortem. The ANS-related polymorphisms are consistent with postmortem data in SIDS infants and the physiologic data in at-risk infants and some infants later dying of SIDS. Overall, these pathophysiologic data are indicative of impaired cardiorespiratory control and arousal regulation.4,34,116 Brainstem muscarinic cholinergic pathways develop from the neural crest and are important in ventilatory responsiveness to CO2. The muscarinic system develops from the neural crest, and the RET proto-oncogene is important for this development. RET knockout mice have a depressed ventilatory response to hypercarbia. Neurotransmitter studies of the arcuate nucleus in SIDS infants have identified receptor abnormalities that involve several receptor types relevant to statedependent autonomic control overall and to ventilatory  and arousal responsiveness in particular. These deficits include significant decreases in binding to kainate, muscarinic cholinergic, and serotonergic (5-HT) receptors. Consistent with the evidence for 5-HT polymorphisms in some SIDS infants (Table  2.1), the neuropathologic data provide compelling evidence for 5-HT dysregulation. 5-HT is an important neurotransmitter and the 5-HT neurons in the medulla project extensively into neurons in the brainstem and spinal cord that influence respiratory drive and arousal, cardiovascular control including blood pressure, circadian regulation and non-REM sleep, thermoregulation, and upper airway

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reflexes.4,29 Medullary 5-HT neurons may be respiratory chemosensors and may be involved with respiratory responses to intermittent hypoxia and respiratory rhythm generation. Decreases in 5-HT 1A and 2A receptor immunoreactivity have been observed in the dorsal nucleus of the vagus, solitary nucleus, and ventrolateral medulla.117 A recent study of multiple serotonergic brainstem abnormalities in SIDS infants further confirms a critical role for medullary 5-HT neuropathology.29 These extensive abnormalities include increased 5-HT neuronal count, a lower density of 5-HT1A receptor binding sites in regions of the medulla involved in homeostatic function, and a lower ratio of 5-HTT binding density to 5-HT neuronal count in the medulla. Of interest, male SIDS infants had lower receptor binding density than female SIDS infants. These findings suggest that the synthesis and availability of 5-HT is altered within 5-HT pathways, and hence alters neuronal firing. It is however not known how these alterations occur. The available neuropathologic data could be explained by an increased number of 5-HT neurons leading to an excess of extracellular 5-HT and secondary down-regulation of 5-HT1A receptors. However, it is also possible that 5-HT synthesis and/or release may be deficient, leading to a deficiency of extracellular 5-HT despite a compensatory overabundance of 5-HT neurons. Thus although the neuropathologic data do not clarify whether medullary 5-HT levels are increased or decreased in SIDS infants, the 5-HTT polymorphism data are consistent with decreased extracellular or synaptic 5-HT concentrations. Thus there are an unknown number of antemortem phenotypes that could be associated with the observed 5-HT polymorphisms and neuropathologic findings, but no overt antemortem phenotype resulting from a defined polymorphism has yet been identified. Further, since many genes are involved in the control of serotonin synthesis, storage, membrane uptake, and metabolism, causal polymorphisms may not be limited to the 5-HTT gene. Although no 5-HT polymorphism was identified, a recent case report does provide proof-ofconcept for a link between altered antemortem physiology (phenotype) data and abnormal 5-HT receptor binding abnormalities at autopsy 2 weeks later.118 As determined by a battery of assessments shortly after birth, this asymptomatic infant exhibited altered autonomic and respiratory function. These alterations, however, were not associated with any clinically recognizable overt phenotype.

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C. E. Hunt and F. R. Hauck

2.5 Gene–Environment Interactions Clinical phenotypes as unmasked by the physiological studies in infants at increased risk for SIDS (a few later dying of SIDS) and neuropathological studies in SIDS infants do not clarify the extent to which causation can be attributed to at-risk genotypes, environmentally induced DNA alterations (epigenetic changes), acute lethal environmental perturbations, or some combination thereof.7 Despite these critical knowledge gaps, however, it is evident that the risk for SIDS in individual infants is determined by complex interactions between genetic and environmental risk factors (Fig. 2.1). These environmental influences or exposures may be prenatal or postnatal, and may be either cumulative (persistent or intermittent) or only present as a sudden or acute perturbation triggering a lethal sequence of events.3-5 There appears, for example, to be an interaction between prone sleep position and impaired ventilatory and arousal responsiveness. Face-down or nearly face-down sleeping does occasionally occur in prone-sleeping infants and can result in episodes of airway obstruction, but healthy infants will arouse before such episodes become life-threatening. Infants with genotypes associated with insufficient arousal responsiveness to asphyxia, however, would be at risk for sudden death. There may

also be interactions between modifiable risk factors such as soft bedding, prone sleep position and thermal stress, and links between genetic risk factors such as ventilatory and arousal abnormalities and temperature or metabolic regulation deficits. Polymorphisms resulting in cardio-respiratory control deficits could be related to 5-HTT, for example, or to genes pertinent to development of the ANS (Table 2.1). Infants with any of these genotypes could be at increased risk for sleeprelated intermittent hypoxemia and hence are more susceptible to adverse effects associated with unsafe sleep position or soft bedding. Infants at increased risk for sleep-related hypoxemia and secondary acidosis could also be at greater risk for fatal arrhythmias in the presence of a cardiac channel polymorphism.119 Recent febrile illness, often related to upper respiratory infection has been observed in 50% or more of SIDS victims.5 Although not considered to be causal per se, such otherwise benign infections could increase the risk for SIDS in combination with genetically determined impaired immune responses or imbalance in inflammatory cytokines (Table 2.1). The reported infection and inflammatory-related polymorphisms would alter the balance between anti- and pro-inflammatory mediators, resulting in at least a relative pro-inflammatory state. The mast cell degranulation which has been reported

Environmental risk factors

Genetic risk factors 5-HTT polymorphism

Smoking

Soft bedding & other sleep environment factors

ANS polymorphism

Impaired autonomic regulation and arousal

Prone or side sleeping

Fig. 2.1  Schematic illustration of potential interactions between representative environmental and genetic risk factors for sudden, unexpected deaths in infancy (SUDI) and  SIDS. Source: adapted from Hunt CE4

Prematurity

Sudden Infant Death

Cardiac ion channel polymorphism

Complement or cytokine polymorphism

Energy production

2  Sudden Infant Death Syndrome: Gene–Environment Interactions

in SIDS infants would be consistent with an anaphylactic reaction to a bacterial toxin, but has not yet been associated with a specific genotype.3 SIDS infants have increased CSF levels of 2 proinflammatory cytokines, IL-6, and VEGF.40,41 These elevations could be related to polymorphisms in these genes (see Table 2.1), but there are no genotype studies in the same infants having postmortem CSF measurements. The higher VEGF levels could also be evidence of intermittent hypoxemic events since VEGF is upregulated by hypoxia. The increased risk for SIDS associated with fetal and postnatal exposure to cigarette smoke may be related at least in part to genetic or epigenetic factors, including those affecting brainstem autonomic control.4,5,34 To date, however, no genetic studies in SIDS infants have identified an increased frequency of any polymorphisms affecting tobacco metabolism.13 However, additional genetic studies are needed, since both animal and infant studies indicate decreased ventilatory and arousal responsiveness to hypoxia following fetal nicotine exposure, and impaired autoresuscitation after apnea has been associated with postnatal nicotine exposure. Decreased brain stem immunoreactivity to selected protein kinase C and neuronal nitric oxide synthase isoforms occurs in rats exposed to cigarette smoke prenatally, another potential cause of impaired hypoxic responsiveness. Smoking exposure also increases susceptibility to viral and bacterial infections and increases bacterial binding after passive coating of mucosal surfaces with smoke components, implicating interactions between smoking, cardiorespiratory control, and immune status. In infants with a sodium or potassium cardiac channelopathy, risk for a fatal arrhythmia during sleep may be substantially enhanced by predisposing perturbations that increase cardiac electrical instability, including REM sleep with bursts of vagal and sympathetic activation, minor respiratory infections, or any other cause of sleep-related hypoxemia/hypercarbia, especially if resulting in acidosis.19-22 The prone sleeping position is associated with increased sympathetic activity.111

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to control infants. The number of implicated genes will likely continue to increase as additional candidate genes and polymorphisms are studied and protein-altering consequences are identified. There are other multiple genes involved with prenatal brain stem development of respiratory control including arousal responsiveness, that may also be fruitful for study in SIDS infants. Despite the emerging evidence confirming genetic risk factors for SIDS, however, we know very little about clinical phenotypes and the perturbations that may be required to unmask antemortem phenotypes having increased risk for sudden infant death. Despite the genetic data implicating cardiac channelopathies to risk for sudden infant death, however, it is not known to what extent antemortem electrocardiograms would be abnormal or would be abnormal if perturbed by a stressor such as hypoxia, acidosis, or epinephrine infusion. No definable antemortem phenotypes for genotypes affecting infection/inflammation have been established. The functional consequences of altered ANS developmental genotypes can be inferred from pathophysiologic data in SIDS infants, but no antemortem clinical phenotypes have been established, and no provocative assessments have sufficient sensitivity and specificity to be clinically useful. Even less is known at present regarding antemortem clinical phenotypes in early infancy in any 5-HT-related polymorphisms in infants destined to die suddenly and unexpectedly. Finally, no effective intervention has been established even if infants destined to die of SIDS could be reliably identified in early infancy. However, the recent identification of multiple genetic risk factors for SIDS, and apparent gene–environment and gene–gene interactions, has substantially advanced the frontier of knowledge related to SUDI and SIDS. The challenge now is to capitalize on these hypothesis-generating opportunities and identify future opportunities for effective assessment and intervention in infants who would otherwise die suddenly and unexpectedly.

References 2.6 Summary An increasing number of studies in SIDS infants have identified polymorphisms in genes with disparate regulatory functions having increased frequency compared

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  59. Carpenter RG, Irgens LM, Blair PS, et  al. Sudden unexplained infant death in 20 regions in Europe: case control study. Lancet. 2004;363:185–191   60. Howard LM, Kirkwood G, Latinovic R. Sudden infant death syndrome and maternal depression. J Clin Psychiatry. 2007;68:1279–1283   61. King-Hele SA, Abel KM, Webb RT, Mortensen PB, Appleby L, Pickles AR. Risk of sudden infant death syndrome with parental mental illness. Arch Gen Psychiatry. 2007;64:1323–1330   62. Mitchell EA, Milerad J. Smoking and the sudden infant death syndrome. Rev Environ Health. 2006;223:81–103   63. Schellscheidt J, Øyen N, Jorch G. Interactions between maternal smoking and other prenatal risk factors for sudden infant death syndrome (SIDS). Acta Paediatr. 1997;86:857–863   64. Golding J. Sudden infant death syndrome and parental smoking – a literature review. Paediatr Perinat Epidemiol. 1997;11:67–77   65. Anderson HR, Cook DG. Passive smoking and sudden infant death syndrome: review of the epidemiological evidence. Thorax. 1999;52:1003–1009   66. Schoendorf KC, Kiely JL. Relationship of sudden infant death syndrome to maternal smoking during and after pregnancy. Pediatrics. 1992;90:905–908   67. Klonoff-Cohen HS, Edelstein SL, Lefkowitz ES, et al. The effect of passive smoking and tobacco exposure through breast milk on sudden infant death syndrome. JAMA. 1995;273:795–798   68. Blair PS, Fleming PJ, Bensley D, et al. Smoking and the sudden infant death syndrome: results from the 1993–5 case-control inquiry into stillbirths and deaths in infancy. Br Med J. 1996;313:195–198   69. Hoffman HJ, Damus K, Hillman L, Krongrad E. Risk factors for SIDS: results of the National Institute of Child Health and Human Development SIDS Cooperative Epidemiological Study. Ann NY Acad Sci. 1988;533:13–30   70. Ward SLD, Bautista D, Chan L, et al. Sudden infant death syndrome in infants of substance-abusing mothers. J Pediatr. 1990;117:876–881   71. Chavez CJ, Ostrea EM, Stryker JC, Smialek J. Sudden infant death syndrome among infants of drug-dependent mothers. J Pediatr. 1979;95:407–409   72. Kandall SR, Gaines J, Habel L, Davidson G, Jessop D. Relationship of maternal substance abuse to subsequent sudden infant death syndrome in offspring. J Pediatr. 1993;123:120–126   73. Iyasu S, Randall LL, Welty TK, et al. Risk factors for sudden infant death syndrome among northern plains Indians. JAMA. 2002;288:2717–2723   74. L’Hoir MP, Engelberts AC, van Well GTHJ, et  al. Casecontrol study of current validity of previously described risk factors for SIDS in The Netherlands. Arch Dis Child. 1998;79:386–393   75. Burd L, Klug MG, Martsolf JT. Increased sibling mortality in children with fetal alcohol syndrome. Addict Biol. 2004;9:179–186   76. Task Force on Sudden Infant Death Syndrome. The changing concept of sudden infant death syndrome: diagnostic  coding shifts, controversies regarding the sleeping ­environment, and new variables to consider in reducing risk. Pediatrics. 2005;116:1245–1255

20   77. Markestad T, Skadberg B, Hordvik E, et al. Sleeping position and sudden infant death syndrome (SIDS): effect of an intervention programme to avoid prone sleeping. Acta Paediatr. 1995;84:375–378   78. Li DK, Petitti DB, Willinger M, et al. Infant sleeping position and the risk of sudden infant death syndrome in California, 1997–2000 Am J Epidemiol. 2003;157:446–455   79. Stastny PF, Ichinose TY, Thayer SD, et  al. Infant sleep positioning by nursery staff and mothers in newborn hospital nurseries. Nurs Res. 2004;53:122–129   80. Henderson-Smart DJ, Ponsonby A-L, Murphy E. Reducing the risk of sudden infant death syndrome: a review of the scientific literature. J Paediatr Child Health. 1998;34: 213–219   81. Ponsonby AL, Dwyer T, Couper D. Sleeping position, infant apnea, and cyanosis: a population-based study. Pediatrics [serial online]. 1997;99e3. Available at: http://www.pediatrics.org/cgi/content/full/99/1/e3; 2003 Accessed 04.02.03   82. Hunt CE, Lesko SM, Vezina RM, et al. Infant sleep position and associated health outcomes. Arch Pediatr Adolesc Med. 2003;157:469–474   83. Brooke H, Gibson A, Tappin D, Brown H. Case-control study of sudden infant death syndrome in Scotland, 1992–5. BMJ. 1997;314:1516–1520   84. Mitchell EA, Scragg L, Clements M. Soft cot mattresses and the sudden infant death syndrome. NZ Med J. 1996;109: 206–207   85. Hauck FR, Herman SM, Donovan M, et al. Sleep environment and the risk of sudden infant death syndrome in an urban population: the Chicago Infant Mortality Study. Pediatrics. 2003;111:1207–1214   86. Fleming PJ, Blair PS, Bacon C, et al. Environment of infants during sleep and the risk of sudden infant death syndrome: results of 1993–95 study for confidential inquiry into stillbirths and deaths in infancy. Br Med J. 1996;313:191–195   87. Ponsonby AL, Dwyer T, Gibbons LE, et al. Factors potentiating the risk of sudden infant death syndrome associated with the prone position. N Engl J Med. 1993;329:377–382   88. Williams SM, Taylor BJ, Mitchell EA. Sudden infant death syndrome: insulation from bedding and clothing and its effect modifiers. Int J Epidemiol. 1996;25:366–375   89. Scheers-Masters JR, Schootman M, Thach BT. Heat stress and sudden infant death syndrome incidence: a United States population epidemiologic study. Pediatrics. 2004;113:e586–e592   90. Horsley T, Clifford T, Barrowman N, et  al. Benefits and harms associated with the practice of bed sharing. Arch Pediatr Adolesc Med. 2007;161:237–245   91. Blair PS, Fleming PJ, Smith IJ, et al. Babies sleeping with parents; case-control study of factors influencing the risk of the sudden infant death syndrome. BMJ. 1999;319:1457–1462   92. Scragg R, Mitchell EA, Taylor BJ, et al. Bed sharing, smoking, and alcohol in the sudden infant death syndrome. New Zealand Cot Death Study Group [see comments]. BMJ. 1993;307:1312–1318   93. Tappin D, Ecob R, Brooke H. Bedsharing, room sharing, and sudden infant death syndrome in Scotland: a case-control study. J Pediatr. 2005;147:32–37   94. McGarvey C, McDonnell M, Chong A, et al. Factors relating to the infant’s last sleep environment in sudden infant death syndrome in the Republic of Ireland. Arch Dis Child. 2003;88:1058–1064

C. E. Hunt and F. R. Hauck   95. Ruys JH, de Jonge GA, Brand R, Engelberts AC, Semmekrot  BA. Bed-sharing in the first four months of life: a risk factor for sudden infant death. Acta Paediatr. 2007;96:1399–1403   96. Mosko S, Richard C, McKenna J, Drummond S. Infant sleep architecture during bedsharing and possible implications for SIDS. Sleep. 1996;19:677–684   97. Mosko S, Richard C, McKenna J. Maternal sleep and arousals during bedsharing with infants. Sleep. 1997;20: 142–150   98. Mitchell EA, Thompson JMD. Co-sleeping increases the risk of SIDS, but sleeping in the parents’ bedroom lowers it. In: Rognum TO, ed. Sudden infant death syndrome. New trends in the nineties. Oslo: Scandinavian University; 1995:266–269   99. Mitchell EA. J Paediatr Child Health. 1992;suppl 1:S13–S16 100. Ip S, Chung M, Raman G, et al. Breastfeeding and maternal and infant health outcomes in developed countries. Evidence Report/Technology Assessment No. 153 (Prepared by Tufts-New England Medical Center Evidence-based Practice Center, under Contract No. 290-02-0022). AHRQ Publication No. 07-E007 Rockville, MD: Agency for Healthcare Research and Quality. April 2007 101. Chen A, Rogan WJ. Breastfeeding and the risk of postneonatal death in the United States. Pediatrics. 2004;113:e435–e439 102. Heininger U, Kleemann WJ, Cherry JD. A controlled study of the relationship between Bordetella pertussis infections and sudden unexpected deaths among German infants. Pediatrics. 2004;114:e9–e15 103. Hauck FR, Omojokun OO, Siadaty MS. Do pacifiers reduce the risk of sudden infant death syndrome? A meta-analysis. Pediatrics. 2005;116:e716–e723 104. Li D-K, Willinger M, Petitti DB, et  al. Use of a dummy (pacifier) during sleep and risk of sudden infant death syndrome (SIDS): population based case-control study. BMJ. 2006;332:18–22 [Epub 2005 Dec 9] 105. Mitchell EA, Blair PS, L’Hoir MP. Should pacifiers be recommended to prevent Sudden Infant Death Syndrome? Pediatrics. 2006;117:1755–1758 106. Franco P, Scaillet S, Wermenbol V, et al. The influence of a pacifier on infants’ arousals from sleep. J Pediatr. 2000;136: 775–779 107. Franco P, Chabanski S, Scaillet S, et al. Pacifier use modifies infant’s cardiac autonomic controls during sleep. Early Hum Dev. 2004;77:99–108 108. de Jonge GA, Lanting CI, Brand R, Ruys JH, Semmekrot BA, van Wouwe JP. Sudden infant death syndrome in child care settings in The Netherlands. Arch Dis Child. 2004;89: 427–430 109. Moon RY, Patel KM, Shaefer SJ. Sudden infant death syndrome in child care settings. Pediatrics. 2000;106(2 Pt 1): 295–300 110. Moon RY, Sprague BM, Patel KM. Stable prevalence but changing risk factors for sudden infant death syndrome in child care settings in 2001 Pediatrics. 2005;116:972–977 111. Moon RY, Horne R, Hauck FR. Sudden infant death syndrome. Lancet. 2007;370:1578–1587 112. Opdahl SH, Rognum TO. The sudden infant death syndrome gene: does it exist? Pediatrics. 2004;114(4):e506–e512 113. Oyen N, Skjaerven R, Irgens LM. Population-based recurrence risk of sudden infant death syndrome compared with

2  Sudden Infant Death Syndrome: Gene–Environment Interactions other infant and fetal deaths. Am J Epidemiol. 1996;144: 300–305 114. Guntheroth WG, Lohmann R, Spiers PS. Risk for sudden infant death syndrome in subsequent siblings. J Pediatr. 1990;116:520–524 115. Carpenter RG, Waite A, Coombs RC, et al. Repeat sudden unexpected and unexplained infant deaths: naturals or unnatural? Lancet. 2005;365:29–35 116. Thompson MW, Hunt CE. Control of breathing. In: MacDonald MG, Mullett MD, Seshia MMK, eds. Neonatology: pathophysiology and management of the

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newborn. 6th ed. Philadelphia: Lippincott Williams and Wilkins; 2005 117. Matturri L, Biondo B, Suarez-Mier MP. Brain stem lesions in the sudden infant death syndrome: variability in the hypoplasia of the arcuate nucleus. Acta Neuropathol.2002;104:12–20 118. Kinney HC, Myers MM, Belliveau RA, et  al. Subtle autonomic and respiratory dysfunction in sudden infant death syndrome associated with serotonergic brainstem abnormalities: a case report. J Neuropathol Exp Neurol. 2005;64:689–694 119. Ackerman MJ. Unmasking concealed long QT syndrome. Heart Rhythm. 2008;5:8–10

Part Arrhythmias and sudden cardiac death. The initial investigation

II

3

Unexplained Syncope Carlos A. Morillo and Víctor Expósito-García

3.1 Unexplained Syncope Syncope is defined as a transitory and self-limited loss of consciousness, with spontaneous recovery. Syncope is a frequent clinical entity, leading to 1–3% of emergency department visits and 1–6% of hospital admissions, with a significant consumption of health care resources.1 Up to 35% of people are expected to present at least one syncopal episode throughout their life time; however it is estimated that less than 50% will seek medical care.2 Syncope in the elderly is of great concern in this growing population due to the high incidence, frequent recurrences, association with falls and injuries, and multicausal nature of syncope.3,4 Evaluation of the patient with syncope is a diagnostic challenge. Syncope can be a harbinger of sudden death; iden­tification of the patient is at risk of dying is of utmost importance, but remains a challenge. This chapter will focus on the diagnostic approach of the patient presenting with syncope based on current guideline recommendations. Risk stratification will also be reviewed.

3.2 Definition and Pathophysiology of Syncope Syncope is defined as a transitory and self-limited loss of consciousness, with loss of postural tone usually of rapid onset, and spontaneous prompt recovery. The underlying

C. A. Morillo (*) Department of Internal Medicine, Cardiology Division, Arrhythmia Service, McMaster University/Hamilton Health Sciences, HGH-McMaster Clinic 5th Floor, 237 Barton Street East, Hamilton, ON, Canada L8L2X2 e-mail: [email protected]

mechanism is a brief transient global cerebral hypo-perfusion. The minimum oxygen requirements necessary to maintain consciousness is 3.5 mLO2/100 g cerebral tissue per minute, while in a healthy young person, cerebral flow is in the range of 50–60  mL/100  g. These requirements are easily reached through perfusion pressure modulation according to cerebrovascular autoregulatory capability characteristics.5 In the same way, cerebral blood flow maintenance in healthy individuals depends on control mechanisms, including: (a) cerebral vasodilatation due to decreases in O2 pressure, or increases in CO2 partial pressure, (b) baroreceptor adjustment in heart rate and peripheral vascular resistance, and (c) regulation of intravascular volume by neurohumoral system.

3.3 Etiology of Syncope The most common causes of syncope are summarized in Table 3.1. By far, the most frequent cause of syncope is neurally-mediated reflex syncope, of which vasovagal syncope is the most frequent clinical presentation. Other manifestations of neurally-mediated reflex syncope include situational syncope, postprandial syncope, and carotid sinus hypersensitivity. Overall, neurallymediated reflex syncope represents 55–60% of the causes of syncope in most series.5 Vasovagal syncope is usually seen in healthy patients without evidence of structural heart disease. Clinical presentation in subjects  < 50 years is usually associated with marked prodromal symptoms such as nausea, vomiting, dizziness, lightheadedness, blurred vision, tinnitus, pallor, and severe diaphoresis that occur a few minutes to seconds prior to the onset of syncope. In elderly patients, clinical manifestations

R. Brugada et al. (eds.), Clinical Approach to Sudden Cardiac Death Syndromes, DOI: 10.1007/978-1-84882-927-5_3, © Springer-Verlag London Limited 2010

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C. A. Morillo and V. Expósito-García

Table 3.1  Etiology of syncope Neurally- mediated reflex syncope

Neurocardiogenic syncope (vasovagal) Carotid sinus syndrome-hypersensitivity Situational syncope Postprandial hypotension

Rhythm disturbances

Bradyarrythmias Sinus node dysfunction AV conduction system disease Tachyarrythmias Atrial fibrilation and atrial flutter Paroxysmal supraventricular tachycardia Ventricular tachyarrythmias Channelopathies (long QT, short QT, Brugada, malignant early repolarization, cathecolaminergic polymorphic ventricular tachycardia)

Orthostatic

Autonomic failure Primary autonomic failure multiple system atrophy Secondary autonomic failure (diabetic neuropathy, amyloidosis) Drugs Volume depletion

Mechanical/structural

Valvulopathies (aortic stenosis) Obstructive cardiomyopathy Atrial myxoma Cardiac tamponade Pulmonary embolus

Cerebrovascular

Vascular steal syndromes

Nonsyncopal attacks

Metabolic disorders (hypoglycemia, hypoxia, hyperventilation – hypocapnia) Epilepsy Transient ischemic attack Somatization disorders

are blunted and often not recognized by the patient in addition to amnesia of the loss of consciousness in up to 40% of cases.6 The prodrome in this population is usually either nonexistent or very short, and overlap with other neurally-mediated reflex causes of syncope such as carotid sinus syndrome, and orthostatic hypotension is not infrequent.7 Carotid sinus syndrome and hypersensitivity are frequently under diagnosed and may manifest as recurrent falls8. Defined by a drop of  > 50  mmHg in systolic blood pressure, associated or not, with severe bradycardia  < 40 bpm, or asystole  > 3 s.9 Carotid sinus hypersensitivity should be suspected in older patients (>50 years old) with history of recurrent unexplained syncope or falls. Orthostatic intolerance leading to syncope related with autonomic dysfunction or triggered by drug administration is more frequent also in elderly patients in which multiple causes of syncope usually co-exist (Table 3.2).10

The second most prevalent cause of syncope is associated with cardiac disorders, which are either due to electrical or mechanical alterations. Electrical causes of syncope include both brady and tachyarrhythmias, and these are the causes of syncope in 20% of cases. Mechanical causes are classified as obstruction to either the left or right ventricular outflow leading to abrupt reduction in stroke volume and syncope.5 The most frequent cause of bradyarrhythmias is sick sinus syndrome, manifested by profound sinus bradycardia or sinus pauses  > 3 s, occasionally associated with atrial fibrillation with increased ventricular rate followed by significant pauses after abrupt termination of tachycardia (brady-tachy syndrome).5,10 Other causes of bradyarrhythmic syncope include atrio-ventricular blocks Mobitz type II, “high grade” and complete heart block. Supraventricular tachyarrythmias per se are infrequently associated with syncope. In this setting, a high ventricular rate (>250 bpm) associated with left

3  Unexplained Syncope

27

Table 3.2  Drugs associated with syncope Drug-induced long QT Drug-induced orthostatic hypotension Sotalol

Diuretics

Cisapride

Calcium antagonists

Amiodarone

Angiotensin-converting enzyme inhibitors

Erythromycin

Nitrates

Ibutilide

Beta blockers

Terfenadine

Antipsychotic drugs

Quinidine

Antihistamines

Clarithromycin

Levo-dopa

Haloperidol

Anticholinergic drugs

Fluoxetine

Narcotics Alcohol

ventricular systolic dysfunction may lead to syncope. Syncope associated with SVT is triggered by a neurally-mediated reflex and not related with the accelerated ventricular response.5,10 One exception is patients with pre-excited supraventricular tachycardias and atrial fibrillation that can lead to ventricular fibrillation (Fig. 3.1). Ventricular tachycardia is associated with syncope in 15% of cases documented at electrophysiological studies. The incidence of syncope during VT is higher

Fig. 3.1  Prexcited atrial fibrillation manifesting with syncope

with rates  > 200  bpm, (30%), compared to only 5% when the rate is  < 200  bpm. There are other factors that determine hemodynamic stability during VT such as baroreceptor reflex gain.11 Polymorphic ventricular tachycardia can be a manifestation of acute ischemia, or congenital channelopathies such as the long QT syndrome and Brugada syndrome. These genetic disorders should be ruled out in young individuals with syncope without prodrome, or triggered by exercise.12 The newly described malignant early repolarization syndrome has also been noted to manifest with syncope or sudden cardiac death associated with polymorphic ventricular tachycardia.13 Acquired long QT syndrome is associated with a myriad of medications, and knowledge of this potential life-threatening adverse effect should always be taken into account when assessing a patient presenting with unexplained syncope (Table 3.2). Rare causes of syncope or neurological causes of transient loss of consciousness represent  < 1% of those referred to emergency units.14 The elderly presenting with recurrent unexplained syncope or falls is at risk of injuries and usually has multiple causes of syncope.5,7 Several age-related changes (disturbances in autonomic function, increased vascular stiffness, decreased coronary vasodilatation, impaired diastolic filling, renal dysfunction, and decreased thirst perception) and age-associated changes (greater incidence of cardiac disease, comorbid illness, and polypharmacy) increase the susceptibility, and

28

pose a challenge from the diagnostic perspective. The atypical presentation usually without prodrome and denial of syncope due to amnesia of the episode is a classic manifestation that delays appropriate and timely diagnosis.7 In summary, neurally-mediated reflex syncope remains the most frequent cause of recurrent episodes of unexplained syncope in all age groups, primarily those without overt heart disease, although the presence of cardiac disease does not rule out neurallymediated reflex causes of syncope.15 Simple clinical markers such as those validated in the Calgary Syncope Score have been devised and aid in determining whether an episode of syncope is indeed due to a neurally-mediated reflex. Namely, typical clinical presentation, age of onset and absence of ECG alterations composes this simple and highly sensitive and specific score.16 Orthostatic hypotension should routinely be sought, particularly in the elderly and deconditioned, as syncope is frequently the cause of unexplained falls and injuries.17,18

3.4 Risk Stratification The main determinant of risk in patients with syncope is the presence and severity of cardiac disease. Cardio­ myopathies are the most important prognostic factor in syncope evaluation, and this is independent of the cause of syncope.19 In fact, patients with cardiac causes of syncope do not have a higher mortality when compared with their matched controls with similar degrees of heart disease.20 In this setting, identifying patients with low risk of cardiovascular events or sudden cardiac death can be easily achieved by obtaining clinical data and electrocardiographic features. The OESIL score can rapidly aid in determining risk of death by estimating a point score based on 4 simple markers namely, age  > 65  years, history of cardiac disease (heart failure, CAD, Valvular disease, LV dysfunction), syncope without prodrome, and baseline ECG abnormalities.21,22 Patients with a score  > 2 have an annual mortality that is greater than 30%. More recently, the STEPS investigators provided further evidence supporting the afore-mentioned markers as powerful risk stratifiers; in addition, short and longterm markers identified included the presence of trauma during syncope and male gender as well as

C. A. Morillo and V. Expósito-García

ventricular arrhythmias respectively.23 Other markers of poor prognosis include the presentation of syncope during exercise and a family history of sudden cardiac death. In summary, patients presenting with syncope older than 65  years have structural heart disease, abnormal ECG, syncope without prodrome, injury during the episode, syncope during exercise, and are males, carrying a higher risk, and should be admitted to hospital for complete assessment and prompt diagnosis.

3.5 Initial Evaluation 3.5.1 History and Physical Examination A detailed history and physical examination remains the cornerstone in the evaluation of the patient with syncope.24 It is important to acknowledge that syncope is a sign, and not a disease in itself. Obtaining information usually from a witness is vital in establishing precipitating circumstances and the presence of prodromic symptoms as sweating, nausea, vomiting, blurred vision, and palpitations. Similarly, exploring the circumstances surrounding the syncopal episode such as angina, exercise, other situational circumstances such as urination or defecation, post prandial or sleep, are indispensable. The presence of family history of unexplained seizures and early sudden death should be systematically obtained. It is of utmost importance to determine whether the episode is indeed syncope or not. Transient loss of consciousness is not always due to syncope and establishing this fact from the onset in the evaluation is critical. Seizures are frequently and inappropriately classified as syncope, which is in fact a misnomer. Several clinical markers described by Sheldon et  al aid in discriminating between syncope and seizures and include the presence of urinary incontinence, tongue biting, déjà vu, and other clinical manifestations that are clearly associated with seizures.25 A thorough physical examination primarily searching for evidence of structural heart disease, orthostatic intolerance, or other potential vascular abnormalities is routinely recommended. An exhaustive and systematic history and physical examination uncovers the cause of syncope in approximately 50% of cases.26

3  Unexplained Syncope

29

3.5.2 Baseline Electrocardiogram

3.6.2 Echocardiogram

The 12-lead ECG can demonstrate abnormalities in up to 75% of patients presenting with syncope at an emergency department; however these alterations are incidental, and are rarely related with the cause of syncope. Nonetheless, a normal ECG carries a low likelihood of an arrhythmia or cardiac cause of syncope.17 ECG abnormalities that should raise suspicion of an arrhythmic cause include: bifascicular block (including LBBB) or other intraventricular conduction disturbances, second-degree AV-block Mobitz II, non sustained ventricular tachycardia; ventricular pre-excitation; QT interval prolongation; Brugada or right ventricular dysplasia patterns, and the so-called malignant early repolarization.13,21,27

Echocardiogram is recommended in patients with syncope when cardiac origin is suspected. Searching for left ventricle hypertrophy, segmental contractility disturbances; valve disease or decreased systolic function should be routinely pursued. Initial evaluation is once again of capital importance, because only 5–10% of unselected patients had been reported to present unsuspected findings.35

3.6 Noninvasive Tests 3.6.1 Ambulatory Monitoring (“Holter”) Ambulatory ECG monitoring (“Holter”) is frequently indiscriminately ordered but rarely identifies the cause of syncope. The main limitation of this test is the lack of correlation between ECG findings and syncope. Overall, the diagnostic capacity with this method is only around 5%. The presence of rhythm disturbances without symptoms is frequently observed and generally irrelevant to determine the cause of syncope.28,29 In fact, ventricular ectopic beats, second-degree AV block, or even sinus pauses of 2 s are considered within normal limits. The significance and prognosis of pauses greater than 3 s in asymptomatic people remains controversial, with arguments in favor and against pacemaker implantation.30-32 In our experience, 24 h in-hospital monitoring following admission after a syncopal episode is more useful than ambulatory recordings. Adding these data to baseline ECG abnormalities allows diagnosis of a presumptive cause of syncope in more than 20% of patients referred to the emergency department particularly if bradyarrythmias such as sick sinus syndrome with significant pauses or high- grade AV block.18 In summary, ambulatory ECG monitoring has a low diagnostic yield in patients with recurrent syncope yield may be higher in patients with baseline under­lying ECG abnormalities and routine use is not recommended.33,34

3.6.3 Exercise Testing Exercise testing is not a part of the routine evaluation of the patent with syncope and should be indicated only in patients with syncope induced by exercise. The induction of repetitive ectopic ventricular beats or sustained monomorphic ventricular tachycardia or polymorphic bi-directional ventricular tachycardia associated with presyncope or syncope diagnostic. Assessment of the dynamic properties of the QT interval is also of value when assessing patients with syncope induced by exercise. In the pediatric population, syncope can be triggered by exercise in patients with congenital coronary artery abnormalities.

3.6.4 Tilt Test Tilt tilt-table test remains a useful diagnostic test primarily in patients with recurrent syncope in the absence of structural heart disease. Clinical manifestations usually clearly identify the patient with neurally reflex syncope of the vasovagal type.36-40 Several protocols are available and this limits the interpretation of the test. Nevertheless, some consensus is available as reported in recent ACC and ESC guidelines.41 We use a tilt angle of 70º, with a passive phase (without medication) of 15 min. If the patient remains asymptomatic and is under 40 years of age, an isoproterenol infusion (1 mcg/min, increasing doses progressively until an increase in heart rate of 25%, or a maximum dose of 3  mcg/min is achieved), or nitroglycerin (0.4 mg) in patients  > 40 years, is started, for another 15  min. The diagnostic accuracy and

30

C. A. Morillo and V. Expósito-García

specificity is higher with pharmacological enhancement and around 90%.42,43 The end-point of the test is induction of syncope with hypotension < 70 mmHg with/without bradycardia < 50 bpm, with a variety of responses that are summarized in Table 3.3. Recent studies suggest that patients with structural heart disease and negative electophysiologic study may undergo tilt-table testing.44

3.6.5 Adenosine/ATP Test The European Society of Cardiology has included the ATP test as an “experimental” test on the diagnosis of unexplained syncope given that there is some evidence that this test may identify patients with a higher rate of spontaneous paroxysmal complete AV block when an 18 mg dose of adenosine is followed by  > 6 s of ventricular asystole due to complete AV block, or > 10  s phase III response (total duration of complete heart block, even if interrupted by escape complexes).45 However, interpretation of response to adenosine test, and therapy according to this response, remains controversial. In a nonrandomized study, patients with positive test treated with pacemaker implantation had a significant lower likelihood of syncope recurrences,46 but later studies failed to confirm these findings.47,48 We currently use the ATP/Adenosine test in older patients with unexplained syncope and a negative work-up that have ECG alterations such as bundle branch block or AV conduction disease. If the test is “positive,” we routinely implant a loop recorder to further confirm the need of a pacemaker. Of note the new

ESC syncope guidelines do not recommend performing this test.

3.7 Invasive Testing 3.7.1 Electrophysiological Study The use of programmed electrical stimulation (PES) to determine the cause of syncope has markedly changed in the last few decades and indications for PES to identify the cause of syncope are more limited. One of the limitations is the lack of direct correlation between the induction of electrophysiological disturbances and spontaneous syncope in a controlled environment49 and the poor specificity in patients with documented bradyarrhythmic causes of syncope.50,51 PES is indeed useful in selected patients.52-57 Current ACC/AHA and ESC guidelines, recommend PES in patients with syncope in the presence of structural cardiomyoptahy as a class I indication.5 From the practical perspective, patients with LV dysfunction £35 with unexplained syncope should receive an ICD, regardless of whether this is related or not, with the cause of syncope. Patients with syncope and mild LV dysfunction may be appropriate candidates for PES evaluation.52 Patients with overt conduction abnormalities in the surface ECG and unexplained syncope particularly, if presenting without prodrome may benefit from PES; however, the specificity of this test is low in this setting and either empiric pacing or an implantable loop recorder, as discussed later may be indicated. PES in patients without evidence of structural heart disease has a very low diagnostic yield and should be avoided. One exception is patients that present with syncope

Table 3.3  Classification of positive responses to tilt testing Type 1

Mixed

Heart rate falls at the time of syncope, but ventricular rate does not fall to less than 40 bpm, or falls to less than 40 bpm for less than 10 s with or without asystole of less than 3 s. Blood pressure falls before the heart rate falls

Type 2A

Cardioinhibition without asystole

Heart rate falls to a ventricular rate less than 40 bpm for more than 10 s, but asystole of more than 3s does not occur. Blood pressure falls before the heart rate falls

Type 2B

Cardioinhibition with asystole

Asystole occurs for more than 3s. Blood pressure fall coincides with or occurs before the heart rate fall

Type 3

Vasodepressor

Heart rate does not fall more than 10% from its peak at the time of syncope

Exception 1: Chronotropic incompetence. No heart rate rise during the tilt testing (i.e., less than 10% from the pretilt rate) Exception 2: Excessive heart rate rise. An excessive heart rate rise, both at the onset of the upright position and throughout its duration before syncope (i.e., greater than 130 bpm)

3  Unexplained Syncope

31

and no prodrome, as these patients are at high risk of having life-threatening arrhythmias (Fig. 3.2).

3.7.2 Implantable Loop Recording The development of an implantable loop recorded (ILR) by the group at the University of Western Ontario paved the way to providing real-time rhythm and symptom correlation during spontaneous episodes of syncope.58 The ILR can provide up to 36  months of monitoring and register events either triggered by the patient or spontaneous, based on the current diagnostic algorithms available (Fig.  3.3). Several studies have validated the use of the ILR in patients with recurrent unexplained syncope identifying the cause of syncope in up to 88% depending on the population selected.59,60

S1: 400

More than a decade of experience with the ILR has been accumulated and the main cause of syncope in most series is a bradyarrhythmia. These patients are invariably older and usually have a baseline conduction disorder (left bundle branch block), although a significant proportion have paroxysmal AV block.61-65

3.8 Diagnostic Approach of Unexplained Syncope Evaluation of a patient with syncope whose etiology remains unknown after the first approach, including noninvasive methods (syncope of unknown origin) remains a challenging task. This has led to the implementation of algorithms for the approach of syncope in the emergency department.66 Adherence to these

500 ms

240 I S2: S3: 230 S4: 200

II aVR V1 HRA RVa HIS d HIS p ABL d ABL p CS 9,10 CS 7,8 CS 5,6 CS 3,4 CS 1,2 S1

Stim 2

S1

S1

S2

S3 S4

Fig.  3.2  Programmed electrical stimulation in a 35-year-old man with 2 episodes of syncope and no prodrome, minor head trauma after one of the episodes, no structural heart disease and no family history of sudden cardiac death. Tracing show surface

ECG lead I, II, aVR, an V1, intracardiac recordings from the high right atrium (HRA) right ventricular apex (RVa), His bundle, and coronary sinus. 3 estrastimulus induce ventricular flutter

32

C. A. Morillo and V. Expósito-García

Fig. 3.3  Implantable loop recording retrieved from a 40-year-old man with recurrent syncope and no prodrome. Tracing shows initially PVC’s and followed by a long sustained episode of ventricular flutter Syncope/TLOC High Risk

Low Risk ECG[−] Prodrome no Injuries <65yr. No SHD [−] Fm Hx SCD

ECG[+] No Prodrome Injuries >65yr. Syncope with exercise SHD [+]Fm Hx SCD

Echocardiogram

DC Home

ADMIT Echo LV >40%

Echo LV <35%

Echo LV 35−40%

no prodrome Tilt Test < 40 yr Isoproterenol > 40 yr NTG

(−)

EPS

(−)

PSVT

VT

(−) investigation

Unstable ICD

Stable Recurrent syncope

Fig. 3.4  Algorithmic approach for the patient with syncope. BBB bundle branch block; DC discharge; EPS electrophysiologic study; Fx family; Hx history; PSVT paroxysmal supraventricular tachycardia; SHD structural heart disease; TLOC transient loss of consciousness

RF ablation

Implantable Loop Recorder BBB: Bundle branch block DC: discharge Fx: family Hx: History

EPS: Electrophysiologic study PSVT: Paroxysmal supraventricular tachycardia SHD: Structural heart disease TLOC: Transient loss of consciousness.

3  Unexplained Syncope

recommendations enables physicians to significantly improve diagnostic rates, reducing unnecessary admissions and thereby decreasing costs.24,67-69 Recently, the implementation and development of Syncope Units has markedly improved diagnostic accuracy and outcomes in the emergency department.70 In spite of systematic evaluations, around 10–20% of patients may remain with unexplained syncope. The main goal in these patients is to determine whether recurrence is high and what is the risk of adverse events. The presence of structural heart disease, in particular the degree of left ventricular systolic dysfunction, old age, presentation without prodrome, and the presence of ECG abnormalities pretty much select the group at higher risk. Overall, the recurrence rate is also related with the underlying cause and neurally-mediated reflex causes remain the most common etiology of syncope, both explained and unexplained; these subjects have a good prognosis and mortality similar to the general population.2 Another population with high recurrence rates and risk of injury and mortality is the elderly, and frequently, multiple causes are responsible.71 Finally, the patient with frequent recurrent episodes that does not have associated injuries or structural heart disease poses a challenge and frequently has pseudo-syncope, and further psychological evaluation is warranted in this subgroup.72 Figure 3.4 summarizes our algorithm for the evaluation of the patient with recurrent syncope, keeping in mind that each patient must be individualized. In summary, unexplained syncope can be caused by multiple etiologies, and neurally-mediated reflexes remain the most frequent cause. A systematic approach and careful history and physical examination may disclose the cause in most patients.73A keen eye should always be kept open when syncope present without overt prodromal symptoms as these patients, even in the absence of structural heart disease carry a significant risk of mortality and sudden cardiac death.

References   1. Kapoor WN. Evaluation and outcome of patients with syncope. JAMA. 1992;268:2553–2560   2. Soteriades ES, Evans JC, Larson MG, et al. Incidence and prognosis of syncope. N Engl J Med. 2002;347:878–885   3. Lipsitz LA, Pluchino FC, Wei JY, et al. Syncope in an elderly institutionalized population: prevalence, incidence and associated risk. Q J Med. 1985;55:45–54

33   4. Roussanov O, Estacio G, Capuno M, et al. New-onset syncope in older adults: focus on age and etiology. J Am Geriatric Cardiol. 2007;16:287–294   5. Brignole M, Alboni P, Benditt DG, et al. Task force on syncope, European Society of Cardiology. Guidelines on management (diagnosis and treatment) of syncope-update 2004 Eur Heart J. 2001;25:2054–2072   6. Ptan MP, Parry SW. Vasovagal syncope in the older patient. J Am Coll Cardiol. 2008;52:599–606   7. Didyk N, Morillo CA. Falls, dizziness and syncope in the very old. In: Heckman G, Turpie I, eds. Aging Issues in Cardiology. Norwell, MA: Kluwer; 2004:115–133   8. Parry SW, Steen IN, Baptist M, Kenny RA. Amnesia for loss of consciousness in carotid sinus syndrome: implications for presentation with falls. J Am Coll Cardiol. 2005;45: 1840–1843   9. Healy J, Connolly SJ, Morillo CA. The management of patients with carotid sinus syndrome: is pacing the answer? Clin Auton Res. 2004; 14(suppl 1):80–86 10. Morillo CA. Diagnostic evaluation and management of syncope. In: Hess ME, ed. Heart Disease in Primary Care. Baltimore: Williams & Wilkins; 1999:266–275 11. Landolina M, Mantica M, Pessano P, et al. Impaired baroreflex sensitivity is correlated with hemodynamic deterioration of sustained ventricular tachycardia. J Am Coll Cardiol. 1997;29:568–575 12. Brugada J, Brugada R, Brugada P. Channelopathies: a new categories of diseases causing sudden death. Herz. 2007; 32:185–191 13. Haissaguerre M, Derval N, Sacher F, et al. Sudden cardiac arrest associated with early repolarization. N Engl J Med. 2008;358:2016–2023 14. Alboni P, Brignole M, Menozzi Z, et al. The diagnosis value of history in patients with syncope with or without heart disease. J Am Coll Cardiol. 2001;37:1921–1928 15. Kapoor W, Snustad D, Peterson J. Syncope in the elderly. Am J Med. 1986;80:419–428 16. Sheldon R, Rose S, Connolly S, et al. Diagnostic criteria for vasovagal syncope based on a quantitative history. Eur Heart J. 2006;27:344–350 17. Ooi WL, Barrett S, Hossain M, et al. Patterns of orthostatic blood pressure change and their clinical correlates in a frail, elderly population. JAMA. 1997;277:1299–1304 18. Luukinen H, Koski K, Laippala P, et  al. Prognosis of diastolic and systolic orthostatic hypotension in older persons. Arch Intern Med. 1999;159:273–280 19. Middlekauff HR, Stevenson WG, Stevenson LW, et al. Syncope in advanced heart failure: high risk of sudden death regardless of origin of syncope. J Am Coll Cardiol. 1993;21: 110–116 20. Kapoor WN, Hanusa B. Is syncope a risk factor for poor outcomes? Comparison of patients with and without syncope. Am J Med. 1996;100:646–655 21. Colivicchi F, Ammirati F, Melina D, et al. Development and prospective validation of a risk stratification system for patients with syncope in the emergency department: the OESIL risk score. Eur Heart J. 2003;24:811–819 22. Martin T, Hanusa B, Kapoor W, et al. Risk stratification of patients with syncope. Ann Emerg Med. 1997;29:459–466 23. Constantino G, Perego F, Diapola F, et al. Short-and longterm prognosis of syncope, risk factors, and role of hospital admission: esultls from the StePS (short-term prognosis of syncope) Study. J Am Coll Cardiol. 2008;52:276–283

34 24. Croci F, Brignole M, Alboni P, et al. The application of a standardized strategy of evaluation in patients with syncope  referred to three syncope units. Europace. 2002;4: 351–355 25. Sheldon R, Rose S, Ritchie D, et al. Historical criteria that distinguis syncope from seizures. J Am Coll Cardiol. 2002; 40:142–148 26. Kapoor W, Karpf M, Wieland S, et al. A prospective evaluation and follow-up of patients with syncope. N Engl J Med. 1983;309:197–204 27. Rodriguez-Entem F, Gonzalez-Enriquez S, Olalla-Antolin JJ, et al. Management of syncope in the emergency department without hospital admission: usefulness of an arrythmya unit  coordinated protocol. Rev Esp Cardiol. 2008;61(1): 22–28. 28. Kapoor W. Syncope-past, present and future. Clin Auton Res. 2004;14(suppl 1):1–3 29. Morillo CA. Evaluacion diagnostica del paciente con sincope. Medicas UIS. 1994;8:174–181 30. Ector H, Rolies L, De Ges H. Dynamic electrocardiographic and ventricular pauses of three seconds and more: etiology and therapeutic implications. PACE. 1983;6:548–551 31. Hilgard J, Ezri MD, Denes P. Significance of ventricular pauses of three seconds and more detected by 24 hour Holter recordings. Am J Cardiol. 1985;55:1005–1008 32. Baranchuk A, Morillo CA. Sincope neurocardiogenico. Alter­nativas actuales de tratamiento. Farmacología Cardiovasc. 2004; 1(2):9–13 33. Kapoor W. Evaluation and outcome of patients with syncope. Medicine. 1990;69:160–175 34. DiMarco JP, Philbrick JT. Use of ambulatory electrocardiographic ( Holter ) monitoring. Ann Intern Med. 1990; 113: 53–68 35. Krumholz HM, Douglas PS, Goldman L, et al. Clinical utility of trans-thoracic two-dimensional and Doppler echocardiography. J Am Coll Cardiol. 1994;24:125–131 36. Kenny RA, Ingram A, Bayliss J, et al. Head-up tilt: a useful test for investigating unexplained syncope. Lancet. 1986;1:1352–1354 37. Tavill CM, Sutton R, Vardas P, et al. Incidence of malignant vasovagal syndrome in patients presenting with syncope. New trends in arrhythmias. 1988;4:769–774 38. Fitzpatrick A, Theodorakis G, Vardas PTI, et  al. The incidence of malignant vasovagal syndrome in patients with recurrent syncope. Eur Heart J. 1991;12:389–394 39. Abi-Samra F, Maloney JD, Fouad-Tarazi FM, et al. Head-up tilt-testing: an important tool in the work-up of recurrent syncope of unknown etiology [ summarize]. J Am Coll Cardiol. 1986;7:126 40. Abi-Samra F, Maloney JD, Fouad-Tarazi FM, et al. The usefulness of head-up tilt testing and hemodynamic investigations in the workup of syncope of unknown origin. PACE. 1988;11:1202–1214 41. Benditt DG, Ferguson DW, Grub BP, et al. ACC expert consensus document. Tilt test for assessing syncope. J Am Coll Cardiol. 1996;28:263–275 42. Morillo CA, Zandri S, Klein GJ, et al. Diagnostic accuracy of a low-dose isoproterenol head-up tilt protocol. Am Heart J. 1995;129:901–906 43. Guzmán JC, Kamath MV, Dillenburg R, et al. Cardiodynamic characterization during head-up tilt test in patients with neurocardiogenic syncope. Clin Auton Res. 2004;14:280

C. A. Morillo and V. Expósito-García 44. García-Civera R, Sanjuán-Máñez R, Ruiz-Granell R, et al. Diagnostic accuracy of a protocol in the evaluation of unexplained syncope. Rev Esp Cardiol. 2001;54:425–430 45. Brignole M, Alboni P, Bemditt DG, et  al. Guidelines on management ( diagnosis and treatment ) of syncope. Eur Heart J. 2001;22:1256–1306 46. Flammang D, Church T, Wayuberger M, et al. Can adenosine 5’-triphosphate be used to select treatment in severe vasovagal syncope? Circulation. 1997;1996:1201–1208 47. Chenng J, Stein K, Markowitz S, et al. Significance of adenosine-induced atrioventricular block in patients with unexplained syncope. Heart Rhytm. 2004;1:664–668 48. Donateo M, Brignole M, Menozzi C, et  al. Mechanism of syncope in patients with positive adenosine triphosphate test. J Am Coll Cardiol. 2003;41:93–98 49. Garcia-Civera R. Estudios electrofisiológicos en pacientes con síncope. Electrofisiología cardíaca clínica y ablación. Madrid: McGraw-Hill; 1999:365–374 50. Fujimura O, Yee R, Klein GJ, et al. The diagnostic sensitivity of electrophysiologic testing in patients with syncope caused by transient bradycardia. N Engl J Med. 1989;321: 1703–1707 51. Klein GJ, Gersh BJ, Yee R. Electrophysiologic testing: the final court of appeal for diagnosing syncope? Circulation. 1995;92:1332–1335 52. Teichman SL, Felder SD, Matos JA, et al. The value of electrophysiologic studies in syncope of indetermined origin: report of 150 cases. Am Heart J. 1985;110:469–479 53. Hess DS, Morady F, Scheinman MM. Electrophysiologic testing in the evaluation of patients with syncope of undetermined origin. Am J Cardiol. 1982;50:1309–1315 54. Galamhuseim S, Naccarelli GV, Ko PT, et al. Value and limitations of clinical electrophysiologic study in assessment of patients with unexplained syncope. Am J Med. 1982;73: 700–705 55. Akhtar M, Shenasa M, Denker S, et al. Role of electrophysiologic studies in patients with unexplained recurrent syncope. PACE. 1983;6:192–201 56. Krol RB, Morady F, Flaker GC, et  al. Electrophysiologic testing in patients with unexplained syncope: clinical and noninvasive predictors of outcome. J Am Coll Cardiol. 1987;10:358–363 57. Muller T, Roy D, Talajic M, et al. Electrophysiologic evaluation and outcome of patients with syncope of unknowm origin. Eur Heart J. 1991;12:139–143 58. Lee BB, Claxton MB, Yee R, et  al. First results using an implantable arrhythmia monitor. PACE. 1993;16:893 59. Krahn AD, Klein GJ, Yee R, et  al. Final results of a pilot study with an implantable loop recorder to determine the ­etiology of syncope in patients with negative noninvasive and invasive testing. Am J Cardiol. 1998;82:117–119 60. García-Civera, in name of International Study on Syncope of Unknown Origin ( ISSUE ). Rendimiento diagnóstico del Holter implantable en pacientes con síncope recurrente de causa desconocida. Rev Esp Cardiol. 1999;52:108 61. Krahn AD, Klein GJ, Norris C, et al. The etiology of syncope in patients with negative tilt table and electrophysiologic testing. Circulation. 1995;92:1819–1824 62. Morillo CA. Utilidad del monitor implantable de síncope. Rev Soc Cardiol Estado de Sao Paulo. 1999;2:267–276 63. Paylos J, Aguilar-Torres R. Usefulness of the implantable loop recorder in the diagnosis of recurrent syncope of unknown etiology in patients without structural heart dis-

3  Unexplained Syncope ease and negative tilt test and electrophysiological study. Rev Esp Cardiol. 2001;54:431–442 64. Brignole M, Menozzi C, Maggi R, et al. The usage and diagnostic yield of the implantable loop-recorder in detection of the mechanism of syncope and in guiding effective therapy in older people. Europace. 2005;7:273–279 65. Rodriguez-Entem F, González-Enríquez S, Olalla JJ, et al. The utility of implantable loop recorders for diagnosing unexplained syncope in clinical practise. Clin Cardiol 2009; 32:28–31 66. Disertori M, Brignole M, Menozzi C, et al. Management of patients with syncope referred urgently to general hospitals. Europace. 2003;5:283–291 67. Brignole M, Ungar A, Bartoletti A, et al. Standardized-care pathway vs usual management of syncope patients presenting as emergencies at general hospitals. Europace. 2006;8: 644–650 68. Brignole M, Alboni P, Benditt D, et al. Guidelines on management (diagnosis and treatment ) of syncope. Eur Heart J. 2001;22:1256–1306

35 69. Strickberger A, Benson W, Biaggioni I, et al. AHA/ACCF Scientific Statement on the evaluation of syncope. Circulation. 2006;113:316–327 70. Shen WK, Decker WW, Smars PA, et al. Syncope Evaluation in the Emergency Department Study ( SEEDS ): a multidisciplinary approach to syncope management. Circulation. 2004;90:52–58 71. Roussanov O, Estacio G, Capuno M, et  al. Outcomes of unexplained syncope in the elderly. Am J Ger Cardiol. 2007; 16:249–254 72. Linzer M, Felder A, Hackel A, et al. Psychiatric syncope: a new look at an old disease. Psychosomatics. 1990;31: 181–188 73 Moya A, Sutton R, Ammirati F, et al. HYPERLINK “/pubm ed/19713422?itool=EntrezSystem2.PEntrez.Pubmed. Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=6 ”Guidelines for the diagnosis and management of syncope (version 2009): The Task Force for the Diagnosis and Management of Syncope of the European Society of Cardiology (ESC). Eur Heart J. 2009 Nov; 30(21):2631–71

4

Arrhythmias and Sudden Cardiac Death in Adult Congenital Heart Disease Paul Khairy

Congenital heart disease is the leading category of birth defects, afflicting an estimated 75 of 1,000 live newborns, 25% of whom have moderate or severe disease.1 Over the last half century, the field of congenital heart disease has witnessed extraordinary strides. Whereas, decades ago, a minority of children with congenital heart defects survived to adulthood, current estimates project that 95% will prosper into their adult years.2-4 As a product of this astounding progress, the population of patients with congenital heart disease is rapidly growing and aging.5 Compellingly, adults now outnumber children with congenital heart disease.6 This remarkable achievement is mitigated, in part, by the recognition that lifelong care is required. Surgical interventions should be viewed as “reparative” rather than “curative”, as once over optimistically declared. The burden of disease is substantial, with high rates of health care resource utilization.7 Arrhythmias are the most common complication that adults with congenital heart disease encounter.8,9 Typically, these occur after lengthy dormant periods and may result from hemodynamic or hypoxic stress, postoperative sequelae, ­residual defects, comorbidities, and/or extracardiac mani­festations.10 Arrhythmias are the leading cause of morbidity and hospitalization.8,9,11,12 Moreover, sudden cardiac death is the most common cause of mortality, often occurring in young adult years.13,14

P. Khairy Montreal Heart Institute, University of Montreal, Montreal, QC, Canada H3A 1A1 e-mail: [email protected]

Arrhythmias in adult congenital heart disease (ACHD) are to be distinguished from congenitally ­inherited forms of suspected or established  genetic etiology.15,16 The majority may be explained by structural defects that support reentrant wavefronts,17-19 while triggered or automatic foci account for a smaller subset.20-22 Intraatrial reentrant tachycardias (IART) and atrial macroreentrant circuits are the most common atrial arrhythmias encountered. However, the entire spectrum of arrhythmias is represented in ACHD, from sinus node dysfunction, impaired intraatrial propagation, atrioventricular (AV) nodal block, and His-Purkinje disease to AV and atriofascicular accessory pathways, junctional rhythms, twin AV nodes, and atrial and ventricular tachyarrhythmias, with several subtypes often co-existing.23 Table 4.1 provides a summary of common arrhythmias according to type of congenital heart disease. The 12-lead electrocardiogram may provide valuable diagnostic and prognostic information.24 Typical electrocardiographic features are listed in Table 4.2. There is a paucity of evidence-based data to guide management decisions. With regards to pharmacological therapy, extrapolations concerning AV nodal blocking agents and antiarrhythmic drugs are made from guiding principles established in other forms of heart disease. These should consider the degree of systemic ventricular dysfunction, sinus node disease, impaired AV node conduction, negative inotropic effects, and potential proarrhythmic consequences. Medical therapy has traditionally faced limited success. In contrast, transcatheter ablation has emerged as a promising alternative in many patients. Anatomical complexities and underdeveloped or obstructed vascular access can pose unique challenges to catheter-based interventions and implantation of pacemakers or cardioverter-defibrillators.25 In certain circumstances, surgery may complement less invasive options.

R. Brugada et al. (eds.), Clinical Approach to Sudden Cardiac Death Syndromes, DOI: 10.1007/978-1-84882-927-5_4, © Springer-Verlag London Limited 2010

37

38

P. Khairy

Table 4.1  Summary of arrhythmias typically encountered in common forms of adult congenital heart disease Congenital heart Bradyarrhythmia Tachyarrhythmia disease type Atrial septal defect

RBBB; complete AV block rare

IART/AF with increasing age, particularly if late closure

Ventricular septal defect

AV block post surgical or transcatheter closure

Nonsustained or sustained VT, especially with pulmonary hypertension

Atrioventricular canal defect

Intraatrial conduction delay; AV block, especially postoperatively

IART/AF following surgical repair

Ebstein’s anomaly

Intraatrial conduction delay; AV block

IART; AV or atriofascicular (Mahaim) AP; sudden death if high risk or multiple APs; ectopic atrial tachycardia; AF; frequent PVCs

Left-sided obstructive lesions

Postoperative AV block

IART/AF with possible rapid conduction; primary VT/VF; sudden death

TGA with intraatrial baffle

Sick sinus syndrome; AV block if ventricular septal defect closure or tricuspid valve surgery

IART, NAFAT, AVNRT; primary VT/VF or secondary to atrial arrhythmia; sudden death

Congenitally corrected TGA

AV block

Accessory pathway if Ebstein-like systemic AV valve; primary VT/VF if dysfunctional systemic right ventricle

Tetralogy of Fallot

RBBB; AV block with coexisting AV canal defect

IART; monomorphic VT; primary VF; frequent PVCs; sudden death

Heterotaxy syndrome

Sick sinus syndrome with left atrial isomerism; bilateral sinus nodes with right atrial isomerism

Possible twin AV node-mediated tachycardia

Single ventricle with Fontan

Sick sinus syndrome; AV block in L-looped ventricles and/or AV canal defects

IART with potential for rapid conduction; NAFAT; AF; VT/VF if ventricle dysfunctional

Eisenmenger’s physiology

AV block in some univentricular hearts and AV canal defects

MAT; IART; AF; nonsustained or sustained VT/VF; sudden death

ALCAPA

AV block following anteroseptal VT/VF from myocardial hypoxemia myocardial infarction RBBB denotes right bundle branch block; AV atrioventricular; IART intraatrial reentrant tachycardia; AF atrial fibrillation; VT ventricular tachycardia; AP accessory pathway; PVC prematrue ventricular contraction; VF ventricular fibrillation; TGA transposition of the great arteries; NAFAT nonautomatic focal atrial tachycardia; AVNRT AV nodal reentrant tachycardia; MAT multifocal atrial tachycardia; ALCAPA anomalous origin of the left coronary artery from the pulmonary artery.

The objective of this chapter is to discuss the most common arrhythmias typically encountered in the various forms of ACHD.

4.1 Atrial Septal Defect The estimated incidence of atrial fibrillation or flutter in adults with atrial septal defects (ASDs) is approximately 20% and increases with age.26,27 Typical isthmus-dependent atrial flutter is the most common arrhythmia subtype in the absence of surgical repair. In the presence of

atriotomy incisions, suture lines, and/or patches, nonisthmus dependent IART may occur or coexist with typical flutter. Common circuits include macroreentry along the lateral right atrial wall or atriotomy incisions, and double-loop or figure-of-eight courses.28-30 ASD closure is generally indicated if associated with symptoms, right-sided volume overload, and/or a left-to-right shunt fraction that exceeds 1.5:1. Some recommend a “proactive” approach, with closure prior to right-sided hemodynamic ramifications.31 Surgical closure may decrease the occurrence of atrial arrhythmias, but less effectively in older patients.26,27,32-34 In a surgical series of 218 adults with isolated ASDs,

1o AVB > 50%

↑PR 10–20%

NSR; PVCs 30%

NSR; ↑IART/AF with age

NSR

NSR

NSR; possible EAR, SVT; AF/ IART 40%

NSR; PVCs; IART 10%; VT 12%

NSR

AV canal defect

Patent ductus arteriosus

Pulmonary stenosis

Aortic coarctation

Ebstein’s anomaly

Surgically repaired TOF

L-TGA

0–180o; RAD; LAD in Holt-Oran or LAHB

Normal or RAD; LAD 5–10%

Normal or mild ↑

LAD

Normal or LAD

1o AVB common; short if WPW

1o AVB > 50%; AVB 2%/year

Normal or LAD

Normal if mild; RAD with moderate/severe

Normal

Normal

Normal

Mod to extreme LAD; normal with atypical

Normal or mild ↑; RAD with BVH; 1o AVB 10% LAD 3–15%

NSR; PVCs

Ventricular septal defect

1o AVB 6–19%

NSR; ↑IART/AF with age

Secundum atrial septal defect

Table 4.2  Typical electrocardiographic features in common forms of ACHD Congenital Rhythm PR interval QRS axis diagnosis

Absence septal q; Q in III, avF and right precordium

RBBB 90%

Low amplitude multiphasic atypical RBBB

Diminutive RV

LVH, especially by voltage criteria

RVH; severity correlates with R:S in V1 and V6

Uncommon

Uncommon in partial; BVH in complete; RVH with Eisenmenger

BVH 23–61%; RVH with Eisenmenger

Uncommon

Ventricular hypertrophy

Not if no associated defects

Not if no associated defects

RVH possible if Peaked P RVOT obstruction waves; RAE or PHT possible

RAE with Himalayan P-waves

Possible LAE

Possible RAE

Normal; severity

Normal

LAE with moderate PDA

Possible LAE

rSr’ or rsR’

Deep S V1, tall R V5 and V6

Possible RAE ± LAE

RAE 35%

Atrial enlargement

Normal or rsr; possible RBBB

rSr’ or rsR’ with RBBBi > RBBBc

QRS configuration

(continued)

Anterior AVN; Positive T precordial; WPW with Ebstein’s

QRS duration ± QTd predictive of VT/ SCD

Accessory pathway common; Q II, III, aVF and V1–V4

Persistent RVH rare beyond infancy

Axis deviation correlates with RVP

Often either clinically silent or Eisenmenger

Infero-posteriorly displaced AVN

Katz-Wachtel phenomenon

“Crochetage” pattern

Particularities

4  Arrhythmias and Sudden Cardiac Death in Adult Congenital Heart Disease 39

Sinus brady 60%; EAR; junctional; IART 25%

Sinus brady 15%; EAR; junctional; IART > 50%

NSR; P-wave axis 105–165o with situs inversus

D-TGA/intraatrial baffle

UVH with Fontan

Dextrocardia

LAD in single RV, TA, single LV with noninverted outlet

Normal in TA; 1o AVB in DILV

RAD

RAD

Normal

Normal

QRS axis

PR interval

Not with situs inversus

RAE in TA

Variable; ↑↑ R and S amplitudes in limb and precordial leads Inverse depolarization and repolarization

RVH; diminutive LV

Possible RAE

Absence of q, small r, deep S in left precordium

Possible AVB if VSD or TV surgery

Particularities

LVH: tall R V1-V2; RVH: deep Q, small R V1 and tall R right lateral

Situs solitus: normal P wave axis and severe CHD

RVH with single RV; Absent sinus node in LAI; AV block possible LVH with with L-loop or single LV AVCD

Ventricular hypertrophy

Atrial enlargement

QRS configuration

ALCAPA

NSR

Normal

Possible LAD

Possible LAE Selective hypertrophy Possible ischemia Pathologic ant-lat of posterobasal Q waves; possible LV ant-sept Q waves NSR denotes normal sinus rhythm; IART intraatrial reentrant tachycardia; AF atrial fibrillation; AVB atrioventricular block; RAD right axis deviation; LAD left axis deviation; LAHB left anterior hemiblock; RBBB right bundle branch block (i, incomplete; c, complete); RAE right atrial enlargement; PVC premature ventricular contraction; AVN AV node; BVH biventricular hypertrophy; LAE left atrial enlargement; PDA patent ductus arteriosus; RVH right ventricular hypertrophy; RVP right ventricular pressure; LVH left ventricular hypertrophy; EAR ectoptic atrial rhythm; SVT supraventricular tachycardia; WPW Wolff-Parkinson-White syndrome; RV right ventricle; TOF tetralogy of Fallot; VT ventricular tachycardia; RVOT right ventricular outflow tract; PHT pulmonary hypertension; SCD sudden cardiac death; LV left ventricle; AVB atrioventricular block; VSD ventricular septal defect; TV tricuspid valve; TA tricuspid atresia; DILV double inlet left ventricle; LAI left atrial isomerism; AVCD atrioventricular canal defect; CHD congenital heart disease; ALCAPA anomalous left coronary artery from the pulmonary artery (reproduced with permission from Ref.24))

Rhythm

Congenital diagnosis

Table 4.2  (continued)

40 P. Khairy

4  Arrhythmias and Sudden Cardiac Death in Adult Congenital Heart Disease

sustained atrial arrhythmias occurred in 19% prior to surgery: atrial flutter alone in 5%, atrial flutter and fibrillation in 2.8%, and atrial fibrillation alone in 11%.26 Over a postsurgical follow-up of 3.8 years, atrial arrhythmias persisted or recurred in 60% of patients diagnosed preoperatively, and 2.3% developed new-onset arrhythmias. All patients with postsurgical atrial arrhythmias were over 40 years of age at time of repair. A subsequent study randomized 521 adults over 40 years of age with a secundum or sinus venosus ASD, shunt fraction > 1.7:1, and pulmonary systolic pressure < 70 mmHg to surgical closure v. medical therapy.27 Over a median of 7.3 years, atrial arrhythmias occurred in a similar proportion of patients (i.e., 7.4% v. 8.7%). The impact of transcatheter ASD closure on atrial arrhythmias is less clear and was assessed by a retrospective study.33 Prior to transcatheter device closure, 15% of 132 patients had atrial tachyarrhythmias. All patients with persistent arrhythmias remained in atrial fibrillation or flutter after closure. Two thirds of patients with prior paroxysmal atrial tachyarrhythmias and sinus rhythm at time of intervention remained symptom-free at a mean of 17 months. Symptomatic paroxysmal atrial arrhythmias occurred in 17% per year and persistent atrial fibrillation or flutter in 11% per year, with older age (³55 years) as a risk factor.

4.2 Ventricular Septal Defect Ventricular septal defects (VSD) are the most common congenital heart malformation, although most either close spontaneously or cause symptoms of congestive heart failure that prompts surgical closure prior to adulthood.35 Although a VSD can affect any portion of the interventricular septum, hemodynamic consequences rather than specific location impact most on the conduction system and arrhythmias in unoperated patients.36 In unoperated VSDs, isolated premature ventricular contractions (PVC), couplets, and multiform PVCs are prevalent.36 Nonsustained or sustained ventricular tachycardia has been observed in 5.7%.36 A higher mean pulmonary artery pressure is associated with high-grade ectopy.36 Nevertheless, in the absence of Eisenmenger’s syndrome, sudden cardiac death is uncommon, but reported in the setting of cardiac hypertrophy and progressive fibrosis of the conduction system.37-40

41

VSD closure is generally recommended in patients with significant shunts (as defined by symptoms, Qp:Qs > 2:1, and pulmonary artery systolic pressure > 50 mmHg), deteriorating ventricular function, right ventricular outflow obstruction, or more than mild aortic insufficiency.35 Late sudden death has been reported in 4% of patients following surgical repair. 41,42 Of 296 patients with surgical VSD closure between 1954 and 1960, 20% of patients had transpired by 30 years of follow-up.42 Risk factors for mortality included surgical repair after 5 years of age, pulmonary vascular resistance greater than 7 Woods units, and complete heart block. In selected patients, transcatheter VSD closure may be feasible. Major complications such as high-grade AV block, infective endocarditis, and device embolization have been noted in 3.8%.43 Larger series with longer-term ­follow-up are required.

4.3 Atrioventricular Canal Defect Atrioventricular canal (AVCD) defects are associated with inferior displacement of the AV node outside of Koch’s triangle, anterior to the mouth of the coronary sinus, adjacent to where posterior rims of atrial and ventricular septae unite.44-46 The His bundle extends along the lower rim of the ventricular septum. This inferior course and relative hypoplasia of the left anterior hemifascicle gives rise to a classical superior QRS axis.24,47,48 With dual AV node physiology, the slow pathway has been located superior to the His bundle, with the fast pathway inferior to the displaced AV node, as shown in Fig. 4.1.49 In 18 patients with AVCDs, preoperative electrophysiologic studies revealed sinus node dysfunction in 1, supra-Hisian first degree AV block in 5, and intraatrial conduction delay in the majority.41 Atrial fibrillation or flutter has been noted in 5% of patients after surgical repair.50,51 Persistent complete AV block occurs in 1–7% in the immediate postoperative period and approximately 2% thereafter.51-54 Prolonged infra-Hisian conduction time may be a marker for increased risk of late AV block, even if the PR interval is normal.55 While frequent ventricular ectopy has been described in 30% of patients, complex ventricular arrhythmias occur most commonly in the setting of left ventricular dysfunction.51

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Fig.  4.1  Cryomapping and cryoablation combined with 3D electroanatomic mapping in a patient with a partial AVCD. Three-dimensional electroanatomic maps of retrograde atrial activation during AV nodal reentrant tachycardia in left anterior oblique (a) and left lateral (b) views. The blue decapolar catheter is positioned in the coronary sinus and red quadripolar catheter in the right ventricle. Green circles indicate sites where

His-bundle electrograms were recorded. Local activation times are color-coded, with the site of earliest atrial activation in white, inferior to the infero-posteriorly displaced His-bundle. The yellow circles represent the site of successful cryomapping and cryoablation of the slow pathway, superior to the His bundle. RAA denotes right atrial appendage; CSO, coronary sinus ostium (reproduced with permission from Ref.49)

4.4 Left Ventricular Outflow Tract Obstruction

4.5 L-Transposition of the Great Arteries (L-TGA)

Congenital heart defects with left ventricular outflow tract obstruction include subvalvar, valvar, and supravalvar aortic stenosis. Increased wall stress with secondary left ventricular hypertrophy is related to severity of obstruction and is thought to predispose to ventricular arrhythmias.8,56-58 In adults with unoperated aortic stenosis, 34% had high-grade ventricular ectopy on Holter monitoring, compared to 6% of controls.56 Correlations with lower left ventricular ejection fraction and higher wall stress were later demon­ strated.57,58 Risk of sudden death appears to persist despite surgical repair, warranting careful follow-up. Indeed, in a population-based study of sudden death after surgery for congenital heart disease, patients with aortic stenosis constituted the highest risk subgroup, with an incidence of 3% at 10 years and 20% at 30 years.13 Aortic coarctation was also among the high-risk lesions.13

“Congenitally corrected” transposition of the great arteries, or L-TGA, involves double discordance at AV and ventriculo-arterial levels such that normal physiology is maintained, but with a systemic right ventricle. Marked displacement of the AV conduction system is noted, with an AV node outside of Koch’s triangle, displaced anteriorly and slightly more laterally.59,60 An elongated His bundle runs medially towards the site of fibrous continuity between the right-sided mitral valve and pulmonary artery. The His bundle then courses along the anterior rim of the pulmonary valve. If a VSD is present, it continues along its upper rim.59,60 In 107 patients with L-TGA and mean age of 22 years, complete AV block occurred in 22%.61 Risk of AV block was estimated to be 2% per year, irrespective of associated anomalies. Electrophysiological studies suggest that AV block occurs above or within the His bundle,62-64 consistent with the following clinical and

4  Arrhythmias and Sudden Cardiac Death in Adult Congenital Heart Disease

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pathological observations: a stable narrow QRS escape rhythm often accompanies complete AV block61 and fibrosis of the His bundle is observed histologically.63,65,66 Since the AV node and His bundle are highly sensitive to catheter or surgical trauma, manipulation near these areas should be exercised with caution. Complete AV block follows surgical repair of an associated VSD in over 25%.61,67-69

If surgical correction is warranted, arrhythmia management should be coordinated with the surgical team.76 This may include a preoperative electrophysiologic evaluation and catheter ablation, as perioperative arrhythmias may lead to hemodynamic instability in the presence of accessory pathways.77 In selected patients, surgical division of accessory pathways may be considered.

4.6 Ebstein’s Anomaly

4.7 Heterotaxy Syndromes

In Ebstein’s anomaly, the tricuspid valve is apically displaced, giving rise to an “atrialized” portion of the right ventricle that is morphologically and electrically right ventricle, but functionally right atrium.70 Mechanical stimulation of “atrialized” ventricular tissue may induce ventricular arrhythmias, although spontaneous ventricular tachycardia is otherwise uncommon in the absence of associated malformations such as aortic coarctation or left ventricular outflow tract obstruction.71 In Ebstein’s anomaly, accessory AV or atriofascicular pathways are found in 25% and are more often right-sided and multiple than in structurally normal hearts.70,72,73 In addition to AV reciprocating tachycardia, ectopic atrial tachycardia and atrial fibrillation or flutter can occur. Tolerance to tachyarrhythmias depends, in part, on the severity of Ebstein’s malformation, which can range from mild and asymptomatic to severe, with tricuspid regurgitation, a large ASD, cyanosis, and hemodynamic compromise.8 Sudden death may arise from rapid conduction of atrial fibrillation or flutter to the ventricles via high-risk or multiple pathways or from increased right-to-shunting via an ASD during tachycardia, with worsening cyanosis.73 In general, mapping and ablation procedures may be challenging due to associated malformations, multiple pathways, catheter instability, sometimes misleading signals within the “atrialized” ventricle, and prosthetic material (Fig.  4.2).74 The true AV groove along which accessory pathways are found may be located by right coronary angiography or insertion of a thin multielectrode catheter inside the right coronary artery.74 Of 65 patients with Ebstein’s anomaly and accessory pathways, short-term success rates ranged from 75–89%, depending on pathway location, with late recurrences in up to 32%.75

Heterotaxy syndromes are disorders of lateralization whereby the arrangement of abdominal and thoracic viscera differ from normal (situs solitus) and mirrorimage of normal (situs inversus).8 Heterotaxy syndromes are estimated to occur in one to two infants per 10,000 births and are frequently associated with severe congenital cardiac malformations.1 Although heterotaxy syndromes represent a heterogeneous group of disorders, they are generally characterized as either right (asplenia syndrome) or left (polysplenia syndrome) atrial isomerism. Patients with right atrial isomerism often have two sinus nodes at the junctions of right-sided and leftsided superior vena cavae with atrial chambers.24,78,79 As shown in Fig. 4.3, this may be reflected electrocardiographically with a P-wave axis that fluctuates as the prevailing pacemaker shifts from one sinus node to the other.24,80 In contrast, the majority of patients with left atrial isomerism do not have a recognizable sinus node. When present, it is hypoplastic and located posteroinferiorly, far from the orifice of the superior vena cava.79,81 Slow atrial rates and junctional escape rhythms are common.81 In left atrial isomerism, spontaneous complete AV block has been noted in 15%, whether present at birth or in later life.80,82 It is less prevalent in right atrial isomerism, but reports have described congenital AV block78 and sudden death.83 In a detailed account of the histopathology of the AV conduction system in 13 patients with isomerism, all four patients with right atrial isomerism had two AV nodes (superior and inferior) and penetrating bundles.79 In only one was there discontinuity between the superior node and His bundle. However, of nine patients with left atrial isomerism, two had anterior and posterior nodes not connected

44

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Fig. 4.2  Catheter ablation of an arrhythmia substrate partially covered by prosthetic material in Ebstein’s anomaly. An electrophysiology study and catheter ablation was performed in a patient with Ebstein’s anomaly, a one and a half ventricular repair (bidirectional Glenn shunt), and prosthetic tricuspid valve. In (a), angiography of the right atrium is shown in an anteroposterior view. Note the tricuspid valve prosthesis and absent right atrium to superior vena cava connection. (b) depicts an electroanatomic map in a left lateral view. Local activation times are

color-coded, with the wavefront spreading from white to red, orange, yellow, green, light blue, dark blue, and purple. A counterclockwise circuit revolving around the prosthetic tricuspid valve is appreciated. The site of successfully irrigated radiofrequency catheter ablation that produced bidirectional isthmus block is shown in right (C) and left (D) anterior oblique view. The arrows indicate the catheter position along the inferior portion of the tricuspid valve prosthesis (reproduced with permission from Ref.25)

to His bundles. Both had L-looped and/or single ventricles. All three patients with D-looping and two ventricles had a single posterior AV node connected to an AV bundle. A connecting sling of tissue, known as Monckeberg’s sling,84 joined the parallel conduction systems in all patients with twin nodes. In patients with heterotaxy syndromes, tachyarrhythmias include IART, Wolff-Parkinson-White syndrome, and twin AV node reciprocating tachycardia.80,84,85 An example of the latter is provided in Fig.  4.4. Since underlying structural abnormalities may predispose to hemodynamic instability, brady- or tachyarrhythmias should be promptly treated when they arise.

4.8 Single Ventricle Physiology “Univentricular heart” encompasses a spectrum of rare and complex congenital cardiac malformations ,whereby both atria predominantly egress into one functional single ventricle.86 In considering the course of the conduction system and potential for AV block, it is important to note the type of ventricular looping (i.e., D or L) and whether the dominant ventricle is morphologically right or left. The most prominent abnormalities in the location of the AV conduction system are found in single ventricles with AV discordance and AVCD. In L-looped single left ventricles with two AV nodes, the posterior

4  Arrhythmias and Sudden Cardiac Death in Adult Congenital Heart Disease

45

Fig. 4.3  12-Lead ECGs in heterotaxy syndrome of the right atrial isomerism type. Note the difference in P wave axis and morphology between (a) and (b), indicating a shift in the governing pacemaker. In (a), the P wave axis is 65o, positive in lead I, monophasic in inferior leads, and predominantly negative in V1. In (b), the P wave axis is 105o, notched in inferior leads, and predominantly positive in V1 (reproduced with permission from Ref.24)

node does not usually make contact with the ventricular septum.46 The elongated course of the His bundle renders it susceptible to fibrous degeneration and complete AV block.87 With ventricular D-looping and a dominant right ventricle, the AV node is within its usual landmarks and the His bundle enters the ventricular septum directly.88 In tricuspid atresia, there is no right-sided AV connection, such that one of the borders of Koch’s triangle is absent. Pathologic studies suggest that the compact AV node is typically located on the floor of the right atrium, adjacent to an abnormally formed central fibrous body.89,90 A small “dimple” lined with endocardium is just anterior to the ostium of the coronary sinus and has been considered to indicate the theoretical site of the absent tricuspid valve.89 The AV node is situated within the confines of

the coronary sinus, tendon of Todaro, and right atrial “dimple”. It pierces the central fibrous body to become the His bundle, along the left side of the septum. The remaining course of the His-Purkinje system is, to some extent, dependant on the presence and location of associated VSDs. In general, the His bundle is further leftward and away from more anterior septal defects.90 In patients with tricuspid atresia, atrial fibrillation, IART, catheter-induced ventricular fibrillation, AV nodal reentrant tachycardia, and asystole have been described.91,92 For AV nodal reentrant tachycardia, the fast pathway may be mapped electroanatomically during tachycardia and with constant rate ventricular pacing. Successful radiofrequency ablation has been reported by ablating adjacent and inferior to the His bundle electrogram on the left side of the septum.92

46

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200 ms

I aVF V1

AVN #1

V

A

b

d

A

H

H

H

AVN #2 distal

V

A

H

H

AVN #2 proximal

V A

A

V

H

V

A

V

200 ms

I aVF V1 AVN #1 proximal AVN #1 distal

Fig. 4.4  Mönckeberg’s sling. In a patient with a double outlet right ventricle, pulmonary atresia, and AVCD, electrode catheter tips in the right atrium indicate location of superior (AVN #1) and inferior (AVN #2) AV nodes in (a) anteroposterior and (b) left anterior oblique views. Supraventricular reciprocating tachycardia through a circuit involving both AV nodes was induced by atrial pacing and one premature impulse. (c) Surface leads I, aVF, and V1 and intracardiac electrograms at both nodal sites are depicted before ablation. Note the distinct His bundle

4.9 Fontan Palliation Developed in 1971 as surgical palliation for tricuspid atresia,93 the Fontan procedure has undergone multiple modifications to become the treatment of choice for various forms of single ventricle physiology.86 In a cohort of 261 patients with Fontan palliation, freedom from death or transplantation in postoperative survivors was 89.9% and 82.6% at 10 and 20 years, respectively.94 Late deaths were classified as sudden in 9.2%,

A

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H

H

AVN #2 distal AVN #2 proximal

V

A

H

V

A

V

d­ eflection at each AV node. A denotes atrial signal; H, His bundle signal; V, ventricular signal. (d) Radiofrequency ablation of the superior node resulted in elimination of the His bundle deflection at AVN #1 and an increased HV interval from 57 to 90 ms at AVN #2. Prolongation of the HV interval in one node following ablation of the second node suggests that conduction tissue connects the two as preexcitation across this “sling” is eliminated. The arrhythmia was not inducible after ablation and has not recurred since (reproduced with permission from Ref.84)

with most of presumed arrhythmic origin. Atrial arrhyth­ mias after Fontan palliation may be associated with substantial morbidity and mortality and are often challenging to manage, with frequently disappointing responses to pharmacological therapy. Rapid hemodynamic deterioration and heart failure may ensue.94 Depending on the particular type of repair, IART or atrial fibrillation may occur in up to 57%.95 Tachycardia circuits may be complex and/or multiple.28,96-99 Occasionally, single circuits are observed, as illustrated

4  Arrhythmias and Sudden Cardiac Death in Adult Congenital Heart Disease

47

Fig. 4.5  Electroanatomic mapping in a right atrium to pulmonary artery Fontan. An electroanatomic map (left) and imported CMR image (right) are shown in a patient with a classic modified Fontan and recalcitrant atrial tachyarrhythmias. The grey regions denote areas of dense scar. Local activation times are color-coded,

from white to red, orange, yellow, green, light blue, dark blue, and purple. Note the narrow channel of tissue between two dense scars. The arrhythmia circuit propagated counterclockwise around the upper scar and was successfully interrupted by ablating this narrow isthmus (reproduced with permission from Ref.25)

in Fig. 4.5. With 3D mapping systems and irrigated-tip radiofrequency ablation, acute success rates in dedicated experienced centers now exceed 80%.100-102 Recurrences or onset of new arrhythmias occur in 30–45% within the first year.100,103,104 A prospective randomized nonblinded study compared irrigated-tip to standard radiofrequency catheter ablation in 26 patients (47 atrial tachyarrhythmias) with congenital heart disease.105 The operator was requested to use the assigned therapy for the first 6 min of ablation. Overall success was greater using irrigated catheters. Patients with failing Fontans and refractory atrial arrhythmias should be considered for surgical conversion to a lateral tunnel or extracardiac conduit with concomitant arrhythmia surgery. This typically includes debulking the right atrium, removing thrombus, excising right atrial scar tissue, epicardial pacemaker implantation, a modified right atrial Maze procedure and, in patients with prior documented atrial fibrillation, a leftsided Maze procedure as well.106,107 Given the longer ischemic time required, left-sided Maze procedures should be guided by the clinical scenario, with review of all documented arrhythmias.106,107 Case series with short-term follow-up report promising results, with arrhythmia recurrence rates of 13–30%.106-110 On short

to medium-term follow-up, advantages of the extracardiac in comparison to the intracardiac lateral tunnel Fontan include a decreased incidence of sinus node dysfunction,111 although not consistently so.112 However, in the event of arrhythmias, access issues are of some concern, as exemplified by Fig. 4.6.23

4.10 Tetralogy of Fallot Tetralogy of Fallot is the most common cyanotic heart disease, accounting for 10% of all congenital heart malformations. 113 Atriotomy incisions are common, predisposing to the late development of IART. 114,115 New-onset IART may herald worsening ventricular function and tricuspid regurgitation. 114-117 Hemodynamic compromise may be precipitated in some. Moreover, sudden cardiac death is the most common cause of mortality late after repair.118,119 In a cohort study of 793 patients with repaired tetralogy of Fallot followed for 35 years, 10% developed atrial flutter, 11.9% experienced sustained ventricular tachycardia, and 8.3% died suddenly.115 Very few arrhythmic events occurred within the first 5–10 years following corrective surgery. Thereafter, a slow but steady decline in freedom

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aVL aVF HRA MAP d MAP p RVA 7:56:39 PM

7:56:40 PM

7:56:41 PM

Fig. 4.6  Catheter ablation in an extracardiac Fontan via a direct atriotomy approach. A patient with hypoplastic left heart syndrome and Ebstein’s malformation of the right-sided AV valve had poorly tolerated incessant orthodromic AV reciprocating tachycardia postoperatively after an extracardiac Fontan with surgical accessory pathway ligation. In (a), an anteroposterior view is shown at the site of successful ablation, portraying the position of the radiofrequency ablation catheter (black arrow). The sternum is splayed open by means of thoracic retractors. Epicardial bipolar atrial and

ventricular pacing leads are seen. Shown in (b) are recordings from surface ECG leads II, aVL, and aVF; epicardial high right atrium (HRA); distal (MAP d) and proximal (MAP p) electrode pairs of the radiofrequency ablation catheter; and epicardial ventricle (RVA). Orthodromic AV reciprocating tachycardia is seen with the mapping catheter positioned at the site of successful ablation (reproduced with permission from Khairy P et  al. Transcatheter ablation via a sternotomy approach as a hybrid procedure in a univentricular heart. PACE 2008; 31(5):639–40. In press)

from atrial and ventricular arrhythmias and sudden cardiac death was appreciable.115,119-121 Actuarial survival rates have been reported to be 94% and 85%, 20 and 36 years after surgery, respectively.119 Given the small but undeniable occurrence of ventricular arrhythmias and sudden cardiac death post tetralogy of Fallot repair, considerable efforts have been directed towards identifying risk factors. In the largest cohort study with a mean follow-up of 21.1 years, noninvasive risk factors for sustained ventricular tachycardia were QRS interval ³ 180 ms and an annual increase in QRS duration.115 Early lengthening of the QRS interval post repair results from surgical injury to the right bundle branch and myocardium,122 whereas later broadening reflects right ventricular dilation.123,124 In addition to QRS duration and its rate of change, independent predictors of sudden death included older age at repair and presence of a transannular right ventricular outflow tract patch.115 Patients with ventricular tachycardia or sudden cardiac death were more likely to have increased cardiothoracic ratios, at least moderate pulmonary and tricuspid regurgitation, and peripheral pulmonary stenosis. A higher QT dispersion was

also noted, believed to reflect increased heterogeneity in myocardial repolarization. Other reported risk factors include frequent ectopic beats,125 increased right ventricular systolic pressures,120,126,127 complete heart block,120,128 and increased JT dispersion.129,130 The prognostic value of programmed ventricular stimulation was assessed in a multicenter cohort of 252 patients.131 Mean follow-up after corrective surgery and electrophysiologic testing was 18.5 ± 9.6 and 6.5 ± 4.5 years, respectively. Clinical ventricular tachycardia and/or sudden cardiac death occurred in 24.6%. Independent risk factors for inducibility of sustained ventricular tachycardia were age at study ³18 years, palpitations, prior palliative surgery, modified Lown’s criteria ³2, and cardiothoracic ratio ³ 0.6. Event-free survival rates in noninducible and inducible patients are shown in Fig. 4.7. Stratification by electrophysiological studies appears most helpful in patients deemed at moderate risk by a combination of static and dynamic noninvasive risk factors.132 A multicenter cohort study explored the role of implantable cardioverter-defibrillators (ICD) in 121 patients with tetralogy of Fallot with primary and

Fig. 4.7  Value of programmed ventricular stimulation in tetralogy of Fallot. Actuarial freedom from ventricular tachycardia (VT) and sudden cardiac death is depicted in patients with no inducible VT, inducible monomorphic VT, and inducible polymorphic VT at 1, 5, 10, and 15 years following programmed ventricular stimulation (adapted from Ref.131)

Actuarial freedom from VT or sudden cardiac death (%)

4  Arrhythmias and Sudden Cardiac Death in Adult Congenital Heart Disease

97.9

80

92.8

49

89.3

89.3

79.4 67.1

63.6

63.6

53.3

No inducible VT Monomorphic VT Polymorphic VT

26.7

0 1 year 5 years

10 years

15 years

Time after programmed ventricular stimulation

secondary prevention indications.133 High rates of appropriate shocks were noted in both groups, i.e., 7.7% and 9.8% per year, respectively. For patients with primary prevention indications, a risk score was derived from surgical, hemodynamic, electrocardiographic, and electrophysiological factors. One point was attributed to QRS duration ³180 ms; two points for prior palliative shunt, inducible sustained ventricular tachycardia, ventriculotomy incision, and nonsustained ventricular tachy­ cardia; and three points for a left ventricular end-diastolic pressure ³12 mmHg. Patients with <3 points (“lowrisk”) experienced no appropriate shocks. In patients with three to five points (“intermediate risk”) and >5 points (“high-risk”), appropriate shocks were received by 3.8% and 17.5% of patients per year, respectively.133 This risk score was derived in selected patients in whom ICDs were deemed indicated a priori and remains to be validated in an independent data set.25,133

4.11 D-Transposition of the Great Arteries (D-TGA) In “complete” transposition of the great arteries, or D-TGA, the AV relationship is preserved but ventriculo-arterial discordance is present. D-TGA accounts for 5–7% of all congenital cardiac malformations.113 In the absence of a shunt with mixing between the parallel systemic and pulmonary circulations, D-TGA is not

compatible with life. 90% of untreated infants die within the first year.134 In 1959, Senning introduced an intraatrial baffle repair to redirect systemic and pulmonary venous return without grafts or prostheses.135 In 1964, Mustard described an alternate technique using a pericardial patch.136 Although arterial switch surgery137 has supplanted atrial correction as the procedure of choice, most adults with D-TGA have had intraatrial baffle repairs. Late complications include sinus node dysfunction, atrial tachyarrhythmias, baffle leaks, obstruction to systemic and/or pulmonary venous return, systemic right ventricular dysfunction, and sudden cardiac death.138,139 The most common cause of late mortality after an intraatrial baffle has consistently been reported to be sudden death.13,140-145 Studies are beginning to address the role of ICDs146 and cardiac resynchronization therapy for failing systemic right ventricles.147,148 Of 478 postoperative survivors with Mustard repair, bradyarrhythmias increased steadily over time.142 The actuarial rate of loss of sinus rhythm was 39% at 10 years and 60% at 20 years. Atrial flutter occurred in 14% and ectopic atrial tachycardia in 1%. The actuarial rate of atrial flutter 20 years after repair was 24%. Loss of coordinated atrial activity and rapid ventricular rates can produce severe symptoms and hemodynamic compromise. Attempts to maintain sinus rhythm are usually warranted. As depicted in Fig. 4.8, catheter ablation of IART may be effective but often requires access to the tricuspid valve isthmus on the pulmonary

50

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b

a

c

I aVF

2900 810

V1

MAP1,2

MAP3,4

LAA1,2

Termination of IART LAA3,4

Fig.  4.8  Transcatheter ablation of IART in a patient with a Senning procedure. (a) depicts angiography of a Senning baffle, outlined in red, in a patient with a dual chamber pacemaker and symptomatic recurrent intraatrial reentrant tachycardia (IART). SVC denotes superior vena cava; IVC inferior vena cava; LAA left atrial appendage; MV mitral valve. The white arrow indicates position of an 8-mm tip radiofrequency ablation catheter at the site of successful IART entrainment and ablation. To access the pulmonary venous atrium, the catheter was positioned across a baffle leak. (b) illustrates a left anterior oblique view of a 3D electroanatomic map. Local activation times in tachycardia are color-coded, using left atrial appendage as a reference. Earliest to latest signals are colored white, red, yellow, green, light blue, dark blue, and purple, respectively. The large curved arrow indi-

cates direction of an IART circuit involving the cavo-tricuspid isthmus. The white dot represents the site of successful entrainment and ablation in the pulmonary venous atrium, corresponding to the arrow in (a). Two additional ablation lesions (red dots) completed the line of block. TV denotes tricuspid valve; RSPV, right superior pulmonary vein. In (c), the first three tracings are surface leads I, aVF, and V1 at 10 mm/s. Map 1,2 and 3,4 record endocardial signals from proximal and distal electrode pairs of the ablation catheter during a radiofrequency application. Intracardiac tracings from the left atrial appendage (LAA 1,2 and 3,4) initially display the IART that terminates during ablation, followed by a 16-s sinus pause with a ventricular paced rhythm, indicative of underlying sinus node dysfunction (reproduced with permission from Ref.8)

4  Arrhythmias and Sudden Cardiac Death in Adult Congenital Heart Disease

venous side of the circulation via a retrograde or transbaffle approach.103 The new onset of atrial arrhythmias is associated with impaired ventricular function149,150 and increased risk of sudden death in some, but not all, studies.151 In a retrospective multicenter case-control study that identified 47 patients with D-TGA and Mustard or Senning surgery with sudden death, risk factors included the presence of symptoms of arrhythmia or heart failure and history of documented atrial fibrillation or flutter.152 The electrocardiogram, chest x-ray, and Holter findings were not predictive of sudden death and medical therapy and pacemakers were not found to be protective. Reports have yielded conflicting opinions as to whether the type of atrial reconstruction portends different risks. Proponents of the Senning procedure advance that minimal, if any, nonviable tissue or prosthetic material favors future growth and optimizes atrial function, with potential reduction in pathway obstruction and arrhythmias.153-156 Supporters of the Mustard procedure have claimed lower mortality, reduction in systemic and pulmonary venous obstruction, and decreased incidence of arrhythmias.138,157-160 In a meta-analysis comparing outcomes in 885 patients from seven studies, sinus node dysfunction was more common in patients with Mustard procedures.161 Data regarding atrial tachyarrhythmias were inconclusive. A trend towards lower mortality favored the Mustard procedure, perhaps in part due to less pulmonary venous obstruction and residual shunting.

4.12 Summary Arrhythmias in ACHD constitute an exciting and challenging branch of electrophysiology, with a uniquely heterogeneous population with diverse diagnoses and issues. Major achievements have been achieved over the last decade in our understanding of arrhythmia mechanisms and therapeutic options. Sudden cardiac death of presumed arrhythmic etiology is the leading cause of mortality, with the highest risk lesions being left-sided obstructive lesions, D-TGA and intraatrial baffles, tetralogy of Fallot, and severe systemic ventricular dysfunction. Sinus node dysfunction is common in left atrial isomerism and Mustard, Senning, Glenn, or Fontan surgery. Complete AV block frequently occurs

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in patients with L-looped ventricles, left atrial isomerism, and AVCD. Atriotomy incisions, sutures, baffles, and conduits may engender scar-based IART circuits, as exemplified by surgically repaired ASD, Mustard and Senning baffles, tetralogy of Fallot, and Fontan palliation. ICDs and cardiac resynchronization therapy are increasingly utilized in ACHD. Unlike standard indications based on multiple randomized clinical trials, evidence supporting this technology in congenital heart disease is limited but growing. Guidelines have begun incorporating issues relevant to this patient population, and targeted training programs are offered. A thorough understanding of conduction system variants, arrhythmia mechanisms, and underlying anatomy and physiology is imperative for the safe and effective management of arrhythmias in ACHD. Acknowledgments  This work was supported in part by the Canada Research Chair in Electrophysiology and Adult Congenital Heart Disease.

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56 147. Khairy P, Fournier A, Thibault B, Dubuc M, Therien J, Vobecky SJ. Cardiac resynchronization therapy in congenital heart disease. Int J Cardiol. 2006;109(2):160–168 148. Khairy P. Defibrillators and cardiac resynchronisation therapy in congenital heart disease. Exp Rev Med Devices. 2008; 5(3):267–271 149. Puley G, Siu S, Connelly M, et al. Arrhythmia and survival in patients >18 years of age after the mustard procedure for complete transposition of the great arteries. Am J Cardiol. 1999;83(7):1080–1084 150. Li W, Somerville J, Gibson DG, Henein MY. Disturbed atrioventricular electromechanical function long after Mustard operation for transposition of great arteries: a potential contributing factor to atrial flutter. J Am Soc Echocardiogr. 2001;14(11):1088–1093 151. Sarkar D, Bull C, Yates R, Wright D, Cullen S, Gewillig M, Clayton R, Tunstill A, Deanfield J. Comparison of longterm outcomes of atrial repair of simple transposition with implications for a late arterial switch strategy. Circulation. 1999;100(19 Suppl):II176–II181 152. Kammeraad JA, van Deurzen CH, Sreeram N, et  al. Predictors of sudden cardiac death after Mustard or Senning repair for transposition of the great arteries. J Am Coll Cardiol. 2004;44(5):1095–1102 153. Smallhorn JF, Gow R, Freedom RM, et al. Pulsed Doppler echocardiographic assessment of the pulmonary venous pathway after the Mustard or Senning procedure for transposition of the great arteries. Circulation. 1986;73(4):765–774 154. Bender HW Jr, Stewart JR, Merrill WH, Hammon JW Jr, Graham TP Jr. Ten years’ experience with the Senning operation for transposition of the great arteries: ­physiological

P. Khairy results and late follow-up. Ann Thorac Surg. 1989; 47(2): 218–223 155. Chin AJ, Sanders SP, Williams RG, Lang P, Norwood WI, Castaneda AR. Two-dimensional echocardiographic assessment of caval and pulmonary venous pathways after the senning operation. Am J Cardiol. 1983;52(1):118–126 156. Dodge-Khatami A, Kadner A, Berger Md F, Dave H, Turina MI, Pretre R. In the footsteps of senning: lessons learned from atrial repair of transposition of the great arteries. Ann Thorac Surg. 2005;79(4):1433–1444 157. Breckenridge IM, Stark J, Bonham-Carter RE, Oelert H, Graham GR, Waterston DJ. Mustard’s operation for transposition of the great arteries. Review of 200 cases. Lancet. 1972;1(7761):1140–1142 158. Rodriguez-Fernandez HL, Kelly DT, Collado A, Haller JA Jr, Krovetz LJ, Rowe RD. Hemodynamic data and angiographic findings after Mustard repair for complete transposition of the great arteries. Circulation. 1972;46(4): 799–808 159. Arciniegas E, Farooki ZQ, Hakimi M, Perry BL, Green EW. Results of the Mustard operation for dextro-transposition of the great arteries. J Thorac Cardiovasc Surg. 1981; 81(4):580–587 160. Meijboom F, Szatmari A, Deckers JW, et  al. Long-term follow-up (10 to 17 years) after Mustard repair for transposition of the great arteries. J Thorac Cardiovasc Surg. 1996; 111(6):1158–1168 161. Khairy P, Landzberg MJ, Lambert J, O’Donnell CP. Longterm outcomes after the atrial switch for surgical correction of transposition: a meta-analysis comparing the Mustard and Senning procedures. Cardiol Young. 2004;14(3):284–292

5

Endurance Sport Practice and Arrhythmias Eduard Guasch and Lluís Mont

Regular exercise reduces risk of cardiovascular disease and enhances a psychological wellness; therefore, exer­ cise and sport practice are being increasingly recognized as beneficial activities, and medical associations and health authorities promote their practice.1 Elite sport practitioners are considered to be among the healthiest group in the society. Sudden death in athletes comes as a shock to the society who considered them to be examples of healthy life. Why do healthy, young athletes get ill? Arrhythmic pathologies in athletes have been studied extensively in the last 40 years. First, EKG alterations and some arrhythmic disorders, like sinus bradycardia or ventricular premature beats, were extensively described. Afterwords an increased incidence of sudden death in comparison to sedentary population was observed. In most athletes suffering sudden death, an underlying heart disease has been identified, hypertrophic cardiomyopathy in young and atherosclerotic coronary disease in the oldest group being the most frequent causes. Nowadays, when a person enters competitive sport, preparticipation screening is recommended in many countries, but recreational sport practitioners may also be concerned of cases of sudden death and look for medical advice. Thus, an increasing population is referred to medical evaluation prior to being engaged in regular sport practices, and this reinforces the need for the cardiologist to know and be familiar with the management of arrhythmias in athletes.

L. Mont (*) Department of Cardiology, Thorax Institute, Hospital Clinic, University of Barcelona, Lluís Mont, Villarroel 170, 08036 Barcelona, Spain e-mail: [email protected]

5.1 Athlete’s Heart: Anatomical and Electrical Considerations Heart of sport practitioners supports changes in volume and pressure conditions during exercise that translates into structural changes, called “athlete’s heart.” In order to study changes that occur during exercise, sports can be classified into two groups, according to cardiac hemodynamic changes. First, static or isometric sports, like weight-lifting or wrestling, raise blood pressure and increase LV wall stress; as a consequence, concentric hypertrophy develops in order to maintain normal wall stress. On the other hand, dynamic or isotonic sports, as marathon runners, may need a higher cardiac output during exercise, and thus, heart is subject to volume overload. Its adaptation consists of increased diameters of cardiac chambers, particularly end-diastolic LV. Although this classification is useful to understand and systematize studies on exercise adaptation mechanisms, most sports cannot be classified in a pure mechanism, but are really a combination of both, and thus, variable hypertrophy and dilatation are seen in all athletes. Structural cardiac adaptation might be present in people who regularly practice more than 3 h of exercise per week,2 and they are seen in up to 50% of athletes.3 Cardiac adaptation is strongly related to training intensity and on the specific sport practiced. It must be noted that, although a sport can be purely dynamic or static, training programs are usually mixed. Cycling and rowing are the sport modalities that are related to more apparent cardiac changes.4,5 Structural changes related to sport practice develops in less than 3 months.6,7 Consequently, great differences can be found depending on whether echocardiographic studies are performed

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on the peak training season or during holidays. On the other hand, cardiac adaptations are reversible after discontinuing training for 2–3 months, thus decreasing ventricular chamber diameters. However, some athletes do not normalize the size despite deconditioning, and some cardiac changes may remain unmodified or reverse only partially up to 30 years after finishing training.8,9 Cardiac chambers are usually enlarged, particularly in its LV end-diastolic diameter. It is increased by a mean of 15%, which stands for 35% increase in volume.4 Furthermore, although chamber measures usually remain within normal values, about 15% of high-level sport practitioners have >60 mm LV enddiastolic diameter, and in extreme, elite cyclists, as far as 50% have dilated ventricles.10 Wall thickness is also enlarged by an average of 10%, both in dynamic and static sports. However, relative wall thickness (ratio between wall thickness and LV end-diastolic diameter) is higher in static sports, thus revealing concentric hypertrophy. Hypertrophy is symmetrical (septal to posterior wall ratio less than 1.5) and must not be consid­ered physiological in case of more than 15 mm thickness.3,4,11 As a result of increased LV diameters or wall thickness, cardiac mass gets increased on a variable intensity depending on training and sport characteristics. Overall, cardiac mass is higher in dynamic sports compared to static ones.2 Left atrium is also affected by sport practice as it is enlarged in athletes, as a result of increased atrial pressure during exercise and higher preload. In general, about 20% of athletes have increased left atrial anteroposterior diameter (more than 40 mm). Right atrium is also enlarged in comparison to sedentary people.12,13 The distinction between athlete’s heart and pathological conditions can be challenging, as no clear cut-off points have been determined. So, a great variety of echocardiographic characteristics or other image techniques must be considered. The evaluation after discontinuation of sport and genetic testing should be considered.

5.1.1 Systolic and Diastolic Function Left ventricle ejection fraction does not differ in athletes compared to sedentary population. It must be

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noted that, although similar in ejection fraction, stroke volume is higher in athletes because of enlarged ventricles. As a consequence, cardiac output at rest is not modified as a result of bradycardia, but on maximal effort, maximum heart rate is not different from that of controls, but increased stroke volume makes it possible to get a higher cardiac output and higher oxygen uptake.4,14,15 Despite LV hypertrophy, ventricular filling is not impaired and thus diastolic function remains normal in most athletes, and even improved in some longdistance runners. An improved LV diastolic function could be of help when great increases in cardiac output are needed, as in long-distance runners. This is in contrast with some other pathological conditions, in which increased ventricular mass increases LV chamber stiffness and worsens its filling. These differences are apparently explained, because regular exercise does not increase collagen nor modify its composition in LV.16

5.1.2 Right Ventricular Involvement Although LV hypertrophy and dilatation is welldefined and characterized in echocardiographic and MRI studies, right ventricle (RV) has not been properly studied until recently. Some factors account for this fact, but mainly its particular geometry has precluded from its characterization, since two-dimensional echocardiography is not able to quantify its volume. Using indirect indexes, in the 1980s and 1990s, a moderate RV dilatation was suggested in sport practitioners. This hypothesis has been confirmed in MRI studies, which are able to exactly delimitate RV shape, and thus, get better RV estimative. They have demonstrated mild to moderate RV hypertrophy and dilatation. This dilatation is balanced with LV measurements, thus indicating that RV changes are proportional to those LV ones.14,15,17 Systolic function in RV seems to be normal or in lower limit of normality in most studies, although it normalizes during exercise.14,18,19 Diastolic function in right ventricle has been less studied than in LV; however it seems to be similar or slightly improved to that of sedentary population.14,20

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5.2 EKG of the Athlete: From Physiological Adaptation to Pathological Condition 5.2.1 Criteria of Left Ventricular Hypertrophy Anatomical changes and imbalance between adrenergic and vagal tone cause some alterations in athletes’ EKG that are considered to be benign, and part of athlete’s heart syndrome. Despite certain EKG changes being representative of normal, physiological adaptation to sport practice, some others may be due to severe cardiac diseases. Thus, precise and correct knowledge and interpretation of physiological EKG changes is essential when evaluating an athlete. Left ventricle hypertrophy is more frequently found in sport practitioners, and this is seen in EKG with higher voltage in precordial leads. In addition to increased voltage, LV hypertrophy fulfilling EKG diagnostic criteria depends largely on which method is used and on training intensity. Thus, LV hypertrophy using Sokolow-Lyon or Rohmilt-Estes criteria ranges from 0.8% in recreational sport practitioners to 45% in elite athletes. Furthermore, both criteria show great differences with low sensibility and specificity in athletes. Also, as it does with LV anatomic hypertrophy and dilatation, cycling is more frequently associated with LV hypertrophy EKG alterations compared to other sports.21-25 Usually, high precordial voltage appears without any other significant abnormalities, in contrast to what occurs in HCM patients. In HCM patients, LV hypertrophy criteria are usually seen in conjunction with pathological Q waves, deep T negatives waves, or depressed ST segments. This association should raise concern about associated myocardiopathies.21,25,26

5.2.2 Negative T Waves Negative, deep, T waves are only slightly more frequent in athletes than in sedentary individuals. Negative T waves are seen in about 0.6–4%21,22,27,28 of sport practitioners, as compared to 0–3% in sedentary population.29,30 Characteristically, inverted T-wave that are seen in athletes normalizes or become less negative

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during a stress test or isoproterenol infusion.27,31 Along with the observation that atropine does not modify them, it has been suggested that inverted T-wave develops as a result of imbalance in adrenergic – vagal tone; this imbalance might produce heterogeneous myocardial depolarization, and thus, alters repolarization.

5.2.3 Increased Vagal Tone Athletes have a lower heart rate in comparison to age and sex matched controls, mainly as a result of increased vagal tone and decreased sympathetic tone at rest. Sinus bradycardia is particularly found in dynamic sports. Thus, sinus bradycardia, which can be as extreme as 25 beats per min at rest, is strongly related to intensity of training and specific exercise practiced. Also wandering pacemaker is more frequently found in athletes as a result of sinus node modification, and can be as frequent as 60%; however, it must be considered a physiological adaptation and does not need further exams. Increased vagal tone in athletes also prolongs PR segment and may cause first degree AV block (from 5 to 35% of screened athletes) and second AV degree Wenckebach block (usually during sleep, in up to 20% athletes).21 They are usually asymptomatic and do not require treatment, but in some cases, atrio-ventricular blocks may cause dizziness or near-syncope that may even preclude sport practice. In those cases, EKG changes are usually reversible after detraining, and pacemaker implantation is not indicated. Second degree Mobitz II and third degree AV blocks are rare in young athletes and probably represent an underlying condition. Accelerated ventricular rhythm (less than 100 bpm) is also found on athletes in athlete’s heart syndrome, and it does not require further evaluation.

5.2.4 Changes in ST Segment Due to increased vagal tone and decreased sympathetic tone, athletes frequently present with ST changes consistent with so-called “early repolarization,” that is, elevation of the QRS-ST junction of at least 1 mm or QRS slurring or notching. These are present in up 45%

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of young athletes and are related to intensity of exercise.21,28 Early repolarization is considered a benign characteristic, although recent studies have suggested its relationship to sudden death in patients without heart disease.32

5.2.5 QT interval In athletes, QT interval is frequently prolonged due to bradicardia. However, less than 1% of athletes have pathological corrected QT interval (440 ms in males, 460 ms in females) and need further evaluation. In the only study that focused in patients with long QT, only patients with very prolonged QTc (mainly > 500 ms) fulfilled long QT diagnostic criteria.21,33,34 There is some concern regarding the presence of extensive repolarization alterations without apparent heart disease. In other settings, like in high blood pressure, repolarization abnormalities have been shown to be predictive of future hypertensive myocardiopathy. Recent, powered prospective studies have shown that, on follow-up, these patients develop myocardiopathy more frequently than those with normal repolarization27; these results have not been reproduced in smaller studies.35

5.3 Sudden Death and Ventricular Arrhythmias Sudden death among athletes has become a matter of social concern, particularly when it occurs in professional players and the cases are being reported in media.36-38 Athletes have an increased risk of sudden death, as compared to an age-matched sedentary population, with a relative risk of 2.1. This increase in SD does not seem to be related to unfavorable effects of sport, but to enhance risk of SD in athletes with underlying heart disease, in whom exercise acts as a trigger for ventricular arrhythmias.34,36,39 This increase in SD risk is particularly high in patients who has abnormal coronary arteries or ARVD; thus, a patient with coronary disease or ARVC has, respectively, 79-fold and 5.6-fold, increase in risk of death when they are regular sport practitioners.

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Its incidence is known to be low, and this fact makes epidemiologic studies difficult to conduct because of practical obstacles, such as complexity of collecting information on all sudden deaths that occur in large populations. The estimated risk of SD is about 0.4 per 100,000 athletes per year. Different sources when collecting information on SD might cause important biases, and recent studies report five to sixfold increases in SD, accounting for about 100 SD per year in the USA. On the other side, in the Veneto region (Italy), where a prospective registry has been conducted since 1979, a higher incidence has been reported, being about 2.3 SD per 100,000 athletes per year.40,41 When focusing on athletes older than 35 years, SD incidence rises and is as high as 7 SD per 100,000 sport practitioners per year. A prospective study in middleage and old men, showed that vigorous exercise was related to an increase in SD; on the contrary, routine vigorous exercise had a protective effect against SD.42 In this way, running a Marathon is associated with a risk of SD of 0.5–0.8 SD per 100,000 runners.43,44 Myocardiopathies causing SD differ greatly in young athletes and in older ones. In fact, while some inherited myocardiopathies are mainly found in young athletes, atherosclerotic coronary disease is widely described as the most frequent disease in athletes older than 35 years. Genetically determined and congenital cardiomyopathies are the leading underlying diseases in young athletes with SD. According to large population studies in the United States, HCM is the most frequent single cause of SD in young athletes, accounting for about one third to a half of all cases.36,37 In contrast, in North eastern Italy, arrhythmogenic right ventricular cardiopathy (ARVC) is present in 25% of young athletes with SD and is also found in one in four athletes in those who are resuscitated from a cardiac arrest.45 Other causes of SD in patients with underlying structural heart disease include aberrant coronary arteries or premature atherosclerotic disease, myocarditis, ruptured aortic aneurism, with or without Marfan syndrome, and aortic stenosis. Non worthless, 10–20% of SD in young athletes occur as a result of ventricular fibrillation in a healthy heart after being hit in precordium by any material used in sport practice, like a puck or baseball. This ventricular induction by a powerful hit in precordium is called “commotio cordis.”

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Because studies regarding sudden death are mainly based on necropsies, and previous EKG are lacking, channelopathies or WPW syndrome are probably underestimated as a cause of sudden death. They are usually reported to account for about 1–2% of SD causes.36 However, they might be responsible for, at least, part of patients without heart disease at necropsy who make about 2–4% of patients with sudden death. Additionally, channelopathies and preexcitation syndromes might be alternative SD causes among 10% of patients who are described as “probable HCM” and other cardiopathies in which direct causality of SD cannot be ascertained, as in mitral valve prolapse or stable coronary disease.

5.4 Hypertrophic Myocardiopathy HCM is the single leading cause of SD in young athletes in the United States. It is a familial, genetically determined, primary cardiomyopathy. In the general population, it is diagnosed in about 1 in 500 people, although it seems to be somewhat lower in athletes, slightly less than 0.1%, as a consequence of selection bias; in fact, worsening functional class prevent them to enter athletic competition.46,47 HCM is caused by mutation in, sarcomeric genes or, less frequently, nonsarcomeric (involved in cardiac metabolism) genes. Beta-myosin heavy chain is the most common affected gene. In histological studies, HCM is characterized by myocardiocite disarray and hypertrophy and sometimes focal fibrosis. Its echocardiographical expression varies largely, ranging from mild to massive (more than 60 mm septal thick) left ventricular hypertrophy, making differential diagnosis difficult with athlete’s heart. Usually LV hypertrophy is defined as asymmetrical, with greater thickening in septum in comparison to posterior wall; less frequently, diffuse or apical hypertrophy can be found. In some cases, LV hypertrophy is associated with septal anterior movement, causing functional mitral regurgitation. Its most terrifying clinical presentation is SD as a first symptom in otherwise asymptomatic patient. SD is usually due to primary ventricular tachycardia or ventricular fibrillation. Several factors present in HCM may originate ventricular arrhythmias. Recent

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studies have suggested that patched fibrosis possibilities reentrant ventricular arrhythmias; additionally, adrenergic predominance during exercise can enhance risk or reentrant ventricular tachycardia.48 In addition, exercise-induced ischemia in severe hypertrophic myocardium might lead to ventricular arrhythmias. Characteristic EKG features include increased precordial voltages, negative T waves and pathological Q waves. These EKG abnormalities are found in about 90% of affected patients, which means that nearly all patients will be detected with an EKG and will probably be diagnosed after echocardiography, and less than 10% patients will be lost during preparticipation screening. On the other hand, as previous symptoms are scarce, probability of detecting HCM without EKG is low.49

5.4.1 Differentiating HCM and Athlete’s Heart Main characteristics of HCM include left ventricular asymmetric hypertrophy and, septal anterior movement. In mildly affected patients, septal anterior movement might not be present, and wall thickness values fall in an overlap zone; in those patients, differential diagnosis can be a challenge, but some features must be of help. When mild to moderate hypertrophy is determined, a dilated LV suggests physiological adaptation to intense exercise. Also, preserved diastolic function can be indicative of normal adaptation. On the contrary, nondilated LV with impaired LV function is suggestive of HCM. Moreover, several echocardiographical indexes have been postulated to better distinguish both entities.50,51 Also, MRI may help in differential diagnosis, ­especially in patients with apical HCM, when deep negative T waves are present and echocardiography is inconclusive. When all characteristics are equivocal, stopping training for 3 months could be helpful. In fact, when hypertrophy reverses in a few months, physiological adaptation can be assumed and training resumed. Another possibility is genetic testing, which is able to diagnose some of the causative mutations of HCM.

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5.4.2 Sport Eligibility When an athlete is diagnosed with HCM, competitive sport must be forbidden, without regard to its clinical or echocardiographic characteristics or previous symptoms. In some cases, especially in patients with low-risk profile, static, low-intensity sports could be allowed, as in golf or bowling.

5.5 Right Ventricular Arrhythmias: Arrhythmogenic Right Ventricle Dysplasia ARVC is the most frequent cause of SD in the Veneto region (Northeastern Italy) and Spanish series45,52. ARVC is histologically defined by cardiomyocite death and replacement of RV myocardium with fibrofatty tissue. It causes free RV wall thinning, enlargement and dysfunction, and when dilatation occurs focally, formation of aneurisms. As a result of anatomopathological abnormalities, ventricular tachycardia and ventricular fibrillation might develop. It has been shown that ARVC is mainly caused by mutations in genes encoding intercellular junction proteins called desmosomes.53 When one or both genes of one of this desmosomes are defective, junctions are nonfunctional. Although it usually affects RV, in some cases, it also comprises left ventricular and causing dilated cardiomyopathy. Furthermore, ARVC phenotype is variable within affected patients in the same family, ranging from mild forms to severe ones.54 In patients with ARVC, EKG abnormalities are demonstrated in up to 85% of patients. These mainly include precordial negative T waves, right bundle branch block, and presence of epsilon wave. Sport practice represents a strong precipitant for arrhythmias in patients with ARVD, mostly during active exercise. However, less than 10% of sudden deaths in ARVC happen during exercise.55 ARVC patients who regularly practice sport have 5.4 times more risk of SD compared to sedentary population.39 Why does sport enhances ventricular arrhythmias in ARVC patients has been studied experimentally. First, it has been demonstrated that phenotypic expression in ARVC affected individuals, including right ventricle dilatation and RV arrhythmias, are related to age and

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intensity of exercise training,56 thus suggesting that exercise might undercover genetically affected but phenotypically unaffected patients. In an effort to explain this fact, it has been shown that myocite stretch induces an increase in intercellular adhesion proteins in healthy people57,58; in this way, increases in RV afterload as a consequence of exercise in patients with genetic deficits could not get to that demand, thus accelerating loss of intercellular junctions and accelerating ventricular dilatation and arrhythmogenesis56 in susceptible people. In addition, this results in death of miocardiocyte during sport, increasing the risk of ventricular arrhythmia. Furthermore, increased sympathetic tone during exercise might trigger ventricular arrhythmias; ARVC patients might be especially sensible to adrenergic states because of denervation that develops in some ARVD patients. When considering patients with RV complexes or symptomatic arrhythmias, only 25% fulfill ARVC criteria. In patients with RV complex arrhythmias, independent of whether diagnosed from ARVC or not, a RV systolic dysfunction compared to athletes without them has been demonstrated, thus suggesting that it could be the anatomical basis for those arrhythmias. This suggests that, in sport practitioners with some kind of predisposition, RV gets slightly dilated and dysfunctional, causing an ARVC-like sport-induced myocardiopathy. In those patients, positive electrophysiological testing and young age are predictors of major arrhythmic event (sustained ventricular arrhythmia or sudden death).59,60 We have also demonstrated an increase in RV fibrosis in an animal model of exercise, which could be the anatomical basis for those arrhythmias. So, both SD in ARVC athletes and presence of ventricular arrhythmias in patients with dysfunctional RV emphasizes the important role of RV involvement in sport practice. However, until recently, most studies have focused on LV, and RV still remains an undiscovered piece of sport adaptation.

5.5.1 Sport Eligibility Exercise is strongly related to ventricular arrhythmias and progression in ARVC patients; competitive sport practice is not recommended, while moderate to highintensity recreational exercise is usually discouraged.

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5.6 Ventricular Premature Beats and Ventricular Complex Arrhythmias Studies on ambulatory recordings of ventricular premature beats in athletes offer ambiguous results, with a prevalence ranging from 10 to 70%, similar to ones found in healthy sedentary population. Complex ventricular arrhythmias, including nonsustained ventricular arrhythmias and polymorphic ventricular beats, are much less frequent, affecting about 20–30% of athletes, this being higher than that found in general population. In general population, ventricular premature beats and nonsustained ventricular tachycardia do not worsen prognosis when they occur in the absence of heart ­disease. Indeed, in sport practitioners, ventricular arrhythmias are representative of athlete’s heart, and do not carry bad vital prognosis in the absence of cardiomyopathy. However, increasing number of ventricular premature beats is related to higher probability of structural disease. Therefore, when ³2,000 ventricular premature beats per 24 h and/or nonsustained ventricular tachycardias were detected, 30% patients had structural heart disease, of which 10% had ARVC. On the other hand, when less than 100 premature extrasystoles, without complex arrhythmias, were detected, no patient had cardiomyopathy; former is comparable to general population.61 Furthermore, when these patients stop sport, so that some of the athlete’s heart characteristics are reversed, most of those patients reduce ventricular arrhythmias and even disappear, independent of whether they have heart disease or not, and independently of cardiac remodeling.62,63 Similar to those of general population, most of ventricular extrasystoles (65–75%) have left bundle branch block, and thus, originate from right ventricle.61 Mechanisms that lead to ventricular arrhythmias are not known; although previous hypothesis identified ventricular hypertrophy as the cause of ventricular extrasystoles, recent reports demonstrated that presence and intensity of ventricular premature beats were independent of ventricular mass. This is consistent with their regression independent of cardiac remodeling when deconditioning and with right ventricle origin of ventricular premature beats.64

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5.7 Commotio Cordis Experimental studies have demonstrated that precise strike in ventricle, about 10–30 ms before T peak, induces ventricular fibrillation, which could be the pathophysiological basis for this phenomenon. Induction of ventricular fibrillation is also strongly related to the energy of hit and the site of impact (with more inducibility when striking left ventricle, less when striking heart base, and no inducibility when the energy is delivered anywhere else in the chest). In order to initiate ventricular fibrillation, KATP+ channels seem to be necessary; they are mechosensitive, so that mechanical stress might activate them. In addition, chest wall thumping can initiate ventricular depolarization and thus, cause ventricular premature beats. “Commotio cordis” cases are produced mainly during baseball (ball) or hockey games (puck), and even though no structural heart disease is diagnosed, mortality remains extremely high, about 85%. It must be stated that although efforts have been made to design reliable chest protections, 40% of “commotio cordis” deaths occur in athletes who already use them.65-67 In addition to ventricular fibrillation, chest blows can also cause atrio-ventricular block, bundle branch block, and ST elevation that are typically transient and occur independently of strike timing.

5.8 Supraventricular Arrhythmias 5.8.1 Paroxysmal Supraventricular Tachycardia and Ventricular Preexcitation Several years ago, It was believed that ventricular preexcitation was a more frequent disease in athletes compared to sedentary population. However, direct comparisons are noteliable because increased vagal tone in athletes might prolong auriculo-ventricular delay time through AV mode, and thus unmask a hidden delta wave representative of ventricular preexcitation. Nowadays, ventricular preexcitation seems to occur similarly in athletes and sedentary people. Generally, when it is asymptomatic, there is no certainty on which is the best approach, although catheter

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ablation is recommended, especially in those considered to be of high risk (in particular, when athlete complains of syncope) or young athletes. Once it has become symptomatic, competitive sport should be precluded until they have been adequately treated and patient has been free of arrhythmia for 2–4 months.68,69

5.8.2 Atrial Fibrillation and Atrial Flutter Increasing evidence links regular exercise and atrial and fibrillation or flutter, as it has been suggested recently in several studies.63,70-74 Additionally, atrial fibrillation is the leading cause of palpitations in athletes.75 Average athlete with atrial fibrillation is a middleaged man, who has practiced regular exercise since he was young and has never stopped completely. This relationship is especially strong in endurance, long-lasting sport. Since mid-1990s, some prospective studies carried out in endurance sportsmen were affected from significantly more AF, with relative risk between 5.9 and 8.8.63,71,73 This was not only restricted to endurance athletes, but to leisure physical activity as demonstrated in retrospective studies in patients with lone AF, with regular exercise providing threefold increase in AF risk. This relationship was stronger as total physical activity increased, particularly significant above 1,500 h life-time exercise. Crucial role for long-lasting exercise is demonstrated in one study in which intensive (not only endurance), sport practitioners did not have increased AF incidence at a young age (mean age 24 years old).12 Conversely, above mentioned studies were carried out in middle-aged athletes, who had trained more hours during whole life. In contrast with leisure or total exercise, work related physical activity was not associated to an increased risk of AF or flutter in one study, although they only registered physical activity at work during last year and did not correlate it to leisure activity Atrial flutter is much less represented in previous studies, so that solid conclusions cannot be done. However, it has been suggested by one study that its incidence was also increased.63 Interestingly, this association is mainly related to men. This fact probably reflects both larger left atrial diameter and increased training intensity. Characteristically, athletes with AF present with paroxysmal AF and remain with paroxysmal AF in

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successive years, progressing to more prolonged forms of AF (persistent, permanent) in about one in four patients.70,76 When referring to therapeutic strategy, no specific guidelines have been issued, although some recommendations are given.68,69 Special attention must be put in betablockers therapy in the way they are among prohibited substances in some sport disciplines. Nonpharmacological approaches, like catheter ablation, seem to be highly effective, although no large studies have been conducted.77 In general, competitive sport could be resumed after 4–6 weeks after an ablation procedure. Little is known as to whether deconditioning could eliminate or reduce AF attacks, but improving of AF symptoms would be consequent with reduction of premature ventricular beats62 and reversibility of anatomical changes after precluding sport practice. In spite of this fact, it is in contrast with already recognized, extensive, beneficial effects of exercise practice; so precluding sport must be reduced to very symptomatic cases, and subjected to individual assessment. Considering that most athletes with atrial fibrillation are middle-aged patients some of them will suffer from comorbidities, and will require anticoagulation therapy. In those cases, sports with bodily collision or trauma risk should be avoided. In other circumstances, only patients with chronic AF without an adequate rate control should be restricted from any kind of sport practice. Atrial flutter management is, in some way, different to that of AF. Due to the safety and high efficacy of atrial flutter procedure ablation, it must be a first line therapy in athletes with atrial flutter.68,69 It must be stated that, despite high efficacy, endurance sport practitioners who undergo atrial flutter ablation develop a higher incidence of subsequent AF.74 Several factors may happen in athletes and explain an increase in atrial fibrillation incidence. At first, it is already known that sport practitioners have an increased vagal tone as a result of long-lasting exercise, especially in endurance training. This increased vagal tone results in bradycardia and shortening of the atrial refractory period, both known to be risk factors for AF.78 Furthermore, sport practitioners usually suffer AF attacks during vagal situations.70 Increased atrial volume increases incidence of AF as it offers a more reliable substrate for AF maintenance; so in small atrium, myocardium might not be enough to allow propagation waves and AF maintenance. Thus, in the way that athletes have increased atrial volumes

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included in athlete’s heart syndrome,12 it is consistent with more frequent AF. Histological alterations also could explain this fact. In fact, although it has been demonstrated that left ventricle histology is not significantly changed, both atria and right ventricle have not been extensively studied. Recently, our group demonstrated that endurance training resulted in left and right atria and right ventricle fibrosis in a rat model (in press). On the other side, atrial fibrosis is related to increased AF inducibility in some other experimental situations and its intensity increases as AF duration does.79 In summary, increased atrial volume, electrical heterogeneity induced by atrial refractory period shortening, and probably atrial fibrosis might confer a proper substrate to maintain AF. In this context, sinusal bradycardia and atrial premature beats could promote AF initiation.

5.9 Screening Athletes The main aim of preparticipation sport screening is diagnosing underlying cardiac disease that could produce sudden death. In that way, there is general agreement that both personal and familial anamnesis and physical exam is essential, despite that they will only allow to detect three patients with underlying heart diseases in 100.36 In spite of this fact, they are recommended by 36th Bethesda Conference and European Society Guidelines. On the contrary, considerable concern exists in the convenience of practicing EKG in preparticipating screening. Its most important benefit is that it can raise suspicion on certain cardiac pathologies related to sudden death. Among these, we can suspect structural cardiomyopathies such as ARVC, HCM or dilated cardiomyopathy, or even preexcitation, long or short QT or Brugada syndromes. It is a less useful tool in patients with anomalous coronary origin or atherosclerotic coronary disease, in which only 25% of affected patients will be suspected. The main concern in practicing EKG in preparticipation screening is whether screening all athletes with EKG abnormalities is efficient enough to justify its costs. Screening procedure must include personal anamnesis, directed to identify patients with any symptom that could suggest cardiomyopathy or any familial history of cardiomyopathy. Even, Bethesda Conference authors have recommended 14 questions that should

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be asked to rule them out; however they are not fully implemented in all American states.80,81 In general, familial history of significant cardiomyopathy, personal symptoms suggestive of heart disease such as palpitations, chest pain, syncope, or disproportionate shortness of breath should be questioned. Physical examination is also mandatory, specifically looking for valvular disease, aortic coarctation, or signs suggestive of Marfan syndrome.68,69 Routine use of EKG in preparticipation screening was first applied in Japan in 1973, but most information we have comes from Italy preparticipation screening. Since 1979, an EKG is mandatory in all athletes entering competitive sport in Italy. It must be interpreted by an experienced physician, and athletes are referred to specialist and to an echocardiography when a suspicious abnormality is found. For classification purposes, EKG are classified as normal when no alterations are detected, mildly abnormal when only subtle alterations are seen, and distinctly abnormal when they raise concern about cardiomyopathy. Even in distinctly abnormal EKG group, prevalence of heart disease remains relatively low and some structural heart diseases are not detected; on the other hand, if more subtle EKG changes are additionally studied, huge proportion of athletes should require supplementary tests. So the question is which EKG abnormalities should guarantee further investigation. No randomized trials have been conducted to delineate which EKG abnormalities would need additional studies. Therefore, European Society of Cardiology guidelines have adopted the Italian preparticipation screening criteria as valid ones (Fig. 5.1).Considering that EKG abnormalities are training intensity-dependent, about 10% of sport practitioners should need further investigation, but could be as much as 40% in elite athletes.21-23,49 It has been demonstrated that an EKG strategy is capable of reducing mortality in athletes. As discussed above, athletes are on increased risk of SD, while preparticipation screening with EKG has reduced mortality and even achieved lower mortality than sedentary population. In this way, rhythm and conduction disturbances were the main pathologies that led to exclusion from competitive sports, affecting 0.7% of athletes. Specifically, single causes that led to disqualification were ventricular arrhythmias in 0.6% of screened athletes, supraventricular arrhythmias in 0.24%, WPW in 0.22% and HCM in 0.07%.34,49 Furthermore, addition of echocardiography in

66 Fig. 5.1  European and American guidelines recommend a medical history and a physical exam before beginning competitive sports. In addition, European ones also include an EKG in the preparticipation screening visit. If any positive finding is identified, further studies such as echocardiography or Holter should be performed in order to discard a cardiopathy

E. Guasch and L. Mont Family history • Premature sudden death in close relatives (<55 years in male, <65 in female) • Familiy history of Marfan syndrome, cardiomyopathy, channelopathy or any other disabling cardiovascular disease. Personal history • Exertional chest pain, unexplained syncope or palpitations. • Shortness of breath out of proportion to the degree of exertion. Physical exam • Characteristic features of Marfan syndrome (ocular and musculoskeletal). • Diminished and delayed femoral artery pulses. • Mid-or end- diastolic clicks. • Any diastolic murmur or systolic murmur intensity grade ≥2/6. • Irregular rhythm. • High blood pressure (>140/90mmHg). ECG • Rhythm and conduction abnormalities Premature ventricular best or any supraventricular tachycardia Short PR interval (<0.12 sec) First,second or third degree atrioventricular block Sinus bradicardia at rest (<40 bpm) with chronotropic incompetence(<100 bpm during exercise) • P-Wave Left atrial enlargement (deep, prolonged negative P-Wave component in V1) Right atrial enlargement (peaked P-Wave) • QRS complex QRS axis deviation (≥+120° or between −30° and −90°) Increased QRS voltage in precordial leads Abnormal Q waves in two or more leads Right or left bundle branch block R or R’ wave in lead V1 (amplitude ≥0.5 mv) • Repolarization ST-segment depression or T-wave flattening or inversion in ≥1 lead. Prolonged Qtc (>0.44 sec in males or >0.46 sec in females)

all patients with preparticipation screening has low power to diagnose additional cardiomyopathies.82 On the basis of these data, routine use of EKG in screening process in athletes is recommended on ESC guidelines and on Lausanne Recommendations by IOC.83,84 On the other hand, in the US, with an estimate of ten million athletes who should undergo preparticipating screening each year, an additional EKG is estimated to cost about $2 billion per year. On the basis of a supposed low efficiency, it is not recommended universally and its use should be based only on physician’s criteria.81

When any of directed anamnesis, physical exam or EKG, when practiced, is not normal, further evaluation would be required. Usually, an echocardiography should be done as first line diagnostic tool, and subsequently exercise testing, ambulatory EKG or loop recorders, MRI, coronary angiography, MRI or electrophysiological testing might be needed. In summary, directed anamnesis and physical exploration is mandatory in a preparticipation screening; added EKG, although increases the number of cardiomyopathies detected, is not universally recommended because of suspected low cost-efficacy.

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5.10 Sport Eligibility Both American and European guidelines have been published to allow or forbid athletes with cardiomyopathy. Overall, Bethesda Conference and European Society of Cardiology recommendations are similar, although former are in some way less restrictive.68,69 In order to allow participation screening, competitive sports are classified according to the intensity of both dynamic and static component. Thus, sports can be low, moderate, or intense, dynamic or static (Fig. 5.2).

5.10.1 Structural Heart Disease Generally, when a significant structural cardiomyopathy is found, like HCM and ARVC, intense, competitive exercise is forbidden. However, sometimes, low or low-to-moderate dynamic and low static sports might be allowed.

5.10.2 Rhythm Disorders • Sinus bradycardia: Usually asymptomatic, it does not preclude from competitive sports if they achieve tachycardization during exercise.

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• Atrioventricular block: Both first degree or Wenckebach AV block are considered part of athlete’s heart syndrome, and when not associated with any cardiomyopathy and does not worsen during exercise, no further investigation is needed and no restrictions in competitive sports are needed. Mobitz II or third degree AV block usually requires pacemaker implantation before athletic competition, except in some well-tolerated, hemodynamic stable complete congenital AV block. • Atrial fibrillation and flutter: Competitive sports are usually allowed if rate is controlled. • Preexcitations: Catheter ablation is recommended, and it is mandatory in symptomatic patients. • Ventricular premature beats: When they are not related to structural heart disease and occur in asymptomatic athletes, they can participate in all competitive sports. When a structural heart disease is found, sport restriction must be based on underlying cardiomyopathy. If ventricular premature beats are symptomatic, deconditioning must be recommended. • Nonsustained ventricular tachycardia: Extensive efforts must be taken to discard cardiomyopathy. When idiopathic ventricular tachycardia is found, catheter ablation is encouraged. Dynamic Intensity

Static intensity

Bowling Golf Cricket

Fig.  5.2  Competitive sports are classified according to their static and dynamic intensity components. This classification might be of importance when advising patients with cardiopathy

Fencing Table tennis Volleyball Baseball

Diving Sailing Gymnastics Karate

Figure skating Running (sprint)

Bobsledding Luge Windsurfing

Body building Wrestling Snow boarding

Badminton Running (marathon)

Squash

Basketball Ice hockey Rugby Soccer Running (mid/long distance)

Boxing Cycling Rowing Speed skating

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5.10.3 Channelopathies • Long QT syndrome: Patients with LQTS should be precluded from all competitive sports. Only patients with genetically proven type 3 LQTS, which is strongly related to ventricular arrhythmias at rest, could be allowed to participate in some competitive sports. On the other hand, strict prohibition to swimming must be issued to patients with type 1 LQTS, as it has been demonstrated that diving largely increases sudden death. • Brugada syndrome: SD in patients with Brugada syndrome is usually related to rest and sleeping, and until now, no relationship has been found with exercise. In spite of this fact, it is already known that increased vagal tone is capable of unmasking typical EKG. Thus, increased vagal tone in athletes could enhance propensity to suffer ventricular arrhythmias in Brugada syndrome patients. Also hyperthermia can unmask Brugada EKG. So, until more data are known, competitive sport should be precluded. • Catecholaminergic ventricular tachycardia: As ventricular arrhythmias are provoked as a result of sympathetic stimulation, all competitive sports are forbidden.

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most patients, underlying heart disease can be the limiting factor in sport eligibility. These recommendations are based on demonstrated increased probability of arrhythmia during sport, theoretical possibility of shock failure because of an increased adrenergic tone during sport, and possible damage to ICD or lead. In fact, clinical studies on ICD and sport are scarce and limited to only some case reports. So, counseling given to patients may vary widely among practitioners. In fact, some authors support the idea that patients with an ICD implanted as primary prevention could participate in competitive sports.85 A major concern in patients with ICD who are allowed to participate in some low-intensity sports is the way the therapies should be programmed. In fact, young patients can achieve heart rates as high as 200 bpm during exercise, which can be identified as ventricular arrhythmia and treated with an inappropriate shock. An exercise testing could be helpful in those circumstances. Otherwise, in sport practitioners who wish to practice allowed sports, dual chamber ICD should be implanted and ventricular and supraventricular discrimination algorithms be used.

5.11 Automated External Defibrillators 5.10.4 Sport and Devices • Pacemaker and sport: Two major concerns must be considered when evaluating a sport practitioner who has had a pacemaker implanted. First, bodily collision can damage pacemaker systems, and so sports with possible strikes over pacemaker should be avoided. Second, adequate tachycardization during exercise must be demonstrated to allow competitive sport. • Implantable cardioverters and sport: When an athlete has been diagnosed with arrhythmogenic cardiopathy, ICD implantation must not be used to allow sport practice again. Otherwise, patients who have received an ICD, either for primary or secondary prevention, are usually precluded from competitive sport, allowing patients who have had an ICD placed after 6 months without shock only low or low-to-moderate intensity sports without bodily contact. Examples of allowed sports are golf, ­curling, and bowling. It must be noted that, in

Although efforts to diagnose all heart diseases in athletes are made, eliminating it is not achievable. Not only athletes are in increased risk of SD, but sports stadiums are also a place where SD must happen in spectators with relatively high probability. Moreover, to great number of people in stadiums, increased anxiety can trigger myocardial ischemia, that can lead to ventricular arrhythmias SD.86 Automated external defibrillators (AED) are recommended in sport events. AED have demonstrated to reduce death among athletes in Marathon runners,87 and they are also present in some of US and Europe stadiums.

5.12 Differences in Race As in some other circumstances, including hypertension, modifications in loading conditions (whatever, pressure or volume) that take place during exercise can

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translate into the heart in different ways according to race. Thus, with a similar workload, Blacks usually develop more hypertrophy compared to Whites, and this fact and others are related to a higher prevalence of abnormal EKGs in Blacks.88,89 Although in past years it was suggested that angiotensin converser enzyme polymorphisms was related to more intense athlete’s heart features, nowadays it is known that it was a race bias, as it included more Black athletes. Both, increased hypertrophy and abnormal EKG must be taken into account when preparticipation screenings are carried out, because higher false-positive EKGs and echocardiograms are predicted. Furthermore, when evaluating underlying heart diseases related to SD, HCM is more frequently found in Black athletes,90 while ARVC in Caucasians.

5.13 Syncope in Athletes Syncope can be the first manifestation of underlying heart disease. However, syncope occurs frequently in healthy people and athletes, with as much as 8% of athletes referring syncope in last 5 years. As in general population, main cause of syncope in athletes is vaso-vagal syncope. As syncope incidence is high, and underlying heart disease is extremely low, directed anamnesis is essential. Risk factors for malignant syncope are otherwise similar to that of general population. Specifically, whether syncope occurs during exercise, postexercise, or at rest is of particular importance; syncope during exercise is most often associated with significant cardiomyopathy, while both syncope at rest or postexercise are usually vaso-vagal or orthostatic. Anyway, further evaluation with at least EKG and echocardiography is required when vaso-vagal syncope cannot be established after anamnesis and physical exam. Thereafter, loop recording, might be an useful tool for athletes with unexplained syncope, When heart disease is excluded, prognosis is good even in the case of exertional syncope. However, recurrences are frequent, reaching 30% at 10 years after the first episode,91-93 that must be taken into account when evaluating for sports eligibility.

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E. Guasch and L. Mont 33. Basavarajaiah S, Wilson M, Whyte G, Shah A, Behr E, Sharma S. Prevalence and significance of an isolated long QT interval in elite athletes. Eur Heart J. 2007;28(23): 2944–2949 34. Corrado D, Basso C, Pavei A, Michieli P, Schiavon M, Thiene G. Trends in sudden cardiovascular death in young competitive athletes after implementation of a preparticipation screening program. JAMA. 2006;296(13):1593–1601 35. Serra-Grima R, Estorch M, Carrio I, Subirana M, Berna L, Prat T. Marked ventricular repolarization abnormalities in highly trained athletes’ electrocardiograms: clinical and prognostic implications. J Am Coll Cardiol. 2000;36(4): 1310–1316 36. Maron BJ, Shirani J, Poliac LC, Mathenge R, Roberts WC, Mueller FO. Sudden death in young competitive athletes. Clinical, demographic, and pathological profiles. JAMA. 1996 July 17;276(3):199–204 37. Maron BJ, Roberts WC, McAllister HA, Rosing DR, Epstein SE. Sudden death in young athletes. Circulation. 1980;62(2):218–229 38. Corrado D, Thiene G, Nava A, Rossi L, Pennelli N. Sudden death in young competitive athletes: clinicopathologic correlations in 22 cases. Am J Med. 1990;89(5):588–596 39. Corrado D, Basso C, Rizzoli G, Schiavon M, Thiene G. Does sports activity enhance the risk of sudden death in adolescents and young adults? J Am Coll Cardiol. 2003; 42(11):1959–1963 40. Maron BJ, Doerer JJ, Haas TS, Tierney DM, Mueller FO. Abstract 3872: profile and frequency of sudden deaths in 1,463 young competitive athletes: from a 25-year U.S. National Registry, 1980 2005. Circulation. 2006 Oct 31;114(18_MeetingAbstracts):II 41. Van Camp SP, Bloor CM, Mueller FO, Cantu RC, Olson HG. Nontraumatic sports death in high school and college athletes. Med Sci Sports Exerc. 1995;27(5):641–647 42. Albert MA, Mittleman MA, Chae C, Min Lee I, Hennekens C, Manson J. Triggering of sudden death from cardiac causes by vigorous exertion. N Engl J Med. 2000;343(19): 1355–1361 43. Maron BJ, Poliac LC, Roberts WO. Risk for sudden cardiac death associated with marathon running. J Am Coll Cardiol. 1996;28(2):428–431 44. Redelmeier DA, Greenwald JA. Competing risks of mortality with marathons: retrospective analysis. BMJ. 2007; 335(7633):1275–1277 45. Furlanello F, Bertoldi A, Dallago M, et al. Cardiac arrest and sudden death in competitive athletes with arrhythmogenic right ventricular dysplasia. PACE. 1998;21(1): 331–335 46. Basavarajaiah S, Wilson M, Whyte G, Shah A, McKenna W, Sharma S. Prevalence of hypertrophic cardiomyopathy in highly trained athletes: relevance to pre-participation screening. J Am Coll Cardiol. 2008;51(10):1033–1039 47. Martin M, Rodriguez-Requero JJ, Calvo D, et al. Usefulness of the ECG in the sports screening of footballers affiliated to a regional sports federation. Rev Esp Cardiol. 2008;61(4): 426–429 48. Adabag AS, Maron BJ, Appelbaum E, et  al. Occurrence and frequency of arrhythmias in hypertrophic cardiomyopathy in relation to delayed enhancement on cardiovascular

5  Endurance Sport Practice and Arrhythmias magnetic resonance. J Am Coll Cardiol. 2008;51(14): 1369–1374 49. Corrado D, Basso C, Schiavon M, Thiene G. Screening for hypertrophic cardiomyopathy in young athletes. N Engl J Med. 1998;339(6):364–369 50. De Castro S, Caselli S, Maron M, et  al. Left ventricular remodelling index (LVRI) in various pathophysiological conditions: a real-time three-dimensional echocardiographic study. Heart. 2007;93(2):205–209 51. D’Andrea A, D’Andrea L, Caso P, Scherillo M, Zeppilli P, Calabrò R. The usefulness of Doppler myocardial imaging in the study of the athlete’s heart and in the differential diagnosis between physiological and pathological ventricular hypertrophy. Echocardiography. 2006;23(2):149–157 52. Suárez-Mier M, Aguilera B. Causes of sudden death during sports activities in Spain. Rev Esp Cardiol. 2002;55(4): 347–358 53. Awad MM, Calkins H, Judge DP. Mechanisms of Disease: molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Nat Clin Pract Cardiovasc Med. 2008;5(5):258–267 54. Corrado D, Basso C, Thiene G, et al. Spectrum of clinicopathologic manifestations of arrhythmogenic right ventricular cardiomyopathy/dysplasia: a multicenter study. J Am Coll Cardiol. 1997;30(6):1512–1520 55. Tabib A, Loire R, Chalabreysse L, et al. Circumstances of death and gross and microscopic observations in a series of 200 cases of sudden death associated with arrhythmogenic right ventricular cardiomyopathy and/or dysplasia. Circulation. 2003;108(24):3000–3005 56. Kirchhof P, Fabritz L, Zwiener M, et al. Age- and trainingdependent development of arrhythmogenic right ventricular cardiomyopathy in heterozygous plakoglobin-deficient mice. Circulation. 2006;114(17):1799–1806 57. Yamada K, Green KG, Samarel AM, Saffitz JE. Distinct pathways regulate expression of cardiac electrical and mechanical junction proteins in response to stretch. Circ Res. 2005;97(4):346–353 58. Zhuang J, Yamada KA, Saffitz JE, Kleber AG. Pulsatile stretch remodels cell-to-cell communication in cultured myocytes. Circ Res. 2000;87(4):316–322 59. Ector J, Ganame J, van der Merwe N, et al. Reduced right ventricular ejection fraction in endurance athletes presenting with ventricular arrhythmias: a quantitative angiographic assessment. Eur Heart J. 2007;28(3):345–353 60. Heidbuchel H, Hoogsteen J, Fagard R, et  al. High prevalence of right ventricular involvementin endurance athletes with ventricular arrhythmias: role of an electrophysiologic study in risk stratification. Eur Heart J. 2003;24(16): 1473–1480 61. Biffi A, Pelliccia A, Verdile L, et al. Long-term clinical significance of frequent and complex ventricular tachyarrhythmias in trained athletes. J Am Coll Cardiol. 2002;40(3): 446–452 62. Biffi A, Maron BJ, Verdile L, et  al. Impact of physical deconditioning on ventricular tachyarrhythmias in trained athletes. J Am Coll Cardiol. 2004;44(5):1053–1058 63. Baldesberger S, Bauersfeld U, Candinas R, et al. Sinus node disease and arrhythmias in the long-term follow-up of former professional cyclists. Eur Heart J. 2008;29(1): 71–78

71 64. Biffi A, Maron BJ, Di Giacinto B, et al. Relation between training-induced left ventricular hypertrophy and risk for ventricular tachyarrhythmias in elite athletes. Am J Cardiol. 2008;101(12):1792–1795 65. Maron BJ, Gohman TE, Kyle SB, Estes NAM III, Link MS. Clinical profile and spectrum of commotio cordis. JAMA. 2002;287(9):1142–1146 66. Doerer JJ, Haas TS, Estes NAM III, Link MS, Maron BJ. Evaluation of chest barriers for protection against sudden death due to commotio cordis. Am J Cardiol. 2007;99(6): 857–9 67. Link MS, Mark Estes N. Mechanically induced ventricular fibrillation (commotio cordis). Heart Rhythm. 2007;4(4): 529–532 68. Zipes DP, Ackerman MJ, Estes NAM, Grant AO, Myerburg RJ, Van Hare G. Task Force 7: arrhythmias. J Am Coll Cardiol. 2005;45(8):1354–1363 69. Pelliccia A, Fagard R, Bjornstad HH, et al. Recommendations for competitive sports participation in athletes with cardiovascular disease: a consensus document from the Study Group of Sports Cardiology of the Working Group of Cardiac Rehabilitation and Exercise Physiology and the Working Group of Myocardial and Pericardial Diseases of the European Society of Cardiology. Eur Heart J. 2005;26(14):1422–1445 70. Mont L, Sambola A, Brugada J, et  al. Long-lasting sport practice and lone atrial fibrillation. Eur Heart J. 2002;23(6): 477–482 71. Molina L, Mont L, Marrugat J, et al. Long-term endurance sport practice increases the incidence of lone atrial fibrillation in men: a follow-up study. Europace. 2008;10(5):618–623 72. Mont L, Tamborero D, Elosua R, Molina I, Coll-Vinent B, Sitges M, et al. Physical activity, height, and left atrial size are independent risk factors for lone atrial fibrillation in middle-aged healthy individuals. Europace 2008 Jan 4;eum263 73. Karjalainen J, Kujala UM, Kaprio J, Sarna S, Viitasalo M. Lone atrial fibrillation in vigorously exercising middle aged men: case-control study. BMJ. 1998;316(7147): 1784–1785 74. Hein Heidbüchel, Wim Anné, Rik Willems, Bert Adriaenssens, Frans Van de Werf, Hugo Ector Endurance sports is a risk factor for atrial fibrillation after ablation for atrial flutter. Int J Cardiol. 2006 Feb 8;107(1):67–72 75. Furlanello C, Bertoldi A, Dallago M, et al. Atrial fibrillation in elite athletes. J Cardiovasc Electrophysiol. 1998;9(8 Suppl):S63-S68 76. Hoogsteen J, Schep G, van Hemel NM, van der Wall EE. Paroxysmal atrial fibrillation in male endurance athletes. A 9-year follow up. Europace 2004 Jan 1;6(3):222–228 77. Furlanello F, lupo P, Pittalis M, Foresti S, Vitali-Serdoz L, Francia P, et al. Radiofrequency catheter ablation of atrial fibrillation in athletes referred for disabling symptoms preventing usual training schedule and sport competition. J Cardiovasc Electrophysiol. 2008;19(5):457–462 78. Dimmer C, Szili-Torok T, Tavernier R, Verstraten T, Jordaens LJ. Initiating mechanisms of paroxysmal atrial fibrillation. Europace. 2003;5(1):1–9 79. Burstein B, Nattel S. Atrial fibrosis: mechanisms and clinical relevance in atrial fibrillation. J Am Coll Cardiol. 2008;51(8):802–809

72 80. Glover DW, Glover DW, Maron BJ. Evolution in the process of screening United States high school student-athletes for cardiovascular disease. Am J Cardiol. 2007;100(11): 1709–1712 81. Maron BJ, Douglas PS, Graham TP, Nishimura RA, Thompson PD. Task Force 1: preparticipation screening and diagnosis of cardiovascular disease in athletes. J Am Coll Cardiol. 2005;45(8):1322–1326 82. Pelliccia A, Di Paolo FM, Corrado D, et al. Evidence for efficacy of the Italian national pre-participation screening programme for identification of hypertrophic cardiomyopathy in competitive athletes. Eur Heart J. 2006;27(18): 2196–2200 83. Corrado D, Pelliccia A, Bjornstad HH, et al. Cardiovascular pre-participation screening of young competitive athletes for prevention of sudden death: proposal for a common European protocol: Consensus Statement of the Study Group of Sport Cardiology of the Working Group of Cardiac Rehabilitation and Exercise Physiology and the Working Group of Myocardial and Pericardial Diseases of the European Society of Cardiology. Eur Heart J. 2005;26(5): 516–524 84. IOC Medical Commission. Lausanne recommendations: preparticipation cardiovascular screening. 2004. http://multimedia olympic org/pdf/en_report_886 pdf 85. Lampert R, Cannom D, Olshansky B. Safety of sports participation in patients with implantable cardioverter defibrillators: a survey of Heart Rhythm Society members. J Cardiovasc Electrophysiol. 2006;17(1):11–5

E. Guasch and L. Mont 86. Wilbert-Lampen U, Leistner D, Greven S, et  al. Cardiovascular events during World Cup Soccer. N Engl J Med. 2008;358(5):475–483 87. Roberts WO, Maron BJ. Evidence for decreasing occurrence of sudden cardiac death associated with the marathon. J Am Coll Cardiol. 2005;46(7):1373–1374 88. Basavarajaiah S, Boraita A, Whyte G, et al. Ethnic differences in left ventricular remodeling in highly-trained athletes: relevance to differentiating physiologic left ventricular hypertrophy from hypertrophic cardiomyopathy. J Am Coll Cardiol. 2008;51(23):2256–2262 89. Magalski A, Maron BJ, Main ML, et al. Relation of race to electrocardiographic patterns in elite American football players. J Am Coll Cardiol. 2008;51(23):2250–2255 90. Maron BJ, Carney KP, Lever HM, et al. Relationship of race to sudden cardiac death in competitive athletes with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2003;41(6):974–980 91. Colivicchi F, Ammirati F, Biffi A, Verdile L, Pelliccia A, Santini M. Exercise-related syncope in young competitive athletes without evidence of structural heart disease. Clinical presentation and long-term outcome. Eur Heart J. 2002 July 2;23(14):1125–1130 92. Colivicchi F, Ammirati F, Santini M. Epidemiology and prognostic implications of syncope in young competing athletes. Eur Heart J. 2004;25(19):1749–1753 93. Gratze G, Mayer H, Skrabal F. Sympathetic reserve, serum potassium, and orthostatic intolerance after endurance exercise and implications for neurocardiogenic syncope. Eur Heart J. 2008;29(12):1531–1541

6

Electrocardiograms Not to Miss Andres Perez-Riera

6.1 Brugada Syndrome 6.1.1 Introduction Brugada syndrome (BrS) is characterized by a typical electrocardiographic pattern of ST segment elevation in leads V1–V3.1 Patients with BrS are at increased risk of sudden cardiac death (SCD) as a result of very fast polymorphic ventricular tachyarrhythmia (PVT)/ ventricular fibrillation (VF). Both repolarization and depolarization abnormalities, especially in the RVOT, constitute the hallmark of BrS.2,3

6.1.2 Eletrocardiographic Features 6.1.2.1 Rhythm Sinus rhythm (SR) is present in approximately 80% of cases. Rhythm disturbances are usually associated with the presence of a channelopathy.4

6.1.2.2 Heart Rate Symptomatic bradychardia secondary to sick sinus syndrome may be present. An overlap syndrome of BrS associated with sick sinus syndrome or sinus node dysfunction is rarely observed.5

A. Perez-Riera Electro-Vectocardiography, ABC Foundation, São Paulo, Brazil e-mail: [email protected]

6.1.2.3 P Wave P wave duration prolongation together with PR and QRS duration prolongation are depolarization abnormalities. Discrete P wave prolongation is frequently observed in BrS patients with positive SCN5A mutation.6 P (max), P-wave dispersion (P(disp)), and left atrial dimensions are not significantly different among BrS patients and controls as predictor of atrial fibrillation (AF).7

6.1.2.4 PR Interval First-degree AV block is observed in »50% of cases of BrS mainly in the presence of SCN5A mutation (Fig. 6.1).

6.1.2.5 QRS Complex QRS axis: Extreme left electrical axis deviation of QRS complex ³30° on the frontal plane (FP) was observed in 9.5% of BrS cases from working adults in the Tokyo area,6 mainly in the presence of SCN5A mutation, which suggests association with left anterior fascicular block (LAFB) or right superior divisional block (RSDB). The differentiation between the RSDB or right superior fascicular block (RSFB) and LAFB is not only important in anatomic and physiologic grounds, but also in a clinical viewpoint. The right superior fascicle or division corresponds to the set of fibers located in the RVOT. Figure  6.2 shows a typical BrS type 1 associated with right superior divisional block QRS duration (QRSd): The mean QRSd in BrS is between 90 and 130 ms (110 ± 2 ms). On 12-lead ECG, QRS duration in lead V6 is longest in BrS patients

R. Brugada et al. (eds.), Clinical Approach to Sudden Cardiac Death Syndromes, DOI: 10.1007/978-1-84882-927-5_6, © Springer-Verlag London Limited 2010

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A. Perez-Riera

Fig. 6.1  Symptomatic (repetitive syncope episodes) male patient with positive familial background, genetic research: positive N927S

Fig. 6.2  Typical ECG of Brugada type 1 pattern with extreme left axis deviation on frontal plane (FP) secondary to right superior divisional block. ECG diagnosis: extreme left axis devia-

tion, SII>SIII, aVR signal (prominent final R wave of unipolar aVR) and Brugada sign. Brugada ECG pattern in right precordial leads

with antecedent of VF than in those who are asymptomatic. QRSd in lead V6 ³90 ms was found to be a possible predictor of recurrence of cardiac events in symptomatic patients. Prolonged QRSd in precordial leads is prominent in symptomatic patients. This ECG marker may be useful for distinguishing high- from low-risk patients with BrS.8 Both an S wave width ³80 ms in V1 and ST elevation ³1.8 mm (0.18mV) in V2 are highly specific indicators of VF high-risk BrS and have a positive predictive value of 40.5% and negative predictive value of 100% for VF, with 100% sensitivity (Fig. 6.3).9

Sometimes, incomplete right bundle branch block (IRBBB) or complete right bundle branch pattern (CRBBB) is observed in BrS. Frequently, these patterns are atypical and characterized by absence of wide final S wave in left leads (DI, aVL, V5 and V6) and without broad terminal R wave in the aVR lead. The phenomenon produced the confusing names of “pseudo RBBB” and “RBBB like.” True RBBB requires terminal wide S wave in left leads; DI, aVL, V5 and V6 and terminal broad R’ or R broad final wave in aVR. QRS pattern in aVR lead: There is a significant correlation between a prominent R wave in lead aVR

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Fig. 6.3  ECG/VCG correlation in FP. RECD: right end conduction delay

(aVR sign) and risk for development of arrhythmic events in BrS. In the presence of BrS, prominent R wave in lead aVR may reflect more right ventricular conduction delay and subsequently more electrical heterogeneity, which in turn is responsible for a higher risk of arrhythmia.10

6.2 Ventricular Repolarization Components In BrS, J point elevation is characteristic in right precordial leads or in anteroseptal wall. During nocturnal bradycardia periods increase of J point is observed. On 12-lead ECG, r-J interval in lead V2 is longer in BrS patients with positive VF antecedent. The r-J interval in lead V2 ³90 ms is found to be a possible predictor of recurrence of cardiac events in symptomatic patients.9 Since the first Consensus on BrS, three electrocardiographic patterns are acknowledged, called types 1, 2, and 3.11 Only type 1 –much rarer- is diagnostic and characterized by presenting in the right precordial

leads (V1 and V2) or in the antero-septal wall (V1–V3) of ECG, coved type or descending rectilinear oblique ST segment elevation ³2 mm followed by T wave of negative polarity (configuration of ST-T in V1 and V2 due to a high take-off J point giving rise to a downsloping ST segment that is followed by a negative T wave) (Fig. 6.4). The coved type and the saddle-back type (types 2, 3) are interchangeable, and the latter is clinically observed much more frequently. Saddleback-type ST-segment elevation is a relatively common finding among patients with lone AF. The familial clustering of the disorder indicates that genetic factors may be involved in the pathogenesis of the ECG abnormality and lone AF in these patients.13 For diagnosis of BrS, confirmation of type 1 pattern is needed (Fig. 6.5 and 6.6). Additionally, there are several references in literature to patients with elevation of the J point and ST segment convex to the top or straight descendent in inferior leads (Brugada sign) or concomitantly ST-segment elevation in the right precordial and inferior leads II, III, and aVF12 in absence of hypothermia, ischemia or electrolytic disorders, which we call “atypical Brugada pattern,” atypical BrS, variant BrS,

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A. Perez-Riera

Fig. 6.4  Type 2 pattern displays in the right precordial leads (V1 and V2) or from V1 through V3, elevation of the J point and the initial portion of ST segment of ³2 mm and in the terminal portion ³1 mm with saddleback appearance, followed by positive or biphasic T wave

Fig. 6.5  In type 3, the ST segment also has saddleback or coved appearance, with elevation in J point and the onset of ST segment ³2 mm and terminal portion £1 mm followed by positive T wave

or BrS variant, or idiopathic VF (a variant of the BrS with ST-segment elevation in inferior leads). The case below is typical of this situation (Fig. 6.7).

6.2.1 The T Wave Macroscopic T wave alternans (TWA) associated with increased occurrence of ventricular arrhythmias has been reported in patients with BrS. TWA is characterized by beat to beat alteration in the amplitude, polarity, and/or morphology of the electrocardiographic T  wave. TWA has been reported in patients with the BrS and is thought to be associated with an increased risk for development of VT/VF. The cellular mechanisms involved are not well-defined and are the subject of this investigation.14 TWA after pilsicainide administration is associated with a high risk of clinical VF in patients with BrS.15 Spontaneous T-wave alternancy at baseline, can be observed in a patient with BrS. After intravenous administration of class I antiarrhythmic drug, glucose tolerance test, and atrial pacing T-wave alternancy diminished.16

6.2.2 QT Interval Relatively normal corrected QT interval is the rule, but a minimal prolongation is eventually observed17 and occasionally this minimal prolongation coincides with ST segment elevation.18 In patients with BrS, the ST elevation is augmented during bradycardia to a similar extent in both symptomatic and asymptomatic patients. However, an inhibited prolongation of the QT interval during bradycardia is characteristic of symptomatic patients. These unique repolarization dynamics could relate to the nighttime occurrence of VF during bradycardia in patients with BrS.19 On the other hand, a new clinical entity was described which consists of an ST-segment, an ST-segment elevation in the right precordial ECG leads, a shorter-thannormal QT interval (corrected QT intervals £360 ms), and a history of SCD consequence of loss-of-function mutations in genes encoding the cardiac L-type calcium channel, in which a BrS phenotype is combined with shorter-than-normal QT intervals.20 Since its original description in 1992,21 there has been tremendous progress in the electrocardiographic features of this disease.

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Fig. 6.6  Types 2 and 3 are found as normal variants with a high rate, being included in the group of RECDs by the fascicles of the right bundle branch of the His bundle

Fig.  6.7  Brugada syndrome with atypical ECG: downsloping ST segment elevation in inferior leads. Name: Y. A. S; sex: male; age: 26 years; race: yellow; weight: 64  Kg; height: 1.68  m; date: 03/05/2002. Downsloping ST segment elevation is present

in inferior leads (Idiopathic J waves or Osborn Wave). Mirror image seen in anterior wall. Absence of hypothermia, ischemia, or electrolytic disorders

6.3 Long QT Syndrome

6.3.2 ECG Parameters in Congenital LQTS

6.3.1 Introduction Congenital long QT syndrome (LQTS) is a rare, but potentially lethal sporadic hereditary channelopaty or electrical disease, caused by mutations in the genes regulating cardiac potassium or sodium currents. The disease is characterized by an inconstant prolonged QT interval in the surface electrocardiogram (ECG) and increased predisposition to a typical polymorphic (Fig. 6.8) ventricular tachycardia (PVT), termed Torsade de Pointes (TdP).

1. Heart Rate. Frequent low heart rate (HR) for age. LQT1 variant has moderate HR dependence of QT interval. In LQT3 variant, there are low heart rates for age; eventually, we observe bradycardia during rising efforts. When HR increases, concomitantly QT interval shorten in more degree in LQT3 variant related to LQT1 and LQT2. 2. PR or PQ interval. Usually normal. 3. ST segment. In LQT3, caused by mutations of the SCN5A gene for the sodium channel, a gain-of-

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function mutation causes persistent inward sodium current in the phase 2 (plateau phase), which contributes to prolongation of the ST segment and late apparition of T wave and Long QT interval secondary to prolongation of ST segment (Fig. 6.9). 4. T wave: (a) Polarity TWA is an infrequently recorded ECG finding in patients with delayed repolarization, and its clinical significance is not clear. Isolated TWA (repolarization alternans) is frequently associated with LQTS. Detection of microvolt T-wave alternans has low sensitivity and high specificity in diagnosing LQTS. The prognostic value of microvolt T-wave alternans has not been studied systematically. T amplitude is generally quite small in the chromosome 7 genotype. TWA is a marker of electrical instability and regional heterogeneity of repolarization and identifies a high-risk subset of patients with prolonged repolarization. Patients with TWA have an increased risk of cardiac events, but this risk is primarily related to the magnitude of QTc prolongation. TWA does not make an independent contribution to the risk of cardiac events after adjustment for QTc length.22 (b) Voltage: T wave with low amplitude is observed in LQT2 variant. (c) Duration: LQT1 is characterized by a broadbased prolonged T waves. T duration is particularly long in the chromosome 11 genotype (lead II); (d) Aspect: Notched T wave in three leads. T wave with notched appearance is typical of LQT2 variant. This variant has low T wave-amplitude with a notched, bifurcated alternant, biphasic or bifid T appearance due to a very significant slowing of repolarization. 5. U wave: Prominent or giant (QU) is more evident from V4 to V6. Polarity: Eventually alternant polarity during low HR. Voltage: Increased. LQT3 variant has increased voltage during bradycardia. 6. QT interval: The QT interval on the ECG, measured from the beginning of the QRS complex to the end of the T wave, represents the duration of depolarization (QRS) and repolarization (ST segment and T wave) of the ventricular myocardium. QT intervals corrected for HR (QTc) longer than 450 ms in men and 460 ms in females are generally considered prolonged. While many individuals with LQTS have persistent ­prolongation of the QT interval, some individuals do not always show the QT prolongation; in these individuals, the QT interval may prolong with the

A. Perez-Riera

a­ dministration of certain medications. QTc is the best diagnostic and prognostic ECG parameter in LQTS families. A single measurement should be obtained in lead II if measurable and then in left precordial leads (preferably V5) as a second choice.23 Most individuals with LQT1 show paradoxical prolongation of the QT interval with infusion of epinephrine.24 The autosomal recessive mutation of LQT1, JervelLange-Nielsen syndrome homozygous mutations in KVLQT1 leads to severe prolongation of the QT interval (due to near-complete loss of the IKs ion channel), TU complexes with remarkable great width giant T waves (“Himalayan T waves”), and is associated with increased risk of TdP and congenital deafness.25 The QTc interval is the value corrected according to HR, which represents the period between electric depolarization onset in the ventricles and the end of their repolarization. The end of T wave is defined as T wave return to the baseline, here called T-P segment. For a proper measurement of the QT interval, we should not include the U wave. To that end, it is advisable to perform the measurement in the aVL lead, because it is usually perpendicular to the U wave axis (SAU). In those cases where there is R-R irregularity, we will conduct the measurement in three consecutive cycles, and then, the mean value is estimated. The normal maximal value that is accepted for the QT interval in males is 446 ms and in females 447 ms ±15. If it exceeds 450 ms in males and 470 ms in females, the QT interval should be considered as prolonged. Values above 500  ms may cause a tendency to TdP. Patients with QTc intervals >600  ms are considered to be in high risk of arrhythmic SCD by TdP. Values of QTc interval by age and gender QTc value(s) Children Men (1–15 years)

Women

Normal

<440 ms

<430 ms

<450 ms

Borderline

440–460 ms

430–450 ms

450–470 ms

Prolonged

>460 ms

>450 ms

>470 ms

Source: Zareba et al26

The QTc interval estimation is performed by applying the Bazett’s formula proposed in 1920: QTc QT/ root of the R-R interval. The Bazett equation is used to

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Fig. 6.8  Name: B.A.S; age: 8 years; sex: fem; race: white; date: 03/12/1998; weight: 25 Kg; height: 1.25 m; medication in use: Nadolol (corgard) 120  mg/day. Clinical diagnosis: congenital long QT syndrome without deafness. ECG diagnosis: sinus

rhythm (SR); HR: 36 bpm: marked sinus bradycardia, QT interval: 110  ms (for this HR, the maximal value in women is 55 bpm). Very prolonged QT interval, biphasic and prominent T wave

calculate the QTc as follows: QTc QT/root of the R-R interval. Athletes and children have marked beat-to-beat variability of the R-R interval. In such cases, long recordings and several measurements are required. The longest QT interval is usually observed in the right precordial leads V1–V2.

around the baseline, with phasic variation of polarity and width of QRS complexes, and that may be suppressed by establishing a higher HR (Fig. 6.10).

7. Arrhythmias in Congenital LQTS

6.4 Electrocardiographic and Electrophysiological Characteristic of Torsade De Pointes Are atypical or helicoidal PVT, associated to long QT interval (generally >600  ms) or increase in U wave width, with possible typical 180° rotation of QRS axis

6.5 Electrophysiological Mechanism Onset by early after depolarization EADs by triggered activity. It depends on the oscillations of action potential (AP), that occur before repolarization is fulfilled at the end of phase 2 and phase 3, which originate potentials that spread during the process of repolarization in phases 2 or 3. EADs are divided into: 1. From Phase 2 (a) Oscillations that occur when in the plateau, dome or phase 2 by increase in inward Ca2+ by the slow I Ca-L channel.

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Fig. 6.9  ECG of congenital long QT syndrome Romano-Ward variant of LQT3. Seven-year-old boy, without sensorineural deafness. LQT3 affects the SCN5A gene in chromosome 3p2124. The affected channel is the Na+ current in the alpha subunit.

A. Perez-Riera

There is abnormal prolongation of QT interval (620  ms) with delayed T wave onset. This patient suffered repetitive syncopes. The patient with LQT3 tends to suffer more events during sleep

Fig. 6.10  “Swinging pattern” typical 180° rotation of QRS axis around the baseline. Rotation of QRS apices of upto 180° along the baseline

(b) There is an additional and persistent inflow of the sodium cation in phase 2 or AP plateau. This is observed in variant 3 or LQT3. This explains the increase in ST segment duration in ECG. QT interval prolongation at the expense of ST segment prolongation. EADs originate TdPs. 2. From Phase 3 of Fast Repolarization (a) These postdepolarizations occur during phase 3 of AP by reduction in the activity of outward K+

channels (Ik–R or Ik–s) as it happens in congenital LQTs LQT2 and LQT1 respectively. The latter differentiate from the former in that they present Ca2+ release from the Ca2+ release channel or ryanodine receptor. Moreover, activation of the INa+- Ca2+ cation exchange channel by electrogenic mechanism (there is exchange of three Na+ molecules by one of Ca2+). TdPs are maintained by re-entry secondary to TDR, where heterogeneous response of ventricular myocardium thickness cells stands out.

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6.6 Cardinal Sign

6.8.2 Main ECG Features

Polymorphic QRS. Rotation of QRS apices of up to 180° along the baseline: swinging pattern of Marriot; Usual Duration: from 5 to 20 QRS complexes; HR: from 150 to 300 bpm (usually 200–250 bpm); Clinical Repercussions: asymptomatic, presyncope, syncope or degeneration into VF with cardiorespiratory arrest; Onset: by extrasystole of long, delayed or telediastolic coupling; however, with R on T phenomenon. Frequent after pauses by “long-short” sequence or in bradyarrhythmias, complete atrioventricular (AV) block and sudden PR interval prolongation. There are three predominant different initiating patterns/modes of TdP:27

Ninety percent of individuals with ARVC/D have some ECG abnormalities. The most commonly seen ECG abnormality is T wave inversion in leads V1–V3. (Fig. 6.11) However, this is a nonspecific finding, and may be considered a normal variant in RBBB, women, and children under 12 years. In absence of CRBBB in patients >12 years old, negative T wave from V1 to V3 is a sign with great value for diagnosis. In normal, young patients, there is usually positive T polarity in V1; however, it may flatten and nearly always has a positive polarity in V2. In symptomatic patient carriers of ARVD, the ECG generally shows T wave inversion in V1 and V2, which may reach up to V6 QRSD ³110 ms has sensitivity of 91%, specificity of 90%, and a total predictive accuracy of 90% in predicting inducibility of VT in ARVC/D patients (Fig. 6.12).29 The so-called Epsilon wave is found in about 33% of those with ARVC/D. This is described as a terminal notch in the QRS complex. It is due to slowed intraventricular conduction. The epsilon wave may be seen on a surface ECG;30 however, it is more commonly seen on SAECGs (Fig. 6.13).

1. A “short-long-short” sequence pattern (65%) defined as one or more short-long cardiac cycles followed by an initiating short-coupled PVC. 2. An “increased sinus rate” pattern (25%) defined as a gradual increase in sinus rate with or without T-wave alternans. 3. A “changed depolarization” pattern (10%) defined as sudden long-coupled PVC or fusion beat followed by short-coupled PVC.

6.7 Most Common Causes Severe bradyarrhythmia, hypopotasemia, drugs; Effective Measures: b-blockers, bretylium tosylate, diphenylhydantoin, association of b-blockers and diphenylhydantoin or b-blockers associated to permanent pacemaker. In refractory cases, left sympathectomy or ICD is indicated.

6.8 Arrhythmogenic Right Ventricular Dysplasia 6.8.1 Introduction Arrhythmogenic right ventricular dysplasia (ARVC/D) is a cardiomypathy that predominantly affects the right side of the heart and causes ventricular arrhythmias. It is characterized by the progressive replacement of myocardial cells by fat and fibrous tissue. Today, the entity is considered a disease of cell adhesion because of mutations in desmosomal genes.28

Fig. 6.11  We observe T wave inversion on right precordial leads in a patient with ARVD/C. Inverted T wave in right precordial leads (V1 and V2) >12 years old, in absence of Complete Right Bundle Branch Block is an important ECG clue for the diagnosis

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Fig.  6.12  QRSD of V1 + V2 + V3/V4, V5 and V6 or ³1.2 in approximately 65% of cases. QRS prolongation located ³ in right precordial leads. QRSD ³ from V1 to V3 with 91% sensitivity, 90% specificity that predicts VT in patient carriers of ARVD

In ARVC/D, sometimes there is evidence of peripheral blocks of the right bundle branch: the IRBBB or CRBBB topography occurs in the divisional portion of the right branch, i.e., in the free wall of the RV after the trunk of the branch splits in the base of the papillary muscle of the tricuspid valve, and its mechanism seems to respond to dysplastic involvement of the free wall, whether in the RVOT, the RVIT, or in the apical region (dysphasia triangle) where the dysplastic area is found.31,32

A. Perez-Riera

Ventricular ectopy seen on a surface ECG in the setting of ARVC/D is typically of LBBB morphology, with a QRS axis of −90 to +110°. The origin of the ectopic beats is usually from one of the three regions of fatty degeneration (the “triangle of dysplasia”): the RV outflow tract, the RV inflow tract, and the RV apex. In ARVC/D, the VT is usually M-VT, sustained or not, and with morphology of LBBB because its origin is in the RV. If its origin is in the RVOT, the SÂQRS is generally deviated to the right between +90° and +120° (QRS of the “qR” or “QS” type in DI). In cases with LBBB morphology and SAQRS to the left, the focus is located in the RVIT, the apex, or the inferior wall of the RV. A VT with LBBB morphology, and SÂQRS to the left, nearly always suggests structural heart disease (Fig. 6.14). 6.8.2.1 ECG with Modified Protocol Protocol for obtaining ECG in patients with suspected ARVC/D 1. Rhythm strips of the precordial leads V1–V6 should be obtained at double speed (50 mm/s) and double amplitude (20  mm/mv) in order to compare the duration of the QRS complex (QRSD) in different leads as well as to record the epsilon wave.

Fig. 6.13  SR, CRBBB, terminal notch located in the J point (EPSILON wave). The EPSILON wave could be the result of delayed activation in the RV. It is visible from V1 to V3 and in the FP leads. T wave inversion is observed in V1 to V3, characteristic of ARVD

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Fig. 6.14  MVT with a heart rate (HR) of 214 bpm, pattern of CLBBB and electrical axis with extreme shift to the left: it originates in the RVIT. This axis indicates presence of structural heart disease

2. Rhythm strips of leads DI-aVF should be obtained at double speed (50  mm/s) and double amplitude (20 mm/mv). Place the left arm lead over the xyphoid process, the right arm lead on the manubrium sternum, and the left leg lead over a rib at the V4 or V5 position in order to elicit the epsilon wave. Localized prolongation of QRSD interval in V1–V3/QRSD interval in > than 1.2 has been found in 97% of cases of V4–V6 ARVC/D. The QRSD is correlated with the amount of fibrous tissue in patients with VT of RV origin The sensitivity of this QRS diagnostic criterion has not been established in patients who do not have overt manifestation of this disease. If difference is equal to or larger than 25 ms, this is in favor of slowing of conduction in the RV. The specificity of this criterion has not yet been completely established in patients without this entity.

6.9 Short QT Syndrome 6.9.1 Introduction Hereditary, congenital, or familial short QT syndrome (SQTS) is a clinic-electrocardiographic entity, clinically

characterized by a large set of signs and symptoms, such as: syncope, sudden death, dizziness, and high tendency to appearance of episodes of paroxysmal runs of AF, high risk of ventricular tachyarrhythmia, and sudden death. A few families have been identified, with 3 types existing: SQT1 (Ikr), SQT2 (Iks) and SQT3 (Ik1).33 The entity is the opposite of long QT syndrome, since they exert opposite effects regarding potassium rectifier channels function: SQTS causes increase in the function of such channels; on the contrary, long QT syndrome causes decrease of function.

6.9.2 Electrocardiographic Characterization T wave: morphology: tall T wave from V3 through V5 with narrow base and a tendency to be symmetrical (the patient does not have serum potassium increase); SAT: +42° in the FP and discretely heading to the front and below in the HP; QT/QTc interval: 302/315: short for this rate (the inferior limit for a 67 bpm HR in men is 324  ms); JT/JTc interval: 182/199  ms: extremely short (QT-QRSD > JT. 302–120 > 182  ms). (The inferior limit for a 67 bpm HR in men is 224 ms).

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Conclusion: (1) Complete RBBB; (2) Short QT interval with no use of drugs, electrolytic disorders, or any associated pathophysiological state; (3) Very short JT interval; (4) Probable early repolarization pattern (Fig. 6.15–6.17). It is important to recognize the ECG pattern of this entity because it is related to a high risk of sudden death in young, otherwise healthy subjects. 1. Rhythm: high tendency to appearance of episodes of paroxysmal runs of AF in family members and no known history of SCD. In KCNH2 mutation, the class Ic agent propafenone could be effective to prevent episodes of paroxysmal AF.34 Approximately 31% of cases have palpitations secondary to AF documented even in young subjects (Fig. 6.18). In this tracing, we can see a short period of gross AF. The patient described palpitations. Congenital short QT syndrome is associated to high incidence of

Fig. 6.15  Name: JSVB; age: 27; sex: male; race: white; weight: 67  Kg. Height: 1.72  m; date: 06/24/2004; medication in use: none. QRS duration (QRSD): 120 ms; QRS morphology: tripha-

A. Perez-Riera

paroxysmal AF, the electrophysiological mechanism of which would be caused by heterogeneous shortening of the cardiac potential and refractory period of atrial cardiomyocytes. Approximately 8  h later during the same test, the patient spontaneously reversed into SR (Fig. 6.19). 2. T wave: T waves of great voltage and narrow base, in which: Polarity: Positive; Voltage: great voltage; Duration: narrow base; Aspect: resemble T wave in “desert tent” of hyperpotasemia. 3. U wave: The form of congenital SQTS caused by the mutation in KCNH2 abolishes rectification of HERG currents and specifically causes gain of function, I(Kr) in the ventricle with minimal effects on the Purkinje fiber action potential duration (APD).35 Such preferential prolongation may explain the separation of the T and U waves observed in the ECG of SQT1 patients and lead to re-excitation of the ventricle endocardium.36

sic rSR’ pattern in V1 and broad S wave in left leads DI, aVL V5 and V6 (right terminal forces); intrinsic deflection in V1>50 ms

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Fig. 6.16  ECG/VCG correlation FP

Fig. 6.17  CG/VCG correlation horizontal plane

4. QT interval: Short QT interval is defined as QTc of less than 350 ms.37 In congenital SQTS, all patients have a constantly and uniformly very short QT/QTc interval, which was £280  ms and QTc £300  ms.7

More recently, the same authors considered the QT interval of £320 ms and QTc £340 ms as maximal superior limit. 5. JT interval: Very short (Fig. 6.20).

86

A. Perez-Riera

Fig. 6.18  Long duration electrocardiogram recording (holter)

6.10 Catecholaminergic Polymorphic Ventricular Tachycardia 6.10.1 Introduction Catecholaminergic polymorphic ventricular tachy­ cardia (CPVT) is a rare, clinically and genetically heterogeneous disease characterized by exercise, adrenergic stress induced or adrenergically-mediated ventricular tachyarryhtmias, with recurrent syncope of uncertain etiology after physical and emotional stress or SCD, usually in the pediatric or juvenile age group.38

2. Rhtyhm: Sinus rhtyhm is the rule. Abnormalities in sinoatrial node function, as well as atrioventricular nodal function, could produce AF, atrial flutter, and atrial standstill (sick sinus syndrome). 3. QTc Interval: normal at resting ECG.39 See proposed algorithm diagnostic scheme for PVT or VF in structurally normal hearts based initially in QT interval duration. 4. U Wave Alternans: U-wave alternans was observed in following clinical circumstances: After ventricular pacing at 160 bpm, during the recovery phase after the exercise stress test, following a pause from sinus arrest and a change in T-wave was also noted, precordial V3–V5 are the leads showing alternans most clearly.40 5. Arrhythmias

6.10.2 Electrocardiographic Features

(a) Supraventricular Arrhythmias

1. HR: baseline bradycardia tendency off drugs is observed in all carriers. (slow HR);

AF, atrial flutter, atrial standstill, and sick sinus syndrome may be present.41 (b) Ventricular Arrhythmias

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Fig. 6.19  This trace shows spontaneously reversion from atrial fibrillation to sinus rhythm in the same Holter Recording, eight hours later

1. Ventricular arrhythmias elicited exclusively by exercise or adrenergic stress. Typically, they are induced by isoproterenol infusion. 2. Premature ventricular complex (PVCs) Calcium channel antagonist, verapamil, can suppress PVCs and nonsustained VT salvoes in CPVT caused by RyR2 mutations.42 3. PVT occurs during physical exercise or emotional stress. Most cases are nonsustained (72%), but 21% are sustained and 7% are associated with VF. 4. PVT and bidirectional VT in association are observed in 21% of cases in pediatric group. 5. There is 100% inducement of CPVT by exercise, 75% by catecholamine infusion, and none by programmed stimulation. No late potential is recorded. Onset is in the right ventricular outflow tract in more than 50% the cases.42 His-Purkinje system is an important source of focal arrhythmias in CPVT. 6. Bidirectional VT is a more typical feature. Its characteristics are:

(b) HR between 140 and 200 bpm. (c) Complete RBBB pattern. (d) Sudden change of QRS morphology by change of SÃQRS, successively from beat to beat. (e) SÂQRS in the FP with differences close to 180°: one beat presents ÂQRS between −60° and −90° (Complete RBBB + LAFB) and the following between +120° and +130° (CRBBB + LPFB). (f) Eventually alternating RBBB and LBBB morphology. The origin of the tachycardia is located near the His bundle bifurcation. This suggested a single focus at the interventricular septum with two exit sites, depolarizing the right and left ventricle in an alternate fashion. Two sets of fairly constant and alternating VA intervals are recorded. This fact is consistent with two ventricular circuits used alternatively. It is postulated that the tachycardia is due to macrore-entry involving the two fascicles of the left branch. Re-entry may be a possible mechanism in some cases of bidirectional tachycardia.

(a) Regular VT.

The Fig. 6.21 shows a typical pattern of bidirectional VT

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A. Perez-Riera

Fig. 6.20  In V1 lead we observe typical Complete Right Bundle Branch Block QRS pattern and very short JT and QT intervals (170ms and 281ms). In V6 lead we can see a broad final S wave typical of RBBB associated with short JT and QT intervals

Fig.  6.21  Female, white, 20-year-old, recurrent syncope of uncertain etiology after physical and emotional stress carrier of familial catecholaminergic cardiomyopathy. Alternans QRS

complexes are observed with alternating right and left bundle branch block morphology. The QRS axis shifts from −60° to +120°

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6.11 Clue for Electrocardiographic Diagnosis of CPVT Association of ECG sinus bradycardia + normal QTc interval + stress-related, bidirectional VT or PVT in the absence of apparent structural heart disease42

References   1. Sovari AA, Prasun MA, Kocheril AG. ST segment elevation on electrocardiogram: the electrocardiographic pattern of Brugada syndrome. MedGenMed. 2007;9:59   2. Hisamatsu K, Kusano KF, Morita H, et  al. Relationships between depolarization abnormality and repolarization abnormality in patients with Brugada syndrome: using body surface signal-averaged electrocardiography and body surface maps. J Cardiovasc Electrophysiol. 2004;15:870–876   3. Morita H, Zipes DP, Morita ST, Wu J. Differences in arrhythmogenicity between the canine right ventricular outflow tract and anteroinferior right ventricle in a model of Brugada syndrome. Heart Rhythm. 2007;4:66–74   4. Torres PI, Nava S, Gómez-Flores J, et al. Association of congenital, diffuse electrical disease in children with normal heart: sick sinus syndrome, intraventricular conduction block, and monomorphic ventricular tachycardia. J Cardiovasc Electrophysiol. 2008;19(5):550–555   5. Probst V, Denjoy I, Meregalli PG, et al. Clinical aspects and prognosis of Brugada syndrome in children. Circulation. 2007;115:2042–2048   6. Yokokawa M, Noda T, Okamura H, et  al. Comparison of long-term follow-up of electrocardiographic features in Brugada syndrome between the SCN5A-positive probands and the SCN5A-negative probands. Am J Cardiol. 2007;100: 649–655   7. Bigi MA, Aslani A, Shahrzad S. Clinical predictors of atrial fibrillation in Brugada syndrome. Europace. 2007;9: 947–950   8. Takagi M, Yokoyama Y, Aonuma K, Aihara N, Hiraoka M; Japan Idiopathic Ventricular Fibrillation Study (J-IVFS) Investigators. Clinical characteristics and risk stratification in symptomatic and asymptomatic patients with Brugada syndrome: multicenter study in Japan. Cardiovasc Electro­ physiol. 2007;18:1244–1251   9. Junttila MJ, Brugada P, Hong K, et al. Differences in 12-lead electrocardiogram between symptomatic and asymptomatic Brugada syndrome patients. J Cardiovasc Electrophysiol. 2008;19(4):380–383 10. Babai Bigi MA, Aslani A, Shahrzad S. aVR sign as a risk factor for life-threatening arrhythmic events in patients with Brugada syndrome. Heart Rhythm. 2007;4:1009–1012 11. Wilde AA, Antzelevitch C, Borggrefe M, Brugada J, Brugada R, Brugada P, Corrado D, Hauer RN, Kass RS, Nademanee K, Priori SG, Towbin JA; Study Group on the Molecular Basis of Arrhythmias of the European Society of Cardiology. Proposed diagnostic criteria for the Brugada syndrome: consensus report. Circulation. 2002;106:2514–2519

89 12. Cau C. The Brugada syndrome. A predicted sudden juvenile death. Minerva Med. 1999;90:359–364 13. Junttila MJ, Raatikainen MJ, Perkiomaki JS, Hong K, Brugada R, Huikuri HV. Familial clustering of lone atrial fibrillation in patients with saddleback-type ST-segment elevation in right precordial leads. Eur Heart J.  2007;28: 463–468 14. Tada T, Kusano KF, Nagase S, et al. Clinical significance of macroscopic T-wave alternans after sodium channel blocker administration in patients with Brugada syndrome. J Cardiovasc Electrophysiol. 2008;19:56–61 15. Nishizaki M, Fujii H, Sakurada H, Kimura A, Hiraoka M. Spontaneous T wave alternans in a patient with Brugada syndrome–responses to intravenous administration of class I antiarrhythmic drug, glucose tolerance test, and atrial pacing. J Cardiovasc Electrophysiol. 2005;16:217–220 16. Morita H, Zipes DP, Lopshire J, Morita ST, Wu J. T wave alternans in an in vitro canine tissue model of Brugada syndrome. Am J Physiol Heart Circ Physiol. 2006;291: H421-H428 17. Bezzina C, Veldkamp MW, van Den Berg MP, et al. A single Na(+) channel mutation causing both long-QT and Brugada syndromes. Circ Res. 1999;85:1206–12013 18. Mizumaki K, Fujiki A, Nishida K, et  al. Bradycardiadependent ECG changes in Brugada syndrome. Circ J. 2006; 70:896–901 19. Pitzalis MV, Anaclerio M, Iacoviello M, et  al. Rizzon P QT-interval prolongation in right precordial leads: an additional electrocardiographic hallmark of Brugada syndrome. J Am Coll Cardiol. 2003;42:1632–1637 20. Antzelevitch C, Pollevick GD, Cordeiro JM, et al. Loss-offunction mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. Circulation. 2007;115:442–449 21. Brugada P, Brugada J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. J Am Coll Cardiol. 1992;20:1391–1396 22. Zareba W, Moss AJ, le Cessie S, Hall WJ. T wave alternans in idiopathic long QT syndrome. J Am Coll Cardiol. 1994;23: 1541–1546 23. Mönnig G, Eckardt L, Wedekind H, et al. Electrocardiographic risk stratification in families with congenital long QT syndrome. Eur Heart J. 2006;27:2074–2080 24. Shimizu W, Noda T, Takaki H, et  al. Diagnostic value of epinephrine test for genotyping LQT1, LQT2, and LQT3 forms of congenital long QT syndrome. Heart Rhythm. 2004;1: 276–283 25. Denjoy I, Lupoglazoff JM, Villain E, et  al. The Jervell and Lange-Nielsen syndrome. Natural history, molecular basis and clinical outcome. Arch Mal Coeur Vaiss. 2007;100:359–364 26. Zareba W. Drug induced QT prolongation. Cardiol J. 2007; 14:523–535 27. Noda T, Shimizu W, Satomi K, et  al. Classification and mechanism of Torsade de Pointes initiation in patients with congenital long QT syndrome. Eur Heart J. 2004;25: 2149–2154 28. Syrris P, Ward D, Asimaki A, et  al. Clinical expression of Plakophilin-2 mutations in familial arrhythmogenic right ventricular cardiomyopathy. Circulation. 2006;113:356–364

90 29. Nasir K, Tandri H, Rutberg J, et al. Filtered QRS duration on signal-averaged electrocardiography predicts inducibility of ventricular tachycardia in arrhythmogenic right ventricle dysplasia. Pacing Clin Electrophysiol. 2003;26:1955–1960 30. Gregor P. Electrocardiography in cardiomyopathies. Vnitr Lek. 2003;49:727–729 31. Fontaine G, Frank R, Guiraudon G, et  al. Significance of intraventricular conduction disorders observed in arrhythmogenic right ventricular dysplasia. Arch Mal Coeur Vaiss. 1984;77:872–879 32. Jaoude SA, Leclercq JF, Coumel P. Progressive ECG changes in arrhythmogenic right ventricular disease. Evidence for an evolving disease. Eur Heart J. 1996;17:1717–1722 33. Brugada R, Hong K, Cordeiro JM, Dumaine R. Short QT syndrome. CMAJ. 2005;173(11):1349–1354 34. Hong K, Bjerregaard P, Gussak I, Brugada R. Short QT syndrome and atrial fibrillation caused by mutation in KCNH2. J Cardiovasc Electrophysiol. 2005;16:394–396 35. Brugada R, Hong K, Dumaine R, et al. Sudden death associated with short-QT syndrome linked to mutations in HERG. Circulation. 2004;109(1):30–35 36. Anttonen O, Junttila MJ, Rissanen H, Reunanen A, Viitasalo M, Huikuri HV. Prevalence and prognostic significance of short QT interval in a middle-aged Finnish population. Circulation. 2007;116:714–720

A. Perez-Riera 37. Laitinen PJ, Swan H, Piippo K, Viitasalo M, Toivonen L, Kontula K. Genes, exercise and sudden death: molecular basis of familial catecholaminergic polymorphic ventricular tachycardia. Ann Med. 2004;36(suppl 1):81–86 38. Postma AV, Denjoy I, Kamblock J, et al. Catecholaminergic polymorphic ventricular tachycardia: RYR2 mutations, bradycardia, and follow up of the patients. J Med Genet. 2005; 42:863–870 39. Aizawa Y, Komura S, Okada S, et  al. Distinct U wave changes in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT). Int Heart J. 2006;47: 381–389 40. Fazelifar AF, Nikoo MH, Haghjoo M, et al. A patient with sick sinus syndrome, atrial flutter and bidirectional ventricular tachycardia: coincident or concomitant presentations? Cardiol J. 2007;6:585–588 41. Swan H, Laitinen P, Kontula K, Toivonen L. Calcium channel antagonism reduces exercise-induced ventricular arrhythmias in catecholaminergic polymorphic ventricular tachycardia patients with RyR2 mutations. J Cardiovasc Electrophysiol. 2005;16:162–166 42. Sumitomo N, Harada K, Nagashima M, et al. Catecholamin­ ergic polymorphic ventricular tachycardia: electrocardiographic characteristics and optimal therapeutic strategies to prevent sudden death. Heart. 2003;89:66–70

7

Sudden Cardiac Death in Forensic Pathology Antonio Oliva and Vincenzo L. Pascali

7.1 Introduction Sudden cardiac death (SCD) is the leading mode of death in all communities of the United States and the European Union, but its precise incidence is unknown. Internationally accepted methods of death certification do not include a specific category of SCD. Estimates for the United States range from 250,000 to 400,000 adult people dying suddenly each year owing to cardiovascular causes, with an overall incidence of 1–2/1,000 population per year.1-3 A task force of the European Society of Cardiology has adopted the incidence ranges from 36 to 128 deaths per 100,000 population per year.4,5 More than 60% of these are because of coronary heart disease. Among the general population of adolescents and adults younger than the age of 30 years, the overall risk of SCD is 1/100,000 and a wider spectrum of diseases can account for the final event.6 The major difficulties in interpreting the epidemiological data on sudden death are the lack of standardization in death certificate coding and the variability in the definition of sudden death. Sudden death has been defined as “a natural, unexpected fatal event occurring within one hour from the onset of symptoms in an apparently healthy subject or whose disease was not so severe as to predict an abrupt outcome.7” This well describes many witnessed deaths in the community or in emergency departments. It is less satisfactory in forensic practice, where autopsies may be requested on patients whose deaths were not witnessed, occurred during sleep, or at an unknown time before their bodies were discovered. Under the

latter circumstances, it is probably more satisfactory to assume that the death was sudden if the deceased was known to be in good health 24 h before the occurrence of death.8 Moreover, for practical purposes, a death can be classified as sudden if a patient is resuscitated after cardiac arrest, survives on life support for a limited period of time, and then dies owing to irreversible brain damage. Forensic pathologists are responsible for determining the precise cause of sudden death, but there is considerable variation in their approach to this increasingly complex task. A variety of book chapters, professional guidelines, and articles have described how pathologists should investigate sudden death,9-14 but there is little consistency among different centers, and even among different countries. Furthermore, recent advances in the field of molecular genetics have expanded our understanding of the etiology of many lethal and heritable channelopathies leading to fatal arrhythmias, such as congenital long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and Brugada syndrome (BrS); thus, forensic pathologists actually play a crucial role in such circumstances because an accurate postmortem diagnosis of the causes of SCD is of particular importance to establish preemptive strategies to avoid other tragedies among the relatives.15 In this chapter, we have summarized the state of the art forensic investigation and autopsy techniques for an adequate assessment of SCD in general population, and have described the main pathological findings at postmortem analysis.

7.1.1 The Range of Pathology A. Oliva () Institute of Forensic Medicine, Catholic University, School of Medicine, Rome, Italy e-mail: [email protected]

Many reports describe the pathological findings in SCD (Tables 7.1 and 7.2). These studies differ in many

R. Brugada et al. (eds.), Clinical Approach to Sudden Cardiac Death Syndromes, DOI: 10.1007/978-1-84882-927-5_7, © Springer-Verlag London Limited 2010

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Table 7.1  Sudden Cardiac Death in Adult Authors Setting

Patients and Methods

Selected Results

Davies et al. 199911

London, England

168 patients (21 female) dying from cardiac disease within 6 h of onset of symptoms. Detailed histology

73% had intraluminal or occlusive coronary thrombosis. Presence of thrombus associated with single vessel disease, acute myocardial infarction and prodromal symptoms

Leach et al. 199516

Nottingham, England

206 out-of-hospital sudden deaths due to coronary heart disease. Detailed histology

Coronary artery thrombosis +/– acute infarction in 48.5% of cases. Presence of these changes decreased with age and a previous history of IHD

Burke et al. 199717

Usa

113 males who died of coronary heart disease. Detailed histology

52% acute coronary thrombosis (10 with acute infarcts) 48% coronary stenosis without thrombosis (two with acute infarcts)

 Chugh et al. 200071

Usa

270 hearts referred to a cardiac pathology unit over 13-year-period. 190 males and 80 females aged > 20 years

 65% coronary artery disease  9% cardiomyopathy  11% myocarditis 14% CHD  5% structurally normal

Bowker et al. 200319

UK

National study of SCD in white males aged 16–64 years, no history of cardiac disease, seen alive within 12 h of death. Limited histology

37% acute coronary thrombosis or acute infarction 20% coronary stenosis with healed infarction 18% coronary stenosis without infarction 8% cardiomyopathy or LVH 4% unexplained

Chase, 200518

Southern England

321 SCDs in males and females aged >16 years, 2002–2003. Limited histology

33% acute myocardial infarction or acute coronary thrombosis 33% coronary stenosis with healed infarction 17% coronary stenosis without healed infarction 14% cardiomyopathy or LVH 2% unexplained

Fabre and Sheppard 200620

UK

453 hearts referred to a cardiac pathology unit, 1994–2003

59% structurally normal 24% cardiac muscle disease

Di Gioia et al. 200672

Italy

100 hearts referred to cardiac pathology unit, 2001-2005

30%, atherosclerotic 22% cardiomyopathies 28% various cardiac abnormalities 20% Inherited cardiac disease CHD, congenital heart disease; IHD, ischaemic heart disease; LVH, left ventricular hypertrophy; SCD, sudden cardiac death. (SOURCE: Data modified from Gallagher PJ 69)

ways, especially with respect to the age and type of patients investigated and the extent of histological sampling. In adults, coronary artery disease (CAD) is by far, the leading cause of death. The proportion of cases with the evidence of acute coronary thrombosis or recent myocardial infarction (MI) is higher in studies in which detailed histology was performed

(Table 7.1). With detailed histology, acute thrombosis was identified in 72, 52, and 47% of the cases.11,16,17 In contrast, recent studies where histology was limited showed acute thrombosis in 37% and 33% of the cases.18,19 Whether this represents a genuine change in the incidence of acute thrombosis in SCD or a failure of the pathologists to recognize thrombi without

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Table 7.2  Sudden Cardiac Death in young patients Authors Setting Patients and Methods

Selected Results

Wren et al. 2000

North England

229 sudden deaths in patients aged 1–20 years, 1985–1994

Asthma, respiratory infection or epilepsy 111 (48.5%) SIDS 20 (8.7%) Previous diagnosis of cardiac disease, chiefly congenital heart disease 33 (14.5%) Cardiomyopathy 8 (3.5%) Myocarditis 5 (2.2%) Coronary atheroma 1 (0.4%) Unexplained 21 (9.2%)

Corrado et al. 200167

Italy

273 SCDs, 218 males, 82 females aged 1–35 years, 1979–1998

Cardiomyopathy 66 (24%) Myocarditis 27 (10%) Coronary atheroma 54 (20%)

Maron 200374

Usa

387 sudden deaths in athletes aged 0–35 years

Unexplained 16 (6%) Cardiomyopathy 122 (32%) Myocarditis 20 (5%) Coronary atheroma 10 (3%) ‘Unexplained’ 2%

Fornes and Lecomte 200375

France

31 sudden deaths during sport, 29 males, 2 females aged 7–60 (mean 30) years

Cardiomyopathy 10 Coronary atheroma 9

Henriques de Gouveia et al. 200376

The Netherlands

11 sudden deaths from coronary heart disease in patients aged 24–35 years. No history of heart disease

Nine plaque erosions and two claque ruptures. Histology and immunohistochemistry suggested that thrombus was fresh in only three cases

Doolan et al. 200477

Australia

193 SCDs in patients aged <35 years, 1994–2002

Unexplained 31% Coronary heart disease 24% Cardiomyopathy 18% Myocarditis 12% Congenital heart disease 7%

73

SCD, sudden cardiac death; SIDS, sudden infant death syndrome. (SOURCE: Data modified from Gallagher PJ [69])

histological confirmation is uncertain. Congenital heart disease, cardiomyopathy, and unexplained left ventricular hypertrophy are of particular importance in younger patients (Table  7.2), especially athletes. Studies with limited histology appear to report a lower incidence of myocarditis. The wide range of uncommon pathology is especially apparent in reports from referral centers.20,21

there is little consistency among the different centers, even among different countries. Forensic investigation of sudden death involves four steps24:

7.1.2 Methods of Investigation

Finally, a forensic report including a clinicopathological summary is written by the pathologist. At this stage, it is critical to establish or consider:

Several book chapters, professional guidelines, and articles have described how pathologists should investigate sudden death.9-14,20,22,23 Despite these guidelines,

1. Circumstances of death and clinical informations relevant to the autopsy 2. Autopsy examination and histology 3. Laboratory tests 4. Formulation of a diagnosis: main findings at postmortem investigation

• Whether the death is attributable to a cardiac disease or to other causes of sudden death

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• The nature of the cardiac disease, and whether the mechanism was arrhythmic or mechanical • Whether the cardiac condition causing sudden death may be inherited, requiring screening and counseling of the next of kin • The possibility of toxic or illicit drug abuse and other unnatural deaths

7.2 Circumstances of Death and Clinical Informations Relevant to the Autopsy Forensic and general pathologists approach sudden death autopsies with different degrees of suspicion. Forensic pathologists may visit the scene of death and carefully examine the clothing and effects of the deceased. Death scene investigation also requires a detailed interrogation of witnesses, if any, family members of the deceased, and physicians of the rescue team who attempted resuscitation. On the other hand, general pathologists usually receive reports from the police or other investigators confirming that no suspicious circumstances have been discovered. Whatever the setting may be, pathologists should be provided with full details of the circumstances of the death of the patient, the previous medical history, and the prescribed medications. In practice, this is often not available. Although the majority of deaths occur at home, many are unwitnessed. Symptoms such as syncope, dizziness, and chest pain are of particular importance. A previous electrocardiogram is especially valuable, but a recent population study found that this was available in less than 40% of the patients who died suddenly and had a previous history of heart disease.18 In practice, the amount of informations that is available before autopsy is extremely variable. Any potential source of information should be interrogated preferentially before autopsy is carried out. Ideally, the following informations are required in detail: • Age, gender, occupation, lifestyle (especially alcohol consumption or smoking), usual pattern of exercise, or athletic activity • Circumstances of death: date, time interval (instantaneous or <1 h), place of death (e.g., at home, at work, in hospital, at recreation), circumstances (at

A. Oliva and V. L. Pascali

•

• •

•

rest, during sleep, during exercise – athletic or nonathletic, during emotional stress), witnessed or unwitnessed, any suspicious circumstances (carbon monoxide, violence, traffic accident, etc.) Medical history: general health status, previous significant illnesses (especially syncope, chest pain, and palpitations, particularly during exercise, myocardial infarction, hypertension, respiratory and recent infectious disease, epilepsy, asthma, etc.), previous surgical operations or interventions, previous ECG tracings and chest X-rays, results of cardiovascular examination, laboratory investigations (especially lipid profiles) Prescription and nonprescription medications Family cardiac history: ischemic heart disease and premature sudden death, arrhythmias, inherited cardiac diseases ECG tracing taken during resuscitation, serum enzyme and troponin measurements

7.3 The Autopsy Procedure The care and attention to detail that pathologists give to sudden death autopsies varies considerably. The vast majority are performed by general or forensic pathologists. Their major professional interests are likely to be in diagnostic surgical histopathology and the investigation of criminal death, rather than in cardiovascular pathology. Details of how to perform autopsies have been summarized by Cohle and Sampson,21 and described and illustrated in detail in a recent textbook.22 The range of pathology in sudden death has also been summarized by Saukko and Knight.24 Moreover, principles and rules relating to autopsy procedures are well delineated through the Recommendations on the Harmonization of Medico-Legal Autopsy Rules produced by the Committee of Ministers of the Council of Europe.10 In our opinion, the procedures reported in the following section are designed to make the diagnosis of SCD more straightforward and logical.

7.3.1 External Examination of the Body The external examination may find clinical signs of the disease, such as alcohol disease, in which patients

7  Sudden Cardiac Death in Forensic Pathology

present a raised risk of sudden death. Trauma lesions, such as contusions, can also be found, particularly in case of fall after brutal loss of consciousness. Trauma due to resuscitation may be found as well. Moreover, it is very important to perform the following procedures: • Establish body weight and height (to correlate with heart weight and wall thickness)25-27 • Check for recent intravenous access, intubation, ECG pads, defibrillator and electrical burns, drain sites, and traumatic lesions • Check for implantable cardioverter defibrillator (ICD)/pacemaker; if in situ, see MDA Safety Notice 2002 for safe removal and interrogation28

7.3.2 Full Autopsy with Sequential Approach to the Causes of Sudden Death 7.3.2.1 Noncardiac Causes of Sudden Death Any natural sudden death can be considered as cardiac in origin after the exclusion of noncardiac causes. Thus, a full autopsy with sequential approach should always be performed to exclude common and ­un-common extra-cardiac causes of sudden death, especially: • Cerebral (e.g., subarachnoid or intra-cerebral hemorrhage, etc.) • Respiratory (e.g., asthma, anaphylaxis, etc.) • Acute hemorrhagic shock (e.g., ruptured aortic aneurysm, peptic ulcer, etc.) • Septic shock (Waterhouse–Friderichsen syndrome)

7.3.2.2 Cardiac Causes of Sudden Death Many cardiovascular diseases can cause SCD, either through an arrhythmic mechanism (electrical SCD) or by compromising the mechanical function of the heart (mechanical SCD). These disorders may affect the coronary arteries, the myocardium, the cardiac valves, the conducting system, the intrapericardial aorta, or the pulmonary artery, the integrity of which is essential for a regular heart function (Table 7.3).

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7.3.2.3 The Standard Gross Examination of the Heart 1. Check the pericardium, open it, and explore the pericardial cavity. 2. Check the anatomy of the great arteries before transecting them 3 cm above the aortic and pulmonary valves. 3. Check and transect the pulmonary veins. Transect the superior vena cava, 2 cm above the point where the crest of the right atrial appendage meets the superior vena cava (to preserve sinus node). Transect the inferior vena cava close to the diaphragm. 4. Open the right atrium from the inferior vena cava to the apex of the appendage. Open the left atrium between the pulmonary veins and then the atrial appendage. Inspect the atrial cavities and the interatrial septum, and determine whether the foramen ovale is patent. Examine the mitral and tricuspid valves (or valve prostheses) from above and check the integrity of the papillary muscles and chordae tendineae. 5. Inspect the aorta, the pulmonary artery, and the aortic and pulmonary valves (or valve prosthesis) from above. 6. Check the coronary arteries: (a) Examine the size, shape, position, number, and patency of the coronary ostia. (b) Assess the size, course, and “dominance” of the major epicardial arteries. (c) Make multiple transverse cuts at 3 mm intervals along the course of the main epicardial arteries and branches, such as the diagonal and obtuse marginal, and check the patency. (d) Heavily calcified coronary arteries can sometimes be opened adequately with sharp scissors. If this is not possible, they should be removed intact, decalcified, and opened transversely. (e) Coronary artery segments containing a metallic stent should be referred intact to labs with facilities for resin embedding and subsequent processing and sectioning. (f) Coronary artery bypass grafts (saphenous veins, internal mammary arteries, radial arteries, etc.) should be carefully examined with transverse cuts. The proximal and distal anastomoses should be examined with particular care. Side-branch

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Table 7.3  Sudden Cardiac Death at post-mortem Mechanical Arrhythmic

Others

Intrapericardial haemorrhage and cardiac tamponade

Coronary arteries (±postmyocardial infarction scar)

Fibromuscular dysplasia

Ascending aorta rupture (hypertension, Marfan, bicuspid aortic valve, coarctation, others)

Congenital anomalies

Intramural small vessel disease

Post myocardial infarction free wall rupture

Origin from the aorta

Coronary artery by-pass (saphenous vein, mammary and radial arteries, etc)

Pulmonary embolism

Wrong sinus (RCA from the left sinus, LCA from the right sinus)

Percutaneous balloon coronary angioplasty, stents

Acute mitral valve incompetence with pulmonary edema

LCx from the right sinus or from RCA

Myocardium

Post myocardial infarction papillary muscle rupture

High take off from the tubular portion

Cardiomyopathy, hypertrophic

Chordae tendineae rupture (floppy mitral valve)

Ostia plication

Cardiomyopathy, arrhythmogenic right ventricular

Intracavitary obstruction (e.g. thrombus/neoplasms)

Origin from the pulmonary trunk

Cardiomyopathy, dilated

Abrupt prosthetic valve ­dysfunction (e.g. laceration, dehiscence, thrombotic block, poppet escape)

 Course: intra-myocardial course (“myocardial bridge”)

Cardiomyopathy, inflammatory (myocarditis)

Secondary cardiomyopathies (storage, infiltrative, sarcoidosis, etc) Hypertensive heart disease Idiopathic left ventricular hypertrophy Unclassified cardiomyopathies (spongy myocardium, fibroelastosis) Valve Aortic valve stenosis Myxoid degeneration of the mitral valve with prolapse Conduction system Sinoatrial disease AV block (Lev–Lenegre disease, AV node cystic tumor) Ventricular pre-excitation (Wolff –Parkinson–White syndrome, Lown Ganong Levine syndrome) Congenital heart disease (operated and un-operated) Eisenmenger syndrome Normal heart (“sine materia” or unexplained SCD or sudden arrhythmic death syndrome) Long and short QT syndromes Brugada syndrome Catecholaminergic polymorphic ventricular tachycardia Idiopathic ventricular fibrillation AV atrioventricular; LCA left coronary artery; LCx left circumflex branch; RCA right coronary artery (SOURCE: Data from Basso C. et al 23) Congenital partial absence of the pericardium with strangulation

Acquired Atherosclerosis Complicated (thrombus, haemorrhage) Uncomplicated Embolism Arteritis Dissection

clips or sutures may facilitate their identification, particularly when dealing with internal mammary grafts.

7. Make a complete transverse (short-axis) cut of the heart at the mid-ventricular level, and then make parallel slices of the ventricles at 1 cm intervals

7  Sudden Cardiac Death in Forensic Pathology

toward the apex and assess these slices carefully for morphology of the walls and cavities. 8. Once emptied of blood, the following measurements are important: (a) Total heart weight: assess the weight of the heart against the tables of normal weights by age, gender, and body weight.10,25,26 (b) Wall thickness: inspect endocardium, measure the thickness of the mid-cavity free wall of the left ventricle, right ventricle, and the septum (excluding trabeculae), against tables of normal thickness by age, gender, and body weight.10,25,26 (c) Heart dimensions: the transverse size is best calculated as the distance from the obtuse to the acute margin in the posterior atrioventricular sulcus. The longitudinal size is obtained from a measurement of the distance between the crux cordis and the apex of the heart on the posterior aspect. 9. Dissect the basal half of the heart in the flow of blood and complete the examination of atrial and ventricular septa, atrioventricular valves, ventricular inflows and outflows, and semilunar valves. In case of ECG-documented ventricular preexcitation, the atrioventricular rings should be maintained intact.

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A suggestion of such protocol is shown in Table 7.4. To this end, appropriate storage of autopsy tissues/fluids is essential in SCD autopsies. If these laboratory tests are needed and no onsite facilities are available, then the stored material needs to be sent to specialized labs.

7.4.1 Histology The standard histological examination of the heart myocardium is based on the collection of mapped and labeled blocks from a representative transverse slice of the ventricles to include the free wall of the left ventricle (anterior, lateral, and posterior), the ventricular septum (anterior and posterior), the free wall of the right ventricle (anterior, lateral, and posterior), and right ventricular outflow tract and one block from each atria. In addition, any area with significant macroscopic abnormalities should be sampled. Hematoxylin and eosin stain (H&E) and a connective tissue stain (van Gieson, trichrome, or Sirius red) are standard. Other special staining and immunohistochemistry should be performed as required. Coronary arteries: in the setting of coronary artery disease, most severe focal lesions should be sampled for histology in labeled blocks and stained as mentioned earlier.

7.4 Laboratory Tests Progress in autopsy diagnosis of SCD also depends on the use of a rigorous protocol, to ensure that the essential biological samples for histology, toxicology, or molecular studies that are maybe required at some stage in the investigation procedure are not forgotten.

7.4.2 Toxicology In investigating out-of-hospital deaths, the question of whether toxic substances are involved is almost always raised. Depending on the circumstances surrounding

Table 7.4  Range of post-mortem laboratory tests in SCD Systematic procedures Samples

Complementary techniques

Histology

All organs including thymus, thyroid, testes

Gram, Grocott and PAS stains if needed

Cytology

Pericardial, pleural and abdominal fluids, CSF

Gram and PAS stains if needed

Neuropathology

Brain in formol during 3–4 week

Histology, immunohistochemistry

Toxicology

Blood, urine, hair, vitreous humor

Biochemistry

Pericardial fluid Vitreous humor

Troponine electrolytes and glucose concentrations

Microbiology

Blood, all recovered fluids, organs with septic lesions and CSF for cultures

HIV, B and C hepatitis serology PCR for viral proteins detection

Molecular biology

Blood, heart

Mutations screening according to pathology and family disease

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the death and toxicological data, the manner of death can be natural, accidental, or criminal. Even when the heart is found to be abnormal at gross and/or microscopic examinations, and death occurred suddenly, the question still remains of whether a substance may have triggered the death, acting as an additional factor to the anatomic substrate. Therefore, toxicology is very important for two reasons: first, to exclude a toxic cause, and second, to help for the determination of a drug-related cardiomyopathy such as cocaine or amphetamine-induced cardiomyopathy, which can be responsible for sudden death. Hair testing is needed even if no or low levels of drug are detected in blood, to show a past history of drug abuse. The results must be compared with cardiac pathological findings suggestive of cocaine or amphetamine cardiac chronic toxicity, such as the association of microfocal fibrosis, contraction band necrosis, and cardiomyocyte hypertrophy. The cardiac toxicity of anabolic steroid abuse must also be taken into account. Proper selection, collection, and submission of specimens for toxicological analyses are mandatory if analytical results are to be accurate and scientifically useful. The types and minimum amounts of tissue specimens and fluids needed for toxicological evaluation are frequently dictated by the analytes that must be identified and quantitated. For the purpose of sudden death investigation, the following amounts are adapted from the Guidelines of the Society of Forensic Toxicologists and the American Academy of Forensic Sciences29: heart blood 25 mL, peripheral blood from femoral veins 10 mL, urine 30–50 mL, and bile 20–30 mL (when urine is not available). All samples are stored at 4°C. A lock of hair (100–200 mg) should be cut from the back head (or from the pubic hair when head hair is not available). Toxicological analyses are generally quantitative.

7.4.3 Molecular Studies Molecular investigations of SCD include both detection of viral genomes in inflammatory cardiomyopathies and gene mutational analysis in both structural and nonstructural genetically determined heart diseases.9,30-32 For these purposes, 10 mL of EDTA blood and 5 g of heart and spleen tissues are either frozen and stored at −80°C, or alternatively stored in RNA later at 4°C for up to 2 weeks.

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7.4.4 Electron Microscopy Investigation In case of suspicion of rare cardiomyopathies (mitochondrial, storage, infiltrative, etc.), a small sample of myocardium (1 mm) should be fixed in 2.5% glutaraldehyde for ultrastructural examination.

7.5 Formulation of a Diagnosis: Main Findings at Postmortem Investigation 7.5.1 Coronary Artery Disease Atherosclerotic CAD remains the predominant substrate for SCD.33,34 From a pathological point of view, CAD is defined by a heart showing at least one of the three coronary arteries narrowed to 75% or more by an atherosclerotic plaque and/or thrombosis. Approximately 80% of SCDs are caused by CAD. An analysis made in the Framingham population of 5,209 men and women free of identified heart disease at baseline showed that 46% of men and 34% of women with SCD had CAD as the most likely etiology of their cardiac arrest.33 However, no specific pattern of coronary artery involvement has been correlated with the risk of SCD,35 and the extent of vessel disease involvement seems to have a greater predictive value than the location of specific lesions in the coronary arteries.36,37 Structural abnormalities of coronary arteries can be characterized as acute or chronic, and healed MI has been reported in 40–70% of SCD-related autopsies.33,38 However, only 20% of those with SCD have shown evidence of recent MI.39 Acute coronary events with recent thrombi, plaque fissuring, and hemorrhage are believed to contribute significantly to SCD, although there has been a low incidence of acute MIs at autopsy in patients with SCD.39 In the pathogenesis of ventricular arrhythmias, transient ischemia and reperfusion, autonomic changes, and systematic derangements (e.g., hypoxemia, acidosis, electrolyte imbalance) play a more significant role in healed myocardial tissue than in normal cardiac muscle.40 Nonatherosclerotic CAD leading to SCD is seen less commonly and can be a manifestation of anomalous origin of left coronary artery (Fig.  7.1),41 embolism, arteritis, and coronary dissection.39,42

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Fig. 7.1  Coronary artery anomaly. ((a) macroscopic view) Left anterior descending (LAD) and circumflex (Cx) coronary arteries arousing from the left sinus of Valsalva with a separate ­origin.

((b) histology) Microscopic appearance of fibrosis: chronic ischemic damage of the left ventricular anterior wall

7.5.2 Cardiomyopathies

made at autopsy (sudden death).44 On gross examination, the heart is typically enlarged to twice the normal weight. The mean heart weight in a series of 40 autopsied cases was 634 g.45 The hypertrophy is secondary to ventricular thickening and may occur almost anywhere in the ventricular mass, but is most often found in the interventricular septum (Fig.  7.2). Heart weight may occasionally be normal or only slightly increased, an observation that has been linked to troponin T mutations in some cases.46 Microscopically, the most characteristic feature is myofiber disarray characterized by disorganized branching myocytes. Other features include myocytye hypertrophy, interstitial fibrosis, and intramural coronary artery thickening. Diagnostic confusion often exists in making the distinction between a true hypertrophic cardiomyopathy and cardiac hypertrophy. Proper sectioning in a case of suspected hypertrophic cardiomyopathy entails sectioning in the short-axis plane or from endocardium to epicardium in the transverse plane. Histological review of multiple cross-sections from the ventricular septum is required to demonstrate myofiber disarray of at least 5% crosssectional area.47 It has been shown that approximately 50–60% of HCM cases are familial with an autosomal dominant pattern of inheritance. Currently, 14 genes and over 150 different mutations have been identified.48 The structural deformities of hypertrophic cardiomyopathy result from mutations in the genes that encode sarcomeric proteins, most commonly beta-myosin heavy chains. High-risk mutations include the beta myosin heavy chain (MYH7) mutations (R403Q,

Cardiomyopathies are a major cause of morbidity and mortality at all ages. They are defined by the World Health Organization as “diseases of the myocardium associated with cardiac dysfunction” and are classified into four major groups: hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy, restrictive cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy. An additional category referred to as “specific” cardiomyopathies, which encompasses a wide variety of specific cardiac or systemic disorders, has also been included in the classification scheme.43 Cardio­myopathies may either be inherited or acquired. In the last 20 years, advances in molecular genetics have improved our understanding of the pathogenesis of cardiomyopathies by identifying the underlying gene mutations that lead to myocardial disease. While many cardiomyopathies result from a single gene defect, and are therefore, inherited in a predictable Mendelian fashion, the resultant disease phenotype may be clinically and pathologically diverse. 7.5.2.1 Hypertrophic Cardiomyopathy HCM is a well-recognized cause of SCD with sudden unexpected death occurring most frequently in young persons. Although the disease may occur at any age, most patients are in their 30s or 40s at the time of diagnosis, and in 16% of the cases, the diagnosis is first

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Fig.  7.2  Hypertrophic cardiomyopathy. (a) Long-axis view of the ventricular septum (VS) and left ventricular free wall (LVFW) from a patient with hypertrophic cardiomyopathy. The ventricular septum shows asymmetric hypertrophy with scarring in the septum (arrow). Note the dilated left atrium (LA). The anterior mitral valve leaflet (AML), aorta (Ao), and right ventricle (RV) are

shown for orientation. (b) Histologically, there is myofiber disarray characterized by myocyte hypertrophy and branching of myocytes (Masson trichrome). (c) Microscopic section of a thickened intramural coronary artery in the ventricular septum. (Hematoxylin and eosin) (Source: Courtesy of Dr. Renu Virmani, CVPath, International Registry of Pathology, Inc. Gaithersburg, MD)

R453C, G716R, and R719W).49 Diagnosis of HCM mandates genetic counseling with serious implications for family members, and thus, should be reserved only for cases fulfilling the diagnostic criteria.

ARVD is the most frequent cause of sudden death in young athletes. The mean age for patients dying suddenly is usually in the third decade.50,51 Although the name implies a purely right-sided disease process, involvement of the left ventricle has been shown to occur in >75% of the cases, and rare cases have been reported, in which the left ventricle is affected exclusively.52 The heart is generally normal in size or slightly enlarged. Grossly, the right ventricle may show focal myocardial wall thinning to 2 mm or less, aneurysm formation, and cavità dilatation. Additionally, the left ventricle may show subepicardial scars on gross

7.5.2.2 Arrhythmogenic Right Ventricular Dysplasia Arrhythmogenic right ventricular dysplasia (ARVD) is a genetic cardiomyopathy often presenting with SCD, particularly in adolescents and young adults. In Italy,

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examination.53 The histological features of ARVD include transmural fatty infiltration of myocardium, fibrosis, and inflammation, principally the lymphocytes (Fig. 7.3). Fat infiltration of the right ventricle is usually considered as a mandatory finding for the diagnosis, but the diagnosis should not be based only on the presence of fat, because normal hearts may show a certain degree of fatty infiltration in the right ventricle. We have shown that it is not unusual to see fat infiltration occupying over 50% of myocardial area in the anterior wall of the right ventricle in trauma victims

(autopsy control subjects54). The pathologic criteria for ARVD remain controversial, and there is still no universal agreement about the definitive diagnostic features. ARVD is a genetic cardiomyopathy that has been associated with mutations of plakoglobin, plakophalin, and desmoplakin genes.55 These genes encode desmosomal proteins that are involved in cell adhesion. Loss of normal desmosomal structure is considered as a crucial event in the pathogenesis of ARVD, but the precise mechanisms underlying the development of the disease are still unknown.

Fig.  7.3  Arrhythmogenic right ventricular dysplasia (ARVD). (a) Right ventricle from a patient with ARVD. Note the fatty infiltration of the right ventricular wall and absence of myocardial tissue with mild focal fibrosis (arrow). (b) Longitudinal section of a heart showing biventricular involvement of ARVD. Note the subepicardial scarring in the left ventricle (arrow) and aneurys-

mal dilatation with fibrofatty infiltration of the right ventricle (double arrows) with marked thinning. (c) Fibrofatty replacement of the right ventricle with interspersed myocytes (red). (d) Subepicardial scarring of the left ventricle corresponding to single arrow in (b) (Source: Courtesy of Dr. Renu Virmani, CVPath, International Registry of Pathology, Inc. Gaithersburg, MD)

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including infectious, toxic, and idiopathic. Examples of inflammatory myopathies include lymphocytic myocarditis (viral), hypersensitivity myocarditis, giant cell myocarditis, toxic myocarditis, infectious myocarditis, and sarcoidosis.

7.5.3.1 Lymphocytic Myocarditis

Fig. 7.4  Left Ventricular noncompaction. Isolated left ventricular noncompaction in an autopsy specimen, shown in short-axis view. Note the compacted epicardial layer and noncompacted endocardial layer with marked hypertrabeculation and deep recesses

7.5.2.3 Left Ventricular Noncompaction Ventricular noncompaction (Fig. 7.4), also known as left ventricular noncompaction (LVNC), is a rare form of cardiomyopathy believed to result from an unexplained arrest in cardiac development. LVNC has been reported as a cause of sudden death in both children and adults.56,57 As the diagnosis is often made initially at autopsy, forensic pathologists should be aware of the diagnostic features. Grossly, the left ventricular wall demonstrates deep recesses extending to the inner half of the ventricle, occurring most prominently in the midventricle to the apex. The recesses show variable patterns including anastomosing broad trabecula, coarse trabecula resembling multiple papillary muscles, and fine interlacing bundles that can only be observed microscopically. The histological features of LVNC are distinct, characterized by anastomosing muscle bundles forming irregular, large branching staghorn recesses in the endocardium. Another pattern shows spongy parenchyma with compressed invaginations that are not grossly apparent. In addition, marked endocardial fibroelastosis with prominent elastin deposition is also present.

7.5.3 Inflammatory Myocardial Diseases Myocarditis is defined as the inflammation of the myocardium, and may be attributed to a number of causes

Viral or lymphocytic myocarditis is seen more commonly in cases of neonatal and childhood SCD, and may follow a recent viral syndrome. Gross examination of the heart is typically unrevealing. Histologically, the inflammation is usually diffuse and primarily consists of lymphocytes, macrophages (Fig.  7.5), and occasional neutrophils with associated evidence of myocyte damage. In cases of SCD, it is presumed that the lesion(s) acts as an inflammatory substrate for arrhythmia, usually ventricular tachyarrhythmias. In North America, enteroviruses, in particular, Coxsackie viruses are common agents producing myocarditis, although adenovirus, cytomegalovirus, and herpes simplex have also been associated with lymphocytic myocarditis. Till date, the most useful and rapid technique for detecting virus in cases of suspected viral myocarditis is polymerase chain reaction (PCR). In one study, PCR analysis detected a viral genome in 68% of endomyocardial biopsies showing lymphocytic myocarditis in a pediatric population.58 Besides viruses, a large number of other pathogens have been associated with infectious myocarditis, including bacteria, fungi, and parasites. The gross and histological features of infectious myocarditis vary depending on the etiologic agent and the stage of the disease.

7.5.3.2 Hypersensitivity Myocarditis Hypersensitivity myocarditis is a rare cause of SCD. More than 20 drugs have been incriminated as possible etiologic agents in hypersensitivity myocarditis, with penicillin, sulfonamides, and methyldopa being the most common. Although often asymptomatic, hypersensitivity myocarditis may cause congestive heart failure, arrhythmias, and rarely sudden death. Most cases of hypersensitivity myocarditis are diagnosed at autopsy; therefore, the true prevalence of nonlethal cases is unknown. The histopathological features of hypersensitivity myocarditis include interstitial and perivascular chronic inflammatory infiltrates consisting

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a

b

c

d

Fig. 7.5  Lymphocytic myocarditis. (a–d) are complexively low- and high-power views of diffuse lymphocytic infiltrate (Source: Courtesy of Professor Arnaldo Capelli, Institute of Pathology, Catholic University, Rome, Italy)

of lymphocytes, plasma cells, and macrophages, with a prominence of eosinophils. There is little associated necrosis and no scarring.

7.5.3.3 Toxic Myocarditis In addition to eliciting a hypersensitivity myocarditis, some drugs may be directly toxic to the myocardium and produce toxic myocarditis, characterized histologically by edema, neutrophil infiltration, and necrosis, sometimes with contraction band necrosis. In addition, endothelial swelling and vasculitis may be present as well. Etiologic agents in this category include catecholamines, arsenicals, venoms, paracetomol, and chemotherapeutic agents.

7.5.3.4 Giant Cell Myocarditis Giant cell myocarditis is a rare disease of unknown etiology most commonly seen in adults 20–50 years of

age. Clinically, it usually presents as a sudden onset of congestive heart failure and is rapidly fatal in most cases. The histopathological features include widespread, often serpiginous, myocardial necrosis with chronic inflammation including multinucleated giant cells (Fig. 7.6). The giant cells are usually seen at the margins of necrosis and have been shown to be derived from the histiocyte.59

7.5.3.5 Sarcoidosis Most patients with cardiac sarcoidosis have clinically apparent systemic involvement, but in some patients, the heart may be the primary site. The clinical manifestations are determined by the extent and location of involvement and may include conduction defects, ventricular arrhythmias, congestive heart failure, mitral regurgitation, and sudden death. Cardiac sarcoidosis is a focal disease involving the myocardium in decreasing order of frequency; left ventricular free wall, base of the ventricular septum, right ventricular free wall,

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Fig. 7.6  Giant cell myocarditis. (a and b) Pronounced lymphoeosinophilic infiltrate is associated with numerous multinucleated giant cells (Source: Courtesy of Professor Arnaldo Capelli, Institute of Pathology, Catholic University, Rome, Italy)

and atrial walls.60 Grossly, the heart may display scarring in a distribution not typical for ischemic disease, also involving the epicardial surface. The histological features of cardiac sarcoid are similar to those of extracardiac sarcoid consisting of noncaseating granulomas, histiocytes, giant cells, lymphocytes, and plasma cells (Fig. 7.7). Special stains should be performed to rule out the presence of fungi and acid-fast bacilli.

7.5.4 Sudden Cardiac Death in the Absence of Autopsy Findings Although cardiac abnormalities evident at autopsy explain the majority of sudden deaths in young people, several population-based studies (Fig. 7.8) show that a significant number of sudden deaths remain unexplained following a comprehensive postmortem investigation, including full autopsy. In fact, in some cases, the underlying defect responsible for a sudden cardiac death is not found on gross, microscopic, or even ultrastructural examination of the heart. For nearly half of the young victims from 1 to 35 years of age, there are no apparent warning signs, and sudden death often occurs as the sentinel event, thus placing extreme importance upon the forensic investigation and autopsy, to determine the cause and manner of death.61 With recent advances in molecular biology, it has become apparent that a proportion of these deaths are due to mutations in the cardiac ion channels that may lead to ventricular arrhythmias and sudden death. The underlying gene defects alter the electrical activity in the  heart, predisposing the patient to fatal cardiac

Fig.  7.7  Sarcoidosis. (a) Sarcoid granulomas located in the myocardium (hematoxylin and eosin). (b) Subepicardial deposition of amyloid (Congo red stain)

arrhythmias, without any morphologic changes seen in the myocardium. Such disorders of ion channels are sometimes referred to as “cardiac channelopathies” – examples of these include LQTS and BrS. Actually, in forensic field, there is unlimited potential for the use of

7  Sudden Cardiac Death in Forensic Pathology

a

Athletic field SC 10%

Structurally normal

b

Australian SCD

Cardiomyopathy

3%

Structurally normal Cardiomyopathy

10%

Myocarditis

4%

5%

Valvular disease

29%

52%

2% 6%

3%

Atherosclerotic CAD

14%

Anomalous coronaries

Anomalous coronaries

25% 16%

Aortic aneurysm/dissection

1%

12%

Other structural caus

Italian SCD

Structurally normal

24%

5%

d

2%

Cardiomyopathy 40%

19%

Atherosclerotic CAD Anomalous coronaries

Anomalous coronaries 10% 20%

11%

Aortic aneurysm/dissection Other structural cause

Myocarditis Valvular disease

Atherosclerotic CAD

10%

Structurally normal

8%

Myocarditis Valvular disease

Aortic aneurysm/dissection Other structural caus

American military recruits SCD

Cardiomyopathy

6%

Myocarditis Valvular disease

2%

Atherosclerotic CAD

19%

c

105

9% 1%

12%

9%

Aortic aneurysm/dissection Other structural cause

Fig. 7.8  Structurally normal heart vs. pathologic heart at postmortem analysis. Comparison of data from four cohorts: (a) Maron et al.65 (N 1/4 134; mean age: 17 years; frequency of cardiomyopathy subtypes: HCM 36%, dilated cardiomyopathy [DCM] 3%, arrhythmogenic right ventricular dysplasia [ARVD] 3%, and unexplained increase in cardiac mass [“possible HCM”] 10%); (b) Puranik et al66 (N 1/4 241 mean age: 27 years; frequency of cardiomyopathy subtypes: HCM 6%, DCM 5%, ARVD 2%, and idiopathic left ventricular hypertrophy [LVH] 3%); (c) Corrado et al67 (N 1/4 273; mean age: 24 years; frequency of cardiomyopathy sub-

types: HCM 7%,DCM4% and ARVD 13%; a significant fraction of those included in “Other structural causes” (24/38) had histological evidence of conduction system abnormalities); (d) Eckart et al.68 (N 1/4 108, mean age: 19 years; frequency of cardiomyopathy subtypes: HCM8%,DCM1%, ARVD 1%). “Structurally normal” includes the diagnosis of arrhythmia disorders, such as LQTS, as well as all SCDs. In some instances, minimal structural abnormalities were noted at autopsy, but these were felt to be insufficient to cause sudden death (Source: Data modified by Tester DJ and Ackerman MJ32)

molecular testing to identify the natural causes of death, resulting in the increasing use of a new investigatory tool known as “gene autopsy” for inherited arrhythmia syndromes as well as for genetic predisposition to acquired arrhythmia.62,63 For instance, a recent study has completed one of the largest molecular autopsy series of SUD to date.64 In this study, comprehensive mutational analysis of all the 60 translated exons in the LQTS-associated genes – KCNQ1, KCNH2, SCN5A KCNE1, and KCNE2 – along with targeted analysis of the CPVT1-associated, RyR2encoded cardiac ryanodine receptor was conducted in a series of 49 medical examiner-referred cases of sudden unexplained death (SUD). Herein, over one-third of SUD cases had a presumably pathogenic cardiac channel mutation, with mutations in RyR2 alone accounting for nearly 15% of the cases. In this series, sudden death was the sentinel event in all but four mutation-

positive SUD cases. According to these results, postmortem genetic testing has provided an answer 35% of the time, indicating that this new tool in forensics could possibly save another family member’s life.64 Considering that autopsy-negative SUD accounts for a significant number of sudden deaths in young people, and that epidemiological, clinical, and now postmortem genetic analyses all suggest that approximately one-third of SUD after the first year of life may stem from a lethal cardiac channelopathy, the cardiac channel molecular autopsy in these cases should be viewed as the standard of care for the postmortem evaluation of SUD. A suggestion of postautopsy care pathways to the relatives of the deceased in case of young or adult SUD or SCD, where an inherited heart disease is suspected is shown in Fig.  7.9. Unfortunately, it is profoundly difficult for the forensic pathologist to provide this level of care, for several reasons. One of these is

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that genetic testing is still time-consuming and expensive; hence, according to these limitations, it should be restricted to selected cases. Regardless of these critical aspects, the role of the forensic pathologist is vital, as current “standard operating procedures” for conducting an accurate diagnosis, derived from either a clinical assessment of surviving relatives or a molecular autopsy, enables informed genetic counseling for families and guides the appropriate commencement of preemptive strategies targeted toward the prevention of another tragedy among those left behind.

7.6 Forensic Report and ClinicoPathological Summary Forensic report represents the official document where the pathologist accurately describes the pathological findings also related to the clinical history, the circumstances of the death, and any investigation performed close to the time of the death. In the majority of SCDs, a clear pathological cause can be identified, although

Fig. 7.9  Postautopsy care pathways service in cases of young or adult SUD or SCD where an inherited heart disease is suspected: *Add suitable statement to postmortem report: SUD: “Unexplained death may be caused by inherited cardiac disease. The deceased individual’s relatives may therefore be at risk. Please refer the deceased individual’s next of kin to Cardiac Genetics Service.” or SCD: “Death has been caused by a cardiac disease which may have a genetic basis. The deceased individual’s relatives may therefore also be at risk. Please refer the deceased individual’s next of kin to Cardiac Genetics Service.” *Ongoing surveillance seems inadvisable; there is a need for written information reporting the individual that he/she will need to be reassessed if he/she develops key symptoms, or if the family history changes

with varying degrees of confidence. Wherever possible, the most likely underlying cause should be stated and the need for familial clinical screening and genetic analysis be clearly indicated. Different degrees of certainty exist in defining the cause–effect relationship between the cardiovascular substrate and the sudden death event. Table 7.5 lists the commonest substrates of SCD, classifying each as certain, highly probable, or uncertain. In the probable, and especially the uncertain categories, each case should be considered on its individual merits. The clinical history and circumstances of death may influence the decision-making process. Finally, there are myocardial diseases in which the border between physiological and pathological changes is poorly defined. Some diagnostic gray zones are generally present in a variable percentage of SCD autopsies. In cases where there is real doubt as to whether the changes are physiological or pathological, an expert opinion from specialized heart centers should be sought. Deaths that remain unexplained after careful macroscopic, microscopic, and laboratory investigation is generally classified as sudden arrhythmic death syndrome.

Store DNA

Forensic Autopsy SUD/SCD

10ml blood in EDTA or 1cm3 fresh spleen of liver or 2cm3 muscle or skin

Refer to Cardiac Genetics Service (CGS)

Notify family members about possible hereditary nature of findings*

CGS

Genetic counsellor

Family history assessment Cardiac assessment

Hereditary cardiac disorder diagnosed

No abnormalities

DISCHARGE** CGS

CARDIOLOGY CLINIC

ARRHYTHMIA SERVICE

Diagnostic genetic testing

Cardiac management

Cardiac management

7  Sudden Cardiac Death in Forensic Pathology Table 7.5  Certainity of diagnosis in SCD autopsies Certain Highly Probable

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Uncertain

Massive pulmonary embolism

Stable atherosclerotic plaque with luminal stenosis >75% with or without healed myocardial infarction

Minor anomalies of the coronary arteries from the aorta (RCA from the left sinus, LCA from the right without inter-arterial course, high take-off from the tubular portion, LCx originating from the right sinus or RCA, coronary ostia plication, fibromuscular dysplasia, intramural small vessel disease)

Haemopericardium due to aortic or cardiac rupture

Anomalous origin of the LCA from the right sinus and inter-arterial course

Intra-myocardial course of a coronary artery (myocardial bridge)

Mitral valve papillary muscle or chordae tendineae rupture with acute mitral valve incompetence and pulmonary edema

Cardiomyopathies (hypertrophic, arrhythmogenic right ventricular, dilated, others)

Focal myocarditis, hypertensive heart disease, idiopathic left ventricular hypertrophy

Acute coronary occlusion due to thrombosis, dissection or embolism

Myxoid degeneration of the mitral valve with prolapse, with atrial dilatation or left ventricular hypertrophy and intact chordae

Myxoid degeneration of the mitral valve with prolapse, without atrial dilatation or left ventricular hypertrophy and intact chordae

Anomalous origin of the coronary artery from the pulmonary trunk

Aortic stenosis with left ventricular hypertrophy

Dystrophic calcification of the membranous septum (±mitral annulus/aortic valve)

Neoplasm/thrombus obstructing the valve orifice

ECG documented ventricular pre-excitation (Wolff– Parkinson–White syndrome, Lown Ganong Levine syndrome)

Atrial septum lipoma

Thrombotic block of the valve prosthesis

ECG documented sinoatrial or AV block

AV node cystic tumor without ECG evidence of AV block, conducting system disease without ECG documentation

Laceration/dehiscence/poppet escape of the valve prosthesis with acute valve incompetence

Congenital heart diseases, operated

Congenital heart diseases, un-operated with or without Eisenmenger syndrome

Massive acute myocarditis   AV atrioventricular; ECG electrocardiogram; LCA left coronary artery; LCx left circumflex branch; RCA right coronary artery (SOURCE: Data from Basso C et al. [23])

7.7 Conclusions Sudden and unexpected cardiac death frequently represents one the most challenging task faced by the forensic pathologist, especially with regard to the difficulties encountered in determining the precise cause of death. The progress in autopsy diagnosis of SCD depends on the death scene investigation, quality of autopsies, which is strictly linked to the use of a rigorous protocol in

collecting essential biological samples or in dissection procedures, and on the use of complementary techniques, especially histology, toxicology, and molecular biology. In other words, SCD scene investigation requires a careful interrogation of witnesses, family members, and physicians of the rescue team who eventually attempted the resuscitation. Recent symptoms before death and past medical history must be sought. Prodromal symptoms are unfortunately often nonspecific, and even those

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employed to indicate ischemia (chest pain), tachyarrhythmia (palpitations), or congestive heart failure symptoms (dyspnea) can only be considered suggestive. Although the vast majority of these deaths may be ascribed to coronary atherosclerosis, there are many other potential causes of sudden cardiac death, such as cardiomyopathies, which are more frequently encountered in people aged less than 35 years. In the majority of cases, only a detailed pathologic examination of the heart, in conjunction with meaningful clinicopathologic correlation, allows the pathologist to determine the underlying disease process leading to death. When no anatomic abnormality is present at autopsy, it may be of benefit to archive DNA for genetic studies if an ionchannel disorder is suspected. In fact, recent advances in the field of molecular genetics have expanded our understanding of the etiology and classification of many of the aforementioned cardiac diseases. These new techniques not only augment our diagnostic capabilities, but also highlight the importance of molecular diagnostics in identifying new ­disease-causing mutations. Thereafter, the major challenge is faced by cardiologists who are directly involved in managing postautopsy care pathways to the relatives of the deceased, especially in identifying asymptomatic subjects at high risk of sudden death. To develop preventive strategies, such as the use of antiarrhythmic agents or implantable cardioverterdefibrillator, the incidence, causes, and circumstances surrounding sudden cardiac death must be better known, and are mainly provided by forensic pathology. Acknowledgments  This work has been supported by Fondi di Ateneo Linea D1–2008, Università Cattolica del Sacro Cuore, Rome, Italy.

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A. Oliva and V. L. Pascali   5. Priori SG, Aliot E, Blomstrom-Lundqvist C, et al. Task force on sudden cardiac death of the European Society of Cardiology. Eur Heart J. 2001;22:1374–1450   6. Corrado D, Basso C, Pavei A, et al. Trends in sudden cardiovascular death in young competitive athletes after implementation of a preparticipation screening program. JAMA. 2006;296:1593–1601   7. Goldstein S. The necessity of a uniform definition of sudden coronary death: witnessed death within 1 hour of the onset of acute symptoms. Am Heart J. 1982;103:156–159   8. Virmani R, Burke AP, Farb A. Sudden cardiac death. Cardiovasc Pathol. 2001;10:211–218   9. Basso C, Calabrese F, Corrado D, et al. Postmortem ­diagnosis in sudden cardiac death victims: macroscopic, microscopic and molecular findings. Cardiovasc Res. 2001;50: 290–330 10. Brinkmann B. Harmonization of medico-legal autopsy rules. Committee of Ministers. Council of Europe. Int J Legal Med. 1999;113:1–14 11. Davies MJ. The investigation of sudden cardiac death. Histopathology. 1999;34:93–98 12. Royal College of Pathologists. Guidelines on autopsy practice 2005, scenario 1: sudden death with likely cardiac pathology. 2005: 1–7. http://www.rcpath.org/index.asp?PageID=687 13. Sheppard M, Davies MJ. Investigation of sudden cardiac death. In: Sheppard M, Davies MJ, eds. Practical cardiovascular pathology. London: Arnold; 1998:191–204 14. Thiene G, Basso C, Corrado D. Cardiovascular causes of sudden death. In: Silver MD, Gotlieb AI, Schoen FJ, eds. Cardiovascular pathology. Philadelphia, PA: Churchill Livingstone; 2001:326–374 15. Behr E, Wood DA, Wright M, et  al. Cardiological assessment of first-degree relatives in sudden arrhythmic death syndrome. Lancet. 2003;362:1457 16. Leach IH, Blundell JW, Rowley JM, et al. Acute ischaemic lesions in death due to ischaemic heart disease: an autopsy study of 333 out of hospital deaths. Eur Heart J. 1995;16: 1181–1185 17. Burke AP, Farb A, Malcolm GT, et al. Coronary risk factor and plaque morphology in men with coronary disease who died suddenly. N Engl J Med. 1997;336:1276–1282 18. Chase DL. Ph.D. thesis. Southampton: University of Southampton; 2006 19. Bowker TJ, Wood DA, Davies MJ, et al. Sudden, unexpected cardiac or unexplained death in England: a national survey. Quart J Med. 2003;96:269–279 20. Fabre A, Sheppard MN. Sudden adult death syndrome an other non-ischaemic causes of sudden cardiac death. Heart. 2006;92:316–320 21. Cohle SD, Sampson BA. The negative autopsy. Sudden cardiac death or other. Cardiovasc Pathol 2001;10:271–4 22. Finkbeiner WE, Ursell PC, Davis RL. Basic post-mortem examination in autopsy pathology. A Manual and Atlas. Philadelphia, PA: Churchill Livingstone; 2004:41–65 23. Basso C, Burke M, Fornes P, et al. Guidelines for autopsy investigation of sudden cardiac death. Virchows Arch. 2008 Jan;452(1):11–18. Epub 2007 Oct 20 24. Saukko P, Knight B. The pathology of sudden death. In: Knight’s Forensic Pathology. 3rd ed. London: Edward Arnold; 2004:492–526 25. Kitzman DW, Scholz DG, Hagen PT, et  al. Age-related changes in normal human hearts during the first 10 decades

7  Sudden Cardiac Death in Forensic Pathology of life. Part II (maturity): a quantitative anatomic study of 765 specimens from subjects 20 to 99 years old. Mayo Clin Proc. 1988;63:137–146 26. Scholz DG, Kitzman DW, Hagen PT, et  al.: Age-related changes in normal human hearts during the first 10 decades of life. Part I (growth): a quantitative anatomic study of 200 specimens from subjects from birth to 19 years old. Mayo Clin Proc. 1988;63:126–136 27. Schulz DM, Giordano DA. Hearts of infants and children: weights and measurements. Arch Pathol. 1962;73:464–471 28. Medical Devices Agency Safety Notice 2002(35) Removal of implantable cardioverter defibrillators (ICDs). 2002. http://www.mhra.gov.uk/home/idcplg?IdcService= SS_GET_PAGE&useSecondary= true&ssDocName=CON0 08731&ssTargetNodeId=420 (pp 1–3) 29. SOFT and AAFS. Forensic toxicology laboratory guidelines. 2002:1–23. www.soft-tox.org/docs/Guidelines.2002. final.pdf 30. Carturan E, Tester DJ, Brost BB, et al. Postmortem genetic testing for conventional autopsy negative sudden unexplained death: an evaluation of different DNA extraction protocols and the feasibility of mutational analysis from archival paraffin embedded heart tissue. Am J Clin Pathol. 2008 Mar;129(3):391–397 31. Chugh SS, Senashova O, Watts A, et al. Postmortem molecular screening in unexplained sudden death. J Am Coll Cardiol. 2004;43:1625–1629 32. Tester DJ. Ackerman MJ The role of molecular autopsy in unexplained sudden cardiac death. Curr Opin Cardiol. 2006;21:166–172 33. Kannel WB, Cupples LA, D’Agostino RB. Sudden death risk in overt coronary heart disease: the Framingham Study. Am Heart J. 1987;113:799–804 34. Zipes DP, Wellens HJJ. Sudden cardiac death. Circulation. 1998;98:2334–2351 35. Weaver WD, Lorch GS, Alvarez HA, et  al. Angiographic findings and prognostic indicators in patients resuscitated from sudden cardiac death. Circulation. 1976;54:895–900 36. Perper JA, Kuller LH, Cooper M. Arteriosclerosis of coronary arteries in sudden unexpected deaths. Circulation. 1975;52(Suppl 6):III27–III33 37. Theroux P, Fuster V. Acute coronary syndromes: unstable angina and non-Q-wave myocardial infarction. Circulation. 1998;97:1195–1206 38. Huikuri HV, Castellanos A, Myerburg RJ. Sudden death due to cardiac arrhythmias. N Engl J Med. 2001;345:1473–1482 39. Basso C, Corrado D, Thiene G. Congenital coronary artery anomalies as an important cause of sudden death in the young. Cardiol Rev. 2001;9:312–317 40. Schwartz PJ, La Rovere MT, Vanoli E. Autonomic nervous system and sudden cardiac death: experimental basis and clinical observations for post-myocardial infarction risk stratification. Circulation. 1992;85(Suppl I):I77–I91 41. Cittadini F, Oliva A, Arena V, et  al. Sudden cardiac death associated with a coronary artery anomaly considered benign. Int J Cardiol. 2008. In press 42. Corrado D, Thiene G, Cocco P, et  al. Non-atherosclerotic coronary artery disease and sudden death in the young. Br Heart J. 1992;68:601–607 43. Richardson P, McKenna W, Bristow M, et al. Report of the 1995 World Health Organization/International Society and

109 Federation of Cardiology Task Force on the Definition and Classification of cardiomyopathies. Circulation. 1996;93: 841–842 44. Codd MB, Sugrue DD, Gersh BJ, et  al. Epidemiology of idiopathic dilated and hypertrophic cardiomyopathy. A population-based study in Olmsted County, Minnesota, 1975– 1984. Circulation. 1989;80(3):564–572 45. Roberts WC, McAllister HA Jr, Ferrans VJ. Sarcoidosis o the heart. A clinicopathologic study of 35 necropsy patients (group 1) and review of 78 previously described necropsy patients (group 11). Am J Med. 1977;63:86–108 46. Moolman JC, Corfield VA, Posen B, et al. Sudden death due to troponin T mutations. J Am Coll Cardiol. 1997;29:549–555 47. Maron BJ, Anan TJ, Roberts WC. Quantitative analysis of the distribution of cardiac muscle cell disorganization in the left ventricular wall of patients with hypertrophic cardiomyopathy. Circulation. 1981;63:882–894 48. Scheffold T, Binner P, Erdmann J, et al. Hypertrophic cardiomyopathy. Herz. 2005;30:550–557 49. Ackerman MJ, VanDriest SL, Ommen SR, et al. Prevalence and age-dependence of malignant mutations in the beta-myosin heavy chain and troponin T genes in hypertrophic cardiomyopathy: a comprehensive outpatient perspective. J Am Coll Cardiol. 2002;39:2042–2048 50. Nava A, Thiene G, Canciani B, et al. Familial occurrence of right ventricular dysplasia: a study involving nine families. J Am Coll Cardiol. 1988;12:1222–1228 51. Corrado D, Basso C, Thiene G, et al. Spectrum of clinicopathologic manifestations of arrhythmogenic right ventricular cardiomyopathy/dysplasia: a multicenter study. J Am Coll Cardiol. 1997;30:1512–1520 52. De Pasquale CG, Heddle WF. Left sided arrhythmogenic ventricular dysplasia in siblings. Heart. 2001;86:128–130 53. Gallo P, d’Amati G, Pelliccia F. Pathologic evidence of extensive left ventricular involvement in arrhythmogenic right ventricular cardiomyopathy. Hum Pathol. 1992;23: 948–952 54. Burke A, Mont E, Kutys R, et al. Left ventricular noncompaction: a pathological study of 14 cases. Hum Pathol. 2005; 36:403–411 55. Norman M, Simpson M, Mogensen J, et al. Novel mutation in desmoplakin causes arrhythmogenic left ventricular cardiomyopathy. Circulation. 2005;112:636–642 56. Oechslin EN, Attenhofer Jost CH, Rojas JR, et al. Long-term follow-up of 34 adults with isolated left ventricular noncompaction: a distinct cardiomyopathy with poor prognosis. J Am Coll Cardiol. 2000;36:493–500 57. Ladich E, Virmani R, Burke A. Sudden cardiac death not related to coronary atherosclerosis. Toxicol Pathol. 2006; 34(1):52–57 58. Martin AB, Webber S, Fricker FJ, et al. Acute myocarditis. Rapid diagnosis by PCR in children. Circulation. 1994;90: 330–339 59. Litovsky SH, Burke AP, Virmani R. Giant cell myocarditis: an entity distinct from sarcoidosis characterized by multiphasic myocyte destruction by cytotoxic T cells and histiocytic giant cells. Mod Pathos. 1996;9:1126–1134 60. Roberts WC, McAllister HA Jr, Ferrans VJ. Sarcoidosis of the heart. A clinicopathologic study of 35 necropsy patients (group 1) and review of 78 previously described necropsy patients (group 11). Am J Med. 1977:63:86–108 61. Liberthson RR. Sudden death from cardiac causes in children and young adults. N Engl J Med. 1996;334:1039–1044

110 62. Oliva A, Pascali VL, Hong K, Brugada R. Molecular autopsy of sudden cardiac death (SCD): the challenge of forensic pathologist to the complexity of genomics. Am J Forensic Med Pathol. 2005;26:369–370 63. Oliva A, D’Aloja E, Pascali VL. Focussing on hard science in forensic medicine: genetics of sudden cardiac death (SCD). Forensic Sci Int. 2007 Oct 25;172(2–3):e2–3 64. Tester DJ, Spoon DB, Valdivia HH, et  al. Targeted mutational analysis of the RyR2-encoded cardiac ryanodine receptor in sudden unexplained death: a molecular autopsy of 49 medical examiner/coroner’s cases. Mayo Clin Proc. 2004;79: 1380–1384 65. Maron BJ, Shirani J, Poliac LC, et al. Sudden death in young competitive athletes: clinical, demographic, and pathological profiles. JAMA. 1996;276:199–204 66. Puranik R, Chow CK, Duflou JA, et al. Sudden death in the young. Heart Rhythm. 2005;2:1277–1282 67. Corrado D, Basso C, Thiene G. Sudden cardiac death in young people with apparently normal heart. Cardiovasc Res. 2001;50:399–408 68. Eckart RE, Scoville SL, Campbell CL, et al. Sudden death in young adults: a 25-year review of autopsies in military recruits. Ann Intern Med. 2004;141:829–834 69. Gallagher PJ. The pathologic investigation of sudden death. Curr Diagn Pathol. 2007;13:366–374

A. Oliva and V. L. Pascali 70. Leach IH, Blundell JW, Rowley JM, Turner DR. Acute ischaemic lesions in death due to ischaemic heart disease: an autopsy study of 333 out of hospital deaths. Eur Heart J. 1995;16:1181–1185 71. Chugh SS, Kelley KL, Titus JL. Sudden cardiac death with apparently normal heart. Circulation. 2000;102:649–654 72. Di Gioia C, Autore C, Romeo D, et al. Sudden cardiac death in younger adults: autopsy diagnosis as a tool for preventive medicine. Hum Pathol. 2006;37:794–801 73. Wren C, O’Sullivan JJ, Wright C. Sudden death in children and adolescents. Heart. 2000;84:410–413 74. Maron BJ. Sudden death in young athletes. N Engl J Med. 2003;349:1064–1075 75. Fornes P, Lecompte D. Pathology of sudden death durino recreational sports activity: an autopsy study of 31 cases. Am J Foren Med Path. 2003;24:9–16 76. Henriques de Gouveia R, van der Wal AC, van der Loos CM, Becker AE. Sudden unexpected death in young adults. Discrepancies between initiation of acute plaque complications and the onset of acute coronary death. Eur Heart J. 2002;23:1433–1440 77. Doolan A, Langois N, Semsarian C. Causes of sudden death in young Australians. Med J Aust. 2004;18:110–112

Part Cardiac genetic syndromes

III

8

Genetic Studies Marie-Pierre Dubé and John Rioux

8.1 Introduction The human genome consists of 3.3 billion base pairs of DNA encoding 20–30 thousand genes in the genome of every individual nucleated cell of the human body. Numerous DNA base-pair differences are observed when comparing the genome of any two individuals. Genetic variation can take different forms, but the most common variation is that of the single nucleotide polymorphism (SNP; pronounced “snip”). Single nucleotide polymorphisms (SNPs) occur in both coding and noncoding sequences at a frequency of approximately 1 per 300 base pairs, totaling approximately 10,000,000 SNPs in the human genome. Although the majority of SNPs are believed not to have a direct physiological outcome, most disease-causing mutations identified to date are of this type than other types of chromosomal changes. According to The Human Gene Mutation Database (HGMD),1 which assembles published genetic lesions responsible for human inherited disease, missense and nonsense mutations (SNPs in protein-coding regions) are responsible for 48,343 of the 85,558 (57%) mutations listed in the database, followed by small deletions (17%), splicing mutations (10%), and small insertions (7%). Large deletions and insertions and more complex chromosomal mutations account for less than 9% of disease-causing mutations.

M.-P. Dubé (*) Department of medicine, Montreal Heart Institute Research Center, and Université de Montréal, 5000, Bélanger, Montreal, QC, Canada H1T1C8 e-mail: [email protected]

Traditionally, genetic traits have been categorized as monogenic or polygenic. In a monogenic trait, the phenotype observed can be explained by variations in a single gene, and their transmission patterns are usually easily traceable within families. Marfan syndrome, Holt-Oram syndrome, DiGeorge syndrome, and sickle-cell disease are examples of monogenic disorders. Polygenic traits, on the other hand, are expressed through the interaction of several genes and can be modulated by environmental influences and thus are commonly named complex genetic traits. Many complex disorders exist, such as inflammatory bowel diseases, cardiovascular diseases, and diabetes. Cardiovascular diseases are among the most prevalent complex disorders. Medical genetic research has had substantial success in finding genes involved in the etiology of rare monogenic diseases with the use of linkage analysis and positional cloning. Nearly 1,500 disease genes have been associated with monogenic diseases mostly by the identification of rare, high-risk mutations.1 Polygenic traits, on the other hand, have proved more difficult to study using familial data. These are often referred to as complex genetic diseases due to the diversity of factors contributing to disease occurrence, including multiple environmental and genetic elements. Examples of complex diseases include type II diabetes, coronary artery disease, and several congenital heart diseases. Until 2006, the vast majority of disease genes for complex genetic traits had been identified by association studies of candidate genes or by association mapping of linkage regions. More recently, the development of tools which test hundreds of thousands or more SNPs in parallel have enabled genome-wide association (GWA) studies. These GWA studies have dramatically changed our ability to identify genetic risk factors for complex human traits.

R. Brugada et al. (eds.), Clinical Approach to Sudden Cardiac Death Syndromes, DOI: 10.1007/978-1-84882-927-5_8, © Springer-Verlag London Limited 2010

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8.2 Genetic Determinants of Disease The first step in the study of potentially genetic diseases is to assess whether the disease clusters in families. Familial resemblance between family members that is stronger than that of unrelated pairs of individuals is a common hallmark of genetic etiology. The extent of familial resemblance is generally measured by using correlation statistics between pairs of relatives. Maximum likelihood procedures can be used to estimate the familial correlations2 and hypotheses can be tested by using a likelihood ratio test. In a simple nuclear family for instance, one can evaluate correlations between father-son, father-daughter, fathermother, mother-son, mother-daughter, son-daughter, son-son, and daughter-daughter. One can test whether the correlations are different from zero, or there are sex-specific correlations. Familial resemblance, however, can be the result of shared genes, environment, or both, and means to distinguish the different sources of relatedness between family members are necessary.3,4 Furthermore, the accuracy and reliability with which a trait is measured can have a considerable effect on the correlation estimates. Heritability is one of the fundamental concepts in genetics. When estimated in extended pedigrees, it allows for the estimation of the genetic heritability without the effects due to shared environment. Classically, heritability is intended to represent the proportion of phenotypic variance that is due to additive genetic effects and generalized heritability represents the proportion of variance that is due to all additive effects including familiarity due to shared environment effects. It should be noted that heritability is not an absolute measurement, and heritability estimates are specific to a given population. Twins provide a simple means of estimating heritability by comparing monozygotic twin pairs which share 100% of their genetic complement to dizygotic twin pairs which share on average 50% of their genetic complement. According to Falconer’s formula, heritability is estimated as h2 > 2(rmz−rdz), where rmz and rdz are the twin correlations.5 Assuming that the shared environment of dizygotic and monozygotic twins is comparable, the difference in correlations can be attributed to genetic effects; if on the other hand, the shared environment is greater for monozygotic twins, then heritability would be overestimated. Adoption studies have been used to

M.-P. Dubé and J. Rioux

estimate heritability while distinguishing genetic from cultural familial effects. It is assumed that that the correlation between an adopted child and the biological parents is due to genetic effects only, while that between the child and adoptive parents is due to familial environmental effects only.6 Extended pedigrees offer the advantage of comparing family members of a variety of relationships and of different degrees, which are less likely to share environmental influences. Another method for the assessment of the genetic component of disease relies on a relative risk ratio involving disease risk in family members. This approach shares parallels with relative risk estimates used when comparing exposed vs. unexposed in classical cohort studies, but they should not be confused with each other. In genetics, we seek to determine the risk to relatives of an individual afflicted with a disease which is regrettably sometimes referred to as the “relative risk” but should rather be referred to as “the risk to relatives” or “recurrence risk” for the sake of clarity. The risk to relatives is commonly compared to the population prevalence risk in a ratio that is referred to as the “recurrence risk ratio” lR,7 where R can stand for different classes of relatives such as siblings (S), offspring (O), and so on. If lR is significantly greater than 1, then one can infer that familial factors including genes explain a greater fraction of the risk than the population prevalence risk and can accordingly be recognized as heritable. The recurrence risk ratio for aortic valve sclerosis, for example, was estimated at 2.31 (1.72–3.11) in a cohort of hypertensive siblings.8

8.3 Mendelian Traits Single-gene traits are often referred to as Mendelian for their shared characteristics with the Gregor Mendel’s study of garden variety peas. Mendelian diseases are classically characterized by their patterns of transmission in families. Familial pedigrees provide an essential tool for genetic research and for the practical application of genetic knowledge into clinical care. The pedigree depicts in a diagram, a convenient single view of multiple generations, illustrating the number of affected relatives, the transmission patterns, and the sex of transmitting individuals (Fig.  8.1). It is, however, not always possible to reach a simple definitive solution to the mode of disease transmission because

8  Genetic Studies

a

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b

Fig. 8.1  Diagram of pedigrees depicting the disease status of family members. Squares represent males, circles females; centered horizontal lines represent a parental union, vertical lines link to descendents, and superior horizontal lines represent sibships. Darkened symbols depict affected individuals and clear symbols unaffected individuals. (a) A dominantly transmitted trait; (b) a recessive trait

of small family sizes, limited information about family history, or modifiers of disease gene penetrance. A dominant trait transmission is the easiest to recognize; it is transmitted at every generation with a probability of 1/2 in the children of a couple consisting of a single affected parent, and will afflict both sexes equally (Fig. 8.1a).There is a 25 % chance that a recessive trait will occur in children of parents who are both unaffected carriers of the responsible genetic mutation. Recessive traits tend to surface in children of consanguineous parents (Fig.  8.1b). Mutations in genes located on the X chromosome display a sex-linked inheritance pattern. Alternatively, transmissions involving chromosomes other than the X and Y chromosomes are labeled autosomal transmissions. As males carry only one X chromosome, they tend to be more susceptible to X-linked genetic disorders than females, who have two copies with a chance of being protected from full disease expression when heterozygous for the mutation in question. Father-son transmission patterns are not possible in X-linked inheritance as the father will obligatorily transmit a Y chromosome to his sons. Penetrance and expressivity are important aspects of pedigree analysis. Penetrance can be reduced or age-dependent. For example, hypertrophic cardiomyopathy shows age-dependent penetrance, with approximately 95% of individuals with a predisposing genotype affected by age 50–60 years. Low penetrance has been reported for specific long Q-T syndrome

mutations. Because of the reduced and age-dependent penetrance observed in these disorders, it is important to identify carriers of the mutation because they can transmit the disease regardless of their phenotype. A wide range in severity of symptoms can also occur which can be explained by genetic and environmental modifying factors. For example, multilocus mutations and double heterozygosity are associated with earlier onset, severe forms of long QT syndrome, and hypertrophic cardiomyopathy, respectively.9,10

8.4 Genetic Linkage Studies Linkage analysis aims to detect the cosegregation of a chromosomal segment with a phenotype of interest in a set of related patients such as a family unit.11,12 The approach is ideally suited for the analysis of Mendelian traits and aims to test whether any particular chromosome segment in the genome cosegregates with the phenotype in a pedigree more frequently than one would expect by chance alone. These tests are traditionally broadly subdivided into two main categories: those in which explicit modeling assumptions are made concerning the behavior of a presumptive causal allele, and those in which no such assumptions are made. These are termed parametric (or model-based) and nonparametric (or model-free) analysis respectively. In model-based analysis, assumptions are made about the disease gene population frequency and the penetrance of the disease alleles in homozygote and heterozygote carriers. When the mode of action of the disease gene cannot be predicted with confidence, as is the case for more complex diseases, model-free analyses are typically used. Generally, these simply test for excess sharing or preferential transmission of particular marker alleles in family units. The most commonly used statistics for model-based linkage analysis is the maximum likelihood ratio. This tests the hypothesis of disease and marker cosegregation vs. the null hypothesis of random segregation. For historical reasons of convenience, the base 10 logarithm of the ratio of the likelihoods is used and referred to as the LOD score (log of odds).13 The conventional significance threshold used in linkage analysis is LOD³3 for Mendelian diseases. The genome-wide significance threshold is sometimes set higher to LOD > 3.3 for complex trait analysis.14 Linkage analysis can

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proceed using a single genetic marker at a time (twopoint linkage, that is disease locus and marker locus), or alternatively using multiple genetic markers simultaneously (multipoint linkage). Multipoint analysis provides phasing information that adds precision and accuracy to the linkage evidence and to the location estimate of the disease gene, provided that the prespecified marker map is accurate for the data at hand. Exact solutions of multipoint linkage, however, are incomputable for very large pedigrees or marker sets, in which case Markov Chain Monte Carlo approximation methods can be used. Haplotype reconstruction of phased alleles over regions of interest is a widely used procedure that allows for manual review of linkage analysis results. Phasing of alleles refers to the assignment of the two alleles of each marker to either the paternal or maternal chromosome. In monogenic as well as complex disorders, mutations in different genes can result in a similar phenotype, so that groups of families displaying a shared phenotype may not segregate a causal variant in the same gene (genetic or locus heterogeneity). Care must be taken, therefore, when pooling pedigrees for linkage analysis. It may be possible, in some instances, to subgroup pedigrees according to subtle phenotypic differences. Alternatively, robust statistical analyses that allow for locus heterogeneity in the calculation of heterogeneity LOD scores (hLOD) can be used. Alternatively, different families may segregate different mutations in the same gene for a given phenotype (allelic heterogeneity). In this case, different families will generate linkage to the same chromosomal interval although not sharing the same marker haplotype. In special cases such as French Canada, Newfoundland, Finland, etc., identical chromosomal segments or haplotypes can often be detected in different family units whose genealogical relationship may not be known.15-17 Such populations are frequently referred to as founder populations or population isolates.

8.5 Genetic Association Studies for Complex Traits GWA studies have revolutionized human genetics by providing a powerful approach for the identification of genetic variants associated with common diseases and complex traits. Compared to candidate gene-based

M.-P. Dubé and J. Rioux

genetic association studies where only a fraction of the genome is surveyed, GWA studies offer the possibility to analyze common genetic variation across the whole genome without a priori assumptions about the expected location. The method relies on testing association between genetic markers such as SNPs and a disease status or other qualitative or quantitative phenotypes. Hundreds of thousands of SNPs covering the entire genome are used. The approach is dependent on the expectation that the underlying disease mutation will be correlated (in linkage disequilibrium) with one or a few of the SNPs being tested with sufficient strength to be detectable. The advent of GWA studies was made possible by the development of better genotyping platforms18 and the creation of a large catalog of common DNA polymorphisms in the human genome across three ethnic groups (The HapMap Project; http://www.hapmap.org/).19,20 Although GWAS are powerful discovery tools, they are limited in the spectrum of genetic variation that they can survey. Genomewide genotyping arrays were designed with the goal to capture common SNPs, without consideration for the rarer variants and other types of possible structural variations. New technologies, in particular nextgeneration DNA sequencers may in a not-so-distant future allow geneticists to comprehensively survey common, rare, and structural genetic variation in wellcharacterized DNA samples. The success in GWA studies has been seen in nearly all complex human phenotypes, both continuous and discrete traits. The number of confirmed genetic risk factors found by GWAS has gotten too long to list in a short text, and is practically kept updated in a database. The public database of the National Human Genome Research Institute (http://www.genome.gov/gwastudies/) currently lists 191 published GWA studies that have identified 412 novel SNPs (i.e., not previously identified by non GWA approaches) that have p-values <9.5 × 10−6 and 235 novel SNPs that have p-values <5 × 10−8; the latter being the threshold for genomewide significance that is now widely accepted.21,22 GWA studies that have successfully identified true genetic risk factors have had a number of key features in common. They relied on a large number of SNPs (>100,000), in order to capture most of the common genetic variation in the human genome, and a large number of clinically well-defined patients and controls. Notably, very stringent quality-control criteria must be used to process genotype and phenotype data.

8  Genetic Studies

Replication in equally large and well-designed cohorts using different genotyping platforms is also important. The effect sizes of the majority of disease risk variants identified by GWA are small, increasing liability by ~10–30%.21-23 Genetic etiologic studies of complex diseases aim to acquire knowledge as to the role of genetic variants with or without environmental factors in the occurrence of disease in populations or families. Different methodologies exist including the case-control design, family-based association tests, and prospective cohort studies. Genetic association studies seek evidence for a statistically significant association between a marker allele such as a SNP and a disease at the population level. Specifically, the association approach involves comparing the frequency of an allele at the marker locus between a sample of unrelated affected individuals and an appropriate, well-matched control sample that is representative of the allelic distribution in the general population or in a disease-free sample.24 Alternatively, the association of a SNP of interest and a continuous trait (blood pressure, cholesterol) can be investigated. Testing for association to disease is either direct (testing the actual mutation) or indirect (testing a genetic variant that acts as a proxy for the mutation) and usually follows one of two common study designs: candidate gene testing or GWA mapping. There are strong arguments favoring the use of the case-control design for genetic association studies.25-27 Genetic markers have the advantage of being stable indicators of susceptibility over time, unlike biological markers of exposure which can involve self-report error, recall bias, and time variation errors. Furthermore, the case-control design helps determine the effects of genes and gene–drug exposure interactions; it is suitable for uncommon disease endpoints and the design is very efficient in terms of cost and time. These advantages compensate for the loss in precision of estimates of parameters describing the relationship between exposure and disease that could have been obtained from a cohort population. The odds ratio calculated in genetic studies is typically the odds of disease in one genotype category vs. the most common genotype as a reference. Different case-control sampling schemes exist. One approach relies on the sampling of cases with a strong family history, or on the basis of extreme or unusual subphenotypic characteristics of the disease, or even geographic clustering. This has the advantage of

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enriching the cases for the putative susceptibility allele. Sampling of newly diagnosed incident cases is preferred, as the sampling of prevalent cases provides a sample that is skewed towards individuals who have had the condition longer and may lead to the identification of different genes. Using the duration of the disease as a covariate in the analysis may also be of benefit.27 Logistic regression is a commonly used approach to analyze case-control data. To determine whether a genetic polymorphism of interest influences a drug response, the odds ratios for groups of subjects with the different genotypes can be evaluated. Three main factors that directly influence the success of association studies are the size of the cohorts under study, the matching of the different groups, and the replication of the discovered association. Originally, association-based genetic studies were often limited to modestly sized cohorts of patients with a small number of genetic variants in one gene or a small number of genes. Unfortunately, this led to a very large number of false positive results. Today, given the focus on complex traits and the modest effects of individual genes, study designs commonly involving thousands of samples and meta-analyses (i.e., combining the data of several independent studies) have become a popular and successful approach to identify genes of very modest effect size. The use of parental controls allows one to compare the frequencies of alleles that were transmitted from parents to their affected children vs. the frequency of alleles that were not transmitted. The genotype of each parent can then be considered a matched pair of alleles, one transmitted and the other not, and the McNemar statistic for matched pairs leads to a valid statistical test, the TDT.28 Alternatively, the haplotype relative risk approach uses all parental alleles, ignoring the matching. The allelic frequencies are compared in transmitted alleles vs. the nontransmitted alleles. The HHRR method is a test of allelic association, but is not a valid method to test for linkage in the presence of association, because the alleles are not independent in the presence of association when analyzed in a Pearson contingency table.29 In contrast, the TDT remains valid.30 The TDT treats parental contributions to the affected child as independent, and therefore assumes a multiplicative genetic model. For case control designs, different tests can be used for specific genetic models (recessive, dominant, additive, multiplicative… ), and similar methods have been presented for the TDT.31 Alternatives to using

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the parental alleles as controls have been proposed, such as the sibTDT,32 where unaffected siblings replace the parents and tests allowing missing parents.33,34 For families where two unaffected siblings replace the parents, 50% more families are required to obtain the same power to detect association.35 There are two broad categories of methods for family based association tests using quantitative traits. The first category is a test for parent-child trios based on the comparison of two linear-regression models.36 The model can be modified to allow for sibling controls, by using random effects for sibships.37 Fulker et al38 and Abecasis et  al39,40 have generalized the linear-model approach, to test both linkage and association, and have added terms to the regression model that enable them to separate out the within- and the betweenassociation effects. The second category of family based association tests builds more directly on the original TDT method. For quantitative traits, the transmission differences among offspring who have high quantitative-trait values and the corresponding transmissions among offspring who have low values can be compared. This approach can be formally derived as a conditional score test.31,41 The approach has been generalized to allow missing parents and tests of association in the presence of linkage.42 In parallel to the case-control study design described above, cohort studies are by far the central epidemiologic approach to study the relationships between exposures and the occurrence of disease. There are specific advantages to using cohort studies for genetic epidemiological studies.43,44 The well-characterized disease–exposure relationships obtained in large cohort can enable the identification of subtle effects of genes on phenotypes, including gene–environment interactions. The use of longitudinal data allows the rate-ofchange of particular phenotypic traits and age-related penetrance to be investigated. But importantly, findings of associations between genetic variants and phenotypes are more easily generalized to the population level when estimated from a large representative cohort study than would be possible in an ascertained sample enriched for extreme phenotypes. Cohort studies have the advantage of allowing the study of a wide range of exposures and characteristics in relation to disease outcomes. However, a cohort study for a particular association would typically require much greater cost and longer duration than a corresponding case-control study, and even more so for rare diseases.

M.-P. Dubé and J. Rioux

8.6 Challenges of Genetic Association Studies Allele frequency differences between populations, and undetected or unaccounted population structure in an association study with unrelated individuals, have the potential to result in confounding biases.45-48 This is particularly relevant when the magnitude of the genetic effect is expected to be small. Population substructure can be ascertained using principal component analysis (PCA).48 PCA makes inferences on the basis of the genotype data without inclusion of any other information, and the analysis results reflect the clustering within the genetic data. PCA analysis can typically be performed with the use of the program Smart PCA developed specifically for large genomic studies. The selected PCA components can then be used as covariates in statistical regression models. Alternatively, statistical matching by ethnic groups can reduce the confounding due to population stratification. The method of genomic control can also be used, which consists of relying on the statistical inflation measured at random SNPs to adjust the test statistic;49-51 alternatively one can use clustering52 or latent population stratification.53,54 The relatives of cases also make an ideal source of controls to reduce the confounding because they are matched on genetic ancestry as implemented in the transmission disequilibrium test (TDT)28 described above. When testing many SNPs in an association study of any type, it becomes necessary to adjust the false positive rate of the tests and the level of statistical significance.55 Some of the tested SNPs express linkage disequilibrium with one another, and the use of the Bonferroni correction for multiple testing can lead to unnecessary loss of power. A common procedure to address the problem is to calculate the empirical ­p-values through the use of Monte Carlo procedures.56 Other useful methods are global multivariate corrections, and empirical Bayes shrinkage estimates.57 Risch and Merikangas55 showed that the conservative Bonferroni correction for 100,000 comparisons raises the required sample size by only a factor of 8. In this case, nested case-control studies for relatively common cardiovascular diseases remains feasible. Replication of results in independent samples is a critical issue in all genetic studies of complex diseases.58 Replication can be performed with a second association study or with a family-based study.

8  Genetic Studies

8.7 In Conclusion Genomics has become an essential tool for the conduct of research in cardiology, and in medicine in general. The new genome technologies and bioinformatics tools offer tremendous power for transforming medicine. The future of medicine and public health looks promising as new opportunities are emerging from these genomic technologies.

References   1. Stenson PD, Ball EV, et al. Human gene mutation database (HGMD): 2003 update. Hum Mutat. 2003;21(6):577–581   2. Hopper JL, Mathews JD. Extensions to multivariate normal models for pedigree analysis. Ann Hum Genet. 1982;46(Pt 4): 373–383   3. McGue M, Wette R, et al. Path analysis under generalized marital resemblance: evaluation of the assumptions underlying the mixed homogamy model by the Monte Carlo method. Genet Epidemiol. 1989;6(2):373–388   4. Rice T, Daw EW, et al. Familial resemblance for body composition measures: the HERITAGE Family Study. Obes Res. 1997;5(6):557–562   5. Falconer DS. Introduction to quantitative genetics.. New York: Ronald; 1960   6. Plomin R, DeFries JC, et al. Behavior genetics: a primer.. New York: Freeman; 1990   7. Risch N. Linkage strategies for genetically complex traits. II. The power of affected relative pairs. Am J Hum Genet. 1990;46(2):229–241   8. Bella JN, Tang W, et al. Genome-wide linkage mapping for valve calcification susceptibility loci in hypertensive sibships: the hypertension genetic epidemiology network study. Hypertension. 2007;49(3):453–460   9. Charron P. Clinical genetics in cardiology. Heart. 2006;92(8): 1172–1176 10. Schwartz PJ, Priori SG, et al. How really rare are rare diseases?: the intriguing case of independent compound mutations in the long QT syndrome. J Cardiovasc Electrophysiol. 2003;14(10):1120–1121 11. Ott J. Analysis of human genetic linkage.. Baltimore: Johns Hopkins University.; 1991 12. Terwilliger JD, Ott J. Handbook of human genetic linkage.. Baltimore: Johns Hopkins University.; 1994 13. Morton NE. Sequential tests for the detection of linkage. Am J Hum Genet. 1955;7:277–318 14. Lander E, Kruglyak L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet. 1995;11(3):241–247 15. Arcos-Burgos M, Muenke M. Genetics of population isolates. Clin Genet. 2002;61(4):233–247 16. de la Chapelle A, Wright FA. Linkage disequilibrium mapping in isolated populations: the example of Finland revisited. Proc Natl Acad Sci USA. 1998;95(21):12416–12423

119 17. Laan M, Paabo S. Mapping genes by drift-generated linkage disequilibrium. Am J Hum Genet. 1998;63(2):654–656 18. McCarroll SA, Kuruvilla FG, et al. Integrated detection and population-genetic analysis of SNPs and copy number variation. Nat Genet. 2008;40:1166–1174 19. International HapMap Consortium. A haplotype map of the human genome. Nature. 2005;437(7063):1299–1320 20. Frazer KA, Ballinger DG, et al. A second generation human haplotype map of over 3.1 million SNPs. Nature. 2007;449(7164):851–861 21. Wellcome Trust Case Control Consortium. Genome-wide association study of 14, 000 cases of seven common diseases and 3, 000 shared controls. Nature. 2007;447(7145):661–678 22. Barrett JC, Hansoul S, et  al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat Genet. 2008;40(8):955–962 23. Lettre G, Rioux JD. Autoimmune diseases: insights from genome-wide association studies. Hum Mol Genet. 2008;17(R2):R116-R121 24. Romero R, Kuivaniemi H, et al. The design, execution, and interpretation of genetic association studies to decipher ­complex diseases. Am J Obstet Gynecol. 2002;187(5): 1299–1312 25. Clayton D, McKeigue PM. Epidemiological methods for studying genes and environmental factors in complex diseases. Lancet. 2001;358(9290):1356–1360 26. Maitland-van der Zee AH, de Boer A, et  al. The interface between pharmacoepidemiology and pharmacogenetics. Eur J Pharmacol. 2000;410(2-3):121–130 27. Zondervan KT, Cardon LR, et al. What makes a good casecontrol study? Design issues for complex traits such as endometriosis. Hum Reprod. 2002;17(6):1415–1423 28. Spielman RS, McGinnis RE, et  al. Transmission test for linkage disequilibrium: the insulin gene region and insulindependent diabetes mellitus (IDDM). Am J Hum Genet. 1993;52(3):506–516 29. Ott J. Statistical properties of the haplotype relative risk. Genet Epidemiol. 1989;6(1):127–130 30. Ewens WJ, Spielman RS. The transmission/disequilibrium test: history, subdivision, and admixture. Am J Hum Genet. 1995;57(2):455–464 31. Schaid DJ. General score tests for associations of genetic markers with disease using cases and their parents. Genet Epidemiol. 1996;13(5):423–449 32. Spielman RS, Ewens WJ. A sibship test for linkage in the presence of association: the sib transmission/disequilibrium test. Am J Hum Genet. 1998;62(2):450–458 33. Lee WC. Transmission/disequilibrium test when neither parent is available in some families: a non-iterative approach. J Cancer Epidemiol Prev. 2002;7(2):97–103 34. Weinberg CR. Allowing for missing parents in genetic studies of case-parent triads. Am J Hum Genet. 1999;64(4): 1186–1193 35. Whittaker JC, Lewis CM. Power comparisons of the transmission/disequilibrium test and sib-transmission/disequilibrium-test statistics. Am J Hum Genet. 1999;65(2): 578–580 36. Allison DB. Transmission-disequilibrium tests for quantitative traits. Am J Hum Genet. 1997;60(3):676–690 37. Allison DB, Heo M, et al. Sibling-based tests of linkage and association for quantitative traits. Am J Hum Genet. 1999; 64(6):1754–1763

120 38. Fulker DW, Cherny SS, et al. Combined linkage and association sib-pair analysis for quantitative traits. Am J Hum Genet. 1999;64(1):259–267 39. Abecasis GR, Cardon LR, et al. A general test of association for quantitative traits in nuclear families. Am J Hum Genet. 2000;66(1):279–292 40. Abecasis GR, Cookson WO, et al. The power to detect linkage disequilibrium with quantitative traits in selected samples. Am J Hum Genet. 2001;68(6):1463–1474 41. Rabinowitz D. A transmission disequilibrium test for quantitative trait loci. Hum Hered. 1997;47(6):342–350 42. Monks SA, Kaplan NL. Removing the sampling restrictions from family-based tests of association for a quantitative-trait locus. Am J Hum Genet. 2000;66(2):576–592 43. Collins FS. The case for a US prospective cohort study of genes and environment. Nature. 2004;429(6990):475–477 44. Elston RC, Olson JM, et al. Biostatistical genetics and genetic epidemiology.. New York: John Wiley and Sons; 2002 45. Freedman ML, Reich D, et al. Assessing the impact of population stratification on genetic association studies. Nat Genet. 2004;36(4):388–393 46. Helgason A, Yngvadottir B, et al. An Icelandic example of the impact of population structure on association studies. Nat Genet. 2005;37(1):90–95 47. Marchini J, Cardon LR, et al. The effects of human population structure on large genetic association studies. Nat Genet. 2004;36(5):512–517 48. Price AL, Patterson NJ, et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet. 2006;38(8):904–909

M.-P. Dubé and J. Rioux 49. Bacanu SA, Devlin B, et al. The power of genomic control. Am J Hum Genet. 2000;66(6):1933–1944 50. Devlin B, Roeder K, et al. Genomic control, a new approach to genetic-based association studies. Theor Popul Biol. 2001;60(3):155–166 51. Reich DE, Goldstein DB. Detecting association in a casecontrol study while correcting for population stratification. Genet Epidemiol. 2001;20(1):4–16 52. Schork NJ, Fallin D, et al. The future of genetic case-control studies. Adv Genet. 2001;42:191–212 53. Pritchard JK, Donnelly P. Case-control studies of association in structured or admixed populations. Theor Popul Biol. 2001;60(3):227–237 54. Satten GA, Flanders WD, et al. Accounting for unmeasured population substructure in case-control studies of genetic association using a novel latent-class model. Am J Hum Genet. 2001;68(2):466–477 55. Risch N, Merikangas K. The future of genetic studies of complex human diseases. Science. 1996;273(5281):1516–1517 56. Dudbridge F, Koeleman BP. Efficient computation of significance levels for multiple associations in large studies of correlated data, including genomewide association studies. Am J Hum Genet. 2004;75(3):424–435 57. Thomas D, Langholz B, et al. Empirical Bayes methods for testing associations with large numbers of candidate genes in the presence of environmental risk factors, with applications to HLA associations in IDDM. Ann Med. 1992;24(5):387–392 58. Palmer LJ, Cookson WO. Using single nucleotide polymorphisms as a means to understanding the pathophysiology of asthma. Respir Res. 2001;2(2):102–112

9

The Long QT Syndrome Ramon Brugada and Oscar Campuzano

9.1 Introduction The hereditary long QT syndrome (LQT) is a disease characterized by lengthened ventricular repolarization, diagnosed by the presence of a prolongation of the QT interval on the electrocardiogram (ECG) (Fig. 9.1) and associated with sudden cardiac death (SCD). The prevalence of the disease is thought to be around 1/5,000 of the general population. While the majority of patients with the LQT syndrome are at present asymptomatic, mainly due to the identification of family members during familial screening, the phenotype is varied and can range from asymptomatic individuals to syncopal episodes, seizures, malignant ventricular arrhythmias, and ventricular fibrillation. Approximately 1/3 of individuals present with syncope or aborted malignant ventricular arrhythmias, including torsades de pointes, which is the most typical ventricular arrhythmia in LQT syndrome. Symptoms in the LQT syndrome are limited to the cardiac system with the exception of individuals with the recessive form or Jervell and Lange-Nielsen who also present with neural deafness.1-6

9.2 Clinical Manifestations Most of the data on the LQT have been obtained from the International Registry on the disease, which has been ongoing for the last three decades.3 Prognosis in symptomatic cases, if untreated, is poor; approximately 1/5 of patients who present with syncope and remain

O. Campuzano () Cardiovascular Genetics Center, UdG-IDIBGI, Girona, Spain e-mail: [email protected]

untreated die within 1 year and 50% within 10 years. In individuals treated with beta-blockers, the rate of events is <1% per year. The majority of symptomatic probands are females, and an average of 20% of family members is symptomatic (syncope, cardiac arrest, SCD).7,8

9.3 Diagnostic Tools Electrocardiogram. The diagnosis of LQT is usually based on the identification of a prolongation of the QT interval on the ECG (Fig. 9.1). The normal QT interval ranges from 370 to 430 ms in males and to 450 ms in females and it is considered prolonged at 450 in males and 470 in females (Table 9.1). This means that there are some values which are considered borderline, and in which there may be an overlap with normal individuals. Due to the presence of the U wave in the right precordial leads, most will measure the QT on lead II or V6. The sensitivity of measuring a single beat is not 100%; thus the measurement of the average of five consecutive beats is recommended, 10 beats in the presence of atrial fibrillation. In addition, the QT interval is highly dependent on the autonomic state, electrolyte levels, drugs, and also heart rate. The latter is incorporated in the formula for corrected QT interval (QTc) (Bazett-corrected).9-11 The Bazett formula has some limitations in heart rate extremes. In this instance, the use of Fridericia´s formula is recommended.12 The presence of notched T waves, beat-to-beat changes in T wave morphology can be frequently observed in LQT and may aid in the diagnosis.10 Long QT score. It is important to consider the diagnosis in the context of disease presentation and family history and not just on the measurement on the ECG

R. Brugada et al. (eds.), Clinical Approach to Sudden Cardiac Death Syndromes, DOI: 10.1007/978-1-84882-927-5_9, © Springer-Verlag London Limited 2010

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R. Brugada and O. Campuzano

Fig.  9.1  Example of ECG with prolonged QT interval

(Table 9.2).1,7,13 Therefore the ECG criteria have been added to clinical features, arrhythmias, and family history in what is called the LQTS score, which defines the risk of an individual to suffer from the disease (Table 9.2).13 Patients with a score of at least four are diagnosed with definitive LQT. Genetic data. Using genetically confirmed individuals and family members, it was shown in 1991 that QT intervals in carriers had an important overlap with measurements in noncarriers individuals.14 A measurement of 470 ms in males would not identify 40% of genetic carriers. However a cut off of 450 would diagnose 10% of noncarriers as affected, 14 confirming the importance of using genetic testing as an aid to clinical diagnostic tools.14-17 Epinephrine testing. The use of isoproterenol or epinephrine has been advocated in recent years as a valuable tool to establish the diagnosis of LQT. The presence of paradoxical response (increase in QT>30 ms during infusion of epinephrine 0.1 mcg/kg/min) and a longer QTc during infusion have been very useful in identification of LQT1 patients, but not in other genotypes. These Table 9.1  Bazett-Corrected QTc Rating 1–15 years (ms) Adult male (ms)

Adult female (ms)

Normal

<440

<430

<450

Borderline

440–460

430–450

450–470

Prolonged >460 >450 Diagnostic values for QT prolongation Reprinted with permission

>470

Table 9.2  Diagnostic criteria for LQTS Finding

Score

Electrocardiographic

a

Corrected QT interval, ms >480

3

460–470

2

450 (in males)

1

Torsades de pointesb

2

T-wave alternant

1

Notched T-wave in three leads

1

Low heart rate for agec

0.5

Clinical history Syncopeb With stress

2

Without stress

1

Congenital deafness

0.5

Family history Family members with definite LQTS

1

Unexplained sudden cardiac death (SCD) 0.5 in immediate family members <30 years old Scoring: <1 point, low probability of long QT syndrome (LQTS); 2–3 points, intermediate probability of LQTS; and >4 points, high probability of LQTS. a Findings in the absence of medications or disorders known to affect these electrocardiographic findings. The corrected QT interval is calculated by Bazett’s formula: QT/RR0.5. b Torsades de pointes and syncope are mutually exclusive. c ­Resting heart rate below the second percentile for age. Adapted from13

9  The Long QT Syndrome

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data have to be taken with caution due to the limited data available on the response in normal controls 18,19. Exercise testing. The basis for using exercise testing in the diagnosis of LQT is based on the fact that individuals with the disease fail to shorten the QT interval at higher heart rates. The use of a burst protocol appears to have higher sensitivity and specificity. Due to the overcorrection of the QTc at higher heart rates and the difficulties in measuring QT in the ECG during exercise, a presence of QT>500 at heart rates <100 beats per minute is accepted as indicative of LQTs. But shorter QTc may be within the physiological range 1,20.

9.5 Molecular Genetics Two patterns of inheritance have been described in the congenital LQT: (1) autosomal dominant disease, described by Romano and Ward 6 and (2) autosomal recessive disease, described by Jervell and Lange Nielsen in 1957,21 which it is also associated with deafness. The alterations in currents in the LQT is mainly related to either decreased potassium outward currents due to mutations in K+ channels or excessive sodium inward currents due to gain-of-function mutations which lead to inadequate closure of the Na+ channels.22-25 However, new forms have also been associated with alterations in calcium channels and ion channelassociated proteins.

9.4 Differential Diagnosis The presence of a long QT interval can be caused by a genetic defect, usually associated with mutations in ion channels, or acquired, which is usually iatrogenic, related to the use of several medications such as antiarrhythmics, antidepressants, and phenothiazides. An up-to-date and growing list of medications is available at www.qtdrugs.org. In addition, electrolyte imbalance such as hypokalemia, hypomagnesemia, and hypocalcemia, especially in the presence of predisposing medications, can cause prolongation of the QT interval 8.

Table 9.3  LQTS Inherited forms Current Disease

9.6 Autosomal Dominant Long QT Syndrome (Romano-Ward Syndrome) The first locus for the autosomal dominant disease was mapped to chromosome 11 in 1991. Since then, 12 types of LQT have been identified (Table 9.3). Long QT Syndrome 1: The causal gene for LQT1 is the KVLQT1 (or KCNQ1), which encodes a voltagegated potassium channel a subunit and is strongly

Inheritance

Locus

Gene

Sodium

Long QT3 Long QT10

Autosomal dominant

3p21-p24 11q23.3

SCN5A SCN4B

Sodium related

Long QT9 Long QT12

Autosomal dominant

3p25 20q11.2

Cav3a SNTA1a

Potassium

Long QT1 Long QT2 Long QT5 Long QT6 Long QT7 JLN1 JLN2

Autosomal dominant

Autosomal recessive Autosomal recessive

11p15.5 7q35-q36 21q22.1 21q22.1 17q23 11p15 21q22

KCNQ1 KCNH2 Mink (KCNE1) MiRP1 (KCNE2) KCNJ2 KCNQ1 Mink (KCNE1)

Potassium related

Long QT11

Autosomal dominant

7q21-q22

AKAP9 (Yotiao)a

Calcium

Timothy syndrome (Long QT8)

Autosomal dominant

12p13.3

CACNA1C

4q25-q27

ANKB (ANK2)a

Calcium related Long QT4 Autosomal dominant a Channel-related proteins, these are not channel-forming proteins

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expressed in the heart.26,27 It consists of 16 exons spanning 400 kb, which form six transmembrane segments. It coassembles with the b-subunit MinK (KCNE1), to form the slow activating potassium current Iks.28,29 Mutations in this gene disrupt the normal function of the protein causing a decrease in the potassium current. Several mutations have been described in KCNQ1 to date.25 Long QT Syndrome 2: The gene responsible for LQT2 is HERG or KCNH2. It was isolated in 1994 from the hippocampus and named human ether-a-go-go related gene due to its homology to Drosophila “ether-a-go-go” gene. The gene is localized on chromosome 7q35-q36 and contains 16 exons spanning approximately 55 Kb of genomic sequence. It encodes a protein that forms six transmembrane segments and is responsible for the rapidly activating delayed rectifier potassium current IKr after coassembly with MIRP1 (KCNE2). As in the case of LQT1, mutations in HERG cause an abnormal protein with a resulting loss of potassium current.6,30-32 Long QT Syndrome 3: The causal gene is SCN5A, located on chromosome three and encodes for the cardiac sodium channel. Mutations in SCN5A also cause Brugada syndrome and progressive conduction system disease. Electrophysiological studies following expression of the mutant proteins in xenopus oocytes showed a gain-of-function mutation evidenced by delayed inactivation and persistent leaking of sodium ions after phase 0 of the action potential.31,33-35 Long QT Syndrome 4: A locus for a French family with 65 affected members with long QT and sinus node dysfunction was mapped to 4q25-q27 in 1995. Very recently, the causal gene was identified as ANKB (also known as ANK2), which encodes ankyrin-B. Mutations in ankyrin B disrupt cellular localization of the sodium pump, the sodium/calcium exchanger and inositol1,4,5-triphosphate receptors, reduce their expression levels and affect Ca2+ signaling in adult cardiac myocytes. This finding suggests that not only mutations in ion channels causes cardiac arrhythmias, but also mutations in ion channel-associated proteins, such as ankyrin B, could induce a similar phenotype.36,37 Long QT Syndrome 5: The gene responsible for LQT5 MinK. It is located on chromosome 21q22.1q22.2. This gene contains 3 exons. Mink coassembles with KVLQT1 to form the cardiac IKs channel. Mutations in this gene have been identified as causing both the autosomal dominant and autosomal recessive disease.38-40

R. Brugada and O. Campuzano

Long QT Syndrome 6: LQT6 is caused by mutations in KCNE2 or MirP1. It is mapped to 21q22.1, next to MinK, arrayed in opposite direction. KCNE2 assembles with HERG to form the IKr current. Mutations in KCNE2 decrease potassium current availability, with slower activation.41-43 Long QT Syndrome 7: Andersen’s syndrome is a rare autosomal dominant inherited disorder characterized by constellation of periodic paralysis, cardiac arrhythmias, long QT, and dysmorphic features such as short stature, scoliosis, clinodactily, hyperthelorism, low set or slanted ears, micrognatia, and broad forehead. The causal gene is KCNJ2, located on chromosome 17q23, which encodes the inward rectifier potassium channel Kir2.1, expressed in skeletal and cardiac muscles. Kir2.1 is a strong inward rectifier channel which prevents passage of any current at potential greater than −40  mV. Electrophysiological studies show that the mutant protein exerts a dominant negative effect on Kir2.1 function with an ultimate decrease in potassium current.44-46 Long QT Syndrome 8: LQT8, also known as Timothy syndrome, is characterized by the presence of facial dysmorphic features, syndactyly, small teeth, mental retardation, and severe QT prolongation. Mutations in CACNA1C, encoding for the alpha subunit of L-Type calcium channel have been identified as being responsible for a syndrome. The mutations cause a gain-of-function defect, increasing the inward current and prolonging the action potential.7,47 Long QT Syndrome 9: Caused by mutations in Caveolin-3 (Cav-3), this occurs in less than 2% of individuals with LQT. The effect is associated with the role of this protein in modification of the Na channel. As in LQT3, mutations in Cav-3 prolong repolarization by increasing the late INa.48 Long QT Syndrome 10: This form of the LQT is caused by mutations in SCN4B, the b-subunit of the sodium channel (NaVb4). The mutation induces a positive shift in inactivation of the Na channel, which increases INa.49 Long QT Syndrome 11: In 2007, Chen et al,50 identified a rare Yotiao (AKAP9) missense mutation in an LQTS family that disrupts binding between KCNQ1 and Yotiao, reduces PKA phosphorylation of KCNQ1, eliminates the response of KCNQ1 to cAMP, and prolongs the action potential. Long QT Syndrome 12: Ueda et  al,51 proposed recently a new susceptibility gene (SNTA1) for

9  The Long QT Syndrome

inherited LQTS. The mutation caused a marked increase in late INa. comparable to the increases seen in patients with LQT3 mutations.33 The data showing a plausible molecular mechanism for the effects of the mutation on the regulation and function of the cardiac sodium channel through the nNOS complex further support the view that the mutation in this gene is pathogenic. If the genotype–phenotype relationship is supported by further studies in additional patients, then SNTA1 would join the LQT9 gene CAV-3,52 and the LQT10 gene SCN4B (4) as a rare LQTS-susceptibility gene (LQT12) that together with CAV-3 and SCN4B produce LQTS through actions on SCN5A to cause a net “gain-of-function” with increased late INa..

9.7 Autosomal Recessive Long QT Syndrome (Jervell and LangeNielsen Syndrome) The autosomal recessive forms of the LQT syndrome have been linked to mutations in the genes encoding IKs current, namely KVLQT1 and MinK. For the LQT phenotype, which is also associated with sensorineuronal deafness, to express, the patients must inherit a mutation from both parents. Therefore, it is less common than the Romano–Ward syndrome but is associated with a more malignant course and longer QT interval. Because up to one third of the individuals with the disease experience cardiac arrest under treatment with beta-blockers, a defibrillator should be considered.21

9.8 Genotype–Phenotype Correlation in LQT Syndrome Penetrance in the LQT is low, varies highly among families, and is probably influenced by genetic background, gender, and environmental factors. Despite these variables, the availability of a large number of families with the LQT syndrome has enabled the performance of several genotype-phenotype correlation studies. These have been performed in order to identify genetic determinants of triggering events, electrocardiographic phenotypes, and response to therapy. The studies predominantly encompass the three most common forms of LQT syndrome, LQT1, LQT2, and LQT3.

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Triggering events: Characteristic features have emerged that in part guide the analysis of patients toward a specific genetic defect. In general, individuals with LQT1 exhibit symptoms during physical activity, especially in swimming activities. Individuals with LQT2 usually develop symptoms related to auditory stimuli. In contrast, subjects with LQT3 are symptomatic during sleep.1 Electrocardiographic phenotypes: LQT1 patients have a T wave which usually begins just after the QRS, becoming long and broad based. LQT2 patients have a small or notched T wave and LQT3 patients show a very late T wave with a prolonged ST segment.15 Clinical phenotypes according to genotype: Mutations also carry prognostic significance in all three genotypes. In general, patients with LQT1 and LQT2 have a higher risk of cardiac events than patients with LQT3.1 The latter, despite having less events, has a relatively higher mortality, which indicates that there are fewer events, but these are typically lethal. Cardiac events appear to be age- and genotype-related. As such, before the age of 18, LQT1 carriers have a higher rate of events, while events are more common in LQT2 in the age range of 18–40.22,25,53 Biophysical phenotypes: There have been few studies which have assessed the biophysical effect and location of the mutation and correlated it with the severity of the phenotype. In 2002, a study made a correlation between the presence of a pore mutation in KCNH2 and increased phenotype severity.54 In 2007, a new study associated the phenotype with the type and location of KCNQ1 mutations, showing that dominantnegative mutations and transmembrane mutations had a higher incidence of events.55 Response to therapy: While b-blockers are considered the first line of therapy in patients with LQT1, they have not shown to be as beneficial in those with LQT3, who have a slower heart rate. Preliminary data suggest that LQT3 patients might benefit from Na channel blockers, such as mexiletine, but long-term data is not yet available.56

9.9 Risk Stratification Several studies have addressed the stratification of individuals with LQT, to try to better define their overall risk and determine the best preventive and therapeutic approach.

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Risk according to gender: It is important to notice that there are important gender differences in the risk of SCD and arrhythmias in the LQT. Males have a higher prevalence of events than females before the age of 12. This trend is reversed after the age of 18; at this age females have higher rates of events. It is unclear whether these differences are related to hormonal changes or genetic interactions. Risk according to QTc: The risk of SCD has been consistently shown to be progressively worse as there is increasing prolongation of the QTc interval. The cutoff which definitively defines a high risk of events has been set at 500 ms.53,57 Risk according to symptoms: It is obvious that asymptomatic patients are at less risk than symptomatic ones, who are at higher risk of recurrence. Syncope and the number of syncopal episodes are very important predictors of events at follow-up, at all age ranges.53,57 Risk according to family history: Family history of SCD appears to be associated with an increased rate of syncope, but is not associated with a higher incidence of SCD.58 In summary, the most important nongenetic risk factors for SCD in the LQT are QTc>500 ms, congenital deafness, syncope, ventricular arrhythmias, family hx of scd, female gender, and medical noncompliance after the event. Different levels of severity can be defined by compiling these data:59

9.10 Management Strategies

• Higher risk: Hx of aborted SCD or documented torsades de pointes. • Intermediate risk: Syncope or QTc>500. • Lower risk: QTc<500.

(a)  Non genetic carriers. In a family with LQT and an identified genetic mutation, an asymptomatic noncarrier with a normal QT interval should not be treated. In those symptomatic noncarriers, other reasons for sudden death or syncope should be investigated. (b)  Genetic carrier, asymptomatic with the phenotype. Treatment has to be decided according to gender, genotype, and phenotype according to the previously described classification of risk.22

Risk according to genotype and QTc: Genotype can also be included in the stratification of risk of events. Three different levels of severity according to QTc, gender, and genotype have been described:22 1. Higher risk (³50%). (a) QTc³500 in LQT1, LQT2, and in male LQT3 2. Intermediate risk (30–50%). (b) QTc<500. Female LQT2, female LQT3, and male LQT3 (c) QTc³500. Female LQT3 3. Lower risk (<30%). (d) QTc<500 in male LQT2 and in LQT1 Treatment strategies, therefore, have to take into account clinical phenotype, gender, genotype, and also consider type of genetic mutation.

9.10.1 Genotype in Family Still Unknown b-blocker therapy is a must in patients with LQT without a genetic diagnosis (high and intermediate risk) and has to be a considered therapy in the low risk. b-blockers have proven to decrease mortality and reduce the rate of cardiac events. The effect of the b-blockers is not related to shortening of the QT interval, as there is a very minimal change of the QTc during therapy. b-blockers thought to work by decreasing the maximal heart rate during exertion. If the disease is associated with mutations in KCNQ1, b-blocker is recommended (class IIa indication) even in the presence of a completely normal phenotype (low risk LQT1). In the disease caused by mutations in SCN5A, long QT3, b-blocker therapy does not appear to be as effective.53 The average dose of beta-blocker is atenolol (65 mg), metoprolol (120 mg), nadolol (80 mg), and propanolol (100 mg). Despite the fact that b-blockers are very efficient, there is a risk of recurrent events.59

9.10.2 Genetic Positive Family

9.10.3 Other Treatment Options Other drugs: Due to the biophysical effect of the genetic mutations (i.e., gain of function in SCN5A and loss of function in potassium channels), there have been attempts to modify these currents with medications. This is the case of the use of mexyletine and

9  The Long QT Syndrome Table 9.4  Prevention strategies Lifestyle modification Avoidance of drugs shown to prolong QT (www.qtdrugs.org) Avoidance of competitive sports or strenuous activity. This is of benefit especially in LQT1 and of unclear benefit in LQT3 Beta-blockers in patients with QT prolongation and in patients with genetic diagnosis, even if they have a normal ECG ICD implantation in patients who survived cardiac arrest, sustained VT or syncope of arrhythmic origin while on beta-blocker

flecainide for LQT3 and potassium and spironolactone for LQT2. The results, while being preliminary, have been promising, as they have shortened the QT interval in limited experiments. However, no conclusions can be drawn, and larger patient populations are required before they can be incorporated into the therapeutic algorithms.56,60 Pacing: DDD pacing may have a role in LQT3 patients as bradycardia is not an uncommon finding. Because there remains a risk of events in these patients, and ICD-DDD should be considered.61 ICD: ICD therapy should be considered in symptomatic patients being treated with b-blockers, survivors of cardiac arrest, and in high-risk patients (strong family history, very long QT intervals, Jervell and Lange-Nielsen) (Table 9.4).62-64

9.11 Prevention There are number of precautions and preventive measures that should be implemented in patients with LQTS. Patients with LQTS have their arrhythmic events frequently triggered by stress, exercise, or sudden awakening. Therefore, patients and their family members should be advised to remove or blunt ringing clocks, phones, and devices. Circumstances where sudden noise (e.g., discotheque) and stress (e.g., roller coaster rides) is likely to occur should be avoided. Patients should avoid getting involved in competitive sports and water sports, because swimming and sudden immersion in water might trigger cardiac events especially in LQT1. This precaution is particularly difficult on adolescents and young adults who are fre-

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quently involved in competitive sport activities. Having automatic external defibrillator at home and at other locations accompanying patients with LQTS is increasingly used as an additional safety measure. Educating patients with LQTS and their family members regarding drugs that might prolong QT interval is of tremendous importance, because a number of cardiac and noncardiac compounds might cause drug-induced QT prolongation and torsade de pointes.8 A continuously updated list of drugs that might have QT prolonging properties is provided at www.qtdrugs.org. Special emphasis should be put on the compliance of patients taking b-blocker, because gaps in b-blocker treatment might contribute to sudden increase in propensity to develop life-threatening ventricular arrhythmias.

References   1. Marijon E, Combes N, Albenque JP. Long-QT syndrome. N Engl J Med. 2008;358(18):1967; author reply 1968   2. Moss AJ, Schwartz PJ, Crampton RS, Locati E, Carleen E. The long QT syndrome: a prospective international study. Circulation. 1985;71(1):17–21   3. Moss AJ, Schwartz PJ, Crampton RS, et  al. The long QT syndrome. Prospective longitudinal study of 328 families. Circulation. 1991;84(3):1136–1144   4. Romano C. Congenital cardiac arrhythmia. Lancet. 1965; 1(7386):658–659   5. Schwartz PJ, Malliani A. Electrical alternation of the T-wave: clinical and experimental evidence of its relationship with the sympathetic nervous system and with the long Q-T syndrome. Am Heart J. 1975;89(1):45–50   6. Ward OC. A new familial cardiac syndrome in children. J Ir Med Assoc. 1964;54:103–106   7. Lehnart SE, Ackerman MJ, Benson DW Jr, et al. Inherited arrhythmias: a National Heart, Lung, and Blood Institute and Office of Rare Diseases workshop consensus report about the diagnosis, phenotyping, molecular mechanisms, and therapeutic approaches for primary cardiomyopathies of gene mutations affecting ion channel function. Circulation. 2007;116(20):2325–2345   8. Zareba W. Drug induced QT prolongation. Cardiol J. 2007; 14(6):523–533   9. Bazett HC. The time relations of the blood-pressure changes after excision of the adrenal glands, with some observations on blood volume changes. J Physiol. 1920;53(5):320–339 10. Goldenberg I, Moss AJ, Zareba W. QT interval: how to measure it and what is “normal”. J Cardiovasc Electrophysiol. 2006;17(3):333–336 11. Moss AJ, Robinson JL. Clinical aspects of the idiopathic long QT syndrome. Ann N Y Acad Sci. 1992;644:103–111 12. Benatar A, Decraene T. Comparison of formulae for heart rate correction of QT interval in exercise ECGs from healthy children. Heart. 2001;86(2):199–202

128 13. Schwartz PJ, Moss AJ, Vincent GM, Crampton RS. Diagnostic criteria for the long QT syndrome. An update. Circulation. 1993;88(2):782–784 14. Vincent GM, Timothy KW, Leppert M, Keating M. The spectrum of symptoms and QT intervals in carriers of the gene for the long-QT syndrome. N Engl J Med. 1992;327(12): 846–852 15. Moss AJ, Zareba W, Benhorin J, et al. ECG T-wave patterns in genetically distinct forms of the hereditary long QT syndrome. Circulation. 1995;92(10):2929–2934 16. Clancy CE, Tateyama M, Kass RS. Insights into the molecular mechanisms of bradycardia-triggered arrhythmias in long QT-3 syndrome. J Clin Invest. 2002;110(9):1251–1262 17. Priori SG, Napolitano C, Schwartz PJ. Low penetrance in the long-QT syndrome: clinical impact. Circulation. 1999; 99(4):529–533 18. Ackerman MJ, Khositseth A, Tester DJ, Hejlik JB, Shen WK, Porter CB. Epinephrine-induced QT interval prolongation: a gene-specific paradoxical response in congenital long QT syndrome. Mayo Clin Proc. 2002;77(5):413–421 19. Shimizu W, Noda T, Takaki H, et al. Epinephrine unmasks latent mutation carriers with LQT1 form of congenital longQT syndrome. J Am Coll Cardiol. 2003;41(4):633–642 20. Swan H, Viitasalo M, Piippo K, Laitinen P, Kontula K, Toivonen L. Sinus node function and ventricular repolarization during exercise stress test in long QT syndrome patients with KvLQT1 and HERG potassium channel defects. J Am Coll Cardiol. 1999;34(3):823–829 21. Jervell A, Lange-Nielsen F. Congenital deaf-mutism, functional heart disease with prolongation of the Q-T interval and sudden death. Am Heart J. 1957;54(1):59–68 22. Priori SG, Schwartz PJ, Napolitano C, et al. Risk stratification in the long-QT syndrome. N Engl J Med. 2003;348(19): 1866–1874 23. Schwartz PJ, Priori SG, Spazzolini C, et  al. Genotypephenotype correlation in the long-QT syndrome: genespecific triggers for life-threatening arrhythmias. Circulation. 2001;103(1):89–95 24. Splawski I, Shen J, Timothy KW, et al. Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation. 2000;102(10): 1178–1185 25. Zareba W, Moss AJ, Schwartz PJ, et al. Influence of genotype on the clinical course of the long-QT syndrome. International Long-QT Syndrome Registry Research Group. N Engl J Med. 1998;339(14):960–965 26. Keating M, Atkinson D, Dunn C, Timothy K, Vincent GM, Leppert M. Linkage of a cardiac arrhythmia, the long QT syndrome, and the Harvey ras-1 gene. Science. 1991;252(5006):704–706 27. Keating M, Dunn C, Atkinson D, Timothy K, Vincent GM, Leppert M. Consistent linkage of the long-QT syndrome to the Harvey ras-1 locus on chromosome 11. Am J Hum Genet. 1991;49(6):1335–1339 28. Barhanin J, Lesage F, Guillemare E, Fink M, Lazdunski M, Romey G. K(V)LQT1 and lsK (minK) proteins associate to form the I(Ks) cardiac potassium current. Nature. 1996;384(6604):78–80 29. Sanguinetti MC, Curran ME, Zou A, et al. Coassembly of K(V)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel. Nature. 1996;384(6604):80–83

R. Brugada and O. Campuzano 30. Anderson CL, Delisle BP, Anson BD, et  al. Most LQT2 mutations reduce Kv11.1 (hERG) current by a class 2 (trafficking-deficient) mechanism. Circulation. 2006;113(3): 365–373 31. Jiang C, Atkinson D, Towbin JA, et al. Two long QT syndrome loci map to chromosomes 3 and 7 with evidence for further heterogeneity. Nat Genet. 1994;8(2):141–147 32. Warmke JW, Ganetzky B. A family of potassium channel genes related to eag in Drosophila and mammals. Proc Natl Acad Sci USA. 1994;91(8):3438–3442 33. Bennett PB, Yazawa K, Makita N, George AL Jr. Molecular mechanism for an inherited cardiac arrhythmia. Nature. 1995;376(6542):683–685 34. George AL Jr, Varkony TA, Drabkin HA, et al. Assignment of the human heart tetrodotoxin-resistant voltage-gated Na+ channel alpha-subunit gene (SCN5A) to band 3p21. Cytogenet Cell Genet. 1995;68(1-2):67–70 35. Wang Q, Shen J, Splawski I, et al. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell. 1995;80(5):805–811 36. Mohler PJ, Schott JJ, Gramolini AO, et al. Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death. Nature. 2003;421(6923):634–639 37. Mohler PJ, Splawski I, Napolitano C, et  al. A cardiac arrhythmia syndrome caused by loss of ankyrin-B function. Proc Natl Acad Sci USA. 2004;101(24):9137–9142 38. Bianchi L, Shen Z, Dennis AT, et al. Cellular dysfunction of LQT5-minK mutants: abnormalities of IKs, IKr and trafficking in long QT syndrome. Hum Mol Genet. 1999;8(8): 1499–1507 39. Krumerman A, Gao X, Bian JS, Melman YF, Kagan A, McDonald TV. An LQT mutant minK alters KvLQT1 trafficking. Am J Physiol Cell Physiol. 2004;286(6): C1453–C1463 40. van den Berg MH, Wilde AA, de Medina EO Robles, et al. The long QT syndrome: a novel missense mutation in the S6 region of the KVLQT1 gene. Hum Genet. 1997;100(3-4):356–361 41. Isbrandt D, Friederich P, Solth A, et  al. Identification and functional characterization of a novel KCNE2 (MiRP1) mutation that alters HERG channel kinetics. J Mol Med. 2002;80(8):524–532 42. Larsen LA, Andersen PS, Kanters J, et  al. Screening for mutations and polymorphisms in the genes KCNH2 and KCNE2 encoding the cardiac HERG/MiRP1 ion channel: implications for acquired and congenital long Q-T syndrome. Clin Chem. 2001;47(8):1390–1395 43. Lu Y, Mahaut-Smith MP, Huang CL, Vandenberg JI. Mutant MiRP1 subunits modulate HERG K+ channel gating: a mechanism for pro-arrhythmia in long QT syndrome type 6. J Physiol. 2003;551(Pt 1):253–262 44. Tawil R, Ptacek LJ, Pavlakis SG, et al. Andersen’s syndrome: potassium-sensitive periodic paralysis, ventricular ectopy, and dysmorphic features. Ann Neurol. 1994;35(3): 326–330 45. Tsuboi M, Antzelevitch C. Cellular basis for electrocardiographic and arrhythmic manifestations of Andersen-Tawil syndrome (LQT7). Heart Rhythm. 2006;3(3):328–335 46. Plaster NM, Tawil R, Tristani-Firouzi M, et al. Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen’s syndrome. Cell. 2001;105(4):511–519 47. Splawski I, Timothy KW, Sharpe LM, et al. Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell. 2004;119(1):19–31

9  The Long QT Syndrome 48. Vatta M, Ackerman MJ, Ye B, et  al. Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome. Circulation. 2006;114(20):2104–2112 49. Medeiros-Domingo A, Kaku T, Tester DJ, et  al. SCN4Bencoded sodium channel beta4 subunit in congenital longQT syndrome. Circulation. 2007;116(2):134–142 50. Chen L, Marquardt ML, Tester DJ, Sampson KJ, Ackerman MJ, Kass RS. Mutation of an A-kinase-anchoring protein causes long-QT syndrome. Proc Natl Acad Sci USA. 2007; 104(52): 20990–20995 51. Ueda K, Valdivia C, Medeiros-Domingo A, et al. Syntrophin mutation associated with long QT syndrome through activation of the nNOS-SCN5A macromolecular complex. Proc Natl Acad Sci USA. 2008;105(27):9355–9360 52. Cronk LB, Ye B, Kaku T, et al. Novel mechanism for sudden infant death syndrome: persistent late sodium current secondary to mutations in caveolin-3. Heart Rhythm. 2007;4(2): 161–166 53. Hobbs JB, Peterson DR, Moss AJ, et al. Risk of aborted cardiac arrest or sudden cardiac death during adolescence in the long-QT syndrome. JAMA. 2006;296(10):1249–1254 54. Moss AJ, Zareba W, Kaufman ES, et  al. Increased risk of arrhythmic events in long-QT syndrome with mutations in the pore region of the human ether-a-go-go-related gene potassium channel. Circulation. 2002;105(7):794–799 55. Moss AJ, Shimizu W, Wilde AA, et al. Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene. Circulation. 2007;115(19):2481–2489

129 56. Schwartz PJ, Priori SG, Locati EH, et al. Long QT syndrome patients with mutations of the SCN5A and HERG genes have differential responses to Na+ channel blockade and to increases in heart rate. Implications for gene-specific therapy. Circulation. 1995;92(12):3381–3386 57. Goldenberg I, Moss AJ, Bradley J, et al. Long-QT syndrome after age 40. Circulation. 2008;117(17):2192–2201 58. Kaufman ES, McNitt S, Moss AJ, et al. Risk of death in the long QT syndrome when a sibling has died. Heart Rhythm. 2008;5(6):831–836 59. Moss AJ, Zareba W, Hall WJ, et al. Effectiveness and limitations of beta-blocker therapy in congenital long-QT syndrome. Circulation. 2000;101(6):616–623 60. Windle JR, Geletka RC, Moss AJ, Zareba W, Atkins DL. Normalization of ventricular repolarization with flecainide in long QT syndrome patients with SCN5A:DeltaKPQ mutation. Ann Noninvasive Electrocardiol. 2001;6(2):153–158 61. Fan K, Lee K, Lau CP. Dual chamber implantable cardioverter defibrillator benefits and limitations. J Interv Card Electrophysiol. 1999;3(3):239–245 62. Groh WJ, Silka MJ, Oliver RP, Halperin BD, McAnulty JH, Kron J. Use of implantable cardioverter-defibrillators in the congenital long QT syndrome. Am J Cardiol. 1996;78(6): 703–706 63. Zareba W, Cygankiewicz I. Long QT syndrome and short QT syndrome. Prog Cardiovasc Dis. 2008;51(3):264–278 64. Udo EO, Baars HF, Winter JB, Wilde AA. Not just any ICD device in patients with long-QT syndrome. Neth Heart J. 2007;15(12):418–421

Brugada Syndrome

10

Begoña Benito, Ramon Brugada, Josep Brugada, and Pedro Brugada

10.1 Introduction The Brugada syndrome was described in 1992 as a new clinical entity characterized by a typical ECG pattern (right bundle branch block and persistent ST segment elevation in right precordial leads) and sudden cardiac death (SD).1 The first description of eight patients was followed by other case reports,2,3 and subsequently numerous works appeared either focusing on clinical characteristics of greater populations of patients,4-8 or defining the genetic, molecular, and cellular aspects of the disease.9-13 In fact, the number of scientific publications dealing with the syndrome has increased substantially in the last few years. Major advances in clinical and mechanistic knowledge have provided very valuable information about the disease, but remaining questions still propel a large research activity on the subject today. This chapter reviews the current knowledge on clinical, genetic, and molecular features of the Brugada syndrome, and provides updated information supplied by recent clinical and basic studies.

10.2 Diagnostic Criteria and General Characteristics After the initial description of the syndrome, several ambiguities appeared in the first few years concerning the diagnosis and the specific electrocardiographic cri-

B. Benito () Research Center, Montreal Heart Institute, 5000 Rue Belanger Montreal, H1T 1C8 Canada

teria. Three repolarization patterns were soon identified (Fig.  10.1)14: (a) type-1 ECG pattern, the one described in the initial report in 1992, in which a coved ST-segment elevation ³2 mm is followed by a negative T-wave, with little or no isoelectric separation, this feature being present in >1 right precordial lead (from V1 to V3); (b) type-2 ECG pattern, also characterized by an ST-segment elevation but followed by a positive or biphasic T-wave that results in a saddle back configuration; (c) type-3 ECG pattern, a right precordial ST-segment elevation £1 mm either with a coved-type or a saddle-back morphology. Although all the three patterns can be present in Brugada patients, only the presence of a type-1 ECG pattern defines the diagnosis of the syndrome, as stated in the first consensus report of the Arrhythmia Working Group of the European Society of Cardiology14 and subsequently confirmed in the second consensus conference published in 2005.15 These two documents helped clarify previous confusion and proposed the current accepted diagnostic criteria for the syndrome, which are depicted in Table 10.1. The Brugada syndrome can be definitely diagnosed when a type-1 ECG pattern is observed in >1 right precordial lead (V1–V3), in the presence or absence of a sodium-blocker agent, and in conjunction with one of the following: documented ventricular fibrillation (VF), polymorphic ventricular tachycardia (VT), a family history of SD at <45 years old, the presence of coved-type ECG in family members, inducibility of ventricular arrhythmias with programmed electrical stimulation, syncope, or nocturnal agonal respiration.14,15 Note that patients displaying the characteristic type-1 ECG without further clinical criteria should be referred as having an idiopathic Brugada ECG pattern and not a Brugada syndrome.14 The Brugada syndrome is currently understood as a  channelopathy, that is, a disorder produced by the

R. Brugada et al. (eds.), Clinical Approach to Sudden Cardiac Death Syndromes, DOI: 10.1007/978-1-84882-927-5_10, © Springer-Verlag London Limited 2010

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Fig. 10.1  Three different ECG patterns in right precordial leads frequently observed in patients with Brugada syndrome: (a) type-1 or otherwise called coved-type ECG pattern, in which a descendent ST-segment elevation is followed by negative T waves; (b) type-2 or saddle-back pattern, a ST-segment eleva-

tion followed by positive or biphasic T waves; (c) type-3, either a coved-type or a saddle-back morphology with ST-segment elevation < 1mm (see text for more detailed description). A type-1 ECG pattern is required to establish the definite diagnosis of Brugada syndrome

Table 10.1  Diagnostic criteria of the Brugada syndrome15 Appearance of a type-1 ST-segment elevation (coved-type) ³ 2 mm in more than one right precordial lead (V1–V3): • Either spontaneously • Or after sodium-blocker exposure AND One of the following: • Documented ventricular fibrillation • (Self-terminating) polymorphic ventricular tachycardia • Inducibility of ventricular arrhythmias with programmed electrical stimulation • Family history of sudden death before 45 years • Presence of a coved-type ECG in family members • Syncope • Nocturnal agonal respiration

  

Documented ventricular arrhythmias

     

Family history Arrhythmia-related symptoms

Other factor(s) accounting for the ECG abnormality should be ruled out

d­ ysfunction of a cardiac channel participating in the action potential, the electrical change favoring the development of arrhythmias. The electrical disorder seems to be primary, that is, without concomitant underlying structural heart disease responsible for the arrhythmic complications. In fact, the Brugada syndrome is thought to be responsible for 4–12% of all SD and for up to 20% of SD in subjects without concomitant cardiopathy.15 Its prevalence has been estimated in 5/10,000 inhabitants, although this rate should be

understood cautiously, first, because many patients present concealed forms of the disease, thus making it likely that the real prevalence be higher; and second, because important ethnic and geographical differences have been described.15 For example, while in a Japanese study a type-1 ECG pattern was observed in 12/10,000 inhabitants,16 the few available data on North American and European populations point a much lower prevalence.17,18 In fact, South East Asian culture have long recognized the so-called sudden unexplained death

10  Brugada Syndrome

syndrome (SUDS), also named Bangungot (in Philippines), Pokkuri (in Japan), or Lai Tai (in Thailand), today known to be phenotypically, genetically, and functionally the same disorder as the Brugada syndrome.19 SUDS is considered to be endemic in these countries and one of the leading causes of death in males younger than 50.

10.3 Genetics of the Brugada Syndrome Inheritance in the Brugada syndrome occurs via an autosomal dominant mode of transmission,15 although in some patients the disease can be sporadic, that is, absent in parents and other relatives.20 The first mutations related to the syndrome were described in 1998 by Chen and coworkers, and were identified in SCN5A, the gene encoding the a-subunit of the cardiac sodium channel (locus 3p21, 28 exons).9 To date, more than 100 other different mutations associated to the syndrome have been found in the same gene.11,12,19-24 Functional studies performed with expression systems have demonstrated, for most of the mutations, a loss of function of the sodium-channel current (INa), which is achieved either through a quantitative decrease in the sodium channels due to a failure in their expression or through a qualitative dysfunction of the sodium channels due to impaired kinetics (a shift in the voltage- and time-dependence activation, inactivation or reactivation; an entry into an intermediate state of inactivation; or an accelerated inactivation).9,11,12,19-24 However, mutations in the SCN5A gene are currently found in only 18–30% of patients with Brugada syndrome.15 In a study by Schulze Bahr et al, the incidence of SCN5A mutations varied widely according to whether the patients were familial or sporadic cases of Brugada syndrome. While SCN5A mutations were present in 38% of familial forms of the disease, the authors could not identify any SCN5A mutation among the 27 sporadic cases (p = 0.001).25 In any case, the low incidence of SCN5A mutations identified in both familial and sporadic Brugada patients suggested a genetic heterogeneity of the disease. According to this hypothesis, a different locus on chromosome 3 (3p22– p24), not linked to SCN5A, was identified by positional cloning in a large family with Brugada syndrome

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in 2002.26 The gene involved has been recently described, the glycerol-3-phosphate dehydrogenase 1-like (GPD-1L), which seems to affect the trafficking of the cardiac sodium channel to the cell surface.27 In fact, the responsible mutation (A280V) reduces inward sodium currents by »50% and SCN5A cell surface by »31%.27 Also very interestingly, a recent report demonstrates that not only mutations leading to a loss of function in the sodium channel (either through SCN5A or GPD-1L) can cause the Brugada syndrome, but also loss-offunction mutations in the cardiac calcium channel CACNA1c (Cav1.2) and its b-subunit CACNB2b can be responsible for a syndrome overlapping short-QT and the Brugada ECG pattern.28 These findings open up new lines of research, in which the concept of Brugada syndrome as a pure sodium channelopathy gives way to the concept of the syndrome as an ionic imbalance between the inward and the outward currents during the phase 1 of the action potential. Supporting this hypothesis, the same group has very recently identified the first family with Brugada syndrome carrying a mutation (R99H) in the KCNE3 gene, which encodes a beta-subunit that is thought to modulate Kv4.3 channels, responsible for transient potassium Ito currents.29 Functional studies demonstrate that cotransfection of the mutation R99H-KCNE3 with KCND3 results in a significant increase in the Ito intensity and underlies the development of Brugada syndrome in this family.29 In the last few years, polymorphisms are acquiring greater importance to explain certain phenotypes of genetic diseases. In the SCN5A locus, the common H558R polymorphism has been shown to restore (at least partially) the sodium current impaired by other simultaneous mutations causing either cardiac conduction disturbances (T512I)30 or Brugada syndrome (R282H).31 Thus this polymorphism seems to give rise to less severe phenotypes by mitigating the effect of nearby mutations. According to this, our data on H558R polymorphism among 75 genotyped Brugada patients demonstrate that those carrying the AA genotype have longer QRS duration in lead II (p = 0.017), higher J-point elevation in lead V2 (p = 0.013), higher rate of “aVR sign” (p = 0.005), and a trend toward more symptoms (p = 0.06) than AG or GG carriers. Thus, in our series, the common variant H558R is confirmed as a genetic modulator of the Brugada phenotype in patients with an SCN5A mutation.95

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10.4 Clinical Manifestations of the Brugada Syndrome Patients with Brugada syndrome usually remain asymptomatic. However, syncope or cardiac arrest, consequence of an arrhythmic complication such as polymorphic VT or VF, have been described in up to 17–42% of diagnosed individuals.32-35 This rate probably overestimates the real prevalence of symptoms among Brugada patients, given that most asymptomatic patients remain underdiagnosed. The age of symptom occurrence (especially cardiac arrest) is consistently around the fourth decade of life in all the series32-35 (Fig. 10.2), with no definite explanation for this observation thus far. Previous syncope may be present in up to 23% of patients who present with ­cardiac arrest.33 Up to 20% of patients with Brugada syndrome may present supraventricular arrhythmias,36 and thus complain of palpitations and/or dizziness. An increased atrial vulnerability to both spontaneous and induced atrial fibrillation has been reported in patients with Brugada syndrome.37 The electrophysiologic basis could be an abnormal atrial conduction.37 Whether atrial vulnerability is correlated to an increased susceptibility for ventricular arrhythmias is thus far unknown. Other symptoms such as neurally mediated syncope have been also recently associated to the Brugada syndrome, but their implication on prognosis has not yet been established.38,39

As in the case of other sodium-channel related disorders like type-3 long-QT syndrome, ventricular arrhythmias in the Brugada syndrome typically occur at rest, especially during nighttime or sleep. In a study by Matsuo et  al, 26 out of 30 episodes of VF documented in ICD recordings of Brugada patients appeared during sleep, suggesting that vagal activity may play an important role in the arrhythmogenesis of Brugada syndrome.40 This finding has been confirmed in more recent series.41 Indeed, recent data on cardiac autonomic nervous system assessed by positron emission tomography confirm that Brugada patients display certain degree of sympathetic autonomic dysfunction, with increased presynaptic norepinephrine recycling and thus a decrease in the concentration of norepinephrine at the synaptic cleft, this imbalance facilitating arrhythmogenicity by decreasing intracellular levels of cAMP.42,43

10.4.1 Gender Differences It is currently accepted that the clinical phenotype of the Brugada syndrome is eight to ten times more prevalent in male than in female patients.44 Consequently, the main clinical studies published thus far include a 71–77% of male population, which generally appear to be more symptomatic with regard to female population.32-35 In fact, the observation that SD mainly occur

60

Fig. 10.2  Incidence of spontaneous ventricular fibrillation (VF) or sudden death (SD) in lifetime among patients with Brugada syndrome. Data from 370 updated patients of the International Registry. SD or VF occurred in n = 120 (32.4%) patients

Number of patients with VF

50

40

30

20

10

0 0-5

6-10 11-15 16-20 21-25 26-30 31-35 36-40 41-45 46-50 51-55 56-60 61-65 66-70 71-75 76-80

Age

10  Brugada Syndrome

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in young males at the time of sleeping has long been recognized in South East Asia for the SUDS, where males from certain small villages use to dress in women bedclothes since the syndrome is understood as a female spirit searching for young males at night. Because specific clinical data on the gender distinction are, however, lacking, we recently conducted a study aimed to analyze gender differences in a large population of patients with Brugada syndrome, prospectively enrolled in Hospital Clinic of Barcelona and in UZ

a

Brussel.45 The study population (n = 384) included 272 males (70.8%) and 112 females (29.2%). General demographic characteristics were similar between males and females (mean age: 45.8), but, at diagnosis, males presented more frequently with symptoms (syncope in 18%, previous aborted SD in 6%) than females (14% and 1%, respectively, p = 0.04). Males also had higher rates of spontaneous type-1 ECG (47% vs. 23%, p = 0.0001) and inducibility of VF during the electrophysiologic study (32% vs. 12% p = 0.0001) (Fig. 10.3a).45

Symptoms p=0.04

Baseline ECG

Inducibility of VF

p=0.0001

p=0.0001

100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%

Male

Male

Female

Asymptomatic

Normal

Syncope

Type-2 ECG

Aborted SD

Spontaneous type-1 ECG

b

Male

Inducible VF

0.8

0.6

Male

0.4

0.2

0.0

Log rank 0.007 0

100

Months of follow-up

Female

No inducibility

Female

1.0

Free of SD or VF

Fig. 10.3  Gender differences in clinical manifestations of Brugada syndrome. (Data from Benito et al45) (a) Differences on clinical characteristics at the time of first evaluation. Males are more symptomatic, display more pathological ECG at baseline, and present more inducibility of ventricular fibrillation than females. (b) Kaplan-Meier analysis of cardiac events defined as sudden death or documented ventricular fibrillation during follow-up. A total of 31/272 males (11.6%) and 3/112 females (2.8%) experienced cardiac events during a mean follow-up period 58 ± 48 months (log-rank test p = 0.007). VF ventricular fibrillation; SD sudden death

Female

200

136

Prognosis also differed between males and females. Cardiac events (defined as SD or documented VF) appeared in 31 males (11.6%) and in three females (2.8%) during a mean follow-up period of 58 ± 48 months (log-rank test p = 0.007). Kaplan-Meier estimate of cardiac event-free survival according to gender is represented in Fig. 10.3b. By univariable analysis, gender was significantly related to cardiac events (HR: 4.45 [95% CI: 1.36–14.58], p = 0.014), but multivariable analysis did not confirm gender as an independent predictor (HR: 2.82 [95% CI: 0.64–12.41], p = 0.18).45 However, in a recent meta-analysis pooling data of 30 studies and including more than 1,500 patients, male gender appeared as an independent predictor of cardiac events defined as SD, syncope, or internal defibrillator shock, with an RR of 3.47 (95% CI: 1.58–7.63) with regard to females.46 In our study, we also assessed possible differences in prognostic factors according to gender. Among male patients, as previously reported for mixed populations,32-35 cardiac events were more frequently observed in those with previous symptoms (18.4% of events among patients with previous syncope and 64.7% of events among those with previous SD, whereas only 5.5% of events in previously asymptomatic), spontaneous type-1 ECG or inducibility of VF in the EPS.45 However, in the presence of an extremely low rate of cardiac events, none of these parameters showed power enough to identify females at risk. Interestingly, conduction parameters such as the PR interval or the HV interval were significantly longer in female patients who developed cardiac events as compared to those who did not. Thus, our data suggest that conduction disturbances could be a marker of risk in female patients with Brugada syndrome.45 Two main hypotheses have been proposed for the gender distinction, perhaps interacting with each other: the sex-related intrinsic differences in ionic currents and the hormonal influence. Di Diego and coworkers showed by whole-cell patch-clamp techniques that Ito density was significantly greater in male than female right ventricle epicardia of arterially perfused canine heart preparations, thus explaining the deeper notch in phase 1 of the action potential in males as compared to females.47 The administration of terfenadine (a Na-Ca blocker) in this model induced transmural dispersion of repolarization and epicardial dispersion of repolarization, leading to ST-segment elevation and providing the basis for phase-2 re-entry and VF, respectively.47 Both phenomena were mainly observed in male samples, due to their deeper phase-1 magnitude at baseline.

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The role of sex hormones is currently less established, although some data exist suggesting they might also play a role in the phenotypic manifestations of Brugada syndrome. For example, regression of the typical ECG features has been reported in castrated men,48 and levels of testosterone seem to be higher in Brugada male patients as compared to controls.49 Some experimental works point out that hormones could modify the ionic membrane currents,50,51 but their effect among human currents is still unclear. Consequently with the hormonal hypothesis, the few available data existing thus far of Brugada syndrome in children have not shown a difference in phenotypic presentation between boys and girls.52

10.4.2 Children Although three of the eight patients reported in the first description of the disease were within pediatric ages, little information has been thus far available on the behavior of the Brugada syndrome during childhood. Probst et al recently provided data from a multicenter study including 30 Brugada patients aged less than 16 years (mean age: 8 ± 5).52 More than half (n = 17) had been diagnosed during family screening, but symptoms were present in 11 patients (one aborted SD and ten syncope). Interestingly, 10 of the 11 symptomatic patients displayed spontaneous type-1 ECG, and in five of them, symptoms were precipitated by fever illnesses. Five patients received an ICD and four were treated with hydroquinidine.52 During a mean ­follow-up period of 37 ± 23 months, three patients (10% of the population) experienced SD (n = 1) or appropriate shock by ICD (n = 2). Importantly, all the three patients had presented with syncope at the time of diagnosis and displayed spontaneous type-1 ECG. The four patients under quinidine remained asymptomatic during 28 ± 24 months of follow-up.52 Our results on 58 pediatric patients with Brugada syndrome are in line with the ones by Probst et al and provide further data on prognosis markers during childhood.53 In our population (mean age: 11.8 ± 4), up to 22 patients (38%) were symptomatic (11 with previous syncope and 11 with aborted SD), while 36 had been diagnosed during family screening. Spontaneous type-1 ECG was present in 18 patients (31%), and the EPS, performed in 31 patients, induced VF in 7 of them. An ICD was indicated to 14 patients. Cardiac events appeared in 6 patients (two SD and four appropriate ICD shocks)

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during a mean follow-up of 48.8 ± 48 months, this rate of 2.5%/year being somewhat lower than the 3.2%/year reported by Probst et al52 Cardiac events occurred more frequently among patients with spontaneous type-1 ECG and among those with inducible VF at the EPS, but, in our series, symptoms at diagnosis was the strongest variable to predict events during follow-up (Fig. 10.4).53 Though small, these studies suggest that: • The Brugada syndrome can manifest during childhood. • Symptoms may appear particularly during febrile episodes. • Symptomatic patients, especially if they present spontaneous type-1 ECG, may be at a high risk of cardiac events in a relatively short period of follow-up. • Patients at risk can be protected with an ICD, although quinidine could be an option in certain patients, particularly the youngest.

10.5 ECG and Modulating Factors As mentioned earlier, three types of repolarization have been described (Fig.  10.1), but only the covedtype ST-segment elevation (type-1 ECG pattern) is

diagnostic of the syndrome. However, it is important to underline that ECG typically fluctuates over time in Brugada patients, and thus can change from type-1 to type-2 or type-3 or even be transiently normal. The prevalence of spontaneous ECG fluctuations has been recently assessed in a work by Veltmann et al, including 310 ECGs on 43 patients followed during 17.7 months.54 Among 15 patients with an initial diagnostic ECG, 14 revealed at least one nondiagnostic ECG in a median time of 12 days, while 8 out of 28 patients with nondiagnostic ECG developed a type-1 ECG pattern in a median time of 16 days.54 On the basis of these results, it seems that repetitive ECG recordings may be mandatory in patients with the syndrome and, on the other hand, that the role of the basal ECG as a risk marker should be understood cautiously (see risk stratification).54,55 It is worthy to note that some factors can account for an ECG abnormality that can closely resemble the Brugada ECG (Table 10.2). Importantly, some of them are conditions different than the syndrome and should be carefully excluded during the differential diagnosis, while others may induce ST-segment elevation probably when an underlying genetic predisposition is present. Modulating factors play a major role in the dynamic nature of the ECG and also may be responsible for the ST-segment elevation in genetically predisposed patients

Asymptomatic (n=36)

0 events

-Spontaneous type-1 ECG: 3/36(8.3%) -Inducibility of VF: 2/19(10.5%)

1.0

Fig. 10.4  Kaplan-Meier estimates of cardiac events (sudden death or ventricular fibrillation) in children according to symptoms. Note that symptomatic patients were also more likely to have type-1 ECG and be inducible at the electrophysiological study.53 SD sudden death; VF ventricular fibrillation

Free of cardiac events

0.8 Syncope (n=11)

2 events

-Spontaneous type-1 ECG: 6/11(54.5%) -Inducibility of VF: 2/6(33.3%)

0.6

0.4

0.2

Aborted SD (n=11)

4 events

-Spontaneous type-1 ECG: 9/11(81.8%) -Inducibility of VF: 3/5(60%) 0.0

Log rank 0.003 0

50

100 Follow-up(months)

150

200

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Table  10.2  ECG abnormalities that can lead to ST-segment elevation in V1–V3 Differential diagnosis Genetic predisposition? Atypical right bundle branch block

Hyperkalemia

Acute myocardial infarction, especially of RV

Hypercalcemia

Acute pericarditis/ miopericarditis

Cocaine intoxication/alcohol intoxication

Hemopericardium

Treatment with:

Pulmonary embolism

Antiarrhythmic drugs:

Dissecting aortic aneurysm

• Na channel blockers (class IC, class IA)

Central and autonomic • Ca channel blockers nervous system disorders Duchenne muscular dystrophy

• B-blockers

Friedreich Ataxia

Antianginal drugs:

LV hypertrophy

• Ca channel blockers

Arrhythmogenic RV cardiomyopathy

• Nitrates

Mechanical compression of RV outflow tract

Psychotropic drugs:

• Mediastinal tumor

• Tricyclic antidepressants

• Pectus excavatum

• Tetracyclic antidepressants

After electrical cardioversion

• Phenothiazines

Early repolarization, especially in athletes

• Selective serotonin reuptake inhibitors

Hypothermia

• Lithium

(Table 10.2). Sympathovagal balance, hormones, metabolic factors, and pharmacological agents, by means of specific effects on transmembrane ionic currents, are thought to modulate not only the ECG morphology but also explain the development of ventricular arrhythmias under certain conditions. Indeed, bradycardia and vagal tone may contribute to ST-segment elevation and arrhythmia initiation by decreasing calcium currents.13 This explains the greater ST-segment elevation recorded in vagal settings,56-59 and the notorious incidence of cardiac arrhythmias and SD at night in patients with Brugada syndrome.40,41 The role of hormones (especially sex hormones) as modulating factors is less established, but is deeply suspected on the basis of some

experimental works and the evident male predominance on the clinical manifestations of the syndrome (see gender differences).48,49,60 Temperature may be an important modulator in some patients with Brugada syndrome. Premature inactivation of the sodium channel has been shown to be accentuated at higher temperatures in some SCN5A mutations, suggesting that febrile states may unmask certain Brugada patients or temporarily increase the risk of arrhythmias.10 In fact, several case reports in which fever precipitate the syndrome or an arrhythmic complication have been published in the last years.61,62 It seems that fever would be a particularly important trigger factor among pediatric population.52 Numerous studies have analyzed the ECG of the Brugada syndrome aiming to identify new electrocardiographic hallmarks or risk markers. Pitzalis and coworkers described a prolongation of the corrected QT interval (QTc) in right but not in left precordial leads after administration of flecainide to patients with Brugada syndrome and nondiagnostic basal ECG.63 Subsequently, other groups have correlated a QTc ³ 460 ms in V2 to the occurrence of life-threatening arrhythmias.64 More recently, the aVR sign (an R wave ³ 3 mm or an R/q ratio ³ 0.75 in lead aVR) has also been defined as a risk marker of cardiac events in Brugada syndrome, the prominent R wave possibly reflecting some right ventricular conduction delay and subsequently more electrical heterogeneity.65 Studies with 12-lead ECG and signal-averaged ECG (SAECG) show that daily fluctuations of ST-segment elevation are more prominent in symptomatic than in asymptomatic patients, with a strong dependence on heart rate and vagal activity.58,59 Also, T-wave alternans has been reported after administration of sodium blockers, and is thought to be associated with an increased risk for development of VF in patients with Brugada syndrome, since it may reflect transmural dispersion of repolarization.66 Indeed, in a very recent study conducted in 77 Brugada patients undergoing a pharmacological test, the presence of T-wave alternans after the sodium-blocker exposure identified a subgroup of patients with higher risk of spontaneous VF (52.9% vs. 8.3%, p < 0.001).67 Cardiac conduction disturbances may be present in patients with Brugada syndrome. Both phenotypes (Brugada syndrome and cardiac conduction disorders) can be explained by a reduction in the sodium current, and have been described within the same family carrying a mutation on the SCN5A gene.68 Consequently,

10  Brugada Syndrome

conduction parameters (specifically PQ interval, QRS duration and HV interval) seem to be longer among those patients with Brugada syndrome who are SCN5A genetic carriers (and do have a mutation in the sodium channel) as compared to non-SCN5A genetic carriers, in which the underlying mechanism or mutation is not identified.69 These differences have been recently shown to progressively accentuate during follow-up.70 Also, we recently identified that some conduction parameters such as QRS duration are increased among symptomatic patients. In a population of 200 Brugada patients, of whom 66 (33%) were symptomatic, QRS duration in V2 was 115 ± 26 ms in symptomatic and 104 ± 19 ms in asymptomatic patients, this difference being statistically significant (p < 0.001). The optimized cut-off point of V2 QRS ³ 120 ms gave an odds ratio (OR) of 2.5 (95% CI: 1.4–4.6, p = 0.003) for being symptomatic.71 Although sinus rhythm is the most common, supraventricular arrhythmias can be found in up to 20% of patients with Brugada syndrome.36 Atrial fibrillation is the most encountered atrial arrhythmia and is thought to be consequence of the electrical dysfunction in the sodium channels present at the atria. Other rhythm disorders, such as bradycardia secondary to sick sinus syndrome or atrial standstill, have also been reported in association to Brugada syndrome.72

10.6 Diagnostic Tools: Drug Challenge Given that the ECG is dynamic and thus the characteristic ECG hallmark may be concealed, drug challenge with sodium blockers, which “increase” the sodium channel dysfunction, has been proposed as a useful tool for the diagnosis of Brugada syndrome.73 Ajmaline, flecainide, procainamide, pilsicainide, disopyramide, and propafenone have been used,15 although the specific diagnostic value for all of them has not yet been systematically studied. The recommended dose regimens for the most commonly used drugs are listed in Table 10.3. The Brugada syndrome can be diagnosed if a coved-type (type-1 ECG pattern) appears after the sodium blocker administration. The pharmacological test should be monitored with a continuous ECG recording and should be terminated when: (1) the diagnostic test is positive; (2) premature ventricular beats or other arrhythmias develop; (3) QRS widens to ³ 130% of baseline.15

139 Table 10.3  Drugs used to unmask Brugada syndrome15 Drug Dosage Administration Ajmaline

1 mg/kg over 5 min

IV

Flecainide

2 mg/kg over 10 min 400 mg

IV PO

Procainamide

10 mg/kg over 10 min

IV

Pilsicainide 1 mg/kg over 10 min IV Source: Modified from Ref.15 with permission

Current data point out that ajmaline is probably the best available drug to unmask the Brugada syndrome. In a study with 147 individuals from four large families with identified SCN5A mutations, ajmaline provided a sensitivity of 80%, a specificity of 94.4%, a positive predictive value of 93.3%, and a negative predictive value of 82.9% for the diagnosis of Brugada syndrome.74 Penetrance of the disease phenotype increased from 32.7 to 78.6% with the use of the sodium-channel blocker.74 These results are considerably higher than those obtained for flecainide in another study with 110 genotyped patients, in which the sensitivity, the specificity, the positive and the negative predictive values for the diagnosis were 77, 80, 96, and 36%, respectively.75 Of note, the low negative predictive value should be taken into account when using flecainide, especially during genetic screening. In fact, Priori et al have reported from their series that, among 115 genetically affected individuals, a type-1 ECG (spontaneous or induced by flecainide) was lacking in 29 patients (25%).76 Ajmaline and flecainide were compared in a study with 22 patients with confirmed Brugada syndrome, who were submitted to both ajmaline and flecainide tests. While the test was positive in 22 of 22 patients following ajmaline administration, only 15 patients showed positive response to flecainide.77 Also, the increase of the ST-segment elevation after the test was larger with ajmaline than with flecainide (Fig.  10.5). Whole-cell patch-clamp experiments revealed that flecainide reduced Ito to a greater extent than ajmaline, thus explaining its lesser effectiveness.77 Given the limitations of genetic analysis and drug availability, new strategies have been searched to accurate the clinical diagnosis. Placement of the right precordial leads in an upper position (second or third intercostal spaces) can increase the sensitivity of the ECG for detecting the Brugada phenotype, both in the presence and the absence of a drug challenge,78,79 although whether the greater sensitivity is at the

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expense of a lower specificity is still uncertain. Recent data demonstrate that the presence of a type-1 ECG pattern recorded at higher intercostal spaces, even when the standard ECG is normal, can identify a subgroup of patients that behaves similarly in terms of prognosis to those with spontaneous type-1 ECG pattern at standard leads (Fig. 10.6).80 Therefore, the diagnosis of Brugada syndrome seems to be improved by recording at upper intercostals spaces, this strategy allowing identify a subset of patients at risk who would otherwise be underdiagnosed.

10.7 Prognosis and Risk Stratification Prognosis and risk stratification are probably the most controversial issues in Brugada syndrome. The main clinical studies arising from the largest databases differ on the risk of SD or VF in the population with

ajmaline (ajm) and flecainide (flec) administration. (c) Example of greater ST-segment elevation in the same patient with ajmaline than with flecainide (modified from Ref.77 with permission)

1.0

Free of cardiac event

Fig.  10.5  Ajmaline versus flecainide in the diagnosis of Brugada syndrome. (a) Flecainide failed in 7 of 22 cases (32%) which were unmasked by ajmaline. (b) Change in maximal ST-segment elevation before (pre) and after (post) intravenous

B. Benito et al.

0.8 0.6 n=68 0.4

Spontaneous type-1 (std ECG)

n=19 Spontaneous type-1 (2 /3 ICS) nd

0.2

rd

n=11 Type-1 after Na-blocker (std or 2 /3 ICS) nd

rd

0 0

400

800

1200

1600

Follow-up (days)

Fig. 10.6  Kaplan-Meier analysis of cardiac events (documented ventricular fibrillation or sudden death) during follow-up in patients with spontaneous type-1 ECG pattern at standard leads (dashed line), patients with spontaneous type-1 ECG recorded only at a higher intercostals space (solid line), and patients with type-1 ECG pattern at standard and/or higher intercostals spaces after receiving a sodium-channel blocker (dotted line). No significant difference was observed in the frequency of cardiac events between the two first groups (modified from Ref.80 with permission)

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Brugada syndrome, and particularly on defining the specific risk markers with regard to prognosis. In our most updated population with Brugada syndrome coming from the international registry, the percentage of patients who experienced SD or VF throughout lifetime was 25% (178 out of 724 patients). The mean age at cardiac events was 42 ± 15 years. Of course, such a high rate might have been influenced by a baseline high-risk population referred for the international registry and included in this analysis. In fact, our reported annual rate of events has decreased from the first patients included in the registry5 to the most recent published series,32,34,81 the change probably reflecting the inherent bias during the first years following the description of a novel disease, in which particularly severe forms of the disease are most likely to be diagnosed. It is important to note that, in the global series, the probability of having a cardiac event during lifetime varied widely (from 3 to 45%) depending on the baseline characteristics of the individuals. Thus, a careful risk stratification of every individual seems mandatory. Several clinical variables have been demonstrated to predict a worse outcome in patients with Brugada syndrome. In all the analysis of our series over time, the presence of symptoms before diagnosis, a spontaneous type-1 ECG at baseline, the inducibility of ventricular arrhythmias at the electrophysiological study (EPS), and male gender have consistently shown to be related to the occurrence of cardiac events in follow-up.5,32,34,45,81 Little controversy exists on the value of a previous cardiac arrest as a risk marker for future events. Our data state that up to 62% of patients recovered from an aborted SD are at risk of a new arrhythmic event within the following 54 months.32 Thus, these patients should be protected with an ICD irrespective to the presence of other risk factors (indication class I).15 Because there is not such a general agreement on the best approach toward patients who have never developed ventricular fibrillation, we conducted a prospective study including 547 individuals with Brugada syndrome and no previous cardiac arrest.34 Of them (mean age: 41 ± 45 years, 408 males), 124 had presented syncope (22.7%) and 423 (77.3%) were asymptomatic and had been diagnosed during routine ECG or family screening. The baseline ECG showed a type-1 ECG pattern spontaneously in 391 patients (71.5%), and after sodium-blocker challenge in 156 (28.5%). During

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a mean follow-up of 24 ± 32 months, 45 individuals (8.2%) developed a first cardiac event (documented VF or SD).34 By univariable analysis, a previous history of syncope (HR: 2.79 [1.5–5.1] 95% CI, p = 0.002), a spontaneous type-1 ECG (HR: 7.69 [1.9–33.3] 95% CI, p = 0.0001), male gender (HR: 5.26 [1.6–16.6] 95% CI, p = 0.001) and inducibility of ventricular arrhythmias at the EPS (HR: 8.33 [2.8–25] 95% CI, p = 0.0001) were significantly related to VF or SD in follow-up. Multivariable analysis identified previous syncope and inducibility of VF as the only independent risk factors for the occurrence of events in followup (Fig. 10.7a).34 Logistic regression analysis allowed define eight categories of risk, of which asymptomatic patients with normal ECG at baseline and noninducible VF at the EPS would represent the lowest-risk population and patients with syncope, spontaneous type-1 ECG, and inducibility at EPS would have the worst outcome (Fig. 10.7b). Further analysis indicated that EPS was particularly useful in predicting cardiac events among asymptomatic patients with no family history of SD (named fortuitous cases, n = 167).81 Indeed, 11 out of 167 patients (6%) presented VF during follow-up, and the only independent predictor was inducibility at EPS, while the lack of an EPS showed to be predictive of effective SD (p = 0.002).81 Other groups agree that previous symptoms and a spontaneous type-1 ECG are risk factors, although they have found a much lower incidence of arrhythmic events for the whole population (6.5% in 34 ± 44 months of follow-up in Priori’s work and 4.2% in 40 ± 50 months of follow-up in Eckardt’s).33,35 The worst outcome in our series may probably reflect a more severely ill baseline population.35 The other large registries also agree that EPS inducibility is greatest among patients with previous SD or syncope,33,35 but failed to demonstrate a value of the EPS in predicting outcome. Several reasons could explain this discrepancy81: (1) the use of multiple testing centers with nonstandardized stimulation protocols; (2) the inclusion of patients with type-2 and type-3 ST-segment elevation (and not type-1) in some series, suggesting that they may contain individuals who do not have the syndrome; (3) the lack of events during follow-up in the other registries. The latter might change when longer follow-ups are available, since events can only increase in follow-up and so does the positive predictive value.81 Because this issue is source of ongoing controversy, we are currently performing a prospective study to

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a Symptoms

Inducibility at EPS Non-inducible

Free of cardiac events

None Free of cardiac events

Fig. 10.7  Cardiac events (sudden death or documented ventricular fibrillation) during follow-up. (a) Kaplan Meier analysis according to previous symptoms and inducibility of ventricular fibrillation in the electrophysiological study, both independent predictors in the series by Brugada et al34 (b) Estimated probability of events in follow-up by logistic regression according to symptoms, inducibility of ventricular arrhythmias at the electrophysiological study and baseline ECG (Data from Ref.34) SD: sudden death; VF: ventricular fibrillation; EPS: electrophysiological study. *Induced type-1 ECG after administration of sodium channel blockers

B. Benito et al.

Syncope

Inducible

p<0.00001

p<0.0005 0 12 24 36 48 60 72 84 96 108 120

0 12 24 36 48 60 72 84 96 108 120

Follow-up (months) Multivariable Syncope

HR

95%CI

2.51

1.2-5.3

Follow-up (months) P 0.017

Multivariable

HR

95%CI

Induciblity of VF

5.88

2.0-16.7

P 0.0001

Estimated probability (%) of cardiac events

b

35 30 25 20 15 10

Syncope AND spontaneous- 1 ECG Asymptomatic AND spontaneous- 1 ECG Syncope AND induced type- 1 ECG* Asymptomatic AND induced type- 1 ECG*

5 0 Inducible

Non inducible

determine the role of EPS in the risk stratification of Brugada syndrome. Male gender has consistently shown a trend to present more arrhythmic events in all the studies and even has been defined as an independent predictor for a worse outcome in a recent meta-analysis.46 A very recent study by our group indicates that males with Brugada syndrome display a higher risk profile than females and thus present a worse prognosis during follow-up (see gender differences).45 Multiple ECG parameters have been assessed in the search for new risk markers, of which a prolonged QTc in right precordial leads, the aVR sign, the presence of T-wave

alternans, and probably a wide QRS complex seem to be the most important (see ECG and modulating factors).64-67,71 Interestingly, a positive family history of SD or the presence of an SCN5A mutation have not been proven to be risk markers in any of the large studies conducted thus far.32-35,46 However, recent data suggest that other genetic findings might have prognostic implications. In a very recent study with 147 patients with Brugada syndrome or progressive cardiac conduction disease carrying 32 different mutations in the SCN5A gene, Meregalli et al found that those with a mutation leading to a premature stop codon (and thus a truncated protein) presented

10  Brugada Syndrome

higher rate of syncope than patients with other types of mutation (25.3% vs. 5.7%, respectively, p = 0.03).82 Nevertheless, the authors could not find differences in the rate of major arrhythmic complications according to the type of mutation.82 Our data on 188 patients (all with Brugada syndrome) carrying 69 different mutations in SCN5A demonstrate that the presence of a mutation leading to a premature stop codon is related to a greater rate of major cardiac events defined as SD or documented VF.83 Indeed, the incidence of lifethreatening episodes was 23.9% in patients with truncated protein, and 7.7% in patients with other mutations, the difference being statistically significant (p = 0.01). Moreover, in our series, the presence of a mutation leading to a truncated protein was confirmed as an independent predictor of cardiac events (HR: 2.9, 95% CI: 1.2–7.2, p = 0.02), together with the classical clinical risk factors.83 Therefore, from these data one can conclude that genetic testing could be useful in the risk stratification of patients with Brugada syndrome who are carriers of an SCN5A mutation. This finding is particularly important because, in contrast to previously defined clinical variables, genetic information is constitutional and thus invariable over time within the same individual.

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patients who have no family history of SD and who develop a type 1 ECG only after sodium blockade should be closely followed up, without enough evidence existing for the usefulness of EPS or a direct indication for ICD.15 From the two main retrospective studies conducted on patients with Brugada syndrome who have received primary prophylactic ICD, it can be concluded that ICD is an effective therapy for patients at risk,84,85 which can have an annual rate of appropriate shocks of up to 3.7%.85 It is important to note that this rate is not only comparable to the one of other ICD trials dealing with other cardiac diseases,86,87 but also is affecting young and otherwise healthy people, whose life expectancy could be more than 30 years. Therefore, should this rate remain constant in time, it seems that most patients would be likely to experience an appropriate shock in lifetime. However, perhaps just because of being young, a noteworthy rate of inappropriate shocks by the device has also been reported. In the study by Saher et al, 45 out of 220 patients (20%) had inappropriate shocks in follow-up.84 In our series, the rate was even higher (36%).85 The reasons for inappropriate therapies were mainly sinus tachycardia, supraventricular arrhythmias, T-wave oversensing, and lead failure in both studies.84,85 On the basis of these results, and because ICD is not affordable worldwide, there is growing effort to find pharmacological approaches to help treat the disease.

10.8 Treatment 10.8.1 ICD

10.8.2 Pharmacological Options

The ICD is the only proven effective treatment for the Brugada syndrome thus far. On the basis of available clinical and basic science data, a II consensus conference was held in September 2003 that focused on risk stratification schemes and approaches to therapy.15 The recommendations for ICD implantation stated by this consensus are summarized in Fig. 10.8. Briefly, symptomatic patients should always receive an ICD. EPS in these patients could be performed to better assess the sensitivity and specificity of the test to predict outcome, and also for the study of supraventricular arrhythmias. Asymptomatic patients may benefit from EPS for risk stratification: ICD should be implanted in those with inducible VF having a spontaneous type-1 ECG at baseline or a sodium-blocker induced ECG with a positive family history of SD. Finally, asymptomatic

With the aim of rebalancing the ion channel currents active during the phase 1 of the action potential, so as to reduce the magnitude of the notch, two main pharmacological approaches have been assessed (Table 10.4): • Drugs that decrease outward positive currents, as Ito inhibitors • Drugs that increase inward positive currents (ICa, INa) Quinidine, a drug with Ito- and IKr-blocking properties, has been the most assayed drug in clinical studies. In a work by Belhassen et al, 25 patients with inducible VF were treated with quinidine (1,483 ± 240 mg p.o.). After treatment, 22 out of 25 patients (88%) were no more inducible at the EPS, and none of the 19 patients with ongoing medical therapy with oral quinidine developed

144

B. Benito et al.

Brugada syndrome

Symptomatic

Aborted SD

Asymptomatic

Syncope of cardiac origin

Spontaneous type1 ECG

EPS (class IIa) Spontaneous type-1 ECG

Type-1 ECG after Nablockers

Family history of SD

Type-1 ECG after Na-blockers Inducibility of VT/VF

No inducibility

EPS (class IIb)

Inducibility of VT/VF

Close follow-up

ICD (class I)

ICD (class I)

No Family history of SD

ICD (class IIa)

ICD (class IIa)

No inducibility

Close follow-up

Close follow-up

ICD (class IIb)

Fig.  10.8  Indications for ICD implantation in patients with Brugada syndrome. Class I designation indicates clear evidence that the procedure or treatment is useful or effective; Class II, conflicting evidence about usefulness or efficacy; Class IIa,

weight of evidence in favor of usefulness or efficacy; Class IIb, usefulness or efficacy less well established (modified from Ref.15 with permission)

arrhythmias in the follow up (56 ± 67 months).88 However, 36% of the patients had transient side effects that led to drug discontinuation.88 Preliminary data have also proven quinidine as a good adjunctive therapy in patients with ICD and multiple shocks,89 and as an effective treatment of electrical storms associated to Brugada syndrome.90 More recently, quinidine has been proposed as a good alternative to ICD implantation in child patients with the syndrome and at high risk for malignant arrhtyhmias.52 However, large, randomized, controlled clinical trials assessing the effectiveness of quinidine (which should be addressed in patients who have already received an ICD) are still lacking.

B-adrenergic agents, through an increase in ICa currents, decrease TDR and EDR in experimental models.13 Clinically they have proven effectiveness in the treatment of electrical storms associated to Brugada syndrome.91 Recently, phosphodiesterase III inhibitors have appeared as a new appealing option, since they would increase ICa and decrease Ito. Indeed, cilostazol was effective in preventing ICD shocks in a patient with recurrent episodes of VF.92 However, a recent publication reports the failure of such drug in another patient with multiple ICD discharges despite sustained therapy.93 Dimethyl lithospermate B (dmLSB), an extract of Danshen, a traditional Chinese herbal remedy which

10  Brugada Syndrome

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Table 10.4  Pharmacological approach to therapy in the Brugada syndrome Action Proved on Ito blockers: – 4-Aminopyridine

Effective in experimental models (suppression of phase-2 re-entry)13 Probable neurotoxicity in humans

– Quinidine

Effective in experimental models (suppression of phase-2 re-entry)13 Initial results showing effectiveness in clinical practice: – ¯ Inducibility of VF88 – ¯ Spontaneous VF in follow-up88,89 – Adjunctive therapy in patients with ICD and multiple shocks89 – Effective in electrical storm90 – A possible option in children52

– Tedisamil

Effective in experimental models (suppression of phase-2 re-entry)

– AVE0118

Effective in experimental models (suppression of phase-2 re-entry)

ICa activators: – Isoproterenol (b-adrenergic agents)

Effective in experimental models (suppression of phase-2 re-entry)13 Effective in electrical storm91

– Cilostazol (phosphodiesterase III inhibitor)

Controversial preliminary results in preventing VF92,93

INa openers: – Dimethyl lithospermate B (dmLSB)

Effective in experimental models (suppression of phase-2 re-entry)94

slows inactivation of INa, has recently been assayed in experimental models, demonstrating a reduction of both EDR and TDR, and abolishing phase 2 re-­entry-induced extrasystoles and VT/VF in nine out of nine preparations. Clinical data with this agent are, however, not yet available, but the results of experimental studies suggest that this agent could be a new candidate for the pharmacological treatment of Brugada syndrome.94

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B. Benito et al. short QT intervals, and sudden cardiac death. Circulation. 2007;115(4):442–449 29. Delpon E, Cordeiro JM, Nunez L, et al Functional effects of KCNE3 mutation and its role in the development of Brugada syndrome. Circ Arrhythm Electrophysiol. 2008;1(3): 209–218 30. Viswanathan PC, Benson DW, Balser JR. A common SCN5A polymorphism modulates the biophysical effects of an SCN5A mutation. J Clin Invest. 2003;111(3):341–346 31. Poelzing S, Forleo C, Samodell M, et al SCN5A polymorphism restores trafficking of a Brugada syndrome mutation on a separate gene. Circulation. 2006;114(5):368–376 32. Brugada J, Brugada R, Antzelevitch C, Towbin J, Nademanee K, Brugada P. long-term follow-up of individuals with the electrocardiographic pattern of right bundle-branch block and ST-segment elevation in precordial leads V1 to V3. Circulation. 2002;105(1):73–78 33. Priori SG, Napolitano C, Gasparini M, et al Natural history of Brugada syndrome: insights for risk stratification and management. Circulation. 2002;105(11):1342–1347 34. Brugada J, Brugada R, Brugada P. Determinants of sudden cardiac death in individuals with the electrocardiographic pattern of Brugada syndrome and no previous cardiac arrest. Circulation. 2003;108(25):3092–3096 35. Eckardt L, Probst V, Smits JPP, et al Long-term prognosis of individuals with right precordial ST-segment-elevation Brugada syndrome. Circulation. 2005;111(3):257–263 36. Eckardt L, Kirchhof P, Loh P, et al Brugada syndrome and supraventricular tachyarrhythmias: a novel association? J Cardiovasc Electrophysiol. 2001;12(6):680–685 37. Morita H, Kusano-Fukushima K, Nagase S, et  al Atrial fibrillation and atrial vulnerability in patients with Brugada syndrome. J Am Coll Cardiol. 2002;40(8):1437–1444 38. Benito B, Brugada J. Recurrent syncope: an unusual presentation of Brugada syndrome. Nat Clin Pract Cardiovasc Med. 2006;3(10):573–577 39. Makita N, Sumitomo N, Watanabe I, Tsutsui H. Novel SCN5A mutation (Q55X) associated with age-dependent expression of Brugada syndrome presenting as neurally mediated syncope. Heart Rhythm. 2007;4(4):516–519 40. Matsuo K, Kurita T, Inagaki M, et al The circadian pattern of the development of ventricular fibrillation in patients with Brugada syndrome. Eur Heart J. 1999;20(6):465–470 41. Takigawa M, Noda T, Shimizu W, et al Seasonal and circadian distributions of ventricular fibrillation in patients with Brugada syndrome. Heart Rhythm. 2008;5(11):1523–1527 42. Wichter T, Matheja P, Eckardt L, et  al Cardiac autonomic dysfunction in Brugada syndrome. Circulation. 2002;105(6): 702–706 43. Kies P, Wichter T, Schafers M, et al Abnormal myocardial presynaptic norepinephrine recycling in patients with Brugada syndrome. Circulation. 2004;110(19):3017–3022 44. Eckardt L. Gender differences in Brugada syndrome. J Cardiovasc Electrophysiol. 2007;18(4):422–424 45. Benito B, Sarkozy A, Mont L, et  al Gender differences in clinical manifestations of Brugada syndrome. J Am Coll Cardiol. 2008;52(19):1567–1573 46. Gehi A, Duong T, Metz L, Gomes J, Mehta D. Risk stratification of individuals with the Brugada electrocardiogram: a meta-analysis. J Cardiovasc Electrophysiol. 2006;17(6): 577–583

10  Brugada Syndrome 47. Di Diego JM, Cordeiro JM, Goodrow RJ, et al Ionic and cellular basis for the predominance of the Brugada syndrome phenotype in males. Circulation. 2002;106(15):2004–2011 48. Matsuo K, Akahoshi M, Seto S, Yan K. Disappearance of the Brugada-type electrocardiogram after surgical castration: a role for testosterone and an explanation for the male preponderance. Pacing Clin Electrophysiol. 2003;26: 1551–1553 49. Shimizu W, Matsuo K, Kokubo Y, et al Sex hormone and gender difference-role of testosterone on male predominance in Brugada syndrome. J Cardiovasc Electrophysiol. 2007;18(4): 415–421 50. Bai CX, Kurokawa J, Tamagawa M, Nakaya H, Furukawa T. Nontranscriptional regulation of cardiac repolarization currents by testosterone. Circulation. 2005;112(12):1701–1710 51. Song M, Helguera G, Eghbali M, Zhu N, Zarei MM, Olcese R, Toro L, Stefani E. Remodeling of Kv4.3 potassium channel gene expression under the control of sex hormones. J Biol Chem. 2001;276(34):31883–31890 52. Probst V, Denjoy I, MeregalIi PG, et al Clinical aspects and prognosis of Brugada syndrome in children. Circulation. 2007;115(15):2042–2048 53. Benito B, Sarkozy A, Berne P et al [Características clínicas y pronóstico del síndrome de Brugada en la población pediátrica]. Rev Esp Cardiol 2007; 60[Suppl 2]:70. Ref Type: Abstract 54. Veltmann C, Schimpf R, Echternach C, et al A prospective study on spontaneous fluctuations between diagnostic and non-diagnostic ECGs in Brugada syndrome: implications for correct phenotyping and risk stratification. Eur Heart J. 2006;27(21):2544–2552 55. Wilde AA. Spontaneous electrocardiographic fluctuations in Brugada syndrome: does it matter? Eur Heart J. 2006;27(21):2493–2494 56. Miyazaki T, Mitamura H, Miyoshi S, Soejima K, Aizawa Y, Ogawa S. Autonomic and antiarrhythmic drug modulation of ST segment elevation in patients with Brugada syndrome. J Am Coll Cardiol. 1996;27(5):1061–1070 57. Mizumaki K, Fujiki A, Tsuneda T, et al Vagal activity modulates spontaneous augmentation of ST elevation in the daily life of patients with Brugada syndrome. J Cardiovasc Electrophysiol. 2004;15(6):667–673 58. Extramiana F, Seitz J, Maison-Blanche P, et al Quantitative assessment of ST segment elevation in Brugada patients. Heart Rhythm. 2006;3(10):1175–1181 59. Tatsumi H, Takagi M, Nakagawa E, Yamashita H, Yoshiyama M. Risk stratification in patients with Brugada syndrome: analysis of daily fluctuations in 12-lead electrocardiogram (ECG) and signal-averaged electrocardiogram (SAECG). J Cardiovasc Electrophysiol. 2006;17(7):705–711 60. Shimizu W. Gender difference and drug challenge in Brugada syndrome. J Cardiovasc Electrophysiol. 2004;15(1):70–71 61. Gonzalez Rebollo JM, Hernandez MA, Garcia A, Garcia de CA, Mejias A, Moro C. Recurrent ventricular fibrillation during a febrile illness in a patient with the Brugada syndrome. Rev Esp Cardiol. 2000;53(5):755–757 62. Porres JM, Brugada J, Urbistondo V, Garcia F, Reviejo K, Marco P. Fever unmasking the Brugada syndrome. Pacing Clin Electrophysiol. 2002;25(11):1646–1648 63. Pitzalis MV, Anaclerio M, Iacoviello M, et  al QT-interval prolongation in right precordial leads: an additional electro-

147 cardiographic hallmark of Brugada syndrome. J Am Coll Cardiol. 2003;42(9):1632–1637 64. Castro Hevia J, Antzelevitch C, Tornés Bárzaga F, et al Tpeaktend and tpeak-tend dispersion as risk factors for ventricular tachycardia/ventricular fibrillation in patients with the Brugada syndrome. J Am Coll Cardiol. 2006;47(9):1828–1834 65. Babai Bigi MA, Aslani A, Shahrzad S. aVR sign as a risk factor for life-threatening arrhythmic events in patients with Brugada syndrome. Heart Rhythm. 2007;4(8):1009–1012 66. Fish JM, Antzelevitch C. Cellular mechanism and arrhythmogenic potential of T-wave alternans in the Brugada syndrome. J Cardiovasc Electrophysiol. 2008;19(3):301–308 67. Tada T, Kusano KF, Nagase S et al. The Relationship between the magnitude of T Wave Alternans and Amplitude of the corresponding T Wave in patients with Brugada syndrome. J Cardiovasc Electrophysiol. 2008;19(1):56–61 68. Kyndt F, Probst V, Potet F, et  al Novel SCN5A mutation leading either to isolated cardiac conduction defect or Brugada syndrome in a large French family. Circulation. 2001;104(25):3081–3086 69. Smits JP, Eckardt L, Probst V, et al Genotype-phenotype relationship in Brugada syndrome: electrocardiographic features differentiate SCN5A-related patients from non-SCN5Arelated patients. J Am Coll Cardiol. 2002;40(2):350–356 70. Yokokawa M, Noda T, Okamura H, et  al Comparison of long-term follow-up of electrocardiographic features in Brugada syndrome between the SCN5A-positive probands and the SCN5A-negative probands. Am J Cardiol. 2007;100(4):649–655 71. Junttila MJ, Brugada P, Hong K et al Differences in 12-Lead Electrocardiogram between Symptomatic and Asymptomatic Brugada syndrome patients. J Cardiovasc Electrophysiol. 2007;19(4):380–3 72. Takehara N, Makita N, Kawabe J, et  al A cardiac sodium channel mutation identified in Brugada syndrome associated with atrial standstill. J Intern Med. 2004;255(1):137–142 73. Brugada R, Brugada J, Antzelevitch C, et al Sodium channel blockers identify risk for sudden death in patients with ST-segment elevation and right bundle branch block but structurally normal hearts. Circulation. 2000;101(5):510–515 74. Hong K, Brugada J, Oliva A, et  al Value of electrocardiographic parameters and Ajmaline test in the diagnosis of Brugada syndrome caused by SCN5A mutations. Circulation. 2004;110(19):3023–3027 75. Meregalli PG, Ruijter JM, Hofman N, Bezzina CR, Wilde AA, Tan HL. Diagnostic value of flecainide testing in unmasking SCN5A-related Brugada syndrome. J Cardiovasc Electrophysiol. 2006;17(8):857–864 76. Priori SG, Napolitano C. Should patients with an asymptomatic Brugada electrocardiogram undergo pharmacological and electrophysiological testing? Circulation. 2005;112(2): 279–292 77. Wolpert C, Echternach C, Veltmann C, et  al Intravenous drug challenge using flecainide and ajmaline in patients with Brugada syndrome. Heart Rhythm. 2005;2(3):254–260 78. Shimizu W, Matsuo K, Takagi M, et al Body surface distribution and response to drugs of ST segment elevation in Brugada syndrome: clinical implication of eighty-seven-lead body surface potential mapping and its application to twelvelead electrocardiograms. J Cardiovasc Electrophysiol. 2000; 11(4):396–404

148 79. Sangwatanaroj S, Prechawat S, Sunsaneewitayakul B, Sitthisook S, Tosukhowong P, Tungsanga K. New electrocardiographic leads and the procainamide test for the detection of the Brugada sign in sudden unexplained death syndrome survivors and their relatives. Eur Heart J. 2001;22(24):2290–2296 80. Miyamoto K, Yokokawa M, Tanaka K, et al Diagnostic and prognostic value of a type 1 Brugada electrocardiogram at higher (third or second) V1 to V2 recording in men with Brugada syndrome. Am J Cardiol. 2007;99(1):53–57 81. Brugada P, Brugada R, Brugada J, et al Should patients with an asymptomatic Brugada electrocardiogram undergo pharmacological and electrophysiological testing? Circulation. 2005;112(2):279–292 82. Meregalli PG, Tan HL, Probst V, et al Type of SCN5A mutation determines clinical severity and degree of conduction slowing in loss-of-function sodium channelopathies. Heart Rhythm. 2009;6(3):341–348 83. Benito B, Campuzano O, Ishac R, Iglesias A, Junttila MJ, Michaud J, Brugada J, Brugada P, Brugada R. Role of genetic testing in risk stratification of Brugada syndrome. Heart Rhythm. 2009;6(5 suppl):S102 (abstract) 84. Sacher F, Probst V, Iesaka Y, et al Outcome after implantation of a cardioverter-defibrillator in patients with Brugada syndrome: a multicenter study. Circulation. 2006;114(22): 2317–2324 85. Sarkozy A, Boussy T, Kourgiannides G, et  al Long-term follow-up of primary prophylactic implantable cardioverterdefibrillator therapy in Brugada syndrome. Eur Heart J. 2007;28(3):334–344 86. Maron BJ, Shen WK, Link MS, et al Efficacy of implantable cardioverter-defibrillators for the prevention of sudden death in patients with hypertrophic cardiomyopathy. N Engl J Med. 2000;342(6):365–373

B. Benito et al. 87. Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R, Domanski M, Troutman C, Anderson J, Johnson G, McNulty SE, Clapp-Channing N, vidson-Ray LD, Fraulo ES, Fishbein DP, Luceri RM, Ip JH. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med. 2005;352(3):225–237 88. Belhassen B, Glick A, Viskin S. Efficacy of quinidine in high-risk patients with Brugada syndrome. Circulation. 2004;110(13):1731–1737 89. Hermida JS, Denjoy I, Clerc J, et al Hydroquinidine therapy in Brugada syndrome. J Am Coll Cardiol. 2004;43(10): 1853–1860 90. Mok NS, Chan NY, Chiu AC. Successful use of quinidine in treatment of electrical storm in Brugada syndrome. Pacing Clin Electrophysiol. 2004;27(6 Pt 1):821–823 91. Ohgo T, Okamura H, Noda T, et al Acute and chronic management in patients with Brugada syndrome associated with electrical storm of ventricular fibrillation. Heart Rhythm. 2007;4(6):695–700 92. Tsuchiya T, Ashikaga K, Honda T, Arita M. Prevention of ventricular fibrillation by cilostazol, an oral phosphodiesterase inhibitor, in a patient with Brugada syndrome. J Cardiovasc Electrophysiol. 2002;13(7):698–701 93. Abud A, Bagattin D, Goyeneche R, Becker C. Failure of cilostazol in the prevention of ventricular fibrillation in a patient with Brugada syndrome. J Cardiovasc Electrophysiol. 2006;17(2):210–212 94. Fish JM, Welchons DR, Kim YS, Lee SH, Ho WK, Antzelevitch C. Dimethyl lithospermate B, an extract of Danshen, suppresses arrhythmogenesis associated with the Brugada syndrome. Circulation. 2006;113(11):1393–1400

Short QT Syndrome

11

Christian Wolpert, Christian Veltmann, Rainer Schimpf, and Martin Borggrefe

11.1 Clinical Manifestations In 2000, for the first time a short QT interval was linked to a sporadic case of sudden cardiac death and an unrelated family with paroxysmal atrial fibrillation.1,2 Three years later, a short QT interval associated with a high risk of sudden cardiac was first described in two unrelated families.3 Subsequently more and more cases have been reported, so at present more than 50 cases have been described in detail including genotype in about half of the patients.4-11 As the name indicates, SQTS is characterized by the presence of a very short QT interval on the electrocardiogram (Fig. 11.1). This is a disease with a very high malignancy, with arrhythmic events occurring very early in life. The clinical presentation is heterogeneous, with atrial fibrillation, syncope and sudden death appearing at all ages. The largest series of patients (n = 29) with a short QT syndrome has been reported by Giustetto et al.4 In this cohort genotyping was performed in all families and sporadic cases, but only in two families was a mutation in HERG found. In the remainder no mutation has been identified as of yet. In this population from the European Short QT registry the median age at diagnosis is 30 years (range 4–80). Eighteen patients (60%) were asymptomatic at the time of the diagnosis. Cardiac arrest occurred in ten patients (34%) and in eight out these ten patients it was the first clinical presentation. Syncope was the first manifestation in seven patients (24%) and atrial fibrillation was found in 31% (Fig. 11.2). In some of the families sudden cardiac

C. Wolpert Department of Medicine-Cardiology, Klinikum Ludwigsburg, Ludwigsburg, Germany e-mail: [email protected]

death has also been observed during the first year of life and thus SQTS is another potential cause of sudden infant death syndrome (SIDS).4 Hong et al reported a case of detection of irregular rhythm and fetal bradycardia in utero, which was diagnosed with short QT syndrome caused by a de novo mutation in KCNQ1.5 The first clinical presentation in another sporadic case with short QT syndrome published by Bellocq et al. was sudden cardiac arrest.6 Finally, Priori et  al. reported on a family with a mutation in KCNJ2, where syncope was documented, but none of the family members had suffered from cardiac arrest at this stage.8 Interestingly, in the first family ever presented by Gussak et al, the same mutation as in one family reported by Gaita et al was identified. However, whereas in the report from Gaita there was a high incidence of syncope and sudden death, in the family reported by Gussak atrial fibrillation was the only clinical presentation, although both the ECG measurements and electrophysiological characteristics assessed by electrophysiological study were identical in both families so that one would assume the same incidence of syncope and/or sudden death.3,7 These facts indicate the phenotype variability existing in this disease.

11.2 Clinical Diagnosis The hallmark of diagnosis is the short QT-interval on baseline ECG. The electrocardiogram of the patients diagnosed with a Short QT syndrome shows first of all an absolute QT interval which is ranging from 210 to 330 ms (Fig. 11.3). Further the QT interval does not adequately adapt to heart rate and remains constantly short. This lack of adaptation of QT interval with heart rate may be one fundamental diagnostic step in the

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Fig. 11.1  This figure depicts the baseline ECG with the chest leads of a patient with recurrent syncope and paroxysmal atrial fibrillation. One can clearly see the early offset of the T wave

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and the impressive shortening of the QT interval with high T wave amplitudes

Fig. 11.2  This figure shows a baseline electrocardiogram of a patient with short QT syndrome and atrial fibrillation

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Fig. 11.3  Chest lead ECG of a female 64-year-old patient who died suddenly. The QT-interval is approximately 220 ms (paper speed 50 mm/s)

identification of the Short QT syndrome. However, because at higher heart rates, e.g., 95 bpm a QT-interval of 300 or 290 ms will be within the normal range at rate correction, the QT interval should always be measured and corrected for heart rate at rates < 80 bpm to avoid this problem. A second finding, which is visible in at least about half the patients, is a tall, symmetrical peaking T wave in the right precordial leads.4 However, this is not seen in every patient. All ECGs have in common, that the T wave initiates immediately from the S wave. In a recently published case of a short QT syndrome caused by a mutation in KCNJ2 the T wave is asymmetrical and the QT interval is shorter than normal, but not as a short as in the patients with the mutation in KCNH2 (HERG).3,7 The association of QT prolongation and life threatening cardiac arrhythmias has been recognized for over 5 decades. The definition of QT interval prolongation has to be considered when QTc > 450 ms (Bazett’s correction) in adult men and QTc > 470 ms in adult woman. At present, there is still no clear consensus for the definition of the lower limit of the QT interval. The first patients with SQTS (Short QT 1–3) presented with corrected QT intervals < 320 ms (QTc).7,10,11,17,19 Bjerregaard and Gussak1,2 proposed, based on Rautaharju’s ECG analysis of 14,379 healthy

individuals, a short QT interval beyond two standard deviations from the mean or  < 350 ms (<88% of the mean predicted value) and an abnormally short QT interval < 320 ms (80% of the mean predicted value). The prevalence of a QT interval < 88% was 2.5% (360 individuals) and a QT interval < 80% was 0.03% (4 of 14,379 individuals) in the study by Rautarharju.12 A retrospective ECG evaluation in 10,822 healthy individuals (mean age 29 ± 10 years) by Anttonen and coworkers13 identified a prevalence of 0.1% for a QTc  < 320 ms and 0.4% for a QTc < 340 ms without an increased mortality compared to individuals with normal QTc. Another recent analysis presented by Moriya and coworkers10 examined the incidence and clinical characteristics of short QT intervals. A total of 19,153 subjects underwent biennal health examinations in the follow-up program in Hiroshima and Nagasaki since 1958. The prevalence for a short QT interval (QTc < 350 ms) was 0.01%. In summary, a short QT interval on the 12-lead ECG does not predict a risk for life threatening tachyarrhythmias per se. However, the rare finding of a short QT interval should initiate a diagnostic work-up including family members. In the case of a short QT interval together with episodes of atrial fibrillation, sustained palpitation, unexplained syncope, ventricular ­fibrillation,

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Fig. 11.4  This tracing displays the induction of ventricular fibrillation using three premature ventricular extrastimuli during programmed electrical stimulation in a patient with short QT syndrome

and/or a positive family history for premature sudden cardiac death, SQTS should be suspected.

11.3 Differential Diagnosis Documentation of a short QT interval should lead to exclusion of potential underlying conditions such as hyperkalemia, hypercalcemia, hyperthermia, acidosis and/or digitalis overdose.2,14 Additional characteristics of patients with SQTS are that QT intervals are constantly shortened and not only intermittently and that in most of the cases the T waves are tall, narrow and symmetrical in the precordial leads. A further diagnostic tool is electrophysiological study. Atrial and ventricular effective refractory periods are significantly shortened in short QT syndrome. An atrial refractory period of, e.g., 140 ms together

with a ventricular effective refractory period of 150 ms or less would further point to a short QT syndrome. A striking finding was the high inducibility of ventricular fibrillation in patients with Short QT syndrome (Fig.  11.4). However, no definite conclusion can be drawn from this limited data as to whether inducibility predicts a future risk of sudden death or conversely non-inducibility is associated with a lower risk.1,4,7

11.4 Risk Stratification Parameters Since the number of patients fully characterized is still low, we are lacking reliable data and relevant follow-up duration for a conclusive statement on risk stratification. In the families with a history of sudden death it was decided in most of the cases to implant a prophylactic ICD in the presence of a short QT interval due to

11  Short QT Syndrome

the high incidence of sudden death and syncope. The future will tell, if antiarrhythmic drugs are a proper choice and a real alternative to this approach. As stated above inducibility at programmed stimulation is high, which may be explained by the extremely short refractory periods, which cause a higher propensity to inducible VT/VF, but final conclusions can not be drawn.1-4,7 If the degree of QT-interval shortening an be used as a marker of risk is still unknown.

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effective refractory periods. However, acute administration of flecainide did cause prolongation of refractoriness, but only slight prolongation of the QT interval.16,17 Finally, Quinidine, a class IA antiarrhythmic agent, has been demonstrated to normalize the QT interval, with prolongation of the ventricular effective refractory period in patients with a gain of function mutation in HERG (KCNH2). Quinidine restored the heart rate dependence of the QT interval towards the normal range. Oral quinidine rendered ventricular tachyarrhythmias noninducible in patients in whom baseline electrophysiologic studies demonstrated reproducible induction of ventricular tachycardias/ ventricular fibrillation.17 Disopyramide has also been shown to be effective in in vitro studies of the N588KHERG mutation and in a pilot study in patients with a SQT-1 syndrome.18,19 Nonetheless, given the genetic heterogeneity of the SQTS and the different electrophysiological properties of each mutation and each affected channel, drug therapy may have very different effects depending on the type of mutation and the affected channel and further studies of pharmacologic therapy are warranted.

The ICD in symptomatic patients with SQTS is the therapy of choice, while antiarrhythmic drug therapy may represent an adjunct or an alternative therapy in children or in newborns, where ICD implantation is technically challenging and often associated with high morbidity. The risk for inappropriate ICD discharges due to T wave oversensing is increased in patients with SQTS, since intracardiac T waves are high and closely coupled to the preceding R wave (Fig. 11.5).15 To date, a variety of antiarrhythmic drugs have been tested in patients with a gain of function mutation in HERG (KCNH2).16-19 The antiarrhythmic effects of IKr blockers such as sotalol and ibutilide have been tested. Sotalol was administered orally or intravenously in three patients, but did not prolong the QT interval. The same lack of QT prolongation was documented in two patients with ibutilide, another IKr blocker. Flecainide, a Na + channel blocker which has also a blocking effect on IKr and the transient outward potassium current (Ito), leads to an increase in ventricular

Genetic screening in the first two reported families with SQTS and familial sudden cardiac death identified two  different missense mutations that resulted in the same amino acid change of the cardiac IKr channel HERG (KCNH2).7,20 Missense mutations at nucleotide 1764 in  KCNH2 substituted the asparagine at codon 588 in KCNH2 (HERG) for a positively charged lysine

Fig.  11.5  Example of T wave oversensing in a patient with a Short QT syndrome. The ventricular markers of the implantable defibrillator annotate the T wave as a ventricular sensed event

(VS). Subsequently, this fulfills the detection criterion for ventricular fibrillation and a 30-J shock is delivered (CD = capacitor discharge). Some beats after the shock T wave oversening recurs

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(N588K). The residue is located in the S5-P loop region of HERG at the outer mouth of the channel. The mutations cause a loss of the normal rectification of the current at plateau voltages, which results in a significant increase of IKr during the action potential plateau and leads to shortening of the action potential and refractoriness. Additionally, the N588K currents showed a much larger relative current at the initial phase of the action potential.20 KCNH2 is also the target of acquired forms of LQTS as a side effect of a variety of antiarrhythmic agents and of noncardiac drugs. Genetic heterogeneity in the SQTS was stressed by findings of Bellocq in 20046 who identified a mutation in a 70-yearold patient with SQTS (QTc 302 ms) and aborted sudden cardiac death. They identified a gain of function mutation in the KCNQ1 gene which encodes the slow component of the delayed rectifier potassium channel (IKs) (SQT-2). A further missense mutation in KCNQ1 (V141M) was identified in a baby with bradycardia and atrial fibrillation in utero.5 The ECG revealed a shortened QT interval and episodes of atrial fibrillation. Another mutation responsible for SQTS was identified in 2005 by Priori and coworkers8 (SQT-3). A gain of function in KCNJ2, encoding the inward rectifier potassium channel (IK1) caused shortening of the QT interval and asymmetrical T waves with a rapid terminal phase. A loss of function in the KCNJ2 gene, identified in patients with the Anderson syndrome, generates prolongation of the QT intervals (LQT-7). Recently, novel mutations of the cardiac L-type calcium channel genes responsible for shortening of the QT interval in families characterized by sudden cardiac death, atrial fibrillation and a Brugada type I ECG pattern have been reported.21 Functional analyses revealed loss of function missense mutations of the CACNA1C (A39V and G490R) and CACNB2b (S481L) genes encoding the a1- and b2b-subunits of the cardiac L-type calcium channel.

11.7 Role of Genetics in Diagnosis, Risk Stratification and Therapy

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symptoms, an asymptomatic non-carrier with a normal QT interval should not be treated. In symptomatic noncarriers other reasons for sudden death or syncope such as Brugada syndrome, etc. should be excluded. (b) Approach to genetic carrier, asymptomatic adult with the phenotype In an asymptomatic carrier with a short QT interval the decision is extremely difficult. The likelihood of sudden death in the series of patients reported so far is high and suggests a prophylactic ICD implantation. However, one of the families with SQT-1 suffered so far only from atrial fibrillation, although they display the same electrophysiological results as a family sharing the same mutation which revealed a high risk of sudden death over three generations. All of these individuals received an ICD, but did not receive any appropriate interventions yet. One can expect heterogeneous penetrance in Short QT syndrome as observed in other channelopathies and therefore it is too early for strong recommendations for drug or ICD therapy. Therapy will in these cases be decided upon an individual basis. (c) Approach to genetic carrier, non penetrant adult A non penetrant carrier has so far not been seen in the present worldwide experience. A clear recommendation cannot be given for this type of setting yet. In all individuals, in whom a mutation was identified, a QT abnormality was seen. However, it is well conceivable, that the penetrance strongly depends on the affected channel and on the type of mutation and that there will be patients with a gain-of-function and a baseline normal to almost normal QT interval but an increased risk of sudden death. (d)  Approach to genetic carrier, children In children with a documented genotype, the decision is difficult, since in a number of cases syncope or sudden death occurred in infancy and early childhood. In symptomatic children one will tend to implant an ICD, whereas in asymptomatic children with a short QT interval and symptomatic family members drug therapy will have to be balanced against an ICD depending on age.

1. Genetic positive family

2. Genotype in family still unknown, approach to

(a)  Approach to nongenetic carriers In a family with a short QT interval and a gene mutation that is pathogenetic for the QT interval and

(a)  Asymptomatic member without the phenotype In an asymptomatic individual in the setting of no identified mutation, the decision depends strongly on

11  Short QT Syndrome

the degree of QT shortening and the family history. If there is strong history of sudden death, the patients may have to be recommended an ICD or at least drug therapy.

11.8 Prevention Strategies In general all QT shortening drugs such as digitalis should be avoided. To what extent psychoactive drugs or other substances are associated with an increased risk is unknown. Similarly it is not known yet to what extent electrolyte levels can play a role in prevention or aggravation of arrhythmias. Syncope and sudden death have been reported to occur at exercise, rest and during sleep. Therefore, no definite answer can be given as to whether exercise should be generally avoided. However, it may be common sense that competitive sports should be avoided. For patients with an ICD, the recommendations for sports and professional activities apply.22

11.8.1 Clinical Case Presentation In September 2004, a 16-year-old adolescent presented after an appropriate intervention by his ICD during sleep [23]. The patient had received an ICD for primary prophylaxis in February 2003 because of a congenital short QT syndrome (QT 248 ms/QTc 252 ms). Although ventricular tachyarrhythmias could not be induced during programmed ventricular stimulation at the initial work-up, an ICD (Marquis VR 7230 with a true bipolar right ventricular lead 6943 Sprint; Medtronic Inc., Minneapolis, MN, USA) was implanted because of a strong positive family history of sudden cardiac death. The patient’s father died suddenly at age 27 years, and the patient’s grandmother died at age 61 years. Testing of the ICD revealed normal pacing and sensing parameters. Interrogation of the ICD memory yielded an electrogram strip showing a spontaneous episode of primary ventricular fibrillation. Out of a normal sinus rhythm with cycle lengths of 960 ms a single premature beat with a coupling interval of 180 ms induced the tachyarrhythmia. Eight seconds after tachyarrhythmia onset, the device delivered a 29-J shock that restored sinus rhythm. This case report

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represents the first successful prevention of sudden cardiac death in a patient with a familial short QT syndrome. The very short-coupled premature ventricular beat that induced ventricular fibrillation is consistent with the extremely short ventricular effective refractory period demonstrated in all patients studied to date (150 ms in the present patient). Furthermore, the case shows that patients with a short QT syndrome should be considered highly vulnerable to premature ventricular beats below 180 ms, to which normal hearts would be refractory. Of note, the present patient is the only one of a series of five consecutive patients who had no inducible ventricular tachyarrhythmias during programmed electrical stimulation. This finding demonstrates that noninducibility does not exclude future risk of ventricular fibrillation and thus should not be used as the only factor for risk stratification. However, this is a single observation and future studies in larger patient populations are needed to further elucidate the role of programmed ventricular stimulation in short QT syndrome.

References   1. Gussak I, Brugada P, Brugada J, et al. Idiopathic short QT interval: a new clinical syndrome? Cardiology. 2000;94: 99–102   2. Gussak I, Brugada P, Brugada J, Antzelevitch C, Osbakken M, Bjerregaard P. ECG phenomenon of idiopathic and paradoxical short QT intervals. Card Electrophysiol Rev. 2002;6(1-2): 49–53   3. Gaita F, Giustetto C, Bianchi F, et al. Short QT syndrome: a familial cause of sudden death. Circulation. 2003;108: 965–970   4. Giustetto C, Di Monte F, Wolpert C, et  al. Short QT syndrome: clinical findings and diagnostic – therapeutic implications. Eur Heart J. 2006;27:2440–2447   5. Hong K, Bjerregaard P, Gussak I, et al. Short QT syndrome and atrial fibrillation caused by mutation in KCNH2. J Cardiovasc Electrophysiol. 2005;16:394–396   6. Bellocq C, van Ginneken AC, Bezzina CR, et al. Mutation in the KCNQ1 gene leading to the short QT-interval syndrome. Circulation. 2004;109:2394–2397   7. Hong K, Piper DR, Diaz-Valdecantos A, et  al. De novo KCNQ1 mutation responsible for atrial fibrillation and short QT syndrome in utero. Cardiovasc Res. 2005;68:433–440   8. Priori SG, Pandit SV, Rivolta I, et al. A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene. Circ Res. 2005;96:800–807   9. Bjerregaard P, Gussak I. Short QT syndrome: mechanisms, diagnosis and treatment. Nat Clin Pract Cardiovasc Med. 2005;2:84–87

156 10. Moriya M, Seto S, Yano K, et  al. Two cases of short QT interval. PACE. 2007;30:1122–1526 11. Maury P, Hollington L, Duparc A, et al. Short QT syndrome: should we push the frontier forward? Heart Rhythm. 2005;2:1135–1137 12. Rautaharju PM, Zhou SH, Wong S, et al. Sex differences in the evolution of the electrocardiographic QT interval with age. Can J Cardiol. 1992;8:690–695 13. Anttonen O, Junttila MJ, Rissanen H, et al. Prevalence and prognostic significance of short QT interval in a middleaged Finnish population. Circulation. 2007;116:714–720 14. Cheng TO. Digitalis administration: an underappreciated but common cause of short QT interval. Circulation. 2004;109:e152 (author reply e152) 15. Schimpf R, Wolpert C, Bianchi F, et al. Congenital short QT syndrome and implantable cardioverter defibrillator treatment: inherent risk for inappropriate shock delivery. J Cardiovasc Electrophysiol. 2003;14:1273–1277 16. Gaita F, Giustetto C, Bianchi F, et al. Short QT syndrome: pharmacological treatment. J Am Coll Cardiol. 2004;43: 1494–1499 17. Wolpert C, Schimpf R, Giustetto C, et al. Further insights into the effect of quinidine in short QT syndrome caused by a mutation in HERG. J Cardiovasc Electrophysiol. 2005; 16:54–58 18. McPate MJ, Duncan RS, Witchel HJ, et al. Disopyramide is an effective inhibitor of mutant HERG K� channels involved

C. Wolpert et al. in variant 1 short QT syndrome. J Mol Cell Cardiol. 2006;41:563–566 19. Schimpf R, Veltmann C, Giustetto C, et al. In vivo effects of mutant HERG K(�) channel inhibition by Disopyramide in patients with a short QT-1 syndrome: a pilot study. J Cardiovasc Electrophysiol. 2007;18:1157–1160 20. Brugada R, Hong K, Dumaine R, et al. Sudden death associated with short- QT syndrome linked to mutations in HERG. Circulation. 2004;109:30–35 21. Antzelevitch C, Pollevick GD, Cordeiro JM, et al. Loss of function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. Circulation. 2005;115:442–449 22. Pelliccia A, Fagard R, Bjornstad H, et al. Recommendations for competitive sports participation in athletes with cardiovascular disease: a consensus document from the Study Group of Sports Cardiology of the Working Group of Cardiac Rehabilitation and Exercise Physiology and the Working Group of Myocardial and Pericardial Diseases of the European Society of Cardiology. Eur Heart J. 2005;26:1422–1445 23. Schimpf R, Bauersfeld U, Gaita F, et  al. Short QT syndrome: successful prevention of sudden cardiac death in an adolescent by implantable cardioverter-defibrillator treatment for primary prophylaxis. Heart Rhythm. 2005;2: 416–417

Catecholaminergic Polymorphic Ventricular Tachycardia

12

M. Juhani Junttila, Olli Anttonen, and Heikki V. Huikuri

12.1 Clinical Manifestations Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by adrenergically provoked polymorphic ventricular arrhythmias in the structurally normal heart. This disorder was first described in 1975,1 and its symptoms are usually syncopal episodes triggered by exercise or emotional stress resembling those observed in LQT syndrome.2 The etiological background for the disorder has been described to be the uncontrolled Ca2+ release from the sarcoplasmic reticulum in cardiomyocytes during electrical diastole.3 This abnormality of the Ca2+ function produces delayed afterdepolarizations and thereafter cardiac arrhythmias.4 CPVT is considered a very malignant disorder, even when compared to other arrhythmia syndromes, as it provokes symptoms in as many as 80% of the patients under the age of 40.5 The disease carries a high mortality, with 30–40% overall incidence by age 40. SCD is often the first manifestation of the disease.5-7 An estimated 30% of probands have a family history of SCD before the age of 40.8 The age of occurrence of first symptoms is usually between 7 and 9 years.6-8 Thus, the typical patient who will present to a physician is a young adult with a history of syncopal episodes since childhood, no structural cardiac abnormalities, and a normal standard 12-lead ECG. In addition, most CPVT patients also present supraventricular arrhythmias, which may range from isolated ectopic beats to atrial

M. J. Junttila (*) Department of Medicine, Institute of Clinical Medicine, University of Oulu, P.O.Box 5000, 90014, Oulu, Finland e-mail: [email protected]

fibrillation, usually during exercise.7-9 It is noted that supraventricular arrhythmias can also act as a trigger for ventricular arrhythmias in some cases.4

12.2 Clinical Diagnosis Echocardiography, MRI, or coronary angiography does not usually reveal any cardiac structural abnormalities among CPVT patients. The disorder does not carry any characteristic ECG marker that can be detected from baseline ECG. Some studies have described lower resting heart rates or prominent U waves, but these findings are not presented in the majority of CPVT patients and thus are not sufficient diagnostic tools for this disorder.6,7 The clinical diagnosis of the CPVT can only be made from exercise ECG or Holter recording during emotional stress. Flow chart of diagnostic examinations is presented in Fig. 12.1. The most common finding in exercise ECG is the growing amount of polymorphic PVCs, which appear with exercise and the occurrence of bidirectional VT episodes (Fig. 12.2). The CPVT characteristic VT can be differentiated from torsades de pointes by the axis of the arrhythmia. In torsades, the QRS axis turns gradually and chaotically, but in CPVT bidirectional VT, the beat to beat axis rotates 180° every time. During the exercise ECG, the findings appear and diminish gradually with the level of exercise.5 In some cases, where exercise ECG is not applicable, isoproterenol infusion can be used. The lack of scientific evidence in borderline exercise ECG findings such as few polymorphic PVCs evokes a dilemma in CPVT diagnosis. So far, only definite bidirectional polymorphic VT in exercise ECG, Holter monitoring, or isoproterenol infusion with family or

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Fig. 12.1  Clinical examinations in CPVT diagnosis. CPVT: catecholaminergic polymorphic ventricular tachycardia; MRI magnetic resonance imaging; VT ventricular tachycardia

Exercise induced syncope

Echocardiogram/MRI Exercise ECG (or isoproterenol challenge) (Coronary angiography)

No abnormalities

Arrhythmias in exercise ECG

Structural abnormalities

No arrhythmias in exercise ECG

Primarily not CPVT

Monomorphic or polymorphic PVCs

Bidirectional VT

CPVT

Holter recording (emotional stress)

Bidirectional VT

PVCs or no arrhythmias during emotional stress

CPVT

Not CPVT

personal history of syncope during exercise or emotional stress can be considered diagnostic for CPVT.

12.3 Differential Diagnosis The key feature in differential diagnostic examinations is the cardiac structure in a patient presenting with syncopal episodes. All patients should undergo echocardiography (or cardiac MRI), exercise ECG, and, in some cases,

coronary angiography to rule out structural abnormalities. Subsequently, in the differential diagnosis of CPVT all possibilities of primary cardiac electrical diseases should be explored. With standard 12-lead ECG or with drug challenge ECG, Brugada syndrome and long QT syndrome can be detected in most cases. In Brugada syndrome, the occurrence of arrhythmias has not been connected to exercise but, on the contrary, to vagotonic states.10 On the other hand, some LQT patients might have borderline QT prolongation, and the clinical presentation of the disease could be quite

12  Catecholaminergic Polymorphic Ventricular Tachycardia

159

Fig. 12.2  Exercise ECG presentation of bidirectional ventricular tachycardia. Leads V3–V5 are presented. During the exercise ECG load level 80 W patient began to have polymorphic extra

systoles and in the load level 120 W she had a run of typical bidirectional VT presented in the figure

similar to that of CPVT with the exercise-induced arrhythmias, but then, the exercise ECG presentation is fundamentally different.11 Some difficulties can arise with ARVD in CPVT diagnosis. Some patients with ARVD present arrhythmias in exercise and the structural abnormalities in the disorder may be very minimal in the early phases of the disease. The exercise ECG finding can differentiate patients with CPVT from ARVD, but only the identification of ARVD typical features during follow-up will make the ARVD diagnosis definite. One elusive differential diagnosis for CPVT is the Andersen-Tawil syndrome (ATS)/LQT7 where bidirectional VT has also been described.12 Nevertheless, there are several differences in the phenotype of the diseases. In ATS, periodical paralysis and facial dysmorphism should be evident and the bidirectional VT in ATS is presented with much slower rate than in CPVT. Furthermore, SCD among ATS patients is very rare.

malignant disorder, as mentioned previously, thus making the diagnosis of CPVT in young patients with syncope critical for management.

12.4 Risk Stratification Risk stratification studies in CPVT have not been successful since no clinical or genetic methods for risk assessment have been described. Electrophysiological studies have also proven incapable of yielding further information on SCD risk.7-9 Even so, CPVT is a very

12.5 Therapeutic Approach to the Disease The first-line treatment for CPVT is beta-blocker therapy, similar to LQT syndrome.13 Beta-blockers decrease and depress the adrenergic tone and thus reduce the occurrence of exercise and emotion-related arrhythmias. Although, in theory, the concept of betablockade fits perfectly with the pathogenesis of this syndrome, the efficacy of the treatment appears to be less than anticipated. Two major studies have addressed the use of ICD therapy. In one the incidence of SCD was 10%7 and in the other study 30% of the patients required ICD therapy despite antiadrenergic medication.8 In the latter, 50% of the patients received appropriate shocks from the device during a 2-year follow-up.8 Nonetheless, it is recommended that all patients with ICD should be treated also with full dose beta-blocker medication as patients may die suddenly in case of an electric storm despite the presence of an ICD.5 Control exercise ECG and Holter monitoring are advisable to obtain maximal beta-blockade dosage. Present-day pharmacological treatment such as

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amiodarone and sodium-channel blockers have been studied in CPVT patients, but the treatment proved insufficient.7,9 One study has also presented cardiac sympathetic denervation as a relevant possibility in CPVT patients’ treatment.14

12.5.1 Molecular Genetics The genetic background for the disease was described first by a Finnish research group when they identified the locus for CPVT to 1q42-q43.15 Subsequently in 2001, the Finnish group and an Italian group simultaneously discovered the first mutations in RyR2 gene.2,16 Major advances in diagnosis and pathogenesis have been made after the genetic background was revealed. After the discovery of the RyR2 mutation in CPVT, mutations in CASQ2 were discovered in the recessive form of CPVT.17 The ryanodine receptor gene mutations have been associated with the autosomal dominant form. The RyR2 gene mutations in CPVT result in abnormal function of ryanodine receptor in the sarcoplasmic reticulum of the cardiac myocytes.3 Ryanodine receptor usually functions in the early part of phase 2 of the action potential and initiate Ca2+ outflow to the intracellular cavity from the sarcoplasmic reticulum. In mutant ryanodine receptors, this Ca2+ flow or leak to the intracellular space after refractory period of the action potential trigger delayed afterdepolarizations and cause cardiac arrhythmias.4

12.6 Role of Genetics in Diagnosis, Risk Stratification, and Therapy The use of molecular genetic testing in CPVT is important with respect to preventive therapy in asymptomatic carrier family members. It has been described that approximately 50–55% of CPVT patients carry RyR2 mutations.18 Diagnostic screening of RyR2 gene is available despite the sheer magnitude of the gene itself, with over 100 exons. There are as well several research laboratories that focus on CPVT and collect patients for sequencing of RyR2. Targeted sequencing of approximately one-fourth of the exons of RyR2 is presently performed, but there is only 40% accuracy

M. J. Junttila et al.

with this method.19 We recommend that subjects with exercise-induced ventricular arrhythmias with family history of SCD or syncope without underlying factors should be screened for RyR2 mutations if possible, and also, sporadic subjects with exercise or emotionrelated VT should undergo RyR2 screening. Family members of a proband with CPVT and RyR2 mutation should be screened for RyR2 mutations for early detection of the possible subclinical disease. If the RyR2 screening is not available or if the RyR2 screening is negative, family members of a CPVT proband should at least be clinically examined with exercise ECG and treated as if they had CPVT when presented with typical findings of the disorder. This would be done solely on the basis of clinical findings of CPVT since these patients without RyR2 mutations might have mutations in other genes so far unknown to cause CPVT. To date, risk stratification or guidance for treatment by genetic testing has not been described. Nevertheless, family members of CPVT patients who carry a RyR2 mutation should also be treated with beta-blockers even though the disorder is subclinical. In the recessive form of CPVT CASQ2 gene screening would be advisable. Flow chart of genetic testing in CPVT is presented in Fig. 12.3.

12.7 Prevention Strategies Since in CPVT symptoms are connected with physical exercise or emotional stress, patients with the disease should avoid these triggering situations. Therefore, CPVT patients cannot perform competitive exercise. Additionally, all substances that increase sympathetic tone, e.g., drugs, medication, caffeine, should be avoided. Also, patients in whom emotional trigger is prominent should refrain from high-stress occupations and activities.

12.8 Controversial Issues in Clinical Diagnosis and Management Although the diagnosis and treatment in CPVT is very straightforward, some controversial issues remain to be solved. One issue lies in the diagnostic decision making of asymptomatic subjects with family history

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Fig. 12.3  Treatment of family members and genetic testing in CPVT. CPVT: catecho­ laminergic polymorphic ventricular tachycardia; ICD: implantable cardioverter defibrillator

CPVT patient

Genetic screening

Negative RyR2 or screening not available

Positive RyR2

RyR2 screening of family members

Negative family members

Clinical examination Exercise ECG of family members

Clinical examination Exercise ECG of family members

If evidence of recessive inheritance CASQ2 screening

Positive family members

Not CPVT

Asymptomatic and normal exercise ECG

Beta-blocker medication

of CPVT and few polymorphic PVCs in the exercise ECG without diagnostic polymorphic VT. In these subjects, beta-blockade is a possibility even though diagnosis of CPVT cannot be made. More scientific evidence in this issue is needed. In another situation wherein a subject with syncope has polymorphic PVCs during exercise without family history of CPVT, in our opinion, the diagnosis of CPVT cannot be made, and medication should not be initiated because polymorphic PVCs in exercise ECG can also occur among healthy subjects without CPVT. Second issue lies in treatment of verified CPVT patients. Discordant scientific evidence on effectiveness of beta-blockers in CPVT has been described.6-9 In our opinion ICD therapy in this very malignant disease is often warranted until further evidence on betablocker efficacy is presented. One interesting treatment

Asymptomatic or symptomatic and bidirectional VT in Holter or exercise ECG

Asymptomatic normal exercise ECG and normal Holter

Beta-blocker medication and ICD

Not CPVT

option in this respect is the cardiac sympathetic denervation which has been suggested to be effective in CPVT patients.

References   1. Reid DS, Tynan M, Braidwood L, Fitzgerald GR. Bidirectional tachycardia in a child. A study using his bundle electrography. Br Heart J. 1975;37:339–344   2. Priori SG, Napolitano C, Tiso N, et al. Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation. 2001; 103:196–200   3. Jiang D, Xiao B, Yang D, et al. RyR2 mutations linked to ventricular tachycardia and sudden death reduce the threshold for store-overload-induced Ca2+ release (SOICR). Proc Natl Acad Sci USA. 2004;101:13062–13067

162   4. Liu N, Colombi B, Memmi M, et al. Arrhythmogenesis in catecholaminergic polymorphic ventricular tachycardia: insights from a RyR2 R4496C knock-in mouse model. Circ Res. 2006;99:292–298   5. Mohamed U, Napolitano C, Priori SG. Molecular and electrophysiological bases of catecholaminergic polymorphic ventricular tachycardia. J Cardiovasc Electrophysiol. 2007; 18:791–797   6. Postma AV, Denjoy I, Kamblock J, et al. Catecholaminergic polymorphic ventricular tachycardia: RYR2 mutations, bradycardia, and follow up of the patients. J Med Genet. 2005; 42:863–870   7. Leenhardt A, Lucet V, Denjoy I, Grau F, Ngoc DD, Coumel P. Catecholaminergic polymorphic ventricular tachycardia in children. A 7-year follow-up of 21 patients. Circulation. 1995;91:1512–1519   8. Priori SG, Napolitano C, Memmi M, et al. Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia. Circulation. 2002; 106:69–74   9. Sumitomo N, Harada K, Nagashima M, et  al. Catecho­ laminergic polymorphic ventricular tachycardia: electrocardiographic characteristics and optimal therapeutic strategies to prevent sudden death. Heart. 2003;89:66–70 10. Antzelevitch C, Brugada P, Borggrefe M, et al. Brugada syndrome: report of the second consensus conference: endorsed by the heart rhythm society and the European Heart Rhythm Association. Circulation. 2005;111:659–670 11. Zareba W, Moss AJ, Schwartz PJ, et al. Influence of genotype on the clinical course of the long-QT syndrome. International long-QT syndrome registry research group. N Engl J Med. 1998;339:960–965

M. J. Junttila et al. 12. Andersen ED, Krasilnikoff PA, Overvad H. Intermittent muscular weakness, extrasystoles, and multiple developmental anomalies. A new syndrome? Acta Paediatr Scand. 1971;60:559–564 13. Sen-Chowdhry S, McKenna WJ. Sudden cardiac death in the young: a strategy for prevention by targeted evaluation. Cardiology. 2006;105:196–206 14. Wilde AA, Bhuiyan ZA, Crotti L, et al. Left cardiac sympathetic denervation for catecholaminergic polymorphic ventricular tachycardia. N Engl J Med. 2008;358:2024–2029 15. Swan H, Piippo K, Viitasalo M, et al. Arrhythmic disorder mapped to chromosome 1q42–q43 causes malignant polymorphic ventricular tachycardia in structurally normal hearts. J Am Coll Cardiol. 1999;34:2035–2042 16. Laitinen PJ, Brown KM, Piippo K, et al. Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia. Circulation. 2001;103:485–490 17. Lahat H, Pras E, Olender T, et al. A missense mutation in a highly conserved region of CASQ2 is associated with autosomal recessive catecholamine-induced polymorphic ventricular tachycardia in bedouin families from Israel. Am J Hum Genet. 2001;69:1378–1384 18. Priori SG, Napolitano C. Cardiac and skeletal muscle disorders caused by mutations in the intracellular Ca2+ release channels. J Clin Invest. 2005;115:2033–2038 19. Tester DJ, Spoon DB, Valdivia HH, Makielski JC, Ackerman MJ. Targeted mutational analysis of the RyR2-encoded cardiac ryanodine receptor in sudden unexplained death: a molecular autopsy of 49 medical examiner/coroner’s cases. Mayo Clin Proc. 2004;79:1380–1384

Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia

13

Michela Bevilacqua, Federico Migliore, Cristina Basso, Gaetano Thiene, and Domenico Corrado

13.1 Introduction

13.2 Clinical Presentation

Arrhythmogenic right ventricular cardiomyopathy/ dysplasia (ARVC/D) is a genetically determined heart muscle disease that predominantly affects the right ventricle (RV).1-4 It is characterized pathologically by myocardial atrophy and fibrofatty replacement of the right ventricular myocardium, and clinically by right ventricular electrical instability, leading to ventricular tachycardia (VT) or ventricular fibrillation (VF), which may precipitate sudden cardiac arrest mostly in young people and athletes.1-6 Later, in the natural history, the RV may become more diffusely involved and the left ventricle progressively affected with subsequent biventricular heart failure.4,5 The condition was initially believed to be a developmental defect of the RV myocardium, leading to the original designation of “dysplasia.” This concept has evolved over the last 25 years into the current perspective of a genetically determined “cardiomyopathy.”7 The advent of the molecular genetic era in ARVC/D has provided new insights in understanding pathophysiology of ARVC/D, showing that it is a desmosomal disease resulting from defective cell adhesion proteins such as plakoglobin, desmoplakin, and plakophilin-2.8 This chapter addresses clinical presentation, diagnosis, and management strategies in patients with ARVC/D, with particular reference to most recent insights on genetics and therapy with implantable defibrillator (ICD) for prevention of sudden death.

A familial incidence is present in more than half the ARVC/D cases. The disease affects men more frequently than women (in a ratio of 3:1), and becomes clinically overt most often in the third or fourth decade of age.5 The most common clinical manifestations consist of ventricular arrhythmias with left bundle branch block morphology, ECG depolarization/repolarization changes mostly localized to right precordial leads, and global and/or regional dysfunction and structural alterations of the RV.1-5 The clinical phenotype varies considerably ranging from healthy gene carriers or asymptomatic family members with concealed RV structural abnormalities and no arrhythmias to patients experiencing arrhythmic cardiac arrest or undergoing cardiac transplantation due to right or biventricular heart failure.1,4 Ventricular arrhythmias in the form of frequent premature ventricular beats, short runs of VT, or sustained monomorphic VT with a left bundle branch block morphology dominate the clinical scenario of the “overt arrhythmic form” of ARVC/D. Associated symptoms include palpitations, syncopal episodes (mostly occurring during physical exercise), and arrhythmic cardiac arrest due to rapid VT which may degenerate into VF. ECG abnormalities consist of T wave inversion and localized prolongation of QRS interval (³110 ms) in the precordial leads exploring the RV (V1–V3), rarely associated with epsilon waves. The spectrum of RV alterations ranges from global RV dilatation/dysfunction to regional wall motion abnormalities and/or bulgings typically localized in the “triangle of dysplasia,” namely subtricuspidal, apical, and infundibular regions; the left ventricle and the septum may be involved usually to a lesser extent. These structural abnormalities can be

D. Corrado (*) Professor of Cardiovascular Medicine, Department of Cardiac, Thoracic and Vascular Sciences, University of Padua Medical School, Via Giustiniani, 2 35121Padua, Italy e-mail: [email protected]

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detected by imaging techniques such as echocardiography,9 cardiac magnetic resonance,10 and angiography.11 Several cases of ARVC/D are not recognized because either the subtle clinical features are difficult to diagnose by conventional testings or patients are asymptomatic until first presentation with sudden death. In patients with “concealed form” of ARVC/D, the ECG may be normal or show not specific repolarization changes, along with only regional RV wall ipo-akinesia without cavity enlargement. Therefore, differential diagnosis with idiopathic VT or VF by means of conventional clinical testings is often not feasible, and ultimate diagnosis may depend on demonstration of fibrofatty replacement of the RV myocardium by endomyocardial biopsy,12 RV delayed enhancement by contrast enhanced-magnetic resonance,13 or electroanatomic scar by endocardial voltage mapping.14 Sudden death may be the first and definitive clinical manifestation of ARVC/D, mostly in young people. In this regard, a prospective clinicopathologic investigation in the Veneto Region of Italy showed that nearly 20% of fatal events in young people and athletes were due to previously undiagnosed ARVC/D.2 In patients with known ARVC/D, “RV or biventricular heart failure” may be the end stage of the disease course as a result of progressive worsening of RV muscle disease and left ventricular involvement that provoke global RV or biventricular dysfunction. At this stage, ARVC mimics dilated cardiomyopathy of other causes leading to congestive heart failure and related complications such as atrial fibrillation and thromboembolic events.4 On the other hand, there are some cases in whom the diagnosis of ARVC/D is not recognized at onset of symptoms but who present years later with congestive heart failure with or without ventricular arrhythmias and are wrongly diagnosed as having idiopathic dilated cardiomyopathy. Finally, clinical presentation of ARVC/D may mimic “acute myocarditis,” characterized by chest pain, transient ST segment and T wave changes, and increased muscle enzyme levels, with or without ventricular arrhythmias.

13.3 Clinical Diagnosis 13.3.1 Task Force Diagnostic Criteria Standardized diagnostic criteria have been proposed by an International Task Force of the European Society

M. Bevilacqua et al.

of Cardiology and the International Society and Federation of Cardiology.15,16 The purpose of the Task Force was to provide diagnostic guidelines helping to overcome several problems with specificity of the ECG abnormalities, different potential etiologies of ventricular arrhythmias with a left bundle branch morphology, assessment of the RV structure and function, and interpretation of endomyocardial biopsy findings. The strategy consists in achieving clinical diagnosis by combining multiple sources of diagnostic information, such as genetic, electrocardiographic, arrhythmic, morphofunctional, and histopathologic findings (Table 13.1). Diagnosis of ARVC/D would be fulfilled in the presence of two major criteria or one major plus two minor or four minor criteria from different groups. Although diagnostic accuracy of Task Force criteria remains to be assessed by prospective studies on large patient population, they have represented over the last 15 years a useful guide in clinical practice and are currently used for ARVC/D diagnosis. Criteria were initially designed to guarantee an adequate specificity for ARVC/D among index cases with overt clinical manifestations.15,16 Task Force guidelines have actually helped cardiologists to avoid misdiagnosis of ARVC/D in patients with dilated cardiomyopathy or idiopathic right ventricular outflow tract tachycardia. However, diagnostic criteria have shown to lack sensitivity for identification of early/minor ARVC/D phenotypes, particularly in the setting of family screening. Hence, such criteria are being updated with the aim to make a diagnosis in first degree relatives with incomplete phenotypic expression during family screening of probands with clinically or pathologically proven ARVC/D.17 According to modified criteria, the presence of any one criterion such as inverted T-waves (V1, V2,V3) in individuals over the age of 14, late potentials on SAECG, VT with a LBBB pattern, premature ventricular beats ³ 200 over 24 h (instead of ³ 1,000) or mild morphofunctional RV abnormalities is considered to be itself diagnostic because the probability that such isolated ECG, arrhythmic, or echocardiographic features represent the expression of ARVC/D is definitively higher in family members who have a 50% chance of inheriting the gene defect (Table 13.1). Of note, because clinical manifestation of ARVC/D occurs during adolescence and young adulthood, diagnostic criteria cannot be used before adolescent growth is completed.18,19 Another important limitation of current Task Force criteria is the lack of quantitative cut points to categorize

13  Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia Table 13.1  Task Force criteria for diagnosis of ARVCa GROUP Major 1. Global and/or regional dysfunction and structural alterations

165

Minor

Severe dilatation and reduction of right ventricular ejection fraction with no (or only mild) left ventricular involvement Localized right ventricular aneurysms (akinetic or dyskinetic areas with diastolic bulgings) Severe segmental dilatation of the right ventricle

2. Tissue characteristics of walls

Fibrofatty replacement of myocardium on endomyocardial biopsy

3. ECG depolarization/ conduction abnormalities

Epsilon waves or localized prolongation (³110 ms) of the QRS complex in the right precordial leads (V1–V3)

Mild global right ventricular dilatation and or ejection fraction reduction with normal left ventricle Mild segmental dilatation of the right ventricle

Regional right ventricular hypokinesia

Late potentials seen on signal averaged electrocardiography

4. ECG repolarization abnormalities

Inverted T waves in right precordial leads (V2 and V3) in people  > 12 years and in the absence of right bundle branch block

5. Arrhythmias

Sustained or nonsustained left bundle branch block type ventricular tachycardia documented on the electrocardiography, Holter monitoring, or during exercise testing Frequent ventricular extrasystoles (more than 1,000/24 h on Holter monitoring)

6. Family history

Familial disease confirmed at necropsy or surgery

Family history of premature sudden death (<35 years) due to suspected ARVC/D Family history (clinical diagnosis based on present criteria) a Diagnosis of ARVC in probands is made when two major criteria or one major plus two minor or four minor criteria from different groups are met. According to the proposed revision, the diagnosis of probable ARVC in a first-degree family member would be fulfilled by the presence of a single minor criteria from groups 1, 3, 4, and 5 Source: Modified from Corrado et al5

the various degree of morphofunctional RV abnormalities.15,16,20 Updated guidelines to ARVC/D diagnosis will provide quantitative echocardiographic, angiographic, and histopathologic measurements for defining normal RV cut-off values and properly grading RV dilatation/ dysfunction and fibrofatty myocardial replacement.

13.3.2 Molecular Genetic Diagnosis Recent availability of genetic testing for screening disease-causing mutations offers the potential to identify genetically affected individuals by DNA characterization. The inherited nature of ARVC/D has been recognized since 1982 when Marcus et  al described 24 affected cases, two in the same family.1 In 1988 a report on eight Italian families suggested the auto-

somal dominant pattern of inheritance with incomplete penetrance and variable expression. The first chromosomal locus (14q23-q24) was published in 1994 after clinical evaluation of a large Venetian family.21 Subsequently, linkage analysis provided evidence for genetic heterogeneity with sequential discovery of several ARVC/D loci on chromosome 1 (1q42-q43), chromosome 2 (2q32.1-q32.2), chromosome 3 (3p23), chromosome 6 (6p24), chromosome 10 (10p12-p14 and 10q22), and chromosome 14 (14q12-q22). Other families analyzed with markers linked to these loci failed to show linkage, indicating further genetic heterogeneity. An autosomal recessive variant of ARVC/D (so-called Naxos disease) in which there is a cosegregation of cardiac (ARVC/D), skin (palmoplantar keratosis) and hair (wooly hair) abnormalities has been mapped on chromosome 17 (locus 17q21). The first disease-causing gene, the JUP gene,

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was identified by McKoy et al in patients with Naxos disease.22 The gene encodes desmosomal protein plakoglobin, which is the major constituent of cell adhesion junction. Its discovery suggested that ARVC/D is a cell-to-cell junction disease and stimulated the research for other related genes (Fig.  13.1). Subsequently, mutations in desmosomal protein genes have been shown also to cause the more common (nonsyndromic) autosomal dominant form of the disease (Table 13.2). Desmoplakin was the first defective gene to be associated with autosomal dominant ARVC/D by Rampazzo et al23 Thus, Gerull et al identified 25 different mutations in the gene-encoding plakophilin-2 (PKP2) in 32 out of 120 ARVC/D probands (27%).24 More recently, mutations of the gene encoding for desmoglein-2 and desmocollin-2 have been involved in the disease pathogenesis.25,26

M. Bevilacqua et al. Table  13.2  Chromosomal loci and disease-causing genes in ARVC/D Chromosomal locus Gene mutations Designation (pattern of inheritance) ARVD1 (AD)

14q23-q24

Transforming growth factor-b3 (TGFb3)

ARVD2 (AD)

1q42-q43

Cardiac ryanodine receptor (RyR2)

ARVD3 (AD)

14q12-q22

?

ARVD4 (AD)

2q32.1-q32.3

?

ARVD5 (AD)

3p23

Transmembrane 43 (TMEM43)

ARVD6 (AD)

10p12-p14

?

ARVD7 (AD)

10q22

?

Naxos disease (AR)

17q21

Plakoglobin (JUP)

ARVD8 (AD)

6p24

Desmoplakin (DSP)

ARVD 9 (AD)

12p11

Plakophilin-2 (PKP2)

ARVD 10 (AD)

18q12.1

Desmoglein-2 (DSG2)

ARVD 11 (AD)

18q12.1

Desmocollin-2 (DSC2)

ARVD 12 (AD) 17q21 Plakoglobin (JUP) AD autosomal dominant; AR autosomal recessive Source: Modified from Corrado et al.5

Fig. 13.1  Schematic representation of components of desmosomes which are specialized cell-to-cell adhesion structures found in tissues subjected to mechanical stress, such as skin and heart. There are three major groups of desmosomal proteins: (1) transmembrane proteins (i.e., desmosomal cadherins) including desmocollins (DSC) and desmogleins (DSG); (2) Desmoplakin (DSP), a plakin family protein that binds directly to intermediate filaments, i.e., desmin (DES) in the heart; and (3) linker proteins (i.e., armadillo family proteins) including plakoglobin (JUP) and plakophilins (PKP) which mediate interactions between the desmosomal cadherin tails and desmoplakin (reproduced from Ref.5 with permission of the publisher)

How the mutations of desmosomal protein genes cause disease remains to be elucidated. It has been hypothesized that the lack of the protein or the incorporation of mutant protein into cardiac desmosomes may provoke detachment of myocytes at the intercalated disks, particularly under condition of mechanical stress (like that occurring during competitive sports activity). As a consequence, there is a progressive myocyte degeneration and death with subsequent repair by fibrofatty replacement.27 Life-threatening ventricular arrhythmias may occur either during the “hot phase” of myocyte death as abrupt ventricular fibrillation or later in the form of scar-related macroreentrant ventricular tachycardias.28 Clinical manifestations of ARVC/D usually develop during the adolescence and young adulthood, and are

13  Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia

preceded by a long “preclinical” phase. Cardiac arrest often occurs in young adults and competitive athletes as the first clinical sign of the disease. The most important clinical impact of genotyping families with ARVC/D is the possibility to identify genetically affected relatives before a malignant clinical phenotype manifests. This opportunity has significant implications for primary prevention of sudden death itself. Our experience in an ARVC/D referral center (University of Padua Medical School) during the past decade showed the favorable clinical outcome (0.08 annual mortality rate) of a large cohort of patients diagnosed with familial ARVC/D who underwent close follow-up and treatment.19 Timely therapy with beta-blockers and/or ICD is highly effective in prevention of sudden death in ARVC/D. This underlines the importance of early ARVC/D diagnosis by molecular genetic analysis in order to establish a focused prevention strategy based on lifestyle modifications (restriction from competitive sport), family planning, clinical follow-up (recognition of alarming symptoms, detection of ECG/echocardiographic abnormalities and ventricular arrhythmias), and prophylactic therapy (­beta-blockers, amiodarone, and ICD) to prevent sudden death.8

167

In this regard, it has been demonstrated that identification of ARVC/D by preparticipation screening in still asymptomatic young competitive athletes is a lifesaving strategy. For more than 20 years a systematic preparticipation screening, based on 12-lead ECG in addition to history and physical examination, has been the practice in Italy. Corrado et al reported the results of a time-trend analysis of the changes in incidence rates and causes of sudden cardiovascular death in young competitive athletes aged 12–35 years in the Veneto region of Italy between 1979 and 2004, after introduction of systematic preparticipation screening.29 Over the same time interval, they carried out a parallel study that examined trends in cardiovascular causes of disqualification from competitive sports in 42,386 athletes undergoing preparticipation screening at the Center for Sports Medicine in Padua. The annual incidence of sudden cardiovascular death in athletes decreased approximately by 90%, from 3.6/100,000 person-years in the prescreening period to 0.4/100,000 person-years in the late-screening period, whereas the incidence of sudden death among the unscreened nonathletic population did not change significantly over that time (Fig.  13.2). Most of the reduced death rate

Sudden death per 100000 person-years

4.5 4.0 3.5

Athletes

3.0

Nonathletes

2.5 2.0 1.5 1.0 0.5

00 -2 03 20

20

01

-2

00

4

2

0 99

-2

00

8 19

-1 97 19

99 -1 95 19

99

6

4 -1 93 19

91

-1

99

99

2

0 19

89

-1

99

8 19

-1 87 19

98 -1 85 19

98

6

4 19

83

-1

98

98 -1 81 19

19

79

-1

98

2

0

0

Years

Fig. 13.2  Annual incidence rates of SCD per 100,000 persons among screened competitive athletes and unscreened nonathletes 12–35 years of age in the Veneto Region of Italy, from 1979 to 2004. During the study period (the nationwide preparticipation screening program was launched in 1982), the annual incidence

of SCD declined by 89% in screened athletes (p for trend  < 0.001). In contrast, the incidence rate of SCD did not demonstrate consistent changes over time in unscreened nonathletes (reproduced from Ref.29 with permission of the publisher)

168

was due to fewer cases of sudden death from cardiomyopathies, mostly ARVC/D. Time-trend analysis showed that the incidence of sudden death from this latter condition fell by 84% over the 24-year span. This decline of mortality from ARVC/D paralleled the concomitant increase in the number of affected athletes who were identified and disqualified from competitive sports over the screening periods.

13.4 Management Strategies 13.4.1 Risk Stratification The clinical outcome of patients with ARVC/D is related to the ventricular electrical instability which can precipitate arrhythmic cardiac arrest at any time during the disease course and to progressive myocardial loss that may induce ventricular dysfunction and heart failure.2-5 At the present time there are no clinical markers assessed by prospective and controlled studies which can predict the occurrence of life-threatening ventricular arrhythmias. Moreover, ARVC/D is a progressive disease and the patient’s risk of sudden death may change with time. Retrospective analysis of clinical and pathologic series including fatal cases identified a series of risk factors such as youthful age, competitive sport activity, malignant familial background, previous syncope or cardiac arrest extensive RV disease with ejection fraction reduction and left ventricular involvement, right ventricular electroanatomic scar, and VT episodes.1-6,30-32 The value of electrophysiologic study with programmed ventricular stimulation in arrhythmic risk stratification of patients with ARVC/D has been recently questioned (see later).

13.4.2 Therapy Therapeutic options include beta blockers, antiarrhythmic drugs, catheter ablation, ICD, and heart trans­ plantation. Pharmacologic therapy is the first choice treatment of patients with well tolerated and not life-threatening ventricular arrhythmias. The evidence available suggests that either sotalol or amiodarone (alone or in

M. Bevilacqua et al.

combination with beta-blockers) are the most effective drugs with a relatively low proarrhythmic risk.33 In the  subset of patients in whom ARVC/D leads to ­progressive right ventricular or biventricular systolic dysfunction, treatment consists of pharmacologic therapy for heart failure including diuretics, angiotensinconverting-enzyme inhibitors, and digitalis, as well as anticoagulant therapy. Nonpharmacological therapy is reserved for drugresistant cases and for patients with previous arrhythmic cardiac arrest. Catheter ablation of the VT re-entry circuit has acute success rates of 60–90%.14,34-36 However, VT relapses are frequent (up to 60% of the cases) and have been attributed to development of new arrhythmogenic zones because of the progressive nature of the underlying disease. Therefore, catheter ablation should be reserved for particular clinical condition such as drug refractory incessant VT or frequent recurrences of VT after defibrillator implantation. ICD is the most logical therapeutic strategy for patients with ARVC/D, whose natural history is characterized by the risk of sudden arrhythmic death and, only secondarily, by contractile dysfunction leading with progressive heart failure. Data from observational studies on a large population of patients with ARVC have recently allowed to establish efficacy and safety of ICD therapy. In the DARVIN (Defibrillator for Arrhyth­ mogenic Right Ventricular cardiomyopathy in Italy and North America) study,28 approximately 50% of the 132 patients had at least one appropriate defibrillator intervention during a mean 3.3-year follow-up, despite antiarrhythmic therapy. Further, 24% of the total patient population experienced one or more episodes of ventricular fibrillation/flutter, documented by stored intracardiac ECG data, that in all likelihood would have been fatal in the absence of the device therapy (Fig.  13.3). Analysis of risk factors showed that a younger age, a history of cardiac arrest or hemodynamically unstable ventricular tachycardia, and left ventricular involvement were independent clinical variables associated with the occurrence of such life-threatening arrhythmias. On the contrary, therapy with ICD did not improve survival in the subgroup of patients presenting with hemodynamically stable monomorphic ventricular tachycardia. This discrepancy in the clinical outcome can be explained by the different mechanism responsible of VT and VF in  patients with ARVC/D. Ventricular fibrillation has been  associated with active phases of myocyte death

13  Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia

a

Survival

The DARVIN study showed that 16% of patients received inappropriate ICD interventions and 14% had device and lead-related complications (mean follow-up of 3.3 years). In the study by Wichter et al,37 complications were found in approximately half of ARVC/D patients during a long-term follow-up of 7 years.

1.00

0.90

Logrank < 0.001

0.80

13.4.3 Programmed Ventricular Stimulation

0.70 Actual patients survival Ventricular fibrillation-free survival

0.60

0.50

0

6

12

18

24

30

36

42

48

Follow-up (months)

Ventricular fibrillation-free survival

b

1.0

Logrank= 0.01

0.8

0.6 Caddiac arrest Ventricular tachyardia with hemodynamic compromise

0.4

Ventricular tachycardia without hemodynamic compromise

0.2

Unexplained syncope

0.0

169

0

6

12

18

24

30

36

42

48

Follow-up (months)

Fig.  13.3  Kaplan-Meier analysis of actual patient survival (upper line) compared with survival free of ventricular fibrillation (inner line) that in all likelihood would have been fatal in the absence of the ICD. The divergence between the lines reflects the estimated mortality reduction by ICD therapy of 24% at 3 years of follow-up. (reproduced from Ref.28 with permission of the publisher)

occurring in younger affected patients with progressive disease, whereas hemodynamically well-tolerated mono­morphic ventricular tachycardia is caused by a reentry mechanism around a stable myocardial scar as the result of a healing process that occurs in a later stage of the disease course. This view is reinforced by the DARVIN finding that younger age is an independent risk factor for ventricular fibrillation/flutter.

The results of the DARVIN study raised concerns on the predictive value of programmed ventricular stimulation for risk stratification of patients with ARVC/D.28 Of 98 patients who were inducible at programmed ventricular stimulation, 50 (51%) did not experience ICD therapy during the follow-up, whereas 7 (54%) of 13 noninducible patients had appropriate ICD interventions. Overall, the positive predictive value of programmed ventricular stimulation was 49%, the negative predictive value was 54%, and the test accuracy was 49%. Moreover, the incidence of appropriate ICD discharge did not differ between patients who were or were not inducible at programmed ventricular stimulation, regardless of clinical presentation. Finally, the type of ventricular tachyarrhythmia inducible at the time of electrophysiological study did not predict the occurrence of ventricular fibrillation/flutter during follow-up. The results of this study indicate that the electrophysiological study is of limited value in identifying patients at risk of lethal ventricular arrhythmias because of a low predictive accuracy (approximately 50% of both false-positive and falsenegative results). This finding is in agreement with the limitation of electrophysiological study for arrhythmic risk stratification of other nonischemic heart disease such as hypertrophic and dilated cardiomyopathy. Wichter et  al37 confirmed that inducibility of VT/VF during electrophysiological study in patients with ARVC/D is not a statistically significant independent predictor of appropriate ICD therapy during follow-up, although Roguin et al38 reported that VT induction was associated with an increased risk for appropriate shock in ARVC/D patients who received an ICD for prevention of arrhythmic sudden death. In conclusion, the high rate of complications and the psychological impact of ICD therapy in young patients are against the indiscriminate use of a prophylactic device implant and point out the importance of

170

an accurate risk stratification and selection of candidate patients. The risk of sudden arrhythmic death is better determined on the basis of patient’s clinical presentation rather than on the results of electrophysiological study with programmed ventricular stimulation. The ICD implantation is justified in ARVC/D patients who survived an episode of cardiac arrest due to ventricular fibrillation or experienced sustained ventricular tachycardia with hemodynamic compromise. In patients with sustained ventricular tachycardia, hemodynamically well tolerated, an alternative approach with antiarrhythmic drugs and/or transcatheter ablation seems to be more appropriate. Prophylactic ICD therapy may be also indicated in young patients with severe right ventricle dysfunction or advanced disease with biventricular involvement.39 Cardiac transplantation represents the last therapeutic option in cases of ventricular tachycardia and/or heart failure refractory to the other therapeutic strategies.

References   1. Marcus FI, Fontaine G, Guiraudon G, Frank R, Laurenceau JL, Malergue C, Grosgogeat Y. Right ventricular dysplasia. A report of 24 adult cases. Circulation. 1982;65:384–398   2. Thiene G, Nava A, Corrado D, Rossi L, Pennelli N. Right ventricular cardiomyopathy and sudden death in young people. N Engl J Med. 1988;318:129–133   3. Basso C, Thiene G, Corrado D, Angelini A, Nava A, Valente ML. Arrhythmogenic right ventricular cardiomyopathy. Dysplasia, dystrophy, or myocarditis? Circulation. 1996; 94:983–991   4. Corrado D, Basso C, Thiene G, et al. Spectrum of clinicopathologic manifestations of arrhythmogenic right ventricular cardiomyopathy/dysplasia: a multicenter study. J Am Coll Cardiol. 1997;30:1512–1520   5. Corrado D, Basso C, Thiene G. Arrhythmogenic right ventricular cardiomyopathy: an update. Heart. 2009;95: 766–773   6. Corrado D, Thiene G, Nava A, Rossi L, Pennelli N. Sudden death in young competitive athletes: clinicopathologic correlation in 22 cases. Am J Med. 1990;89:588–596   7. Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D, Moss AJ, Seidman CE, Young JB; American Heart Association; Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; Council on Epidemiology and Prevention. Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and

M. Bevilacqua et al. Council on Epidemiology and Prevention. Circulation. 2006;113:1807–1816   8. Corrado D, Thiene G. Arrhythmogenic right ventricular cardiomyopathy/dysplasia: clinical impact of molecular genetic studies. Circulation. 2006;113:1634–1637   9. Blomstrom-Lundqvist C, Beckman-Suurkula M, Wallentin I, Jonsson R, Olsson SB. Ventricular dimensions and wall motion assessed by echocardiography in patients with arrhythmogenic right ventricular dysplasia. Eur Heart J. 1988; 9:1291–302 10. Menghetti L, Basso C, Nava A, Angelini A, Thiene G. Spinecho nuclear magnetic resonance for tissue characterization in arrhythmogenic right ventricular cardiomyopathy. Heart. 1996;76:467–470 11. Daliento L, Rizzoli G, Thiene G, et al. Diagnostic accuracy of right ventriculography in arrhythmogenic right ventricular cardiomyopathy. Am J Cardiol. 1990;66:741–745 12. Angelini A, Basso C, Nava A, Thiene G. Endomyocardial biopsy in arrhythmogenic right ventricular cardiomyopathy. Am Heart J. 1996;132:203–206 13. Tandri H, Saranathan M, Rodriguez ER, et al. Noninvasive detection of myocardial fibrosis in arrhythmogenic right ventricular cardiomyopathy using delayed-enhancement magnetic resonance imaging. J Am Coll Cardiol. 2005;45: 98–103 14. Corrado D, Basso C, Leoni L, et al. Three-dimensional electroanatomical voltage mapping and histologic evaluation of myocardial substrate in right ventricular outflow tract tachycardia. J Am Coll Cardiol. 2008;51:731–739 15. McKenna WJ, Thiene G, Nava A, et al. Diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Br Heart J. 1994;71:215–218 16. Corrado D, Fontaine G, Marcus FI, et  al. Arrythmogenic right ventricular dysplasia/cardiomyopathy. Need for an international registry. Circulation. 2000;101:e101-e106 17. Hamid MS, Norman M, Quraishi A, et al. Prospective evaluation of relatives for familial arrhythmogenic right ventricular cardiomyopathy/dysplasia reveals a need to broaden diagnostic criteria. J Am Coll Cardiol. 2002;40(8): 1445–1450 18. Nava A, Thiene G, Canciani B, et al. Familial occurrence of right ventricular dysplasia: a study involving nine families. J Am Coll Cardiol. 1988;12:1222–1228 19. Nava A, Bauce B, Basso C, et al. Clinical profile and longterm follow-up of 37 families with arrhythmogenic right ventricular cardiomyopathy. J Am Coll Cardiol. 2000;36: 2226–2233 20. Yoerger DM, Marcus F, Sherrill D, Calkins H, Towbin JA, Zareba W, Picard MH. Multidisciplinary Study of Right Ventricular Dysplasia Investigators. Echocardiographic findings in patients meeting task force criteria for arrhythmogenic right ventricular dysplasia: new insights from the multidisciplinary study of right ventricular dysplasia. J Am Coll Cardiol. 2005;45:860–865 21. Rampazzo A, Nava A, Danieli GA, et  al. The gene for arrhythmogenic right ventricular cardiomyopathy maps to chromosome 14q23–q24. Hum Mol Genet. 1994;3:959–962 22. McKoy G, Protonotarios N, Crosby A, et al. Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease). Lancet. 2000;355:2119–2124

13  Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia 23. Rampazzo A, Nava A, Malacrida S, et al. Mutation in human desmoplakin domain binding to plakoglobin causes a dominant form of arrhythmogenic right ventricular cardiomyopathy. Am J Hum Genet. 2002;71:1200–1206 24. Gerull B, Heuser A, Wichter T, et al. Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy. Nat Genet. 2004; 36:1162–1164 25. Pilichou K, Nava A, Basso C, et al. Mutations in Desmoglein-2 gene are associated to arrhythmogenic right ventricular cardiomyopathy. Circulation. 2006;113(9):1171–1179 26. Syrris P, Ward D, Evans A, et al. Arrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in the desmosomal gene desmocollin-2. Am J Hum Genet. 2006;79:978–984 27. Sen-chowdhry S, Syrris P, Mckenna WJ. Genetics of right ventricular cardiomyopathy. J Cardiovasc Electrophysiol. 2005;16:927–935 28. Corrado D, Leoni L, Link MS, et  al. Implantable cardioverter-defibrillator therapy for prevention of sudden death in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia. Circulation. 2003;108:3084–3091 29. Corrado D, Basso C, Pavei A, Michieli P, Schiavon M, Thiene G. Trends in sudden cardiovascular death in young competitive athletes after implementation of a preparticipation screening program. JAMA. 2006;296:1593–1601 30. Buja G, Estes NA 3rd, Wichter T, Corrado D, Marcus F, Thiene G. Arrhythmogenic right ventricular cardiomyopathy/dysplasia: risk stratification and therapy. Prog Cardiovasc Dis. 2008;50:282–293 31. Turrini P, Corrado D, Basso C, Nava A, Bauce B, Thiene G. Dispersion of ventricular depolarization-repolarization: a noninvasive marker for risk stratification in arrhythmogenic right ventricular cardiomyopathy. Circulation. 2001;103:3075–3080

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32. Corrado D, Basso C, Leoni L, et al. Three-dimensional electroanatomic voltage mapping increases accuracy of diagnosing arrhythmogenic right ventricular cardiomyopathy/ displasia. Circulation. 2005;111:3042–3050 33. Wichter T, Borggrefe M, Hoverkamp W, Chen X, Breithardt G. Efficacy of antiarrhythmic drugs in patients with arrhythmogenic right ventricular disaese. Results in patients with inducible and noninducible ventricular tachycardia. Circulation. 1992;86:29–37 34. Wichter T, Hindricks G, Kottkamp H, Breithardt G, Borggrefe M. Catheter ablation of ventricular tachycardia. In: Nava A, Rossi L, Thiene G, eds. Arrhythmogenic right ventricular cardiomyopathy-dysplasia. Amsterdam: Elsevier; 1997:376–391 35. Verma A, Kilicaslan F, Schweikert RA, et  al. Short- and long-term success of substrate-based mapping and ablation of ventricular tachycardia in arrhythmogenic right ventricular dysplasia. Circulation. 2005;111:3209–3216 36. Dalal D, Jain R, Tandri H, et al. Long-term efficacy of catheter ablation of ventricular tachicardia in patients with arrhythmogenic right ventricular displasia/cardiomyopathy. J Am Coll Cardiol. 2007;50:432–440 37. Wichter T, Paul M, Wollmann C, et al. Implantable cardioverter/defibrillator therapy in arrhythmogenic right ventricular cardiomyopathy: single-center experience of long-term follow-up and complications in 60 patients. Circulation.. 2004;109:1503–1508 38. Roguin A, Bomma CS, Nasir K, et al. Implantable cardioverter-defibrillators in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy. J Am Coll Cardiol. 2004;43:1843–1852 39. Basso C, Corrado D, Marcus FI, Nava A, Thiene G. Arrhythmogenic right ventricular cardiomyopathy. Lancet. 2009;373:1289–1300

Atrial Fibrillation

14

Oscar Campuzano and Ramon Brugada

14.1 Introduction

14.1.1 Genetic Mechanisms

Atrial fibrillation (AF) is defined as an unpredictable activation of the atria, causing an irregular ventricular response. It is characterized electrocardiographically by irregular fibrillatory waves, usually associated with an irregular ventricular response, which manifests clinically as an irregular pulse. AF is the most common sustained rhythm disorder or arrhythmia encountered in clinical practice with a prevalence of 1% in the general population, which increases with age to about 6% in people over the age of 65,1-3 and it is responsible for over one-third of all cardioembolic episodes.4 Recent guidelines suggested that AF be classified on the basis of the temporal pattern of the arrhythmia.5,6 AF episodes may be transient (paroxysmal) or persistent. While AF is usually associated with cardiac pathology, including hypertensive heart disease cardiomyopathy, valvular disease, or atherosclerotic cardiovascular disease, it can also present without previous cardiac pathology (lone AF). Lone AF accounts for 2–16% of all cases. The natural history of lone AF has not been well studied. However, accumulating data suggest that it is associated with a low risk of progression to permanent AF, mortality, congestive heart failure, and stroke/transient ischemic attack.7,8

Continuous advances in genetics have given new insights into the development of AF. Research efforts are focused principally on two areas: genetic alterations and gene expression regulation in ion channels. The study on alterations in gene expression is usually performed in animal models of the disease but can also be performed, in a more limited scale (because of tissue availability), in the human. These experiments principally provide information on the molecular changes triggered by the disease and the mechanisms by which the arrhythmia becomes chronic.9-11 Research in the identification of genetic defects provides a direct link into the etiology for the disease. Study in genetics of AF can be attained from different perspectives: (1) the analysis of AF as a monogenic disease in which different members of a family have the arrhythmia as a primary electrical disease, (2) the analysis of the arrhythmia presenting in the setting of another familial disease, and (3) the analysis of genetic background that may predispose to the disease without it segregating in a family. The first two, analysis of familial forms of the disease, provide a definitive insight into the etiology of the disease and require the analysis of families with disease segregating in several members, with or without structural pathology. The latter is achieved by comparing cases of non-Mendelian inheritance patters for AF to age- and gender-matched controls. The analysis is performed as an association study, aimed at identifying differences in segregation of genetic backgrounds between both groups, which may explain the development of and susceptibility to the disease.

O. Campuzano () Cardiovascular Genetics Center, School of Medicine, Universitat de Girona, Girona, Spain

R. Brugada et al. (eds.), Clinical Approach to Sudden Cardiac Death Syndromes, DOI: 10.1007/978-1-84882-927-5_14, © Springer-Verlag London Limited 2010

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O. Campuzano and R. Brugada

14.2 Genetic Disease AF was not generally appreciated to be a familial inherited disorder. AF was first reported as a familial form in 1943.12 In last 5 years, published studies have shown several lines of evidence supporting the genetically determined heritable basis to AF.13,14 A study by Darbar et  al.15 indicated that the familial form of the disease may have a higher prevalence than previously suspected and emphasizes the importance of expanding genetics studies. Familial AF may be a monogenic disorder and is often identified as AF being present in many members of the same family (Table 14.1). Unlike familial AF, in which a genetic alteration is the major contributing factor, research in nonfamilial AF is characterized by being multifactorial, the result of the interaction of environment and genetic factors, which play a smaller role in the disease, albeit an important one.

14.2.1 Identification of the First Locus for Familial Atrial Fibrillation in 10q22 Three families with AF inherited with an autosomal dominant pattern were identified in 1996. With techniques of linkage analysis, the locus was identified in 10q22, which was segregating with the affected individuals.16 These families were later expanded to six with a total of 132 individuals. Fifty of them presented with AF, with an age of diagnosis of the arrhythmia from 0 to 45 years (two patients were diagnosed in utero). The Table 14.1  Familial AF as a monogenic disease Locus Inheritance Gene 11p15.520

Autosomic dominant

KCNQ1

3p2128

Autosomic dominant

SCN5A

12p1326

Autosomic dominant

KCNA5

11q13-q1424

Autosomic dominant

KCNE3

21q2223

Autosomic dominant

KCNE2

17q23-q2425

Autosomic dominant

KCNJ2

1p36-3530

Autosomic dominant

NPPA

5p1331

Autosomic recessive

NUP155

echocardiograms were within the normal range when the patients were diagnosed. Some of them have subsequently developed dilatation of the left atrium on followup. Two patients have mild left ventricular dysfunction, one of them probably related to her advanced age and the other due to tachycardiomyopathy secondary to poorly controlled heart rate. In six patients, electrical cardioversion was unsuccessful, despite a structurally normal heart. A second locus in 6q14-16, identified in a large family in 2003 by Ellinor et  al,17 also harbors genetic defect that is responsible for AF segregating as an autosomal dominant disease. In this family, AF started as paroxysmal AF in younger individuals and became permanent in older family members. These genes have remained elusive so far because the causative gene has not been identified yet. Other loci in 10p11 and 5p15 have been identified in the last years.18,19

14.2.2 Atrial Fibrillation Associated with Genetic Alterations in Potassium Currents Most of the single-gene mutations that have been discovered in families with AF cause cardiac K+-channel defects. The first gene responsible for familial AF, KCNQ1, was identified in 2003, linking the disease to an ion channelopathy.20 KCNQ1 encodes the poreforming a-subunit of the cardiac slow delayed-rectifier (IKs) channel, and its loss of function had been previously associated with long QT syndrome. The analysis of KCNQ1 identified a missense mutation resulting in the aminoacid change S140G. Electrophysiological studies revealed a gain of function in IKs current when the mutated channel was expressed with the b-subunits MinK and MirP1. This gain of function explained well the shortening of the action potential duration and effective refractory period which are thought to be the culprits of the disease. Considering that loss of function mutations in KCNQ1 had been described before as responsible for long QT syndrome type 1, it was interesting to observe that despite the gain of function observed in this mutation, 9 out of 16 individuals also presented QT prolongation of the electrocardiogram.20 This is an issue which is yet unresolved. In an interesting new finding, a gain-of-function mutation in codon 141, next to the one described in the aforementioned family, was found responsible for a severe form of AF,

14  Atrial Fibrillation

in utero, and short QT syndrome.21 In a family with AF, Otway R et  al., identified a mutation in KCNQ1 (R14C) that induces a mutant protein that only showed increase IKs upon cell-stretch with a hypotonic solution opening a new and stimulating debate on the role of genetic-environmental interaction in the development of the disease.22 Identification of mutations in KCNE2 in two families with AF23 confirmed that defects in genes encoding for potassium currents are responsible of AF. The mutation R27C caused a gain of function when coexpressed with KCNQ1 but had no effect when expressed with HERG. A third genetic defect was described in KCNE324 however, the functional analysis did not demonstrate a different biophysical effect caused by the mutant genetic defect, indicating that it could be a rare polymorphism. Finally, a gain-of-function mutation in Kir2.1, caused by a mutation in KCNJ2,25 was found in 2005 in a new kindred. The biophysical findings therefore indicated a role of gain-of-function mutations in potassium channels in AF highlighting the pathophysiological role of shortened atrial action potentials. When Olson et al.26 described a loss of function mutation in KCNA5, the gene that encodes KV1.5, the debate became more stimulating as it initiated the hypothesis that a prolongation of the action potential can also be a basic mechanism for AF progress.

14.2.3 Atrial Fibrillation Associated with Genetic Alterations in Sodium Current The a-subunit of the cardiac sodium channel gene, SCN5A, responsible for the phase 0 of the cardiac action potential, has been studied extensively. Because of its key role in phase of the cardiac action potential, SCN5A is involved in several primary arrhythmia syndromes. Gain-of-function mutations, mainly due to their inability to inactivate, have been associated with long QT syndrome type 3, and loss of function have been associated to Brugada syndrome, sudden infant death syndrome, Lev-Lenègre syndrome, Sudden unexplained death syndrome in the South East Asia, and dilated cardiomyopathy.27 Variants in SCN5A have been linked with lone and familial AF,28 and also associated with long QT syndrome 29.

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14.2.4 Atrial Fibrillation Associated with Genetic Alteration in Nonion Channels Atrial natriuretic peptide precursor (NPPA) encodes atrial natriuretic peptide (ANP). ANP modulates ionic currents in cardiac myocytes and can play a role in shortening of the atrial conduction time, which could be a potential substrate for atrial re-entrant arrhythmias. In 2008, Hodgson-Zingman et  al identified a frame shift mutation in NPPA in a large family with AF.30 The latest gene to be linked to the disease is the one identified by Zhang et al31 The clinical phenotype was characterized by a neonatal onset, with autosomal recessive inheritance. They identified a mutation in NUP155, which encode a member of the nucleoporins. While still unknown, the mechanism by which NUP155 may be associated with AF could be related to modulation of calcium-handling proteins and ion channel and expression of its possible target genes, such as HSP70. The mutation was associated with inhibition of both export of HSP70 mRNA and nuclear import of Hsp70 protein, indicating that loss of function of NUP155 caused the disease by altering mRNA and protein transport. This gene is located in 5p13 and had been also associated with sudden death in the family.

14.2.5 Somatic Mutations in Atrial Fibrillation In 2006 three missense mutations in GJA5 were identified in atrial tissue specimens from patients with idiopathic AF.32 GJA5 encodes the gap junction protein connexin 40, which is involved in electrical coupling and its disruption may cause atrial arrhythmias.

14.3 Genetic Predisposition to Nonfamilial AF The familial AF cases are a rare entity, principally acquired and related to structural abnormalities. However, not all individuals with the same cardiac pathology develop AF, indicating that there are probably genetic factors that predispose some of them to the arrhythmia.

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It is tested in one report from Japan33 the hypothesis that genetic factors that increase cardiac fibrosis would be a determinant for the development of lone AF. These investigators analyzed a polymorphism in the ACE gene, an enzyme that interacts with angiotensin II and affects cardiac remodeling. ACE gene can be inherited with an intronic deletion, which has been linked to higher circulating levels of enzyme and higher degree of hypertrophy and myocardial fibrosis.34 While this cardiac fibrosis has been described at the ventricular level, they hypothesized that it would also affect the atria and cause the arrhythmia. They compared the genotypes of 77 patients with lone AF to 83 controls. They did not find any difference in the distribution of the ACE genotypes between the affected individuals and controls. There was no correlation with the type of AF, namely, paroxysmal or chronic and the genotype. However, a larger study in 2004 has shown that there may be a relation between nonfamilial structural AF and polymorphisms in the renin– angiotensin system.35 A second study has looked at a polymorphism in MinK and relation with the disease. There was an association with the 38G allele and AF. Interestingly this is one of the rare exceptions where an additional study could demonstrate the functional impact of this common variant on AF. The 38G allele in a heterologous expression system when coexpressed with KCNQ1 is associated with decreased repolarizing IKs potentially facilitating AF.36 Further studies will be required to confirm this association.37 In 2008, Chen et al. found an association between the SCN5A polymorphism H558R with AF vulnerability, presumably by causing conduction slowing and favoring re-entry.38 Another study has addressed the relationship between inflammation and the risk of developing postoperative AF. This study is focused to highlight the importance of selecting a specific phenotype, following a specific pathophysiological hypothesis as a prerequisite to identify genetic contributions to AF. The authors investigated the role of the -174G/C Interleukin-6 polymorphism in 110 patients undergoing coronary artery bypass surgery.39 This polymorphism had been previously associated with postoperative Interleukin-6 levels. Twenty-six patients developed AF in the postoperative period. Analysis of the polymorphism revealed a significant prevalence of the GG genotype (34% v. 10%) in patients with AF. Likewise, the levels of interleukin and fibrinogen were higher in patients with GG

O. Campuzano and R. Brugada

phenotype. Therefore, this study has shown a possible role of inflammatory component in the development of AF. Positive association findings have also been achieved with connexin-40, with the identification of a promoter haplotype linked with the predisposition to the arrhythmia.40 As in all association studies, larger patient populations with a comparable and homogeneous phenotype will be required to confirm the findings in independent replication studies.

14.3.1 Genome-Wide Studies A recent genome-wide association study has found a strong association between AF and two SNPs on chromosome 4q25.41,42 The mechanism for this observed association remains unknown; however, both variants are adjacent to the PITX2, a gene critical for cardiac development.

14.4 Future The discovery of the structure of the ion channels, their function, and pathophysiology have helped unravel in part the role played by the different ionic currents in both the electrical activity, electromechanical coupling and arrhythmogeneity. The advances in genetics, biophysics, and experimental models have permitted the detection of mutations causing familial diseases that have opened new insights into preventive and therapeutic options for the disease. Arrhythmias such as AF will therefore undoubtedly benefit from these expanding technologies for discovering novel genes that cause the familial forms of the disease and genetic variants that modulate the risk for AF. The interaction of all these genes with the structural cardiac abnormalities will probably shed light not only on the factors that induce the first episode but on the determinants that prolong this episode into a chronic form. The largest benefit that will be drawn from all the data is the much improved understanding of the disease, how it is initiated, how it chronifies. Like it has happened in the previously mentioned diseases, once the preliminary data are obtained, the development of better therapeutic and preventive measures will be a possibility.

14  Atrial Fibrillation

14.5 Clinical Implications in Familial Atrial Fibrillation There is no difference in the clinical approach to the patient with AF whether it is familiar or not. It has been observed though that the familial forms are very difficult to cardiovert, even in those cases with a completely normal atrial structure and size.

References   1. Benjamin EJ, Wolf PA, D’Agostino RB, Silbershatz H, Kannel WB, Levy D. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation. 1998; 98(10):946–952   2. Dries DL, Exner DV, Gersh BJ, Domanski MJ, Waclawiw MA, Stevenson LW. Atrial fibrillation is associated with an increased risk for mortality and heart failure progression in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: a retrospective analysis of the SOLVD trials. Studies of Left Ventricular Dysfunction. J Am Coll Cardiol. 1998;32(3):695–703   3. Feinberg WM, Blackshear JL, Laupacis A, Kronmal R, Hart RG. Prevalence, age distribution, and gender of patients with atrial fibrillation. Analysis and implications. Arch Intern Med. 1995;155(5):469–473   4. Wolf PA, Singer DE. Preventing stroke in atrial fibrillation. Am Fam Physician. 1997;56(9):2242–2250   5. Fuster V, Ryden LE, Asinger RW, et  al. ACC/AHA/ESC Guidelines for the Management of Patients With Atrial Fibrillation: Executive Summary A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation) Developed in Collaboration With the North American Society of Pacing and Electrophysiology. Circulation. 2001;104(17):2118–2150   6. Fuster V, Ryden LE, Cannom DS, et  al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006;114(7):e257-e354   7. Gersh BJ, Solomon A. Lone atrial fibrillation: epidemiology and natural history. Am Heart J. 1999;137(4 pt 1):592–595   8. Korantzopoulos P, Liu T, Milionis HJ, Li G, Goudevenos JA. “Lone” atrial fibrillation: hunting for the underlying causes and links. Int J Cardiol. 2009;131(2):180–185   9. Brugada R. Molecular biology of atrial fibrillation. Minerva Cardioangiol. 2004;52(2):65–72

177 10. Barth AS, Merk S, Arnoldi E, et al. Reprogramming of the human atrial transcriptome in permanent atrial fibrillation: expression of a ventricular-like genomic signature. Circ Res. 2005;96(9):1022–1029 11. Barth AS, Hare JM. The potential for the transcriptome to serve as a clinical biomarker for cardiovascular diseases. Circ Res. 2006;98(12):1459–1461 12. Wolff L. Familial auricular fibrillation. New Engl J Med. 1943;229:396 13. Fox CS, Parise H, D’Agostino RB Sr, et al. Parental atrial fibrillation as a risk factor for atrial fibrillation in offspring. JAMA. 2004;291(23):2851–2855 14. Arnar DO, Thorvaldsson S, Manolio TA, et  al. Familial aggregation of atrial fibrillation in Iceland. Eur Heart J. 2006;27(6):708–712 15. Darbar D, Herron KJ, Ballew JD, et al. Familial atrial fibrillation is a genetically heterogeneous disorder. J Am Coll Cardiol. 2003;41(12):2185–2192 16. Brugada R, Tapscott T, Czernuszewicz GZ, et  al. Identification of a genetic locus for familial atrial fibrillation. N Engl J Med. 1997;336(13):905–911 17. Ellinor PT, Shin JT, Moore RK, Yoerger DM, MacRae CA. Locus for atrial fibrillation maps to chromosome 6q14–16. Circulation. 2003;107(23):2880–2883 18. Volders PG, Zhu Q, Timmermans C, et al. Mapping a novel locus for familial atrial fibrillation on chromosome 10p11– q21. Heart Rhythm. 2007;4(4):469–475 19. Darbar D, Hardy A, Haines JL, Roden DM. Prolonged signal-averaged P-wave duration as an intermediate phenotype for familial atrial fibrillation. J Am Coll Cardiol. 2008; 51(11):1083–1089 20. Chen YH, Xu SJ, Bendahhou S, et al. KCNQ1 gain-of-function mutation in familial atrial fibrillation. Science. 2003;299 (5604):251–254 21. Hong K, Piper DR, Diaz-Valdecantos A, et  al. De novo KCNQ1 mutation responsible for atrial fibrillation and short QT syndrome in utero. Cardiovasc Res. 2005;68(3):433–440 22. Otway R, Vandenberg JI, Guo G, et  al. Stretch-sensitive KCNQ1 mutation A link between genetic and environmental factors in the pathogenesis of atrial fibrillation? J Am Coll Cardiol. 2007;49(5):578–586 23. Yang Y, Xia M, Jin Q, et al. Identification of a KCNE2 gainof-function mutation in patients with familial atrial fibrillation. Am J Hum Genet. 2004;75(5):899–905 24. Zhang DF, Liang B, Lin J, Liu B, Zhou QS, Yang YQ. [KCNE3 R53H substitution in familial atrial fibrillation.]. Chin Med J (Engl). 2005;118(20):1735–1738 25. Xia M, Jin Q, Bendahhou S, He Y, Larroque MM, Chen Y, et al. A Kir2.1 gain-of-function mutation underlies familial atrial fibrillation. Biochem Biophys Res Commun. 2005;332 (4):1012–1019 26. Olson TM, Alekseev AE, Liu XK, Park S, Zingman LV, Bienengraeber M, et al. Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation. Hum Mol Genet. 2006;15(14):2185–2191 27. Viswanathan PC, Balser JR. Inherited sodium channelopathies: a continuum of channel dysfunction. Trends Cardiovasc Med. 2004;14(1):28–35 28. Darbar D, Kannankeril PJ, Donahue BS, et  al. Cardiac sodium channel (SCN5A) variants associated with atrial fibrillation. Circulation. 2008;117(15):1927–1935

178 29. Benito B, Brugada R, Perich RM, et al. A mutation in the sodium channel is responsible for the association of long QT syndrome and familial atrial fibrillation. Heart Rhythm. 2008;5(10):1434–1440 30. Hodgson-Zingman DM, Karst ML, Zingman LV, et al. Atrial natriuretic peptide frameshift mutation in familial atrial fibrillation. N Engl J Med. 2008;359(2):158–165 31. Zhang X, Chen S, Yoo S, et  al. Mutation in nuclear pore component NUP155 leads to atrial fibrillation and early sudden cardiac death. Cell. 2008;135(6):1017–1027 32. Gollob MH, Jones DL, Krahn AD, et al. Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation. N Engl J Med. 2006;354(25):2677–2688 33. Yamashita T, Hayami N, Ajiki K, et al. Is ACE gene polymorphism associated with lone atrial fibrillation? Jpn Heart J. 1997;38(5):637–641 34. Nakai K, Itoh C, Miura Y, et al. Deletion polymorphism of the angiotensin I-converting enzyme gene is associated with serum ACE concentration and increased risk for CAD in the Japanese. Circulation. 1994;90(5):2199–2202 35. Tsai CT, Lai LP, Lin JL, et  al. Renin-angiotensin system gene polymorphisms and atrial fibrillation. Circulation. 2004;109(13):1640–1646 36. Ehrlich JR, Zicha S, Coutu P, Hebert TE, Nattel S. Atrial fibrillation-associated minK38G/S polymorphism modulates

O. Campuzano and R. Brugada delayed rectifier current and membrane localization. Cardiovasc Res. 2005;67(3):520–528 37. Lai LP, Lin JL, Huang SK. Molecular genetic studies in atrial fibrillation. Cardiology. 2003;100(3):109–113 38. Chen LY, Herron KJ, Tai BC, Olson TM. Lone atrial fibrillation: influence of familial disease on gender predilection. J Cardiovasc Electrophysiol. 2008;19(8):802–806 39. Gaudino M, Andreotti F, Zamparelli R, Di Castelnuovo A, Nasso G, Burzotta F, et al. The -174G/C interleukin-6 polymorphism influences postoperative interleukin-6 levels and postoperative atrial fibrillation. Is atrial fibrillation an inflammatory complication? Circulation. 2003;108(suppl 1): II195–II199 40. Splawski I, Tristani-Firouzi M, Lehmann MH, Sanguinetti MC, Keating MT. Mutations in the hminK gene cause long QT syndrome and suppress IKs function. Nat Genet. 1997; 17(3):338–340 41. Gudbjartsson DF, Arnar DO, Helgadottir A, et al. Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature. 2007;448(7151):7353–7357 42. Kaab S, Darbar D, van Noord C, et al. Large scale replication and meta-analysis of variants on chromosome 4q25 associated with atrial fibrillation. Eur Heart J. 2009;30 (7):813-819

Dilated Cardiomyopathy

15

Michelle S. C. Khoo, Luisa Mestroni, and Matthew R. G. Taylor

15.1 Introduction Dilated cardiomyopathy (DCM) is a primary heart muscle disease that is characterized by progressive ventricular dilatation and impaired systolic function.1-3 DCM is the most common cardiomyopathy, accounting for 60% of all primary cardiomyopathies4 and is a leading cause of heart failure and arrhythmia. Due to its significant prevalence, high morbidity, and mortality, including frequent hospitalizations, DCM remains a major public health concern. DCM is defined as idiopathic (sometimes termed “IDC”) when the family history appears “sporadic,” with DCM isolated in a single member of a family and without known cause; or it is defined familial when occurring in two or more related family members.1,2 Importantly, genetic factors are now understood to be the underlying cause of both idiopathic and familial forms, and the familial form may be referred to as “FDC,” which is typically applied when the family history reveals multiple affected members. DCM may present with either a pure and isolated myocardial involvement or with a complex DCM phenotype.2 In the pure form, the pathologic features are dominated by ventricular dilation and systolic dysfunction and are frequently the result of mutations in a growing list of DCM-genes such as ACTC, DES, DYS, MYH7, SGCD, TNNT2, and TTN (Table 15.1). Complex forms of DCM are accompanied by extracardiac manifestations such as skeletal muscle dystrophy. Since DCM

M. S. C. Khoo () University of Colorado Denver, 12401 East 17th. Avenue, Leprino Building, Room 559, Aurora, CO 80045, USA e-mail: [email protected]

is a relatively common disease a basic understanding of DCM genetics is required to evaluate DCM patients and their families. These concepts, along with a discussion of the expanding role of diagnostic molecular genetic testing, are the focus of this chapter. Throughout this chapter, we commonly refer to both the idiopathic and the familial forms of dilated cardiomyopathy as “DCM,” except when we specifically emphasize features of the familial form as “FDC.”

15.2 Epidemiology and Genetic Basis DCM has a prevalence of one case per 2,500 individuals5 and an incidence of 7/100,000/year.6 The incidence of DCM has been increasing, perhaps reflecting improved diagnostics and increased awareness among health care providers and the population. DCM probably remains underdiagnosed, especially in its early stages, due to the fact that affected subjects usually remain asymptomatic until the disease has progressed and when marked ventricular dysfunction has occurred. Many cases of DCM have a clear genetic origin. Studies suggest that between 30 and 50% of DCM have a genetic origin.7-9 The high frequency of genetic cases means the cardiologist should maintain a high suspicion for a genetic etiology in each DCM patient. The importance of genetic factors is reflected in the new DCM classification that considers this disorder as a “mixed” cardiomyopathy with contributing genetic and acquired factors.3 FDC is most commonly inherited in an autosomal dominant fashion wherein males and females are roughly equally affected, and the disease risk is passed from parent to 50% of offspring.5,8,10 As shown in Table 15.1, many genes have been linked to DCM, but in many instances, a genetic

R. Brugada et al. (eds.), Clinical Approach to Sudden Cardiac Death Syndromes, DOI: 10.1007/978-1-84882-927-5_15, © Springer-Verlag London Limited 2010

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Table 15.1  Known familial dilated cardiomyopathy (FDC) genes and their Online Mendelian Inheritance in Man (OMIM) references Phenotype Frequency (%) Chromo-somal Locus OMIM Gene symbol Gene location CMD1V CMDID CMDIG CMD11 CMDIK CMDIB CMDIC CMDIM CMD1T CMDIA CMD1S CMD1U CMDIN

600759 191045 102573 191040 188840 125660 172405 600884 193065 600958 600824 188380 160760 160710 104311 102540 191010 604488 605906 601439 608517

PSEN2 TNNT2 ACTN2 TNNC1 TTN DES PLN VCL MYBPC3 CSRP3 TMPO MYH7 MYH6 PSEN1 ACTC TPM1 TCAP LDB3 ABCC9 MYPN

Presenilin 2 Cardiac troponin T a-2 Actinin Cardiac troponin C Titin Desmin Phospholamban Metavinculin Myosin-binding protein C Cysteine-glycine-rich protein 3 Thymopoietin Cardiac b-myosin heavy chain Cardiac a-myosin heavy chain Presenilin 1 Cardiac actin a-Tropomyosin Tinin-cap (teletonin) Cipher/ZASP Regulatory SUR2A subunit of cardiac KATP channel Myopalladin52

191044 212110

TNN13

Cardiac troponin 1

Autosomal dominant FDC

56

1q31 1q32 1q42-q43 3p21.1 2q31 2q35 6q12-q16 9 10q21-q23 11p11 11p15.1 12q22 14q11.2-13 14q12 14q24.3 15q14 15q22 17q12 10q23.2 12p12.1 10q21.1

Autosomal recessive FDC

16

19q13.42 unknown

X-linked DCM

10

Xp21

XLCM

300377 DMD

Dystrophin

Autosomal dominant FDC with skeletal muscle disease

7.7

1q11-q23 5q33-34 4q11 6q23

LGMDIB LGMD2F LGMD2E CMDIF

150330 601411 600900 602067

LMNASGCD SGCB

Lamin A/C d-sarcoglycan b-Sarcoglycan

Autosomal dominant 2.6 FDC with cardiac conduction defects

1q1-q1 2q14-q22 3p22.2

CMDIA CMDIH CMDIE

150330 604228 600163

LMNASCN5A

Lamin A/C Na channel, voltage-gated, type V, a polypeptide

Xq28 18q12.1-q12.2 10q23.2 6q23-q24 6p24 Xq28

CMDIJ

300069 601239 605906 605362 125647 300069

TAZDTNA LDB3 EYA4 DSP TAZ

G4.5 (tafazzin) a-Dystrobrevin Cipher/ZASP Transcriptional coactivator EYA4 Desmoplakin G4.5 (tafazzin)

Rare FDC (a) LV noncompaction (b) Autosomal recessive with retinitis pigmentosa and deafness (c) Autosomal recessive with wooly hair and keratoderma (d) X-linked congenital DCM Mitochondrial DCM

7.7

mtDNA

defect cannot be found, and the familial nature of the disease is suspected based on the family history. Dysfunction of these DCM genes leads to consequent alterations in myocyte function through a variety of proposed mechanisms. Presently, there are no reliable

51000

clinical or morphologic parameters (other than the family history) that distinguish the familial form from the nongenetic form. As a result, a detailed family history is critical when evaluating these patients and families.

15  Dilated Cardiomyopathy

15.3 Clinical Diagnosis The diagnosis of DCM is suspected on the basis of heart failure symptoms and the presence of documented ventricular dilation and systolic dysfunction. The heart failure symptoms in DCM are not substantially different from other causes of heart failure. However, DCM is more likely to occur in young individuals with no obvious risk factors for heart failure (other than family history), and a history of chronic skeletal muscle weakness may also be present. The formal diagnosis relies on criteria provided by the World Health Organization/International Society and Federation of Cardiology (WHO/ISFC),1 the Guidelines of the National Heart, Lung, and Blood Institute Workshop on the Prevalence and the Etiology of Dilated Cardiomyopathy,4 and the more recent update contained in the American Heart Association Scientific Statement on Contemporary Definitions and Classification of the Cardiomyopathies.3 Useful and detailed criteria that account for familial forms of DCM as well are described in the Guidelines for the Study of Familial Dilated Cardiomyopathies.2 Patients initially present with typical symptoms and signs of heart failure, because of either volume overload or low cardiac output, or both. Usually, by the time of the diagnosis, probands (the first individual diagnosed within a family) have severe impairment of the left ventricular systolic function. Affected relatives, on the other hand, can be asymptomatic with mild ventricular dilatation and dysfunction. Increasingly, the diagnosis is being made on the basis of family screening of clinically asymptomatic relatives of DCM cases. Educated patients may request such screening on the basis of having an affected family member diagnosed with DCM. Twenty to thirtyfive percent of patients present with chest pain, mostly during exercise, and the electrocardiogram (ECG) may show pseudoinfarction Q waves. Angina pectoris is thought to be due to limited coronary vascular reserve. Fatigue is common and is present in almost one-third of patients. Palpitations are very common, due to ventricular arrhythmias; nevertheless, syncope and sudden death rarely constitute the first symptom of the disease. Pulmonary and systemic thromboembolisms occur, as first manifestation of the disease, at a rate of 1–6%/ year. Most of them can be found in cases with severe left ventricular dilatation and dysfunction.

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Subtle skeletal muscle disease can complicate DCM, and at times, this is a valuable clinical clue. The explanation for skeletal muscle involvement is that mutations in DCM genes often affect proteins that also function in skeletal muscle. This is also exemplified in primary skeletal muscle myopathies, in which cardiac disease is a frequent and often morbid secondary manifestation. The importance of recognizing the clinical link between skeletal and cardiac muscle disease was recently reviewed.11 A particular form of familial DCM due to mutation of the lamin A/C gene12,13 presents with mild dilatation and severe dysfunction of the left ventricle, conduction abnormalities, supraventricular arrhythmias, variable skeletal muscle involvement, and variable serum creatine kinase (CPK) levels. The prognosis for many of these patients is not favorable. X-linked FDC, due to mutations in the dystrophin gene, also presents with increased CPK, muscular abnormalities, and the typical findings of dystrophinopathy at the skeletal muscle biopsy.14-17

15.4 Clinical Diagnosis Echocardiography is the most common diagnostic modality used to identify and monitor progression of DCM. Other approaches including data from nuclear studies, magnetic resonance imaging, and cardiac catherization may also suggest the diagnosis. DCM is diagnosed in the presence of (a) fractional shortening of less than 25% (>2 standard deviations) and/or ejection fraction less than 45%, and (b) left ventricular end-diastolic diameter (LVEDD) greater than 117% (>2 standard deviations) of the predicted value corrected for age and body surface area),18 excluding any known cause of myocardial disease. Familial DCM (FDC) is defined by the presence of (a) two or more affected relatives with DCM meeting the earlier criteria, or (b) a relative of a DCM patient with unexplained sudden death before the age of 35 years. In FDC, family members may be classified as affected, unaffected, or unknown.2 This classification is based on major and minor criteria that have been developed to account for the high frequency of minor cardiac abnormalities within families with FDC and the need of more sensitive criteria5,10 In relatives, the affected status is defined by the presence of (a) two major criteria consisting of left ventricular systolic

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dysfunction (fractional shortening < 25% and/or ejection fraction < 45%) and dilatation (LVEDD > 117% of the predicted value corrected for age and body surface area), (b) left ventricular dilatation (as defined earlier) and one minor criterion, or (c) three minor criteria. Persons with normal heart function or who have another cause of myocardial dysfunction present are considered unaffected with respect to DCM. The unknown status is defined by the presence of one or two minor criteria and sometimes identifies persons transitioning from unaffected to affected status. Minor criteria of disease are: (a) unexplained supraventricular arrhythmias (atrial fibrillation or sustained arrhythmias), or frequent (>1,000/24 h) or repetitive (three or more ectopic beats with a heart rate > 120 beats/min) ventricular arrhythmias before the age of 50; (b) modest left ventricular dilatation (LVEDD > 112% of the predicted value); (c) left ventricular dysfunction (ejection fraction < 50% or fractional shortening < 28%); (d) unexplained cardiac conduction system disease (grade II or III atrioventricular blocks, complete leftventricular bundle branch block, or sinus node dysfunction); (e) unexplained sudden death or stroke before 50 years of age; (f) segmental wall motion abnormalities (>1 segment, or one if not previously present) in the absence of intraventricular conduction defect or ischemic heart disease. Laboratory studies, outside molecular genetic testing (reviewed later), are generally unhelpful in the diagnosis of DCM. Elevated B-type natriuretic peptide levels are present in affected patients but do not distinguish DCM from other causes of heart failure. In some cases, elevated serum creatine kinase levels are seen, reflecting underlying skeletal muscle disease. This abnormality may precede overt echocardiographic changes and can be useful in FDC families to identify asymptomatic family members who are at risk to develop DCM in the future. Our practice is to screen at-risk relatives using creatine kinase levels, although a normal result probably has a low specificity. The importance of the family history cannot be overstated, as a careful family history will frequently uncover evidence of an underlying FDC. In general, data should be collected on all living and deceased relatives over three or more generations. Attention should be paid more to adult relatives than children, who may be too young to present with disease even if they are carrying genetic mutations. In addition to asking about DCM, heart failure, and unexplained early

M. S. C. Khoo et al.

deaths, the physician should ask if any relatives have: skeletal muscle weakness, elevated creatine kinase levels, cognitive problems (in males this could be a sign of dystrophin mutations or Danon disease), arrhythmias, syncope, pacemakers, defibrillators, and cardiac transplantation. Prior studies have shown that the yield of family history data increases when echocardiograms have been performed on relatives (most often firstdegree relatives) of an affected individual. Reported data about living and deceased family members should also be confirmed by evaluating relatives and/or reviewing relatives’ medical records. The collection and interpretation of family history data represents an inexpensive tool, but it is time consuming. Data in the primary care literature have shown that clinicians infrequently take a complete family history and that time constraints are a major barrier to collection of these data. The authors’ impression is that similar time limitations affect cardiologists. The introduction of computer-based software to facilitate family history data collection and reporting by patients may improve the accuracy and completeness of the family history.

15.5 Differential Diagnosis In one sense, DCM is a diagnosis of exclusion to be considered when other secondary causes of cardiac dysfunction are not present. Thus, other risk factors for heart failure represent exclusion criteria for idiopathic/ familial DCM, including (a) blood pressure more than 160/110 mmHg, documented and confirmed through repeated measurements; (b) obstruction (more than 50%) of a major branch of the coronary artery; (c) alcohol intake more than 100 g/day; (d) persistent high rate supraventricular arrhythmia or frequent ventricular ectopy; (e) systemic diseases; (f) pericardial diseases; (g) congenital heart diseases; and (h) cor pulmonale. The exclusion criteria probably are not absolute and should be evaluated in the context of the family history. In the presence of a strong family history of multiple affected relatives, a diagnosis of FDC should be strongly considered, even if some members also have exclusion criteria. DCM should be distinguished from other forms of secondary dilatation and dysfunction of the ventricles due to known cardiac or systemic processes.1 These were referred to as specific cardiomyopathies in the

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previous WHO classification and are named for the disease process with which they are associated, such as ischemic cardiomyopathy, valvular heart cardiomyopathy, hypertensive cardiomyopathy, alcoholic cardiomyopathy, and myocarditis. Importantly, the authors note multiple instances of FDC where cardiac dysfunction was initially attributed to myocarditis on the basis of suspected, but poorly documented, viral exposure. The specific or “secondary” forms are now excluded by the 2006 American Heart Association classification scheme which considers “cardiomyopathies” as only primary myocardial disorders.3 Instead, cardiomyopathies are classified etiologically into genetic, mixed (genetic and nongenetic), and acquired categories. Genetic cardiomyopathies include hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy/dysplasia, left ventricular noncompaction, conduction system disease, and the various ion channelopathies. Mixed cardiomyopathies have both genetic and nongenetic causes and include DCM and primary restrictive nonhypertrophied cardiomyopathy. Acquired cardiomyopathy includes inflammatory cardiomyopathy (myocarditis), stress cardiomyopathy (tako-tsubo syndrome), peripartum cardiomyopathy, tachycardiainduced cardiomyopathy, and infants of insulin-dependent diabetic mothers. Secondary cardiomyopathies have multiple causes, of which some are listed in Table 15.2. It should be noted that cases of myocarditis and peripartum cardiomyopathy can occur in a familial setting, where cases of DCM can also be present, and therefore, it may be difficult to classify these forms.10 Table 15.3 shows the diagnostic tools available for differentiating the different forms of DCM.

15.6 Diagnosis The basic evaluation in the proband consists of an accurate detailed family history, physical examination with specific attention to the neuromuscular exam, serum creatine kinase level, chest X-ray, electrocardiogram, and echocardiogram (Fig.  15.1). In selected cases, an exercise stress test or a pharmacological stress test, such as dobutamine echocardiography or adenosine nuclear imaging, may be indicated to induce ischemia and unmask an ischemic cardiomyopathy. More specific diagnostic tests for selected patients include hemodynamic and coronary angiographic 2

Table 15.2  Secondary cardiomyopathies3 Infiltrative Amyloidosis (primary, familial autosomal dominant†; secondary forms) Gaucher disease† Hurler’s disease† Hunter’s disease†

Storage Hemochromatosis Fabry’s disease† Glycogen storage disease (type II, Pompe) Niemann-Pick disease† Danon disease†

Toxicity Drugs, heavy metals, chemical agents

Inflammatory (granulomatous) Sarcoidosis

Endocrine Diabetes Mellitus† Hyperthyroidism Hypothyroidism Hyperparathyroidism Phaeochromocytoma Acromegaly

Neuromuscular/neurological Friedreich’s ataxia† Duchenne-Becker muscular dystrophy† Emery-Dreyfuss muscular dystrophy† Myotonic dystrophy† Neurofibromatosis† Tuberous sclerosis†

Cardiofacial Noonan syndrome† Lentiginosis†

Nutritional deficiencies Beriberi (thiamine), pellagra, scurvy, selenium, carnitine, kwashiorkor

Autoimmune/collagen Systemic lupus erythematosis Dermatomyositis Rheumatoid arthritis Scleroderma Polyarteritis nodosa

Infectious Viral myocarditis HIV (human immunodeficiency virus) Chagas’ disease (Trypanosoma cruzi) Lymes disease (Borrelia burgdoferi) Whipple’s disease (Trypanosoma whippeili)

Endomyocardial Consequence of cancer Endomyocardial fibrosis therapy Anthracyclines: doxorubicin Hypereosinophillic syndrome (Ló´effler’s endocarditis) (adriamycin), daunorubicin Cyclophosphamide Radiation Other Electrolyte imbalance Tako-Tsubo (psychological stress) † Genetic origin

study, cardiac magnetic resonance imaging, cardiac CT, radionuclide ventriculography, and endomyocardial biopsy. Arrhythmia monitoring utilizing ECG Holter or event monitor may also be required if there is suspicion for tachyarrhythmias or bradyarrhythmias. In the presence of neuromuscular abnormalities, skeletal muscle biopsy is indicated.

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Table 15.3  Etiology and diagnostic tools in Dilated Cardiomyopathy (DCM) Causes of % Cases Pertinent Diagnostic Tools Cardiomyopathy Frequent Idiopathic/Familial

20 – 50

Family history, echocardiogram, cardiac MRI, detailed evaluation of first degree relatives, coronary angiography, edomyocardial biopsy

Ischemic

50 – 70

History, coronary angiography

Valvular

1.5 – 4

History, echocardiogram, cardiac MRI

Hypertensive

2–4

History, physical exam, echocardiography

Alcoholic

3 – 40

History, echocardiography

Myocarditis

5 – 10

History, echocardiography, cardiac MRI, endomyocardial biopsy

Rare Peripartum

History, echocardiogram

Amyloidosis

Extra-cardiac findings, echocardiogram, cardiac MRI, endomyocardial biopsy

Hemochromatosis

Extra-cardiac signs, iron studies, echocardiogram, endomyocardial biopsy

Sarcoidosis

Extra-cardiac signs, echocardiogram, cardiac MRI, endomyocardial biopsy

Anthracycline-induced cardiotoxicity

History of chemotherapy

Other toxic substances

History

Metabolic

Pediatric age, laboratory tests

Algorithm for Assessing DCM/FDC DCM Suspected (in Proband)

Evalution: history, physical, ECG, Echo, CXray, CK, 3-generation family history

Longitudinal Echos: asymptomatic at-risk relatives (~2−3 years) ONLY Mutation ALL at risk Carriers

>2 cases of DCM in family?

No

Yes

Secondary Cardiomyopathy Present?

No

Yes*

Treat/Manage 2° Cardiomyopathy

Treat / Manage: DCM

Consider molecular genetic testing

Fig.  15.1  Algorithm assessing DCM/FDC

FDC

No

Yes

Mutation Found?

• Treat/Manage DCM/FDC in proband and relatives • prophylactic defibrillators for LMNA mutations • Genetic Counseling • Test relatives

for * if secondary cardiomyopathy had genetic basis, genetic counseling and evaluation of relatives is indicated

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Molecular genetic diagnosis should be considered when the test is available and may impact the clinical management. Since a DCM diagnosis carries potential impact to biological relatives, genetic testing in the proband may be justified to identify which at-risk relatives actually carry the genetic defect and need longterm monitoring. At present, molecular genetic analysis is available for only a subset of all described DCM genes. The principal logistic limitations on genetic testing have been related to the large number of genes, many of which are lengthy genes, and the high costs of molecular genetic sequencing of multiple genes. More recently, newer technologies have improved the outlook of such testing and while still moderately expensive, DCM-gene panels allow for the simultaneous testing of multiple genes in a single assay. Larger gene panels have the added benefit of higher clinical sensitivity for mutation detection. While testing represents a significant up front expense, when a mutation is detected other at-risk relatives can be tested so that echocardiographic screening of family members is only applied to the subset of relatives carrying the genetic defect. The most commonly mutated (8%) gene is lamin A/C (LMNA). LMNA mutations appear to carry a poor prognosis, which may impact management; consequently, clinical testing for LMNA mutations should be considered in all DCM patients, especially in those with family history, conduction system disease, and elevated creatinine kinase levels.13,19,20 The poor prognosis associated with LMNA mutations has led some to argue for prophylactic defibrillator therapy in LMNA patients who appeared to benefit from device therapy in one study even when the degree of systolic dysfunction was not severe.20

15.7 Genetic Basis In FDC, there is evidence of Mendelian segregation of disease phenotype in the family history. Clinically and genetically, FDC is a heterogeneous entity and ­different forms may sometimes be distinguished based on patterns of transmission and characteristics of the ­phenotype.10 When classifiable, the clinical patterns encountered include: autosomal dominant FDC without extracardiac manifestations; autosomal recessive FDC; FDC with X-linked transmission; autosomal dominant FDC with subclinical skeletal muscle involvement;

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autosomal dominant FDC with conduction defects; autosomal dominant left ventricular noncompaction; unclassifiable FDC with retinitis pigmentosa and hearing loss.8,10 Right ventricular cardiomyopathy/or arrhythmogenic right ventricular dysplasia is considered a distinct entity.1 There is clear evidence of incomplete penetrance (proportion of persons with the genetic defect who manifest the disease) as well as age-­ dependent penetrance (increasing penetrance with age), exemplified by the fact that FDC is typically an adultonset disease and many persons carrying mutations do not develop overt disease until their fifth or sixth decade of life.21 Carefully designed studies of larger FDC families (by genetic linkage analysis and other methods) have implicated over 28 chromosomal loci as containing FDC genes. Several different genes at these loci have been identified to date (Table 15.1). The majority of these genes encode proteins that have cytoskeletal and/or contractile properties. However, genes of the nucleoskeleton and, more recently, ion channel encoding genes are also relevant in FDC patients.13,22,23 In the case of ion channel DCM mutations, arrhythmogenic problems such as sick sinus syndrome may provide clues to ion channel involvement.23 The family history can be useful when an inheritance pattern other than autosomal dominant is suggested. X-linked inheritance can provide a clue for mutations in the dystrophin gene (DMD). In some cases the family history is positive for actual Duchenne or Becker muscular dystrophy due to DMD mutations in one or more males. In these families, females may be spared any significant skeletal muscle symptoms but may develop DCM later in midlife. DMD mutations have also been reported in males where DCM is the only manifestation, and this might be suspected if the family history shows two affected male relatives connected through an ostensibly healthy female (e.g., uncle/nephew relationship through a healthy female). When cases of Woff-Parkinson White syndrome and/ or hypertrophic cardiomyopathy are also present in the family history, Danon disease should be suspected. Danon disease is due to mutations in the LAMP-2 gene and was classically described as an X-linked disorder causing hypertrophic cardiomyopathy, skeletal myopathy, and mental retardation in males. More recently it has been shown that some Danon families have DCM, particularly in females with LAMP-2 mutations and occasionally the condition presents as an X-linked

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DCM pedigree.24 Other findings in Danon disease include elevated creatine kinase levels and retinal pigmentary changes in males and females, which may precede the onset of cardiomyopathy.25 In pedigrees where matrilineal inheritance is observed, mitochondrial mutations should be considered. Most mutations described so far have been private mutations and are not shared between unrelated families. Unfortunately, this limits the body of knowledge available for each reported mutation and makes predictions about prognosis imprecise. To date, studies have primarily focused on highly selected families and/or on relatively small numbers of families. Consequently, the genetic epidemiology of mutations in FDC genes across all FDC families remains unknown. Furthermore, as mutations have now been described in seemingly nonfamilial cardiomyopathies (sporadic or truly “idiopathic” DCM), the contribution of FDC gene mutations to isolated or sporadic dilated cardiomyopathies is still not properly understood. Several DCM mutation databases now exist and presumably will increase the understanding of the features of the more commonly reported mutations.

15.8 Management and Treatment Strategies The management of DCM focuses on limiting the progression of the cardiomyopathic process, preventing decompensated heart failure and controlling arrhythmia and preventing sudden death. Overall, this management is not substantially different from general heart failure therapy and includes judicious use of medications and evaluation for heart transplant in selected cases.

15.9 General Measures These are best achieved within a disease management program and include patient education, salt and fluid restriction, treatment of hypertension, limitation of alcohol intake, control of body weight, and encouraging moderate exercise, preferably aerobic in a controlled environment.

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15.9.1 Pharmacological Therapy Pharmacotherapy includes a multitude of agents utilized in the standard approaches to heart failure.26 Only selected agents in each class will be mentioned here. Angiotensin-converting enzyme (ACE) inhibitors reduce mortality, hospitalization, and heart failure progression, as shown in several trials including CONSENSUS,27 SOLVD,28 and SAVE29 These drugs are generally started at low doses and are gradually titrated up to doses equivalent to those showing efficacy in randomized trials. Captopril is increased to a maximum of 50 mg three times/day. The maximum dose of Enalapril is 20 mg twice/day and that for Lisinopril is 40 mg once/day. The highest tolerated doses provide the most benefit. Angiotensin receptor blockers (ARBs) are an acceptable alternative to ACE inhibitors in patients who are intolerant to these agents. The use of ARB is based on trials such as ELITE-I and II,30 Val-HeFT,31 and OPTIMAAL.32 The dose of Losartan used in these trials was 50 mg once/day. The maximum dose of Valsartan is 160 mg twice/day. The addition of an ARB to an ACE inhibitor likely offers little additional benefit based on the Val-HeFT trial.28 In general, the frequency of cough in ARB-treated patients has consistently been lower than patients who receive ACE inhibitors.33-35 Angioedema is a potentially fatal but rare side effect in ACE therapy.36 Although the incidence of angioedema in ARB therapy is less than ACE therapy, it has been recommended that ARBs should be used cautiously, if at all, in patients who have experienced ACE-related angioedema.37 First-generation calcium channel blockers are generally not recommended in heart failure patients. Endothelin antagonists have been disappointing and these agents are not recommended in standard guidelines. Diuretics have not been assessed in a randomized study to verify their effect on survival in heart failure. Furosemide is used at daily doses of 20–600 mg daily. Bumetanide and ethacrynic acid are other loop diuretics currently in use. Torsemide has better bioavailability when taken orally and is used in some patients who do not respond to oral furosemide. Frequently, the dose is half of that of furosemide for a similar effect. When high doses of loop diuretics are needed and, especially if the patient has diuretic resistance, metolazone is added, usually at a dose of 2.5 mg once/day to 5 mg twice/day. Acetazolamide is used at

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a dose of 250–500 mg daily in some patients with metabolic alkalosis. Aldosterone inhibitors such as spironolactone and eplerenone reduce mortality, as noted in RALES38 and EPHESUS39, respectively. Spironolactone is used at doses ranging from 12.5 to 50 mg once/day. Eplerenone was started with a dose of 25 mg orally once/day, increased to 50 mg once/day as tolerated. Eplerenone is more selective for the aldosterone receptor and avoids some of the side-effects associated with spironolactone, such as gynecomastia. Vasopressin antagonists are still under investigation. Natriuretic peptides are available only intravenously for acute decompensation. The only inotrope which is still accepted for use in heart failure is digoxin. It is dosed at 0.125–0.25 mg once/day and is adjusted to renal function. A post hoc analysis of the Digitalis Investigators Group divided the patients on the basis of their digoxin serum level and showed that all-cause mortality was reduced by 6.3% in the subgroup of patients whose level was between 0.5 and 0.8 ng/mL40, and at higher serum concentrations, digoxin reduced hospitalizations but did have any effect on mortality.41 Beta-adrenergic blockers are considered a major advance in the therapy of heart failure. CIBIS-II42 and MERIT-HF43 showed a 34% relative reduction in allcause mortality using bisoprolol and metoprolol succinate (both beta-1 selective blockers). Carvedilol, a nonselective beta-blocker with alpha-blocking properties, reduced mortality by 35% in severe heart failure (COPERNICUS).44 Beta-blocking agents must be titrated gradually toward their target doses. The target dose of carvedilol is 25 mg twice/day in patients less than 70 kg, and 50 mg twice/day in heavier patients. The use of anticoagulants/antiplatelet agents is a controversial subject, and more studies are underway to identify which therapy to use, and in whom. In clinical practice, anticoagulation is commonly used in patients with a left ventricular ejection fraction less than 30%.

15.9.2 Device Therapy Cardiac resynchronization therapy (CRT) with biventricular pacing is now well established to improve symptoms and, in many cases, improve left ventricular function in advanced heart failure, leading to reduced hospitalizations and overall mortality. In the COMPANION45 trial,

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CRT reduced the risk of death and hospitalization for any cause by approximately 20%, with a 50% reduction in the risk of death for any cause in the subgroup of patients with nonischemic DCM randomized to receive CRT-defibrillator. The CARE-HF46 trial showed a 35% relative risk reduction in combined mortality in patients with all forms of dilated cardiomyopathy and congestive heart failure who received CRT. In the treatment and prevention of sudden death from ventricular arrhythmias, implantable cardioverter defibrillators (ICDs) are more effective in reducing mortality from sudden death compared to antiarrhythmic drugs.47,48 The SCD-HeFT49 trial showed a 23% relative risk reduction of the primary endpoint of death from any cause in the prophylactic ICD arm compared with placebo. Radiofrequency catheter ablation therapy can be considered in patients who have received appropriate recurrent ICD discharges for ventricular tachycardia in order to reduce the frequency of further ICD shocks.50,51 Supraventricular arrhythmias can cause inappropriate ICD discharges and can also be successfully ablated in patients with DCM. The use of left ventricular assist devices (LVAD) was evaluated in REMATCH52 All-cause mortality was 52% at 1 year in the LVAD group v. 25% in the medical group. The benefits of LVADs are tempered by a multitude of device-related complications. Finally, patients with severe heart failure, severe reduction of the functional capacity, and depressed left ventricular ejection fraction have a low survival rate and may require heart transplant. In this setting, heart transplantation improves survival and quality of life.

15.10 Asymptomatic Left Ventricular Dysfunction The genetic nature of DCM raises novel challenges for the cardiologist, in particular the attention that must be paid to at-risk relatives as well as the identification (through family screening) of patients with asymptomatic left ventricular dysfunction. So far, no trials exist on the usefulness of therapy in asymptomatic affected relatives. However, based on studies on ischemic heart disease, it is believed that an early use of ACE inhibitors and/or beta adrenergic blockers could be significant in slowing disease progression. Anecdotally, we have observed short-term improvement in asymptomatic

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cases with such therapy; whether and for how long such responses can be sustained remains unknown.

15.11 Genetic Counseling Genetic counseling approaches for familial FDC are still in development and consensus guidelines are lacking. The importance of genetic counseling is widely acknowledged53-55 and ideally evaluations of FDC should occur in specialized cardiomyopathy centers, although this interest and expertise is not available in many settings. In general, a detailed family history including data from three generations should be obtained. Attention should be paid to DCM as well as cases of unexplained early death or heart failure presumed to be due to viral infections or even post partum causes. If DCM remains possible, then echocardiography of first-degree relatives should be encouraged. In many instances, relatives are not available, willing, or living to be evaluated. The sensitivity of echocardiography in children is modest at best given the adultonset nature of most cases of DCM. In addition to collecting family history data, the role of the genetic counselor includes an explanation of the likelihood of a genetic defect contributing to a DCM diagnosis and discussions of inheritance patterns, disease risks to offspring, and the benefits and limitations of proceeding to genetic testing. Increasingly, reproductive decision making will utilize genetic testing results to help patients with family planning. Given the adult-onset nature of most cases of DCM, genetic testing in young children is not usually recommended in most cases. The limited sensitivity of echocardiography in children along with the substantial expenses of echocardiography screening in all relatives in a large family argue for consideration of genetic testing to identify which relatives carry DCM gene mutations. For FDC under an autosomal dominant model only 50% of ­at-risk relatives can be expected to inherit a DCM gene mutation. When successful in detecting a DCM mutation, genetic testing offers the potential to identify those relatives who need genetic counseling and echocardiographic monitoring from family members who are not at elevated risk. Several laboratories now offer genetic testing (www.genetests.org) which should usually be used in the context of formal genetic counseling. Importantly, genetic testing should be initiated

M. S. C. Khoo et al.

in affected individuals whenever possible; if testing reveals a pathogenic mutation then testing can be extended to at-risk relatives. Testing of healthy asymptomatic patients with normal echocardiograms and creatine kinase levels just because of their family history is expected to have limited yield. The high degree of genetic heterogeneity, uncertainty as to which familial DCM genes are commonly mutated, and the propensity to uncover private mutations, all conspire to make DCM genetic testing complex. Limited knowledge of DCM genetics and the lack of thorough evaluation of relatives at risk by practicing generalists and cardiologists likely also contribute to under-recognition of this condition. An accurate family history and screening of first-degree relatives has fundamental importance in the evaluation of DCM but is not widely or uniformly performed. When possible, each first-degree relative should undergo a detailed physical examination, electrocardiogram, and echocardiogram. Serum creatinine kinase levels can also be useful, especially if the proband has elevation of this marker. Signal averaged electrocardiography has also been suggested as an additional diagnostic tool.56 The thorough evaluation of relatives of patients is standard for the research studies of DCM. For families where a pathogenetic mutation has been detected, the evaluation of relatives at risk can include molecular testing to confirm the presence or absence of the pathologic mutation. This approach means that relatives who are not at risk can be reassured of their status. For individuals harboring a mutation, this information can be integrated into the genetic counseling provided to each individual within that family. Asymptomatic carriers who are at increased risk of disease may be considered for regular evaluations (including echocardiogram) to screen for the development of early disease. As incomplete penetrance is a feature of this disease, the counseling session of asymptomatic mutation carriers should focus on the increased risk of developing DCM for mutation carriers, rather on models that implies a certainty of disease for all mutation carriers. In families where a disease-causing mutation has not been detected, genetic counseling is understandably less precise. A detailed examination and analysis of the pedigree is essential to define, if possible, the likely mode of inheritance. Implicit in this exercise is that historical information provided about relatives should be confirmed through either direct evaluation of relatives or reviewing medical records and/or autopsy reports. In

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performing the genetic counselling, careful attention to the problems of age dependent and incomplete penetrance should be integrated into the discussion.

15.12 Unresolved Questions Our understanding of DCM continues to evolve. The past decade was deeply focused on DCM gene discovery, whereas research has now moved deeply into understanding the mechanisms underlying the condition. The different genes involved suggest potentially different pathways that are dysfunctional and raise the possibility of several avenues for developing therapy. In the clinical arena, the expansion of genetic testing and the improved sensitivity of DCM gene-panels are increasing the number of DCM cases for which a genetic diagnosis is obtained. Since genetic testing can identify patients with early-stage or even presymptomatic disease, increased interest in contemplating the institution of early therapy or even preventive measures represents an exciting new area of research. Lastly, genetic counseling continues to evolve in this field, and as cardiologists are increasingly comfortable, this area will likely become a common part of the clinical cardiology visit.

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189 idiopathic dilated cardiomyopathy. N Engl J Med. 1992;326: 77–82   6. Codd MB, Sugrue DD, Gersh BJ, Melton LJ. Epidemiology of idiopathic dilated and hypertrophic cardiomyopathy. A population-based study in Olmsted County, Minnesota, 1975–1984. Circulation. 1989;80:564–572   7. Gregori D, Rocco C, Miocic S, Mestroni L. Estimating the frequency of familial dilated cardiomyopathy in the presence of misclassification errors. J Appl Stat. 2001;28:53–62   8. Grünig E, Tasman JA, Kucherer H, Franz W, Kubler W, Katus HA. Frequency and phenotypes of familial dilated cardiomyopathy. J Am Coll Cardiol. 1998;31:186–194   9. Baig MK, Goldman JH, Caforio ALP, Coonar AS, Keeling PJ, McKenna WJ. Familial dilated cardiomyopathy: cardiac abnormalities are common in asymptomatic relatives and may represent early disease. J Am Coll Cardiol. 1998;31: 195–201 10. Mestroni L, Rocco C, Gregori D, et al. Familial dilated cardiomyopathy: evidence for genetic and phenotypic heterogeneity. J Amer Coll Cardiol. 1999;34:181–190 11. McNally EM, Towbin JA. Cardiomyopathy in muscular dystrophy workshop. 28–30 September 2003, Tucson, Arizona. Neuromuscul Disord. 2004;14:442–448 12. Brodsky GL, Muntoni F, Miocic S, Sinagra G, Sewry C, Mestroni L. A lamin A/C gene mutation associated with dilated cardiomyopathy with variable skeletal muscle involvement. Circulation. 2000;101:473–476 13. Taylor MR, Fain PR, Sinagra G, et  al. Natural history of dilated cardiomyopathy due to lamin A/C gene mutations. J Am Coll Cardiol. 2003;41:771–780 14. Muntoni F, Wilson L, Marrosu MG, et al. A mutation in the dystrophin gene selectively affecting dystrophin expression in the heart. J Clin Invest. 1995;96:693–699 15. Milasin J, Muntoni F, Severini GM, et al. A point mutation in the 5’ splice site of the dystrophin gene first intron responsible for X-linked dilated cardiomyopathy. Hum Mol Genet. 1996;5:73–79 16. Muntoni F, Di Lenarda A, Porcu M, et al. Dystrophin gene abnormalities in two patients with idiopathic dilated cardiomyopathy. Heart. 1997;78:608–612 17. Muntoni F, Cau M, Ganau A, et al. Brief report: deletion of the dystrophin muscle-promoter region associated with X-linked dilated cardiomyopathy. N Engl J Med. 1993;329: 921–925 18. Henry WL, Gardin JM, Ware JH. Echocardiographic measurements in normal subjects from infancy to old age. Circulation. 1980;62:1054–1061 19. van Tintelen JP, Hofstra RM, Katerberg H, et al. High yield of LMNA mutations in patients with dilated cardiomyopathy and/or conduction disease referred to cardiogenetics outpatient clinics. Am Heart J. 2007;154:1130–1139 20. Meune C, Van Berlo JH, Anselme F, Bonne G, Pinto YM, Duboc D. Primary prevention of sudden death in patients with lamin A/C gene mutations. N Engl J Med. 2006;354: 209–210 21. Mestroni L, Krajinovic M, Severini GM, et  al. Familial dilated cardiomyopathy. Br Heart J. 1994;72:35–41 22. Bienengraeber M, Olson TM, Selivanov VA, et al. ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating. Nat Genet. 2004;36: 382–7

190 23. McNair WP, Ku L, Taylor MR, et al. SCN5A mutation associated with dilated cardiomyopathy, conduction disorder, and arrhythmia. Circulation. 2004;110:2163–2167 24. Taylor MR, Ku L, Slavov D, et al. Danon disease presenting with dilated cardiomyopathy and a complex phenotype. J Hum Genet. 2007;52:830–835 25. Prall FR, Drack A, Taylor M, et al. Ophthalmic manifestations of Danon disease. Ophthalmology. 2006;113:1010–1013 26. Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation. 2005;112:e154–235 27. Anon. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group. N Engl J Med. 1987;316:1429–1435 28. Anon. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators. N Engl J Med. 1991;325: 293–302 29. Pfeffer MA, Braunwald E, Moye LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med. 1992;327:669–677 30. Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial – the Losartan Heart Failure Survival Study ELITE II. Lancet. 2000;355: 1582–1587 31. Cohn JN, Tognoni G. A randomized trial of the angiotensinreceptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345:1667–1675 32. Dickstein K. Kjekshus J. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan. Lancet. 2002;360:752–760 33. Pfeffer MA, McMurray JJ, Velazquez EJ, et  al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003;349:1893–1906 34. Benz J, Oshrain C, Henry D, Avery C, Chiang YT, Gatlin M. Valsartan, a new angiotensin II receptor antagonist: a double-blind study comparing the incidence of cough with lisinopril and hydrochlorothiazide. J Clin Pharmacol. 1997; 37:101–107 35. Lacourciere Y, Brunner H, Irwin R, et al. Effects of modulators of the renin-angiotensin-aldosterone system on cough. Losartan Cough Study Group. J Hypertens. 1994;12: 1387–1393 36. Vleeming W, van Amsterdam JG, Stricker BH, de Wildt DJ. ACE inhibitor-induced angioedema. Incidence, prevention and management. Drug Saf. 1998;18:171–188 37. Sica DA, Black HR. Angioedema in heart failure: occurrence with ACE inhibitors and safety of angiotensin receptor blocker therapy. Congest Heart Fail. 2002;8:334–341; 345

M. S. C. Khoo et al. 38. Pitt B, Zannad F, Remme WJ. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341:709–717 39. Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003; 348:1309–1321 40. Peter M, Nakagawa J, Doree M, Labbe JC, Nigg EA. In vitro disassembly of the nuclear lamina and M phase-specific phosphorylation of lamins by cdc2 kinase. Cell. 1990;61: 591–602 41. Ahmed A, Rich MW, Fleg JL, et  al. Effects of digoxin on morbidity and mortality in diastolic heart failure: the ancillary digitalis investigation group trial. Circulation. 2006;114: 397–403 42. Anon. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999;353:9–13 43. Effect of metoprolol CR/XL in chronic heart failure. Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999;353: 2001–2007 44. Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001;344:1651–1658 45. Bristow MR, Mestroni L, Bohlmeyer TJ, Gilbert EM. Dilated Cardiomyopathies. In: al FVe, ed. Hurst’s The Heart. New York: McGraw-Hill; 2001:1947–1966 46. Caforio ALP, Bonifacio E, Stewart JT, et  al. Novel organspecific circulating cardiac autoantibodies in dilated cardiomyopathy. J Am Coll Cardiol. 1990;15:1527–1534 47. Anon. A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from nearfatal ventricular arrhythmias. The Antiarrhythmics versus Implantable Defibrillators (AVID) Investigators. N Engl J Med. 1997;337:1576–1583 48. Goldberger Z, Lampert R. Implantable cardioverter-defibrillators: expanding indications and technologies. Jama. 2006; 295:809–818 49. Bardy GH, Lee KL, Mark DB, et  al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med. 2005;352:225–237 50. Stevenson WG, Soejima K. Catheter ablation for ventricular tachycardia. Circulation. 2007;115:2750–2760 51. Hsia HH, Marchlinski FE. Characterization of the electroanatomic substrate for monomorphic ventricular tachycardia in patients with nonischemic cardiomyopathy. Pacing Clin Electrophysiol. 2002;25:1114–1127 52. Rose EA, Gelijns AC, Moskowitz AJ, et  al. Long-term mechanical left ventricular assistance for end-stage heart failure. N Engl J Med. 2001;345:1435–1443 53. Taylor MR, Carniel E, Mestroni L. Cardiomyopathy, familial dilated. Orphanet J Rare Dis. 2006;1:27 54. Robin NH, Tabereaux PB, Benza R, Korf BR. Genetic testing in cardiovascular disease. J Am Coll Cardiol. 2007; 50:727–737 55. Schönberger J, Seidman CE. Many roads lead to a broken heart: the genetics of dilated cardiomyopathy. Am J Hum Genet. 2001;69:249–260 56. Yi G, Keeling PJ, Hnatkova K, Goldman JH, Malik M, McKenna WJ. Usefulness of signal-averaged electrocardiography in evaluation of idiopathic-dilated cardiomyopathy in families. Am J Cardiol. 1997;79:1203-1207

Hypertrophic Cardiomyopathy

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Abbreviations LVH Left ventricular hypertrophy VF/VT Ventricular fibrillation/ventricular tachycardia

success depends on early detection of those at risk, particularly, the asymptomatic individuals in order to prevent tragic events. Increased awareness of the physicians along with robust and comprehensive means of early detection, risk stratification, and intervention would be necessary to successfully mitigate the risk of SCD in patients with HCM.

16.1 Introduction Since the original description of hypertrophic cardiomyopathy (HCM) in the nineteenth century, sudden cardiac death (SCD) has been the most dreadful but fortunately uncommon manifestation of HCM. The death is tragic as it often occurs without distinct warning signs or symptoms in apparently healthy and young athletes. Consequently, HCM has received considerable media coverage and publicity because of occasional catastrophic death of professional athletes in the field or soon after participation in competitive sports. However, despite the recognition of SCD as a catastrophic outcome in HCM, the efforts to resolve the problem have been compounded by the lack of reliable predictors of the risk of SCD as well as the relatively low prevalence of HCM in the general population and hence inadequate awareness about the disease on routine daily medical practice. The advent of the automatic internal cardioverter/defibrillator (AICD) has somewhat alleviated the risk of SCD. However, the

A. J. Marian  Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, 6770 Bertner Street, Texas Heart Institute at St. Luke’s Episcopal Hospital, DAC 900A Houston, TX 77030, USA e-mail: [email protected]

16.2 Clinical Manifestations HCM is a relatively benign disease with an annual mortality of slightly less than 1% per year in the adult population.1-3 Patients with HCM are generally asymptomatic or minimally symptomatic. However, they could exhibit a diverse array of clinical symptoms including progressive dyspnea, chest pain, palpitations and lightheadedness, and, less commonly, syncope and SCD. Cardiac hypertrophy and accompanying fibrosis by leading to diastolic dysfunction are important determinants of clinical symptoms, such as dyspnea. Chest pain is thought to be caused by the increased demand of the hypertrophic myocardium. However, concomitant coronary artery disease should be considered in middle-aged and older individuals. Palpitation is often due to supraventricular arrhythmias including atrial fibrillation and nonsustained ventricular tachycardia. Atrial fibrillation and nonsustained ventricular tachycardia are the two most common cardiac arrhythmias and are associated with adverse clinical outcome.4,5 Syncope, while infrequent, is an important symptom as it often but not always suggests serious cardiac arrhythmias and heralds SCD.6,7 SCD is the most dreadful clinical manifestation of HCM and usually the primary concern of the patients and physicians alike. Not uncommonly, SCD is the

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first manifestation of HCM, particularly in young and apparently healthy individuals.8,9 HCM is the most common discernible cause of SCD in the competitive athletes younger than 35 years of age, accounting for almost half of all cases.8,9 While there are no largescale data, it appears that the risk of SCD is greater during or immediately after exercise. Fortunately, in the general HCM population, the risk of SCD and overall mortality is relatively low.1-3 Nevertheless, a subgroup of patients with HCM is considered at high risk of SCD and should be identified and managed accordingly. Clinical, genetic and nongenetic factors that are associated with an increased risk of SCD in patients with HCM are discussed later.

16.3 Clinical Diagnosis HCM is a primary disease of cardiac myocytes and more specifically myocyte sarcomeres. Clinically, it is diagnosed by the presence of primary cardiac hypertrophy, i.e., cardiac hypertrophy not due to secondary causes such as valvular heart diseases, hypertension, metabolic disorders, and others.10 Cardiac hypertrophy is usually detected on an electrocardiogram and/or an echocardiogram. The left ventricle is typically hyperdynamic, as defined by indices of global cardiac systolic function (ejection fraction), and has a small cavity. The definition, however, is not necessarily completely specific or sensitive, as cardiac hypertrophy is the common response of the heart to various forms of stress/ injury, whether genetic such as that in HCM or acquired as in increased afterload. The most common diagnostic challenge is the presence of a moderate degree of concentric hypertrophy in patients with mild hypertension. Hypertension affects one-third of the adult population in the USA. Thus, it will not be surprising for HCM to be also present in a fraction of patients who have concomitant hypertension. Often, the clinical clues such as a hyperdynamic left ventricle, asymmetric septal hypertrophy, severity of cardiac hypertrophy being disproportionate to the severity of hypertension, and the presence of outflow tract obstruction could aid the diagnosis of concomitant HCM. “Unexplained” cardiac hypertrophy could also occur in storage diseases, mitochondrial diseases, triplet repeat syndromes, and others.11 These conditions are referred to as “phenocopy” because they phenotypically

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mimic HCM. Phenocopy conditions could comprise 5–10% of the cases of clinically diagnosed HCM, particularly in children. The distinction between true HCM and phenocopy states, while difficult in most cases, is crucial since pathogenesis and hence the treatment of the two conditions differ.12 For example, enzyme replacement therapy for Fabry disease could impart beneficial effects,12 while the conventional therapies for HCM will not benefit these patients. Differences in the pathogenesis of the phenotype between HCM and phenocopy states are best illustrated for the HCM phenocopy caused by mutations in the g2 subunit of adenosine monophosphate-activated protein kinase (AMPK). Cardiac hypertrophy in the latter condition is due to storage of glycogen in the heart.13,14 Cardiac hypertrophy caused by AMPK mutations is typically accompanied with conduction defects and a pre-excitation pattern on the electrocardiogram. The presence of depressed global cardiac systolic function, conduction defects or involvement of other organs, such as deafness, neurological abnormalities, and skeletal myopathy could favor the phenocopy states as opposed to true HCM. It also merits noting that individuals who carry the disease-causing mutations may not show significant cardiac hypertrophy and hence, may not be diagnosed with HCM, which is classically diagnosed when the left ventricular wall thickness is 13 mm or greater. This is partly because of incomplete and age-dependent penetrance of the causal mutations. Likewise, certain causal mutations, such as those in cardiac troponin T (cTnT), are associated with relatively mild hypertrophy but carry an increased risk of SCD.15 Thus, a young individual family member who does not exhibit clinical HCM at the time of physical examination may not be totally free of the risk of SCD and could develop HCM later in life. Nonetheless, the risk of SCD would be expected to be greater in those with the expressed phenotype, i.e., cardiac hypertrophy. In general, in familial setting wherein the pretest likelihood of HCM is about 50% (autosomal dominant disease), subtle electrocardiographic or echocardiographic abnormalities could indicate inheritance of the causal mutation and hence, underlying HCM. Another diagnostic challenge is the distinction between physiological hypertrophy in athletes and HCM. Since HCM is the most common cause of SCD in the competitive athletes, the distinction carries significant implications.8 Cardiac chamber size, which is

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cardiac troponin I, respectively; each accounts for approximately 3–5% of the HCM cases.29-31 A small fraction of HCM cases are caused by mutations in genes encoding a-tropomyosin (TPM1), titin (TTN), cardiac a-actin (ACTC1), essential myosin light chain (MYL3), and regulatory myosin light chain (MYL2). Recently, mutations in genes encoding Z disk proteins, namely MYOZ2 and TCAP, encoding myozenin 2 (calsarcin 1) and telethonin were also identified.32,33 Finally, several putative causal genes/mutations also have been identified in HCM cases. However, the causality remains to be established. The list includes genes coding for cardiac troponin C (TNNC1), a-MyHC (MYH6), myosin light chain kinase (MYLK2), phospholamban (PLN), and caveolin 3 (CAV3) (reviewed in Ref.34). It is also noteworthy that a small fraction of patients with HCM may have two mutations in the sarcomeric proteins.35,36 Collectively, the known causal genes and mutations account for approximately two-third of all HCM cases. An important finding of genetic studies of HCM that has implications for genetic based-diagnosis and treatment is the “personal” or “private” nature of the 16.4 Molecular Genetics causal mutations. The point is that that the prevalence of each causal mutation is relatively low, and there is HCM is a familial disease in approximately half of the no common or a set of predominant mutations to screen cases with an autosomal dominant mode of inheri- for. Overall, the prevalence of each mutation is <1% in tance.23,24 Unless one is focused on inquiring specifi- a garden variety of HCM population. The vast majority cally about a family history, one may not elicit a family of mutations are missense mutations. However, inserhistory and hence, consider the disease sporadic. True tion/deletion or splice junction mutations also have HCM (i.e., excluding phenocopy) is a genetic disease, been described and reported more commonly in the regardless of whether it is familial or sporadic. The MYBPC3 than others.29,30 It is also important to note seminal discovery of a point mutation in MHY7 encod- that not all variants in the sarcomeric proteins are ing b-myosin heavy chain (MyHC) by Dr. Seidman causal mutations and many could be polymorphisms and colleagues in 1990 led to elucidation of molecular (“no protein is a perfect molecule”). Causal mutations are important determinants of genetic basis of HCM.25 Subsequent identification of mutations in TNNT2 and TPM1, encoding cardiac tro- the phenotype. However, clinical manifestations of ponin T and a-tropomyosin, respectively, rendered HCM vary considerably not only among individuals HCM as a disease of the sarcomeric proteins.26 During with different causal mutations but also among indithe last 18 years, several hundred mutations in over a viduals with identical causal mutations.37 The interindozen genes in patients and families with HCM have dividual variability is, in part, due to differences in been identified. The causal genes (excluding pheno- the genetic background of the individuals, comprising copy conditions) encode sarcomeric proteins including single nucleotide polymorphisms (SNPs) and structural variations; the latter is also referred to as copy thin and thick filaments and Z disk proteins. The two most common causal genes for HCM are number variants (CNV). Recent data suggest the MYH7 and MYBPC3, the latter encoding myosin-­ presence of extensive variability in the genome.38 binding protein C.27-29 Each accounts for approximately Variations in the genomic sequence of patients with 25% of HCM cases.27-29 The next two most common HCM, which are referred to as the modifier alleles (or genes are TNNT2 and TNNI3, encoding cTnT and genes), are expected to affect the phenotypic generally enlarged in athletes and tissue Doppler imaging, which shows reduced velocities in HCM could help differentiate the two conditions. Indeed, reduced myocardial tissue Doppler velocities are considered an early diagnostic marker for those who carry HCMcausing mutations.16 The pathological hallmark of HCM is cardiac myocyte disarray, which is defined as mal-aligned, distorted, and often short and hypertrophic myocytes oriented in different directions. Myocyte disarray typically comprises more than 20% of the ventricle.17,18 Disarray is more prominent in the interventricular septum, but it could involve the entire myocardium.18 Other pathological features of HCM include cardiac myocyte hypertrophy, interstitial fibrosis, thickening of media of intramural coronary arteries, and sometimes malpositioned mitral valve with elongated leaflets. Cardiac hypertrophy, interstitial fibrosis, and myocyte disarray are associated with the risk of SCD, mortality, and morbidity in patients with HCM.19-22

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expression of HCM. Unlike the causal genes, which are necessary and pre-requisite for development of HCM, modifier genes are neither necessary nor sufficient to cause HCM. However, when present, the modifier variants affect expression of the phenotype, such as the degree of cardiac hypertrophy. We recently mapped five modifier loci affect expression of cardiac hypertrophy caused by the Ins791G mutation in the MYBPC3 in a large family.39 The effect sizes, while variable and influenced by other genetic and nongenetic factors, are quite considerable, particularly in homozygous state for the modifier alleles.39 Among the plausible candidates are GRB2 on 17q24, which encodes growth factor receptor-bound protein 2, which is considered essential for cardiac hypertrophic and fibrotic responses.40l Likewise, ITGA8, encoding integrin a8 is a plausible modifier candidate on mapped 10p13 locus.41 In addition, the ACE gene encoding angiotensin-1-converting enzyme 1 and several others also have been implicated as modifier genes for HCM (reviewed in Ref.42).

16.5 Risk Factors for SCD in HCM Overall, HCM is a relatively benign disease. It is associated with an annual mortality of about 1% per year.1,43 However, SCD, particularly in the young, depicts HCM as a frightful disease. In fact, SCD is the primary reason of concern of patients with HCM and the physicians who take care of them. The concern is highlighted by the fact that SCD often occurs in young individuals and without heralding symptoms. Indeed, HCM is the most common discernible cause of SCD in the young individuals, particularly young athletes.8 Despite the heightened interest for the past few decades, it has been difficult to identify reliable predictors of risk of SCD in patients with HCM. The difficulty partly reflects the presence of considerable heterogeneity in clinical expression of HCM and partly the genetic heterogeneity of HCM. Accordingly, HCM caused by different causal genes could implicate different molecular pathway for the pathogenesis of the phenotype. For example, HCM caused by mutations in TNNT2 could invoke increased sensitivity of myofibrillar force generation and ATPase activity as the basis of cardiac phenotype.44 In contrast, those caused by mutations in MYH7 could cause hypertrophy by

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impairing interaction between actin and myosin in generation of force of contraction.45 Thus, despite the apparent phenotypic similarities, clinically diagnosed as HCM, different genotype-dependent pathways could be operating to induce the phenotype and affect the risk of SCD. The relatively low prevalence of HCM in the general population, estimated at 1:500,46 also has rendered compilation of large datasets somewhat difficult. The latter along with the, fortunately, low incidence of SCD in HCM patients and hence, a small number of patients to identify the predictors of SCD, limits the statistical power for reliable detection of the predictors. Moreover, there is the issue of phenocopy, which may comprise ~5% of clinically diagnosed cases of HCM. Finally, in the assessment of the risk of SCD in patients with HCM, a comprehensive approach that takes into account all determinants of the phenotype should be pursued (Fig. 16.1). Clinical Risk Factors: In spite of the difficulties, several clinical predictors have been implicated in SCD. The most commonly acknowledged clinical risk factors for SCD in patients with HCM are summarized in Table 16.1. Among the strongest and most obvious is the prior history of aborted SCD, due to ventricular fibrillation or sustained ventricular tachycardia, which mandates implantation of an AICD. Other strong risk factors for SCD include a strong family history of SCD, typically defined as SCD of two young family members. The strong family history probably reflects the shared causal mutations and modifier alleles. One also has to be cognizant of the presence of considerable phenotypic variability among the affected family members. Likewise, syncope should be considered a strong predictor and investigated thoroughly to delineate its etiology. Presence of repetitive nonsustained ventricular tachycardia on Holter monitoring or event recorders, severe left ventricular hypertrophy, and drop in blood pressure during exercise should also be considered major risk factors for SCD in patients with HCM. The clinical phenotype results from complex interactions between genes and host environment. Accordingly, the risk of SCD is determined by various genetic and nongenetic factors. Among them are the causal mutations, the modifier SNPs, interactions between genes (epistasis), transcriptional and posttranscriptional regulation of gene expression, mircoRNAs, posttranslational modification of proteins, and the environmental factors. Therefore, in assessment of the risk SCD, all the aforementioned components, whenever known, should be considered.

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Fig. 16.1  (a) The index case or proband, identified by an arrow, sought genetic testing for hypertrophic cardiomyopathy (HCM) because her 35-year-old apparently healthy and athletic sister died from SCD while jogging. The victim was diagnosed at autopsy to have HCM. The proband’s mother also had died from SCD in her 40s. She asked: “Have I inherited my Mom’s mutation?” and “Have I passed it along to my son?” (b) We recruited the family and phenotyped the members. The index case was diagnosed with HCM based on electrocardiographic and echocardiographic findings. However, her young son was phenotypically normal. (c). We genotyped the family members, performed linkage analysis, and mapped the causal gene to MYH7 locus. We sequenced the family members and identified the

R719Q as the causal mutation. It cosegregated with inheritance of the disease except in the son of the proband, who had inherited the mutation but was normal phenotypically. The R719Q mutation has been associated with a high incidence of SCD in a few families. (d) Because of the high incidence of SCD in the family, they were monitored frequently. Five years later, proband’s son presented with an episode of near syncope. ECG and echocardiography showed expression of cardiac hypertrophy and, hence, the clinical diagnosis of HCM. The etiology of syncope was determined as ventricular arrhythmias. Because of a strong family history of SCD and an episode of near syncope he underwent an AICD implantation to prevent SCD (primary prevention)

Genetic Risk Factors: The causal mutations are necessary for the development of HCM and are likely major determinants of the severity of the phenotype including the risk of SCD.15,27,28,47-51 Nonetheless, there is a considerable degree of variability and the risk of SCD is not restricted to a specific set of causal mutations. In general, mutations in MYH7 are associated with an early onset of disease, extensive hypertrophy, and a higher incidence of SCD as opposed to mutations in MYBPC3.48-50,52 In contrast, mutations in

MYBPC3 are generally considered benign often presenting with a mild degree of cardiac hypertrophy expressing later in life.28,50,53 Mutations in TNNT2, TNNI3, and TPM1, while exhibiting variable clinical phenotype, are generally associated with a relatively high incidence of SCD, which may appear disproportionate to the degree of cardiac hypertrophy.22 Finally, double mutations, which are associated with a more pronounced phenotype, are likely to increase the risk of SCD. It merits noting that genotype–phenotype

196 Table 16.1  Risk factors for SCD in patients with HCM Established risk factors Prior episode of aborted SCD (ventricular fibrillation and/or tachycardia) Family history of SCD (particularly more than one young member) • Causal mutations, including double mutations • Modifier genes • Other genetic factors

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SCD only can be deduced. It is important to note that HCM is the primary structural heart disease responsible for SCD in the young competitive athletes.8,56 Therefore, patients with HCM are advised to avoid heavy exercise and competitive sports.

16.6 Genetic Testing and SCD in HCM

History of syncope (particularly arrhythmic syncope) Sustained and repetitive nonsustained ventricular tachycardia on Holter monitoring Severe cardiac hypertrophy (typically greater than 30-mm wall thickness) Exercise-induced hypotension Potential risk factors Outflow tract obstruction Severe interstitial fibrosis and myocyte disarray Early onset of clinical manifestations (young age) Presence of myocardial ischemia

correlation studies in general are performed in small subset of families, and hence, their findings may not be applicable to the garden variety of HCM in the general population. In addition, it is important to consider variability in phenotypic expression of the causal mutations and that no phenotype is specific to a single mutation. The so-called benign or malignant phenotype has been observed for the known causal genes. Other determinants of risk of SCD: All phenotypes, whether in single-gene disorders or in multigene diseases are complex traits, i.e., are affected by the complex interplay between the genetic and nongenetic factors. SCD in HCM is no exception. Hence, the risk of SCD in HCM is determined not only by the causal and modifier genes but also by transcriptional and translation regulation of gene expression, epigenetic factors, microRNAs, and the environmental factors. Experimental data even implicate dietary intake in modulating cardiac hypertrophic phenotype.54 Likewise, exercise has been shown to impart salutary effects on cardiac hypertrophy in an experimental model.55 As in humans, however, the impact of each potential determinant of the clinical phenotype including dietary intake and physical exercise on the risk of

The potential clinical utility of genetic testing is primarily based on the ability for an accurate diagnosis of those at risk of HCM, preclinical diagnosis of mutation carriers, distinction of true HCM from the phenocopy conditions, and possibly risk stratification for SCD. The best clinical scenario is familial setting (Fig. 16.2), wherein the causal mutation in one or more affected members is known or could mapped through linkage analysis and DNA sequencing. Often the occurrence of SCD in a family member is the impetus for inquiry about genetic testing. If the causal mutation in the family is known, the task is relatively easy and one with near certainty could identify those who do not carry the causal mutation and hence, are not at the risk of HCM and SCD. The only caveat is the potential presence of a second mutation in the same gene or another causal gene, which

Fig. 16.2  Clinical Predictors of Risk of SCD in patients with HCM. A coronal section of the heart of a patient who died from SCD is shown in the middles along with major established risk factors for SCD on the corners

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will not be detected by testing for the known mutation. However, the possibility is low. Accordingly, one can identify those family members who carry the causal mutation and hence focus on further risk stratification for SCD through further clinical phenotyping. In most situations, the causal gene and the mutation are unknown. In families with several affected and normal individuals one could map the causal gene through linkage analysis and then identify the causal mutation through sequencing of the candidate genes. However, most frequently either the families are small, hence, the power for map the causal gene is small, or there is no clear family history (sporadic cases). The current approach in such patients is to sequence the exons and intron-exon boundaries of the most common causal genes for HCM, namely MYH7, MYBPC3, TNNI3, TNNT2, and TPM1. The approach offers the chance of finding the causal mutation is approximately 50–60% of the cases. Screening of additional known causal genes could increase the chance of finding the causal mutation modestly. Genetic testing based on sequencing of selected known causal genes is available through research laboratories and commercial sources. The incentive for genetic testing for risk stratification for SCD is to identify the so-called malignant mutations, which could lead to implantation of AICD in order to prevent SCD. However, currently, there are no data to support this approach. Hence, while the causal mutations should be considered a determinant of the phenotype, implantation of an AICD solely based on genetic information is not recommended. As in any clinical scenario, the approach to risk stratification of HCM patients for SCD has to encompass all  components, whether clinical, environmental, or genetic. The challenge is that many determinants of the risk have not yet been fully elucidated.

16.7 Evaluation and Management of Risk of SCD The goals in management of patients with HCM are to prevent SCD, relieve symptoms and reverse, attenuate, and prevent expression of cardiac hypertrophy and fibrosis. In view of clinical and genetic heterogeneity of HCM, evaluation and management of patients for the risk of SCD has to be individualized. Thus, any guideline for assessment of the risk of SCD has to be

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considered a general guideline and should be individualized. Accordingly, there is digression of expert opinions in evaluation and management of the risk of SCD in patients with HCM. In general, the focus of the evaluation is to elicit and identify the risk factors that are strongly associated with SCD, particularly the established risk factors as described earlier. Typically, all patients with HCM should undergo detailed medical history that includes a focus on family history of premature SCD, history of syncope, and palpitations. Careful physical examination also could provide clues to phenocopy states. ECG and echocardiography are obtained to assess the severity of cardiac hypertrophy and detect presence of left ventricular outflow tract obstruction as well as Holter monitoring to detect ventricular and supraventricular tachyarrhythmias. Those with near syncope or syncope with no discernible history of palpitation or arrhythmias on Holter or event monitoring are evaluated by exercise test and/or exercise echocardiography. Invasive electrophysiological studies have low positive predictive values, particularly if an aggressive arrhythmia induction protocol is pursued. They are not routinely performed in the assessment of risk of SCD. Likewise, routine exercise echocardiography or dobutamine echocardiography in asymptomatic or mildly symptomatic patients is not recommended, as the significance of the findings in assessment of risk of SCD has not been shown. Genetic data on the causal gene and mutation should be incorporated into decision making, whenever available, while keeping in mind the limitations discussed earlier. Asymptomatic or minimally symptomatic patients, who comprise the majority of the patients with HCM, are managed according to the risk of SCD. Likewise, the risk of SCD is determined in symptomatic patients according to presence or absence of established risk factors. Those at low risk for SCD are managed conservatively and treated for symptomatic relief, whenever indicated. In general, routine additional risk stratification in those without established risk factors for SCD is not pursued. Albeit, exceptions may exist according to individual’s situation. In addition, whenever new symptoms such as palpitation develop during follow up, further investigation would be warranted. Implantation of AICD could reduce the risk of SCD in asymptomatic or symptomatic patients with two or more major risk factors for SCD, as shown in recent observational studies.57,58 The decision to implant an AICD in those with one established risk factor for SCD

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is less settled. Many may opt to implant AICD in patients with HCM who have only one established risk factor for SCD but no prior episode of aborted SCD or sustained ventricular tachycardia/fibrillation. However, the decision to implant an AICD in this subset is supported by the results of a recent observational study.58 Nonetheless, there are significant adverse effects of AICD implantation including inappropriate shocks, anxiety, and potential loss of job for certain occupations. Thus, the decision in those with one risk factor has to be based on comprehensive evaluation to further stratify the risk of SCD and should be individualized. It merits noting that the existing pharmacological therapies, which include b-blockers, verapamil, disopyramide, low-dose diuretics and amiodarone, have not been shown to reduce the risk of SCD. In symptomatic patients with significant resting outflow tract obstruction (>50 mmHg) who do not adequately respond to medical therapy, surgical myectomy (Morrow procedure), and transcatheter septal ablation, typically performed by infusion of ethanol into the septal branches of left anterior descending coronary artery, are highly effective in improving symptoms.59-65 Whether surgical myectomy or transcatheter septal ablation reduces or affects the risk of SCD in patients with HCM is less settled. It is also important to realize that neither surgical myectomy nor transcoronary septal ablation cures HCM. Surgical myectomy is preferred in those with concomitant coronary artery disease or valvular disorders. The overall surgical mortality is 1–5% but higher in elderly patients and in those undergoing concomitant surgeries, such as coronary bypass or valve surgery.59,61,66,67 Surgical myectomy offers sustained symptomatic relief, a low recurrence rate of outflow tract obstruction, and excellent survival.59,61,64,66-69 Transcoronary septal ablation is also highly effective in reducing the left ventricular outflow tract gradient and symptoms.62,70,71 It is best reserved in symptomatic patients with interventricular septal thickness of >15 mm and a left ventricular outflow tract gradient of >50 mmHG at rest who are refractory to medical therapy. The perioperative morbidity and mortality of percutaneous septal ablation is low.71 Failure to achieve a significant reduction in the gradient and the recurrence rate of outflow tract obstruction are about 5–10%. It is also associated with advanced conduction system defect requiring implantation of a permanent pacemaker in approximately 20% of the

A. J. Marian

patients.72-74 Occasional late ventricular arrhythmias have been documented in patients undergoing percutaneous alcohol septal ablation.74-77 Finally, implantation of dual-chamber pacemaker is reserved for rare situations whereby medical therapy fails, and surgical myectomy or transcatheter septal ablation is not considered as an option. Dual-chamber pacing could reduce left ventricular outflow tract gradient and lead to improvement in symptoms.78,79 The poor results of two randomized clinical studies have reduced the overall enthusiasm in the clinical utility of dual-chamber pacing in treatment of patients with HCM.79

16.8 Concluding Remarks SCD remains the primary concern of patients with HCM and physicians alike. Several clinical and genetic indicators of the risk factors have been identified, but  none alone is sufficiently a powerful predictor. Therefore, a global approach to risk stratification that encompasses all determinants of the phenotype is necessary. AICD implantation is expected to reduce the risk of SCD in those with two or more established risk factors for SCD and possibly even in those with one risk factor. In all cases, the decision to implant an AICD has to be individualized based on the clinical, family, and genetic information as well as the overall social, professional, and lifestyle of the individual.

References   1. Cannan CR, Reeder GS, Bailey KR, Melton LJ, III, Gersh BJ. Natural history of hypertrophic cardiomyopathy. A population-based study, 1976 through 1990. Circulation. 1995; 92(9):2488–2495   2. Maron BJ, Olivotto I, Spirito P, et  al. Epidemiology of hypertrophic cardiomyopathy-related death: revisited in a large non-referral-based patient population. Circulation. 2000;102 (8):858–864   3. Nugent AW, Daubeney PEF, Chondros P, et al. Clinical features and outcomes of childhood hypertrophic cardiomyopathy: results from a national population-based study. Circulation. 2005;112(9):1332–1338   4. Olivotto I, Cecchi F, Casey SA, Dolara A, Traverse JH, Maron BJ. Impact of atrial fibrillation on the clinical course of hypertrophic cardiomyopathy. Circulation. 2001;104(21): 2517–2524

16  Hypertrophic Cardiomyopathy   5. Monserrat L, Elliott PM, Gimeno JR, Sharma S, Penas-Lado M, McKenna WJ. Non-sustained ventricular tachycardia in hypertrophic cardiomyopathy: an independent marker of sudden death risk in young patients. J Am Coll Cardiol. 2003;42(5):873–879   6. Nienaber CA, Hiller S, Spielmann RP, Geiger M, Kuck KH. Syncope in hypertrophic cardiomyopathy: multivariate analysis of prognostic determinants. J Am Coll Cardiol. 1990; 15(5):948–955   7. Elliott PM, Poloniecki J, Dickie S, et  al. Sudden death in hypertrophic cardiomyopathy: identification of high risk patients. J Am Coll Cardiol. 2000;36(7):2212–2218   8. Maron BJ, Shirani J, Poliac LC, Mathenge R, Roberts WC, Mueller FO. Sudden death in young competitive athletes. Clinical, demographic, and pathological profiles. JAMA. 1996; 276(3):199–204   9. McKenna W, Deanfield J, Faruqui A, England D, Oakley C, Goodwin J. Prognosis in hypertrophic cardiomyopathy: role of age and clinical, electrocardiographic and hemodynamic features. Am J Cardiol. 1981;47(3):532–538 10. Maron BJ. Hypertrophic cardiomyopathy: a systematic review. JAMA. 2002;287(10):1308–1320 11. Elliott P, McKenna WJ. Hypertrophic cardiomyopathy. Lancet. 2004;363(9424):1881–1891 12. Wilcox WR, Banikazemi M, Guffon N, et  al. Long-term safety and efficacy of enzyme replacement therapy for Fabry disease. Am J Hum Genet. 2004;75(1):65–74 13. Arad M, Benson DW, Perez-Atayde AR, et al. Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy. J Clin Invest. 2002;109(3):357–362 14. Gollob MH, Green MS, Tang AS, et al. Identification of a gene responsible for familial Wolff-Parkinson-White syndrome. N Engl J Med. 2001;344(24):1823–1831 15. Watkins H, McKenna WJ, Thierfelder L, et al. Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy. N Engl J Med. 1995;332(16): 1058–1064 16. Nagueh SF, Bachinski L, Meyer D, et  al. Tissue Doppler imaging consistently detects myocardial abnormalities in patients with familial hypertrophic cardiomyopathy and provides a novel means for an early diagnosis prior to an independent of hypertrophy. Circulation. 2001;104:128–130 17. Maron BJ, Roberts WC. Quantitative analysis of cardiac muscle cell disorganization in the ventricular septum of patients with hypertrophic cardiomyopathy. Circulation. 1979;59(4):689–706 18. Maron BJ, Anan TJ, Roberts WC. Quantitative analysis of the distribution of cardiac muscle cell disorganization in the left ventricular wall of patients with hypertrophic cardiomyopathy. Circulation. 1981;63(4):882–894 19. Shirani J, Pick R, Roberts WC, Maron BJ. Morphology and significance of the left ventricular collagen network in young patients with hypertrophic cardiomyopathy and sudden cardiac death. J Am Coll Cardiol. 2000;35(1):36–44 20. Spirito P, Bellone P, Harris KM, Bernabo P, Bruzzi P, Maron BJ. Magnitude of left ventricular hypertrophy and risk of sudden death in hypertrophic cardiomyopathy. N Engl J Med. 2000;342(24):1778–1785 21. Varnava AM, Elliott PM, Baboonian C, Davison F, Davies MJ, McKenna WJ. Hypertrophic cardiomyopathy: histo-

199 pathological features of sudden death in cardiac troponin t disease. Circulation. 2001;104(12):1380–1384 22. Varnava AM, Elliott PM, Mahon N, Davies MJ, McKenna WJ. Relation between myocyte disarray and outcome in hypertrophic cardiomyopathy. Am J Cardiol. 2001;88(3): 275–279 23. Greaves SC, Roche AH, Neutze JM, Whitlock RM, Veale AM. Inheritance of hypertrophic cardiomyopathy: a cross sectional and M mode echocardiographic study of 50 families. Br Heart J. 1987;58(3):259–266 24. Maron BJ, Nichols PF III, Pickle LW, Wesley YE, Mulvihill JJ. Patterns of inheritance in hypertrophic cardiomyopathy: assessment by M-mode and two-dimensional echocardiography. Am J Cardiol. 1984;53(8):1087–1094 25. Geisterfer-Lowrance AA, Kass S, Tanigawa G, et al. A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation. Cell. 1990;62(5):999–1006 26. Thierfelder L, Watkins H, MacRae C, et  al. Alphatropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere. Cell. 1994;77(5):701–712 27. Charron P, Dubourg O, Desnos M, et  al. Clinical features and prognostic implications of familial hypertrophic cardiomyopathy related to the cardiac myosin-binding protein C gene. Circulation. 1998;97(22):2230–2236 28. Erdmann J, Raible J, Maki-Abadi J, et al. Spectrum of clinical phenotypes and gene variants in cardiac myosin-binding protein C mutation carriers with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2001;38(2):322–330 29. Richard P, Charron P, Carrier L, et al. Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation. 2003;107(17):2227–2232 30. Mogensen J, Murphy RT, Kubo T, et al. Frequency and clinical expression of cardiac troponin I mutations in 748 consecutive families with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2004;44(12):2315–2325 31. Torricelli F, Girolami F, Olivotto I, et  al. Prevalence and clinical profile of troponin T mutations among patients with hypertrophic cardiomyopathy in tuscany. Am J Cardiol. 2003;92(11):1358–1362 32. Osio A, Tan L, Chen SN, et al. Myozenin 2 Is a Novel Gene for Human Hypertrophic Cardiomyopathy. Circ Res. 2007; 100(6):766–768 33. Hayashi T, Arimura T, Itoh-Satoh M, et al. Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy. J Am Coll Cardiol. 2004;44(11):2192–2201 34. Marian AJ. Clinical and molecular genetic aspects of hypertrophic cardiomyopathy. Current Cardiology Reviews. 2005; 1(1):53–63 35. Van Driest SL, Vasile VC, Ommen SR, et al. Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy. J Am Coll Cardiol. 2004;44(9): 1903–1910 36. Blair E, Price SJ, Baty CJ, Ostman-Smith I, Watkins H. Mutations in cis can confound genotype-phenotype correlations in hypertrophic cardiomyopathy. J Med Genet. 2001; 38(6):385–388 37. Marian AJ. On genetic and phenotypic variability of hypertrophic cardiomyopathy: nature versus nurture. J Am Coll Cardiol. 2001;38(2):331–334

200 38. Levy S, Sutton G, Ng PC, et  al. The Diploid Genome Sequence of an Individual Human. PLoS Biol. 2007; 5(10):e254 39. Daw EW, Chen SN, Czernuszewicz G, et  al. Genome-wide mapping of modifier chromosomal loci for human hypertrophic cardiomyopathy. Hum Mol Genet. 2007;16(20):3463–3471 40. Zhang S, Weinheimer C, Courtois M, et al. The role of the Grb2–p38 MAPK signaling pathway in cardiac hypertrophy and fibrosis. J Clin Invest. 2003;111(6):833–841 41. Bouzeghrane F, Mercure C, Reudelhuber TL, Thibault G. [alpha]8[beta]1 integrin is upregulated in myofibroblasts of fibrotic and scarring myocardium. J Mol Cell Cardiol. 2004;36(3):343–353 42. Marian AJ. Modifier genes for hypertrophic cardiomyopathy. Curr Opin Cardiol. 2002;17(3):242–252 43. Kofflard MJ, Waldstein DJ, Vos J, ten Cate FJ. Prognosis in hypertrophic cardiomyopathy observed in a large clinic population. Am J Cardiol. 1993;72(12):939–943 44. Lombardi R, Bell A, Senthil V, Sidhu J, Noseda M, Roberts R, et al. Differential interactions of thin filament proteins in two cardiac troponin T mouse models of hypertrophic and dilated cardiomyopathies. Cardiovasc Res. 2008;79(1):109–17 45. Nagueh SF, Chen S, Patel R, et al. Evolution of expression of cardiac phenotypes over a 4-year period in the [beta]-myosin heavy chain-Q403 transgenic rabbit model of human hypertrophic cardiomyopathy. J Mol Cell Cardiol. 2004;36(5): 663–673 46. Maron BJ, Gardin JM, Flack JM, Gidding SS, Kurosaki TT, Bild DE. Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA Study. Coronary Artery Risk Development in (Young) Adults. Circulation. 1995;92(4):785–789 47. Tesson F, Richard P, Charron P, et al. Genotype-phenotype analysis in four families with mutations in beta-myosin heavy chain gene responsible for familial hypertrophic cardiomyopathy. Hum Mutat. 1998;12(6):385–392 48. Watkins H, Rosenzweig A, Hwang DS, et al. Characteristics and prognostic implications of myosin missense mutations in familial hypertrophic cardiomyopathy. N Engl J Med. 1992;326(17):1108–1114 49. Fananapazir L, Epstein ND. Genotype-phenotype correlations in hypertrophic cardiomyopathy. Insights provided by comparisons of kindreds with distinct and identical betamyosin heavy chain gene mutations. Circulation. 1994; 89(1):22–32 50. Charron P, Dubourg O, Desnos M, Isnard R, Hagege A, Bonne G, et al. Genotype-phenotype correlations in familial hypertrophic cardiomyopathy. A comparison between mutations in the cardiac protein-C and the beta-myosin heavy chain genes. Eur Heart J. 1998;19(1):139–145 51. Kubo T, Kitaoka H, Okawa M, et al. Lifelong left ventricular remodeling of hypertrophic cardiomyopathy caused by a founder frameshift deletion mutation in the cardiac myosinbinding protein C gene among Japanese. J Am Coll Cardiol. 2005;46(9):1737–1743 52. Van Driest SL, Jaeger MA, Ommen SR, et al. Comprehensive analysis of the beta-myosin heavy chain gene in 389 unrelated patients with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2004;44(3):602–610

A. J. Marian 53. Niimura H, Bachinski LL, Sangwatanaroj S, et al. Mutations in the gene for cardiac myosin-binding protein C and lateonset familial hypertrophic cardiomyopathy. N Engl J Med. 1998;338(18):1248–1257 54. Stauffer BL, Konhilas JP, Luczak ED, Leinwand LA. Soy diet worsens heart disease in mice. J Clin Invest. 2006; 116(1):209–216 55. Konhilas JP, Watson PA, Maass A, et al. Exercise can prevent and reverse the severity of hypertrophic cardiomyopathy. Circ Res. 2006;98(4):540–548 56. Maron BJ, Roberts WC, Epstein SE. Sudden death in hypertrophic cardiomyopathy: a profile of 78 patients. Circulation. 1982;65(7):1388–1394 57. Maron BJ, Shen WK, Link MS, et al. Efficacy of implantable cardioverter-defibrillators for the prevention of sudden death in patients with hypertrophic cardiomyopathy. N Engl J Med. 2000;342(6):365–373 58. Maron BJ, Spirito P, Shen WK, et al. Implantable CardioverterDefibrillators and Prevention of Sudden Cardiac Death in Hypertrophic Cardiomyopathy. JAMA. 2007;298(4):405–412 59. van der Lee C, ten Cate FJ, Geleijnse ML, et al. Percutaneous versus surgical treatment for patients with hypertrophic obstructive cardiomyopathy and enlarged anterior mitral valve leaflets. Circulation. 2005;112(4):482–488 60. Nagueh SF, Ommen SR, Lakkis NM, et al. Comparison of ethanol septal reduction therapy with surgical myectomy for the treatment of hypertrophic obstructive cardiomyopathy. J Am Coll Cardiol. 2001;38(6):1701–1706 61. Ralph-Edwards A, Woo A, McCrindle BW, et al. Hypertrophic obstructive cardiomyopathy: Comparison of outcomes after myectomy or alcohol ablation adjusted by propensity score. J Thorac Cardiovasc Surg. 2005;129(2):351–358 62. Firoozi S, Elliott PM, Sharma S, Murday A, Brecker SJ, Hamid MS, et al. Septal myotomy-myectomy and transcoronary septal alcohol ablation in hypertrophic obstructive cardiomyopathy. A comparison of clinical, haemodynamic and exercise outcomes. Eur Heart J. 2002;23(20): 1617–1624 63. Qin JX, Shiota T, Lever HM, et al. Outcome of patients with hypertrophic obstructive cardiomyopathy after percutaneous transluminal septal myocardial ablation and septal myectomy surgery. J Am Coll Cardiol. 2001;38(7):1994–2000 64. Heric B, Lytle BW, Miller DP, Rosenkranz ER, Lever HM, Cosgrove DM. Surgical management of hypertrophic obstructive cardiomyopathy. Early and late results. J Thorac Cardiovasc Surg. 1995;110(1):195–206 65. Kimmelstiel CD, Maron BJ. Role of percutaneous septal ablation in hypertrophic obstructive cardiomyopathy. Circulation. 2004;109(4):452–456 66. Merrill WH, Friesinger GC, GrahamJr TP, et al. Long-lasting improvement after septal myectomy for hypertrophic obstructive cardiomyopathy. The Annals of Thoracic Surgery. 2000;69(6):1732–1735 67. SchonbeckMH, Brunner-La Rocca H, Vogt PR, Lachat ML, Jenni R, Hess OM, et al. Long-term follow-up in hypertrophic obstructive cardiomyopathy after septal myectomy. Ann Thorac Surg. 1998;65(5):1207–1214 68. Maron BJ, Dearani JA, Ommen SR, et al. The case for surgery in obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol. 2004;44(10):2044–2053

16  Hypertrophic Cardiomyopathy 69. Schulte HD, Bircks WH, Loesse B, Godehardt EA, Schwartzkopff B. Prognosis of patients with hypertrophic obstructive cardiomyopathy after transaortic myectomy. Late results up to twenty-five years. J Thorac Cardiovasc Surg. 1993;106(4):709–717 70. Frank S, Braunwald E. Idiopathic hypertrophic subaortic stenosis. Clinical analysis of 126 patients with emphasis on the natural history. Circulation. 1968;37(5):759–788 71. Faber L, Meissner A, Ziemssen P, Seggewiss H. Percutaneous transluminal septal myocardial ablation for hypertrophic obstructive cardiomyopathy: long term follow up of the first series of 25 patients. Heart. 2000;83(3):326–331 72. Qin JX, Shiota T, Lever HM, et  al. Conduction system abnormalities in patients with obstructive hypertrophic cardiomyopathy following septal reduction interventions. Am J Cardiol. 2004;93(2):171–175 73. Chang SM, Lakkis NM, Franklin J, Spencer WH III, Nagueh SF. Predictors of outcome after alcohol septal ablation therapy in patients with hypertrophic obstructive cardiomyopathy. Circulation. 2004;109(7):824–827 74. Minamino T, Gaussin V, DeMayo FJ, Schneider MD. Inducible gene targeting in postnatal myocardium by cardiac-specific expression of a hormone-activated Cre fusion protein. Circ Res. 2001;88(6):587–592

201 75. McGregor JB, Rahman A, Rosanio S, Ware D, Birnbaum Y, Saeed M. Monomorphic ventricular tachycardia: a late complication of percutaneous alcohol septal ablation for hypertrophic cardiomyopathy. Am J Med Sci. 2004;328(3): 185–188 76. Boltwood CM Jr, Chien W, Ports T. Ventricular tachycardia complicating alcohol septal ablation. N Engl J Med. 2004; 351(18):1914–1915 77. Kaplan SR, Gard JJ, Carvajal-Huerta L, Ruiz-Cabezas JC, Thiene G, Saffitz JE. Structural and molecular pathology of the heart in Carvajal syndrome. Cardiovasc Pathol. 2004; 13(1):26–32 78. Fananapazir L, Epstein ND, Curiel RV, Panza JA, Tripodi D, McAreavey D. Long-term results of dual-chamber (DDD) pacing in obstructive hypertrophic cardiomyopathy. Evidence for progressive symptomatic and hemodynamic improvement and reduction of left ventricular hypertrophy. Circulation. 1994;90(6):2731–2742 79. Maron BJ, Nishimura RA, McKenna WJ, Rakowski H, Josephson ME, Kieval RS. Assessment of permanent dualchamber pacing as a treatment for drug-refractory symptomatic patients with obstructive hypertrophic cardiomyopathy. A randomized, double-blind, crossover study (M-PATHY). Circulation. 1999;99(22):2927–2933

Genetic Lipoprotein Disorders and Cardiovascular Disease

17

Khalid Alwaili, Khalid Alrasadi, Zari Dastani, Iulia Iatan, Zuhier Awan, and Jacques Genest

Abbreviations ABCA1 ATP-binding cassette transporter A1 ABCG1 ATP-binding cassette transporter G1 ACAT Acetyl-CoA acetyltransferase Apo Apolipoprotein ApoBec Apo B editing complex C Cholesterol CE Cholesteryl ester CETP Cholesteryl ester transfer protein CoA Coenzyme A EL Endothelial lipase FFA Free fatty acids HDL High-density lipoprotein HL Hepatic lipase HMG CoA Red Hydroxymethylglutaryl coenzyme A reductase HSL Hormone-sensitive lipase IDL Intermediate-density lipoprotein IDL Intermediate-density lipoprotein LCAT Lecithin cholesterol acyltransferase LDL Low-density lipoprotein LDL-R Low-density lipoprotein receptor Lp(a) Lipoprotein (a) LRP Low-density lipoprotein receptor– related peptide NPC1L1 Niemann-Pick disease type C protein (NPC) like 1 PLTP Phospholipid transfer protein

J. Genest (*) Division of Cardiology, McGill University Health Center/Royal Victoria Hospital, 687 Pine Avenue West, Montreal, QC, Canada H3A 1A1 e-mail: [email protected]

PLTP sER SR- B1 TG TIA TRL VLDL VLDL-R

Phospholipid transfer protein Smooth endoplasmic reticulum Scavenger receptor B1 Triglycerides Transient ischemic attack Triglyceride-rich lipoproteins Very-low-density lipoprotein Very-low-density lipoprotein receptor

17.1 Introduction Plasma (or serum) levels of lipids and lipoprotein lipids have proven among the most potent and best substantiated risk factors for atherosclerosis in general and coronary heart disease (CHD) in particular. The present chapter deals with the fundamentals of lipid metabolism, the genetic lipoprotein disorders, and a practical approach to their diagnosis. Although the term hyperlipidemia has long been used in clinical practice, the term dyslipoproteinemia more appropriately reflects the disorders of the lipid and lipoprotein transport pathways associated with arterial diseases. Dyslipidemia encompasses disorders often encountered in clinical practice such as low highdensity lipoprotein (HDL) cholesterol level and elevated triglyceride level but an average total plasma cholesterol level. Certain rare lipoprotein disorders can cause overt clinical manifestations, but most common dyslipoproteinemias themselves only rarely cause symptoms or produce clinical signs that are evident on physical examination. Rather, they require laboratory tests for detection. Dyslipoproteinemias constitute a major risk factor for atherosclerosis and coronary artery disease, and their proper recognition and management can reduce cardiovascular and total mortality

R. Brugada et al. (eds.), Clinical Approach to Sudden Cardiac Death Syndromes, DOI: 10.1007/978-1-84882-927-5_17, © Springer-Verlag London Limited 2010

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rates. Thus the fundamentals of lipidology presented here have importance for the daily practice of cardiovascular medicine.

17.2 Lipoprotein Transport System 17.2.1 Biochemistry of Lipids The lipid transport system has evolved to carry hydrophobic molecules (fat) from sites of origin to sites of utilization through the aqueous environment of plasma. The proteins (apolipoproteins) that mediate this process are conserved throughout evolution in organisms with a circulatory system. Most apolipoproteins derive from an ancestral gene and contain both hydrophilic and hydrophobic domains. This amphipathic structure enables these proteins to bridge the interface between the aqueous environment of plasma and the phospholipid constituents of the lipoprotein.1 The major types of lipids that circulate in plasma include cholesterol and cholesteryl esters, phospholipids, and trigly­cerides. Cholesterol constitutes an essential component of mammalian cell membranes and furnishes substrate for steroid hormones and bile acids. Many cell functions depend critically upon membrane cholesterol, and cells tightly regulate cholesterol content. Most of the cholesterol in plasma circulates in the form of cholesteryl esters, in the core of lipoprotein particles. The enzyme lecithin:cholesterol acyltransferase (LCAT) forms cholesteryl esters in the blood compartment by transferring a fatty acyl chain from phosphatidyl choline to cholesterol. Triglycerides consist of a three-carbon glycerol backbone covalently linked to three fatty acids. The fatty acid composition varies in terms of chain length and presence of double bonds (degree of saturation). Triglyceride molecules are nonpolar and hydrophobic; they are transported in the core of the lipoprotein. Hydrolysis of triglycerides by lipases generates free fatty acids (FFA) used for energy. Phospholipids constituents of all cellular membranes consist of a glycerol molecule linked to two fatty acids. The fatty acids differ in length and in the presence of a single (monounsaturated) or multiple (polyunsaturated) double bonds. The third carbon of the glycerol moiety carries a phosphate group to which

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one of four molecules is linked: choline (phosphatidyl choline – or lecithin), ethanolamine (phosphatidylethanolamine), serine (phosphatidyl serine), or inositol (phosphatidylinositol). A related phospholipid, sphingomyelin, has special functions in the plasma membrane in the formation of membrane microdomains, such as rafts and caveolae. The structure of sphingomyelin resembles that of phosphatidylcholine. The backbone of sphingolipids uses the amino acid serine rather than glycerol. Phospholipids are polar molecules, more soluble than triglycerides or cholesterol or its esters. Phospholipids participate in signal transduction pathways: hydrolysis by membrane-associated phospholipases generates second messengers such as diacyl glycerols, lysophospholipids, phosphatidic acids, and free fatty acids such as arachidonate that can regulate many cell functions.

17.2.2 Lipoproteins, Apolipoproteins, Receptors, and Processing Enzymes Lipoproteins are complex macromolecular structures, composed of an envelope of phospholipids and free cholesterol, a core of cholesteryl esters and triglycerides. The apolipoproteins comprise the protein moiety of lipoproteins. Lipoproteins vary in size, density in the aqueous environment of plasma, and lipid and apolipoprotein content (Fig.17.1). The classification of lipoproteins reflects their density in plasma (1.006 g/mL) as gauged by flotation in the ultracentrifuge. The triglyceride-rich lipoproteins consisting of chylomicrons and very-low-density lipoprotein (VLDL) have a density less than 1.006 g/mL. The rest of the ultracentrifuged plasma consists of low-density lipoprotein (LDL), HDL, and lipoprotein (a) [(Lp(a)]. Apolipoproteins have four major roles: (1) assembly and secretion of the lipoprotein (apo B100 and B48); (2) structural integrity of the lipoprotein (apo B, apo E, apo AI, apo AII); (3) coactivators or inhibitors of enzymes (apo AI, CI, CII, CIII); and (4) binding or docking to specific receptors and proteins for cellular uptake of the entire particle or selective uptake of a lipid component (apo AI, B100, E). The role of several apolipoproteins (AIV, AV, D, and J) remains incompletely understood.

17  Genetic Lipoprotein Disorders and Cardiovascular Disease

0.95

Chylomicron

Chylomicron VLDL

1.006 Density (g/mL)

205

IDL Chylomicron remnant

1.02 LDL

1.06 HDL2 1.10

HDL3

1.20 5

10

20

40 Diammeter (nm)

60

80

1000

Fig. 17.1  Relative size of plasma lipoproteins according to their hydrated density. HDL high-density lipoprotein; IDL intermediatedensity lipoprotein; LDL low-density lipoprotein

Many proteins regulate the synthesis, secretion, and metabolic fate of lipoproteins; their characterization has provided insight in molecular cellular physiology and provided targets for drug development (Table 17.1). The discovery of the LDL receptor furnished a landmark in understanding cholesterol metabolism and receptor-mediated endocytosis. The LDL receptor regulates the entry of cholesterol into cells, as tight control mechanisms alter its expression on the cell surface, depending on need. Other receptors for lipoproteins include several that bind VLDL but not LDL. The LDL receptor–related peptide, which mediates the uptake of chylomicron remnants and VLDL, preferentially recognizes apolipoprotein E (apo E).2 The LDL receptor– related peptide interacts with hepatic lipase. A specific VLDL receptor exists.3 The interaction between hepatocytes and the various lipoproteins containing apo E is complex and involves cell surface proteoglycans that provide a scaffolding for lipolytic enzymes (lipoprotein lipase and hepatic lipase) involved in remnant lipoprotein recognition.4-6 Macrophages express recep-

tors that bind modified (especially oxidized) lipoproteins. These scavenger lipoprotein receptors mediate the uptake of oxidized LDL into macrophages. In contrast to the exquisitely regulated LDL receptor, high cellular cholesterol content does not suppress scavenger receptors, enabling the intimal macrophages to accumulate abundant cholesterol, become foam cells, and form fatty streaks. Endothelial cells can also take up modified lipoproteins through a specific receptor, such as Lox-1.7 At least two physiologically relevant receptors bind HDL particles: the scavenger receptor class B (SR-B1; also named CLA-1 in humans)8 and the adenosine triphosphate–binding cassette transporter A1 (ABCA1).9 SR-B1 is a receptor for HDL (also for LDL and VLDL, but with less affinity). SR-B1 mediates the selective uptake of HDL cholesteryl esters in steroidogenic tissues, hepatocytes, and endothelium. The ABCA1 mediates cellular phospholipid (and possibly cholesterol) efflux and is necessary and essential for HDL biogenesis.9

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Table 17.1  Lipoprotein processing enzymes, receptors, modulating proteins Abreviation Name Role

Chromosome

Human disease

ABCA1

ATP binding cassette AI

Cellular phospholipid efflux

9q31

Tangier disease

ABCG5/G8

ATP binding cassette G5 and G8

Intestinal sitosterol transporter

21

Sitosterolemia

ACAT1 cellular cholesterol

Acetyl-CoA acetyltransferase 1

Cellular cholesterol esterification

1q22.3

ACAT2

Acetyl-CoA acetyltransferase 2

Cellular cholesterol esterification

6q25.3

ApoE-R

ApoE-containing lipoprotein receptor

TRL uptake

1p34

CD36

Fatty acid translocase

Fatty acid transport

7q11.2

CETP

Cholesteryl ester transfer protein

Lipid exchange in plasma

16q21

EL

Endothelial lipase

PL hydrolysis

18q21.1

HL

Hepatic lipase

Tg hydrolysis

15q21

HSL (LIPE)

Hormone-sensitive lipase

Fatty acid release from adipocytes

19q13.2

LCAT

Lecithin:cholesterol acyltransferase

Cholesterol esterification (Plasma)

16q22.1

LCAT deficiency, low HDL

LDL-R

Low-density lipoprotein receptor

LDL uptake

19p13

Familial hypercholesterolemia

Lox1

Scavenger receptor

OxLDL uptake, endothelium

12p12–13

Oxidized lipoprotein uptake

LPL

Lipoprotein lipase

Tg hydrolysis

8p22

Hyperchylomicronemia

LRP1

LDL-R–related protein

Protease uptake, many ligands

19q12

LRP2

LDL-R–related protein 2 (megalin)

Protease uptake, apo J

2q24–31

MTP

Microsomal triglyceride transfer protein

Apo B assembly

4q22–24

Abetalipoproteinemia

NPC1

Niemann-Pick C gene product

Cellular cholesterol transport

18q11–12

Niemann-Pick type C

NPC1L1

Niemann-Pick C1-like 1 protein

Intestinal cholesterol absorption

7p13

PLTP

Phospholipid transfer protein

Lipid exchange in plasma

20q12

PCSK9

Proprotein convertase, subtilisin/kexin-9

Protein cleavage

1p34.1

Hypercholesterolemia

SMPD1

Sphingomyelinase phosphodiesterase

Sphingomyelin hydrolysis

11p15.4

Niemann-Pick types A and B

SRA

Scavenger receptor A

OxLDL uptake, macrophages

8p21

SR-B1

Scavenger receptor B1

HDL CE uptake

12

VLDL-R

Very-low-density lipoprotein receptor

VLDL uptake

9q24

Elevated HDL cholesterol

Remnant accumulation

17  Genetic Lipoprotein Disorders and Cardiovascular Disease

17.2.3 Lipoprotein Metabolism and Transport The lipoprotein transport system has two major roles: the efficient transport of triglycerides from the intestine and the liver to sites of utilization (fat tissue or muscle) and the transport of cholesterol to peripheral tissues, for membrane synthesis and for steroid hormone production or to the liver for bile acid synthesis. • Intestinal pathway (chylomicrons to chylomicron remnants). Life requires fats. The human body derives essential fatty acids that it cannot make from the diet. Fat typically furnishes 20–40% of daily calories. Triglycerides comprise the major portion of ingested fats. For an individual consuming 2,000 kcal/day, with 30% in the form of fat, this represents approximately 66 g of triglycerides per day and approximately 250 mg (0.250 gm) of cholesterol. Upon ingestion, pancreatic lipases hydrolyze triglycerides into free fatty acids and mono- or diglycerides. Emulsification by bile salts leads to the formation of intestinal micelles. Micelles resemble lipoproteins

1

in that they consist of phospholipids, free cholesterol, bile acids, di- and monoglycerides, free fatty acids, and glycerol. The mechanism of micelle uptake by the intestinal brush border cells still engenders debate. The Niemann-Pick C1-like 1 (NPC1-L1) protein is part of an intestinal cholesterol transporter complex, and the target for the selective cholesterol absorption inhibitor ezetimibe10 (see later). The advent of inhibitors of cholesterol uptake has rekindled interest in the mechanisms of intestinal fat absorption. After uptake into intestinal cells, fatty acids undergo re-esterification to form triglycerides and packaging into chylomicrons inside the intestinal cell and enter the portal circulation (Fig. 17.2, part 1). Chylomicrons contain apo B48, the amino-terminal component of apo B100. In the intestine, the apo B gene is modified during transcription into mRNA with a substitution of a uracil for a cytosine by an apo B48 editing enzyme complex (ApoBec). This mechanism involves a cytosine deaminase and leads to a termination codon at residue 2153 and a truncated form of apo B. Only intestinal cells express ApoBec. Chylomicrons rapidly enter the plasma compartment after meals. In capillaries of adipose tissue or muscle cells in the peripheral circulation, chylomicrons encounter lipoprotein lipase (LPL), an enzyme

FFA

2 Chylomicron

207

LPL

3

Chylomicr. Remnant ApoA-I, A-II ApoC-I, C-II, C-III Phospholipids Free cholesterol 8

Free Cholesterol

5

2 4

VLDL

HDL3

Peripheral Cells

7

Steroidogenic Cells

HDL2

LDL

Triglycerides

ApoA-I, A-II ApoC-I, C-II, C-III Phospholipids Free cholesterol LPL

10

HL, EL 6

LCAT Nascent HDL

Intestinal Pathway

CETP 9 PLTP cholesteryl esters

7 Hepatic Pathway 3

HL 6

IDL FFA

Fig.  17.2  Schematic diagram of the lipid transport system. Numbers in circles refer to explanation in text. Apo apolipoprotein; CETP cholesteryl ester transfer protein; EL endothelial lipase; FFA free fatty acids; HL hepatic lipase; HDL high-­density

lipoprotein; IDL intermediate-density lipoprotein; LCAT lecithin cholesterol acyltransferase; LDL low-density lipoprotein; LPL lipoprotein lipase; PLTP phospholipid transfer protein; VLDL very-low-density lipoprotein

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attached to heparan sulfate and present on the luminal side of endothelial cells (Fig. 17.2, part 2). LPL activity is modulated by apo CII (an activator) and by apo CIII (an inhibitor). Lipoprotein lipase has broad specificity for triglycerides; it cleaves all fatty acyl residues attached to glycerol, generating three molecules of free fatty acid for each molecule of glycerol. Muscle cells rapidly take up fatty acids. Adipose cells can store triglycerides made from fatty acids for energy utilization, a process that requires insulin. Fatty acids can also bind to fatty acid–binding proteins and travel to the liver, where they are repackaged in VLDL. Peripheral resistance to insulin can thus increase the delivery of free fatty acids to the liver with a consequent increase in VLDL secretion and increased apo B particles in plasma. As discussed later, this is one of the consequences of the metabolic syndrome (Chap. 43). The remnant particles, derived from chylomicrons following LPL action, contain apo E and enter the liver for degradation and reutilization of their core constituents (Fig. 17.2, part 3). • Hepatic pathway (very-low-density lipoprotein to intermediate-density lipoprotein). Food is not always available, and dietary fat content varies. The body must ensure readily available triglyceride to meet energy demands. Hepatic secretion of VLDL particles serves this function (Fig. 17.2, part 4). VLDLs are triglyceride-rich lipoproteins smaller than chylomicrons (Fig.  17.1). They contain apo B100 as their main lipoprotein. As opposed to apo B48, apo B100 contains a domain recognized by the LDL receptor (the apo B/E receptor). VLDL particles follow the same catabolic pathway through lipoprotein lipase as chylomicrons (Fig. 17.2, part 2). During hydrolysis of triglyceride-rich lipoproteins by LPL, an exchange of proteins and lipids takes place: VLDL particles (and chylomicrons) acquire apo Cs and apo E, in part from HDL particles. VLDLs also exchange triglycerides for cholesteryl esters from HDL (mediated by cholesteryl ester transfer protein [CETP]) (Fig. 17.2, part 9). Such bidirectional transfer of constituents between lipoproteins serves several purposes, allowing lipoproteins to acquire specific apolipoproteins that will dictate their metabolic fate; transfer of phospholipids onto nascent HDL particles mediated by phospholipid transfer protein (PLTP) (during the loss of core triglycerides, the phospholipid envelope becomes redundant and is shed off to apo AI to form new HDL particles); and transfer

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of cholesterol from HDL to VLDL remnants so it can be metabolized in the liver. This exchange constitutes a major part of the “reverse cholesterol transport pathway.” After hydrolysis of triglycerides partly depletes VLDL of triglycerides, VLDL particles have relatively more cholesterol, shed several apolipoproteins (especially the C apolipoproteins), and acquire apo E. The VLDL remnant lipoprotein, called intermediate-density lipoprotein (IDL), is taken up by the liver via its apo E moiety (Fig. 17.2, part 3) or further delipidated by hepatic lipase to form an LDL particle (Fig. 17.2, part 6). There are at least four receptors for triglyceride-rich lipoprotein (TRL), TRL remnants, and apo B–containing lipoproteins: the VLDL receptor, the remnant receptor, the LDL receptor (also called the apo B/E receptor), and the LDL receptor–related peptide. Most hepatic receptors share in their ability to recognize apo E, an engagement which mediates uptake of several classes of lipoproteins, including VLDL and intermediate-density lipoprotein. The interaction between apo E and its ligand is complex and involves the “docking” of TRL on heparan sulfate proteoglycans before presentation of the ligand to its receptor. • Low-density lipoproteins. LDL particles contain predominantly cholesteryl esters packaged with the protein moiety apo B100. Normally, triglycerides constitute only 4–8% of the LDL mass. In the presence of elevated plasma triglyceride levels, LDL particles can become enriched in triglycerides and depleted in core cholesteryl esters. LDL particle size variation results from changes in core constituents, with an increase in triglycerides and a relative decrease in cholesteryl esters leading to smaller, denser LDL particles. The LDL particles in most higher mammals, including humans and nonhuman primates, serve as the main carriers of cholesterol. In other mammals, such as rodents or rabbits, VLDL and HDL particles transport most of the cholesterol. Cells can either make cholesterol from acetate through enzymatic reactions requiring at least 33 steps or obtain it as cholesteryl esters from LDL particles. Cells internalize LDL via the LDL receptor (LDL-R). LDL particles contain one molecule of apo B. While several domains of apo B are highly lipophilic and associate with phospholipids, a region surrounding residue 3,500 binds saturabily and with high affinity to the LDL-R. The LDL-R localizes in a

17  Genetic Lipoprotein Disorders and Cardiovascular Disease

region of the plasma membrane rich in the protein clathrin (Figs. 17.2, part 7 and 5A). Once bound to the receptor, clathrin polymerizes and forms an endosome that contains LDL bound to its receptor, a portion of the plasma membrane, and clathrin. This internalized particle then fuses with lysosomes whose catalytic enzymes (cholesteryl ester hydrolase, cathepsins) release free cholesterol and degrade apo B. The LDL-R will detach itself from its ligand and recycle to the plasma membrane. Cells tightly regulate cholesterol content by (1) cholesterol synthesis in the smooth endoplasmic reticulum (via the rate-limiting step hydroxymethylglutaryl coenzyme A [HMG-CoA] reductase); (2) receptormediated endocytosis of LDL (two mechanisms under the control of the steroid-responsive element binding protein [SREBP]); (3) cholesterol efflux from plasma membrane to cholesterol acceptor particles (predominantly apo AI and HDL) via the ABCA1 transporter; and (4) intracellular cholesterol esterification via the enzyme acyl-CoA: cholesteryl acyltransferase (ACAT). The SREBP coordinately regulates the first two pathways at the level of gene transcription. Cellular cholesterol binds to a protein called SCAP (SREPB cholesterol-activated protein), which is located on the endoplasmic reticulum. Cholesterol inhibits the interaction of SCAP with SREPB. In the absence of cholesterol, SCAP will mediate the cleavage of SREBP at two sites by specific proteases and release an amino (NH2) fragment of SREBP. The SREBP NH2 fragment will migrate to the nucleus and increase the transcriptional activity of genes involved in cellular cholesterol and fatty acid homeostasis. Cleavage of SREBP depends on a proprotein convertase related to the subtilisin/kexin family of convertases. Another member of the convertase superfamily, proprotein convertase subtilisin/kexin 9 (PCSK9) may participate in the cellular processing of the LDL-R; gain-of-function mutations in this gene cause dominant familial hypercholesterolemia, while loss of function increases LDL-R and lowers LDL-C significantly.11 The ACAT pathway regulates cholesterol content in membranes.12 Humans express two separate forms of ACAT. ACAT1 and ACAT2 derive from different genes and mediate cholesterol esterification in cytoplasm and in the endoplasmic reticulum lumen for lipoprotein assembly and secretion. Regulation of cholesterol efflux depends in part on the ABCA1 pathway, controlled in turn by hydroxys-

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terols (especially 24- and 27-OH cholesterol, which act as ligands for the liver-specific receptor [LXR] family of transcriptional regulatory factors). In conditions of cholesterol sufficiency, the cell can decrease its input of cholesterol by decreasing the de novo synthesis of cholesterol. The cell can also decrease the amount of cholesterol that enters the cell via the LDLR, increase the amount stored as cholesteryl esters, and promote the removal of cholesterol by increasing its movement to the plasma membrane for efflux. • High-density lipoprotein and reverse cholesterol transport. Epidemiological studies consistently have shown an inverse relationship between plasma levels of HDL cholesterol and the presence of coronary artery disease. HDL promotes reverse cholesterol transport and can prevent lipoprotein oxidation and exert antiinflammatory actions in vitro. The metabolism of HDL is complex and incompletely understood. The complexity arises because HDL particles acquire their components from several sources while these components also are metabolized at different sites. Apolipoprotein AI, the main protein of HDL, is synthesized in the intestine and the liver. Approximately 80% of HDL originates from the liver13 and 20% from the intestine14 (Fig 17.2 part 5). Lipidfree apo AI acquires phospholipids from cell membranes and from redundant phospholipids shed during hydrolysis of triglyceride-rich lipoproteins. Lipid-free apo AI binds to ABCA1 and promotes its phosphorylation via cyclic adenosine monophosphate, which increases the net efflux of phospholipids and cholesterol onto apo AI to form a nascent HDL particle (Fig.  17.2, part 10).15,16 This particle, containing apo AI and phospholipids (and little cholesterol), resembles a flattened disk in which the phospholipids form a bilayer surrounded by two molecules of apo AI arranged in a circular fashion at the periphery of the disk. These nascent HDL particles will mediate further cellular cholesterol efflux. Currently, standard laboratory tests do not measure these HDL precursors because they contain little or no cholesterol. Upon reaching a cell membrane, the nascent HDL particles will capture membrane-associated cholesterol and promote the efflux of free cholesterol onto other HDL particles (Fig. 17.2, part 10). Conceptually, the formation of HDL particles appears to involve two steps, the first

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step ABCA1-dependent and the second probably does not require ABCA1.17 The efflux of cellular cholesterol from peripheral cells, such as macrophages, does not contribute importantly to overall HDL-C mass but may have an important effect on export of cholesterol from atheromata. Macrophage can efflux cholesterol onto apo AI and apoE, onto nascent HDL particles via the ABCA1 transporter or onto spherical HDL particles, via the ABCG1 transporter. ABCG1 transporter does not promote cellular cholesterol efflux to lipidfree or lipid-poor apo AI but to mature HDL particles. The plasma enzyme LCAT, an enzyme activated by apo AI, then esterifies the free cholesterol (Figs. 17.2, part 8). LCAT transfers an acyl chain (a fatty acid) from the R2 position of a phospholipid to the 3’-OH residue of cholesterol, resulting in the formation of a cholesteryl ester. In a process called selective uptake of cholesterol, HDL also provides cholesterol to steroid hormone–producing tissues and the liver through the scavenger SR-B1 receptor.18 Because of their hydrophobicity, cholesteryl esters move to the core of the lipoprotein and the HDL particle now assumes a spherical configuration (a particle denoted HDL3). With further cholesterol esterification, the HDL particle increases in size to become the more buoyant HDL22. Cholesterol within HDL particles can exchange with triglyceride-rich lipoproteins via cholesteryl ester transfer protein (CETP), which mediates an equimolar exchange of cholesterol from HDL to triglyceride-rich lipoprotein and triglyceride movement from triglyceride-rich lipoprotein onto HDL (Fig.  17.2, part 9). Inhibition of CETP increases HDL-C in the blood and represents a therapeutic target for cardiovascular disease prevention. Phospholipid transfer protein (PLTP) mediates the transfer of phospholipids between triglyceride-rich lipoprotein and HDL particles. Triglyceride-enriched HDL are denoted HDL2b. Hepatic lipase can hydrolyze triglycerides and endothelial lipase can hydrolyze phospholipids within these particles, converting them back to HDL3 particles. One mechanism of reverse cholesterol transport includes the uptake of cellular cholesterol from extrahepatic tissues, such as lipid-laden macrophages, and its esterification by LCAT, transport by large HDL particles, and exchange for one triglyceride molecule by CETP. Originally on an HDL particle, the cholesterol molecule can now be taken up by hepatic receptors on a triglyceride-rich lipoprotein or LDL particle. HDL

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particles, therefore, act as shuttles between tissue cholesterol, triglyceride-rich lipoprotein, and the liver. Most HDL originates in the liver13 and intestines.14 Reverse cholesterol transport by HDL constitutes a small but potentially important portion of the plasma HDL mass. Indeed, selective inactivation of macrophage ABCA1 does not change HDL-C levels in mice, but there is an increase in atherosclerosis.19 The catabolism of HDL particles has engendered debate among lipoprotein researchers. The protein component of HDL particles is exchangeable with lipoproteins of other classes. The kidneys appear to be a route of elimination of apolipoprotein AI and other HDL apolipoproteins. The lipid component of HDL particles also follows a different metabolic route.

17.3 Lipoprotein Disorders 17.3.1 Definitions Time and new knowledge have stimulated changes to the classification of lipoprotein disorders. The original classification of lipoprotein disorders by Fredrickson, Lees, and Levy was based on the measurement of total plasma cholesterol and triglycerides and analyzed lipoproteins patterns after separation by electrophoresis. This classification recognized elevations of chylomicrons (type I), VLDL or prebeta lipoproteins (type IV), “broad beta” disease (or type III hyperlipoproteinemia), beta lipoproteins (LDL) (type II), and elevations of both chylomicrons and VLDL (type V). In addition, the combined elevations of prebeta (VLDL) and beta (LDL) lipoproteins were recognized as type IIb hyperlipoproteinemia. Though providing a useful conceptual framework, this classification has some drawbacks: it does not include HDL cholesterol, and it does not differentiate severe monogenic lipoprotein disorders from the more common polygenic disorders. Subsequently, the World Health Organization, the European Atherosclerosis Society and, more recently, the National Cholesterol Education Program have classified lipoprotein disorders on the basis of arbitrary cut-points. A practical approach describes the lipoprotein disorder by the absolute plasma levels of lipids (cholesterol and triglycerides) and lipoprotein cholesterol levels (LDL and HDL cholesterol) and considers

17  Genetic Lipoprotein Disorders and Cardiovascular Disease

clinical manifestations of hyperlipoproteinemia in the context of biochemical characterization. For example, a young patient presenting with eruptive xanthomas and a plasma triglyceride level of 11.3 mmol/L (1,000 mg/dL) likely has familial hyperchylomicronemia. An obese, hypertensive middle-aged man with a cholesterol level of 6.4 mmol/L(247 mg/dL), a triglyceride level of 3.1mmol/L (274 mg/dL), an HDL cholesterol level of 0.8 mmol/L (31 mg/dL), and a calculated LDL cholesterol level of 4.2 mmol/L (162 mg/dL) likely has the metabolic syndrome, and should spur identification of its components including hypertension and hyperglycemia, should be sought. The clinical usefulness of apolipoprotein levels has stirred debate. Although a useful research tool in general, the measurement of apolipoproteins AI and B practically may add little substantial information to that provided by the conventional lipid profile. Taken as a single measurement, the apo B level provides information on the number of potentially atherogenic particles and can be used as a goal of lipid-lowering therapy.20 Similarly, LDL particle size correlates highly with plasma HDL cholesterol and triglyceride levels, and most studies do not show it to be an independent cardiovascular risk factor. Small, dense LDL particles tend to track with features of the metabolic syndrome, which usually involves dyslipoproteinemia with elevated plasma triglycerides and reduced HDL cholesterol levels.21 It remains uncertain whether in addition to LDL particle number reduction, a change in LDL particle size will bring further clinical benefit. • Secondary causes of hyperlipidemia and the metabolic syndrome Several clinical disorders lead to alterations in lipoprotein status (Table 17.2). Hormonal causes: Hypothyroidism, a not infrequent cause of secondary lipoprotein disorders, often manifests with elevated LDL cholesterol, triglycerides, or both. An elevated level of thyroid-stimulating hormone is key to the diagnosis, and the lipoprotein abnormalities often revert to normal after correction of thyroid status. Rarely, hypothyroidism may uncover a genetic lipoprotein disorder such as type III hyperlipidemia. Estrogens can elevate plasma triglycerides and HDL cholesterol levels, probably because of increases in both hepatic VLDL and apo AI production. In postmenopausal women, estrogens may reduce LDL cholesterol by up to 15%. The use of estrogens for the

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treatment of lipoprotein disorders is no longer recommended because of the slight increase in cardiovascular risk with prolonged use of estrogens in the postmenopausal period (see Chaps. 42 and 73).46 Rarely, pregnancy causes severe increases in plasma triglycerides, on a background of lipoprotein lipase deficiency. Such cases present a serious threat to mother and child and require referral to specialized centers. Male sex hormones and anabolic steroids can increase hepatic lipase activity and have been used in the treatment of hypertriglyceridemia in men. Growth hormone can reduce LDL cholesterol and augment HDL cholesterol but is not recommended in the treatment of lipoprotein disorders. Metabolic causes: The most frequent secondary cause of dyslipoproteinemia is probably the constellation of metabolic abnormalities seen in patients with the metabolic syndrome. The finding of increased visceral fat (abdominal obesity), elevated blood pressure, and impaired glucose tolerance often clusters with increased plasma triglycerides and a reduced HDL cholesterol level and comprise the major components of the metabolic syndrome.21,47 The lack of internationally recognized uniform criteria for the metabolic syndrome among other issues casts doubt on the usefulness of this syndrome as a diagnostic entity.48 Overt diabetes, especially type 2 diabetes, frequently elevates plasma triglycerides and reduces HDL cholesterol. These abnormalities have prognostic implications in patients with type 2 diabetes. Poor control of diabetes, obesity, and moderate to severe hyperglycemia can yield severe hypertriglyceridemia with chylomicronemia and increased VLDL cholesterol levels. Subjects with type I diabetes can also have severe hypertriglyceridemia when poorly controlled. Familial lipodystrophy (complete or partial) may be associated with increased VLDL secretion. Dunnigan lipodystrophy, a genetic disorder with features of the metabolic syndrome, is caused by mutations within the Lamin A/C gene and is associated with limb-girdle fat atrophy. Excess plasma triglycerides often accompany glycogen storage disorders. Renal disorders: In subjects with glomerulonephritis and protein-losing nephropathies, a marked increase in secretion of hepatic lipoproteins can raise LDL cholesterol levels, which may approach the levels seen in subjects with familial hypercholesterolemia. By contrast, patients with chronic renal failure have a pattern  of hypertriglyceridemia with reduced HDL

212 Table 17.2  Genetic lipoprotein disorders Disorder Triglyceride-rich lipoproteins Lipoprotein lipase deficiency Apo CII deficiency Apo AV Familial hypertriglyceridemia polygenic Familial combined hyperlipidemia Remnant lipoproteins Dysbetalipoproteinemia type III Hepatic lipase deficiency LDL particles Familial hypercholesterolemia Familial defective apo B-100 Autosomal dominant hypercholesterolemia

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Gene

Fig 17.2

LPL Apo CII Apo AV

 2 2

Polygenic Apo E HL

 3 6

LDL-R Apo B PCSK9

7 7 7

Autosomal recessive hypercholesterolemia Abetalipoproteinemia Hypobetalipoproteinemia Familial sitosterolemia Familial lipoprotein(a) hyperlipoproteinemia

ARH MTP Apo B ABCG5/ABCG8 Apo (a)

7

HDL particles Apo AI deficiency Tangier disease/familial HDL deficiency Familial LCAT deficiency syndromes CETP deficiency Niemann-Pick disease types A and B Niemann-Pick disease tyoe C

Apo AI ABCA1 LCAT CETP SMPD1 NPC1

cholesterol. Patients with end-stage renal disease, including those on hemodialysis or chronic ambulatory peritoneal dialysis, have a poor prognosis and accelerated atherosclerosis and should undergo aggressive treatment of lipoprotein disorders. This approach, however, has been recently challenged when a recent trial of statins in diabetic patients on dialysis showed no reduction in cardiovascular end-points. After organ transplantation, the immunosuppressive regimen (glucocorticoids and cyclosporine) typically elevates triglycerides and reduces HDL cholesterol levels. Because transplant patients generally have an increase in cardiovascular risk, a secondary hyperlipidemia may warrant treatment. Patients receiving the combination of statin plus cyclosporine merit careful dose titrations and monitoring for myopathy. Liver disease: Obstructive liver disease, especially primary biliary cirrhosis may lead to the formation of an abnormal lipoprotein termed lipoprotein-x. This type of lipoprotein is found in cases of LCAT

10 8 9 

deficiency and consists of an LDL-like particle but with a marked reduction in cholesteryl esters. Extensive xanthoma formation on the face and palmar areas can be the result from accumulation of lipoprotein-x. Lifestyle: Factors contributing to obesity, such as an imbalance between caloric intake and energy expenditure, lack of physical activity, and a diet rich in saturated fats and refined sugars, contribute in large part to the lipid and lipoprotein lipid levels within a population. Medication: Several medications can alter lipoproteins. Thiazide diuretics can increase plasma triglyceride levels. Beta blockers, especially nonbeta-1 selective, increase triglycerides and lower HDL cholesterol levels. Retinoic acid and estrogens can increase triglyceride levels, sometimes dramatically. Corticosteroids and immunosuppressive agents can increase plasma triglyceride levels and lower HDL cholesterol levels. Estrogens can increase plasma HDL cholesterol significantly and often increase triglyceride concentrations.

17  Genetic Lipoprotein Disorders and Cardiovascular Disease

In clinical practice, many dyslipoproteinemias, other than the genetic forms mentioned earlier, share an important environmental cause. Lifestyle changes (diet, exercise, reduction of abdominal obesity) should be the foundation for the treatment of most dyslipidemias. The effects of marked alterations in lifestyle, reduction in dietary fats, especially saturated fats, and exercise can improve cardiovascular prognosis. Translating these findings into practice, however, has been more difficult. For example, dietary manipulations as performed in a physician’s office lead to relatively small reductions in plasma lipid and lipoprotein cholesterol levels.

17.3.2 Genetic Lipoprotein Disorders Understanding of the genetics of lipoprotein metabolism has expanded rapidly. Classification of genetic lipoprotein disorders usually requires a biochemical phenotype in addition to a clinical phenotype. With the exception of familial hypercholesterolemia, monogenic disorders tend to be infrequent or very rare. Disorders considered heritable on careful family study may be difficult to characterize unambiguously because of age, gender, penetrance, and gene–gene and environmental interactions. Most common lipoprotein disorders encountered clinically result from the interaction of increasing age, lack of physical exercise, weight gain, and a suboptimal diet with individual genetic make-up. Genetic lipoprotein disorders can affect LDL, lipoprotein (a) [Lp(a)], remnant lipoproteins, triglyceriderich lipoproteins (chylomicrons and VLDL), or HDL (Table  17.2). Within each of these, genetic disorders can cause an excess or a deficiency of a specific class of lipoprotein. • Triglyceride-rich lipoproteins (TRL) In subjects with the metabolic syndrome and in diabetic patients, elevation of plasma triglyceride level occurs most often in the presence of visceral (abdominal) obesity and a diet rich in calories, carbohydrates, and saturated fats. Severe elevation of plasma triglycerides can result from genetic disorders of the processing enzymes or apolipoproteins and poorly controlled diabetes.

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Familial hypertriglyceridemia (type IV hyperlipoproteinemia): Familial hypertriglyceridemia is not associated with clinical signs such as corneal arcus, xanthoma, and xanthelasmas. Plasma triglycerides, VLDL cholesterol, and VLDL triglycerides are moderately to markedly elevated; LDL cholesterol level is usually low as is and HDL cholesterol. Total cholesterol is normal or elevated, depending on VLDL cholesterol levels. Fasting plasma concentrations of triglycerides are in the range of 2.3–5.7 mmol/L (200– 500 mg/dL). After a meal, plasma triglycerides may exceed 11.3 mmol/L (1,000 mg/dL). The disorder is found in first-degree relatives, but phenotypic variability is related to gender, age, hormone use (especially estrogens), and diet. Alcohol intake potently stimulates hypertriglyceridemia in these subjects, as does caloric or carbohydrate intake. The relationship with coronary artery disease is not as strong as with familial combined hyperlipidemia and has not been seen in all studies. Depending on criteria used, the prevalence of familial hypertriglyceridemia ranges from 1 in 100 to 1 in 50. The disorder is highly heterogeneous and likely results from several genes, with a strong environmental influence. An unrelated disorder, familial glycerolemia, a chromosome X-linked genetic disorder may mimic familial hypertriglyceridemia because most measurement techniques for triglycerides use the measurement of glycerol after enzymatic hydrolysis of triglycerides.22 The diagnosis of familial hyperglycerolemia requires ultracentrifugation of plasma and analysis of glycerol. Hepatic overproduction of VLDL causes familial hypertriglyceridemia is (Fig. 17.2, part 4); the catabolism (uptake) of VLDL particles can be normal or reduced. Lipolysis by LPL appears not to be a limiting factor, although the triglyceride load, especially in the postprandial state, may limit processing of VLDL particles. The genetic basis of familial hypertriglyceridemia is unknown, and the candidate approach to find the gene or genes involved (apo B, LDL, apo CIII) has not yielded fruit thus far. Treatment is based first on lifestyle modifications, including withdrawal of hormones (estrogens and progesterone), limiting alcohol intake, reducing caloric intake, and increasing exercise. The decision to treat this disorder with medications (see later) depends on global cardiovascular risk. An infrequent disorder characterized by severe elevation in plasma triglyceride levels (both VLDL and

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chylomicrons) is associated with a fat-rich diet, obesity, and poorly controlled diabetes. Recognized as type V hyperlipidemia, the pathogenesis is multifactorial and results from overproduction of both VLDL and chylomicrons and from decreased catabolism of these particles. Familial hyperchylomicronemia (type I hyperlipidemia): This rare disorder of severe hypertriglyceridemia associates with elevations in fasting plasma triglycerides greater than 11.3 mmol/L (>1,000 mg/ dL). These patients have recurrent bouts of pancreatitis and eruptive xanthomas. Interestingly, severe hypertriglyceridemia can also be associated with xerostomia, xerophthalmia, and behavioral abnormalities. The hypertriglyceridemia results from a markedly reduced or absent LPL activity or, more rarely, the absence of its activator, apo CII (Fig. 17.2, part 2).23 These defects lead to a lack of hydrolysis of chylomicrons and VLDL and their accumulation in plasma, especially after meals. Extreme elevations of plasma triglycerides (>113 mmol/L; >10,000 mg/dL) can result. Plasma from a patient with very high triglycerides is milky white, and a clear band of chylomicrons can be seen on top of the plasma after it stands overnight in a refrigerator. Populations with a founder effect can have high prevalence of LPL mutations. At least 60 LPL mutations can cause LPL deficiency. LPL188, LPLasn291ser, and LPL207 are frequently associated hyperchylomicronemia. Heterozygotes for the disorder tend to have an increase in fasting plasma triglycerides and smaller, denser LDL particles. Many patients with complete LPL deficiency present in childhood fail to thrive and have recurrent bouts of pancreatitis. To underscore the importance of LPL’s role, the LPL deficient mouse leads to a perinatal lethal phenotype.24 The treatment of acute pancreatitis includes intravenous hydration and avoidance of fat in the diet (including in parenteral nutrition). Plasma filtration is required only rarely. Chronic treatment includes avoidance of alcohol and dietary fats. To make the diet more palatable, short-chain fatty acids (which are not incorporated in chylomicrons) can be used to supplement the diet. Type III hyperlipoproteinemia: Type III hyperlipoproteinemia, also referred to as dysbetalipoproteinemia or broad beta disease, is a rare genetic lipoprotein disorder characterized by an accumulation in plasma of remnant lipoprotein particles. On lipoprotein agarose gel electrophoresis, a typical pattern of a broad

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band between the pre-beta (VLDL) and beta (LDL) lipoproteins is observed, hence the name “broad beta disease.” Patients with this disease clearly have increased cardiovascular risk. The clinical presentation consists of pathognomonic tuberous xanthomas and palmar striated xanthomas. The lipoprotein profile shows increased cholesterol and triglyceride levels and reduced HDL cholesterol. Remnant lipoproteins (partly catabolized chylomicrons and VLDL) accumulate in plasma and accumulate cholesterol esters. The defect results from abnormal apo E, which does not bind to hepatic receptors that recognize apo E as a ligand (Fig. 17.2, part 3).25 The ratio of VLDL cholesterol to triglycerides, normally less than 0.7 mmol/L (<0.30 mg/dL), is elevated in patients with type III hyperlipoproteinemia, owing to cholesteryl ester enrichment of remnant particles. The diagnosis includes plasma ultracentrifugation for lipoprotein separation, lipoprotein electrophoresis, and apo E phenotyping or genotyping. Patients with type III hyperlipoproteinemia have the apo E2/2 phenotype or genotype. There are three common alleles for apo E: apo E2, E3, and E4. The apo E2 allele has markedly decreased binding to the apo B/E receptor. In a normal population, the prevalence of the apo E2/2 phenotype is approximately 0.7–1.0%. Type III hyperlipoproteinemia occurs in approximately 1 percent of subjects bearing the apo E2/2 phenotype. The reasons for the relative rarity of type III dyslipoproteinemia are not fully understood. As discussed previously, a second “hit” is thought to impart the full expression of the disorder. Other rare mutations of the apo E gene can cause type III hyperlipoproteinemia.25 In general, type III dyslipoproteinemia responds well to dietary therapy, correction of other metabolic abnormalities (diabetes, obesity), and, in cases requiring drug therapy, fibric acid derivatives or statins. The importance of the apo E gene and protein is underscored by the widespread use of the apo E deficient mouse which develops experimental atherosclerosis.26 Familial combined hyperlipidemia: One of the most common familial lipoprotein disorders is familial ­combined hyperlipoproteinemia (FCH). Described initially in survivors of myocardial infarction, the definition of familial combined hyperlipoproteinemia has undergone several refinements. It is characterized by the presence of elevated total cholesterol and/or triglyceride levels based on arbitrary cut-points in several members of the same family. Advances in analytical

17  Genetic Lipoprotein Disorders and Cardiovascular Disease

techniques have added the measurement of LDL cholesterol and, in some cases, apo B levels. Because of the lack of a clear-cut clinical or biochemical marker, considerable overlap exists between familial combined hyperlipoproteinemia, familial dyslipidemic hypertension, the metabolic syndrome, and hyperapobetalipoproteinemia. Genetic heterogeneity probably underlies familial combined hyperlipoproteinemia, which has a prevalence of approximately 1 in 50 and accounts for 10–20% of patients with premature CAD. The condition has few clinical signs; corneal arcus, xanthomas, and xanthelasmas occur infrequently. The biochemical abnormalities include elevation of plasma total and LDL cholesterol levels (>90th to 95th percentile) and/ or an elevation of plasma triglycerides (>90th to 95th percentile) – a type IIb lipoprotein phenotype, often in correlation with low HDL cholesterol and elevated apo B levels; small, dense LDL particles are seen frequently. For a diagnosis of familial combined hyperlipoproteinemia, the disorder must be identified in at least one first-degree relative. The underlying metabolic disorder appears to be hepatic overproduction of apo B–containing lipoproteins, delayed postprandial triglyceride-rich lipoprotein clearance, and increased flux of free fatty acids (FFA) to the liver. Experimental data have shown that substrate levels drive hepatic apo B secretion, the most important substrates being FFA and cholesteryl esters. Increased delivery of FFA to the liver, as occurs in states of insulin resistance, leads to increased hepatic apo B secretion. Familial combined hyperlipoproteinemia has complex genetics. It was initially considered an autosomal codominant trait; modifying factors include gender, age of onset, and comorbid states such as obesity, lack of exercise, and diet. Initial reports of linkage with the apo AI-CIII-AIV and LPL genes remain unsubstantiated. A novel locus on chromosomes 1 and 16 in Finnish families currently appears to be a promising candidate gene related to familial combined hyperlipoproteinemia.27 Recent reports of the acylation-stimulating protein (ASP), also known as complement C3desARG pathway, suggest that abnormal peripheral uptake of FFA may underlie some cases of familial combined hyperlipoproteinemia and the insulin-resistance metabolic syndrome.28 A putative receptor for ASP has been identified recently as the orphan receptor C5L2, the complement C5 receptor that also binds complement C3desARG. Abnormal binding of ASP to peripheral

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cells has been reported in subjects with familial combined hyperlipoproteinemia. Abnormal ASP binding causes decreased uptake of FFAs into adipocytes and subsequent increased flux of FFAs to the liver. FFAs are a major substrate for hepatic apo B-containing lipoprotein assembly and secretion. • Low-density lipoproteins (type II hyperlipidemia) Familial hypercholesterolemia: Familial hypercholesterolemia is the most thoroughly studied lipoprotein disorder. The elucidation of the pathway by which complex molecules enter the cell by receptor-mediated endocytosis and the discovery of the LDL receptor represent landmarks in cell biology and clinical investigation. Affected subjects have an elevated LDL cholesterol level greater than the 95th percentile for age and gender. In adulthood, clinical manifestations include corneal arcus, tendinous xanthomas over the extensor tendons (metacarpophalangeal joints, patellar, triceps and Achilles tendons), and xanthelasmas. Transmission is autosomal codominant. Familial hypercholesterolemia affects approximately 1:500, although this prevalence is higher in populations with founder effects. Patients with familial hypercholesterolemia have a high risk of developing coronary artery disease (CAD) by the third to fourth decade in men and approximately 8–10 years later in women. Diagnosis is based on elevated plasma LDL cholesterol level, family history of premature CAD, and the presence of xanthomas. A molecular diagnosis is sometimes required. Defects of the LDL-R gene cause an accumulation of LDL particles in plasma and thus alter the function of the LDL-R protein and cause familial hypercholesterolemia (Fig.  17.2, part 7). To date, there are well over 600 identified mutations of the LDL-R gene (see http://www.umd.necker.fr).29 Familial defective apo B: Mutations within the apo B gene that lead to an abnormal ligand-receptor interaction can cause a form of familial hypercholesterolemia clinically indistinguishable from the primary form. Several mutations at the postulated binding site to the LDL-R cause familial defective apo B100 (Fig. 17.2, part 7). These consist of apo BArg3500Gln, apo BArg3500Trp, and apo BArg3531Cys.30 The apo BArg3500Gln results from a G → A substitution at nucleotide 3500 within exon 26 of the apo B gene. The defective apo B has a reduced affinity (20–30% of control) for the LDL-R. LDL particles with defective apo B have a plasma half-life three- to fourfold greater than the

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half-life of normal LDL. Because of their increased persistence, these LDL particles can more readily undergo oxidative modifications that can enhance their atherogenicity. Affected subjects usually have elevated LDL cholesterol levels up to 400 mg/dL (10.4 mmol/L) but may also have normal levels. Familial defective apo B 100 has a prevalence similar to that of familial hypercholesterolemia (1/500). In subjects with the classic presentation of familial hypercholesterolemia, the prevalence of familial defective apo B 100 is reported to be 1 in 50 to 1 in 20. The reasons for the variability of plasma LDL cholesterol levels remain unexplained. An autosomal dominant form of hypercholesterolemia that maps to chromosome 1p34.1 involves a mutation within the proprotein convertase, subtilisin/ kexin type 9 gene (PCSK9). PCSK9 codes for a protein identified as neural apoptosis-regulated convertase 1 (NARC1), a novel proprotein convertase belonging to the subtilase family of convertases. It is related to subtilisin/kexin isoenzyme-1 (site-1 protease) required for cleavage of SREBP.11 Subjects with loss of function mutation of PCSK9 have a markedly lower LDL-C than subjects without the mutation. Black Americans have a higher prevalence of this protective mutation than whites In the Atherosclerosis Risk in Communities study, subjects with lifelong low LDL-C because of a mutation at the PCSK9 gene locus had a marked reduction in coronary events,31 confirming that genetic low LDL-C states confer cardio protective advantage. An autosomal recessive form of familial hypercholesterolemia has been identified in kindred from Sardinia and is caused by mutations in the ARH gene that encodes a protein involved in the recycling of the LDLreceptor.32

17.3.3 Hypobetalipoproteinemia and Abetalipoproteinemia Mutations within the apo B gene can lead to truncations of the mature apo B100 peptide. Many such mutations cause a syndrome characterized by reduced LDL and VLDL cholesterol but little or no clinical manifestations and no known risk of cardiovascular disease, a condition referred to as hypobetalipoproteinemia. Apo B truncated close to its amino terminus loses the ability to bind lipids, producing a syndrome similar to

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abetalipoproteinemia, a rare recessive lipoprotein disorder of infancy that causes mental retardation and growth abnormalities. Abetalipoproteinemia is caused by a mutation in gene coding for the microsomal triglyceride transfer protein (MTP) required for assembly of apo B–containing lipoproteins in the liver and the intestine. The resulting lack of apo B–containing lipoproteins in plasma causes a marked deficiency of fatsoluble vitamins (A, D, E, and K) that circulate in lipoproteins. In turn, this results in mental and developmental retardation in affected children. Sitosterolemia: A rare condition of increased intestinal absorption and decreased excretion of plant sterols (sitosterol and campesterol) can mimic severe familial hypercholesterolemia, with extensive xanthoma formation. Premature atherosclerosis, often apparent clinically well before adulthood, occurs frequently in patients with sitosterolemia. Diagnosis requires specialized analysis of plasma sterols demonstrating an elevation in sitosterol, campesterol, cholestanol, sitostanol, and campestanol. Interestingly, plasma cholesterol is normal or reduced, and triglycerides are normal. Positional cloning techniques have localized the defect to chromosome 2p21. Mutations in the adenosine triphosphate binding cassette G5 and G8 genes (ABCG5 and ABCG8) have been found in patients with sitosterolemia. The gene products of ABCG5 and ABCG8 are half ABC transporters and are thought to form a heterodimer characteristic of the full ABC transporters. The complex is located in the villous border of intestinal cells and actively pumps plant sterols back into the intestinal lumen. A defect in either of the genes renders the complex inactive, and absorption of plant sterols (rather than their elimination) ensues. ABCG5 and ABCG8 mutations leading to sitosterolemia are very rare.33 Lipoprotein (a): Lipoprotein (a) (pronounced “lipoprotein little a”) consists of an LDL particle linked covalently with one molecule of apo (a). The apo (a) moiety consists of a protein with a high degree of homology with plasminogen. The apo (a) gene appears to have arisen from the plasminogen gene by nonhomologous recombination. The apo (a) gene has multiple repeats of one of the kringle motifs (kringle IV), varying in number from 12 to more than 40 in each individual. Plasma lipoprotein(a) levels depend almost entirely on genetics and correlate inversely with the number of kringle repeats and, therefore, with the molecular weight of apo (a).34 Few environmental

17  Genetic Lipoprotein Disorders and Cardiovascular Disease

factors or medications modulate plasma lipoprotein(a) levels. The pathogenesis of lipoprotein(a) may result from an antifibrinolytic potential and/or ability to bind oxidized lipoproteins. Some prospective epidemiological studies have shown a positive (albeit weak) association between lipoprotein(a) and coronary artery disease.35 • High-density lipoproteins Reduced plasma levels of HDL cholesterol consistently correlate with the development or presence of CAD. Most cases of reduced HDL cholesterol result from elevated plasma triglycerides or apo B levels and often keep company with other features of the metabolic syndrome. Primary forms of reduced HDL cholesterol which occur in cases of premature CAD and helped shed light on the complex metabolism of HDL particles. Genetic disorders of HDL can result from decreased production or abnormal maturation and increased catabolism.36 Genetic lipoprotein disorders leading to moderate to severe elevations in plasma triglycerides cause a reduction in HDL cholesterol levels. Familial hyperchylomicronemia, familial hypertriglyceridemia, and familial combined hyperlipoproteinemia are all associated with reduced HDL cholesterol levels. In complex disorders of lipoprotein metabolism such as familial combined hyperlipidemia, the metabolic syndrome, and common forms of hypertriglyceridemia, several factors most likely correlate to low HDL cholesterol level. Plasma triglycerides and HDL cholesterol levels vary inversely. For several reasons, patients with elevated apo B levels also have reduced HDL cholesterol levels. First, decreased lipolysis of triglyceride-rich lipoproteins (each VLDL contains one molecule of apo B) decreases the substrate (phospholipids) available for HDL maturation. Second, triglyceride enrichment of HDL increases their catabolic rate and hence reduces their plasma concentration. Third, exchange of lipids between HDL and triglyceride-rich lipoprotein is reduced, leading to a more rapid disappearance of HDL from plasma.37 The inverse relationship between HDL cholesterol levels and plasma triglycerides reflects the interdependency of the metabolism of triglyceride-rich lipoproteins and HDL particles. Apo AI gene defects: Primary defects affecting production of HDL particles consist predominantly of apo AI-CIII-AIV gene defects. More than 46 mutations affect the structure of apo AI,38 leading to a marked

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reduction in HDL cholesterol levels. Not all these defects are associated with premature cardiovascular disease. Clinical presentations can vary from extensive atypical xanthomatosis and corneal infiltration of lipids to no manifestations at all. Treatment of these apo AI gene defects generally fails to raise HDL cholesterol levels. Other mutations of apo AI lead to increased catabolic rate of apo AI and may not be associated with cardiovascular disease. One such mutation, apo AIMilano (apo AIArg173Cys), appears to confer longevity despite very low HDL levels.38 LCAT, CETP deficiency: Genetic defects in the HDL-processing enzymes give rise to interesting phenotypes. Deficiencies of LCAT, the enzyme that catalyzes the formation of cholesteryl esters in plasma, cause corneal infiltration of neutral lipids and hematological abnormalities due to abnormal constitution of red blood cell membranes. LCAT deficiency can lead to an entity called “fish eye disease” because of the characteristic pattern of corneal infiltration observed in affected individuals.39 Patients without CETP have very elevated HDL cholesterol levels, enriched in cholesteryl esters. Because CETP facilitates the transfer of HDL cholesteryl esters into triglyceride-rich lipoproteins, a deficiency of this enzyme causes accumulation of cholesteryl esters within HDL particles. CETP deficiency is not associated with premature CAD but may not afford protection against CAD.40 Tangier disease and familial HDL deficiency: A rare disorder of HDL deficiency was identified in a proband from the Chesapeake Bay island of Tangier in the United States. The proband, whose sister was also affected, had markedly enlarged yellow tonsils and nearly absent HDL cholesterol levels, an entity now called Tangier disease. The cellular defect in Tangier disease consists of a reduced cellular cholesterol efflux in skin fibroblasts and macrophages from affected subjects.41 A more common entity, familial HDL deficiency, was also found to result from decreased cellular cholesterol. The genetic defect in Tangier disease and in familial HDL deficiency results from mutations at the ATP binding cassette A1 gene (ABCA1) that encodes the ABCA1 transporter.42 At least 100 mutations have been reported within ABCA1, causing Tangier disease (homozygous or compound heterozygous mutations) or familial HDL deficiency (heterozygous mutations). Although subjects with Tangier disease and familial HDL deficiency are at increased

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risk for CAD, their very low levels of LDL cholesterol appear to have a protective effect. ABCA1 appears to shuttle from the late endosomal compartment to the plasma membrane and act as a membrane-bound transporter of phospholipids (and cholesterol) onto acceptor proteins such as apo AI and apo E. Hydroxysterols regulate ABCA1 via the LxR/RxR nuclear receptor pathway. ABCA1 undergoes phosphorylation via protein kinase A and acts as a receptor for apo AI. Other cholesterol transport defects: Niemann-Pick type C disease is a disorder of lysosomal cholesterol transport. In patients with Niemann-Pick type C disease, mental retardation and neurological manifestations occur frequently. The cellular phenotype involves markedly decreased cholesterol esterification and cellular cholesterol transport defect to the Golgi apparatus. Unlike Tangier disease/familial HDL deficiency, the cellular defect in Niemann-Pick type C disease appears proximal to the transport of cholesterol to the plasma membrane. The gene for Niemann-Pick type C disease (NPC1) has been mapped to 18q21 and the gene codes for a 1278-amino acid protein, the role of which appears to be involved in cholesterol shuttling between the late endosomal pathway and the plasma membrane. The NPC1 gene product shares homology with the morphogen receptor patched and the SREBP cleavage activating protein (SCAP).43 Niemann-Pick type C cells lack NPC1 protein and cholesterol sequestration within the late endosome compartment prevents upregulation of ABCA1, and these patients thus have impaired cellular cholesterol efflux and HDL assembly.44 Niemann-Pick type I disease (subtypes A and B), caused by mutations at the sphingomyelin phosphodiesterase-1 (SMPD-1) gene, associates with a low HDL cholesterol level. The SMPD-1 gene codes for a lysosomal (acidic) and secretory sphingomyelinase. The low HDL cholesterol level in Niemann-Pick A and B patients appears to result from a decrease in LCAT reaction because of abnormal HDL constituents.45

17.4 Practical Approach 17.4.1 Approach to the Diagnosis The diagnosis of genetic lipoprotein disorders is made only after ruling out the secondary cause of hyperlipidemia (Table  17.3). The main secondary causes of

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hyperlipidemia in adults are dietary, alcohol intake, oral contraceptives, diabetes mellitus, and pharmacological agents (e.g., retinoic acid derivatives, steroids, and betablockers). The most frequent secondary cause of dyslipoproteinemia is probably the constellation of metabolic abnormalities seen in patients with the metabolic syndrome. A practical approach describes the lipoprotein disorder by the absolute plasma levels of lipids (cholesterol and triglycerides) and lipoprotein cholesterol levels (LDL and HDL cholesterol) and considers clinical manifestations of hyperlipoproteinemia in the context of biochemical characterization.

17.4.2 Laboratory Test and Their Orders The diagnosis of lipoprotein disorders depends on laboratory measurements (Table  17.4). The fasting lipid profile generally suffices for most lipoprotein Table 17.3  Secondary causes of dyslipoproteinemias Metabolic

Diabetes Lipodystrophy Glycogen storage disorders

Renal

Chronic renal failure Glomerulonephritis

Hepatic

Cirrhosis

Hormonal

Estrogens Progesterones Growth hormone Thyroid disorders (hypothyroidism) Corticosteroids

Lifestyle

Physical inactivity Obesity Diet rich in fats, saturated fats Alcohol intake

Medications

Retinoic acid derivatives Glucocorticoids Exogenous estrogens Thiazide diuretics Beta-adrenergic blockers (selective) Testosterone Immunosuppressive medications (cyclosporine) Antiviral medications (human immunodeficiency virus protease inhibitors)

17  Genetic Lipoprotein Disorders and Cardiovascular Disease

disorders, and specialized laboratories can refine the diagnosis and provide expertise for extreme cases. Additional tests often involve considerable expense and may not increase the predictive value beyond that of the lipid profile, although they can help in refining the diagnosis. To assess baseline risk in individuals on lipid-lowering therapy, the medication should be stopped for 1 month before a lipid profile is measured. Many advanced lipid tests are available in specialized centers (Table  17.4) but seldom add to the clinical assessment specified earlier.

17.4.3 Genetic Testing • Prenatal screening in the general population Prenatal diagnosis of genetic lipoprotein disorders is very rarely indicated and presently not recommended as these disorders do not require immediate treatment after birth and do not lead to severe morbidity and mortality in early life with the exception of sitsterolemia. In addition there is a risk of pregnancy loss as a consequence of the sampling procedure (0.5–1% by chorionic villous biopsy, 0.5% by amniocentesis). • Newborn screening The inclusion of genetic lipoprotein disorders as a whole in newborn screening panel is not presently recommended, because their incidence, natural history, prospective screening experience, and effectiveness of early treatment have not been defined yet. In addition, some genetic lipoprotein disorders can be missed by

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genomic sequencing (e.g., CNV and French Canadian LDL-R mutations). • Testing symptomatic Patient and families affected by FH The most common Genetic Lipoprotein disorder is Familial hypercholesterolemia and the others are frankly rare. Symptomatic patients should be screened for elevated cholesterol with routine laboratory tests first, and if LDL-c was higher than 5 mmol/L then genetic testing can be done to confirm the presence of FH. Genetic Testing is available for FH specifically targeting the LDLR gene by DNA-sequencing and Apo-B by mutation analysis. Genotypic-positive individuals should still be managed based on routine cholesterol assays and cholesterol guidelines; however, the likelihood for required multiple drug therapy is elevated. Patients and families affected by FH may benefit from genetic testing by providing early screening for the phenotypic appearance of elevated cholesterol levels and risk-factor modification before onset of disease.

17.4.4 Gene Therapy Gene therapy is a potential future therapy. Severe, homozygous, monogenic disorders may eventually be treated by gene therapy. The initial trials of gene therapy in cases of homozygous familial hypercholesterolemia have not led to a major improvement and have largely been abandoned. However, the lifelong burden of these rare disorders and the potential for cure make

Table 17.4  Laboratory tests for the diagnosis of lipoprotein disorders Lipid profile May help in diagnosis Specialized centers Cholesterol

LDL particle size

Lipoprotein separation by UTCa

Triglycerides

Apo B

LPL assay LCAT assay

HDL cholesterol

Apo AI

Apo E levels

LDL cholesterol

Apo E genotype/phenotype

Apolipoprotein separation by PAGE Apo CII, CIII

b

Research tools Molecular diagnosis

Lipoprotein(a) LDL-R assay Apo apolipoprotein; HDL high-density lipoprotein; LCAT lecithin cholesterol acyltransferase; LDL low-density lipoprotein; LDL-R LDL receptor; LPL lipoprotein lipase a Ultracentrifugation b Calculated as LDL cholesterol + total cholesterol – [(triglycerides/2.2)-HDL-cholesterol) in mmol/L) (or triglycerides divided by 5 in mg/dL); valid for triglycerides < 4.5mmol/L (<400 mg/dL). LDL cholesterol can also be directly measured in plasma

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this approach very appealing. Other diseases, such as abetalipoproteinemia, LPL deficiency, Niemann-Pick type C disease, sitosterolemia, and Tangier disease, may become targets for gene therapy. If the approach to correct these disorders is successful, the more widespread applications of gene-based therapies for the purpose of reducing potential cardiovascular risk will become a daunting medical, social, and ethical problem.

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K. Alwaili et al. 12. Willner EL, Tow B, Buhman KK et al. (2003) Deficiency of acyl CoA:cholesterol acyltransferase 2 prevents atherosclerosis in apolipoprotein E-deficient mice. Proc Natl Acad Sci USA 100:1262 13. Timmins JM, Lee JY, Boudyguina E et al. (2005) Targeted inactivation of hepatic Abca1 causes profound hypoalphalipoproteinemia and kidney hypercatabolism of apoA-I. J Clin Invest 115(5):1333–1342 14. Brunham LR, Kruit JK, Iqbal J, Fievet C, Timmins JM, Pape TD, Coburn BA, Bissada N, Staels B, Groen AK, Hussain MM, Parks JS, Kuipers F, Hayden MR (2006) Intestinal ABCA1 directly contributes to HDL biogenesis in  vivo. J Clin Invest 116(4):1052–1062 15. Denis M, Haidar B, Marcil M, Krimbou L, Genest J (2004) Molecular and cellular physiology of apolipoprotein A-I lipidation by the ATP biding cassette A1 (ABCA1). J Biol Chem 279:7384–7394 16. Haidar B, Denis M, Marcil M, Krimbou L, Genest J. Apolipoprotein A-I activates cellular camp signaling through the ABCA1 receptor. Evidence for molecular interactions between ABCA1 receptor and G protein. J Biol Chem. 2004;279:9963–9969 17. Chau P, Nakamura Y, Fielding CJ, Fielding PE (2006) Mechanism of prebeta-HDL formation and activation. Biochemistry. 45(12):3981–3987 18. Li XA, Titlow WB, Jackson BA et al. (2002) High density lipoprotein binding to scavenger receptor, class B, type I activates endothelial nitric-oxide synthase in a ceramidedependent manner. J Biol Chem 277:11058 19. Van Eck M, Singaraja RR, Ye D, Hildebrand RB, James ER, Hayden MR, Van Berkel TJ (2006) Macrophage ATP-binding cassette transporter A1 overexpression inhibits atherosclerotic lesion progression in low-density lipoprotein receptor knockout mice. Arterioscler Thromb Vasc Biol 26(4):929–934 20. Barter PJ, Ballantyne CM, Carmena R et al. (2006) Apo B versus cholesterol in estimating cardiovascular risk and in guiding therapy: report of the thirty-person/ten-country panel. J Intern Med 259(3):247–258 21. Grundy SM, Cleeman JI, Daniels SR, et al.; American Heart Association; National Heart, Lung, and Blood Institute. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005; 112(17):2735–2752 22. Sjarif DR, Sinke RJ, Duran M et al. (1998) Clinical heterogeneity and novel mutations in the glycerol kinase gene in three families with isolated glycerol kinase deficiency. J Med Genet 35:650 23. Santamarina-Fojo S: The familial chylomicronemia syndrome. Endocrinol Metab Clin North Am. 1998;27:551, viii 24. Weinstock PH, Bisgaier CL, Aalto-Setala K et  al. (1995) Severe hypertriglyceridemia, reduced high density lipoprotein, and neonatal death in lipoprotein lipase knockout mice: Mild hypertriglyceridemia with impaired very low density lipoprotein clearance in heterozygotes. J Clin Invest 96: 2555 25. Mahley RW, Huang Y, Rall SC Jr (1999) Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia): Questions, quandaries, and paradoxes. J Lipid Res 40:1933 26. Zhang SH, Reddick RL, Piedrahita JA, Maeda N (1992) Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science 258:468

17  Genetic Lipoprotein Disorders and Cardiovascular Disease 27. Pajukanta P, Lilja HE, Sinsheimer JS et al. (2004) Familial combined hyperlipidemia is associated with upstream transcription factor 1 (USF1). Nat Genet 36(4):371–376 28. Kalant D, MacLaren R, Cui W, Samanta R, Monk PN, Laporte SA, Cianflone K (2005) C5L2 is a functional receptor for acylation-stimulating protein. J Biol Chem 280(25): 23936–23944 29. Wilson DJ, Gahan M, Haddad L et al. (1998) A World Wide Web site for low-density lipoprotein receptor gene mutations in familial hypercholesterolemia: Sequence-based, tabular, and direct submission data handling. Am J Cardiol 81:1509 30. Whitfield AJ, Barrett PH, van Bockxmeer FM, Burnett JR (2004) Lipid disorders and mutations in the APOB gene. Clin Chem 50(10):1725–1732 31. Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH (2006) Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 354(12): 1264–1272 32. Garuti R, Jones C, Li WP, Michaely P, Herz J, Gerard RD, Cohen JC, Hobbs HH. The modular adaptor protein autosomal recessive hypercholesterolemia (ARH) promotes low density lipoprotein receptor clustering into clathrin-coated pits. J Biol Chem. 2005;280(49):40996–41004 33. Berge KE, Tian H, Graf GA et al. (2000) Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science 290:1771 34. Mooser V, Mancini FP, Bopp S et al. (1995) Sequence polymorphisms in the apo(a) gene associated with specific levels of Lp(a) in plasma. Hum Mol Genet 4:173 35. Danesh J, Collins R, Peto R (2000) Lipoprotein(a) and coronary heart disease: Meta-analysis of prospective studies. Circulation 102:1082 36. Dastani Z, Engert JC, Genest J, Marcil M. Genetics of highdensity lipoproteins. Curr Opin Cardiol. 2006;21(4): 329–335 37. Lewis GF, Rader DJ (2005) New insights into the regulation of HDL metabolism and reverse cholesterol transport. Circ Res 96(12):1221–1232 38. Sorci-Thomas MG, Thomas MJ (2002) The effects of altered apolipoprotein A-I structure on plasma HDL concentration. Trends Cardiovasc Med 12:121

221 39. Boekholdt SM, Kuivenhoven JA, Hovingh GK, Jukema JW, Kastelein JJ, van Tol A (2004) CETP gene variation: relation to lipid parameters and cardiovascular risk. Curr Opin Lipidol 15(4):393–398 40. Calabresi L, Pisciotta L, Costantin A et  al. (2005) The molecular basis of lecithin:cholesterol acyltransferase deficiency syndromes: a comprehensive study of molecular and biochemical findings in 13 unrelated Italian families. Arterioscler Thromb Vasc Biol 25(9):1972–1978 41. Brooks-Wilson A, Marcil M, Clee SM et al. (1999) Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nat Genet 22(4):336–345 42. Marcil M, Brooks-Wilson A, Clee SM et al. (1999) Mutations in the ABC1 gene in familial HDL deficiency with defective cholesterol efflux. Lancet 354:1341 43. Carstea ED, Morris JA, Coleman KG et al. (1997) NiemannPick C1 disease gene: Homology to mediators of cholesterol homeostasis. Science 277:228 44. Choi HY, Karten B, Chan T, Vance JE, Greer WL, Heidenreich RA, Garver WS, Francis GA (2003) Impaired ABCA1-dependent lipid efflux and hypoalphalipoproteinemia in human Niemann-Pick type C disease. J Biol Chem 278(35):32569–32577 45. Lee CY, Lesimple A, Denis M, Vincent J, Larsen A, Mamer O, Krimbou L, Genest J, Marcil M (2006) Increased sphingomyelin content impairs HDL biogenesis and maturation in human Niemann-Pick disease type B. J Lipid Res 47(3): 622–632 46. Anderson GL, Limacher M, Assaf AR (2004) Effects of conjugated equine estrogen in post-menopausal women with hysterectomy: The Women’s Health Initiative randomized controlled trial. JAMA 291:1701 47. Meigs JB, Wilson PW, Fox CS, Vasan RS, Nathan DM, Sullivan L, D’Agostino RB. Body mass index, metabolic syndrome and risk of type 2 diabetes or cardiovascular disease. J Clin Endocrinol Metab. 2006 May 30 48. Kahn R, Buse J, Ferrannini E, Stern M; American Diabetes Association; European Association for the Study of Diabetes. The metabolic syndrome: time for a critical appraisal: joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2005;28(9):2289–2304

A Systematic Approach to Marfan Syndrome and Hereditary Forms of Aortic Dilatation and Dissection

18

Peter N. Robinson and Yskert von Kodolitsch

18.1 Introduction

ruptured thoracic aortic aneurysm is between 97% and 100% with a mean survival of 3 days.2 Most cases of thoracic aortic aneurysm are related to one of three Marfan syndrome (MFS) is a relatively common disoretiologies: monogenic diseases including MFS, bicusder of connective tissue with autosomal dominant pid aortic valve, and atherosclerotic degeneration. A inheritance and highly variable, age-dependent manicorrect diagnosis is clearly essential to determine festations involving the skeletal, ocular, and cardiovasprognosis, treatment, and recurrence risk. This chapcular systems. The differential diagnosis of Marfan ter is mainly concerned with monogenic forms of aorsyndrome is made difficult by the lack of a simple test tic aneurysm, but occasionally persons with other to interpret and readily available molecular test, by the forms of thoracic aortic aneurysm present for exclurange of related disorders, by the extreme intra- and sion of a hereditary disorder (Table 18.1). Therefore, interfamilial variability of MFS, and by the age-­ geneticists and other physicians involved in the care dependent manifestation of most of the clinical signs. of persons with MFS need to be aware of the full difThis chapter intends to provide an overview of MFS ferential diagnosis and need to refer to colleagues and other hereditary disorders characterized by dilatafrom other disciplines as indicated. A recent review tion or dissection of the ascending thoracic aorta, to covers the differential diagnosis of nonhereditary outline the steps needed to identify the correct diagnoaneurysms and dissection of the thoracic ascending sis, and to provide pointers regarding clinical followaorta.3 up and treatment of affected persons.

18.2 The Causes of Aortic Aneurysm and Dissection The word “aneurysm” refers to an abnormal widening or ballooning of a blood vessel. Thoracic aneurysms have an incidence of 5 per 100,000 person years and are thus rarer than aneurysms of the abdominal aorta, which are responsible for about 1.3% of all deaths among 65–85-year-old men.1 The mortality of a P. N. Robinson () Institut für Medizinische Genetik, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany e-mail: [email protected]

18.3 Marfan Syndrome MFS is the most common hereditary disorder associated with aortic aneurysm and has an estimated prevalence of 2–3 per 10,000 persons.4 Life expectancy in untreated persons with MFS is markedly shortened, with the cause of death most often related to aortic complications.5 Classic signs of MFS include scoliosis, long hands and fingers (arachnodactyly), disproportionately long and thin extremities (dolichostenomelia), tall stature, scoliosis, pectus excavatum or carinatum, striae atrophicae, high myopia or lens subluxation (ectopia lentis), mitral valve prolapse or insufficiency, and aortic root dilatation with the risk of ascending aortic dissection.

R. Brugada et al. (eds.), Clinical Approach to Sudden Cardiac Death Syndromes, DOI: 10.1007/978-1-84882-927-5_18, © Springer-Verlag London Limited 2010

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224 Table 18.1  Differential diagnosis of ascending aortic aneurysm Atherosclerosis

P. N. Robinson and Y. von Kodolitsch

18.4 The Fibrillin-1 Gene and Type-1 Fibrillinopathies

Hereditary (monogenic) Bicuspid aortic valve Prestenotic, aortic coarctation Traumatic Autoimmune Infectious Toxic

Although it is relatively straightforward to make the diagnosis in persons with classic and severe manifestations of MFS, it can be challenging to establish or exclude the diagnosis in patients with oligosymptomatic presentations or in children with evolving features of MFS. Over a decade ago, a panel of experts developed diagnostic criteria for the Marfan syndrome in the Belgian city of Ghent, after which they are now known as the Ghent nosology.6 The Ghent nosology weights clinical features according to their specificity for MFS. For instance, ectopia lentis and aortic dilatation have a relatively high specificity for MFS, but many other features often found in persons with MFS such as tall stature, scoliosis, or myopia are also quite common in the general population and thus have a low specificity. The diagnosis of MFS can be made if two major criteria in two different organ systems and the involvement of a further organ are present. If a first-degree relative is affected by Marfan syndrome, the person under consideration must have involvement of at least two systems (skeletal, cardiovascular, ocular), and at least one major manifestation (Table  18.2). In general, a full clinical evaluation including echocardiography and ophthalmologic examination is a necessary part of the diagnostic process. Persons with the autosomal recessively inherited disorder homocystinuria may have ectopia lentis and some of the skeletal manifestations of MFS in addition to other signs such as a predisposition to thrombotic events. Although homocystinuria is a rare disorder, it is important to rule it out by plasma or urine amino acid analysis in the absence of pyridoxine supplementation because an effective dietary treatment is available.7

Mutations in the gene encoding fibrillin-1 (FBN1) cause MFS. FBN1 spans about 235 kb genomic DNA on chromosome 15q21,8 possessing 65 coding and 3 noncoding exons with an open reading frame of 8,613 nucleotides and 5’ and 3’ untranslated regions of 134 and 916 nt. Fibrillin-1, the protein product of FBN1, is a cysteine-rich monomeric glycoprotein with a molecular weight of about 350 kDa. Fibrillin microfibrils are widely distributed extracellular matrix multimolecular assemblies comprising fibrillin and other proteins. The microfibrils endow elastic and nonelastic connective tissues with long range elasticity, direct tropoelastin deposition during elastic fibrillogenesis, and form an outer mantle for mature elastic fibers. Microfibril arrays are also abundant in dynamic tissues that do not express elastin, such as the ciliary zonules of the eye. Initial concepts of the pathogenesis of MFS held that it is a dominant-negative disorder, in which the abnormal protein derived from the mutant allele interferes with the normal protein produced from the wildtype allele, thereby disrupting the structure and function of the polymeric microfibrils. A series of experiments within the last 5 years have demonstrated that haploinsufficiency contributes to disease progression,9 that dysregulation of TGF-b metabolism is a key aspect of the molecular pathogenesis of MFS,10-12 and that proteolysis of fibrillin-rich microfibrils also contributes to aneurysm progression by stimulating the expression of metalloproteinases and macrophage chemotaxis.13,14 Recent reviews have summarized the salient aspects of the molecular pathogenesis of MFS.15,16 Mutation screening in the FBN1 gene currently detects mutations in up to 90% of persons with classic MFS.17 Although mutation screening is not needed to confirm the diagnosis in many cases of classic MFS in which the criteria of the Ghent nosology are clearly fulfilled, there are situations where mutation analysis brings a clear clinical benefit to affected persons and families. This is especially the case for families ­demonstrating high clinical variability and in children with evolving MFS. The mutation detection rate is much lower in persons not fulfilling the criteria of the Ghent nosology;18 however, the clinical utility of FBN1 mutation detection in such cases can be

18  A Systematic Approach to Marfan Syndrome and Hereditary Forms of Aortic Dilatation and Dissection

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Table 18.2  Ghent nosology Skeletal system Major criterion

Involvement

Presence of at least four of the following:   Pectus carinatum   Pectus excavatum requiring surgery   Upper to lower segment ratio < 0.86 or span/height > 1.05   Wrist and thumb signs (Arachnodactyly)   Scoliosis > 20° or spondylolithesis   Reduced elbow extension (<170°)   Pes planus   Protrusio acetabulae (X-ray)

Two of the features for a major criterion or one feature and at least two of the following   Pectus excavatum of mild severity   Joint hypermobility   High palate with dental crowding Characteristic face (dolicocephaly,malar hypoplasia, enophthalmos, retrognathia, down-slanting palpebral fissures)

Ocular system Major criterion

Involvement

Ectopia lentis

Presence of at least two of the following   Flat cornea   Increased axial length of globe (causing myopia)   Hypoplastic iris or ciliary muscle (causing decreased miosis)

Cardiovascular system Major criterion

Involvement

  Aortic root dilation dissection of the ascending aorta

Presence of at least one of the following   Mitral valve prolapse   Dilation of the pulmonary artery (<40 years)   Calcified mitral annulus in individuals (<40 years)   Dilation or dissection of the descending thoracic or abdominal aorta (<50 years)

Pulmonary system Major criterion

Involvement

–

Spontaneous pneumothorax or radiographic evidence of apical blebs

Skin and integument Major criterion

Involvement

–

Striae atrophicae or recurrent or incisional hernia

Dura Major criterion

Involvement

Lumbosacral dural ectasia (MRT or CT)

–

Family and genetic history Major criterion

Involvement

  Parent, child, or sibling meets the criteria independently   FBN1 mutation known to cause MFS   Haplotype around FBN1 locus inherited by descent and associated with MFS in family

–

particularly high. For instance, we identified an FBN1 mutation in a 40-year-old man with isolated aortic dissection without any skeletal or ocular features of

MFS. The same mutation was identified in his 17-yearold son who also has no external features of MFS. The son has normal aortic dimensions at present but is

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P. N. Robinson and Y. von Kodolitsch

presumably at risk of aortic dilatation and dissection. The son might have been dismissed as not at risk without the molecular information. Individualized decisions concerning the utility of mutation analysis need to be made on a case-to-case basis; we have a relatively low threshold to recommend mutation analysis in our own practice. Further descriptions of clinical scenarios in which mutation analysis is particularly useful are given in reference.19 It is important to note that the identification of a presumed pathogenic mutation in FBN1 does not in itself justify the diagnosis of MFS. Approximately 5% of FBN1 mutation carriers show one of a number of alternate phenotypes, some of which are associated with an (apparently) lower risk of aortic complications. The entire group of phenotypes associated with FBN1 mutations has been termed type-1 fibrillinopathies. We note here that due to the potential of age-dependent development of serious aortic complications and to the potential of clinical variability even between family members carrying an identical FBN1 mutation, one should use great caution before making the diagnosis of a “mild” fibrillinopathy (if at all). Table 18.3 gives an overview of currently recognized type 1 fibrillinopathies with links to the literature.

18.5 Loeys Dietz Syndrome In 1993, only 2 years after the discovery of mutations in FBN1 in persons with MFS, evidence for a second gene linked to an MFS-like phenotype was obtained for a locus on chromosome 3p24.2–p25.35 Affected family members showed skeletal and cardiovascular manifestations of MFS but not ectopia lentis. Finally, in 2004, a mutation in the gene for the TGFb receptor 2 (TGFBR2) was identified in this and several other families.36 This finding provided another important line of evidence in addition to the mouse studies mentioned earlier that dysregulation of TGFb signaling is involved in the pathogenesis of MFS and related disorders. In 2005, Bart Loeys and Harry C. Dietz identified TGFBR1 and TGFBR2 mutations in persons with a syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development.37 This syndrome has since come to be known as Loeys Dietz syndrome (LDS). LDS shares a number of manifestations of MFS but is characterized by multiple clinical signs not associated with MFS, which generally allow clinical delineation of LDS from MFS (Table 18.4). The vascular type of Ehlers Danlos syndrome is caused by mutations in the gene for type III

Table 18.3  Type-1 fibrillinopathies. The most salient clinical features are indicated. See references for further details. Note that in addition to the autosomal dominant form of Weill–Marchesani syndrome associated with FBN1 mutations, an autosomal recessive form associated with ADAMTS10 mutations has also been described.34 Only a minority of cases of Shprintzen Goldberg syndrome appear to be caused by FBN1 mutations Syndrome Clinical features Reference MFS

See text

20

Neonatal MFS

Severe manifestations. Death usually in the first year of life owing to congestive heart failure.

21

Shprintzen–Goldberg syndrome

Craniosynostosis and marfanoid habitus

22

Familial arachnodactyly

Arachnodactyly, dolichostenomelia, no cardiovascular manifestations

23

Ectopia lentis

Bilateral ectopia lentis, in some cases scoliosis and (rarely) cardiovascular manifestations

24,25

Ascending aortic aneurysm and dissection

Ascending aortic aneurysm and dissection, no ectopia lentis, no specific skeletal findings

26,27

MASS phenotype

Mitral valve prolapse, aortic root dilatation without dissection, skeletal and skin abnormalities

28

New variant of the MFS

Skeletal features of MFS with joint contractures and knee joint effusions. Ectopia lentis. no cardiovascular manifestations

29,30

Isolated skeletal features

Tall stature, scoliosis, pectus excavatum, arachnodactyly

31

Weill–Marchesani syndrome

Ectopia lentis, brachydactyly, stiff joints, short stature

32

Kyphoscoliosis

Kyphoscoliosis and vertebral dysplasia

33

18  A Systematic Approach to Marfan Syndrome and Hereditary Forms of Aortic Dilatation and Dissection

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Table 18.4  Distinguishing clinical features of MFS and LDS. The column “MFS and LDS” shows features that are common in both disorders. The columns “MFS” and “LDS” list features that are common in one disorder but rare in the other37 Organ system MFS and LDS MFS LDS Eye

Retinal detachment

Extreme myopia Ectopia lentis

– Blue sclerae

Skeleton

Pectus excavatum or carinatum Scoliosis Arachnodactyly Dolichostenomelia

–

Talipes equinovarus

Cardiovascular system

Dilatation/dissection of the ascending aorta Mitral valve prolapse

–

Aneurysms or dissections of other large arteries Arterial tortuosity Patent ductus arteriosus Atrial septum defect

Craniofacial

Malar hypoplasia High-arched palate Micrognathia Downslanting palpebral fissures

–

Hypertelorism Craniosynostosis Uvula bifida, cleft palate

Other

Striae distensae

–

Developmental delay Dystrophic scars Translucent veins

procollagen (COL3A1) and is characterized clinically by easy bruising, thin skin with visible veins, characteristic facial features, and rupture of arteries, uterus, or intestines.38 Dissection of the ascending aorta can be observed in vascular Ehlers Danlos syndrome.39 A second type of LDS has been described associated with TGFBR1 or TGFBR2 mutations in which affected persons do not show craniofacial involvement consisting of cleft palate, craniosynostosis, or hypertelorism but rather show at least two of the findings associated with vascular Ehlers-Danlos syndrome (visceral rupture, easy bruising, wide and atrophic scars, joint laxity, and translucent skin, velvety skin, or both).40 The question of whether some TGFBR2 mutations are associated with a syndrome termed MFS type II consisting of skeletal and cardiovascular manifestations of MFS without ectopia lentis and without further manifestations of LDS has been controversially discussed in the literature. There have been reports of patients with TGFBR1 and TGFBR2 mutations with more or less classic manifestations of MFS.41 It is important for clinicians to be aware of the fact that many, if not all, carriers of TGFBR1 and TGFBR2 mutations are at risk of more aggressive vascular disease than are most persons with FBN1 mutations.

18.6 Other Hereditary Forms of Thoracic Aortic Aneurysm and Dissection A growing number of syndromes characterized primarily by dilatation and dissection of the ascending thoracic aorta (TAAD) have been described. The high degree of genetic heterogeneity coupled with the fact that many affected families do not display genetic linkage to known loci makes it difficult or impossible to identify causative gene mutations in most patients, and molecular mutation analysis has not yet become a routine diagnostic procedure for this patient group, although this may change with the advent of next-generation sequencing technologies. With the exception of FBN1 and TGFBR1/TGFBR2, relatively little is known about the range of phenotypes associated with mutations in individual TAAD genes, although more or less subtle differences do seem to exist. As mentioned earlier, certain FBN1 mutations are associated with isolated aortic involvement.26 Mutations at Arg460 of TGFBR2 have been associated with isolated TAAD,42 although some other features of LDS may be present.43 A mutation in a person with TAAD has also been identified in TGFBR1.44

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Mutations in the gene encoding myosin heavy chain 11 (MYH11) were found to cause a syndrome of thoracic aortic aneurysm and dissection associated with patent ductus arteriosus.45 Myosin heavy chain 11 is one of the components of myosin, a contractile protein of smooth muscle cells, and MYH11 mutations are associated with abnormalities of the vascular smooth muscle cells in the ascending aorta.46 Mutations in the gene for smooth muscle alpha-actin (ACTA2) were identified in families with thoracic aortic aneurysms and dissections. Smooth muscle alpha-actin interacts with the beta-myosin heavy chain to generate contractile force.47 These findings underscore the importance of vascular smooth muscle cells for the homeostasis of the ascending thoracic aorta. Presently unidentified loci for TAAD include TAAD1 on chromosome 5q13–1448 and FAA1 on chromosome 11q23–24.49 The locus at 5q13–14 is thought to be a major locus for TAAD because 9 of 15 tested families showed linkage to it. However, larger studies have yet to be performed. The arterial tortuosity syndrome (ATS), in contrast to all the previously discussed forms of TAAD, is inherited in an autosomal recessive fashion. This disorder is characterized by tortuosity of the large and medium-sized arteries, which can result in death at young age. Other typical features include aneurysms of large arteries and dysmorphic facial features.50,51 Cutis laxa syndromes are characterized by excessive skin wrinkling. This is a heterogeneous group of disorders, some of which are also characterized by aortic abnormalities, especially autosomal dominant cutis laxa associated with elastin gene mutations52 or fibulin-5 (FBLN5) mutations,53 and autosomal recessive cutis laxa associated with mutations in fibulin 4 (FBLN4)54 or FBLN5.55 In general, the diagnostic delineation of these syndromes against other forms of TAAD should be clear because of the striking dermatological findings. Finally, persons with congenital contractural arachnodactyly, which is characterized by skeletal features of MFS, congenital contractures that tend to improve with time, and crumpled external ears, appear to have some risk of developing aortic dilatation,56 so that regular echocardiographic surveillance appears to be a worthwhile precaution. At present, there is no consensus concerning the role of mutation analysis in persons with isolated aortic

P. N. Robinson and Y. von Kodolitsch

dilatation or dissection. Mutations in ACTA2 may be responsible for up to 14% of familial cases,47 mutations in TGFBR2 for up to 5%, and mutations in FBN1 are rare. Mutations in the other genes described earlier are presumably also rare in unselected cohorts, although large-scale screening studies have yet to be performed. At present, it is too early to make general recommendations concerning the role of mutation analysis in the many TAAD genes, and decisions need to be made on an individualized basis. It is also currently unknown what proportion of persons with isolated thoracic aortic aneurysms have monogenic defects. However, in large cohorts of persons with thoracic aortic aneurysms, up to 20% of the non-MFS cases show a familial pattern.57 We therefore recommend that all first-degree relatives of persons with thoracic aortic aneurysms should receive a thorough cardiological evaluation with imaging of the ascending aorta.

18.7 Bicuspid Aortic Valve Isolated bicuspid aortic valve (BAV) is a relatively common cause of aortic dissection.58 Aortic dissection seen in persons with BAV usually occurs without other cardiovascular risk factors and affected persons occasionally present in genetic clinics to exclude a monogenic form of aortic disease. BAVs have two semilunar valves and sinuses of Valsavae instead of the normal three, and represent one of the most common congenital cardiovascular malformations with an estimated prevalence of 1–2%. Persons with BAV have an increased risk of aortic stenosis or insufficiency, infectious endocarditis, and aortic dissection. Although genetic factors are thought to play an important role in determining risk for formation of a BAV, to date only one clear association has been shown. Mutations in the gene for NOTCH1 have been found in several families with bicuspid, heavily calcified aortic valves, and other cardiovascular malformations.59 BAV is genetically heterogeneous and at least three other loci exist.60 It is currently unknown what the basis for the majority of cases of BAV is, since a clear familiar pattern can be found in only a minority of cases. At the moment, therefore, mutation analysis in persons with BAV is not routinely indicated, although consultation with specialist centers is recommended for familial cases.

18  A Systematic Approach to Marfan Syndrome and Hereditary Forms of Aortic Dilatation and Dissection

18.8 Clinical Management The first step in proper management is to make the correct diagnosis. The differential diagnosis for familial forms of thoracic aortic dilatation and dissection is summarized in Fig. 18.1. If the Ghent criteria are fulfilled, then the diagnosis of MFS is certain (an exception to this rule is that persons with Loeys Dietz syndrome may fulfill the Ghent criteria but generally also have additional signs). In adult patients presenting with a small number of nonspecific manifestations listed in the Ghent nosology, the diagnosis is unlikely, but a full clinical evaluation is indicated. In our experience, about half of all persons presenting in specialized MFS clinics actually do have classic MFS. Among the remaining patients, a specific diagnosis of one of the earlier-described syndromes can be made in roughly 10%. About 20% of persons presenting to such clinics have a few nonspecific manifestations commonly associated with MFS but not sufficient to comprise a major criterion of the Ghent nosology. Essentially no information concerning the molecular causes of such presentations is available today. At present, detailed clinical recommendations are available only for MFS. The classical standards include: (1)

229

counseling on lifestyle modification including moderate restriction of physical activity; (2) endocarditis prophylaxis; (3) serial imaging of the aorta with echocardiography and/or magnetic resonance tomography; (4) b-blocker medication for aortic protection; and (5) prophylactic replacement of the aortic root. Current guidelines for managing the cardiovascular complications of MFS are given in Table 18.5. Recommendations concerning other clinical manifestations of MFS can be found in reference.4, 61 The American Association of Pediatrics has published guidelines for caring for children with MFS.62 Although b-blockers represent the current standard medication for MFS, recent results in a mouse model12 have suggested that losartan may be greatly superior. Losartan, an angiotensin II type 1 receptor (AT1) antagonist, is widely used to decrease blood pressure, a desirable effect in individuals with MFS and aortic root aneurysm. Losartan also has the effect of antagonizing TGFb signaling, which was thought to be responsible for the advantage of losartan over b-blockers in the above mentioned mouse study.12 A large-scale randomized clinical trial of b-blocker therapy versus losartan is currently underway.63 There are observations in the medical literature that would seem to suggest both a disadvantage and an

Thoracic aortic aneurysm or thoracic aortic dissection (TAAD)

FBN1

Rarely with TAAD: MASS, Familial ectopia lentis, Familial Marfan-like habitus, Sphrintzen-Goldberg syndrome (SGS), Weill-Marchesani syndrome (autosomal dominant)

With high risk for TAAD: Marfan syndrome (MFS), Familial TAAD

FBN2

With risk for TAAD: Congenital contractural arachnodactyly (CCA)

With no rsik for TAAD:Congenital contractural arachnodactyly (CCA)

Syndromic disorders unrelated to fibrillinopathy

TGFBR1/ TGFBR2

With risk for TAAD: LoeysDietz syndrome type I and type 2 Marfan type 2 (MFS2), Familial TAAD (only TGFBR2)

With Marfan-like manifestations

Without Marfan-like manifestations

Risk for TAAD: Ehlers-Danlos syndrome (EDS)with vascular involvement (COL3A1),

Risk for TAAD: Turner syndrome, Noonan syndrome (PTPN11), Alagille syndrome (JAG1)

Low risk for TAAD: Sphrintzen-Goldberg syndrome(SGS), Ehlers-Danlos syndrome (EDS)without aortic involvement (COL1A1t, COL1A2, COL5A1, ADAMTS2, PLOD), Weill-Marchesani syndrome (ADAMTS10)

Rarely with TAAD: Polycystic kidney disease (OMIM#173900)

Nonsyndromic disorders unrelated to fibrillinopathy

High risk for TAAD: Familial TAAD mapping to TAAD1, Familial TAAD mapping to FAA1

Risk for TAAD: Familial bicuspid aortic valve (NOTCH1)

Fig. 18.1  Differential diagnosis of familial thoracic aneurysms and dissections based on clinical and mocular findings. PDA patent ductus arteriosus (Modified from reference75)

230 Table  18.5  Clinical guidelines for managing cardiovascular manifestations of MFS (adapted from70). General measures for all adults with MFS Moderate restriction of physical activity Echocardiography at regular intervals Medical therapy (b-blockers, newer agents currently undergoing clinical trials) Counseling for pregnancy 50% probability of transmitting FBN1 mutation to children High-risk pregnancy if aortic root diameter ³ 40 mm or previous cardiovascular surgery or severe heart disease Consider prepartum aortic root replacement with aortic root diameter ³ 40 mm Serial echocardiography until 3 months postpartum Indications for prophylactic surgery of the aortic root in adults Aortic root diameter > 45–50 mm Aortic root diameter > 45 mm in patients with high risk for aortic complications (including family history positive for aortic dissection or rapid growth of aortic root) Aortic ratio > 1.5 Ratio of the diameters of the aortic root and the descending aorta > 2 Indications for prophylactic surgery of the aortic root in children If possible, surgery should be delayed until adolescence Aortic root diameters with similar thresholds as in adults Aortic root diameters outside the upper confidence interval cross centiles on serial echocardiograms Indications for mitral valve surgery

P. N. Robinson and Y. von Kodolitsch

the AT2 receptor plays an important role in promoting apoptosis of vascular smooth muscle cells and cystic medial degeneration in MFS,66 and an ACE inhibitor, but not an AT1 blocker, prevented cystic medial degeneration in a rat model of cystic medial degeneration.67 A small clinical study showed that perindopril, a modern ACE inhibitor, reduced both aortic stiffness and aortic root diameter when given in addition to standard b-blocker therapy in patients with Marfan syndrome.68 Further studies will be required to define the place of AT1 blockers, ACE inhibitors, or of other novel classes of medication in the treatment of persons with MFS.69 Finally, it has become clear that the complexity of diagnosis and treatment of MFS and related disorders requires multidisciplinary expert centers for patient care.70 In the optimal situation, a broad generalist coordinates a team consisting of geneticists, cardiologists and cardiothoracic surgeons, orthopedic surgeons, ophthalmologists, pediatricians, and social workers. With optimal treatment at such centers, it is now possible to extend the average life expectancy of persons with MFS to over 60 years of age,5 which represents a great improvement compared the estimated 32-year life expectancy cited in 1972.71 Current developments in our understanding of the molecular pathogenesis of MFS and related conditions have the potential to further improve life expectancy and quality of life for affected individuals.

Follow the general recommendations of the AHA72 Endocarditis prophylaxis At a minimum, current AHA recommendations should be applied73 Valve dysfunction such as mitral valve prolapse with mitral regurgitation or aortic valve regurgitation is a relative indication for endocarditis prophylaxis AHA: American heart association. See ref.74 for more information about indications for prophylactic aortic surgery

advantage for angiotensin-converting enzyme (ACE) inhibitors compared to angiotensin II type 1 (AT1) receptor blockers such as losartan. Signaling through the angiotensin II type 2 (AT2) receptor antagonizes many of the effects promoted by AT1 signaling in the formation of abdominal aortic aneurysm, and the use of a selective AT2 blocker increased the severity of abdominal aneurysms in ApoE null mice after angiotensin II infusion.64 Therefore, it has been proposed that selective AT1 blockade with losartan may be preferable to a combined AT1/AT2 blockade as is achieved by ACE inhibitors.65 On the other hand, activation of

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18  A Systematic Approach to Marfan Syndrome and Hereditary Forms of Aortic Dilatation and Dissection 10. Neptune ER, Frischmeyer PA, Arking DE, et al. Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat Genet. 2003;33:407–411 11. Ng CM, Cheng A, Myers LA, et  al. TGF-beta-dependent pathogenesis of mitral valve prolapse in a mouse model of Marfan syndrome. J Clin Invest. 2004;114:1586–1592 12. Habashi JP, Judge DP, Holm TM, et  al. Losartan, an at1 antagonist, prevents aortic aneurysm in a mouse model of marfan syndrome. Science. 2006;312:117–121 13. Booms P, Ney A, Barthel F, et al. A fibrillin-1-fragment containing the elastin-binding-protein GxxPG consensus sequence upregulates matrix metalloproteinase-1: biochemical and computational analysis. J Mol Cell Cardiol. 2006; 40:234–246 14. Guo G, Booms P, Halushka M, et  al. Induction of macrophage chemotaxis by aortic extracts of the mgR Marfan mouse model and a GxxPG-containing fibrillin-1 fragment. Circulation. 2006;114:1855–1862 15. Robinson PN, Arteaga-Solis E, Baldock C, et al. The molecular genetics of marfan syndrome and related disorders. J Med Genet. 2006;43:769–787 16. Ramirez F, Dietz HC. Marfan syndrome: from molecular pathogenesis to clinical treatment. Curr Opin Genet Dev. 2007;17:252–258 17. Loeys B, Backer JD, Acker PV, et al. Comprehensive molecular screening of the FBN1 gene favors locus homogeneity of classical Marfan syndrome. Hum Mutat. 2004;24:140–146 18. Katzke S, Booms P, Tiecke F, et al. TGGE screening of the entire FBN1 coding sequence in 126 individuals with marfan syndrome and related fibrillinopathies. Hum Mutat. 2002;20:197–208 19. Faivre L, Collod-Beroud G, Child A et al (2008) Contribution of molecular analyses in diagnosing Marfan syndrome and type I fibrillinopathies: an international study of 1009 probands. J Med Genet. 45:384–90 20. Faivre L, Collod-Beroud G, Loeys BL, et al. Effect of mutation type and location on clinical outcome in 1, 013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study. Am J Hum Genet. 2007; 81: 454–466 21. Booms P, Cisler J, Mathews KR, et al. Novel exon skipping mutation in the fibrillin-1 gene: two “hot spots” for the neonatal Marfan syndrome. Clin Genet. 1999;55:110–117 22. Robinson PN, Neumann LM, Demuth S, et al. ShprintzenGoldberg syndrome: fourteen new patients and a clinical analysis. Am J Med Genet A. 2005;135:251–262 23. Hayward C, Porteous ME, Brock DJ. A novel mutation in the fibrillin gene (FBN1) in familial arachnodactyly. Mol Cell Probes. 1994;8:325–327 24. Adès LC, Holman KJ, Brett MS, Edwards MJ, Bennetts B. Ectopia lentis phenotypes and the FBN1 gene. Am J Med Genet A. 2004;126:284–289 25. Vanita V, Singh JR, Singh D, Varon R, Robinson PN, Sperling K. A recurrent fbn1 mutation in an autosomal dominant ectopia lentis family of indian origin. Mol Vis. 2007; 13:2035–2040 26. Francke U, Berg MA, Tynan K, et al. A Gly1127Ser mutation in an EGF-like domain of the fibrillin-1 gene is a risk factor for ascending aortic aneurysm and dissection. Am J Hum Genet. 1995;56:1287–1296 27. Milewicz DM, Michael K, Fisher N, Coselli JS, Markello T, Biddinger A. Fibrillin-1 (fbn1) mutations in patients with thoracic aortic aneurysms. Circulation. 1996;94:2708–2711

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28. Dietz HC, McIntosh I, Sakai LY, et  al. Four novel FBN1 mutations: significance for mutant transcript level and EGFlike domain calcium binding in the pathogenesis of Marfan syndrome. Genomics. 1993;17:468–475 29. Ståhl-Hallengren C, Ukkonen T, Kainulainen K, et  al. An extra cysteine in one of the non-calcium-binding epidermal growth factor-like motifs of the fbn1 polypeptide is connected to a novel variant of marfan syndrome. J Clin Invest. 1994;94:709–713 30. Black C, Withers AP, Gray JR, et al. Correlation of a recurrent FBN1 mutation (R122C) with an atypical familial Marfan syndrome phenotype. Hum Mutat. 1998;suppl 1: S198-S200 31. Milewicz DM, Grossfield J, Cao SN, Kielty C, Covitz W, Jewett T. A mutation in fbn1 disrupts profibrillin processing and results in isolated skeletal features of the marfan syndrome. J Clin Invest. 1995;95:2373–2378 32. Faivre L, Gorlin RJ, Wirtz MK, et  al. In frame fibrillin-1 gene deletion in autosomal dominant Weill-Marchesani syndrome. J Med Genet. 2003;40:34–36 33. Adès LC, Sreetharan D, Onikul E, Stockton V, Watson KC, Holman KJ. Segregation of a novel FBN1 gene mutation, G1796E, with kyphoscoliosis and radiographic evidence of vertebral dysplasia in three generations. Am J Med Genet. 2002;109:261–270 34. Dagoneau N, Benoist-Lasselin C, Huber C, et al. ADAMTS10 mutations in autosomal recessive Weill-Marchesani syndrome. Am J Hum Genet. 2004;75:801–806 35. Collod G, Babron MC, Jondeau G, et al. A second locus for Marfan syndrome maps to chromosome 3p24.2-p25. Nat Genet. 1994;8:264–268 36. Mizuguchi T, Collod-Beroud G, Akiyama T, et  al. Heterozygous TGFBR2 mutations in Marfan syndrome. Nat Genet. 2004;36:855–860 37. Loeys BL, Chen J, Neptune ER, et al. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet. 2005;37:275–281 38. Pepin M, Schwarze U, Superti-Furga A, Byers PH. Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type. N Engl J Med. 2000;342:673–680 39. Ascione R, Gomes WJ, Bates M, Shannon JL, Pope FM, Angelini GD. Emergency repair of type A aortic dissection in type IV Ehlers-Danlos syndrome. Cardiovasc Surg. 2000; 8:75–78 40. Loeys BL, Schwarze U, Holm T, et al. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med. 2006;355:788–798 41. Singh KK, Rommel K, Mishra A, et al. TGFBR1 and TGFBR2 mutations in patients with features of Marfan syndrome and Loeys-Dietz syndrome. Hum Mutat. 2006;27:770–777 42. Pannu H, Fadulu VT, Chang J, et al. Mutations in transforming growth factor-beta receptor type II cause familial thoracic aortic aneurysms and dissections. Circulation. 2005; 112:513–520 43. Law CJ, Bunyan D, Castle B, et  al. Clinical features in a family with a R460H mutation in TGFBR2. J Med Genet 2006;43:908–916 44. Mátyás G, Arnold E, Carrel T, et  al. Identification and in silico analyses of novel TGFBR1 and TGFBR2 mutations in Marfan syndrome-related disorders. Hum Mutat. 2006;27: 760–769

232 45. Zhu L, Vranckx R, Kien PKV, et  al. Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus. Nat Genet. 2006;38:343–349 46. Pannu H, Tran-Fadulu V, Papke CL, et al. MYH11 mutations result in a distinct vascular pathology driven by insulin-like growth factor 1 and angiotensin II. Hum Mol Genet. 2007;16:2453–2462 47. Guo DC, Pannu H, Tran-Fadulu V, et al. Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic aortic aneurysms and dissections. Nat Genet. 2007;39:1488–1493 48. Guo D, Hasham S, Kuang SQ, et al. Familial thoracic aortic aneurysms and dissections: genetic heterogeneity with a major locus mapping to 5q13–14. Circulation. 2001;103: 2461–2468 49. Vaughan CJ, Casey M, He J, et al. Identification of a chromosome 11q23.2-q24 locus for familial aortic aneurysm disease, a genetically heterogeneous disorder. Circulation. 2001; 103:2469–2475 50. Coucke PJ, Willaert A, Wessels MW, et al. Mutations in the facilitative glucose transporter GLUT10 alter angiogenesis and cause arterial tortuosity syndrome. Nat Genet. 2006; 38:452–457 51. Callewaert BL, Willaert A, Kerstjens-Frederikse WS, et  al. Arterial tortuosity syndrome: clinical and molecular findings in 12 newly identified families. Hum Mutat. 2008;29:150–158 52. Szabo Z, Crepeau MW, Mitchell AL, et al. Aortic aneurysmal disease and cutis laxa caused by defects in the elastin gene. J Med Genet. 2006;43:255–258 53. Markova D, Zou Y, Ringpfeil F, et al. Genetic heterogeneity of cutis laxa: a heterozygous tandem duplication within the fibulin-5 (fbln5) gene. Am J Hum Genet. 2003;72:998–1004 54. Hucthagowder V, Sausgruber N, Kim KH, Angle B, Marmorstein LY, Urban Z. Fibulin-4: a novel gene for an autosomal recessive cutis laxa syndrome. Am J Hum Genet. 2006;78:1075–1080 55. Loeys B, Maldergem LV, Mortier G, et al. Homozygosity for a missense mutation in fibulin-5 (FBLN5) results in a severe form of cutis laxa. Hum Mol Genet. 2002;11:2113–2118 56. Gupta PA, Wallis DD, Chin TO, et al. FBN2 mutation associated with manifestations of Marfan syndrome and congenital contractural arachnodactyly. J Med Genet. 2004; 41:e56 57. Albornoz G, Coady MA, Roberts M, et al. Familial thoracic aortic aneurysms and dissections–incidence, modes of inheritance, and phenotypic patterns. Ann Thorac Surg. 2006; 82:1400–1405 58. Homme JL, Aubry MC, Edwards WD, et al. Surgical pathology of the ascending aorta: a clinicopathologic study of 513 cases. Am J Surg Pathol. 2006;30:1159–1168 59. Garg V, Muth AN, Ransom JF, et al. Mutations in NOTCH1 cause aortic valve disease. Nature. 2005;437:270–274 60. Martin LJ, Ramachandran V, Cripe LH, et  al. Evidence in favor of linkage to human chromosomal regions 18q, 5q and 13q for bicuspid aortic valve and associated cardiovascular malformations. Hum Genet. 2007;121:275–284 61. Robinson P, Godfrey M, eds. Marfan Syndrome: a Primer for Clinicians and Scientists. Georgetown, TX/New York, NY: Series: Medical Intelligence Unit, Landes Bioscience/ Kluwer; 2004 62. Committee on Genetics. Health Supervision for Children with Marfan Syndrome. Pediatrics. 1996;98:978–982

P. N. Robinson and Y. von Kodolitsch 63. Lacro RV, Dietz HC, Wruck LM, et al. Rationale and design of a randomized clinical trial of beta-blocker therapy (atenolol) versus angiotensin II receptor blocker therapy (losartan) in individuals with Marfan syndrome. Am Heart J. 2007;154:624–631 64. Daugherty A, Manning MW, Cassis LA. Antagonism of AT2 receptors augments angiotensin II-induced abdominal aortic aneurysms and atherosclerosis. Br J Pharmacol. 2001; 134:865–870 65. Matt P, Habashi J, Carrel T, Cameron DE, Eyk JEV, Dietz HC. Recent advances in understanding Marfan syndrome: should we now treat surgical patients with losartan? J Thorac Cardiovasc Surg. 2008;135:389–394 66. Nagashima H, Sakomura Y, Aoka Y, et  al. Angiotensin II type 2 receptor mediates vascular smooth muscle cell apoptosis in cystic medial degeneration associated with Marfan’s syndrome. Circulation. 2001;104:I282-I287 67. Nagashima H, Uto K, Sakomura Y, et  al. An angiotensinconverting enzyme inhibitor, not an angiotensin II type-1 receptor blocker, prevents beta-aminopropionitrile monofumarate-induced aortic dissection in rats. J Vasc Surg. 2002; 36:818–823 68. Ahimastos AA, Aggarwal A, D’Orsa KM, et  al. Effect of perindopril on large artery stiffness and aortic root diameter in patients with Marfan syndrome: a randomized controlled trial. JAMA. 2007;298:1539–1547 69. Williams A, Davies S, Stuart AG, Wilson DG, Fraser AG. Medical treatment of Marfan syndrome: a time for change. Heart. 2008;94:414–421 70. von Kodolitsch Y, Robinson PN. Marfan syndrome: an update of genetics, medical and surgical management. Heart. 2007;93:755–760 71. Murdoch JL, Walker BA, Halpern BL, Kuzma JW, McKusick VA. Life expectancy and causes of death in the Marfan syndrome. N Engl J Med. 1972;286:804–808 72. American College of Cardiology/American Heart Association Task Force on Practice Guidelines; Society of Cardiovascular Anesthesiologists; Society for Cardiovascular Angiography and Interventions; ACC/AHA 2006 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 (writing committee to revise the 1998 Guidelines for the management of patients with valvular heart disease): developed in collaboration with the Society of Cardiovascular Anesthesiologists: endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. Circulation. 2006;114:e84-e231 73. Wilson W, Taubert KA, Gewitz M, et al. Prevention of infective endocarditis: guidelines from the American heart association: a guideline from the American heart association rheumatic fever, endocarditis and kawasaki disease committee, council on cardiovascular disease in the young, and the council on clinical cardiology, council on cardiovascular surgery and anesthesia, and the quality of care and outcomes research interdisciplinary working group. J Am Dent Assoc. 2008;139(suppl):3S-24S 74. Braverman AC. Timing of aortic surgery in the Marfan syndrome. Curr Opin Cardiol. 2004;19:549–550 75. von Kodolitsch Y, Rybczynski M, Detter C, Robinson PN. Diagnosis and management of Marfan syndrome. Future Cardiol. 2008;4:85–96

Inherited Metabolic Diseases: Emphasis on Myocardial Disease and Arrhythmogenesis

19

Eduardo Back Sternick

19.1 Introduction In his chapter, we will discuss the myocardial diseases caused by inborn errors of the metabolism with emphasis on myocardial disease and arrhythmogenesis. A number of gene mutations causing a variety of enzymatic deficiencies are responsible for two paramount consequences: impairment of the cellular process of energy (ATP) production and accumulation either of polysaccharides or lipids, which will be responsible for the myocardial abnormalities, such as hypertrophy, atrioventricular conduction impairment, ventricular pre-excitation, atrial and ventricular arrhythmias, heart failure, and sudden death. Over the past 15 years, the lysosomal storage diseases have become paradigms for the specific treatment of monogenic disorders, particularly those affecting children, due to advances in molecular biology which unraveled the pathophysiology of the different enzymatic deficiencies. When initiated early in the course of the disease, enzyme reconstitution/ replacement therapy can reverse some disease manifestations like in Fabry disease, infantile Pompe disease, and the mucopolysacccharidosis, albeit it may not completely alleviate the disease progression. Another therapeutic modality, transgene suppression by specific drug administration during early postnatal development has recently been reported to prevent the development of accessory AV pathways in PRKAG2 disease.1-3

E. B. Sternick Arrhythmia and Electrophysiology Unit, Biocor Instituto, Nova Lima, Minas Gerais, Brazil e-mail: [email protected]

19.2 Limitations to Classification of Secondary Cardiomyopathies Cardiomyopathies caused by inherited metabolic diseases are usually categorized as secondary cardiomyopathies associated or not with systemic disorders due to inherited genetic errors of the metabolic pathways. As time went by, the distinction between primary and secondary heart muscle disease has become increasingly unclear, as the etiology of previously idiopathic disorders has been discovered. An expert committee of the American Heart Association has recently proposed a new classification in which the term primary is used to describe diseases in which the heart is the sole or predominantly involved organ and secondary to describe diseases in which myocardial dysfunction is part of a systemic disorder.4 However, the challenge of distinguishing primary and secondary disorders in this way is twofold: on one hand, many of the diseases classified as primary cardiomyopathies can be associated with major extra-cardiac manifestations, and on the other hand, pathology in many of the diseases classified as secondary cardiomyopathies can predominantly or exclusively involve the heart. As many cardiomyopathies are caused by mutations in genes that encode various cardiac proteins, an alternative approach is to reclassify cardiomyopathies according to the causative genetic defect (Table 19.1).5 However, in clinical practice, the pathway from diagnosis to treatment rarely begins with the identification of an underlying genetic mutation; more usually, patients present with symptoms or are incidentally found to have clinical signs on abnormal screening tests. Even when a genetic defect is known in a family, the identification of a clinically relevant disease in gene-carriers still requires the demonstration of a morphological phenotype. For

R. Brugada et al. (eds.), Clinical Approach to Sudden Cardiac Death Syndromes, DOI: 10.1007/978-1-84882-927-5_19, © Springer-Verlag London Limited 2010

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234 Table 19.1  Different disorders causing cardiac hypertrophy Familial: Sarcomeric protein mutations (iHCM)a Glycogen storage diseasea – Pompe, Danon, PRKAG2, Forbes-Cori Lysosomal storage diseases – Fabry,a Hurler’s Disorders of fatty acid metabolism Carnitine deficiency Mitochondrial cytopathies Syndromic HCM – Noonan syndrome, Friedereich ataxia, LEOPARD syndrome, Swyer’s syndrome Phospholamban promoter Non-familial: Obesity Infants of diabetic mothers Athletic training Amyloida May also cause restrictive cardiomyopathy

a

these arguments, a clinically-oriented classification system has recently been suggested,6 in which heart muscle disorders are grouped according to ventricular morphology and function, which probably remains the most useful method for diagnosing and managing patients and families with heart muscle disease. Notwithstanding, the complexities of some disease phenotypes, particularly among patients with inherited metabolic cardiomyopathies reveal the problems of this clinical classification scheme. Some of the most commonly encountered clinical problems include the occurrence of different cardiomyopathies caused by the same genetic mutation (in related or unrelated individuals); the same cardiomyopathy resulting from many different mutations, and the evolution of one disease phenotype into another over time.

19.3 The Elusive Concept of Hypertrophy Myocyte hypertrophy is an anatomo-pathologic concept. However, with the development of cardiac imaging techniques cardiac hypertrophy becomes more of a ­clinical concept. Historically, hypertrophic cardiomyopathy (HCM) has been defined by the presence of myocar-

E. B. Sternick

dial hypertrophy in the absence of hemodynamic stresses sufficient to account for the degree of hypertrophy and systemic diseases such as amyloidosis and glycogen storage disease (GSD). The aim of this distinction was to separate conditions, in which there is myocyte hypertrophy, from those in which left ventricular (LV) mass and wall thickness are increased by interstitial infiltration or intracellular accumulation of metabolic substrates. In everyday practice, however, it is often impossible to differentiate these two entities using noninvasive techniques such as echocardiography or magnetic resonance imaging. This conundrum could be solved by histological demonstration (on myocardial biopsy) of myocyte hypertrophy. However, the focal, patchy and complex nature of most myocardial pathologies means that this distinction can sometimes only be reliably made at postmortem. Athletic training at a high level is associated with physiological changes in the left ventricular morphology that can be confused with a pathological type, but myocardial thickness similar to those seen in patients with HCM are rare (<2% of male athletes).7 The differentiation between hypertrophy with myocyte enlargement, disarray, and cardiac fibrosis caused by sarcomere mutations from hypertrophy caused by intracellular accumulation of metabolites such as glycogen, where the myocardial architecture is well preserved, is of utmost importance, particularly in the absence of systemic abnormalities, due to prognostic factors. The presence of cardiac amyloid is conceptually consistent as to fit into the definition of hypertrophy due to the increased ventricular wall thickness as detected by imaging techniques. However, its interstitial accumulation (rather than intracellular), and unlike other causes of myocardial thickening, amyloid has distinctive features on electrocardiography and cardiac imaging that suggest the diagnosis. The importance of hypertrophy as a diagnostic clue to the presence of glycogen storage diseases in patients with minimal or without systemic abnormalities has been recently demonstrated (Fig.  19.1).8 Genetic ­analysis was performed in a cohort of 75 consecutive unrelated patients with unexplained left ventricular hypertrophy. Forty sarcomere-protein mutations (familial as well as sporadic HCM) have been detected. In the remaining 35 patients, one PRKAG2, and two lysosome-associated membrane protein 2 (LAMP2) mutations were found. These results prompted the study of two additional, independent series of patients. Genetic analysis of 20 subjects with massive hypertrophy (left

19  Inherited Metabolic Diseases: Emphasis on Myocardial Disease and Arrhythmogenesis Fig. 19.1  Transthoracic echocardiogram: (a) Familial PRKAG2 mutation. Absence of myocardial hypertrophy (male, 42 years old); (b) Familial PRKAG2 mutation. Nonobstructive asymmetric septal hypertrophy (IV septum = 18, posterior wall = 12 mm) (male 40 years old); (c) Familial sarcomeric hypertrophic cardiomyopathy. Asymmetric septal hypertrophy, and dynamic LV systolic gradient of 103 mmHg (IV septum = 23 mm, posterior wall = 13 mm) (male, 45 years old)

235

a

b

c

ventricular wall thickness ³ 30 mm) but without electrophysiologic abnormalities revealed mutations in neither LAMP2 nor PRKAG2. Genetic analysis of 24 subjects with increased left ventricular wall thickness and electrocardiograms suggesting ventricular preexcitation revealed four LAMP2 and seven PRKAG2 mutations. LAMP2 mutations typically cause multisystem glycogen-storage disease (Danon’s disease) but can also present as a primary cardiomyopathy. The glycogenstorage cardiomyopathy produced by LAMP2 or PRKAG2 mutations resembles HCM, but is distinguished by electrophysiological abnormalities, particularly ventricular preexcitation. Table 19.1 lists inherited metabolic diseases associated with myocardial hypertrophy.

19.4 Hypertrophy in Children Current information on the epidemiology and outcomes of HCM in children is limited by disease diversity and small case series. Myocardial hypertrophy represents a heterogeneous group of disorders, and this diversity is most apparent in children. In adults, results of molecular studies conducted in familial cases have implicated sarcomeric protein defects in a high percentage of patients, leading some investigators to suggest that the use of the term HCM should be restricted to only patients with documented or suspected sarcomeric defects. This convention has not been adopted in pediatric cardiology, in which the overwhelming majority of cases are genetically uncharacterized and most cases are not

236

familial. Even in adults, systematic screening for sarcomeric defects accounts for at most 60% of the cases and cause other than sarcomeric defects has been increasingly recognized. The Pediatric Cardiomyopathy Registry (PCMR) has collected prospective and retrospective data on children diagnosed with HCM since 1990.9 Various causes of HCM have been identified in childhood as well as determination of the relationship between outcomes, cause, and age at presentation (see Diagram 19.1). Of 855 patients  < 18 years of age with HCM, 8.7% (n = 74) had inborn errors of the metabolism, 9% (n = 77) had malformation syndromes, 7.5% (n = 64) had neuromuscular disorders (NMD), and 74.2% (n = 634) had idiopathic HCM. As a group, patients with inborn errors of the metabolism (IEM) and neuromuscular disorders (NMD) were characterized by concentric hypertrophy, whereas the idiopathic HCM group had a median septal thickness 1.4 times that of the posterior wall. Although many different specific causes were identified, a single cause predominated in each group: Pompe disease accounted for 33.8% of the cases with IEM, Noonan syndrome accounted for 77.9% of the cases with MFS (malformation syndromes), and Friedereich ataxia accounted for 87.5% of the cases with NMD. Children with HCM associated with IEM and MFS presenting with HCM before 1 year of age have a particularly poor prognosis, with a 5-year survival post-HCM diagnosis of 26.3% and 65.8%, respectively.

19.5 Pathophysiology of Myocardial Abnormalities 19.5.1 Intracellular Lipid Accumulation in the Heart (Mitochondrial Disorders) During the fetal stages of the developing mammalian heart, glucose is the primary energy substrate for energy production, while FAO (fatty acid oxidation) rates are very low. Shortly after birth (and in the normal adult heart), a fall in plasma insulin levels, coupled with decreased availability of glucose and increased availability of fatty acids, leads to enzymatic changes, including increased expression of mitochondrial FAO enzymes that result in a parallel increase in the production of adenosine triphosphate from myocardial FAO.

E. B. Sternick

Under normal physiologic conditions, cardiac myocytes in the post natal mammalian heart rely on b-oxidation of long-chain fatty acids (LCFAs) to generate ATP. Since these cells have little capacity for de novo biosynthesis or storage of LCFAs, and since unbound FFA concentrations are in the low nanomolar range, cardiac myocytes require an efficient mechanism for importing this metabolic substrate. Several proteins have shown to facilitate movement of LCFAs across the plasma membrane of mammalian cells, including the fatty acid transport protein (FATP1) and long-chain acyl-CoA synthetase (ACS1). ACS1 is highly expressed in the heart and catalyzes esterification of LCFAs with coenzyme A (CoA), the initial step in fatty acid metabolism (Fig. 19.2). In a number of pathophysiologic states, evidence is emerging that mismatch between uptake and utilization of LCFAs leads to abnormally high intracellular LCFA concentrations. First, myocardial metabolism switches from utilization of LCFAs to utilization of glucose during the development of cardiac hypertrophy and in the ischemic and failing heart. While this metabolic switch may initially serve as an adaptive function, accumulation of intracellular LCFAs in these acquired conditions has been proposed to contribute to contractile dysfunction and the generation of cardiac arrhythmias.2 Second, increased cardiac myocyte triglyceride stores are observed in animal models of obesity and in diabetes, disease states in which high serum FFA levels are thought to promote LCFA uptake in excess of tissue capacity for utilization. This lipid accumulation has been proposed to contribute to cardiac myocyte apoptosis and congestive heart failure. Third, inherited defects in the mitochondrial fatty acid oxidation pathway have been associated with cardiomyopathy and sudden death in children and young adults.10 Postmortem pathologic studies demonstrate marked intracellular lipid accumulation in the heart, the result of persistent LCFA import in the face of blocked LCFA metabolism.11 It remains unclear whether the cardiomyopathy in these pathologic states results from toxic lipid accumulation or whether cardiomyopathy results directly from altered myocyte metabolism (e.g., energy starvation), but well-designed experimental studies are consistent with a direct toxicity of lipid accumulation.12 Inborn errors of fatty acid oxidation result in metabolite buildup proximal to the enzyme defect and in deficient formation of energy-yielding substrates after the block. In the defects downstream from CPT-1, the

19  Inherited Metabolic Diseases: Emphasis on Myocardial Disease and Arrhythmogenesis

237

UNEXPLAINED LEFT VENTRICULAR HYPERTROPHY VENTRICULAR PREEXCITATION ?

WITHOUT DELTA WAVE BUT WITH SHORT PR

YES

NO

SINUS BRADYCARDIA. RBBB, LBBB, AV BLOCK, SHORT PR, AF, FLUTTER

YOUNG MALE

NEONATE

hypotonia macroglossia resp. distress

MASSIVE LV HYPERTROPHY

YES

YES

AAT / CK

POMPE DISEASE

LAMP 2 mutation +

Glucosidase activity

CARDIAC DANON

LAMP 2 mutation -

PRKAG2 OR OTHER GLYCOGEN STORAGE DISEASE

PRKAG2 mutation ?

CARDIAC FABRY

GLYCOGEN storage disease

YES

NO

YES

NO

AV BLOCK, FASCICULAR BLOCK, RBBB/ LBBB, PROGRESSIVE EXTERNAL OPHATALMOPLEGIA, PIGMENTARY RETINITIS

SEVERE MUSCLE WEAKNESS

ADULT POMPE

SARCOMERIC PROTEIN MUTATION

KEARNS SAYRE SYNDROME

HCM

Galactosidase activity

Diagram 19.1  Algorithm of the differential diagnosis of the most common disorders causing unexplained left ventricular hypertrophy. AAT alanine aminotransferase, CK creatine-kinase, D  Dis = disease, HCM hypertrophyc cardiomyopathy

acylcarnitine that accumulates has detergent properties, which may explain its toxicity. Indeed, amphiphilic lipid metabolite, long-chain acylcarnitine, and lysophosphatidylcholine accumulate during myocardial ischemia and play a pivotal role in the production of arrhythmias. Incorporation of long-chain acylcarnitine in the sarcolemma elicited electrophysiological anomalies analogous to those seen in acute myocardial ischemia.13 These toxic effects on ion currents were not observed with short- and medium-chain acylcarnitine, demonstrating that the proarrhythmic effects of lipid metabolites depend on chain length and require a free carboxyl group. It has been observed that no arrhythmias occur in patients harboring a fatty acid oxidation defect upstream of CPT-1, in which no accumulation of acylcarnitines occurs. Similarly, no arrhythmias occurred in patients with a medium-chain acyl-CoA dehydrogenase deficiency because these fatty acids do not use carnitine-acylcarnitine shuttling to reach the mitochondrial matrix.14

19.5.2 Intracellular Glycogen Accumulation in the Heart with Mild or No Systemic Manifestations The accumulation of glycogen in the heart occurs in a number of inherited disorders caused by different mutations affecting the activity of the AMP kinase. Missense mutations affecting the g2 regulatory subunit of AMPactivated protein kinase (PRKAG2) regulate substrate use for energy production. Persistent activity of AMP kinase in the heart could account for dominant expression of a heterozygous mutation. Nonphysiologic activation of cardiac AMP kinase by these mutations should increase glucose uptake (by stimulating translocation of the glucose transporter GLUT-4 to the plasma membrane) and increase hexokinase activity, thereby leading to glycogen accumulation (“gain of function” in basal AMPK activity). Polysaccharide

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E. B. Sternick

Fig.  19.2  Likely pathophysiology of cardiac arrhythmias in fatty acid oxidation disorders: in defects downstream from CPT1, the accumulation of acylcarnitine may have toxic effects on

the phospholipids of the sarcolemma and interact with different ionic channels (Adapted from Ref.14)

storage and vacuole formation in myocytes containing a PRKAG2 mutation is therefore highly compatible with inappropriately increased baseline AMP kinase activity (Fig. 19.3). The cardiac histopathology is very distinctive and characterized by enlarged myocytes with vacuoles containing glycogen derivatives; notably, myocyte disarray is absent and intersticial fibrosis is minimal, in contrast with the situation encountered in sarcomeric mutations in ten different genes causing HCM.15 These data indicate that PRKAG2 mutation causes a form of cardiomyopathy associated with polysaccharide storage in the heart.16,17 This disorder had been reproduced in animal models.18,19 The mean age at diagnosis of the PRKAG2 associated cardiomyopathy is between 20 and 30 years, but more rarely, a fatal infantile variety of cardiac glycogenesis can occur.20 Mutations in the gene encoding lysosome-associated membrane protein 2 (LAMP2), which is located on the X chromosome, cause massive left ventricular hypertrophy in boys in whom systemic manifestations (the Danon’s disease) may also develop. Because LAMP2 mutations are usually clinically silent in female carriers, affected boys appear to have sporadic rather than inherited disease.

19.5.3 Intracellular Glycogen Accumulation in the Heart with Systemic Manifestations Pathologic vacuoles containing glycogen or intermediary metabolites also occur in conditions causing extra cardiac disease as in Pompe’s disease, a recessively inherited lysosomal acid a-1,4-glucosidase (GAA) deficiency, Danon’s disease (X-linked lysosome-associated membrane protein (LAMP2) deficiency), Fabry’s disease (an X-linked lysosomal hydrosilase a-galactosidase (GLA) deficiency). These multisystem disorders cause neuromuscular deficits, abnormal liver and kidney function, and abnormalities of the central nervous system as well as cardiac hypertrophy. Although some atypical patients with Fabry’s disease have mild systemic manifestations, and, predominantly cardiac disease, the pleiotropic manifestations of Pompe’s disease and Danon’s disease rarely prompt the consideration of these disorders in the differential diagnosis of unexplained left ventricular hypertrophy. Left ventricular hypertrophy as part of a systemic disorder, can also be found in patients with glycogen

19  Inherited Metabolic Diseases: Emphasis on Myocardial Disease and Arrhythmogenesis

Fig. 19.3  Principal pathways of glycogen metabolism in muscle: Proteins (blue lettering) involved in glycogen storage diseases (GSDs) associated with cardiomyopathy (red lettering) are shown. Glucose enters muscle cells through transport proteins and undergoes phosphorylation by hexokinase, after which it is targeted for glycolysis or glycogen synthesis by glycogen synthetase. Glycogen, a branched glucose polymer containing 93% 1–4 glucose bonds and 7% branched 1–6 glucose bonds, is a dynamic reservoir of energy for muscles; synthesis or degradation depends on the activity of specific enzymes that undergo reversible phosphorylation by kinases. Glycogen metabolism is further influenced by AMP-activated protein kinase, which associates with glycogen and regulates glucose uptake, and by lyso-

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some activity. Defects in glycogen-degradation pathways (involving phosphorylase, phosphorylase kinase, phosphoglucomutase, phosphofructokinase, phosphoglycerate kinase, lacticdehidrogenase, and brancher and debrancher enzymes) result in glycogen accumulation and exercise induced skeletal muscle symptoms and myoglobinuria, with or without cardiac manifestations. AMPK, which consists of a, b, and g subunits, also regulates fatty acid oxidation through phosphorylation of acetyl CoA carboxylase (acetyl CoA carboxylase ~ P). Defects in PRKAG2 (the regulatory g-subunit of AMPK), LAMP,2 or acid glucosidase cause insidious glycogen accumulation, resulting in cardiac hypertrophy and electrophysiological abnormalities (adapted from Ref.8)

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storage diseases (types I through VI), DiamondBlackfan anemia, muscular dystrophies, skeletal myopathies, or mitochondrial diseases.8

19.6 Clinical Course and Management of the Inherited Metabolic Disorders Associated with Cardiomyopathy and Arrhythmogenesis (Diagram 19.1) 19.6.1 Fatty Acid Oxidation Disorders Clinical findings in fatty acid b-oxidation deficiencies vary according to the specific enzymatic defect and even among patients with the same genotype. A simultaneous dysfunction of the heart, liver, skeletal muscle, associated with hypoketotic hypoglycemia, is highly suggestive of a fatty acid oxidation disorder. However, the clinical presentation may be puzzling. Indeed, the diversity of the presenting signs and the need to collect blood and urine specimens for metabolite investigation at an appropriate time in relation to the illness, frequently limit the recognition of these diseases. Prompt recognition of these inborn disorders is warranted because they can often be treated. In addition, a precise diagnosis of the enzymatic defect is crucial for genetic counseling: prenatal or presymptomatic diagnosis can be performed in siblings. Cardiac involvement is frequent (50% of the patients). Cardiomyopathy is the chief clinical manifestation of several inherited disorders of mitochondrial fatty acid b-oxidation. The mean age at admission is 3.5 months (range 1 day to 13 months), and nearly 50% are newborns.14 In addition, arrhythmias and conduction defects, in association with hepatomuscular symptoms, have been previously mentioned in isolated cases of fatty acid oxidation disorders. Severe ventricular arrhythmias are suspected as the cause of sudden infant death syndrome or unexpected death in young children harboring these defects. In a series of 55 patients with cardiac manifestations, 24 patients had rhythm disturbances and in 18, arrhythmia or conduction defects were the revealing symptom of the metabolic disorder. Although neonatal ventricular or atrial tachycardias in infants with a structurally and functionally normal heart are usually

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considered idiopathic, not uncommonly, arrhythmias or conduction defects can be the presenting symptom of various fatty acid oxidation disorders.14 In the same series, fifteen patients had ventricular tachycardia, with transition from polymorphic ventricular tachycardia to ventricular fibrillation in 6 of the 15. Conduction abnormalities were observed in ten patients: six had atrioventricular blocks (three first degree blocks, one Mobitz I block and one complete AV block associated with ventricular tachycardia) and four had left bundle branch blocks. Among the 24 patients with arrhythmias, only three survived with an adequate diet (one CPT-II deficiency, one VLCAD deficiency, and one carnitine-acylcarnitine translocase deficiency). The other 21 patients died 1 day to 2 years (median 1 month) after the diagnosis of the arrhythmia, except one patient with a long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency who survived 18 years and then died suddenly. Despite symptomatic therapy of the arrhythmia, eight patients (all aged  < 1 year) died within the first week after the onset of the disease (retrospective diagnosis). The most convenient metabolic investigations of urine and plasma to determine the diagnosis of fatty acid oxidation disorders are as follows: determination of urinary acid organic profile, which can give a highly specific pattern or nonspecific dicarboxylic aciduria. Plasma and urine free and total carnitine concentrations and plasma acylcarnitine profile by tandem mass spectrometry. In many instances, the diagnosis will be retrospective, in patients who will not survive acute neonatal distress. Acylcarnitine profiling can be performed using tandem mass spectrometry on a blood spot collected on a Guthrie card, which can be easily mailed to reference labs. l-carnitine administration plays a key role in the treatment of fatty acid oxidation deficiencies. Some have proposed using it to prevent arrhythmias in acute myocardial infarction.21 The inhibition of CPT-I prevents the accumulation of long-chain acylcarnitines in the sarcolemma and, as a consequence, the incidence of lethal arrhythmias induced by ischemia in the rat heart.22 Some antiarrhythmic drugs, like perhexiline and amiodarone, inhibit CPT-I.23 Today, the treatment of fatty acid oxidation disorders aims to provide sufficient glucose to prevent adipose tissue lipolysis. Carnitine therapy is also useful in lowering the accumulation of acyl-CoA and restoring the CoA pool in

19  Inherited Metabolic Diseases: Emphasis on Myocardial Disease and Arrhythmogenesis

the mitochondria. Long-term dietary therapy is aimed at preventing any period of fasting that would require the use of fatty acids as a fuel by continuous nocturnal intragastric feeding or by use of uncooked corn starch at bed time. We have to keep in mind that fatty acid disorders are rare, often misdiagnosed, inborn errors with an equivocal clinical presentation. Arrhythmias may be the presenting symptom of such deficiencies, particularly in newborn infants.

19.6.2 Glycogen Storage Diseases Glycogen storage diseases (GSD) with clinically prominent cardiac involvement can be caused by various gene defects (Fig.  19.3). The lysosomal glycogenosis GSD II (Pompe disease) and GSD IIb (Danon disease) are systemic disorders that also affect either skeletal muscle, smooth muscle, and liver (GSD II) ,or skeletal muscle and the nervous system (GSD IIb) (Fig.  19.4). However, cardiac involvement usually dominates the clinical picture and is life limiting in GSD IIb and in the classic infantile form of GSD II, whereas the adolescent- and adult-onset forms of GSD II are typically governed by muscle involvement. The infantile form of GSD II has an autosomal recessive mode of inheritance, manifests perinatally, and leads to death within the first year of life, whereas GSD IIb can be X-linked dominant or recessive, has a juvenile or early-adult clinical onset, and leads to death, typically during the second to fourth decades of life. Fabry’s disease, caused by lysosomal a-galactosidade A deficiency results from the progressive accumulation of globotriaosylceramide and related glycosphingolipids in microvascular endothelium of the kidneys, heart, skin, and brain. Among the nonlysosomal glycogenosis, GSD III (Cori or Forbes disease – with debranching enzyme deficiency) and GSD IV (Andersen disease with branching enzyme deficiency) are also systemic disorders. Liver and/or less frequently muscle involvement usually dominates the clinical picture. However, patients with prominent cardiac involvement (manifesting during the first or second decade of life) have also been reported. Mutations in the PRKAG2 gene, give rise to a moderate, essentially heart-specific, nonlysosomal glycog-

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enosis, with autosomal dominant inheritance with full penetrance (Fig. 19.5). Clinical onset occurs typically in late adolescence or in the third decade. Rare sporadic cases of severe prenatal- or neonatalonset nonlysosomal cardiac and skeletal muscle GSD, with normal a-1,4-glucosidase and LAMP-2, an infantile-fatal course, are in most cases due to R531Q missense mutation in PRKAG2,20 previously attributed to a heart-specific variant of phosphorylase kinase deficiency. This variant leads to death within weeks to a few months after birth, through heart failure and respiratory compromise. Given the complete penetrance of PRKAG2 mutations even in the less-severe, juvenile onset R302Q mutation, this suggests that R531Q mutations invariably cause an infantile-fatal disease, which are therefore not passed on by carriers, and always occur de novo. We will focus on four GSD which are by far the most important in clinical practice.

19.6.2.1 Danon Disease Danon disease is a lysosomal glycogen storage disease, caused by mutations in the LAMP2 gene, which is an X-linked gene that encodes lysosome-associated protein-2 (LAMP2).24 The disease is characterized clinically by cardiomyopathy, skeletal myopathy, and variable mental retardation with intracytoplasmic vacuoles containing autophagic material and glycogen in skeletal and cardiac muscle cells. Clinical presentation: asymptomatic patients may be referred to medical attention because of an abnormal ECG; others complain of chest pain, palpitations, or syncope. Sudden death can be the presenting event. The onset of symptoms in the series of Arad et  al.8 occurred between the age of 8 and 15 years, which is younger than the average for patients with sarcomere or PRKAG2 mutations. Female carriers manifest cardiomyopathy during adulthood, whereas affected males usually develop symptoms before the age of 20 years. Female carriers also have skeletal myopathy and mental retardation less commonly than affected males. Other manifestation of Danon disease can include Wolff–Parkinson–White (WPW) syndrome, increased serum creatinine kinase (CK), increased serum alanine aminotransferase (by a factor of 2 or more), and ophthalmic abnormalities. The ECG is abnormal in most of the patients, and besides the short PR interval and ventricular preexcitation, left ventricular voltage is

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Fig.  19.4  Histopathological findings in cardiac tissue from a patient with a LAMP2 mutation. A light micrograph of cardiac tissue from Proband CZ (a) shows diffusely enlarged cardiomyocytes with prominent cytoplasm, pleomorphic nuclei, and numerous cytoplasmic vacuoles. A vacuolated myocyte with a “spider cell” (inset) resembles rhabdomyoma cells (H&E; bar = 100 mm). Immunohistochemical analysis with LAMP2specific antibodies reveals positive (red) staining within vacuoles (b). In normal myocardium, strong granular perinuclear staining of lysosomes is evident (inset). Vacuoles (c), containing

large PAS positive inclusions, are homogeneous, with welldefined borders. An electron micrograph of myocytes (d) shows large, densely osmophilic perinuclear inclusions (arrow) containing fibrillogranular material with variable density and absence of visible membranes. The nucleus is poorly preserved (asterisk) (bar = 2 mm). Western blotting (e) detected LAMP2 protein in lymphocyte extracts of unaffected (UA) control samples and samples from Probands CZ and MFE. The motility of 83 and 175 Kd is indicated (adapted from Ref.8)

significantly greater than in patients with HCM and PRKAG2 mutations. Patients with the cardiac form of the disease can also present with atrial fibrillation. There are no reports of atrioventricular conduction disturbances, in contrast with patients with PRKAG2 mutation. Arad et al.8 identified LAMP2 mutations in 2 out of 35 patients with unexplained LV hypertrophy (5.7%) and in 4 out of 24 (16.6%) patients with hypertrophy associated with ventricular preexcitation. Yang et al25 investigated the prevalence of LAMP2 mutations in a population of 50 probands (33 male and 17 female) with pediatric- or juvenile-onset LV

hypertrophy. Age at diagnosis ranged from 1 day to 15 years (mean 6 years), and identified nonsense mutations in 2 of 50 (4%), close to Arad’s findings. The cardiac phenotype of Danon disease is severe with early onset and poor prognosis, even in some manifesting female carriers. In a series of 20 male patients, the mean age at onset was 17 years (range, 10 months to 19 years), and all patients except one died before the age of 30 years.26 Deaths were due to heart failure or sudden cardiac death in all cases. On the basis of these findings, it is recommended that patients with unexplained left ventricular hypertrophy with evidence of skeletal myopathy and/or WPW be

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Fig.  19.5  Histopathology of left ventricular sections obtained from individuals with PRKAG2 mutations. (a) Longitudinal section of left ventricular myocardium from a 26-year-old individual with PRKAG2 mutation Asn488IIe who died suddenly. Note vacuolated myocytes, and lack of myofiber disarray or fibrosis (H&E; bar = 100 mm). (b) High-power magnification of an endomyocardial biopsy (H&E; bar = 100 mm) from a 39-yearold individual with PRKAG2 mutation Thr400Asn shows pro-

found vacuolization (arrows). (c) Homogenous micrograph (uranyl acetate and lead citrate) of a sample described in a (bar = 1 mm). Note the large, irregular sarcoplasmic inclusion (arrows) within a large vacuole, and normal-appearing sarcomeres (arrowhead). (d) Higher magnification (bar = 1 mm) demonstrates that the inclusion is composed of a central core of homogenous, electron-dense droplets surrounded by osmiophilic granular and fibrillar material (star) (adapted from Ref.16)

screened for mutations in LAMP2, except in familial cases in which X-linked inheritance can definitely be excluded (male-to-male transmission). A family with several cases of severe cardiomyopathy and moderate myopathy was reported by Lobrinus et al..27 One boy died suddenly at 17 years of age. His two brothers were treated with ICD, and their mother died suddenly at 40 years of age. Muscle biopsy in males showed vacuolar myopathy in two of three brothers. Complete absence of LAMP2 was demonstrated by immunohistochemistry on the vacuolated skeletal and cardiac muscle, but also on morphologically normal skeletal muscle. Pathology: marked cardiomegaly and diffuse hypertrophy are common findings. Histopathological examination discloses myocyte hypertrophy and prominent intersticial fibrosis. Enlarged myocytes have extensive sarcoplasmic vacuolation with spiderweb-like appearance; some with large, polymorphic, PAS positive perinuclear inclusions. Electron microscopy shows that some sarcoplasmic vacuoles are empty, without recognizable membranes, whereas other vacuoles contained inclusions consisting of amorphous, osmophilic, and focally granular material of variable density (Fig. 19.4).

Complete absence of LAMP2 was demonstrated by immunohistochemistry on the vacuolated skeletal and cardiac muscle, but also on morphologically normal skeletal muscle. Danon disease can also manifest as a primary cardiomyopathy. In those patients, genetic analysis showed de  novo mutations rather than inherited, and most mutations affected spliced signals, whereas most previous ones have been nonsense mutations. The differential diagnosis between sarcomeric HCM and Danon disease may be achieved by clinical assessment that includes skeletal muscle testing, measurement of CK and troponins, liver enzyme chemistries, and evaluation of WPW. Mental retardation is a major finding and is reported to occur in more than 70% of the cases. Some patients, however, manifest attention deficit disorder instead of overt retardation. Arad et al reported8 that females only presented with symptoms of cardiac disease, complicating the differential diagnosis in families without affected males. Roos et  al28 in a letter to the editor of the New England Journal of Medicine raised criticism to the fact that Arad et al8 did not acknowledge that mental retardation commonly accompanies Danon disease. In

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their paper, Arad et  al reported that none of their patients with LAMP2 mutations had mental retardation exception made to an “adolescent response to cardiac disease.” Roos et  al also mentioned that many authors including Danon himself24 reported incidence of 70–100% of mental retardation in male patients, and none of the patients reached other neurodevelopment milestones – most did not walk until they were 18 years old and many had learning difficulties. They concluded recommending that patients who present with unexplained LV hypertrophy be asked about their educational performance. In case of a history of learning difficulties, they should be referred for further evaluation. The authors29 concurred with the criticism raised, but emphasized what they called as the central theme of their manuscript: whereas many LAMP2 mutations cause Danon’s disease, with its associated neurologic and muscular abnormalities, some LAMP2 mutations produce primary cardiac disease that mimics HCM without neuromuscular or behavioral abnormalities. According to them, only two of the six patients had even mild behavioral or psychological abnormalities- relatively common problems among adolescents with cardiac disease. If their patients had been cared according to standard cardiologic practice,7 which does not include genetic testing, the cause of their cardiomyopathy would not have been identified.

19.6.2.2 Fabry’s Disease Fabry’s disease is an X-linked inborn error of glycosphingolipid catabolism caused by deficient activity of a-galactosidase A, a lysosomal exoglycosidase. In males with the classic form of the disease, there is little, if any a-galactosidase A activity. As a result, undegraded glycosphingolipids accumulate, particularly in the vascular endothelium. In other words, in the glycosphingolipid catabolic pathway, a-galactosidase A removes the third sugar residue, a galactose, attached to a ceramide. Without this enzyme, glocotriaosylceramide accumulates within the vascular epithelium, heart, kidneys, cornea, brain, and other tissues (Fig. 19.6). These large deposits cause the characteristic angiokeratomas (Fig.  19.7), painful acroparesthesias (not rarely the first symptom of the disease), hypohidrosis, and corneal opacities of Fabry’s disease. Death in early adulthood in affected male heterozygotes (an average of 41 years) may be due to renal failure, myocardial infarction, or stroke. These abnormalities are absent in males with the cardiac variant of the disease (they have residual a-galactosidase A activity – approximately 5–10% of normal, enough to preclude the classic phenotype). Those with the cardiac variant typically present with a mild, late-onset disorder limited to the heart, and there is no involvement of the vascular endothelium. The

Natural history in Fabry’s disease (375 pts at FOS, 2006)

Fig. 19.6  Natural history in 375 male patients with Fabry’s disease. Symptoms can occur very early, particularly in male patients (before 5 years of age as a consequence of peripheral neuropathy and gastrointestinal tract involvement) (adapted from the Fabry Outcome Survey (Beck M. In: Metha A et al (eds))

0

10

20

30

40

50

age (mean, standard deviation)

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infusions cleared the glycosphingolipid deposits in the vascular endothelium of the kidney, heart, and skin. It has been reported that residual a-galactosidase A activity can be increased by the addition of galactose to the medium of cultured fibroblasts from patients with specific mutations. Moreover, certain reversible competitive inhibitors of a-galactosidase A, such as 1-deoxygalactonojirimycin, can also increase the activity of the enzyme.32,33 These findings suggested that treatment with galactose, or a nontoxic, reversible competitive enzyme inhibitor may enhance the residual activity of the a-galactosidase A, thereby improving the pathological and clinical manifestations of the cardiac variant of the disease. Reversal of the cardiac abnormalities of the cardiac variant of Fabry’s disease can be quite impressive (Fig.  19.9). Frustaci et  al1 reported after 2 years of galactose infusions, reduction of the number and complexity of ventricular premature beats (from Lown V to Lown I), interventricular septum thickness (from 20 to 16 mm), increase in LVEF from 33 to 55%, and important improvement in biopsy specimens (myocardium fibers appeared smaller and much less extensively vacuolated). The patient was in NYHA functional class IV, in the heart transplant waiting list, and after 2 years, he returned to his full-time work as a bus driver. Patients with unexplained left ventricular hypertrophy or hypertrophic cardiomyopathy should be evaluated for Fabry’s disease by means of assays of their plasma a-galactosidase A activity.

19.6.2.3 Pompe’s Disease

Fig.  19.7  Angiokeratomas around the umbilicus, in the lips, and at the back of a patient with Fabry’s disease

12-lead ECG usually depicts sinus rhythm with short PR interval, left ventricular hypertrophy, and negative T waves in the precordial leads (Fig. 19.8). Ventricular preexcitation with paroxysmal tachycardia (WPW syndrome) has been reported in patients with the cardiac variant of the disease. With advancing age, however, cardiac involvement progresses and leads to death.30,31 Enzyme-replacement therapy is safe and effective in patients with classic Fabry’s disease. Enzyme

Glycogen storage disease type II or Pompe disease is a fatal genetic neuromuscular disorder caused by deficiency of lysosomal acid a-glucosidase. 34 Glycogen accumulates abnormally in the lysosome of skeletal, cardiac, and smooth muscle, and contributes to clinically progressive and debilitating muscle weakness. The disorder has an autosomic recessive inheritance pattern. There are a number of clinical phenotypes and the myocardial is affected in two. Infantile Pompe disease- Classic infantile Pompe disease is the most severe variety, and death occurs around the first year of life due to cardiorespiratory failure. The affected neonates develop progressive hypotonia, cardiomyopathy, hepatomegaly, and macroglossia. The neonate develops dyspnea, feeding is

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Fig. 19.8  Transthoracic echocardiogram and 12-lead ECG in an adult patient with Fabry’s disease with a non-obstructive and concentric left ventricular hypertrophy

Fig. 19.9  Magnetic resonance before and 6 months after enzyme replacement therapy for Fabry’s disease showing reduction in left ventricular wall thickness from 15 to 12 mm

laborious, and without any treatment, the child will be dead before 2 years of age usually due to respiratory failure. The 12-lead ECG shows a short PR interval, high voltage QRS complex, and signs of left ventricular hypertrophy. Association with the WPW syndrome is well-known. Infiltration of septal myocytes has been correlated with the shortened PR intervals observed in some Pompe patients, and corrective increase in the PR interval has been noted in conjunction with enzyme replacement therapy (ERT).35 Echocardiogram shows a massive left ventricular (LV) hypertrophy and diastolic and systolic dysfunction. Overall, there is an inverse correlation between disease severity and the level of residual enzyme activity, with the most severely affected infants having no detectable enzyme activity. Glycogen accumulation in motor neurons of the spinal cord raises the question as to whether neuronal

involvement is a secondary component contributing to muscle weakness.36 Until the recent development of ERT, little, other than symptomatic treatment, was available for these patients. With the advent of enzyme replacement therapy using recombinant human acid a-glucosidase (rhGAA), and increased life span, more infantile Pompe patients will likely reach adulthood. However, the sooner the treatment is begun, the better the response. Griffin et al37 proposed a lysosomal rupture hypothesis, asserting that during normal contraction, the unique contractile nature of myocytes subjects the glycogen containing lysosomes to stress forces during the increased rigidity of surrounding myofibrils. Once the lysosomes reach a critical size, these forces cause lysosomal rupture and release of glycogen and lytic enzymes into the cytoplasm. The lytic enzymes cause

19  Inherited Metabolic Diseases: Emphasis on Myocardial Disease and Arrhythmogenesis

damage to myofibrils, leading to loss of myofibrils and loss of contractile function. In more advanced stages, myocytes filled with lakes of cytoplasmic glycogen and devoid of contractile elements were considered to represent end-stage disease. These changes are particularly relevant to ERT, since this cytolasmic glycogen released from lysosomes is probably inaccessible to the membrane receptor-dependent targeting mechanism. The current available data suggest that the therapeutic window in infantile Pompe disease is narrow, and it is probably critical to do prenatal diagnosis for improving therapeutic results.38 An important issue in those patients is the occurrence of lethal cardiac arrhythmias, including torsade de pointes, following anesthesia induction.39 In contrast with the adult form of the disease, infantile Pompe disease is associated with marked myocardial hypertrophy and increased risk of arrhythmia. Wang et  al40 retrospectively reviewed the experience of 139 patients enrolled in clinical trials with rhGAA. Adverse effects were screened for those involving anesthesia. Nine patients (6%) experienced an arrhythmia or cardiopulmonary arrest soon after induction of general anesthesia. Of these events, propofol was involved in four; sevofluorane without propofol in two. For these reasons, it is recommended that anesthesia for infantile Pompe disease patients specifically avoid propofol or high sevofluorane and, instead, use an agent such as ketamine as the cornerstone for induction in order to better support coronary perfusion, avoiding decreasing blood pressure with vasodilator agents. Juvenile and adult Pompe disease- The typical adult patient with Pompe disease presents after 20 years of age with proximal muscular weakness resembling polyomiositis. A third of the patients present with respiratory distress due to a localized diaphragmatic muscle weakness, usually evolving to the indication of assisted mechanical ventilation. There is neither hepatomegaly nor cardiomyopathy. The 12-lead ECG might show signs of pulmonary hypertension due to chronic respiratory failure. Involvement of vascular smooth muscle noted in juvenile and adult forms of Pompe disease was reportedly responsible for vascular aneurysms resulting in severe headaches, cerebellar infarction, and fatal rupture.41 Although Pompe disease is often included in the differential diagnosis of LV hypertrophy, the true frequency of cardiac involvement in adults with Pompe disease is debated. Soliman et al34 investigated forty-six

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consecutive adult patients with Pompe disease (mean age 48 years, 22 men). Each patient underwent clinical examination, ECG, and rest and low-dose dobutamine 2-D echocardiogram, including contrast and TDI. All patients had limited exercise tolerance: a rollator walking aid was used in 15%, a wheelchair in 28%, and assisted ventilation in 30%. Prior to the study, one patient had atrial fibrillation, His bundle ablation, and a VVI pacemaker. The patient with atrial fibrillation had decreased LVEF and increased LV end-diastolic diameter. One patient with fluid retention, wheelchair bound, and dependent on 24-h assisted ventilation had right and left ventricular hypertrophy (septum 16 mm, posterior wall 15 mm). LV hypertrophy was not seen in any of the other patients. Mean global systolic LV function in patients with Pompe disease was not decreased. In adult patients with Pompe disease without objective signs of cardiac disease by 12-lead ECG or physical examination, echocardiographic screening for LV hypertrophy does not seem effective.34

19.6.2.4 PRKAG2 Mutations Mutations in the PRKAG2 gene (chromosome 7), which encode the regulatory g2-subunit of AMP-activated protein kinase (AMPK) cause glycogen storage cardiomyopathy. The clinical phenotype varies among mutations, and even in individuals from the same family with the same genotype. Histopathology: findings from five cardiac specimens with three different mutations were similar. There was marked ventricular hypertrophy on gross inspection, and myocytes were enlarged (Figs.  19.5 and 19.1b), but myofiber disarray was not detected in any sample. Intersticial fibrosis was minimal and focal. A common finding was isolated, large cytosolic vacuoles in cardiomyocytes, containing inhomogeneous granular material that stained strongly with PAS, and was diastase resistant, a pattern that is characteristic of polyglucan. Electron microscopy revealed amylopectine, a non soluble product of glycogen metabolism inside the vacuoles. Such findings are typical of type IV glycogenosis and have also been found in hearts of patients with adult-onset Pompe disease.16 Clinical features are a combination of hypertrophy, ventricular pre-excitation, atrial tachyarrhythmias, and progressive severe cardiac conduction system disease.16,41-44 AMPK, a serine/threonine kinase, is

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a heterotrimeric complex that consists of catalytic a-subunit by AMPK kinases under conditions of metabolic substrate limitation, hypoxia, exercise, and heat shock. Once activated by a rise in AMP/ATP ratio, AMPK alters enzyme activities in ATP-producing and consuming pathways and maintains essential homeostatic systems.43,45 Activation of AMPK during acute low-energy states switches off ATP-consuming pathways, such as glycogen, cholesterol, and fatty acid synthesis, and activates ATP-producing pathways such as fatty acid oxidation and increased glucose uptake46 (Fig. 19.3). Mutations in the g2-subunit of AMP produce human cardiac disease previously classified as HCM with WPW.47 Affected individuals develop ventricular hypertrophy and cardiac conduction system abnormalities such as sinoatrial and atrioventricular nodal dysfunction, which often necessitates pacemaker implantation. Syncope and sudden cardiac death can result from atrial fibrillation with fast ventricular rates or from complete AV block (Fig. 19.10). However, there are no reports of sudden death due to ventricular tachyarrhythmias in PRKAG2 mutations in different published series; some patients with PRKAG2 mutations received an automatic implantable defibrillator. The most likely explanation is that those patients seek medical care due to recurrent syncope, and as severe LV hypertrophy is found, they

Fig. 19.10  (Case 6 of Fig. 11). 12-lead ECG of a 32-year-old male patient with frequent bouts of atrial fibrillation with fast ventricular rate (up to 260 bpm), who died suddenly

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are diagnosed as having HCM and an ICD is implanted for primary prophylaxis. Notwithstanding, Murphy et  al.48 found that three patients from a family with Arg302Gln (two of three had severe hypertrophy) had non-sustained VT during 24-h Holter monitoring and one patient who underwent an electrophysiologic study developed ventricular fibrillation during atrial pacing. In a transgenic mouse model of PRKAG2 mutation18,19 ventricular preexcitation developed within the first month of life, and histopathology revealed that the annulus fibrosis, which normally electrically insulates the ventricles from the atria, was disrupted by glycogen-filled myocytes.49 Disease manifestations are mediated through increased activity of a2-sunit complexes.50 Cardiac hypertrophy in patients with PRKAG2 mutations often evolves into a phase characterized by systolic dysfunction and left ventricular dilation, which resembles features of dilated cardiomyopathy, and progresses to heart failure.8,42 This course resembles other glycogen storage and metabolic cardiomyopathies, but is dissimilar from HCM caused by sarcomere mutations. Echocardiographic pattern of LV hypertrophy can be indistinguishable from hypertrophy caused by sarcomeric mutations (Fig. 19.1). However, LV hypertrophy in PRKAG2 mutation is nonobstructive. Clinical course is quite variable. Some patients with glycogen-storage-

19  Inherited Metabolic Diseases: Emphasis on Myocardial Disease and Arrhythmogenesis

Fig. 19.11  12-lead ECG of six brothers with PRKAG2 mutation (Bonfim family). Their ECG pattern is strikingly similar. Major characteristics include short PR interval, right bundle branch block, normal QRS frontal plane axis, absence of ST segment abnormality, and a pseudo-delta wave pattern. Cases 1 and 4 evolved to third degree AV block, while cases 2 and 3 received a pacemaker due to symptomatic sick sinus syndrome (between 35 and 45 years old). Case 5, had no RBBB at presentation (18 years old) but evolved in 4 years to the same familial RBBB pattern

associated cardiomyopathy have a poor prognosis due to severe cardiac dysfunction; however, long-term survival is possible, although progressive conduction system disease may necessitate the implantation of a pacemaker and aggressive control of arrhythmias. The pseudo-WPW pattern: we have seen in 12 of 20 patients from two unrelated families43 with PRKAG2 mutations (all with a missense mutation – Arg302Gln) showing a peculiar ECG pattern consisting of sinus bradycardia, short PR interval, associated with a right bundle branch block suggestive of ventricular preexcitation (Fig.  19.11). The incidence of atrial tachyarrhythmias in this cohort was 53%. Five patients, who presented with atrial flutter, underwent a successful cavotricuspid isthmus ablation, but three of the five patients evolved to atrial fibrillation (Fig.  19.12). Three other patients presented with atrial fibrillation. Eight patients underwent electrophysiologic assessment (EPS). All patients

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had either sinus node dysfunction and/or multilevel atrioventricular conduction disturbances - prolongation of intraatrial, intrahisian, infrahisian, and/or intraventricular conduction times (Fig. 19.13a, b). The distinctive pseudo-delta wave pattern found in 12 of 20 patients (60%) was caused by a striking association of a conduction block in one structure (the right bundle) with fast conduction in another (the AV node). The presence of a fasciculoventricular pathway was ruled out in the eight patients who underwent an EPS, because the HV interval was within normal range. Hypertrophy was not an explanation for the pseudo-delta wave, because only two (10%) of our patients had LV hypertrophy. One patient died suddenly, probably due to atrial fibrillation and very fast ventricular rate. Those patients are at risk of sudden death due to fast conducting atrial fibrillation (either due to a fast conducting AV node or an accessory AV pathway) early in life and at risk of sudden death from AV block later (age between 25 and 40 years). After pacemaker implantation, none of our patients had syncope or sudden death in a follow-up of more than 10 years (35% received a pacemaker). PRKAG2 and skeletal myopathy: Murphy et  al. described for the first time a skeletal myopathy as part of this disorder. Fifteen percent (seven patients) of a family with Arg302Gln mutation had evidence of proximal weakness. They complained of myalgia, during or immediately after short bursts of aerobic exercise. Electromyography was normal in most patients. Light microscopy of the vastus lateralis showed that muscle fibers were of normal size. The major finding in biopsy samples were the presence of excess glycogen, occasionally appearing within mitochondria.48 The presence of a symptomatic skeletal myopathy highlights the extracardiac clinical manifestations of PRKAG2 mutations. Analogous mutations in porcine PRKAG2 cause glycogen accumulation in pig skeletal muscle, which makes it commercially useless. The proportion of AMPK activity in human cardiac muscle accounted for by the g2-subunit is more than twice the proportion provided for in skeletal muscle, which may account for the milder skeletal muscle clinical manifestations in the series reported by Murphy et al,48 and probably by the lack of significant symptoms and/or subclinical myopathy in other published series. PRKAG2 transgene regulation in mice has shown that critical development timing of glycogen depletion in the heart prevents or reverses cardiac hypertrophy, dysfunction, and conduction system disease. In the era

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Fig. 19.12  (Case 2 of Fig. 11). Counterclockwise atrial flutter with 2:1 AV block

of advanced therapeutic approaches such as gene therapy51 and enzyme replacement,1,2 these data imply that myocardial dysfunction and cardiac conduction system disease in glycogen-storage cardiomyopathy could potentially be treated by modulation of cardiac glycogen content, and that early initiation treatment is critical to preclude the development of accessory pathways. Lowering cardiac glycogen content significantly ameliorates morbidity in PRKAG2 cardiomyopathy.3 In the coming years, targeting AMPK could be a viable alternative therapeutic option to device implantation and heart transplantation for patients who have PRKAG2 mutations with glycogen – storage cardiomyopathy and arrhythmias.

19.6.3 Other Mitochondrial Diseases with Emphasis on Maternally Inherited Cardiomyopathy (MICM) and Kairnes-Sayre syndrome Mitochondrial diseases can affect many organ systems but most often involve the brain and muscles. They were discovered in the 50’s, but their causes have been

identified only 2 decades ago. More than 50 different mtDNA point mutations have been associated with a wide variety of human diseases, and these mutations can cause disease in practically every system of the body. Since mitochondrial disease often involve muscle (skeletal and heart) and brain clinically, perhaps because of the high energy requirements of these tissues, they have frequently been termed “encephalomyopathies”. The term “mitochondriopathy” is concise and consistent with the multisystemic nature of the diseases, which can include the heart (heart block and cardiomyopathy), endocrine disease (diabetes, exocrine pancreatic failure, and primary and secondary gonadal failure), bone marrow disorders (hyporegenerative anemia), and abnormalities of the eye (retinitis and cataracts). With each new discovered manifestation of a mitochondriopathy, the question arises as to how often a common disorder such as cataract, deafness, or diabetes mellitus actually represents the first sign of a mitochondrial disease. How to recognize a mitochondrial disease: The dominant symptom is a nearly lifelong history of exercise intolerance, either presenting as myalgia, cramps, or muscle fatigability. However, given the high

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a

b

Fig. 19.13  (a) (Case 4 of Fig. 11). 12-lead ECG showing sinus bradycardia. Note the pseudo delta wave pattern (short PR and slurring of the upstroke of the R wave particularly in the inferior leads and V1-3). The P wave is enlarged. (b) (Case 4 of Fig. 2). Atrial pacing at 420 ms: PA interval is enlarged (85 ms); AH

interval is short; there is an intrahisian Wenckebach type block; HV interval is normal (35 ms). Multilevel AV conduction disturbances associated with fast AV nodal conduction explains the pseudo ventricular preexcitation pattern (paper speed at 100 mm/s)

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frequency of those symptoms in the general population a number of tests are required: measurement of blood lactate and pyruvate, a muscle biopsy to identify ragged-red fibers (a hallmark of MICM), and histochemical measurement of succinic dehydrogenase and cytochrome oxidase activities. Nuclear magnetic resonance spectroscopy of muscle, which is noninvasive, may disclose abnormal findings. A mutation in the mitochondrial cytochrome b gene has been reported in 5 patients presenting with severe exercise limitation, muscle fatigability as well as muscle pain and cramps.52 A further clue to the diagnosis of a mitochondriopathy is the predominantly matrilineal inheritance. The children of affected women are affected, whereas none of the children of affected men have the disease. However, there are other familial mitochondrial diseases that are due to alterations in nuclear genes and that are autosomal dominant. To complicate matters, the mutation can manifest as a de novo mutation. In this case, only muscle fibers will harbor the mutation in mitochondrial DNA (mtDNA); genomic DNA in lymphocytes and cultured fibroblasts will not have it. This finding is consistent with the occurrence of a new mutation in the mtDNA of a muscle progenitor cell during early embryogenesis. Thus, no family history of the disease would be expected, and the disease would not be transmitted from affected patients to their children. Somatic mutation of mtDNA (i.e., multiple random deletions) also occurs in the weak muscles of elderly patients. MICM often occurs in the frame of a multisystem disorder. An example, about 20% of patients with the syndrome of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes have a cardiomyopathy (MELAS), mostly hypertrophic.53 On the other hand, mtDNA mutations have been reported in patients with cardiomyopathy as the sole or dominant clinical feature, a condition known as MICM.54 However, the clinical description of MICM is often incomplete. Its specific features are poorly recognized and it is unclear how it can be differentiated from other forms of familial cardiomyopathy. A large family with MICM shed some light in this regard.55 All patients (from 5 generations (with a maternal mode of inheritance) presented with a pure non-obstructive hypertrophic cardiomyopathy without symptoms of other system dysfunction, including the central nervous system. Neurologic examination was

E. B. Sternick

normal in all individuals. In particular, no signs of skeletal or extraocular muscle involvement were found. Hypertrophy was more often symmetrical; almost all patients showed an increase wall thickening of the posterior wall, which was predominant in two cases. In HCM, hypertrophy is asymmetric in 99% of the cases. In addition, significant myofiber disarray, a hallmark of HCM, was not observed in MICM. In the proband, serial echocardiograms demonstrated an evolution from a hypertrophied, nondilated left ventricle to left ventricular cavity enlargement and impaired systolic function, which is a rare event in HCM.56 The illness often had an adverse clinical course, with three deceased members, and a fourth individual received a transplant. Only five subjects showed echocardiographic signs of hypertrophy, while asymptomatic. These findings suggest a more severe form than HCM with a relatively common rapidly progressive course. Interestingly, neither atrial fibrillation nor sudden death were relevant features. Whether this clinical presentation is related to specific mtDNA mutation or represents a common feature of MICM remains to be established. The latter hypothesis seems to be supported by other reports.57-59 All studied subjects harbored the A4300G mutation in the tRNA gene. However, no obvious correlation was found between disease status or severity and abundance of mutated genomes in peripheral leukocytes. In fact >95% of mutated mtDNAs was found both in affected members and healthy subjects. This lack of correlation is not infrequent in other disorders associated with mtDNA mutations.60 Since no patient had overt skeletal myopathy, biopsy was not indicated. As a result, the assessment of the presence of mutated mtDNA in tissues other than blood was done only in the proband, and it was found in all tissues, although in slightly higher concentrations in skeletal muscle and in the heart. It remains to be explained the complexities of genotypephenotype correlations. How does a patient benefit from knowing that he has a mitochondriopathy? Patients with hereditary disorders, which are inherited either mitochondrially or in an autosomal dominant fashion, need genetic counseling. Because many cardiologists are unfamiliar with mitochondrial disorders, a matrilinear lineage of cardiomyopathy may be confused with an autossomal dominant one. Patients with sporadic disorders, benefit from knowing that there is no risk of transmission to their heirs. The offspring of male patients can be safely

19  Inherited Metabolic Diseases: Emphasis on Myocardial Disease and Arrhythmogenesis

excluded as potential affected subjects, whereas all the children of an affected mother should be considered at risk.

19.6.3.1Kearns-Sayre syndrome (KSS) KSS is a rare mitochondrial cytopathy associated with the phenotypic triad of progressive external ophtalmoplegia, atypical pigmentary degeneration of the retina, and complete heart block (Fig. 19.14) 61. Other features include sensorineural deafness, impaired intellectual function, short stature, and endocrine and renal abnormalities 62. Large-scale deletions of mitochondrial DNA in skeletal muscle strongly suggest an underlying mitochondrial disorder in KSS 63. Cardiac histopathological studies show fatty infiltration and fibrosis of the bundle branches and sinoatrial and atrioventricular (AV) nodes 64. Cardiac involvement in KSS classically takes the form of complete heart block. However, cases studies have shown that a variety of conduction defects precede the development of complete AV block. These conduction defects include

a

c

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fascicular blocks and first-degree AV block that tend to progress rapidly to complete AV block. Pathologic studies show preferential involvement of the cardiac conduction system over the myocardium, with fatty infiltration and fibrosis of the bundle branches and sinoatrial and AV nodes on histology 65. Conduction defects tend to appear later in the disease after signs in other organ systems are apparent, but once present, the conduction defect is progressive. Intraventricular conduction defects progress to fascicular blocks and complete AV block more rapidly than is seen with other diseases, with the development of complete heart block occurring typically in the second or third decade of life 66 . This was generally considered to be the cause of syncope and sudden death in KSS, but seven recent reports have demonstrated an association with a long QT interval and torsades de pointes 66–72). The mechanism by which QT prolongation occurs in KSS is unknown. Hypokalemia and bradycardia are commonly present. However, torsades de pointes had been reported in patients with normal potassium serum levels, and in patients with a pacemaker 67, 69. In one case there was coinheritance of KSS mitochondrial deletion

b

d

Fig.  19.14  Two patients with Kearns-Sayre syndrome:(a)15-years old male patient with an apathetic facies, bilateral ptosis and ophtalmoplegia; (b) “Red-free” retinography showing retinal atrophy and choriocapillaris of the posterior pole; (c) 30

years-old female patient with a marked bilateral ptosis unable to raise the eyelids; (d) Color retinography showing pigmentary mottling of the retina (“salt and pepper pattern”) (modified from ref. 61)

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and a cardiac channelopathy, KCNQ1 P630A 72. A mitochondrial mutation was per si associated with abnormal repolarization 73. One may postulate that the mitochondrial failure in KSS may exacerbate the dysfunction of the cardiac potassium channel. Clinical implications: As far as mtDNA analysis is concern, it should be included in the working-up of familial as well as sporadic cases of HCM, especially when hypertrophy is symmetrical or when the family history is consistent with maternal inheritance. It is estimated that 25% of children with mitochondrial disorders will have cardiomyopathy 74. Is there a cardiological phenotype that we should recognize as “mitochondrial”?. Hypertrophic, non-obstructive cardiomyopathy appears to be the most consistent finding, although dilated cardiomyopathy is also reported. More information is needed to judge whether dilatation is simply a later stage in the process and whether the finding of concentric hypertrophy is sufficient to act as a trigger. In some patients the echocardiographic pattern shows a restrictive pattern, consistent with an infiltrative pathology (like amyloid) 75. Cardiomyopathy can be the first feature of mitochondrial disease. In many instances, however, deafness, a resting metabolic acidosis, short stature with or without diabetes, and a positive family history may be sufficient to alert one to the possibility of a mitochondrial etiology. Another question concerns the choice of cardiological investigation in patients that have defined mitochondrial respiratory chain (MRC) disease?. A chest X-ray and ECG are relatively minor and simple tests, but may not show early signs of hypertrophy. It seems reasonable that all patients with defined MRC disease should be referred for echocardiography. In case of absence of cardiac abnormalities it is advisable to repeat cardiac assessment periodically, because changes in clinical state can also occur quickly. The presence of cardiomyopathy carries a poor prognosis. Mortality among patients with no cardiac disease was 26% compared with 71% in those having cardiomyopathy 76. Patients with symptoms at younger age and cytochrome oxidase deficiency did the worst of all, with 100% mortality and 75% dying of cardiac causes. These figures mean that for those who care for patients with mitochondrial disorders must be alert to the possibility of subclinical disease. Once the disease is detected, these cases must be monitored carefully.

E. B. Sternick

19.7 Approaching the Child with Suspicion of Having an Inborn Error of the Metabolism (IEM) 77 There are very few pathognomonic cardiac features associated with cardiomyopathy due to IEM, such as the short PR interval (and delta wave) with huge QRS voltages characteristic of the ECG of Pompe disease. The correct diagnosis can be achieved by a number of physical and laboratorial findings. Patients with IEM involving impaired energy production or the accumulation of toxic metabolites often have signs and symptoms of multiple organ dysfunctions. Situations causing imbalance between available storage and demand of energy (like during acute illness, physical stress); patients with impaired energy metabolism are unable to maintain homeostasis, which may lead to hypoglycemia, metabolic acidosis, and/or hyperammonemia. Indications to screen for a biochemical abnormality include acute or chronic encephalopathy, muscle weakness, hypotonia, growth retardation, failure to thrive, recurrent vomiting, and lethargy. In contrast, patients with storage diseases who cannot degrade certain structural components of cells typically develop coarse or dysmorphic facial features, organomegaly, skeletal deformities, short stature, or chronic encephalopathy associated with a neurodegenerative course. Dysmorphic features characterize malformation syndromes as well as storage disorders, and therefore other minor and major malformations should also be sought. Skeletal muscle weakness without encephalopathy, although sometimes due to a disorder of the energy metabolism, may also indicate a primary neuromuscular disorder. In these patients, skeletal muscle weakness usually precedes cardiomyopathy and dominates the clinical picture. Occasionally, however, skeletal myopathy is subtle, and the first symptom of disease may be heart failure. The absence of associated clinical or biochemical abnormalities at presentation may signify an isolated cardiomyopathy disorder or alternatively the early manifestation of a multisystem disease that warrants investigation. Although in most cases, isolated cardiomyopathy is considered idiopathic, identifications of specific DNA mutations or protein abnormalities can help in etiologic identification. Endomyocardial biopsy may narrow the genetic differential diagnosis or provide evidence for a nongenetic cause. Not uncommonly,

19  Inherited Metabolic Diseases: Emphasis on Myocardial Disease and Arrhythmogenesis

clinical unsuspected cardiomyopathy is diagnosed at autopsy or by post mortem biochemical analysis.

19.7.1 Biochemical Abnormalities Presence of hypoglycemia, primary metabolic acidosis with an increased anion gap, or hyperammonemia should alert the physician to the possibility of a metabolic disorder. Blood and urine samples must be obtained as soon as possible after presentation, before initiation of any therapeutic measure, in sufficient amount to allow immediate tests and further specialized testing (from frozen specimens). Initial laboratory analysis should focus on determining which metabolic pathway is the most likely site of a biochemical defect. Normal infants and young children may become hypoglycemic, ketotic, and/or acidotic in response to oral intake during a severe illness. Hypoketotic hypoglycemia is a distinctly abnormal response and is the hallmark of a defect in fatty acid metabolism (free fatty acid levels are high, and insulin levels are low). Hyperketotic hypoglycemia is characteristic of defects in organic acid metabolism. However, the presence of ketones is nonspecific and can be associated with a high lactate level. Hypoketotic hypoglycemia can also occur in the insulin-excess states of BeckwithWiedemann syndrome, the infant of a diabetic mother, but are distinguished by low free fatty acid levels and characteristic clinical features. Further diagnostic assessment must distinguish between defects of fatty acid b-oxidation or of carnitine-dependent transport, and it can be accomplished assessing quantitative carnitine levels in blood, urine , and tissue; acylcarnitine profile in blood; urine organic acids (fatty acids, dicarboxylic and hydrocarboxylic acids), CPT, AST, ALT and CK. When metabolic acidosis with an increased anion gap is present, the identification of the organic acid in urine and/or blood responsible for the increased anion gap is often the key to diagnosis. The major metabolites of concern are free fatty acids, ketoacids, dicarboxylic acids, lactate, and pyruvate. When feasible, specific diagnoses should be confirmed by enzyme assay or DNA mutation analysis. Specialized laboratory testing may be necessary to identify metabolites that are diagnostic of an IEM. These tests include plasma acylcarnitine profile (tan-

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dem mass spectrometry, and urinary acylglycine analysis by stable isotope dilution and gas chromatography-mass spectroscopy. These tests can detect low levees of diagnostic metabolites in asymptomatic patients who have no gross biochemical changes in their blood or urine, making feasible an outpatient evaluation. Once a pattern of diagnostic metabolites has been identified, certain in vivo tests may be useful to confirm the diagnosis or to evaluate the benefits of therapy, include glucose loading for pyruvate dehydrogenase complex deficiency, medium- and long-chain triglyceride loading for fatty acid oxidation defects, and carnitine loading for systemic carnitine deficiency. These tests should be performed by metabolism specialists under closely monitored conditions, because they may precipitate an acute metabolic crisis and therefore are potentially hazardous.

19.7.2 Encephalopathy Encephalopathy, broadly defined as any alteration in brain function that leads to impaired mental status, development delay, coma, seizures, apnea, autonomic dysfunction, dystonia, or stroke-like episodes, can be important discriminating clinical feature in the evaluation of cardiomyopathy. The mechanisms for biochemical encephalopathy, probably include a combination of chronic and acute energy deprivation in the brain and an accumulation of toxic intermediate metabolites. Acute encephalopathy often occurs during a metabolic decompensation. It is characteristically seen in the mitochondrial syndromes MELAS (Mitochondrial Encephalopathy, Lactic acidosis, and Stroke-like episodes), MERRF (Myoclonic Epilepsy, Ragged Red Fibers), Kearns-Sayre syndrome, and Leigh disease. Acute worsening can occur in these syndromes in association with intercurrent illness or metabolic stressors. In general, the neurologic features predominate (epilepsy, stroke-like episodes, dementia, and ophtalmoplegia), and cardiomyopathy occurs late in clinical course. The diagnosis is based on measurement of blood and cerebrospinal fluid lactate and pyruvate levels, histological analysis of skeletal muscle, assay of respiratory chain enzymes, and/or mitochondrial DNA analysis. A neurodevelopment decline associated with valvar heart

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disease, coarse facies, organomegaly, skeletal deformities, or cloudy corneas suggests the possibility of an underlying lysosomal storage disease such as a mucopolysaccharidosis or mucolipidosis.

19.7.3 Pathological Findings Endomyocardial biopsies provide significant diagnostic information in cases of apparently idiopathic HCM and can be performed safely in children. Some of the features are specific for a particular group of disorders (e.g., glycogen storage diseases) or for a particular disease (Fabry´s disease). The presence of endomyocardial fibroelastosis, although nonspecific, usually indicates a poor prognosis. In addition, tissues other than the endomyocardium are frequently used to diagnose some disorders, particularly storage and mitochondrial disease and those characterized by the accumulation of neutral fat (e.g., skeletal muscle, liver, and occasionally skin).

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258 62. Berenberg RA, Pellock JM, DiMauroS, et al. Lumping or splitting? Ohptalmoplegia-Plus” or Kearns-Sayre syndrome? Ann Neurol. 1977;1:37–54 63. Zeviani M, Moraes CT, DiMauro S, et al. Deletions of mithocondrial DNA in Kearns-Sayre syndrome. Neurology. 1988;38:1339–1346 64. Gallastegui J, Hariman RJ, Handler B, et al. Cardiac involvement in Kearns-Sayre syndrome. Am J Cardiol. 1987;60:385-388 65. Charles R, Holt S, Kay JM, et al. Myocardial ultrastructure and the development of atrioventricular block in KearnsSayre syndrome. Circulation. 1981;63:214–219 66. Biard F, Philippe C, Berrut G, et al. Syndrome de KearnsSayre: bloc auriculoventriculaire complet, torsade de pointes et fibrillation ventriculaire (abstract). Ann Cardiol Angeiol. 1988;37:529–534 67. Rashid A, Kim MH. Kearns-Sayre syndrome: association with long QT syndrome? J Cardiovasc Electrophysiol. 2002; 13:184–185 68. Nakano T, Imanaka K, Uchida H, et al. Myocardial ultrastructure in Kearns-Sayre syndrome. Angiology. 1987;38:28–35 69. Subbiah RN, Kuchar D, Baron D. Torsades de pointes in a patient with Kearns-Sayre syndrome: a fortunate finding. Pacing Clin Electrophysiol. 2007;30:137–139 70. Lee KT, Lai WT, Lu YH. Atrioventricular block in KearnsSayre syndrome: a case report. Kaohsiung J Med Sci. 2001; 17:336–339

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Clinical Genetics in Congenital Heart Disease

20

Georgia Sarquella Brugada and Gregor Andelfinger

Cardiac malformations have an estimated prevalence of 4–50 per 1,000 live births and are the leading cause of death in infants less than 1 year of age.1 These values may be underestimated owing to underdiagnosed heart malformations such as bicuspid aortic valve or other asymptomatic congenital heart diseases (CHD), which contribute to cardiovascular morbidity and mortality in adulthood. Recent advances in medical and surgical care of children with CHD have led to increasing survival into adulthood, reversing the demographics of the patient population. At the time of the Bethesda Conference in 2000, the size of the adult population with CHD already exceeded that of the pediatric CHD population.2 From this change arise clear recommendations for the clinical care of both the pediatric and adult CHD patients, making multidisciplinary teams of pediatric cardiologist, adult cardiologist, cardiovascular surgeons, internists, and obstetricians imperative.3 As an example, these teams are increasingly faced with questions of adult CHD patients about recurrence risks for their own children (Table 20.1). Classically, congenital heart malformations were considered multifactorial in origin caused by the interaction of various undetermined genetic and environmental factors.4-6 Traditional models to explain the occurrence of CHD included many epidemiological factors, such as exposure to teratogens, prenatal infections, seasonal incidence, or sex ratios. Heart malformations were mostly explained outside of genetic contexts, i.e., on the basis of sporadic occurrence, with the exception of syndromic cases and the very rare G. S. Brugada (*) Service of Cardiology. Department of Pediatrics. CHU Sainte Justine, University of Montreal, Canada e-mail: [email protected]

families exhibiting classic Mendelian inheritance. This notion has evolved greatly over the two last decades, sparked by the Baltimore Washington Infant Study, a large regional case-control study carried out in a defined Mid-Atlantic region of the United States from 1981 to 1989.7 This study clearly showed familial clustering as well as an increased incidence of karyotype anomalies for many heart malformations. Over the past 10 years, molecular genetics studies have demonstrated that the genetic contribution to CHD has been significantly underestimated in the past.8 In any CHD clinic, there is a widespread variety of patients: from the fetus – when cardiac malformation has been diagnosed in utero − to the newborn and adult with CHD, with or without other concomitant noncardiac abnormalities and very heterogeneous outcomes even for morphologically similar lesions. Parental counseling is of particular importance when CHD was diagnosed in prior pregnancies or one of the progenitors is affected with a cardiac malformation.9 This chapter provides a short overview on the genetic aspects of clinical problems in CHD, with an emphasis on nonsyndromic CHD patients. For further details, the interested reader may also consult a recent consensus statement 10 or a textbook of genetics in particular for cases with a syndromic phenotype. The genetic makeup of any two individuals differs greatly, and numerous techniques are used in the search for genetic anomalies contributing to congenital heart defects. Standard karyotype analysis still is a cornerstone of genetic analysis as a first screening test and informs about the number of chromosomes, for example, to rule out trisomy (21, 13, and 18) or monosomy (Turner syndrome). A more sensitive test, high-resolution banding karyotype, analyzes chromosomal structural abnormalities such as duplications, translocations, or deletions. More advanced cytogenetic techniques, such

R. Brugada et al. (eds.), Clinical Approach to Sudden Cardiac Death Syndromes, DOI: 10.1007/978-1-84882-927-5_20, © Springer-Verlag London Limited 2010

259

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G. S. Brugada and G. Andelfinger

Table 20.1  Risk of recurrence in offspring of parents who have CHD 61,62 CHD Risk to offspring (%) from Mother

Father

Atrio-ventricular septal defect

7.9–11.6

4.3–7.7

Aortic stenosis

8

3.8

Coarctation of the aorta

6.3

3.0

Pulmonary stenosis

5.3

3.5

Atrial septal defect

6.1

3.5

Ventricular septal defect

6.0

3.6

Persistent ductus arteriosus

4.1

2.0

Tetralogy of Fallot

2.0

1.4

Anomalous pulmonary venous drainage

5.9

Abnormal situs and misconnections

7.1

15.4

All CHDs

5.8

3.1

as FISH (fluorescence in situ hybridization), diagnose more subtle structural abnormalities such as submicroscopic deletions/duplications – hence the term microdeletion/duplication – and subtle translocations. Finally, DNA mutation analysis can provide specific information concerning changes in the coding sequence of a gene. The technical armamentarium of genetic analysis is evolving at a very rapid pace, and it is to be expected that new technologies will find their way into clinical practice over the coming years. In particular, array-based techniques can provide molecular karyotypes at a very high resolution not achievable with any microscopic method, and will most likely complement or replace standard karyotype analysis in the near future. This approach can identify small chromosomal aberrations, in which the copy number of a gene deviates from the normal copy number of 2 for all autosomal genes and X-chromosomal genes in females and 1 for all X-chromosomal genes in males. This leads to a structural variation in the genome – termed copy number variation or CNV – which can contribute to congenital heart disease.11 Once anomalies are found in a CHD patient using one of the techniques named earlier, a causative link to the disease can be established using previously defined criteria. From a genetic standpoint, any genetic variation found in a CHD patient should be predicted to change or abolish the function of a gene and cosegregate with disease in other affected family members. Unaffected controls should not exhibit the same variation. In addition to the

literature searches, databases containing information on mutations and normal or pathologic structural variation now facilitate the search for previously detected normal or pathologic variants,12 (https://decipher. sanger.ac.uk/). Up-to-date information on gene tests has been made more readily accessible at publicly funded websites (www.genetests.org). DNA for subsequent genetic studies is routinely obtained from lymphocytes in peripheral blood. For ease of sampling and shipping, DNA can also be sampled in high quality from saliva self-collection kits.13 Other sources include cord blood, skin, or other tissues. In prenatal diagnostics, amniotic fluid cells are commonly used, but for early diagnosis, chorionic villous sampling is preferred. In eventual cases when preimplantation selection of embryos has to be performed, genetic diagnosis can be provided by blastocyst analysis.

20.1 Genetic Basis in CHD: Clinical Implications On the basis of our knowledge of cardiac development in the mouse as well as insight from human studies, single gene defects can cause isolated heart defects as well as recognizable syndromes. Also, the phenotypic consequences of a given gene defect may vary greatly between different affected individuals, a phenomenon termed variable expressivity. As an example, mutations

20  Clinical Genetics in Congenital Heart Disease

in the cardiac transcription factor Nkx2.5 have been linked to atrial septal defect, Tetralogy of Fallot, and AV-block.14,15 Also, some mutation carriers are asymptomatic, a phenomenon termed reduced penetrance. Therefore, in each patient newly diagnosed with CHD, a thorough three-generation family history should be obtained. Increasing use of echocardiography and other diagnostic means in family members of CHD patients, in particular those with left-sided lesions, shows that the incidence of subclinical CHD may have been underestimated in the past.16,17 The algorithm presented in Fig. 20.1 will help one to extract a maximum amount of information and to keep the increase in clinical workload within reasonable limits.

20.2 Decision Trees for Cardiac Defects 20.2.1 Known Chromosomal Aberrations Many recognizable aneuploidy syndromes exist, of which trisomies 13, 18, and 21, DiGeorge, and Turner

Fig. 20.1  Decisional tree for the work-up of a nonsyndromic CHD patient. Lesions with high recurrence rates include in particular left-sided obstructive lesions and atrial septal defect

261

syndrome are of particular importance for the pediatric cardiologist and general practitioner. Trisomy 13 (Patau syndrome) is characterized by ASD, VSD, PDA, hypoplastic left heart syndrome, and laterality defects. Extracardiac malformations include polydactyly, cleft lip/palate, malformations of the eye and the brain, profound mental retardation, and malformations of the urogenital tract. Eighty percent of the children die within the first year of life. Infants born with trisomy 18 (Edwards syndrome) exhibit ASD, VSD, PDA, Tetralogy of Fallot, doubleoutlet right ventricle, d-TGA, coarctation, and semilunar valve dysplasia. Extracardiac features include kidney malformations, omphalocele/diaphragmatic hernia, esophageal atresia/tracheoesophageal fistula, severe mental retardation, developmental delays, growth deficiency, feeding difficulties, breathing difficulties, arthrogryposis, short sternum, and overlapping digits. Trisomy 21 (Down syndrome) is characterized by septal defects in approximately 50% of cases, with atrioventricular septal defects or other septal defects being the most common, and Tetralogy of Fallot occurring in approximately 6% of cases.18 Extracardiac features include hypotonia, epicanthic folds, palmar and plantar simian creases, and mental retardation. In DiGeorge syndrome (microdeletion 22q11), typical cardiac lesions include isolated and complex aortic arch anomalies, such as right aortic arch and interrupted aortic arch type B, truncus arteriosus, Tetralogy of Fallot, and conoventricular VSD. Key extracardiac features are hypertelorism, micrognathia, immunodeficiency due to thymus hypoplasia/aplasia, hypoparathyroidism, velopharyngeal insufficiency, palate malformations, cognitive and language impairments, hearing loss, and renal and skeletal anomalies (Fig.20.2). Microdeletion 22q11 is inherited in 5–10% of all cases19 and testing should be offered to parents and siblings of affected children owing to the very broad range of phenotypes observed in this condition. Turner syndrome (monosomy X; 45,X) is associated with various left-sided heart lesions such as bicuspid aortic valve, aortic stenosis, coarctation, hypoplastic left heart syndrome, as well as aortic dissection. Partial anomalous pulmonary venous drainage has been observed in Turner syndrome. Extracardiac features can be subtle and include lymphedema (in particular, of the feet at birth), widely spaced nipples, pterygium (webbed neck), and short stature. Primary amenorrhea is also present. Intelligence is normal in Turner syndrome.

262

Fig. 20.2  Typical facial traits in DiGeorge syndrome: long face and tubular shaped nose, micrognathia, mild hypertelorism, hooded eyelids, and cleft palate (Netter images)

When should a child undergo cytogenetic studies? In addition to the characteristic phenotypes of aneuploidy described earlier, karyotyping should be considered in any infant with CHD with complex congenital heart disease, multiple congenital anomalies, unexplained growth retardation, or developmental impairment. Also, a family history of multiple cases of birth defects or multiple miscarriages should prompt further molecular investigation. It can be anticipated that molecular karyotyping will become the mainstay of diagnosis in such cases. Results of such studies can inform both the family and the medical team and help to tailor treatment strategies. The medical needs of children with congenital heart disease and a chromosomal aberration are complex. Care is best coordinated by the child’s primary physician and a geneticist, with special attention to the following: • Developmental impairment: delays in developmental milestones are frequent and can often be alleviated by early intervention, such as ergotherapy and physiotherapy. Special needs may exist for schooling. Regular developmental testing can identify progress and specific areas for assistance.

G. S. Brugada and G. Andelfinger

• Endocrinology: children with Trisomy 21 (associated with hypothyroidism) and microdeletion 22q11 (hypoparathyroidism) often need follow-up and treatment. Short stature may be treatable in some instances. • Cleft palate and feeding: children with a microdeletion 22q11 often suffer from velopharyngeal insufficiency (often manifest as nasal discharge during feeding) and palatal malformations, even in the absence of overt cleft palate. However, specialized intervention often is beneficial and can improve feeding as well as language development. • ENT and audiology: palatal problems and frequent ear infections can predispose to hearing loss, leading to further language impairment; evaluation should be undertaken jointly with a cleft palate team. • Hematology/Immunology: children with Trisomy 21 (increased incidence of leukemia) and DiGeorge syndrome (immune dysfunction) require careful evaluation of hematologic parameters. • The index of suspicion to involve other medical specialists in the care of these children with complex disease should be low. Those specialists may include orthopedists (atlantoaxial instability in Trisomy 21; scoliosis and foot problems in DiGeorge syndrome), neurologists, and urologists (frequent urinary tract infections due to malformations of the urogenital tract).

20.2.2 Specific Cardiac Lesions The following section focuses on certain cardiac malformations, and the association with other abnormalities that should be ruled out.

20.2.3 Pulmonary Outflow Obstruction 20.2.3.1 Pulmonary Valve Stenosis Noonan Syndrome Noonan syndrome occurs in 1 per 1,000–2,500 live births that includes short stature, typical facial dimorphism (Fig.20.3), thorax deformity, bleeding diathesis, cryptorchidism, developmental delay, and cardiovascular

20  Clinical Genetics in Congenital Heart Disease

263

LEOPARD Syndrome Multiple malformation disorder including multiple Lentigines, Electrocardiographic disturbances, Ocular hypertelorism, Pulmonary stenosis, Abnormal genitalia, Retardation on growth, and neurosensorial Deafness. Mutations in PTPN11 and RAF1 have been described in LEOPARD syndrome, underscoring the allelic spectrum of these two entities.25

20.2.3.2 Pulmonary Artery Branch Stenosis Alagille Syndrome

Fig. 20.3  Typical facial traits in Noonan syndrome: triangular face shape, broad forehead, posterior rotated ears, blue-green irides, epicanthal eye folds, short webbed neck

abnormalities (typically pulmonary valve stenosis and hypertrophic cardiomyopathy, but also ASD, AVSD, mitral valve abnormalities, aortic coarctation, and Tetralogy of Fallot) among others. Typically, pulmonary stenosis in Noonan syndrome is associated with dysplastic pulmonary valve. Detailed family history is mandatory in this syndrome, since autosomal dominant transmission occurs in up to 25% of cases. Four genes have been associated with Noonan syndrome (PTPN11, SOS1, KRAS, and RAF1).20-23 PTPN11 mutations account for 50% of cases and are more likely to be associated with pulmonary stenosis than with hypertrophic cardiomyopathy.

Costello Syndrome This is a rare sporadic syndrome that associates pulmonary stenosis or hypertrophy cardiomyopathy with failure to thrive, mental retardation, and typically thick lips. Mutations in HRAS gene have been described, and phenotypic and molecular overlap with Noonan syndrome, caused by mutations in PTPN11, has been noted.24

Autosomal dominant disorder typically associated with peripheral pulmonary hypoplasia, but also with Tetralogy of Fallot and pulmonary valve stenosis.26 Variable incidence of cholestasis can be seen owing to paucity of intrahepatic bile ducts, as well as ophthalmologic affectation (anterior chamber defects, pigmentary retinal anomalies, posterior embryotoxon), vertebral anomalies, bleeding diathesis, and renal affectation. Patients suspected of having Alagille syndrome should be screened with FISH analysis for 20q12 microdeletion,27 and mutations in JAG1 gene.28 More than 50% of cases arise from de novo mutations, which is important for familial counseling.

Other Entities That Can Associate Peripheric Pulmonary Stenosis Congenital rubella, Ehler–Danlos syndrome, Noonan syndrome, and LEOPARD syndrome.

20.2.4 Left Ventricular Outflow Tract Obstructions Left ventricular outflow tract obstructions encompass a wide spectrum of disease ranging from bicuspid aortic valve to aortic stenosis to hypoplastic left heart syndrome. Evidence for a strong genetic basis for these disorders comes from several studies, which have shown high heritability and high recurrence rates of disease among family members in these disorders.17,29-32 To date, several chromosomal regions have been

264

G. S. Brugada and G. Andelfinger

implicated in these disorders. Taken together, LVOTO most likely is an oligogenic trait, in which several rare genetic factors interact in disease pathogenesis. In all females with aortic valve disease or coarctation, signs of Turner syndrome should be carefully evaluated.

20.2.4.1 Bicuspid Aortic Valve Bicuspid aortic valve is by far the most common congenital heart malformation and occurs in 1–2% of the general population. Strong underlying genetic factors and familial clustering have been described and should prompt detailed family history and echocardiographic screening of all first-degree relatives.33

20.2.4.2 Aortic Valve Stenosis Mutations in NOTCH1 have been described and most likely contribute to disease in up to 5% of patients.34 Clinical genetic testing is currently not available. Rare chromosomal rearrangements have been described in aortic stenosis. Owing to the high recurrence of other LVOTO cases, sequential evaluation of other family members is highly recommended.

20.2.4.3 Aortic Atresia/Hypoplastic Left Heart Syndrome Echocardiographic studies with systematic workup of families ascertained from hypoplastic left heart index cases show that more than one individual is affected in more than 50% of the cases. Inheritance patterns point toward a complex trait with strong familial clustering. Familiar screening is highly recommended and reveals high rates of bicuspid aortic valve. Deletions of 11q (Jacobsen syndrome), Turner syndrome, Trisomies 13 and 18, and deletion of 4p have been described in hypoplastic left heart syndrome.35-39

Figure 20.4  Typical facial traits in Williams syndrome: short nose, full nasal tip, midface hyoplasia, long philtrum, full lips, wide mouth, and prominent ear lobes (courtesy of Williams ­syndrome association)

elfin face, social personality, connective tissue abnormalities, hypercalcemia with subsequent nephrocalcinosis, and with systemic hypertension and thyroid disorders (Fig.  20.4). Supraaortic stenosis often progresses over time, which is not the case for supravalvular pulmonary stenosis. The microdeletion 7q11.23 encompasses the elastin gene, which causes the cardiovascular phenotype. Adjacent genes contribute to the extracardiac phenotype.40,41 Nonsyndromic supravalvar aortic stenosis is caused by mutations in the elastin gene and can occur with an autosomal dominant inheritance pattern.

20.2.5 Atrial Septal Anomalies

20.2.4.4 Supravalvular Stenosis

20.2.5.1 Secundum ASD

Williams–Beuren Syndrome

Atrial septal defects can occur both as sporadic and familial cases. Familial screening is recommended since recurrence rates are high.42 Autosomal dominant forms without atrioventricular block have been associated with

Williams–Beuren syndrome is caused by a microdeletion on chromosome 7q11.23. It is associated with

20  Clinical Genetics in Congenital Heart Disease

mutations in GATA4, MYH6, and ACTC1.43,44 In cases caused by GATA4 mutations, pulmonary stenosis and VSD have been noted. Autosomal dominant forms with progressive atrioventricular block and other cardiovascular malformations, in particular Tetralogy of Fallot, have been associated with mutations in NKX2.5.15,45

265

(Rubinstein–Taybi, Kabuki, Williams, Goldenhar, VACTERL, Costello, Cornelia de Lange, Alpert, and Carpenter). From a clinical standpoint, genetic testing for a microdeletion 22q11 should be performed in all conotruncal VSDs and VSDs associated with aortic arch anomalies (Table 20.2).

Holt–Oram Syndrome

20.2.7 Atrioventricular Septal This is an autosomal dominant syndrome, associating Abnormalities: AVSD, septal defects (ASD, VSD) with preaxial limb defects Partial or Complete and alterations on the thumbs. Mutations of TBX5 have been identified in 74% of patients.46-48

Others Numerous chromosomal abnormalities have been noted in ASD, including deletions of 1, 4, 4p, 5p, 6, 10p, 11, 13, 17, 18, and 22, trisomy 18 and 21, and Klinefelter syndrome. ASD can be part of polymalformative syndromes, both known (Rubinstein–Taybi, Kabuki, Williams, Goldenhar, thrombocytopenia – absent radius and Marfan) and unknown.49

20.2.7.1 Chromosome Abnormalities Isolated partial or complete AVSD has been described to recur within families, and an autosomal dominant form of this entity can be caused by mutations in CRELD1.52 Concordance of the phenotype is high in families with multiple members affected by AVSD. Karyotyping is recommended, since chromosomal anomalies have been recognized in a large number of patients, including trisomies 13, 18, and 21, as well as several deletions/duplications and more complex rearrangements. Atrioventricular septal defects have also emerged to be part of the disease spectrum in Noonan syndrome.53

20.2.5.2 Single Atrium Ellis–van Creveld Syndrome This rare syndrome associates defects of primary atrial septation, most commonly a single atrium, with short limbs and ribs, postaxial polydactyly, prenatal tooth eruption, and fingernail dysplasia. Mutations in genes EVC and EVC2, both located head-to-head on chromosome 4p16, have been described.50,51

20.2.6 Ventricular Septal Abnormalities

20.2.8 Conotruncal Defects 20.2.8.1 Tetralogy of Fallot Nonsyndromic Tetralogy of Fallot can be caused by mutations in NKX2.5 and FOG2, which together account for approximately 8% of cases.15,54 Mutations in JAG1 are usually associated with Alagille syndrome and branch pulmonary artery stenosis.28 Microdeletion 22q11 has to be excluded in all patients with Tetralogy of Fallot.

20.2.6.1 Ventricular Septal Defects Ventricular septal defects have been described in a variety of chromosomal abnormalities such as deletions, duplications, and trisomies (13, 18, and 21). Also, they can be part of polymalformative syndromes

20.2.8.2 Truncus Arteriosus/Interruption of the Aortic Arch Associated with chromosome abnormalities such as 22q11 deletion syndrome and trisomy 8 and 10p.55

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

CHD7

CHARGE

VATER acronym for vertebral defects, anal atresia, tracheoesophageal fistula with esophageal atresia, and radial dysplasia; VACTERL acronym for vertebral defects, cardiac anomalies, anal atresia, tracheoesophageal fistula, renal anomalies, and limb anomalies; CHARGE acronym for coloboma of the eye, heart anomaly, atresia, choanal, retardation of mental and somatic development, microphallus, and ear abnormalities or deafness. VSD ventricular septal defect. ASD atrial septal defect. AV-block atrioventricular block. Syndromic genetic defects

Yes

Yes

Supravalvular

Pulmonary stenosis

Yes

Yes

Yes

Yes

Yes

Yes

Yes

yes

Yes(supravalvular)

Yes

Yes

Yes

RAS cascade(PTPN11, SOS1, KRAS, RAF1)

Aortic stenosis/ yes hypoplastic left heart syndrome

Atrioventricular canal defects

Transposition of the great arteries

Ebstein

Tetralogy of Fallot

Yes

Yes

VSD

AV-block

Yes

ASD

Microdeleion 7q11

JAG1

Microdeletion 22q11

TBX5

Trisomy 21

Genetic cause

45,X

Alagille

Holt-Oram

Table 20.2  Compilation of several clinically important syndromic genetic defects associated with congenital heart disease. Turner Down DiGeorge Williams Noonan VATER/VACTERL syndrome

266 G. S. Brugada and G. Andelfinger

20  Clinical Genetics in Congenital Heart Disease

267

20.2.8.3 Transposition of Great Arteries

Visceral abnormalities include asplenia, symmetrical liver, gastrointestinal malrotation, and others (genitourinary, bronchopulmonary, axial skeletal, and central nervous systems abnormalities).

Chromosome abnormalities such trisomy 18 and 21, rarely 22q11 deletion syndrome, and others are observed in the transposition of great arteries. Mutations in PROSIT240 have been also described.56

20.2.11.2 Polysplenia or Left Atrial Isomerism 20.2.8.4 Double-Outlet Right Ventricle Chromosome abnormalities such as trisomies 9, 13, and 18, duplication of 2p, 12p, and rarely 22q11 deletion syndrome have been associated with this malformation.

20.2.9 Tricuspid Atresia and Ebstein Anomaly Even though most cases are sporadic, series of familiar clustering have been reported in association with conotruncal malformations.

20.2.10 Total Anomalous Pulmonary Venous Return Even though most cases are sporadic, series of familiar clustering have been reported, in association with scimitar syndrome.

20.2.11 Laterality Defects (Heterotaxy, Asplenia/Polysplenia) Several genes have been linked to laterality defects; they include LEFTYA (1q14),55 ACVR2B (3p22),56 CFC1 (2q21),57 NODAL (10q22),58 and ZIC3 (Xq26),59 the latter one causing X-linked situs anomalies.57,59

20.2.11.1 Asplenia or Right Atrial Isomerism In these cases, usually numerous other cardiovascular malformations are associated, such as conotruncal defects, AVSD, and inferior vena cava abnormalities.

In these cases, associated cardiac malformations include septal defects, interrupted inferior vena cava, bilateral superior vena cava, and partial anomalous pulmonary venous return. Visceral abnormalities include polysplenia, gastrointestinal malrotation, inverted liver, extra hepatic biliary atresia, and others (genitourinary, bronchopulmonary, axial skeletal, and central nervous system abnormalities) (Table 20.3).

20.3 Conclusion With improved interventional and surgical techniques, patients with congenital heart disease survive to adulthood and reproductive age. High index of suspicion is required to ascertain other family members affected with congenital heart disease. As an example, many families will not perceive aortic valve replacement due to a bicuspid valve in adulthood as a congenital disease, since it may become manifested only at a later age. Increasing knowledge of genetic factors causative in these lesions can improve management by anticipating possible problems and stratification of therapies. Genetic counseling can help patients and families to make informed choices in this process. Since genetic information has important consequences for privacy, insurability, and relationships, the pros and cons of testing have to be carefully weighed. No clinical genetic testing is indicated in minors if there is no evidence for an individual benefit. Genetic information also has the potential to harm; it can stigmatize or bring unwanted information, such as pertaining to future reproductive risks and decision-making.60 On the other hand, the sole knowledge of the cause of disease can come as a great relief to parents and families. The field of genetic testing in congenital heart disease has only started to emerge, and we anticipate that over the coming years, genetic research studies will greatly increase our current diagnostic armamentarium. In analogy to the progress made in the fields of

Yes

Yes

Yes

Yes

No

No

Yes

VSD

AV-block

Tetralogy of fallot

Ebstein

Transposition of the great arteries

Atrioventricular canal defects

Aortic stenosis/ hypoplastic left heart syndrome

Yes

Yes

Yes

DORV

Yes

Yes

Yes

Note the wide phenotypic spectrum for allelic conditions

Other

Yes

ASD

Yes

Yes

Yes

Table 20.3  Compilation of phenotypes caused by selected cardiac specific genes. Nkx2.5 GATA4 GDF1 Notch1 Prosit240

Tricuspid atresia

Yes

FOG2

Yes

Yes

Yes

Yes

Cited2

Yes

ACTC1

Hypertrophic and dilated cardiomyopathy

Yes

Myh6

Yes

CRELD1

268 G. S. Brugada and G. Andelfinger

20  Clinical Genetics in Congenital Heart Disease

hypertrophic cardiomyopathy and arrhythmia, it can be expected that therapeutic stratification and targeted intervention will be greatly improved once the underpinnings of cardiac malformations are understood at molecular level.

References   1. Hoffman JI. Congenital heart disease: Incidence and inheritance. Pediatr Clin North Am. 1990;37:25–43   2. Williams RG, Pearson GD, Barst RJ, et  al. Report of the national heart, lung, and blood institute working group on research in adult congenital heart disease. J Am Coll Cardiol. 2006;47:701–707   3. Brickner ME, Hillis LD, Lange RA. Congenital heart disease in adults. First of two parts. N Engl J Med. 2000;342: 256–263   4. Gelb BD. Genetic basis of syndromes associated with congenital heart disease. Curr Opin Cardiol. 2001;16:188–194   5. Jenkins KJ, Correa A, Feinstein JA, et al. Noninherited risk factors and congenital cardiovascular defects: current knowledge: a scientific statement from the American Heart Association Council on cardiovascular disease in the young: Endorsed by the American Academy of Pediatrics. Circulation. 2007;115:2995–3014   6. Nora JJ. Multifactorial inheritance hypothesis for the etiology of congenital heart diseases. The genetic-environmental interaction. Circulation. 1968;38:604–617   7. Ferencz C, Rubin, JD, Loffredo,CA, Magee,CM. The epidemiology of congenital heart disease, the BaltimoreWashington Infant Study (1981–1989), New York/ MountKisco: Futura Publishing Co. Inc.; 1993   8. Schott JJ, Benson DW, Basson CT, et  al. Congenital heart disease caused by mutations in the transcription factor nkx2–5. Science. 1998;281:108–111   9. Welch KK, Brown SA. The role of genetic counseling in the management of prenatally detected congenital heart defects. Semin Perinatol. 2000;24:373–379 10. Pierpont ME, Basson CT, Benson DW Jr, et al. Genetic basis for congenital heart defects: current knowledge: a scientific statement from the American Heart Association Congenital Cardiac Defects Committee, Council on Cardiovascular Disease in the Young: Endorsed by the American Academy of Pediatrics. Circulation. 2007;115:3015–3038 11. Thienpont B, Mertens L, de Ravel T, et al. Submicroscopic chromosomal imbalances detected by array-cgh are a frequent cause of congenital heart defects in selected patients. Eur Heart J. 2007;28:2778–2784 12. Iafrate AJ, Feuk L, Rivera MN, et al. Detection of large-scale variation in the human genome. Nat Genet. 2004;36: 949–951 13. Rogers NL, Cole SA, Lan HC, Crossa A, Demerath EW. New saliva DNA collection method compared to buccal cell collection techniques for epidemiological studies. Am J Hum Biol. 2007;19:319–326 14. Benson DW, Silberbach GM, Kavanaugh-McHugh A, Cottrill C, Zhang Y, Riggs S, Smalls O, Johnson MC, Watson

269 MS, Seidman JG, Seidman CE, Plowden J, Kugler JD. Mutations in the cardiac transcription factor nkx2.5 affect diverse cardiac developmental pathways. J Clin Invest. 1999; 104:1567–1573 15. Goldmuntz E, Geiger E, Benson DW. Nkx2.5 mutations in patients with tetralogy of fallot. Circulation. 2001;104: 2565–2568 16. McBride KL, Pignatelli R, Lewin M, et al. Inheritance analysis of congenital left ventricular outflow tract obstruction malformations: Segregation, multiplex relative risk, and heritability. Am J Med Genet A. 2005;134A:180–186 17. Cripe L, Andelfinger G, Martin LJ, Shooner K, Benson DW. Bicuspid aortic valve is heritable. J Am Coll Cardiol. 2004; 44:138–143 18. Freeman SB, Bean LH, Allen EG, et al. Ethnicity, sex, and the incidence of congenital heart defects: a report from the national Down syndrome project. Genet Med. 2008;10: 173–180 19. Fernandez L, Lapunzina P, Pajares IL, Criado GR, GarciaGuereta L, Perez J, Quero J, Delicado A. Higher frequency of uncommon 1.5–2 mb deletions found in familial cases of 22q11.2 deletion syndrome. Am J Med Genet A. 2005;136: 71–75 20. Razzaque MA, Nishizawa T, Komoike Y, et  al. Germline gain-of-function mutations in raf1 cause noonan syndrome. Nat Genet. 2007;39:1013–1017 21. Tartaglia M, Pennacchio LA, Zhao C, et al. Gain-of-function sos1 mutations cause a distinctive form of Noonan syndrome. Nat Genet. 2007;39:75–79 22. Roberts AE, Araki T, Swanson KD, et al. Germline gain-offunction mutations in sos1 cause Noonan syndrome. Nat Genet. 2007;39:70–74 23. Jamieson CR, van der Burgt I, Brady AF, et al. Mapping a gene for Noonan syndrome to the long arm of chromosome 12. Nat Genet. 1994;8:357–360 24. Kerr B, Delrue MA, Sigaudy S, et al. Genotype-phenotype correlation in Costello syndrome: Hras mutation analysis in 43 cases. J Med Genet. 2006;43:401–405 25. Schubbert S, Bollag G, Shannon K. Deregulated ras signaling in developmental disorders: New tricks for an old dog. Curr Opin Genet Dev. 2007;17:15–22 26. McElhinney DB, Krantz ID, Bason L, et al. Analysis of cardiovascular phenotype and genotype-phenotype correlation in individuals with a jag1 mutation and/or alagille syndrome. Circulation. 2002;106:2567–2574 27. Krantz ID, Rand EB, Genin A, et al. Deletions of 20p12 in alagille syndrome: Frequency and molecular characterization. Am J Med Genet. 1997;70:80–86 28. Warthen DM, Moore EC, Kamath BM, et al. Jagged1 (jag1) mutations in alagille syndrome: Increasing the mutation detection rate. Hum Mutat. 2006;27:436–443 29. Hinton RB Jr, Martin LJ, Tabangin ME, Mazwi ML, Cripe LH, Benson DW. Hypoplastic left heart syndrome is heritable. J Am Coll Cardiol. 2007;50:1590–1595 30. McBride KL, Zender GA, Fitzgerald-Butt SM, Koehler D, Menesses-Diaz A, Fernbach S, Lee K, Towbin JA, Leal S, Belmont JW. Linkage analysis of left ventricular outflow tract malformations (aortic valve stenosis, coarctation of the aorta, and hypoplastic left heart syndrome). Eur J Hum Genet. 2009 Jun; 17(6): 811-9 31. McBride KL, Marengo L, Canfield M, Langlois P, Fixler D, Belmont JW. Epidemiology of noncomplex left ventricular

270 outflow tract obstruction malformations (aortic valve stenosis, coarctation of the aorta, hypoplastic left heart syndrome) in texas, 1999–2001. Birth Defects Res A Clin Mol Teratol. 2005;73:555–561 32. Loffredo CA, Chokkalingam A, Sill AM, et al. Prevalence of congenital cardiovascular malformations among relatives of infants with hypoplastic left heart, coarctation of the aorta, and d-transposition of the great arteries. Am J Med Genet A. 2004;124A:225–230 33. Huntington K, Hunter AG, Chan KL. A prospective study to assess the frequency of familial clustering of congenital bicuspid aortic valve. J Am Coll Cardiol. 1997;30:1809–1812 34. Garg V. Molecular genetics of aortic valve disease. Curr Opin Cardiol. 2006;21:180–184 35. Tennstedt C, Chaoui R, Korner H, Dietel M. Spectrum of congenital heart defects and extracardiac malformations associated with chromosomal abnormalities: Results of a seven year necropsy study. Heart. 1999;82:34–39 36. Gembruch U, Baschat AA, Knopfle G, Hansmann M. Results of chromosomal analysis in fetuses with cardiac anomalies as diagnosed by first- and early second-trimester echocardiography. Ultrasound Obstet Gynecol. 1997;10: 391–396 37. van Egmond H, Orye E, Praet M, Coppens M, DevlooBlancquaert A. Hypoplastic left heart syndrome and 45x karyotype. Br Heart J. 1988;60:69–71 38. Natowicz M, Kelley RI. Association of turner syndrome with hypoplastic left-heart syndrome. Am J Dis Child. 1987; 141:218–220 39. Velinov M, Gu H, Yeboa K, et al. Hypoplastic left heart in a female infant with partial trisomy 4q due to de  novo 4;21 translocation. Am J Med Genet. 2002;107:330–333 40. Ewart AK, Morris CA, Atkinson D, et al. Hemizygosity at the elastin locus in a developmental disorder, williams syndrome. Nat Genet. 1993;5:11–16 41. Wu YQ, Nickerson E, Shaffer LG, Keppler-Noreuil K, Muilenburg A. A case of williams syndrome with a large, visible cytogenetic deletion. J Med Genet. 1999;36:928–932 42. Caputo S, Capozzi G, Russo MG, et al. Familial recurrence of congenital heart disease in patients with ostium secundum atrial septal defect. Eur Heart J. 2005;26:2179–2184 43. Ching YH, Ghosh TK, Cross SJ, et al. Mutation in myosin heavy chain 6 causes atrial septal defect. Nat Genet.. 2005; 37:423–428 44. Matsson H, Eason J, Bookwalter CS, et  al. Alpha-cardiac actin mutations produce atrial septal defects. Hum Mol Genet. 2008;17:256–265 45. Garg V, Kathiriya IS, Barnes R, et al. Gata4 mutations cause human congenital heart defects and reveal an interaction with tbx5. Nature. 2003;424:443–447 46. McDermott DA, Bressan MC, He J, et al. Tbx5 genetic testing validates strict clinical criteria for holt-oram syndrome. Pediatr Res. 2005;58:981–986 47. Li QY, Newbury-Ecob RA, Terrett JA, et al. Holt-oram syndrome is caused by mutations in tbx5, a member of the brachyury (t) gene family. Nat Genet. 1997;15:21–29

G. S. Brugada and G. Andelfinger 48. Basson CT, Bachinsky DR, Lin RC, et  al. Mutations in human tbx5 [corrected] cause limb and cardiac malformation in holt-oram syndrome. Nat Genet. 1997;15:30–35 49. Newbury-Ecob RA, Leanage R, Raeburn JA, Young ID. Holt-oram syndrome: A clinical genetic study. J Med Genet.. 1996;33:300–307 50. Ruiz-Perez VL, Tompson SW, Blair HJ, et al. Mutations in two nonhomologous genes in a head-to-head configuration cause ellis-van creveld syndrome. Am J Hum Genet. 2003; 72:728–732 51. Ruiz-Perez VL, Ide SE, Strom TM, et al. Mutations in a new gene in ellis-van creveld syndrome and weyers acrodental dysostosis. Nat Genet. 2000;24:283–286 52. Robinson SW, Morris CD, Goldmuntz E, et  al. Missense mutations in creld1 are associated with cardiac atrioventricular septal defects. Am J Hum Genet. 2003;72:1047–1052 53. Marino B, Digilio MC, Toscano A, Giannotti A, Dallapiccola B. Congenital heart diseases in children with noonan syndrome: an expanded cardiac spectrum with high prevalence of atrioventricular canal. J Pediatr. 1999;135:703–706 54. Pizzuti A, Sarkozy A, Newton AL, et al. Mutations of zfpm2/ fog2 gene in sporadic cases of tetralogy of fallot. Hum Mutat. 2003;22:372–377 55. Takahashi K, Kido S, Hoshino K, Ogawa K, Ohashi H, Fukushima Y. Frequency of a 22q11 deletion in patients with conotruncal cardiac malformations: A prospective study. Eur J Pediatr. 1995;154:878–881 56. Muncke N, Jung C, Rudiger H, et  al. Missense mutations and gene interruption in prosit240, a novel trap240-like gene, in patients with congenital heart defect (transposition of the great arteries). Circulation. 2003;108:2843–2850 57. Bamford RN, Roessler E, Burdine RD, Saplakoglu U, dela Cruz J, Splitt M, Goodship JA, Towbin J, Bowers P, Ferrero GB, Marino B, Schier AF, Shen MM, Muenke M, Casey B. Loss-of-function mutations in the egf-cfc gene cfc1 are associated with human left-right laterality defects. Nat Genet. 2000;26:365–369 58. Mohapatra B, Casey B, Li H, Ho-Dawson T, Smith L, Fernbach SD, Molinari L, Niesh SR, Jefferies JL, Craigen WJ, Towbin JA, Belmont JW, Ware SM. Identification and functional characterization of nodal rare variants in heterotaxy and isolated cardiovascular malformations. Hum Mol Genet. 2008;18:861–871 59. Schon P, Tsuchiya K, Lenoir D, et al. Identification, genomic organization, chromosomal mapping and mutation analysis of the human inv gene, the ortholog of a murine gene implicated in left-right axis development and biliary atresia. Hum Genet. 2002;110:157–165 60. Clayton EW. Ethical, legal, and social implications of genomic medicine. N Engl J Med.. 2003;349:562–569 61. Burn J, Brennan P, Little J, et al. Recurrence risks in offspring of adults with major heart defects: Results from first cohort of British collaborative study. Lancet. 1998;351:311–316 62. Nora JJ. From generational studies to a multilevel geneticenvironmental interaction. J Am Coll Cardiol. 1994;23: 1468–1471

Part Polygenic cardiovascular genetics

IV

Pharmacogenomics

21

Simon de Denus, Michaels Phillips, and Jean-Claude Tardif

21.1 Introduction Numerous clinical trials have led to significant advancement in the pharmacological treatment of cardiovascular diseases in the past decades, which have greatly reduced the risk of mortality and morbidity in patients with cardiovascular diseases.1-19 Nonetheless, it is currently impossible for clinicians to precisely identify patients most likely to benefit or experience adverse drug reactions (ADRs) from these drugs. Hence, in clinical practice, the initiation of a pharmacological treatment is primarily based on the efficacy and safety of the drug in a given population and only to a limited extent based on an individual’s potential risks and benefits. For example, antihypertensive agents have been reported to be effective in 50–70% of individuals,20,21 while a marked interindividual variability in the cholesterol reduction by statins has been documented.22 In many cases, pharmacological treatment is based on a trial-and-error approach. Individual characteristics, such as age, ethnicity, and renal function20,21,23,24 appear to play a role in modulating these effects in some cases, but it remains virtually impossible for clinicians to differentiate responders from nonresponders before initiating a pharmacological agent. Hence, the clinician must adjust the dosage of the medication used or substitute it for another agent based on the improvement of intermediate phenotypes, such as blood pressure in the treatment of hypertension25 or LDL cholesterol in the case of dyslipidemias.26

S. de Denus () University of Montreal/Montreal Heart Institute, Montreal, QC, Canada e-mail: [email protected]

Even more problematic than this trial-and-error approach is the treatment of cardiovascular diseases for which no known intermediate phenotype of drug efficacy is available, such as heart failure (HF). Clinical treatment guidelines recommendations for HF are based on published clinical trials demonstrating reductions in mortality or morbidity.27-29 Patients are treated with combinations of angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, diuretics, digoxin, aldosterone antagonists, angiotensin II receptor blockers (ARBs), nitrates, and hydralazine.27-29 Drugs are initiated and added to the patient’s pharmacotherapy on the basis that he/she presents clinical characteristics similar to the inclusion and exclusion criteria of the clinical trials. The drug is then titrated, as tolerated, to the dose used in the clinical trials with the hope that the drug will alter the progression of the disease and eventually result in the prolongation of life or prevention of hospitalization. As drug efficacy cannot be ascertained, all patients are treated using this “one size fits all” approach, potentially exposing nonresponders and patients who would benefit from alternative dosing strategies to an unnecessary risk of ADRs. ADRs are now recognized as one of the leading causes of death, hospitalizations, and cost in the United States.30-32 More specifically, ADRs may be responsible for approximately 2 million hospitalizations per year.32 In elderly patients, 175,000 emergency room visits each year are attributable to ADRs, and the three culprit drugs most frequently responsible, namely warfarin (17.3%), insulin (13%), and digoxin (3.32%), are commonly used drugs in patients with cardiovascular diseases.33 Globally, it is estimated that costs attributable to ADRs are of up to 130 billion dollars each year.34,35 In addition, the clinicians treating cardiovascular diseases are also faced with evaluating the risk of idiosyncratic ADRs with commonly used drugs, such as ­statin-induced

R. Brugada et al. (eds.), Clinical Approach to Sudden Cardiac Death Syndromes, DOI: 10.1007/978-1-84882-927-5_21, © Springer-Verlag London Limited 2010

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myopathies36 and ACE-inhibitor-induced cough and angioedema.37,38 Hence, clinical tools useful to predict the benefits and risks of commonly used drugs would be welcomed additions in the clinical arena. In recent years, investigators have turned toward pharmacogenomics to explain and predict interindividual variability in drug response.39 Two of the earliest cardiovascular drugs that were identified as having variable metabolism were hydralazine and procainamide.40-42 The underlying gene behind the variable pharmacokinetics of those drugs has since then been identified to be NAT2, which encodes for N-acetyltransferase 2. The goal of this chapter is not to provide an extensive review of all cardiovascular pharmacogenomics, but to illustrate how pharmacogenomics can eventually contribute to clinical practice through examples, and the challenges associated with unraveling the impact of genetic variations on drug efficacy and tolerability. Indeed, although extensive research has already been performed in this area, there is currently no pharmacogenomic test widely used clinically in the treatment of cardiovascular patients to guide pharmacotherapy.

Fig. 21.1  The complex relationship between genetic and nongenetic factors that contribute to inter-individual differences in drug response

S. de Denus et al.

21.2 The Complexity of Drug Effects Drug response is the result of a combination of demographic, genetic, and environmental factors specific to the individual (Fig.  21.1). Two major processes are involved: pharmacokinetics (what the body does to the drug, i.e., the relationship between the dose administered and the plasma concentration obtained) and pharmacodynamics (what the drug does to the body, i.e., the relationship between the plasma concentration and the drug effect).43 Pharmacokinetics is classically subdivided into absorption, distribution, metabolism, and excretion (ADME) of the drug. Briefly, absorption is the transfer of the drug from its site of administration to the bloodstream.44 For orally administered agents, several factors can influence the absorption across the gut wall into the portal venous system such as the physicochemical characteristics of the drug (molecular size and shape, degree of ionization of the compound, liposolubility), drug formulation, interaction with other drugs (for example antacids) or food, and physiological factors such as gastric emptying and blood flow to the absorption

21  Pharmacogenomics

site.44,45 For many drugs, the process of absorption in the gut also implicates influx and efflux transporters present on enterocyte membranes and local metabolizing enzymes present in the gut wall.46 Bioavailability is the portion of the administered drug, which is available to reach the site of drug action. For a drug given orally, bioavailability mainly depends on the degree of absorption of the drug across the gut wall and the extent to which the drug is removed before reaching the systemic circulation after passing through the liver where metabolism and biliary excretion can occur (a process called the first-pass effect).44 The distribution of a drug, which is also dependent on its physiochemical properties as well as physiological variables, implicates its passage from the systemic circulation into interstitial and intercellular fluids to reach its target.44 Drug transporters and local metabolism enzymes may also influence this process, and thus, the amount of drug that reaches specific tissues.46 Although the liver is the most important organ implicated in drug metabolism, it is now known that most tissues have xenobiotic metabolizing enzymes. Metabolizing enzymes are divided into Phase I or Phase II enzymes.47 Phase I enzymes introduce a functional group through the reactions of oxidation, reduction, or hydrolysis.47,48 These reactions generally have little effects on water solubility, but can nonetheless significantly modify the biological properties of a compound by transforming it to an inactive metabolite or by converting a prodrug to an active form.48 Phase II reactions are conjugation reactions (acetylation, glucuronidation, methylation, sulfation) that lead to highly polar metabolites that are more easily excreted.47,48 Excretion, which is the process by which the drugs are eliminated from the body, is mainly performed by the kidneys, although the biliary tract is also implicated in the excretion of a more limited number of agents.48

21.3 Cytochromes P450 The initial focus of the majority of pharmacogenetic studies has been the cytochrome P450 enzymes (CYP). CYP are a superfamily of enzymes. They are implicated in the metabolism of nearly 50% of commonly used drugs, making them the most important

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enzymes implicated in Phase I drug metabolism.47 CYPs are present not only in the liver, but also in a number of other tissues, which could influence the response to some agents.49,50 For example, the renal expression of CYP3A5, the most abundant member of the CYP3A family in the kidney,49 has been inversely correlated with the risk of cyclosporineinduced nephrotoxicity.50 The potential use of CYP genetic variants as therapeutic guides to identify patients at higher risk of toxicity was illustrated in a systematic review that demonstrated that 59% of 27 frequently cited drugs in ADRs studies were metabolized by an isoenzyme for which a poor metabolizer variant existed, when compared with 7–22% of randomly selected drugs.51 Interestingly, for one of these drugs (warfarin), current data support that CYP2C9 poor metabolizers are at a greater risk of experiencing over anticoagulation and possibly bleeding from this drug.52-55

21.3.1 Cytochrome P450 2D6 Cytochrome P-450 2D6 (CYP2D6) is one of the most extensively studied modulators of drug metabolism. To date, more than 100 alleles have been shown to influence CYP2D6 activity.56 These genetic variants can alter amino acid sequence, mRNA splicing, and result in the complete deletion of CYP2D6 or multiple copies of the functional gene (up to 13).56 Individuals are generally classified as poor, intermediate, extensive, or ultrarapid (multiple copies of the functional gene) metabolizers based on the impact of these alleles on the CYP2D6 activity.56 CYP2D6 metabolizes many cardiovascular drugs; the most commonly used being the beta-blockers, carvedilol, and metoprolol.57-59 Several studies have shown the impact of genetic polymorphisms on the pharmacokinetics of these two drugs.57-62 Nevertheless, these differences have not consistently resulted in an impact on the pharmacodynamics of these agents.59-61 This probably reflects the small sample sizes of the studies and/or the fact that genetic variants involved in the pharmacodynamics of the drugs were not always evaluated. Nonetheless, data by Wuttke suggested that poor metabolizers are at higher risk of ADRs during metoprolol treatment.63

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21.3.2 Cytochrome P450 2C9 Another widely studied isoenzyme of the CYP family is CYP2C9. Two alleles are particularly frequent in the Caucasian population (CYP2C9*2 and CYP2C9*3), which result in reduced catalytic activity.47 Examples of drugs metabolized by CYP2C9 are listed in Table  21.1. An interesting example on how genetic variants could have opposite clinical effects on the agents of a given class concerns the two ARBs, irbesartan and losartan. Indeed, CYP2C9 is implicated in the transformation of irbesartan from its active form to its inactive metabolite.64 In the case of losartan, CYP2C9 converts losartan which has minimal pharmacological effect, to its active metabolite E-3174.65-67 Hence, slow metabolizers would be expected to have more important blood pressure reductions during treatment with irbesartan because of the accumulation of the active drug, whereas the same patients would only have a limited response to losartan, because of the limited biotransformation of the prodrug to the active metabolite. Limited data support these theoretical considerations,64-67 and further studies are required before CYP2C9 genotyping is introduced into clinical practice to guide the selection of ARBs. The most extensively studied substrate of CYP2C9 in cardiovascular pharmacogenomics is probably warfarin. The most pharmacologically active enantiomer of warfarin, the S-enantiomer, is metabolized by CYP2C9.68 Warfarin is an agent with a narrow therapeutic index that presents marked interindividual dosing requirements, and requires meticulous monitoring of its anticoagulant effects with the international normalized ratio (INR) to maximize benefit while

minimizing the risk of bleeding. There is much hope that pharmacogenomics will help to guide treatment with this agent.68 In this respect, it has been consistently demonstrated that patients carrying the CYP2C9*2 and/or CYP2C9*3 alleles have lower dose requirements when compared with CYP2C9*1/*1 patients.24,55,69-72 The potential impact of pharmacogenomics for patients treated with warfarin is further discussed in Sect. 7.3.

21.3.3 Cytochrome P450 3A Of all the CYP subfamilies, the CYP3A subfamily is responsible for the metabolism of the greatest proportion of available medications.73 The two most abundant isoenzymes of the CYP3A family in the liver are CYP3A4 and CYP3A5. No common polymorphism of CYP3A4 has been demonstrated to affect its activity or expression. On the other hand, among the CYP3A5 genetic polymorphisms identified, the CYP3A5*3 polymorphism has been identified as a major determinant of CYP3A5 expression.74-77 This polymorphism, located in intron 3, is a splice variant that results in a premature stop codon and the early termination of protein transcription at amino acid 109, which results in the nonexpression of the isoenzyme in homozygotes for the *3 allele.76,78 This genetic polymorphism may have a major impact on the pharmacokinetic of many commonly used drugs (Table 21.1). Interestingly, a small (n > 137) retrospective case–control study reported that nonexpressors of CYP3A5 (CYP3A5*3/*3) have a greater

Table 21.1  Selected examples of genetic variations possibly influencing the absorption, distribution, metabolism, or excretion of drugs Gene Gene description Substrate Reference Phase I metabolizing enzymes CYP2D6 Cytochrome P450 2D6 CYP2C9 Cytochrome P450 2C9 CYP2C19 Cytochrome P450 2C19 CYP3A5 Cytochrome P450 3A5

Metoprolol, carvedilol, codeine Warfarin, irbesartan, losartan Clopidogrel Atorvastatin, simvastatin, tacrolimus

62,63,156,157

Phase II metabolizing enzymes NAT2 N-acetyltransferase

Hydralazine, procainamide

164

Drug transporters SLCO1B1 ABCB1

Pravastatin, simvastatin, rosuvastatin Digoxin

94,165,166

OATP1B1 P-glycoprotein (PGP)

52,64-67,119,124 82,84,158-160 74,79,161-163

167

21  Pharmacogenomics

severity of muscle damage, defined as a higher creatine kinase elevation, when experiencing myalgia while receiving atorvastatin.79 The genetic variant was not associated with the risk of experiencing this ADR. However, whether this polymorphism can be useful in clinical practice to identify patients who are at a higher risk of developing statin-induced muscle toxicity or a more severe phenotype of this ADR requires further investigation. As the incidence of myositis (<0.01– 0.5% depending on the statin and the dose used)36,80 is significantly lower than the frequency of this genotype in any population, this candidate genetic polymorphism most probably only represents a genetic risk factor for this ADR when present with other genetic polymorphisms or in the presence of nongenetic risk factors, such as drug interactions.

21.3.4 Possible Impact of Differences in the Frequencies of CYP Genetic Variants Between the Populations An important factor to consider in the discussion of the importance of genetic variants of these metabolizing enzymes is frequencies of the varations in different populations. Indeed, this could have a significant impact on the interpretation and generalization of clinical trials in various populations. A good example is the Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT), a study with a two-bytwo factorial design conducted in China that evaluated the impact of metoprolol and clopidogrel, when compared with placebo in patients with an acute myocardial infarction.18,81 As indicated in Table  21.1, metoprolol is metabolized to its inactive metabolites by CYP2D6, while clopidogrel is metabolized to its active form by different CYPs, including CYP2C19. Moreover, current data indicate that variants from genes encoding these isoenzymes have a significant impact on the pharmacokinetics, and particularly, in the case of clopidogrel,82-84 the pharmacodynamics of these respective agents. Therefore, it can be anticipated that the differences in the frequency of slow metabolizers for these enzymes between South Asians (CYP2D6: 1–2%, CYP2C19: 10–25%) and Caucasians (CYP2D6: 5–10%, CYP2C19: 3%)40,85,86 could impact the benefits and risks observed in this clinical trial.

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Similarly, the variation in the frequency of CYP2C9 genetic variants between the populations would be anticipated to contribute to the differences in the dosing requirement among Caucasians, African-Americans, and Asians.86

21.4 Drug Transporters Although CYPs were the initial focal point of pharmacogenomic research, more recently, the importance of drug transporters has been studied. There are two major superfamilies implicated in transmembrane drug transport: the solute carrier superfamily (SLC) and the adenosine triphosphate binding cassette (ABC) transporter superfamily.87 Although it is beyond the scope of this chapter to detail the numerous members of this family, selected examples of drug transporters and their substrates are included in Table 21.2. These transporters are implicated in the uptake (facilitate uptake of compound in the cell) or efflux (prevent entry in selected tissues and facilitate excretion) of a wide array of substances in various tissues (gut, liver, kidneys, biliary tract).45,88 Hence, genetic polymorphisms modifying the expression or function of these transporters may have a significant impact on the ADME of drugs.45 The potential influence on the distribution of drugs in specific tissues deserves to be underlined. Indeed, this would suggest that, even for a given drug plasma concentration, tissue concentrations between individuals could markedly differ depending on the expression or activity of such transporters of this drug in a tissue, thereby potentially influencing the efficacy and/or toxicity. One of the most widely studied drug transporters is the ABC transporter P-glycoprotein (PGP), which is encoded by the ABCB1 gene.89 This energy-dependent efflux transporter prevents the absorption of many drugs in the intestine while increasing their excretion in the kidneys and in the biliary tract.89 Moreover, PGP prevents drug distribution in many tissues in which it is expressed (including the liver, kidneys,90 heart,91 and brain.92) Nonetheless, despite the large amount of pharmacogenetic data currently available for the ABCB1 gene, the impact of currently identified genetic polymorphisms on the activity and expression of PGP is conflicting, as is their influence on the pharmacokinetics of its substrates.93

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Table 21.2  Examples of genetic variations influencing the pharmacodynamics of the drugs Gene Gene description Drug

Reference

ACE

Angiotensin-converting enzyme (ACE)

ACE inhibitors

100,106

ADD1

Alpha-adducin

Antihypertensive agents

23

APOE

Apolipoproteine E

Statins

129,130

ADBR1

Beta1-adrenergic receptor

Beta-blockers

108-113,117,168

ADBR2

Beta2-adrenergic receptor

Beta-blockers

115,169

AGT

Angiotensinogen

Angiotensin II receptor blockers (ARBs)

101,102

AGTR1

Angiotensin II receptor, type 1.

ARBs

102

GNB3

b3-subunit of G-coupled proteins

Antihypertensive agents

23

HMGCR

3-hydroxy-3-methylglutaryl coenzyme A reductase

Statins

170,171

KIF6

Kinesin-like protein 6

Statins

133,134

NPPA

Atrial natriuretic peptide precursor

Antihypertensive agents

172

REN

Renin

Aliskiren

99

VKORC1

Vitamin K epoxide reductase

Warfarin

9,11,70,120,173

More definitive data have recently been made available for the potential clinical impact of the organic anion-transporting polypeptide OATB1B1 coding gene, SLCO1B1, a SLC family member which is implicated in the hepatic uptake of statins. Indeed, a common variant of the SLCO1B1 gene was associated with the risk of simvastatin-induced myopathy in a genome-wide association study of participants from the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH), an association that was then replicated in patients participating in the Heart Protection Study (HPS).94 Hence, in the event that other lipid-altering drugs, such as ezetimibe, are eventually proven to reduce cardiovascular events, the SLCO1B1 may become important to identify patients who are the most likely candidates to receive these alternatives to statins.

21.5 Pharmacodynamics Genetic variations are also expected to modulate the pharmacodynamics of the drugs. Here, we propose to illustrate this concept by using selected examples of commonly used drugs for the treatment of cardiovascular diseases.

21.5.1 Renin–Angiotensin–Aldosterone System Antagonists The heritability for many of the neurohormones and enzymes of the renin–angiotensin–aldosterone system (RAAS) has been documented.95-97 Reduced to its simplest expression, genetic variations would be expected to modulate the pharmacodynamics of a drug if genetic polymorphisms of the drug target exist. This is the case for the angiotensin converting enzyme (ACE) inhibitors and the ACE gene.98 For the majority of the cardiovascular drugs, the complexity of pharmacodynamics goes beyond this simple assumption. Hence, for ACE inhibitors, although ACE variants may be anticipated to have the greatest impact, genetic variations of the multiple components of the RAAS and the associated intracellular signaling pathways may potentially contribute to the interindividual variability of response to ACE inhibitors or other modulators of the RAAS (Fig. 21.2). Nonetheless, despite this anticipated complexity, existing data, albeit contradictory, support that variants in RAAS genes (ACE, AGT, REN, AGTR1, CYP11B2) could modulate the effects of renin inhibitors,99 ACE inhibitors,100 ARBs,99,101-104 and aldosterone antagonists.105 Data from the HF population have suggested that the benefit of using high-dose ACE inhibitors in these patients is significantly modulated by the

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Fig. 21.2  The renin–angiotensin system and intracellular signaling related to the angiotensin II AT1 receptor. Adapted from154 and155 with permission

ACE I/D polymorphism.106 Nonetheless, because of the existence of conflicting data107 and the generally small sample sizes of the studies, the use of these genetic markers is not yet recommended in clinical practice. The complexity of RAAS pharmacogenomics is, in fact, even more important when considering the relationship between the RAAS and numerous other systems, such as the bradykinin–kallikrein pathway (ACE is responsible for bradykinin degradation) and the adrenergic pathway (beta1-adrenergic receptor stimulation of the juxtaglomerular cells increases renin secretion). Hence, genetic variants of both the systems are expected to influence the response to modulators of the RAAS system.

21.5.2 Beta-Blockers Genetic variants of the adrenergic system have also been extensively studied. Amongst them, gene variants encoding the beta-1 adrenergic receptor (ADBR1) and,

to a lesser extent, the beta-2 adrenergic receptor (ADBR2), have been associated with response to betablockers in hypertensive patients and patients with HF.108-115 The ADBR1 Arg389Gly has constituted the primary focus of many of these studies. As the 389Arg allele is associated with a higher cyclic adenosine monophosphate (cAMP) production when compared with the 399Gly allele,114,116 many have hypothesized that “hyperresponders” carrying the 399Arg allele should benefit to a greater extent from beta-blockers. The most important of these studies is a substudy from the BEST trial, which investigated the impact of the beta-blocker bucindolol in patients with HF. In this substudy of 1,040 patients,117 Liggett et al observed that homozygotes for the Arg389 allele experienced a significant reduction in mortality and hospitalization with bucindolol, whereas the carrier of the Gly allele did not.117 The potentially greater benefit in patients with HF is also supported by small mechanistic studies of carvedilol114 and metoprolol.112 Nonetheless, some studies have reported more equivocal results including a substudy of 600 patients of MERIT-HF.118 Given the significant heterogeneity in the

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pharmacological properties of beta-blockers, and more specifically, the sympatholytic effects of bucindolol, these inconsistencies could reflect differences between these agents or the analysis of a smaller sample size in the MERIT-HF substudy.

21.5.3 Warfarin Another gene that has been the focus of a significant amount of research is the VKORC1 gene, which encodes vitamin K epoxide reductase, the target of warfarin. Current data suggest that genetic variations within this gene can explain approximately 20–25% of variability in response to warfarin, in addition to the approximately 10% related to the genetic polymorphisms of CYP2C9.119-121 When added to the demographic characteristics such as age, gender, and concomitant drugs, current models explain 50–60% of the variance in dose requirements.119,121 One recent prospective pilot study has suggested that the use of dosing algorithms that incorporates these genetic markers and demographic data may improve warfarin dosing resulting in smaller and fewer dose changes. This study was underpowered to evaluate the impact of this approach on more robust clinical outcomes, but nonetheless, supports the concept that pharmacogenomics can have a significant impact on clinical practice.121 Larger trials are ongoing.122 Because more than 30 genes could be implicated in the pharmacokinetics and pharmacodynamics of warfarin, a more comprehensive approach in larger populations could lead to more precise dosing algorithms.24 Given the impact of many nongenetic factors on warfarin dosing, such as vitamin K intake,123 it is unlikely that the use of genetic markers will make the INR unnecessary. Nevertheless, this should not lessen the potential importance of genetic markers in predicting drug response to warfarin, as those markers may enable reaching a stable effective dose more rapidly, which would result in reduced INR monitoring. Moreover, preliminary data suggest that, independently of these dosing considerations, these genetic markers could be useful in identifying patients at a higher risk of over anticoagulation or bleeding when receiving warfarin.52,55,124,125 Hence, these genetic variants could, for example, be used concomitantly with or added to commonly used risk scores of stroke in patients with atrial

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fibrillation126 to more precisely evaluate the risk-benefit ratio of warfarin.

21.5.4 Statins Another good example of a genetic marker from a pharmacodynamic-related drug pathway is the APOE gene that encodes for the apolipoprotein E.127 Many studies have associated genetic variants of the APOE to the lipid lowering effect of statins, although some studies have provided inconsistent results.128 Moreover, this possible genetic risk factor of CAD has been associated with clinical outcomes in patients treated with a statin. Indeed, substudies from the GISSI prevenzione and the 4S trials have suggested that the clinical benefits of statins are mainly apparent in carriers of the APOE e4 variant, although the treatment by apoE interaction did not reach statistical significance in these studies.129,130 Given the cost and current wide use of statins, the incorporation of these genetic markers in clinical practice to identify responders to statin therapy could have a significant clinical and economic impact if these interesting results are confirmed in larger populations. In addition to genetic variants directly implicated in the pharmacokinetics and pharmacodynamics of the drugs, modifier genes unrelated to drug pathways may also contribute to the variability of the effects of cardiovascular medications. A good example of such a modifier gene is KIF6, which encodes kinesin family member six. Recent data have associated KIF6 Trp719Arg genetic polymorphism with CAD.131,132 Moreover, in the CARE and WOSCOPS pharmacogenomics substudies,133 the 719Arg allele was associated with a higher risk of cardiovascular events in the placebo arm.133 Furthermore, in both these trials, these high-risk patients derived the greatest benefit from pravastatin, although the p value for the interaction between treatment and genotype did not reach statistical significance in the CARE substudy.133 Figure 21.3 describes the absolute benefits of both these trials in carriers of the 719Arg allele and in noncarriers. Additional replication data were obtained from the PROVE-IT TIMI 22 study, which initially compared the benefit of high-dose atorvastatin to pravastatin.12 In the pharmacogenomic substudy from this trial, a significant interaction was again observed in the benefit

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21.6.1 Disease Treated and Comorbidities

10

Absolute reduction in cardiovascular events, %

9 8 7 6 5 4 3 2 1 0 WOSCOPS

CARE

PROVE IT-TIMI 22

Fig. 21.3  The impact of the KIF6 gene on the benefit of statins in clinical trials. Black bars 719Arg carriers; grey bars 719Arg noncarriers. Cardiovascular events defined in WOSCOPS as: death from coronary heart disease, nonfatal MI, revascularization procedures; in CARE: fatal and nonfatal MI; and in PROVE IT-TIMI 22: death from any cause or major cardiovascular events. p values of interaction with genotype: WOSCOPS (p > 0.01), CARE (p > 0.39), PROVE IT-TIMI 22 (p > 0.018)

of the high-dose statin strategy, with patients carrying the 719Arg allele deriving the greatest benefit.134 Hence, the KIF6 Trp719Arg genetic polymorphism represents another candidate marker to select patients who will benefit the most from statin therapy. The major question regarding this gene is that its role in cardiovascular diseases is currently uncertain and thus, it is difficult to exactly explain from a physiological perspective regarding how it modulates the cardiovascular risks or benefits of statins.

21.6 Impact of Nongenetic Factors on Associations Between Genotypes and Phenotypes In complex genetics such as pharmacogenomics, nongenetic factors can significantly influence the associations between genotypes and phenotypes. Indeed, ignoring these factors can minimize or completely blur the genetic associations in cardiovascular diseases.135 These factors include, but are not limited to, the disease treated, comorbidities, drug interactions, dietary components, and other lifestyle differences.

The disease for which an agent is used may affect the impact of a genotype on a given phenotype. For example, the hypotensive effect of the ARB candesartan greatly differs between patients with prehypertension,136 hypertension,137 and HF.138 This could be attributed in part to the differences in RAAS activation among these patients, in addition to the hemodynamic and myocardial abnormalities that are the characteristics of the patients with HF.139-144 Hence, the strength of associations between candidate genetic variants and blood pressure reductions may differ among individuals presenting these different conditions, or even for a given individual in his/her lifetime. Comorbidities can also have a significant impact on the phenotypes studied, and thus, the genetic association studies. For example, diabetes and renal dysfunction are known risk factors for RAAS inhibitor-induced hyperkalemia.145

21.6.2 Drug Interactions Drug interactions may be another confounding factor in many pharmacogenomic studies. Indeed, the use of inhibitors of the selected CYPs can modify a phenotype from a rapid metabolizer to a slow metabolizer.146 Pharmacodynamic drug interactions should not be ignored as well. For example, concomitant antiplatelet therapy in patients treated with warfarin significantly increases the risk of bleeding, possibly masking the genetic associations or resulting in false positives.147

21.6.3 Life Habits Life habits are potentially important confounding factors that have been largely ignored in pharmacogenomic studies. Tobacco, for example, is a powerful inducer of CYP1A2 activity and smoking status has been shown to modify the pharmacokinetics of numerous drugs metabolized by this isoenzyme, such as theophylline, clozapine, and possibly, warfarin.148,149

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Diet is another nongenetic confounder that is extremely difficult to quantify, and therefore, to control in pharmacogenomics studies. The impact of vitamin K consumption on warfarin dosing requirements has been previously discussed. Sodium consumption is an important dietary factor that influences blood pressure and therefore, possibly the response to antihypertensive agents.150 Data from the EPOGH investigators and others have shown that sodium excretion, a surrogate marker of sodium intake, is a powerful modulator of the relationship between cardiovascular phenotypes and candidate genes.135,151-153 The authors demonstrated that when the interaction between sodium excretion and genotypes was not considered, some associations between the genotypes and the phenotypes were not apparent.

21.7 Pharmacogenomics: Hope or Hype? The hope for personalized medicine generated by pharmacogenomics has recently faced some skepticism, because many associations have not been replicated in subsequent studies. Indeed, the road to individualized medicine is a long and tortuous one. This, of course, by no means should imply that it is a road not worth exploring and using. These inconsistencies between the studies can be attributed to a number of factors such as limited statistical power, poorly phenotyped individuals, or ignoring nongenetic factors. Hence, future efforts should address and correct these shortcomings to fulfill the promise of pharmacogenomics to give the right drug, at the right dose, to the right patient at the right time.

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21  Pharmacogenomics   88. Beringer PM, Slaughter RL. Transporters and their impact on drug disposition. Ann Pharmacother. 2005;39(6): 1097–1108   89. Eichelbaum M, Fromm MF, Schwab M. Clinical aspects of the MDR1 (ABCB1) gene polymorphism. Ther Drug Monit. 2004;26(2):180–185   90. Koziolek MJ, Riess R, Geiger H, et al. Expression of multidrug resistance P-glycoprotein in kidney allografts from cyclosporine A-treated patients. Kidney Int. 2001;60(1): 156–166   91. Meissner K, Sperker B, Karsten C, et  al. Expression and localization of P-glycoprotein in human heart: effects of cardiomyopathy. J Histochem Cytochem. 2002;50(10): 1351–1356   92. Schwab M, Eichelbaum M, Fromm MF. Genetic polymorphisms of the human MDR1 drug transporter. Annu Rev Pharmacol Toxicol. 2003;43:285–307   93. Chowbay B, Li H, David M, et  al. Meta-analysis of the influence of MDR1 C3435T polymorphism on digoxin pharmacokinetics and MDR1 gene expression. Br J Clin Pharmacol. 2005;60(2):159–171   94. Link E, Parish S, Armitage J, et al. SLCO1B1 variants and statin-induced myopathy–a genomewide study. N Engl J Med. 2008;359(8):789–799   95. Vinck WJ, Fagard RH, Vlietinck R, et  al. Heritability of plasma renin activity and plasma concentration of angiotensinogen and angiotensin-converting enzyme. J Hum Hypertens. 2002;16(6):417–422   96. Newton-Cheh C, Guo CY, Gona P, et al. Clinical and genetic correlates of aldosterone-to-renin ratio and relations to blood pressure in a community sample. Hypertension. 2007;49(4): 846–856   97. Rice GI, Jones AL, Grant PJ, et al. Circulating activities of angiotensin-converting enzyme, its homolog, angiotensinconverting enzyme 2, and neprilysin in a family study. Hypertension. 2006;48(5):914–920   98. Rigat B, Hubert C, Alhenc-Gelas F, et al. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest. 1990;86(4):1343–1346   99. Moore N, Dicker P, O’Brien JK, et al. Renin gene polymorphisms and haplotypes, blood pressure, and responses to renin-angiotensin system inhibition. Hypertension. 2007; 50(2):340–347 100. Bhatnagar V, O’Connor DT, Schork NJ, et al. Angiotensinconverting enzyme gene polymorphism predicts the timecourse of blood pressure response to angiotensin converting enzyme inhibition in the AASK trial. J Hypertens. 2007; 25(10):2082–2092 101. Kurland L, Liljedahl U, Karlsson J, et al. Angiotensinogen gene polymorphisms: relationship to blood pressure response to antihypertensive treatment. Results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs Atenolol (SILVHIA) trial. Am J Hypertens. 2004;17(1):8–13 102. Kurland L, Melhus H, Karlsson J, et al. Polymorphisms in the angiotensinogen and angiotensin II type 1 receptor gene are related to change in left ventricular mass during antihypertensive treatment: results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) trial. J Hypertens. 2002;20(4):657–663

285 103. Kurland L, Melhus H, Karlsson J, et  al. Aldosterone synthase (CYP11B2) -344 C/T polymorphism is related to antihypertensive response: result from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) trial. Am J Hypertens. 2002;15(5):389–393 104. Kurland L, Melhus H, Karlsson J, et al. Angiotensin converting enzyme gene polymorphism predicts blood pressure response to angiotensin II receptor type 1 antagonist treatment in hypertensive patients. J Hypertens. 2001;19(10): 1783–1787 105. Cicoira M, Rossi A, Bonapace S, et al. Effects of ACE gene insertion/deletion polymorphism on response to spironolactone in patients with chronic heart failure. Am J Med. 2004;116(10):657–661 106. McNamara DM, Holubkov R, Postava L, et  al. Pharmacogenetic interactions between angiotensin-converting enzyme inhibitor therapy and the angiotensin-converting enzyme deletion polymorphism in patients with congestive heart failure. J Am Coll Cardiol. 2004;44(10): 2019–2026 107. Arnett DK, Davis BR, Ford CE, et  al. Pharmacogenetic association of the angiotensin-converting enzyme insertion/deletion polymorphism on blood pressure and cardiovascular risk in relation to antihypertensive treatment: the Genetics of Hypertension-Associated Treatment (GenHAT) study. Circulation. 2005;111(25):3374–3383 108. Sofowora GG, Dishy V, Muszkat M, et  al. A common beta1-adrenergic receptor polymorphism (Arg389Gly) affects blood pressure response to beta-blockade. Clin Pharmacol Ther. 2003;73(4):366–371 109. Liu J, Liu ZQ, Yu BN, et  al. beta1-Adrenergic receptor polymorphisms influence the response to metoprolol monotherapy in patients with essential hypertension. Clin Pharmacol Ther. 2006;80(1):23–32 110. Liu J, Liu ZQ, Tan ZR, et al. Gly389Arg polymorphism of beta1-adrenergic receptor is associated with the cardiovascular response to metoprolol. Clin Pharmacol Ther. 2003;74(4):372–379 111. Lobmeyer MT, Gong Y, Terra SG, et al. Synergistic polymorphisms of beta1 and alpha2C-adrenergic receptors and the influence on left ventricular ejection fraction response to beta-blocker therapy in heart failure. Pharmacogenet Genomics. 2007;17(4):277–282 112. Terra SG, Hamilton KK, Pauly DF, et al. Beta1-adrenergic receptor polymorphisms and left ventricular remodeling changes in response to beta-blocker therapy. Pharmacogenet Genomics. 2005;15(4):227–234 113. Johnson JA, Zineh I, Puckett BJ, et  al. Beta 1-adrenergic receptor polymorphisms and antihypertensive response to metoprolol. Clin Pharmacol Ther. 2003;74(1):44–52 114. Mialet Perez J, Rathz DA, Petrashevskaya NN, et al. Beta 1-adrenergic receptor polymorphisms confer differential function and predisposition to heart failure. Nat Med. 2003;9(10):1300–1305 115. Kaye DM, Smirk B, Williams CJ, et al. Beta-adrenoceptor genotype influences the response to carvedilol in patients with congestive heart failure. Pharmacogenetics. 2003; 13(7):379–382 116. Mason DA, Moore JD, Green SA, et al. A gain-of-function polymorphism in a G-protein coupling domain of the human beta1-adrenergic receptor. J Biol Chem. 1999; 274(18):12670–12674

286 117. Liggett SB, Mialet-Perez J, Thaneemit-Chen S, et  al. A polymorphism within a conserved beta(1)-adrenergic receptor motif alters cardiac function and beta-blocker response in human heart failure. Proc Natl Acad Sci USA. 2006;103(30):11288–11293 118. White HL, de Boer RA, Maqbool A, et al. An evaluation of the beta-1 adrenergic receptor Arg389Gly polymorphism in individuals with heart failure: a MERIT-HF sub-study. Eur J Heart Fail. 2003;5(4):463–468 119. Sconce EA, Khan TI, Wynne HA, et  al. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood. 2005;106(7):2329–2333 120. Rieder MJ, Reiner AP, Gage BF, et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med. 2005;352(22):2285–2293 121. Anderson JL, Horne BD, Stevens SM, et al. Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation. 2007;116(22):2563–2570 122. Shurin SB, Nabel EG. Pharmacogenomics–ready for prime time? N Engl J Med. 2008;358(10):1061–1063 123. Franco V, Polanczyk CA, Clausell N, et al. Role of dietary vitamin K intake in chronic oral anticoagulation: prospective evidence from observational and randomized protocols. Am J Med. 2004;116(10):651–656 124. Schwarz UI, Ritchie MD, Bradford Y, et al. Genetic determinants of response to warfarin during initial anticoagulation. N Engl J Med. 2008;358(10):999–1008 125. Veenstra DL, Blough DK, Higashi MK, et  al. CYP2C9 haplotype structure in European American warfarin patients and association with clinical outcomes. Clin Pharmacol Ther. 2005;77(5):353–364 126. Fuster V, Ryden LE, Cannom DS, et  al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation–executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation). J Am Coll Cardiol. 2006;48(4):854–906 127. Bennet AM, Di Angelantonio E, Ye Z, et al. Association of apolipoprotein E genotypes with lipid levels and coronary risk. JAMA. 2007;298(11):1300–1311 128. Mangravite LM, Thorn CF, Krauss RM. Clinical implications of pharmacogenomics of statin treatment. Pharmacogenomics J. 2006;6(6):360–374 129. Chiodini BD, Franzosi MG, Barlera S, et al. Apolipoprotein E polymorphisms influence effect of pravastatin on survival after myocardial infarction in a Mediterranean population: the GISSI-Prevenzione study. Eur Heart J. 2007;28(16): 1977–1983 130. Gerdes LU, Gerdes C, Kervinen K, et al. The apolipoprotein epsilon4 allele determines prognosis and the effect on prognosis of simvastatin in survivors of myocardial infarction: a substudy of the Scandinavian simvastatin survival study. Circulation. 2000;101(12):1366–1371 131. Shiffman D, Chasman DI, Zee RY, et al. A kinesin family member 6 variant is associated with coronary heart disease

S. de Denus et al. in the Women’s Health Study. J Am Coll Cardiol. 2008; 51(4):444–448 132. Shiffman D, O’Meara ES, Bare LA, et al. Association of gene variants with incident myocardial infarction in the Cardiovascular Health Study. Arterioscler Thromb Vasc Biol. 2008;28(1):173–179 133. Iakoubova OA, Tong CH, Rowland CM, et al. Association of the Trp719Arg polymorphism in kinesin-like protein 6 with myocardial infarction and coronary heart disease in 2 prospective trials: the CARE and WOSCOPS trials. J Am Coll Cardiol. 2008;51(4):435–443 134. Iakoubova OA, Sabatine MS, Rowland CM, et  al. Polymorphism in KIF6 gene and benefit from statins after acute coronary syndromes: results from the PROVE IT-TIMI 22 study. J Am Coll Cardiol. 2008;51(4):449–455 135. Stolarz K, Staessen JA, Kawecka-Jaszcz K, et al. Genetic variation in CYP11B2 and AT1R influences heart rate variability conditional on sodium excretion. Hypertension. 2004;44(2):156–162 136. Julius S, Nesbitt SD, Egan BM, et al. Feasibility of treating prehypertension with an angiotensin-receptor blocker. N Engl J Med. 2006;354(16):1685–1697 137. McClellan KJ, Goa KL. Candesartan cilexetil. A review of its use in essential hypertension. Drugs. 1998;56(5): 847–869 138. Granger CB, McMurray JJ, Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensinconverting-enzyme inhibitors: the CHARM-Alternative trial. Lancet. 2003;362(9386):772–776 139. Danser AH, van Kesteren CA, Bax WA, et  al. Prorenin, renin, angiotensinogen, and angiotensin-converting enzyme in normal and failing human hearts. Evidence for renin binding. Circulation. 1997;96(1):220–226 140. Zisman LS, Asano K, Dutcher DL, et al. Differential regulation of cardiac angiotensin converting enzyme binding sites and AT1 receptor density in the failing human heart. Circulation. 1998;98(17):1735–1741 141. Matsubara H. Renin-angiotensin system in human failing hearts: message from nonmyocyte cells to myocytes. Circ Res. 2001;88(9):861–863 142. Serneri GG, Boddi M, Cecioni I, et al. Cardiac angiotensin II formation in the clinical course of heart failure and its relationship with left ventricular function. Circ Res. 2001;88(9):961–968 143. Pieruzzi F, Abassi ZA, Keiser HR. Expression of reninangiotensin system components in the heart, kidneys, and lungs of rats with experimental heart failure. Circulation. 1995;92(10):3105–3112 144. Yoshimura M, Nakamura S, Ito T, et  al. Expression of aldosterone synthase gene in failing human heart: quantitative analysis using modified real-time polymerase chain reaction. J Clin Endocrinol Metab. 2002;87(8):3936–3940 145. de Denus S, Tardif JC, White M, et al. Quantification of the risk and predictors of hyperkalemia in patients with left ventricular dysfunction: a retrospective analysis of the Studies of Left Ventricular Dysfunction (SOLVD) trials. Am Heart J. 2006;152(4):705–712 146. Hamelin BA, Bouayad A, Methot J, et al. Significant interaction between the nonprescription antihistamine diphen-

21  Pharmacogenomics hydramine and the CYP2D6 substrate metoprolol in healthy men with high or low CYP2D6 activity. Clin Pharmacol Ther. 2000;67(5):466–477 147. Johnson SG, Rogers K, Delate T, et al. Outcomes associated with combined antiplatelet and anticoagulant therapy. Chest. 2008;133(4):948–954 148. Kroon LA. Drug interactions with smoking. Am J Health Syst Pharm. 2007;64(18):1917–1921 149. Millican EA, Lenzini PA, Milligan PE, et al. Genetic-based dosing in orthopedic patients beginning warfarin therapy. Blood. 2007;110(5):1511–1515 150. Dickinson BD, Havas S. Reducing the population burden of cardiovascular disease by reducing sodium intake: a report of the Council on Science and Public Health. Arch Intern Med. 2007;167(14):1460–1468 151. Kuznetsova T, Staessen JA, Thijs L, et al. Left ventricular mass in relation to genetic variation in angiotensin II receptors, renin system genes, and sodium excretion. Circulation. 2004;110(17):2644–2650 152. Wojciechowska W, Staessen JA, Stolarz K, et al. Association of peripheral and central arterial wave reflections with the CYP11B2–344C allele and sodium excretion. J Hypertens. 2004;22(12):2311–2319 153. Kuznetsova T, Staessen JA, Brand E, et al. Sodium excretion as a modulator of genetic associations with cardiovascular phenotypes in the European Project on Genes in Hypertension. J Hypertens. 2006;24(2):235–242 154. Salazar NC, Chen J, Rockman HA. Cardiac GPCRs: GPCR signaling in healthy and failing hearts. Biochim Biophys Acta. 2007;1768(4):1006–1018 155. Schmieder RE, Hilgers KF, Schlaich MP, et  al. Reninangiotensin system and cardiovascular risk. Lancet. 2007 ;369(9568):1208–1219 156. Kirchheiner J, Schmidt H, Tzvetkov MK, et  al. Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication. Pharmacogenomics J. 2007;7(4):257–265 157. Takekuma Y, Takenaka T, Kiyokawa M, et al. Contribution of polymorphisms in UDP-glucuronosyltransferase and CYP2D6 to the individual variation in disposition of carvedilol. J Pharm Pharm Sci. 2006;9(1):101–112 158. Geisler T, Schaeffeler E, Dippon J, et  al. CYP2C19 and nongenetic factors predict poor responsiveness to clopidogrel loading dose after coronary stent implantation. Pharmacogenomics. 2008;9(9):1251–1259 159. Trenk D, Hochholzer W, Fromm MF, et  al. Cytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents. J Am Coll Cardiol. 2008;51(20):1925–1934 160. Hulot JS, Bura A, Villard E, et al. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of

287 clopidogrel responsiveness in healthy subjects. Blood. 2006;108(7):2244–2247 161. Zheng H, Webber S, Zeevi A, et al. Tacrolimus dosing in pediatric heart transplant patients is related to CYP3A5 and MDR1 gene polymorphisms. Am J Transplant. 2003;3(4): 477–483 162. Zheng H, Zeevi A, Schuetz E, et  al. Tacrolimus dosing in adult lung transplant patients is related to cytochrome P4503A5 gene polymorphism. J Clin Pharmacol. 2004;44(2): 135–140 163. Kim KA, Park PW, Lee OJ, et  al. Effect of polymorphic CYP3A5 genotype on the single-dose simvastatin pharmacokinetics in healthy subjects. J Clin Pharmacol. 2007;47(1):87–93 164. Ladero JM. Influence of polymorphic N-acetyltransferases on non-malignant spontaneous disorders and on response to drugs. Curr Drug Metab. 2008;9(6):532–537 165. Pasanen MK, Neuvonen M, Neuvonen PJ, et  al. SLCO1B1 polymorphism markedly affects the pharmacokinetics of simvastatin acid. Pharmacogenet Genomics. 2006;16(12):873–879 166. Ho RH, Choi L, Lee W, et  al. Effect of drug transporter genotypes on pravastatin disposition in European- and African-American participants. Pharmacogenet Genomics. 2007;17(8):647–656 167. Aarnoudse AJ, Dieleman JP, Visser LE, et al. Common ATPbinding cassette B1 variants are associated with increased digoxin serum concentration. Pharmacogenet Genomics. 2008;18(4):299–305 168. Beta-Blocker Evaluation of Survival Trial Investigators. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med. 2001;344(22): 1659–1667 169. Lanfear DE, Jones PG, Marsh S, et  al. Beta2-adrenergic receptor genotype and survival among patients receiving beta-blocker therapy after an acute coronary syndrome. JAMA. 2005;294(12):1526–1533 170. Donnelly LA, Doney AS, Dannfald J, et  al. A paucimorphic variant in the HMG-CoA reductase gene is associated with lipid-lowering response to statin treatment in diabetes: a GoDARTS study. Pharmacogenet Genomics. 2008;18(12): 1021–1026 171. Krauss RM, Mangravite LM, Smith JD, et al. Variation in the 3-hydroxyl-3-methylglutaryl coenzyme a reductase gene is associated with racial differences in low-density lipoprotein cholesterol response to simvastatin treatment. Circulation. 2008;117(12):1537–1544 172. Lynch AI, Boerwinkle E, Davis BR, et al. Pharmacogenetic association of the NPPA T2238C genetic variant with cardiovascular disease outcomes in patients with hypertension. JAMA. 2008;299(3):296–307 173. Cooper GM, Johnson JA, Langaee TY, et  al. A genomewide scan for common genetic variants with a large influence on warfarin maintenance dose. Blood. 2008;112(4): 1022-1027

22

Polygenic Studies in the Risk of Arrhythmias Moritz F. Sinner and Stefan Kääb

22.1 Polygenic Studies in the Risk of Arrhythmias

22.2 Common Genetic Variants as Modifiers of Arrhythmia Risk in the Context of Monogenic Diseases Research into rare genetic variants causing cardiovascular diseases in general and cardiac arrhythmias in particular has led to a tremendous accumulation of knowledge and insight into disease mechanisms within the last decade. These genetic cardiovascular disorders are commonly viewed as monogenic diseases following largely Mendelian inheritance with a variable penetrance, which accounts for the widely seen lack of strong genotype−phenotype correlation. Increasingly, research efforts focus on the role of common genetic variants, the so-called polymorphisms (or single nucleotide polymorphisms or SNPs) as modifier alleles to disease susceptibility. Historically, the initial studies on common genetic variants investigated exonic common variants in candidate genes that had been linked to arrhythmia risk by experimental data or in the context of monogenic diseases. Recently, the search for disease modifying common genetic variants has reached a more systematic approach based on public data on the human genome allowing for the systematic evaluation of larger numbers of SNPs in the genomic region of candidate genes or in the whole genome (e.g., http://www.hapmap.org, http://genome. ucsc.edu, http://snpper.chip.org or http://www.ncbi. nlm.nih.gov/sites/entrez?db > snp). M. F. Sinner (*) Ludwig-Maximilians University Klinikum Grosshadern, Medizinische Klinik und Poliklinik I, Marchioninistrasse. 15, 81377 Munich, Germany e-mail: [email protected]

Though we have learned a lot in the past decade about the primary defects and general aspects of arrhythmogenesis as well as underlying primary arrhythmia syndromes such as the congenital long QT syndromes, advances in a more specific genotype−phenotype correlation are slow. In the context of monogenic diseases, the term “modifiers” is also and importantly used for common genetic variants that account for the interindividual variability among patients harboring the same mutation. Few studies have tried to gain a deeper insight into the consequence of mutations by incorporating in their models at least another factor that may influence the phenotype.1 Baroudi et al were the first to introduce the concept that the interaction of common polymorphisms and rare mutations may exert profound effects on functional consequences. The combination of a mutation in the SCN5A gene (T1620M), known to affect channel gating, resulted in impaired protein trafficking when expressed in tsA201 cells.2 Splawski et al suggested that the polymorphism SCN5A-Y1102, which is present in 13.2% of the African-American population, is strongly associated with the development of arrhythmias, namely drug-induced long QT syndrome in the absence of a clinical phenotype of LQT3 or any other heritable arrhythmia that has been linked to mutations in the Na+ channel gene.3

R. Brugada et al. (eds.), Clinical Approach to Sudden Cardiac Death Syndromes, DOI: 10.1007/978-1-84882-927-5_22, © Springer-Verlag London Limited 2010

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22.3 Common Genetic Variants in Candidate Genes Modify the Risk for Supraventricular Arrhythmias

22.4 Common Genetic Variants in Candidate Genes Modify the Risk for Ventricular Arrhythmias

Recent evidence increasingly identifies familial clustering of atrial fibrillation (AF), the most common cardiac arrhythmia in humans, suggesting that genetic components are relevant also in common forms of AF. Results from the Framingham Heart Offspring Study4 and a large investigation on the Icelandic population5 indicate a relative risk of up to 3.2 for AF if one parent was affected before age 75 and up to 4.7 if one parent had the onset of AF before the age of 60. Though this kind of heritable component is implying a polygenic substrate with multiple alleles defining the individual’s risk for AF, until today only a small number of common variants have been associated with AF. An overview is given in Table 22.1 (with the genetic variants listed in chromosomal order).6-30 Among these are SNPs in the KCNE1, KCNE5, and SCN5A genes as well as in those coding for Connexin 40, Angiotensinogen, Angiotensin Converting Enzyme, and G-protein b3. However, unfortunately all these association studies for AF have been underpowered or have not been replicated reliably. A significant association has been observed between AF and the coding variant K897T (rs1805123) in KCNH2 as the first candidate gene based SNP association study in AF with robust replication.16 A genome-wide association study in Icelanders identified a locus on Chromosome (Chr) 4q25 associated with undifferentiated AF in subjects of all ages.13 Within this locus, two noncoding SNPs were independently associated with AF and these findings were replicated in two populations of European descent and one of Asian descent. The SNP most strongly associated with AF, rs2200733, conferred a 1.71-fold increased odds of AF (p > 6.1 × 10−41) and the other SNP, rs10033464 conferred a 1.42-fold increased odds of AF (p > 3.1 × 10−11). Recently, the association with these two variants on Chr4q25 could be replicated in subjects of all ages. Over 3,500 affected individuals with AF and 12,000 referent subjects were genotyped, originating from four studies of European descent: the Framingham Heart Study, Rotterdam Study, Vanderbilt AF Registry, and German AF Network.14 A meta-analysis of all four studies revealed an OR of 1.90 (95% CI, 1.61–2.25; 1.0 × 10−13) for rs2200733 and 1.35 (95% CI, 1.25–1.46; 3.8 × 10−14) for rs10033464.

The lack of serologic biomarkers to predict ventricular tachycardia (VT), ventricular fibrillation (VF), and sudden cardiac death has made systematic searches for common genetic variants influencing these traits extremely important.31 To date, only a small number of candidate gene based studies with a focus on exonic SNPs are available. The majority of these association studies are underpowered and lack independent replication (Table 22.2).32-47 The polymorphism SCN5A-Y1103, as mentioned earlier, is present in 13.2% of the AfricanAmerican population. It is strongly associated with the development of arrhythmias, namely drug-induced long QT syndrome.3 This common variant has been recognized as an independent marker of arrhythmia risk and sudden infant death syndrome in the African population.48,49 To date, systematic large-scale SNP association studies with independent replication studies are missing. The first genome-wide association efforts in defined populations with ventricular arrhythmias are currently under way and will hopefully identify novel genetic loci and alleles contributing to ventricular arrhythmia risk.

22.5 Searching for the Genetic Susceptibility to Common Cardiac Arrhythmias Cardiac arrhythmias are electrical disorders of the heart ranging from harmless single ectopic beats to common atrial arrhythmias such as AF to lethal ventricular arrhythmias that cause sudden cardiac death (SCD). When searching for the polygenic contribution of a complex trait such as cardiac arrhythmias, it is essential to focus on a specific phenotype and collect a large cohort with a high degree of homogeneity as well as a substantial evidence for heritability to limit the degrees of complexity (Fig. 22.1). Data from the first genome-wide association study in AF patients demonstrate the validity of this rationale leading to the identification of a novel genetic locus associated with an increased risk for AF.13,14

M235T

−6 g>a

−217 g>a

T174M, −20 a>c, −152 g>a

−6 g>a (I/D)

A985G

−44A

−592 a>c

E145D

A1166C

H558R

chr4: 111929618 c>t, chr4: 111940210 g>t

−174 g>c

K897T

−786 t>c

4a, 4b (tandem repeat, intron4)

E298D

20210 g>a

P448R, R519H, G643S

AGT

AGT

AGT

AGT

AGT (ACE)

EDN2

GJA5 (Cx40)

IL10

KCNE4

AGTR1

SCN5A

Unknown (PITX2 ?)

IL 6

KCNH2 (HERG)

NOS3

NOS3

NOS3

F2

KCNQ1

Atrial fibrillation/atrial flutter

rs1799963

rs1799983

rs2070744

rs1805123

11

11

7

7

7

7

7

4

rs2200733, rs10033464

rs1800795

3

3

2

1

1

1

1

1

1

1

1

rs1805124

rs12621643

rs18007872

rs35594137

rs5800

rs5051

rs5049

rs5051

rs699

Table 22.1  Common variants in supraventricular rhythm disorders Gene Variant/SNP rs-number Chromosome

142

336

[51–331]

[51–331]

[51–331]

1,207

26

[143–3,508]

157

250

142

196

173

26

968

250

250

250

250

Cases (n/[n-range])

238

336

[289–441]

[289–441]

[289–441]

2,475

84

[738–17,714]

314

250

238

873

232

84

8,267

250

250

250

250

Controls (n/ [n-range])

n.a.

2.4

[1.19–3.2]

[n.a.–0.81]

[1.23–2.67]

1.3

3.25

[1.72–2.50], [1.34–1.39]

1.6

n.a.

1.66

n.a.

1.514

5.89

1.1 (1.2)

n.a.

2

3.3

2.5

OR

n.s.

<0.05

[<0.001–0.4]

[n.s.–0.6]

[0.002–0.3]

0.00023

0.006

[3.3 × 10−41– 6.6 × 10−55], [0.0015– 6.9 × 10−11]

0.008

n.s.

0.044

0.0006

0.006

0.014

0.05 (0.06)

n.s.

0.002

0.005

<0.001

p value

11

19

17,18

17,18

17,18

16

15

13,14

12

6

11

10

9

8

7

6

6

6

6

(continued)

Reference

22  Polygenic Studies in the Risk of Arrhythmias 291

Taq1B

−1306 c>t

I/D

S38G

D85N

P33T

CETP

MMP2

ACE

KCNE1 (minK)

KCNE1 (minK)

KCNE5

GJA5 (C × 40)

−44a>g

C825T

GNB3

Atrial standstill

rs583362

−65 g>c

SLN

rs35594137

rs17003955

rs1805218

rs1805127

rs243865

rs708272

rs5443

rs-number

Table 22.1  (continued) Gene Variant/SNP

1

X

21

21

17

16

16

12

11

Chromosome

158

142

[69–331]

[51–510]

196

97

291

147

Cases (n/[n-range])

96

238

[60–441]

[83–520]

873

97

292

92

Controls (n/ [n-range])

0.52

n.a.

1.55–2.67

[0.9–3.24]

n.a.

0.35

0.46

n.a.

OR

0.007

n.s.

0.024–0.002

[0.418– <0.0001]

0.0016

<0.05

0.02

0.011

p value

29,30

28

11

11,18,26,27

6,17,23-25

10

22

21

20

Reference

292 M. F. Sinner and S. Kääb

3

rs1805124

19

46

85

Cases

Long QT syndrome/drug induced Long QT syndrome/torsades de pointes/sudden cardiac death IL10 −1082 g>a, −592 c>a n.a., rs18007872 1 23 CERKL chr2:182281500 t>c rs993648 2 183 SCN5A S1103Y rs7626962 3 ANK2 T1404I, V1516D, T1552N, 4 190 V1777M, E1813K ANK2 P2835S rs3733617 4 34 PALLD chr4:169904988 t>c rs17054392 4 183 ADRB2 Gly16/Gln27 Haplotype 5 93 TNF −238 g>a, −308 g>a 6 23 KCNH2 K897T rs1805123 7 KCNH2 K897T rs1805123 7 8 KCNH2 R1047L rs36210421 7 7 NRG3 chr10:83809105 g>t rs4933824 10 183 KCNJ11 K23E rs5219 11 86 KCNJ11 A190A rs5218 11 86 KCNJ11 L267V 11 86 KCNJ11 L267L rs5216 11 86 KCNJ11 L270V rs1800467 11 86 KCNJ11 K381K rs8175351 11 86 KCNQ1 G643S rs1800172 11 6 NUBPL chr14:31163299 g>a rs7142881 14 183 SLCO3A1 chr15:90246877 t>c rs3924426 15 183 BRUNOL4 chr18:33182637 t>c rs4799915 18 183 KCNE2 T8A rs2234916 21

3

1

Arrhythmogenic right ventricular cardiomyopathy RYR2 G1886S rs3766871 rs1805124

22

Ventricular extrasystole CYP2D6 CYP2D6*10

Brugada syndrome SCN5A H558R VT/VF SCN5A H558R

Chromosome

Table 22.2  Common variants in ventricular rhythm disorders Gene Variant SNP-rs-number

84 84 84 84 84 84 89

14 98

226 12/100

95

n.a.

12/100

n.a.

120

463

n.a.

Controls

1.60 × 10−6 2.05 × 10−6 3.30 × 10−6

1.98 × 10−6 n.s. n.s. n.s. n.s. n.s. n.s.

n.a.

3.48 × 10

−6

n.a. 2.83 × 10−6

n.a.

n.s.

0.05

<0.05

p value

SIDS QTL GWAS SCD; SNP rare in whites LQT; experimental in vitro data TdP QTL GWAS diLQT SIDS LQT; functional in vitro data TdP TdP QTL GWAS Post MI SCD Post MI SCD Post MI SCD Post MI SCD Post MI SCD Post MI SCD LQT QTL GWAS QTL GWAS QTL GWAS diLQT

Functional in vitro study

Allele overrepresented in BS

comment

47

37

37

37

46

45

45

45

45

45

45

37

44

43

42

36

41

37

40

39

38

37

36

35

34

33

32

Reference

22  Polygenic Studies in the Risk of Arrhythmias 293

294

Fig. 22.1  Searching for the polygenic contribution to common cardiac arrhythmias. Genetic studies of a complex trait such as cardiac arrhythmias require a heritable component and a homogeneous phenotype

Likewise, evidence has emerged from large-scale epidemiological studies that have demonstrated familial associations of SCD. A recent case control study of more than 500 SCD survivors demonstrated that family history was a relevant risk factor and independent predictor of SCD with an odds ratio 1.6.50 A second study followed a cohort of 7,000 subjects for 23 years including 118 SCD patients51 and also confirmed family history as a strong independent predictor of SCD susceptibility with an odds ratio between 1.8 when only one other family member was affected and a remarkable odds ratio of 9.4 when a positive history for SCD was present in both parental lines. Another study elegantly demonstrated that a positive family history of SCD is the single strongest predictor of VT or VF in the context of the first myocardial infarction (high degree of homogeneity in the phenotype).52 These studies provide evidence for the existence of factors in addition to the established risk predictors making common genetic variants a likely candidate. To address the contribution of common genetic variation, the method of genome-wide association analysis (GWA) has offered vastly expanded scientific capabilities within the last 2 years. GWA has made common genetic sequence variation – SNPs and other common variants in allelic association (linkage disequilibrium, LD) with SNPs – accessible to molecular research. In studies of arrhythmogenic diseases, GWA promises to enable a systematic accounting of a sizeable fraction of what used to be subsumed as “genetic background variation.”

M. F. Sinner and S. Kääb

In addition to the analysis of qualitative traits such as specific arrhythmias, GWA studies are well suited to evaluate genetic modifiers of quantitative traits as potential markers of arrhythmia risk. Quantitative traits from the ECG that represent distinct myocardial electrical properties such as conduction (PR- and QRSinterval) and repolarization (QT-interval) show a heritable component ranging between 20 and 50% of the overall variance.53 Particularly, the prolongation or shortening of the QT-interval reflects alterations of cardiac repolarization known to trigger VT/VF and predispose to SCD. Importantly, QT interval prolongation has been associated with increased cardiovascular mortality in patients with heart disease,54 as well as in the general population.55 Therefore, studies on genetic variants modulating the QT interval are particularly attractive and have led to the identification of novel genetic markers of the repolarization process56 and will serve as potential candidates in patients who are at the risk of SCD in the future. The idea that polymorphisms in genes encoding cardiac ion channels or other genes that alter cardiac de- or repolarization may also contribute to enhanced arrhythmia susceptibility in more common forms of cardiac disease (e.g., hypertrophy and heart failure) represents a probable, but as yet unproven hypothesis. Preliminary data indicate that multiple, small, individually insignificant genetic contributions add up to a detectable quantitative trait.56,57 Whether these polymorphisms will combine to enhance the overall susceptibility to arrhythmias remains to be investigated.

References 1. Priori SG. Inherited arrhythmogenic diseases: the complexity beyond monogenic disorders. Circ Res. 2004;94: 140–145 2. Baroudi G, Acharfi S, Larouche C, et  al. Expression and intracellular localization of an SCN5A double mutant R1232W/T1620M implicated in Brugada syndrome. Circ Res. 2002;90:E11-E16 3. Splawski I, Timothy KW, Tateyama M, et  al. Variant of SCN5A sodium channel implicated in risk of cardiac arrhythmia. Science. 2002;297:1333–1336   4. Fox CS, Parise H, D’Agostino RB, et  al. Parental atrial fibrillation as a risk factor for atrial fibrillation in offspring. JAMA. 2004;291:2851–2855   5. Arnar DO, Thorvaldsson S, Manolio TA, et  al. Familial aggregation of atrial fibrillation in Iceland. Eur Heart J. 2006;27:708–712

22  Polygenic Studies in the Risk of Arrhythmias   6. Tsai CT, Lai LP, Lin JL, et  al. Renin-angiotensin system gene polymorphisms and atrial fibrillation. Circulation. 2004; 109:1640–1646   7. Ravn LS, Benn M, Nordestgaard BG, et al. Angiotensinogen and ACE gene polymorphisms and risk of atrial fibrillation in the general population. Pharmacogenet Genomics. 2008; 18:525–533   8. Nagai T, Ogimoto A, Okayama H, et al. A985G polymorphism of the endothelin-2 gene and atrial fibrillation in patients with hypertrophic cardiomyopathy. Circ J. 2007;71: 1932–1936   9. Juang JM, Chern YR, Tsai CT, et  al. The association of human connexin 40 genetic polymorphisms with atrial fibrillation. Int J Cardiol. 2007;116:107–112 10. Kato K, Oguri M, Hibino T, et al. Genetic factors for lone atrial fibrillation. Int J Mol Med. 2007;19:933–939 11. Zeng Z, Tan C, Teng S, et al. The single nucleotide polymorphisms of I(Ks) potassium channel genes and their association with atrial fibrillation in a Chinese population. Cardiology. 2007;108:97–103 12. Chen LY, Ballew JD, Herron KJ, et al. A common polymorphism in SCN5A is associated with lone atrial fibrillation. Clin Pharmacol Ther. 2007;81:35–41 13. Gudbjartsson DF, Arnar DO, Helgadottir A, et al. Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature. 2007;448:353–357 14. Kääb S, Darbar D, Noord CV, et al. Large scale replication and meta-analysis of variants on chromosome 4q25 associated with atrial fibrillation. Eur Heart J. 2009;30(7): 813–819 15. Gaudino M, Andreotti F, Zamparelli R, et al. The -174G/C interleukin-6 polymorphism influences postoperative interleukin-6 levels and postoperative atrial fibrillation. Is atrial fibrillation an inflammatory complication? Circulation. 2003;108(suppl 1):II195-II199 16. Sinner MF, Pfeufer A, Akyol M, et al. The non-synonymous coding IKr-channel variant KCNH2–K897T is associated with atrial fibrillation: results from a systematic candidate gene-based analysis of KCNH2 (HERG). Eur Heart J. 2008;29:907–914 17. Bedi M, McNamara D, London B, et al. Genetic susceptibility to atrial fibrillation in patients with congestive heart failure. Heart Rhythm. 2006;3:808–812 18. Fatini C, Sticchi E, Genuardi M, et al. Analysis of minK and eNOS genes as candidate loci for predisposition to non-valvular atrial fibrillation. Eur Heart J. 2006;27:1712–1718 19. Poli D, Antonucci E, Cecchi E, et al. Thrombophilic mutations in high-risk atrial fibrillation patients: high prevalence of prothrombin gene G20210A polymorphism and lack of correlation with thromboembolism. Thromb Haemost. 2003;90:1158–1162 20. Nyberg MT, Stoevring B, Behr ER, et al. The variation of the sarcolipin gene (SLN) in atrial fibrillation, long QT syndrome and sudden arrhythmic death syndrome. Clin Chim Acta. 2007;375:87–91 21. Schreieck J, Dostal S, von Beckerath N, et al. C825T polymorphism of the G-protein beta3 subunit gene and atrial fibrillation: association of the TT genotype with a reduced risk for atrial fibrillation. Am Heart J. 2004;148:545–550 22. Asselbergs FW, Moore JH, van den Berg MP, et al. A role for CETP TaqIB polymorphism in determining susceptibility to

295 atrial fibrillation: a nested case control study. BMC Med Genet. 2006;7:39 23. Fatini C, Sticchi E, Gensini F, et al. Lone and secondary nonvalvular atrial fibrillation: role of a genetic susceptibility. Int J Cardiol. 2007;120:59–65 24. Gensini F, Padeletti L, Fatini C, et al. Angiotensin-converting enzyme and endothelial nitric oxide synthase polymorphisms in patients with atrial fibrillation. Pacing Clin Electrophysiol. 2003;26:295–298 25. Yamashita T, Hayami N, Ajiki K, et al. Is ACE gene polymorphism associated with lone atrial fibrillation? Jpn Heart J. 1997;38:637–641 26. Lai LP, Su MJ, Yeh HM, et  al. Association of the human minK gene 38G allele with atrial fibrillation: evidence of possible genetic control on the pathogenesis of atrial fibrillation. Am Heart J. 2002;144:485–490 27. Prystupa A, Dzida G, Myśliński W, et al. MinK gene polymorphism in the pathogenesis of lone atrial fibrillation. Kardiologia polska. 2006;64:1205–1211; discussion 12–13 28. Ravn LS, Hofman-Bang J, Dixen U, et al. Relation of 97T polymorphism in KCNE5 to risk of atrial fibrillation. Am J Cardiol. 2005;96:405–407 29. Makita N, Sasaki K, Groenewegen WA, et  al. Congenital atrial standstill associated with coinheritance of a novel SCN5A mutation and connexin 40 polymorphisms. Heart Rhythm. 2005;2:1128–1134 30. Groenewegen WA, Firouzi M, Bezzina CR, et al. A cardiac sodium channel mutation cosegregates with a rare connexin40 genotype in familial atrial standstill. Circ Res. 2003;92:14–22 31. Arking DE, Chugh SS, Chakravarti A, et  al. Genomics in sudden cardiac death. Circ Res. 2004;94:712–723 32. Cai WM, Xu J, Chen B, et al. Effect of CYP2D6*10 genotype on propafenone pharmacodynamics in Chinese patients with ventricular arrhythmia. Acta Pharmacol Sin. 2002;23:1040–1044 33. Milting H, Lukas N, Klauke B, et al. Composite polymorphisms in the ryanodine receptor 2 gene associated with arrhythmogenic right ventricular cardiomyopathy. Cardiovasc Res. 2006;71:496–505 34. Chen JZ, Xie XD, Wang XX, et al. Single nucleotide polymorphisms of the SCN5A gene in Han Chinese and their relation with Brugada syndrome. Chin Med J. 2004;117:652–656 35. Hu D, Viskin S, Oliva A, et al. Genetic predisposition and cellular basis for ischemia-induced ST-segment changes and arrhythmias. J Electrocardiol. 2007;40:S26-S29 36. Perskvist N, Skoglund K, Edston E, et  al. TNF-alpha and IL-10 gene polymorphisms versus cardioimmunological responses in sudden infant death. Fetal Pediatr Pathol. 2008;27:149–165 37. Volpi S, Heaton C, Mack K, et al. Whole genome association study identifies polymorphisms associated with QT prolongation during iloperidone treatment of schizophrenia. Mol Psychiatry. 2009;14:1024–1031 38. Chen S, Chung MK, Martin D, et  al. SNP S1103Y in the cardiac sodium channel gene SCN5A is associated with cardiac arrhythmias and sudden death in a white family. J Med Genet. 2002;39:913–915 39. Mohler PJ, Le Scouarnec S, Denjoy I, et al. Defining the cellular phenotype of “ankyrin-B syndrome” variants: human

296 ANK2 variants associated with clinical phenotypes display a spectrum of activities in cardiomyocytes. Circulation. 2007; 115:432–441 40. Mank-Seymour AR, Richmond JL, Wood LS, et  al. Association of torsades de pointes with novel and known single nucleotide polymorphisms in long QT syndrome genes. Am Heart J. 2006;152:1116–1122 41. Kanki H, Yang P, Xie HG, et  al. Polymorphisms in betaadrenergic receptor genes in the acquired long QT syndrome. J Cardiovasc Electrophysiol. 2002;13:252–256 42. Crotti L, Lundquist AL, Insolia R, et al. KCNH2–K897T is a genetic modifier of latent congenital long-QT syndrome. Circulation. 2005;112:1251–1258 43. Pollevick GD, Oliva A, Viskin S, et al. Genetic predisposition to post-myocardial infarction long QT intervals and torsade de pointes [abstract]. Heart Rhythm. 2007;4:S121 44. Sun Z, Milos PM, Thompson JF, et  al. Role of a KCNH2 polymorphism (R1047 L) in dofetilide-induced Torsades de Pointes. J Mol Cell Cardiol. 2004;37:1031–1039 45. Jeron A, Hengstenberg C, Holmer S, et al. KCNJ11 polymorphisms and sudden cardiac death in patients with acute myocardial infarction. J Mol Cell Cardiol. 2004;36:287–293 46. Kubota T, Horie M, Takano M, et al. Evidence for a single nucleotide polymorphism in the KCNQ1 potassium channel that underlies susceptibility to life-threatening arrhythmias. J Cardiovasc Electrophysiol. 2001;12:1223–1229 47. Sesti F, Abbott GW, Wei J, et al. A common polymorphism associated with antibiotic-induced cardiac arrhythmia. Proc Natl Acad Sci USA. 2000;97:10613–10618 48. Plant LD, Webster NJ, Boyle JP, et al. Amyloid beta peptide as a physiological modulator of neuronal ‘A’-type K+ current. Neurobiol Aging. 2006;27:1673–1683

M. F. Sinner and S. Kääb 49. Van Norstrand DW, Ackerman MJ. Sudden infant death syndrome: do ion channels play a role? Heart Rhythm. 2008; 6(2):272–278 50. Friedlander Y, Siscovick DS, Weinmann S, et al. Family history as a risk factor for primary cardiac arrest. Circulation. 1998;97:155–160 51. Jouven X, Desnos M, Guerot C, et  al. Predicting sudden death in the population: the Paris Prospective Study I. Circulation. 1999;99:1978–1983 52. Dekker LR, Bezzina CR, Henriques JP, et al. Familial sudden death is an important risk factor for primary ventricular fibrillation: a case-control study in acute myocardial infarction patients. Circulation. 2006;114:1140–1145 53. Pfeufer A. Genetics of the ECG: QT or not QT- A genetic analysis of a complex electrophysiological trait confirms several previously detected associations. Eur J Hum Genet. 2007;15:909–910 54. Vrtovec B, Delgado R, Zewail A, et al. Prolonged QTc interval and high B-type natriuretic peptide levels together predict mortality in patients with advanced heart failure. Circulation. 2003;107:1764–1769 55. Schouten EG, Dekker JM, Meppelink P, et al. QT interval prolongation predicts cardiovascular mortality in an apparently healthy population. Circulation. 1991;84:1516–1523 56. Arking DE, Pfeufer A, Post W, et  al. A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization. Nat Genet. 2006;38:644–651 57. Pfeufer A, Jalilzadeh S, Perz S, et al. Common variants in myocardial ion channel genes modify the QT interval in the general population: results from the KORA study. Circ Res. 2005;96:693–701

The Genetic Challenge of Coronary Artery Disease

23

Robert Roberts, George Wells, and Li Chen

23.1 The Genetic Challenge of Coronary Artery Disease

23.2 A Significant Porportion of Susceptibility for CAD Is Genetic

Coronary artery disease (CAD) is a major health and economic problem for most of the world. In 2002, it accounted for one third of all the deaths in the world1 and is said to account for 38% of all deaths in the United States. Over thirteen million Americans experience CAD annually at a yearly cost of about four hundred billion dollars.2 Current epidemiological estimates suggest that at the time of birth, one can predict that, in their lifetime, they will have a 47% chance of experiencing a cardiac event and if combined with cerebrovascular disease more than 60%.3 The fundamental defect responsible for CAD is atherosclerosis which occurs in major blood vessels throughout the body, but the consequences are more devastating when it occurs in vessels that supply blood to organs such as the heart, brain, and kidney. The presence of coronary atherosclerosis with the superimposition of a thrombus can lead to the clinical manifestation of angina, myocardial infarction, and sudden cardiac death. CAD has long been the most common cause of death in the western world. It is rapidly increasing worldwide with the prediction of being number one killer in the world by 2010.2

It is evident from the tremendous progress in recent decades that a significant component of atherosclerosis is preventable.4 The mortality from CAD has decreased more than 50% in the past three decades primarily due to treatment of conventional risk factors along with improved treatment of the clinical sequela. It is claimed by some4 that if prevention is vigorously pursued, CAD will be markedly attenuated, if not eliminated in this century. Since atherosclerosis is a life long developing disease, there is ample evidence to indicate that comprehensive prevention needs to be implemented early in life. It is also evident that for prevention of CAD to be comprehensive it must include the genetic risk component. Data from epidemiological studies indicate that over 50% of susceptibility for CAD is due to genetic factors.5

23.2.1 Evidence Supporting a Genetic Basis for CAD 23.2.1.1 Familial Aggregation Studies

R. Roberts (*) Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON Canada, K1Y 4W7 e-mail: [email protected]

Studies investigating case control families have shown on an average a two- to threefold increase in risk for CAD in first-degree relatives.6-9 A family history of CAD in a first-degree relative before the age of 60 is an independent risk factor for early myocardial infarction even after controlling traditional risk factors.10,11 Several prospective studies have shown up to a twofold increase in CAD risk associated with a family history of CAD after adjusting traditional risk factors.12-18 There is also

R. Brugada et al. (eds.), Clinical Approach to Sudden Cardiac Death Syndromes, DOI: 10.1007/978-1-84882-927-5_23, © Springer-Verlag London Limited 2010

297

298

a clustering of susceptibility to CAD in families that have risk factors associated with abnormalities such as lipid metabolism, hypertension, diabetes, and obesity indicating a genetic basis for these risk factors.19-25 The extent of coronary occlusion in patients with CAD also relates to a parental history of myocardial infarction.26 In families with CAD onset before the age of 46, heritability was estimated to be 92–100%, whereas within families of older cases, the heritability range from 15 to 30%.9 Premature CAD in the young is transmitted as an even greater genetic load to their offspring.27 The Danish twin registry, of 8,000 twin pairs, show a higher incidence of CAD and deaths in monozygotic twins compared with dizygotic twins, 44 vs. 14%.28

23.2.1.2 Family History: A Powerful Risk Factor In a study of early onset of CAD, it was estimated that the heritability for early onset was at 0.63. After exclusion of apparent lipid abnormalities, the heritability estimate was 0.56 suggesting that more than half of CAD diagnosed before the age of 50 is genetic.2,29 A first-degree relative with a family history of myocardial infarction occurring before the age of 55 years is said to increase the risk sevenfold of that individual having a myocardial infarction.30 This was based on a study of 207 cases of myocardial infarction occurring before the age of 55, and 621 agematched controls. Perhaps, the most outstanding illustration of the importance of family history to CAD is studies from the state of Utah. In the state of Utah, 14% has a family history of CAD and it was within this cohort that 72% of patients with early onset myocardial infarction and 48% of all coronary events occurred. Similarly, approximately 11% of the population of the state of Utah have a history of cerebrovascular stroke and this cohort accounted for 86% of all strokes.14 Family history remains a significant risk factor and an important simple and easy means to stratify for risk. This, of course, is particularly important for early onset CAD, while for later onset, it becomes perhaps less discriminating as a means of planning prevention and future therapy.

23.2.1.3 Atherosclerosis Inherited as Mendelian Disorders Several mutations inherited in Mendelian patterns induce premature CAD. Although these disorders are

R. Roberts et al.

rare (less than 1%), they have important implications for the etiology of atherosclerosis as well as illustrating the influence of a genetic defect. Most of the single gene disorders that have been identified involve lipid abnormalities. The most common is that of autosomal dominant hypercholesterolemia due to an underlying defect in at least three different genes. The most common of these is that of the low-density lipoprotein receptor gene31 and the apolipoprotein B gene32 together with mutations in the PCSK9 gene.32 The LDL receptor gene, located on chromosome 19 (19p13),33 in the heterozygous form occurs in 1 in 500 individuals, and over 700 mutations have been identified. This disorder probably accounts for 5% of all myocardial infarctions that occur in individuals below the age of 50.33 Individuals homozygous for this defect often have myocardial infarctions in their twenties.

23.2.1.4 Genetically Induced Animal Models of Atherosclerosis There is considerable evidence from animal models of a strong genetic component to atherosclerosis.34 The ApoE knockout mouse shows increased susceptibility to CAD which is markedly increased in the presence of a high cholesterol diet.35 Several studies expressing human genes as transgenes in the mouse have been shown to induce a phenotype of increased CAD.35

23.3 Single Gene vs. Polygenic Disorders The mapping and identification of genes responsible for single gene disorders has met with remarkable success in the past two decades. Disorders such as the Brugada syndrome, cardiomyopathies, and Long QT syndrome have been identified with hundreds of mutations.36 These disorders are discussed elsewhere and have played a major role in our understanding of cardiovascular disease. Linkage analysis, used to map the chromosomal location of genes is applicable for single gene disorders inherited in Mendelian fashion such as autosomal dominant or recessive. One can genotype with DNA markers of known chromosomal location that span the genome on an average, every 10 million bases (about 300 markers) utilizing a pedigree of two

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or three generations. Knowing the location of these markers, if one or more of the markers is co-inherited with affected individuals more often than by chance, one can determine that the marker is in close physical proximity to the gene responsible for this disorder. It is then possible to more finely map the region with additional markers and ultimately clone and identify the responsible gene and its mutation. These disorders are extremely rare occurring in 1 in 500 to 1 in 10,000 of the population, and as indicated previously have a dominant effect on the phenotype such that phenotypic patterns of inheritance emerge, referred to as Mendelian inheritance. While single gene disorders are enjoying their day in the sun, mapping and identification of genes responsible for multigene disorders such as CAD and cancer have remained until very recently in its infancy. It is claimed that 20 diseases account for 80% of all deaths in the world.37 All of these diseases are common multigenic complex diseases with cardiovascular and cancer accounting for over half of them.37 There have been several stumbling blocks. In multigene disorders such as CAD, there are multiple genes each contributing only a modest effect as opposed to the predominant phenotypic effect in single gene disorders. Second, in single gene disorders, the mutation is both necessary and adequate to induce the phenotype as opposed to multigene disorders in which any one mutation is neither necessary nor sufficient to induce the phenotype. Third, the phenotype of a multigene disorder results from the interaction of multiple genes and environmental risk factors. Fourth, since multiple genes predispose to the phenotype of CAD, it does not exhibit the phenotype pattern of recessive or dominant inheritance needed for the application of genetic linkage analysis. Fifth, since each gene may contribute to only 5% of the phenotype; detection of a chromosomal locus requires DNA markers spanning the whole genome at intervals of at least 6,000 base pairs or less requiring the genotyping of at least 500,000 markers per sample. This is in marked contrast to single gene disorders in which one can span the genome with markers at intervals of 10 million base pairs, requiring only 300 markers. Sixth, the technique of identifying predisposing genes referred to as association studies requires a population of unrelated individuals rather than pedigrees. Seventh, it requires thousands of cases and thousands of controls utilizing high throughput phenotyping and genotyping which was not available until recently even at prohibitive cost.

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23.4 Genetic Basis for Predisposition to Disease In single gene disorders, the mutations are rare with a frequency of 1 in 50,000 to 1 in 10,000, but maybe as common as 1 in 500.38 The mutations that predispose to common polygenic disorders are more common and are the same as those responsible for the variation in phenotype among humans such as height, skin, eye color, or disease predisposition. Since the DNA sequences of the human genome are 99.5% identical, all of the variations in human features are due to the 0.5% sequence difference. The DNA sequence responsible for disease predisposition is also contained within this 0.5% sequence difference. Over 80% of these differences are due to single nucleotides. These single nucleotides which give rise to the genetic polymorphism are referred to as single nucleotide polymorphisms (SNP). Each human has about three million SNPs (0.1% of the DNA sequence). The remainder of the sequence difference (0.4%) is due to insertions or deletions often referred to as copy number variation. Furthermore, evidence suggests that over 80% of human variation and predisposition to disease is accounted for by the SNPs and only 20% due to copy number variation.39-41 These percentages are only estimates and may change as more data is obtained. Essentially, all genes exist in more than one form referred to as alleles which circulate in the population. The DNA sequence of the alleles (sometimes referred to as the genetic variant) implied previously often differs by only one nucleotide. The alleles that occur with greater frequency are referred to as major alleles and those that occur less frequently are referred to as minor alleles (MA). There is significant evidence to indicate the MA are primarily responsible for disease predisposition. Each individual has two alleles for each gene (one from each parent). If the two alleles are identical, the individual is said to be homozygous for that allele and if different, heterozygous. Despite being less common than the major allele, these disease predisposing alleles are still relatively common compared to rare Mendelian disorders (0.1%). Most of these MA occur at a frequency of more than 5% and can occur in up to 50% of the population. Alleles that occur with a frequency of ³5% are said to be common alleles. It is claimed that most of the individual variation of human beings including predisposition for or against disease is transmitted by the common alleles. However, there

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are many rare alleles (<5%) that contribute to genetic predisposition.42 It is also recognized that these rare alleles42,43 tend to have a much greater effect on the phenotype than common alleles.

23.5 Case Control Association Studies It has been recognized for some time that case control association studies would be more sensitive and appropriate for multigene disorders than genetic linkage analysis.44,45 Case controlled association studies are classified into the indirect approach and direct approaches. The direct approach is often referred to as the candidate gene approach. The basic concept behind case controlled studies is very simple. One collects unrelated cases of the specific disease and unrelated individuals for controls. In performing association studies, one determines the genotype, meaning, which alleles are present in each individual (cases and controls) by a process referred to as DNA genotyping. The frequency of minor alleles (MAF) in cases is then compared to controls. If a particular MAF is greater in cases than in controls, it is referred to as a risk allele, while if more common in the controls, is referred to as a protective allele.

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(SLSJ) region of Quebec.46 The group tested 1,536 DNA markers (SNPs). Those showing a positive association were assessed for replication in an independent sample size of 806 individuals. The investigators expressed surprise that none of the candidate genes replicated. In another study, there was an equally disturbing result; 70 genes exhibiting 85 alleles previously shown to be associated with CAD were analyzed in 811 patients with acute coronary syndrome and 650 controls matched for age and sex.51 Only one of the variants (−455 promoter variant in beta-fibrinogen) replicated with statistical significance. These 70 genes included the A and B haplotypes of 5-lipoxygenase activating protein (ALOX5AP) and variants in the ABCA1 gene. The former variant was reported to be strongly associated with myocardial infarction in the Icelandic population.52 Several large reviews concluded that none of the candidate genes for CAD had reached an association robust to be considered of clinical significance.44,45,53 However, the studies utilizing the candidate gene approach usually had inadequate sample size for their screening population and seldom attempted replication in independent populations. Thus, until the studies are repeated appropriately, it remains to be determined whether the claims for candidate genes are appropriate. It probably require appropriate genome-wide association studies followed by replication to properly determine which of the candidate genes are indeed predisposing to disease.

23.6 Direct Association Studies Using the Candidate Gene Approach Have Been Relatively Unsuccessful

23.7 Genome-Wide Case Control Association Studies: A New Era for Common Polygenic Disorders The direct approach referred to as the candidate gene approach consists of comparing the frequency of alleles in cases with controls to determine if the suspected candidate allele is more common in the cases. The candidate gene approach is less expensive, less time consuming, and has been the predominant approach for the past decade.46 The candidate genes selected usually involves known risk factors for CAD such as hypertension,47 obesity,48 or diabetes.49,50 Over 100 candidate genes suspected for their involvement in atherosclerosis or its sequelae46 have been analyzed in various populations. In a recent study, 103 candidate genes shown in various genetic studies to be associated with atherosclerosis or CAD were re-assessed in >1,400 individuals from the Saguenay Lac St-Jean

The background to the current GWA studies relates to observations of two studies published in 1996.54,55 The authors suggested that common complex diseases would be related to common genetic variants. The corollary to this would be that population association studies would be more appropriate to identify these variants than family-based linkage studies. Following many attempts to detect these variants, it is now well recognized that the genome-wide case control association studies of unrelated individuals are more appropriate and more sensitive than family-based linkage analysis. The recent genome-wide studies by Hinds et  al40 utilizing one million SNPs again confirm that

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most of human variation is due to SNPs with a frequency ³5%.40,44,45,56 This markedly reduced the sample size necessary. In fact, it may never be possible to have the sample size large enough for GWAS to detect a variant that has a frequency of only 1%. Thus, in estimating sample sizes for genome-wide genotyping, the parameter for allele frequency was selected to be ³5%. An important corollary is that the currently designed GWAS will only detect common alleles. The GWAS requires hundreds of thousands of markers at intervals of at least every 6,000  bps.56 A new era emerged with the HapMap project which annotated hundreds of thousands of the SNP. These SNPs while usually not encoding regions occur randomly throughout the genome at an average of 1 SNP per 1,000 bps.57 This provided the necessary markers for genome-wide studies. Affymetrix generated an array consisting of over 500,000 SNPs and more recently, 1 million SNPs. Other commercial arrays are also available such as Illumina.58 This was the beginning of an explosion for genome-wide studies in large populations. This marker set is selected to detect most of the common SNPs either from being in close physical proximity or occurring on the same haplotype as the common SNP, referred to in genetic parlance, as genetic disequilibrium. This means the marker SNP and the adjacent SNPs are co-inherited as a block. Common SNPs are thought to be the genetic variants accounting for over 80% of human variation and predisposition to disease.40 There are over 11 million SNPs recognized in the general population. Commercial platforms, to perform high throughput genotyping, while still expensive, are rapidly coming into an affordable range enabling genome-wide studies with 1,000 K markers to be performed on large sample sizes. Thus, genome-wide association studies in large populations with dense marker arrays have been catapulted into plausibility. This approach makes no prior assumption and so it is an unbiased search for genes associated with CAD on a genome-wide basis. For CAD, high throughput phenotyping also received a boost with the development of the multislice fast CT making it possible to obtain noninvasive coronary angiograms. Screening such large numbers for millions of genotypes is by definition prone to many false positives. If one selects, for example, 0.05 as the level of significance for an association genotyping with 1 million markers, one can expect 50,000 associations by chance alone or 10,000 with a p-valve at 0.01 or 1,000 at

301 Table 23.1  Perimeters for genome-wide scans Minor allele frequency Level of increased risk to be detected Power function Statistical significance for association Size difference to be detected between controls and cases

0.001. In selecting the initial discovery population, one must arbitrarily decide on the numeric value of several parameters, namely, the level of allelic risk expected, the minor allele frequency, the power function and the size effect between the two populations (Table 23.1). The Ottawa Heart Genomics Study (OHGS),59 designed to detect genes responsible for CAD, illustrates these features in estimating sample size as well as the phenotyping criteria. If the initial screening population is designed to detect genes with increased risk of CAD ³1.2,59 with a minor allele frequency ³15% and a size difference between controls and affecteds of ³0.2 at a power function of 0.80 and a p-value of ³5.0 ´ 10–8 for an association the sample size is 16,000 (8,000 cases/8,000 controls). The p-value of 5.0 ´ 10–8 is required since it must be corrected for all the multiple hits (1 million SNPs), referred to as the bonferroni correction. The bonferroni method simply divides 0.05 by the 1 million markers used in the genome wide association study. It is now conventionally accepted, albeit arbitrary, that for an association to be significant in a genome-wide scan using 1 million SNPs, the p-value must be ³ 5.0 ´ 10–8, commonly referred to as genome wide significance. It is essential in association studies that results be replicated in an independent population of the same ethnic group as the screening population. In selecting the sample size for the replication population the sample size is determined by the number of associations carried forward for confirmation. A p-value of 0.05 ³ is required and if only one association is taken forward, no correction is necessary. If more than one association is taken forward for confirmation, the bonferroni correction applies, namely, .05 divided by the number. Genome wide genotyping of the screening population has been completed in 9,000 individuals consisting of over 6 billion genotypes. Analysis show multiple SNPs exhibiting a significant association with CAD,59 which are currently undergoing replication analysis in an independent population.

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23.8 Overview of Statistical Interpretation of GWAS Associations with the two alleles of each SNP can be tested in a relatively straight-forward manner by comparing the frequency of each allele in cases and controls. However, the allele test is not recommended because it requires an assumption of Hardy-Weinberg equilibrium (HWE) in cases and controls combined and does not lead to interpretable risk estimates. The association between a single SNP and case-control status can also be tested by comparing the frequency of each of three possible genotypes among cases and controls. Genotype tests can be carried out using a Pearson chi-square test (2 degrees of freedom) or a Fisher exact test. The Fisher exact test is preferred as it does not reply on the chi-square approximation. Exploratory analyses may also include testing of different genetic models (dominant, recessive, or additive), although the additive model (also known as the Cochran-Armitage trend test), in which each copy of the allele is assumed to increase risk by the same amount, tend to be the most common.60 There is no generally accepted answer to the question as to which test to use. We could select the optimal test if we knew the true underlying disease model. A search for disease-related SNPs with their risk effects governed by a particular disease model might miss SNPs following other risk patterns. For example, adopting the Cochran-Armitage trend test implies sacrificing power if the genotypic risk are far from additive. Furthermore, for complex disease with low penetrance, usually none of the above simplified models is appropriate. Under these circumstances, efficiency robust tests, which retain high power across all scientifically plausible genetic models, are preferable. One commonly used robust test is based on the MAX statistics, the maximum of three trend statistics derived under the recessive, additive, and dominant models respectively.60 Empirical results showing the advantages of using the MAX statistics over the CochranArmitage trend test are derived from the additive model, to prioritize SNPs or to detect disease-associated SNPs. Under the null hypothesis of no association, the MAX statistic does not follow the standard normal distribution asymptotically. Thus, a computationally intensive re-sampling-based procedure is required to estimate its p-value, which is computationally challenging for the analysis of GWAS. Recently, Li et  al61 proposed a simple approximation for the

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p-value of the MAX test, which avoids resampling steps and thus makes the MAX test readily applicable to GWAS. It is of interest to consider which statistical models best describe the data and between loci that are strongly associated with disease status. Biological interpretation of these statistical models is not straightforward, but they can help in choosing more powerful statistical tests for detecting association. Complexity in analysis emerges due to the multiple testing carried out in GWAS, in that the association tests is performed with 1 million SNPs assayed. The preferred way of dealing with this problem is to reduce the false positive rate by applying the Bonferroni correction in which 0.05 is divided by 1 million and 5 ´ 10–8 is considered genome wide significance. This correction has been criticized as overly conservative because it assumes independent associations of each SNP with disease even though individual SNPs are known to be correlated to some degree due to linkage disequilibrium. Another approach proposed is to attempt to estimate the false discovery rate (FDR), namely, the proportion of significant associations that are actually false positive association.62 This method has not been confirmed and there remains skepticism as to whether it is appropriate for GWAS.

23.9 Results of Recent GWAS for Noncardiac Causes Genome-wide scans with a limited number of markers (50,000–100,000) covering only 20–30% of the genome have been performed and despite this limitation, several loci have been identified. Loci have been identified showing genetic association with macular degeneration,63 diabetes mellitus,64 lupus,65 and prostate cancer66 and all have been replicated in independent populations.67

23.10 The First Common Genetic Variant for CAD: 9p21 May Unravel a Novel Pathway Prior to the availability of a dense microarray of markers, we initiated a GWA study with several international collaborators using the 72,000 array. In an initial

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Ottawa population of 322 cases vs. 312 controls utilizing 72,864 SNPs, a locus on chromosome 9p21 was shown to be associated with CAD. This association with CAD68 was replicated in six independent Caucasian populations comprising 23,000 individuals. This first common genetic variant for CAD68 was simultaneously confirmed to be associated with myocardial infarction.69 Subsequently, it was confirmed for CAD and myocardial infarction in independent studies in the UK,70 Germany,71 and Central Europe.72 It has been confirmed in over 55,000 Caucasians. The frequency of this allele is very high being present in the heterozygous form in 50% of Caucasians and homozygous in 25% with increased risk of 15–20% and 30–40% respectively. The major surprise is that the risk is independent of known risk factors. This is very exciting, because it implies a new mechanism and a novel risk factor for atherosclerosis. The intrigue is further enhanced by the fact that the 9p21 region of 58,000  bps does not contain any protein encoding gene. There is an ANRIL gene which encodes for a noncoding antisense RNA (Fig.  23.1). It is recently recognized that RNAs play a large role in regulating genes, and thus, if RNA is the culprit, it will require significant effort to determine which genes are being

regulated.73 Recently, the deCODE Group74 showed that 9p21 is also a risk factor for abdominal and intracranial aneurysms, and the population at risk is estimated to be about 26%. This would suggest that the defect is within the arterial wall, since atherosclerosis is not a prominent feature of abdominal aortic aneurysms or intracranial aneurysms.

23.11 The Importance of Phenotyping and Selecting Controls GWA studies are likely to be a major thrust for the next 5–10 years as a means of mapping common genetic variants for diseases such as CAD, hypertension and the metabolic syndrome. The mapping of rare genetic variants (MAF <5%) will probably have to wait until deep, rapid, and cheap DNA sequencing is available. The phenotyping is a major factor, particularly as we refine our efforts to search for variants predisposing to subphenotying. A major scientific goal for the medical community over the next 10–15 years will be to identify and determine the function of thousands of SNPs as they relate to disease and therapy. The phenotyping challenge should

9p21 Region 1

9 8 7 6 5 4

3 2

DNA

1

19 18 17 16 15 14 13 12 11 10

ANRIL

P15/CDKN

p14/ARF

p16/CDKN2A

2B

Fig.  23.1  This illustrates the Chromosome 9p21 risk region for CAD. The SNPs showing an association with CAD are all included in the bracketed region referred to as the 9p21 region. The exons 1–19 represent the ANRIL gene which encodes for a noncoding RNA. Downstream from this region as indicated

on the right are three other genes, p15, p14, and p16 which encode for kinases that inhibit the life cycle, often referred to as cyclin kinases inhibitors. These genes do not show a coorelation with CAD even though they have been related to diabetes

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be a call to arms by the medical community and particularly the physician scientists to participate as their involvement will be necessary to attain this goal. A major breakthrough for high throughput phenotyping for coronary atherosclerosis recently occurred with the introduction of the multislice CT scanner. This enables one to obtain a coronary angiogram noninvasively and rapidly with imaging time being less than one minute. Ongoing studies have accepted <50% coronary obstruction for normal coronary arteriograms obtained by invasive cardiac catheterization and <30% for multislice CT (Table  23.2). Several populations collected in the past have used the criteria of a documented coronary event such as myocardial infarction on ECG or an abnormal myoperfusion scan. Documented myocardial infarction or inadequate perfusion on myocardial imaging would appear to be adequate without coronary arteriograms. The criteria used to phenotype controls such as atherosclerosis or CAD are much more difficult for disease. There is at this time no agreement on the criteria for controls for atherosclerosis or CAD. Since atherosclerosis or CAD onset is age-dependent, it presents even greater concern (Table  23.3). We are recommending that individuals should be asymptomatic and ³65 years for males and ³70 years for females. The ideal in addition to the criteria of elderly and asymptomatic would be to obtain a normal coronary arteriogram. This latter is now possible with the fast CT or multislice. The criteria for controls in the OHGS serve as a template, but is likely to be significantly altered as we acquire more knowledge of both the phenotype and the genotype of atherosclerosis and its cardiac sequelae. Table 23.2  Criteria for early onset coronary artery disease Male <55 years or female <65 years Absence of diabetes (untreated HbA1c <0.060) Absence of LDL-C <5.0 mmol/L, TC/HDL-C <7.0 (not on lipid modifying medication) CAD confirmed by coronary angiography (catheterization or fast CT)

Table 23.3  Criteria for controls without CAD Asymptomatic men >65 years or women >70 years Matched for sex, plasma lipids, HbA1c, and blood pressure Myocardial perfusion scan or coronary angiogram preferred (cardiac catheterization or fast CT)

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23.12 Gene To Gene Combinations and Their Interaction with the Environment It is anticipated that large sample size of several populations will be genotyped with millions of markers selected to span the whole genome. This would cast a wide nonspecific and nonprejudiced search for genes predisposing to atherosclerosis in a population, carefully and appropriately phenotyped. Replication in similar and different ethnic populations will ultimately identify those genes predisposing to atherosclerosis common to all populations and those unique to certain ethnic groups. Genes superimposing additional predisposition for sequelae such as ischemia or myocardial infarction will be separately determined in populations enriched for these sequeale. Results of genome-wide scans performed in populations with specific risk factors for atherosclerosis such as hypertension, obesity, or diabetes enable analysis of the separate effect of each risk factor and in combinatorial arrangements, for their integrated impact. It is only after such studies, will it be possible to more precisely quantify the genetic and environmental components. This will lay the necessary infrastructure to begin to assess gene to gene interactions and how they are impacted by the environment.

23.13 Personalized Medicine: The Beginning of a Reality There is hope that the genes or, at least most of them, will be mapped in the next 5–10 years. The concept of personalized medicine is about to occur. However, there are many legal, social, and ethical issues to be resolved. Legislature to protect individual privacy will be foremost to assure that one’s genotype is not used inappropriately, such as denial of life or medical insurance. Technology for cheap, rapid, and accurate genome-wide genotyping will probably arrive before the social, legal, and ethical issues are resolved. Sequencing of a genome for a few thousand dollars is considered feasible in the near future. Application of genetic screening will be the beginning of a new paradigm in the prevention of atherosclerosis and CAD.

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Genetic screening of those with a family history of heart disease or risk factors could occur in individuals at an age to enable early comprehensive prevention. In males, it should occur in the second or third decade, if not earlier and for females, before the fifth decade. Concomitant with the discovery of CAD risk alleles, one can expect surprises which will lead to a broader understanding of the pathways leading to atherosclerosis and provide targets for novel therapy. It is to be expected that other devastating common chronic diseases will similarly succumb to the genome-wide search and hopefully with beneficial results. Identifying genes responsible for common disorders such as atherosclerosis should be a compelling reason for the physician and scientist to work together. The technology, the need, and the benefit should provide the impetus required to enable new therapies, genetic screening, prevention, and ultimate elimination of this disease.

23.14 Functional Analysis of Genetic Variant: A Challenge for the Future The success of the GWA studies to map genetic variants predisposing to common complex diseases has been remarkable. It is important to understand that the SNPs are markers and not the genetic mutation. Second, the marker simply indicates the haplotype containing the mutation. The haplotype can vary from 20,000 to 100,000 bps. Thus, GWA studies can have tremendous power to map the chromosomal location of a predisposing variant but it has limitations. First, it cannot determine the causative sequence for the predisposition. Second, it provides very little, if any, information on function. Third, GWAS as designed currently cannot detect disease-related alleles whose frequency is rare (<5%). This is very much illustrated by the 9p21 variant which does not contain a protein encoding gene, yet is present in almost 50% of all Caucasians and increases the risk of about 30% for CAD.68 All of the confirmatory studies for the 9p21 locus have been in Caucasians. Preliminary findings in African Americans68 suggest that it is not a risk factor in this race. However, recent data suggest 9p21 is a risk factor with a similar prevalence in Korean and Chinese populations.75

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References   1. Heart Disease and Stroke Statistics – 2005 update. American Heart Association 2005   2. American Heart Association: Heart and Stroke Statistical Update. American Heart Association; 2000. Dallas, ed   3. Chaer RA, Billeh R, Massad MG. Genetics and gene manipulation therapy of premature coronary artery disease. Cardiology. 2004;101(1–3):122–130   4. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ. 2003;326:1419–1423   5. Chan L, Boerwinkle E. Gene-environment interactions and gene therapy in atherosclerosis. Cardiol Rev. 1994;2(3): 130–137   6. Gertler M, White PD. Coronary Heart Disease in Young Adults: A Multidisciplinary Study.Cambridge: Harvard University Press; 1954   7. Lusis AJ, Mar R, Pajukanta P. Genetics of atherosclerosis. Annu Rev Genomics Hum Genet. 2004;5:189–218   8. Rose GC. Familial patterns in ischemic heart disease. Br J Prev Soc Med. 1964;(18):75–80   9. Rissanen A. Familial occurrence of coronary heart disease: effect of age at diagnosis. Am J Cardiol. 1979;44:60–66 10. Hamsten A, de Faire U. Risk Factors for coronary artery disease in families of young men with myocardial infarction. Am J Cardiol. 1987;59:14–19 11. ten Kate LP, Boman H, Daiger SP, et al. Familial aggregation of coronary heart disease and its relation to known genetic risk factors. Am J Cardiol. 1982;50:945–953 12. Sholtz RI, Rosenman RH, Brand RJ. The relationship of reported parental history to the incidence of coronary heart disease in the Western Collaborative Group Study. Am J Epidemiol. 1975;102:350–356 13. Colditz GA, Rimm EB, Giovannucci E, et al. A prospective study of parental history of myocardial infarction and coronary artery disease in men. Am J Cardiol. 1991;67:933–938 14. Barrett-Connor E, Khaw K. Family history of heart attack as an independent predictor of death due to cardiovascular disease. Circulation. 1984;(69):1065–1069 15. Colditz GA, Stampfer MJ, Willett WC, et al. A prospective study of parental history of myocardial infarction and coronary heart disease in women. Am J Epidemiol. 1986;123: 48–58 16. Schildkraut JM, Myers RM, Cupples LA, et  al. Coronary risk associated with age and sex of parental heart disease in the Framingham Study. Am J Cardiol. 1989;64:555–559 17. Phillips AN, Sharper AG, Pocock SJ, et  al. Parental death from heart disease and the risk of heart attack. Eur Heart J. 1988;9:243–251 18. Hopkins PN, Williams RR, Kuida H, et al. Family history as an independent risk factor for incident coronary artery disease in a high-risk cohort in Utah. Am J Cardiol. 1988;62: 703–707 19. Adlersberg D, Parets AD, Boas EP. Genetics of atherosclerosis: studies of families with xanthoma and unselected patients with coronary artery disease under the age of fifty years. JAMA. 1949;141:246–254 20. Blumenthal S, Jesse MJ, Hennekens CH, et al. Risk factors for coronary artery disease in children of affected families. J Pediatr. 1975;87:1187–1192

306 21. Rissanen A, Nikkila EA. Identification of the high-risk groups in familial coronary heart disease. Br Heart J. 1977;39:875 22. Hamby RI. Hereditary aspects of coronary artery disease. Am Heart J. 1981;101:639–649 23. Berg KA, Dahlen G, Borresen AL. La(a) phenotypes, other lipoprotein parameters and a family history of coronary heart disease in middle-aged males. Clin Genet. 1979;16(5): 347–352 24. Becker DM, Becker L, Pearson TA, et  al. Risk factors in siblings of people with premature coronary heart disease. J Am Coll Cardiol. 2004;12(1273):1280 25. Rosengren A, Wilhelmsen L, Eriksson E, et al. Lipoprotein (a) and coronary heart disease: a prospective case-control study in a general population sample of middle aged men. Br Med J. 2004;301:1248–1251 26. Anderson AJ, Loeffler RF, Barboriak JJ, et  al. Occlusive coronary artery disease and parental history of myocardial infarction. Prev Med. 1979;8:419–428 27. Falconer DS. The inhertiance of liability to certain diseases estimated from the incidence among relatives. Ann Hum Genet. 1965;29:51–71 28. Allen G, Harvald B, Shields JP. Measures of twin concordance. Acta Genet. 1967;17:475–481 29. Lloyd-Jones DM, Larson MR, Beiser A, et al. Lifetime risk of developing coronary heart disease. Lancet. 1999;353: 89–92 30. Nora JJ, Lortshcher RH, Spangler RD, et  al. Genetic– epidemiologic study of early-onset ischemic heart disease. Circulation. 1980;(61):503–508 31. Goldstein J, Hobbs H, Brown M. Familial hypercholeserterolemia. In: Scriver C. Beaudet A, Sly W, Valle D (eds) The metabolic and molecular bases of inherited disease. Vol II. McGraw Hill, New York, pp. 2862–2913 32. Innerarity TL, Mahley RW, Weisgraber KH, et al Familial defective apolipoprotein B-100: a mutation of apolipoprotein B that causes hypercholesterolemia. J Lipid Res 1990:31;1337–1349 33. Kotowski, I.K. et al. A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol. Am. J. Hum. Genet. 2006:78;410–422 34. Austin MA, Hutter CM, Zimmern RL, Humphries SE. Familial hypercholesterolemia and coronary heart disease: A HuGE Association Review. Am J Epidemiol. 2004;160(5): 421–429 35. Lusis AJ, Rotter JL, Sparkes RS. Genetic markers for studies of atherosclerosis and related risk factors. In: Lusis AJ, Rotter JL, Sparkes RS, eds. Molecular Genetics of Coronary Artery Disease. Candidate Genes and Processes in Atherosclerosis.New York: Karger; 1992:363–418 36. Breslow JL. Genetics of lipoprotein abnormalities associated with coronary artery disease susceptibility. Annu Rev Genet. 2000;34:233–254 37. Marian AJ, Brugada R, Roberts R. Cardiovascular diseases caused by genetic abnormalities. In: O’Rourke RA, Fuster V, Alexander RW, Roberts R, eds. Hurst’s The Heart – Manual of Cardiology. 12th ed. New York: McGraw Hill; 2007 38. Investing in our Future: Preventing Chronic Diseases in Canada. Chronic Disease Prevention Alliance of Canada 2003 39. Marian AJ, Roberts R. The molecular genetic basis for hypertrophic cardiomyopathy. J Mol Cell Cardiol. 2001; 33(4):655–670

R. Roberts et al. 40. Goncalo A, Kwong-Hang Tam P, Bustamante C, Ostrander EA, Scherer SW, et  al. Human Genome Variation 2006: emerging views on structural variation and large-scale SNP analysis. Nat Genet. 2007;39(2):153–155 41. Hinds DA, Stuve LL, Nilsen GB, et al. Whole-genome patterns of common DNA variation in three human populations. Science. 2005;307:1072–1079 42. Iles MM. What can Genome-wide Association studies tell us about the genetics of common disease? PLoS Genetics. 2008;4(2):1–7 43. Cohen JC, Kiss RS, Pertsemlidis A, Marcel YL, McPherson R, Hobbs HH. Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science. 2004;305(5685): 869–872 44. Peng B, Kemmel M. Simulations provide support for the common disease-common variant hypothesis. Genetics. 2007;175:763–776 45. Wang WY, Barratt B, Clayton DG, Todd JA. Genome-Wide Association Studies: theoretical and practical concerns. Nat Rev Genet. 2005;6:109–118 46. Hirshhorn JN, Daly MJ. Genome-wide association studies for common diseases and complex traits. Nat Rev Genet. 2005;6:95–108 47. Pare G, Serre D, Brisson D, et al. Genetic analysis of 103 candidate genes for coronary artery disease and associated phenotypes in a founder population reveals a new association between endothelin-1 and high-density lipoprotein cholesterol. Am Hum Genet. 2007;80(4):673–682 48. Krushkal J, Xiong M, Ferrell RE, et al. Linkage and association of adrenergic and dopamine receptor genes in the distal portion of the long arm of chromosome 5 with systolic blood pressure variation. Hum Mol Genet. 2005;7:1379–1383 49. Heinonen P, Koulu M, Pesonen U, et al. Identification of a three-amino acid deletion in the alpha2B-adrenergic receptor that is associated with reduced basal metabolic rate in obese subjects. J Clin Endocr Metab. 1999;84:2429–2433 50. Horikawa Y, Oda N, Cox NJ, et al. Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nat Genet. 2000;26:163–175 51. Stone LM, Kahn SE, Fujimoto WY, et al. A variation at position -30 of the beta-cell glucokinase gene promoter is associated with reduced beta-cell function in middle-aged Japanese-American men. Diabetes. 2005;45:422–428 52. Morgan TM, Krumholz HM, Lifton RP, Spertus JA. Nonvalidation of reported genetic risk factors for acute coronary syndrome in a large-scale replication study. JAMA. 2007;297(14):1551–1561 53. Helgadottir A, Manolescu A, Thorleifsson G, et al. The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nat Genet. 2004;36(3): 233–239 54. Thomas DC, Haile RW, Duggan D. Recent developments in genomewide association scans: A workshop summary and review. Am J Hum Genet. 2005;77:337–345 55. Risch N, Merikangas K. The future of genetic studies of complex human diseases. Science. 1996;273(5281): 1516–1517 56. Lander ES. The new genomics: global views of biology. Science. 1996;274:536–539 57. Kruglyak L. Prospects for whole-genome linkage disequilibrium mapping of common disease genes. Nat Genet. 1999;22:139–144

23  The Genetic Challenge of Coronary Artery Disease 58. The International HapMap Consortium. The International HapMap Project. Science. 2003;426:789–796 59. Roberts R. “New Gains in Understanding Coronary Artery Disease”, Interview with Dr. Robert Roberts. Affymetrix Microarray Bull. 2007;3(2):1–4 60. Roberts R, Stewart AFR. Personalized medicine: a future prerequisite for the prevention of coronary artery disease. Am Heart J. 2006;4(3):222–227 61. Zheng G, Friedlin B, Gastwirth JL. Comparison of robust tests for genetic association using case-control studies. In: IMS Lecture Notes, editor. Eric L. Lehmann Symposium 2006. IMS Lecture Notes-Monograph Series; 2nd. Ref Type: Sound Recording 62. Li Q, Zheng G, Li Z, et al. Efficient approximation of p-value of the maximum of correlated tests, with application to genome-wide association studies. Ann Hum Genet. 2008;72: 397–406 63. Sabatti C, Service S, Freimer N. False discovery rate in linkage and association genome screens for complex disorders. Genetics. 2003;162(2):829–833 64. Klein RJ, Zeiss C, Chew EY, et  al. Complement factor H polymorphism in age-related macular degeneration. Science. 2005;308(5720):385–389 65. Sladek R, Rocheleau G, Rung J, et al. A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature. 2007;445(7130):881–885 66. Graham RR, Kozyrev SV, Baechler EC, et  al. A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus. Nat Genet. 2006;38(5): 550–555 67. Amundadottir LT, Sulem P, Gudmundsson J, et al. A common variant associated with prostate cancer in European

307 and African populations. Nat Genet. 2006;38(6): 652–658 68. Glazier AM, Nadeau J, Ajioka J. Finding genes that underlie complex traits. Science. 2002;298:2345–2349 69. McPherson R, Pertsemlidis A, Kavaslar N, et al. A common allele on Chromosome 9 associated with coronary heart disease. Science. 2007;316:1488–1491 70. Helgadottir A, et  al. A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science. 2007; 316(5830):1491–1493 71. Wellcome Trust Case Consortium. Genome-wide association study of 14, 000 cases of seven common diseases and 3, 000 shared controls. Nature. 2007;447(7145):661–678 72. Samani NJ, Erdmann J, Hall AS, et al. Genomewide association analysis of coronary artery disease. New Engl J Med. 2007;357(5):443–453 73. Broadbent HM, Peden JF, Lorkowski S, Goel A, Ongen H, Green F, et al. Susceptibility to coronary artery disease and diabetes is encoded by distinct, tightly linked, SNPs in the ANRIL locus on chromosome 9p. Hum Mol Genet. 2007;29: ddm352 74. Pasmant E, Laurendeau I, Heron D, Vidaud M, Vidaud D, Bieche I. Characterization of a germ-line deletion, including the entire INK4/ARF locus, in a melanoma-neural system tumor family: identification of ANRIL, an antisense noncoding RNA whose expression coclusters with ARF. Cancer Res. 2007;67(8):3963–3969 75. Helgadottir A, et al. The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm. Nat Genet. 2008;40(2): 217–224 76. Hinohara K, et al. Replication of the association between a chromosome 9p21 polymorphism and coronary artery disease in Japanese and Korean populations. J Hum Genet. 2008;53(4):357–359

Part Ethical, legal and Social implications

V

Psychological Implications of Genetic Investigations

24

April Manuel, Fern Brunger, and Kathy Hodgkinson

The psycho-social effects of DNA testing for syndromes that cause a sudden cardiac death (SCD) are both variable and context-dependent. The meanings of risk and the experiences of vulnerability related to genetic testing are shaped by multiple factors, including relationships with other family members, the experience of living in the family at risk for a particular disease; one’s perception of self, sense of control, and understanding of the disease; and the modalities of treatment used.1-4 Importantly, DNA testing for SCD, in the absence of any clinical symptoms, marks the onset of the illness experience and in this respect, testing for SCD and the concomitant prophylactic treatment raises unique psycho-social issues that may be different from those associated with cardiac disease in general. In this chapter, we examine the psychological and social implications of genetic testing for SCD and highlight areas of particular need for attention by health care providers.

24.1 Psycho-Social Effects of Genetic Testing Genetic testing for a hereditary disease typically allows for screening and early detection, followed by the implementation of interventions or behavioral changes, which may slow progression of the disease.3,5-7 The expectation is that genetic testing also provides psychological and A. Manuel (*) School of Nursing, Memorial University of Newfoundland and Labrador, 300 Prince Phillip Drive, St John’s, Newfoundland, Canada, A1B 3V6 e-mail: [email protected]

social benefits. For example, awareness of one’s genetic predisposition may decrease stress and facilitate coping. Testing may be of psychological value to an individual who suspects they may be a carrier of a mutation due to kinship ties to an affective relative. Testing may enable one to anticipate symptoms early in the disease process and prepare for future consequences of the disease.8 A hereditary disorder for which DNA testing is available has many psychological and social implications that are not solely related to carrier well-being; test results may also have implications for the family and even a wider social group. Most obviously, financial stressors associated with a positive test result may impact the family in multiple ways. Financial concerns include inability to get health care insurance coverage,3 cost of medications, loss of work time, and the cost associated with travel to receive treatment. Quite often medical management for illness symptoms is complex and requires hospitalization, further exacerbating financial stressors. A positive hereditary genetic test result will also have implications for kin beyond the social network and for the “potential” kin of subsequent generations. One may feel a sense of guilt that they are responsible for passing the gene to their offspring.7 There may be a reluctance to disseminate genetic risk information to other family members in an effort to protect them psychologically and preserve the hope that the disease would not become part of their lives.9 Choices regarding reproduction and marriage are often called into question. If a family member tests positive for a genetic disease, reassignment of roles within the family may occur. There may have to be a renegotiation of the daily running of the household, child care considerations, management of finances and workplace obligations. There may also be changing communication patterns as alliances between affected relatives become stronger

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and unaffected relatives weaker. Affected people may be no longer invited into in-depth family decisions in anticipation of their death and efforts of the family to start the inevitable grieving process. Unaffected members find themselves having to deal with a sense of survivor guilt because their DNA test was negative whereas, another relative’s test was positive.10

24.2 Living with Hereditary SCD Syndrome Little is known about the particular psycho-social effects of undergoing predictive DNA testing for hereditary SCD. Research on cardiac disease in general reports accounts of efforts to cope with a failing body, living under a threat of illness, enduring a heightened sense of uncertainty and increased vulnerability, losing control of one’s body, dealing with an altered body image, losing track of one’s life and struggling to balance activities of life.11-15 Coping mechanisms are reported to include: accepting limitations, believing in the future, using available supports,14 achieving some sense of normalcy,12 having a positive outlook, knowledge seeking, and lifestyle management.11 One might argue that the experience of living with a cardiac disease is similar to living with a SCD syndrome as these individuals face similar psycho-social challenges. However, it is the predictive nature of DNA testing that permeates one’s illness experience and alters one’s perception of risk that causes stress in this population. To explain the psycho-social effects of living in a family with a history of SCD and receiving treatment, we use the example of arrhythmogenic right ventricular cardiomyopathy (ARVC). ARVC is a lethal autosomal dominant genetic linked disease with high mortality due to ventricular tachyarrhythmias.16,17 One genetic subtype of ARVC is prevalent in Newfoundland, where 15 families, sometimes comprising up to 9 generations manifest the disease. This subtype of ARVC is caused by a mutation in the TMEM43 gene on the short arm of chromosome three, which codes for TMEM43, a transmembrane protein of unknown function, but which is conserved throughout evolution.18 The gene was linked to this location in 1998, and genetic testing in the form of linkage analysis of a founder haplotype has been available since this time.19 Thus, prior to 1998, individuals were provided with a pedigree risk

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of 50% of inheriting the ARVC gene, if they had an affected parent, and the only way to refine that risk was to provide clinical cardiac testing. If anomalies occurred, or the individual became symptomatic, then the diagnosis would be considered. Post 1998, the genetic haplotype was utilized, thus individuals, following informed consent and genetic testing, would be provided with a high risk, or low-risk result. In effect, their risk would be either raised from their 50% pedigree risk to 95%, or decreased to 5%. Pretreatment analysis of the natural history of the disease confirms that which families have always known: death is often the first symptom. Robust analysis over the generations demonstrate that 50% of men will be dead by age 40 years, 80% by age 50 years, the equivalent figures for women being 5% and 20%, respectively.16 The research has also confirmed that this is an arrhythmic disorder, and that if death does not occur due to those arrhythmias, then heart failure is a possibility, followed by heart transplantation. Treatment modalities for ARVC include pharmacological interventions such as beta blockers to suppress arrthymias, cardiac catheter ablation to restore normal electrical activity to the heart, and the use of an implantable cardioverter defibrillator (ICD).17 The ICD is a device implanted in the chest wall. The ICD is programmed to recognize life threatening cardiac arrthymias and prevents their occurrence by either pacing, converting or by delivering an electrical shock called defibrillation.20 Research on the effectiveness of ICD on mortality from ARVC has reported that it is a life saving treatment, preventing lethal cardiac arrthymias associated with SCD.21-24 Research in the province of Newfoundland has shown treatment of ARVC with an ICD to decrease the mortality rates to 0% within 5 years post insertion.16 For individuals at risk for SCD, particularly those with no signs or symptoms, it is the treatment that follows a high risk test result and less frequently a low risk test result that truly marks the onset of the illness experience. SCD is similar to other genetic tests in that the test itself marks the transition to being ill. Research on genetic testing for hereditary disease in general has shown that the availability of testing has meant that people define themselves as ill and experience psychosocial effects of the potential illness in the absence of symptoms. That is, the perception of risk, in the absence of disease symptoms, marks the onset of and shapes the illness experience. Nelkin, in her research

24  Psychological Implications of Genetic Investigations

on predictive testing for hereditary cancers, highlighted how in the absence of disease, individuals who test positive and are asymptomatic gain a new status – the “presymptomatic ill”.25 However, for genetic testing for SCD, the treatment that follows a positive test result itself elicits symptoms and marks the onset of an even more profound illness experience.

24.3 The Firing of the ICD as Symptom Implantation of an ICD is the standard of care for treating individuals at risk for SCD syndromes such as ARVC. Affected individuals face both behavioral and psychological challenges in their lives as they live in constant fear of triggering the ICD. The ICD responds to ventricular cardiac arrthymias by providing an electrical shock to the heart in order to prevent SCD. Sometimes inappropriate shocks occur when a fast sinus rhythm will trigger a firing, rather than a ventricular rhythm. Whether the ICD has fired appropriately or inappropriately, will be definable when the device is read by the ICD clinic computer system. Thus, any uncertainty about the firing of the ICD will last from the firing until the device is interrogated. Usually, if it has fired due to a rhythm, it will be recalibrated to prevent its reoccurrence. Theoretically, the issue of provoking the device should be minimized. There are cases however, where individuals are at the terminal stage in the disease and they have frequent episodes of ventricular tachycardia. In these cases, the ICD is firing a lot and can be very stressful for the affected individual. Thus, an individual with an ICD can experience anxiety surrounding their perception of the types of activities or events that will provoke the ICD to fire; therefore, these individuals are consciously engaged in constant surveillance of their heart rate in an effort to predict the next firing of the ICD. It is this conscious awareness of the body’s functioning capacity, of the body’s potential for failure, and of the body’s reliance on the ICD that causes anxiety.26 For example, a random increase in heart rate due to some simple, routine, physical activity (such as bringing in groceries, which had been done weekly for years with no health problem resulting) might trigger the ICD. Once the patient recovers from the incident, they rush to the clinic and earnestly wait to download the ICD computer information to see if the reason for the

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firing of the ICD was an arrthymia, or a mistake. The firing of the ICD confirms the patient’s illness, is a reminder of their genetic condition, and represents the progression of and loss of control over the disease. The firing of the ICD confirms that the individual cannot function autonomously anymore but relies on the ICD to sustain life.20 Depression and anxiety have been found to escalate with frequency of ICD shocks.27 Although the firing of the ICD may be considered an isolated event by caregivers, it reflects and hardens the experience. As the individual increasingly takes on the illness role, they may also monitor environmental triggers to, and solutions for, the potential ICD firing. For example, locations of essential objects such as chairs, phones, bathrooms and water fountains are all visualized for quick access. There is also avoidance of activities, objects and places that are deemed to trigger the ICD to fire, such as mobile phones, stairs, and physical activities outside the house. This manipulation of the physical environment becomes essential for establishing a sense of safety.28 An individual may avoid being alone in case the ICD fires, or in public in case they receive a shock in the vicinity of people not familiar with ICD management.20 Social encounters may be increasingly difficult as individuals become embarrassed if the ICD fires and results in a syncope episode: one’s personal health quickly becomes public knowledge in seconds if the ICD fires and reveals the presence of the disease. The end result is often anxiety and depression rooted in feelings of social isolation. This sense of isolation may be exacerbated if repeat firings lead to the loss of social privileges out of a concern for public safety. The loss of one’s driver’s permit, trucking license, or pilot’s license can further facilitate social isolation and add to financial losses. Individuals whose privileges are removed may feel punished for having symptoms of the disease. A feeling of having little control over one’s life may feed into a negative cycle of fear, loss of control, fatalism and uncertainty. Aside from illness experiences related to the firing of the ICD, psychological distress due to side effects of treatments may be common with SCD syndromes. Common medications such as beta-blockers and antiarrthymics can make a person tired, interfere with their work commitments, suppress their appetite or cause nausea, any of which may result in an inability to participate in regular daily activities of living. The side

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effects of treatment, like the firing of the ICD, are a constant reminder of one’s genetic vulnerability; a reminder of the limitations put on activities of daily living, and increasingly influences how being at risk shapes their illness experience.

24.4 Variations on the Illness Experience Importantly, a burgeoning literature on genetic testing for hereditary illness shows that the psycho-social effects of testing are neither straightforward nor uniform, even for individuals receiving the same test result for the same condition. For example, some researchers assume that individuals with a positive test result will use the information to be proactive about their health. Davison gives the example that someone with an inherited susceptibility to coronary thrombosis and musculo-skeletal problems may decide never to eat high-fat foods nor play impact or contact sports.29 Another person with a quite different “genetic read-out” may become particularly wary of entering smoky rooms, or being exposed to bright sunlight His research has shown that while one person may decide “I have inherited a particularly high risk of lung disease, so I must not smoke” another may have a quite different response: “I am genetically programmed to get lung disease, so it doesn’t much matter what I do.”30 Davison concludes that what individuals and communities do with their risk information will become increasingly important in defining who they are and who they appear to be.29 This may be particularly true for SCD. In particular, individuals who perceive their test as either high or low risk and receive prophylactic therapy may challenge activity restrictions in efforts to evoke disease and confirm its existence, and live under a constant burden of uncertainty. Drawing from feelings of uncertainty surrounding the reality of their disease, and living with the fact that the disease may be lurking and waiting for the opportunistic time to manifests itself, people with genetic-linked disorders may live their lives with a constant fatalist attitude.7 In the absence of research on how risk is managed by patients with hereditary SCD, health care professionals must be particularly attentive to the translation of risk into a fatalistic attitude.

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24.5 Children as the “Presymptomatic Ill” The research on SCD reports significant psychological distress associated with having a child at risk for SCD.31 Parents with children with long QT syndromes report close monitoring of their child’s activities, particularly sports activities. While parents understand treatments such as the ICD as important “safety nets” for their child, they also face stressful challenges as they try to balance adherence to medications with maintaining some sense of normalcy.32

24.6 Future Directions Research on genetic testing in general has shown a wide variation in the psycho-social experiences of being tested for a genetic condition. This variability can be attributed to differences in the disease and its penetrance; on the availability of support networks and coping strategies; on one’s perceived susceptibility to the disease; on the accuracy of test results; and on the range and types of available medical treatments.1-4,33 The lack of consensus in the research literature on the impact of genetic testing on the lives of at-risk individuals illustrates the importance of further examination of the experiences of those who test positive. For example, some studies suggest that genetic testing does not cause psychological distress.33 Others report that, in fact, there is little difference in the level of psychological distress for individuals with a positive or negative test result.8,34-37 Moreover, several research findings report no changes, slight changes or transient changes in psychological outcomes in carriers and noncarriers of a genetic disease post testing.36,38-41 These research studies suggest that efforts should not focus on psychological counseling but on practices to promote individual coping skills in response to genetic risk information.42 Another body of literature, which examines the psychological impact of genetic testing on individuals and their families reports a marked increase in psychological distress of carriers,9,41,43-49 and a corresponding decrease in psychological distress in noncarriers.40,42-44,48-50 These studies support the role of psychological counseling throughout the entire genetic testing process.

24  Psychological Implications of Genetic Investigations

For SCD, it is imperative to examine the variability of psycho-social effects of testing on individuals and families of those receiving positive and negative test results. Moreover, little is known about the psychosocial implications of waiting for test results, receiving an inconclusive test result, being denied testing because of not fulfilling the criteria, or declining to have testing. These are critical areas of inquiry if the needs of the population at-risk for SCD are to be adequately addressed. Further qualitative research in this area is needed if health care professionals are to achieve a better understanding of the impact of genetic testing on the lives of families susceptible to SCD.

24.7 Conclusion In this paper, we argued that the psycho-social implications of genetic testing for SCD are most keenly felt through the availability of testing and use of treatment. In particular, the initial firing of the ICD represents the transition from being at risk to taking on the illness role. If health care professionals are to advocate for the families living with the uncertainty of SCD, they must gain a fuller understanding of the psychological impact of predictive genetic testing on patient’s lives. The mere offer of genetic testing will have an impact on individuals and families; but how that impact is felt, understood and managed will vary considerably. In the absence of research on the wide range of experiences of individuals living in families with SCD, health care professionals must be diligent about inquiring into the psychological and social impact that the availability of the test is having on individuals and their families.

References   1. Bleiker EMA, Hahn EE, Aaronson NK. Psycho-social issues in cancer genetics. Acta Oncologica. 2003;42(4):276–286   2. Braithwaite D, Emery J, Walter F, et al. Psychological impact of genetic counseling for familial cancer: a systematic review and meta-analysis. Fam Cancer. 2006;5:61–65   3. Lerman C, Shields AE. Genetic testing for cancer susceptibility: the promise and the pitfalls. Nat Rev. 2004;4: 235–241   4. Salkovskis PM, Rimes KA. Predictive genetic testing: psychological factors. J Psychosom Res. 1997;43(5):477–487

315   5. Hodge JG. Ethical issues concerning genetic testing and screening in public health. Am J Med Genet C. 2004;125(1): 66–70   6. Roberts JS. Anticipating response to predictive genetic testing for Alzheimer’s disease: a survey of first-degree relatives. Gerontologist. 2000;40(1):43–52   7. Walter FM, Emery J. ‘Coming down the line’ – patients’ understanding of their family history of common chronic disease. Ann Fam Med. 2005;3:405–414   8. Decruyenaere M, Evers-Kiebooms G, Cloostermans T, et al. Psychological distress in the 5-year period after predictive testing for Huntington’s disease. Eur J Hum Genet. 2003;11(1):30–38   9. Holt K. What do we tell the children? Contrasting the disclosure choices of two HD families regarding risk status and predictive genetic testing. J Genet Couns. 2006;15(4): 253–265 10. Sobel S, Cowan CB. Ambiguous loss and disenfranchised grief: the impact of DNA predictive testing on the family as a system. Fam Process. 2003;42(1):47–55 11. Bergman E, Bertero C. Grasp life again. A qualitative study of the motive power in myocardial infarction patients. Eur J Cardiovasc Nurs. 2003;2:303–310 12. Claessens P, Moons P, Dierckx de Castle B, et al.What does it mean to live with a congenital heart disease? A qualitative study on the lived experiences of adult patients. Eur J Cardiovasc Nurs. 2005;4:3–10 13. Frich JC, Ose L, Malterud K, et al. Perceived vulnerability to heart disease in patients with familial hypercholesterolemia: a qualitative interview study. Ann Fam Med. 2006;4: 198–204 14. Martensson J, Karlsson JE, Frilund B. Male patients with congestive heart failure and their conception of the life situation. J Adv Nurs. 1997;25(30):579–586 15. Nordgren L, Asp M, Fagerberg I. Living with moderatesevere chronic heart failure as a middle-aged person. Qual Health Res. 2007;17(1):4–13 16. Hodgkinson KA, Parfrey PS, Bassett AS, et al. The impact of implanatable cardioverter-defibrillator therapy on survival in autosomal-dominant arhythmogenic right ventricular cardiomyopathy (ARVD5). J Am Coll Cardiol. 2005;45(3): 400–408 17. Indik JH, Marcus FI. Arrhythmogenic right ventricular cardiomyopathy/dysplasia. Indian Pacing Electrophysiol J. 2003;3(3):148–156 18. Merner ND, Hodgkinson KA, Haywood AFM, et  al. Arrthymogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrthymic disorder caused by a missense mutation in the TMEM43 gene. Am J Hum Genet. 2008;82:809–821 19. Ahmad F, Li D, Gonzalez, et  al. Localization of a gene responsible for arrthymogenic right ventricular dysplasia to chromosomes 3p23. Circulation. 1998;98:2791–2795 20. Kamphuis H, Verhoeven N, de Leeuw R, et al. ICD: a qualitative study of patient experience the first year after implantation. J Clin Nurs. 2004;13:1008–1016 21. Corrado D, Leoni L, Link M, et al. Implantable cardioverterdefibrillator therapy for the prevention of sudden death in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia. Circulation. 2003;108:3084–3091

316 22. Roguin A, Bomma CS, Nasir K, et al. Implanatable cardioverter-defibrillators in patients with arrhythmogenic right ventriculardysplasia/cardiomyopathy. J Am Coll Cardiol Foundation. 2004;43:1843–1852 23. Tavernier R, Gevaert S, DeSutter J, et al. Long-term results in cardioverter-defibrillator implantation in patients with right ventricular dysplasia and malignant ventricular tachyarrhythmais. Heart. 2001;85:53–56 24. Wichter T, Paul M, Wollman C, et al. Implanatable cardioverter/defibrillator therapy in arrhytmogenic right ventricular cardiomyopathy. Single–center experience of long-term follow-up and complications in 60 patients. Circulation. 2004;109:1503–1508 25. Nelkin D. The social power of genetic information. In: Kevles DJ, Hood L, eds. The Code of Codes: Scientific and Social Issues in the Human Genome Project. Cambridge: Harvard University Press; 1992:177–190 26. Hegel MT, Griegel LE, Goulden L, et al. Anxiety and depression in patients receiving implanted cardioverter-defibrillators: a longitudinal investigation. Int J Psychiatry Med. 1997;27(1):57–69 27. Bostwick JM, Sola CL. An updated review of implantable cardioverter/defibrillators, induced anxiety, and quality of life. Psychiatric Clin North Am. 2007;30:677–688 28. Lemon J, Edelman S, Kirkness, A. Avoidance behavior in patients with implantable cardioverter defibrillators. Heart Lung. 2004;33(3):176–182 29. Davison C. Predictive genetics: the cultural implications of supplying probable futures. In: Marteau T, Richards M, eds. The Troubled Helix: Social and Psychological Implications of the New Human Genetics. Cambridge: Cambridge University Press; 1996:321–329 30. Davison C, Frankel S, Smith GD. The limits of lifestyle: reassessing “Fatalism” in the popular culture of illness prevention. Soc Sci Med. 1992;34(6):675–685 31. Hendriks KSWH, Grosfield FJM, van Tintelen JP, et al. Can parents adjust to the idea that their child is at risk for a sudden death?: psychological impact of risk for long QT syndrome. Am J Med Genet. 2005;138A (20):107–112 32. Farnsworth M, Fosyth D, Haglund C, et al. When I go in to wake them…I wonder: parental perceptions about congenital long QT syndrome. J Am Acad Nurse Pract. 2006;18:284–290 33. Meiser B. Psychological impact of genetic testing for cancer susceptibility: an update of the literature. Psych-Oncology. 2005;14:1060–1074 34. Cordori A, Zawacki K, Petersen GM, et al. Genetic testing for hereditary colorectal cancer in children: Long-term psychological effects. Am J Med Genet. 2003;116A:117–128 35. Evers-Kiebooms G, Decruyenaere M. Predictive testing for Huntington’s disease: a challenge for persons at risk

A. Manuel et al. and for professionals. Patient Educ Couns. 1998;1: 15–26 36. Reichelt JG, Heimdal K, Moller P, et  al. BRCA1 Testing with definitive results. A prospective study of psychological distress in a large clinical-based sample. Fam Cancer. 2004; 3:21–28 37. Gritz ER, Peterson SK, Vernon SW, et  al. Psychological impact of genetic testing for heredity non-polyposis colorectal cancer. J Clin Oncol. 2005;23(9):1902–1910 38. Shaw C, Abrams K, Marteau TM. Psychological impact of predicting individuals’ risks of illness: a systematic review. Soc Sci Med. 1999;49:1571–1598 39. Aktan-Collan K, Haukkala A, Mecklin JP, et  al. Comprehension of cancer risk one and 12 months after predictive genetic testing for hereditary non-polyposis colorectal cancer. J Med Genet. 2001;38:787–792 40. Schwartz M, Peshkin B, Hughs C, et al. Impact of BRCA1/ BRCA2 mutation testing on psychological distress in a clinic- based sample. J Clin Oncol. 2002;20:514–520 41. Meiser B, CollinsV, Warren R, et al. Psychological impact of genetic testing for hereditary non- polyposis colorectal cancer. Clin Genet. 2004;66(6):502–511 42. Lerman C, Croyle RT, Tercyak KP, et  al. Genetic testing: psychological aspects and implications. J Consult Clin Psychol. 2002;70(3):784–797 43. Lodder L, Frets PG, Trijsburg RW, et  al. Psychological impact to receiving a BRCA1/BRCA2 test result. Am J Med Genet. 2001;98:15–24 44. Mitchie S, Bobrow M, Marteau T. Predictive genetic testing in children and adults. A study of the emotional impact. J Med Genet. 2001;38:519–526 45. Meiser B, Butow P, Friendlander M, et  al. Psychological impact of genetic testing for breast cancer susceptibility. Eur J Cancer. 2002;38:2025–2033 46. Michie S, French DP, Marteau TM. Predictive genetic testing: mediators and moderators of anxiety. Int J Behav Med. 2002;9(4):309–321 47. Van Roosmalen MS, Stalmeier PF, Verhoef LC, et al. Impact of BrCA1/2 testing and disclosure of a positive result on women affected and unaffected with breast or ovarian cancer. Am J Med Genet. 2004;124A:346–355 48. Claes E, Denayer L, Evers-Kiebooms G, et  al. Predictive testing for hereditary non-polyposis colorectal cancer: motivation, illness representation and short-term psychological impact. Patient Educ Couns. 2004;55(2):265–274 49. Watson M, Foster C, Eeles R, et al. Psychological impact of breast/ovarian (BRCA1/2) cancer-predictive testing in a UK multi-centre cohort. Br J Cancer. 2004;91(10):1787–1794 50. Croyle RT, Smith KR, Botkin JR, et  al. Psychological responses to BRCA1 mutation testing: preliminary findings. Health Psychol. 1997;16:63–72

Participation in Recreational Sports for Young Patients with Genetic Cardiovascular Diseases

25

Barry J. Maron

Portions of the text are reproduced with permission of the American Heart Association, from Maron et  al. Circulation. 2004;109:2807-2816.

25.1 Introduction Genetic cardiovascular diseases (GCVDs) include hypertrophic cardiomyopathy (HCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), Marfan syndrome, and the ion-channel diseases, i.e., long-QT syndrome (LQTS), Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia (CPVT).1-16 Although relatively uncommon in the general population and most cardiology practices, these conditions are nevertheless frequently associated with an increased risk of sudden death during exercise, events which are devastating to the families, community, and physicians, particularly in light of the youthful age of the victims. GCVDs account for a substantial proportion of the unexpected and usually arrhythmic, fatal events occurring during adolescence and young adulthood.1-27 Recently, much of the attention of the medical community has been directed toward trained athletes with cardiovascular disease engaged in organized, competitive sport programs for whom sudden death often occurs during or shortly after vigorous exertion on the athletic field, i.e., the American College of Cardiology

B. J. Maron (*) Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, 920 E 28th Street, Suite 620, Minneapolis, MN 55407, USA e-mail: [email protected]

Bethesda Conferences recommendations for eligibility and disqualification28-30 and the similar European Society of Cardiology (ESC) guidelines.31 These scientific statements are predicated on the view that intense physical exertion may create greater susceptibility to sudden death in athletes with underlying heart disease and unstable electrophysiological substrates;17,19,23-25,30,31 conversely, restriction from the unique lifestyle of competitive sports is likely to diminish risk for an arrhythmia-based catastrophe.30,31 Nevertheless, most individuals with GCVDs are not involved in competitive athletics or have been removed from these activities because of their diagnosis. Furthermore, the majority of sudden deaths which occur in individuals with GCVD are unassociated with involvement in competitive sports.25 The practicing clinician is frequently confronted with the dilemma of designing noncompetitive exercise programs for those athletes with GCVDs after disqualification from competition, as well as for those patients who do not aspire to organized sports. Indeed, many asymptomatic (or mildly symptomatic) patients with GCVDs desire a physically active lifestyle and participate in recreational and leisure-time activities to take advantage of the many established benefits of exercise.32-34 Previously published guidelines for recreational sports have focused narrowly on individuals participating in settings such as health and fitness facilities32 or in competitive Master’s sports.34 The guidelines for physical activity related to competitive sports participation in trained athletes are well documented in the American College of Cardiology Bethesda Conference #3630 and the ESC guidelines,31 and are not discussed here. The conflict between the known benefits and potentially adverse consequences of exercise and the desire of young individuals with GCVDs to participate in various levels of physical

R. Brugada et al. (eds.), Clinical Approach to Sudden Cardiac Death Syndromes, DOI: 10.1007/978-1-84882-927-5_25, © Springer-Verlag London Limited 2010

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activity creates a demand for appropriate information to resolve uncertainty in these difficult clinical decisions. The American Heart Association (AHA) consensus panel recommendations35 represent the most appropriate systematic practice guidelines currently available, concerning the risks associated with recreational (noncompetitive) exercise in adolescents and young adults with GCVDs. These recommendations form the basis of this chapter.

25.2 Definitions Sports activity. For the purpose of this discussion, recreational sports activities are defined in juxtaposition to competitive sports. A competitive athlete is one who participates in organized team or individual sport that requires systematic training and regular competition against others and places a high premium on athletic excellence and achievement.30 Characteristic of competitive athletes is the strong inclination to extend themselves to extremely high levels of exertion, often exceeding their native physical limits and sometimes for prolonged periods of time, regardless of other considerations. Conversely, individuals participating in a variety of informal recreational sports and circumstances engage in a range of exercise levels from modest to vigorous on either a regular or an inconsistent basis, which do not require systematic training or the pursuit of excellence and are without the pressure to excel against others which characterize competitive sports. The lack of systematic athletic conditioning in the definition of recreational sports is expected to decrease the risk of cardiovascular events. Sudden cardiac death. The interaction between certain acute triggers and underlying heart disease (i.e., the arrhythmic substrate) can result in sudden death in susceptible young active people. Triggers for lifethreatening ventricular tachyarrhythmias and sudden death during sports include emotional stress, environmental factors, myocardial ischemia, sympatheticvagal inbalance, and hemodynamic changes. Intensive and systematic athletic training itself may increase the risk of sudden death in the presence of heart disease by promoting disease progression or worsening of the arrhythmogenic substrate (either structurally or electrically) over time.

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For example, in patients with HCM, recurrent episodes of exercise-induced myocardial ischemia during intensive training may result in cell death and myocardial replacement fibrosis, which in turn enhances ventricular electrical instability.36 In ARVC, regular and intense physical activity may provoke right ventricular volume overload and cavity enlargement which in turn may accelerate fibro-fatty atrophy.37 In patients with Marfan syndrome, the hemodynamic stress placed on the aorta by increased blood pressure and stroke volume during intense activity (particularly with rapid acceleration and deceleration) may promote and increase the rate of aortic enlargement.38 However, in the majority of patients with Brugada syndrome, the malignant ventricular arrhythmias occur at rest and, in many cases, at night as a consequence of an increased vagal activity and/or withdrawal of sympathetic activity.7,39 Enhanced adrenergic drive, such as that which occurs during sports activity, could have an inhibitory effect and theoretically reduce sudden death risk. In formulating these definitions, it should be underscored that some individuals participating in recreational sports nevertheless train systematically (similar to, and as a surrogate for, competitive athletics). Indeed, it is far easier to formulate recommendations for competitive sports, which are easily defined forms of exercise, than for recreational sports, which may include a multitude of physical activities that are part of ordinary daily life.

25.3 Scope of the Problem A number of largely congenital and/or inherited cardiovascular disease have been linked causally to unexpected sudden cardiac death in young people, including those engaged in either leisure sporting activities or organized and truly competitive athletics.6,7,17-27,35,39,40 Although regional differences have been reported, in US-based surveys, the most common cause of these deaths have been HCM, and congenital coronary artery anomalies with origin from the wrong sinus of Valsalva.17,19,20,22,23,25,40,41 In Italy, ARVC37 and premature atherosclerotic coronary artery disease predominate as causes of sudden death in young athletes.42 On the basis of data from the United States, GCVDs account for at least 40% of sudden death in young athletes.25,35,40 Many patients with the conditions aspire to

25  Participation in Recreational Sports for Young Patients with Genetic Cardiovascular Diseases

participate in a variety of recreational sporting activities, and some may have been previously withdrawn from competitive sports in accordance with the recommendations of Bethesda Conference #36.30 Furthermore, the number of young patients and family members identified with these cardiac diseases has greatly increased because of advances in diagnostic molecular genetics and enhanced survival attributable to contemporary management strategies. Therefore, there is now a substantial population of youthful active patients with GCVDs who require prudent recommendations regarding exercise programs. The health benefits of exercise at all ages have been emphasized repeatedly and promoted as a national public health agenda.32-35,43,44 Certainly, there is substantial evidence that considerable medical advantage is derived from even regular moderate exercise and fitness, such as improvement in aerobic power and maximum oxygen uptake, blood lipid levels and glucose tolerance, as well as enhanced self-assurance, a sense of psychological and physical well-being, and improved overall quality of life.33,35,43,44 Undoubtedly, similar benefits from regular and moderate exercise probably also accrue in a young patient population with GCVDs. However, extreme and intense exertional training, as it occurs with competitive athletics has been associated with increased risk for arrhythmiamediated sudden death.25 In addition, recent recognition in the United States that obesity is an emerging major health problem in young people has focused attention on the importance of regular exercise as a weight loss and maintenance strategy in adults.45 In general terms, we believe that these principles are also relevant to young patients with GCVD. Certainly, involvement in sports is of particular importance to the physical and psychological wellbeing of children and adolescents, and abrupt removal from such activities can be emotionally devastating. The recommendations from AHA focus on physical activity for young people with inherited and nonischemic cardiovascular diseases implicated most often in sudden death, and specifically for HCM, the ion-channel diseases (LQTS and Brugada syndrome), ARVC, and diseases of connective tissue such as Marfan syndrome (and related vascular conditions, i.e., EhlerDanlos syndrome, and other fibrillin disorders). Other familial conditions such as dilated cardiomyopathy or certain congenital heart malformations such as atrial or ventricular septal defect and mitral valve prolapse have

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not been specifically addressed here. However, it is possible to draw reasonable inferences from the recommendations presented and extrapolate generally to these and other conditions. Of particular note, these AHA recommendations assume both the absence of important limiting cardiac symptoms and the presence of an unequivocal cardiac diagnosis previously made on the basis of clinically overt features. Therefore, young people with negligible manifestations of disease, who may harbor only preclinical (i.e., molecular) evidence of a particular disease-causing mutation predisposing to GCVD are considered independently. Given current information, these genotype-positive/phenotype-negative individuals probably do not warrant particular restrictions from most recreational sports. Based on Bethesda Con­ ference #36 recommendations such individuals are not disqualified from competitive athletics30 although the ESC guidelines do restrict such athletics.31

25.4 Premises Recommendations for GCVDs are formulated and predicated on several major conceptual premises. First, vigorous physical activity may trigger sudden death in susceptible individuals with underlying heart disease.17-27,33,35,46,47 Undoubtedly, there are also other potential mechanisms, because sudden death also occurs with modest or sedentary activity or even frequently during sleep (such as in Brugada syndrome), and can be triggered by abrupt or loud noises (such as in LQTS). Second, sudden death in GCVDs are usually due to primary ventricular tachyarrhythmias, although in the Marfan syndrome, the mechanism is most frequently aortic dissection and rupture;38 however, arrhythmic sudden death has also been reported.18 Third, the risk of cardiac events associated with exercise in patients with GCVDs is in part theoretically modifiable, and therefore avoidable to a large extent. This latter tenet supports the principle that sudden death risk may be prevented (or the risk substantially reduced) through lifestyle management and restriction of exercise30,31,35,48 and/or by the use of implantable defibrillators.49-53 These AHA recommendations are not intended to be rigid dicta, but rather should be viewed as general guidelines to those physicians advising patients with GCVD, which allow sufficient latitude for individual clinical

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judgment. Finally, these recommendations should not be used to restrict all physical exercise that could conceivably be associated with some increase in risk, but only to develop a prudent balance between risk and benefit. Given the relative paucity of evidence in this area of medicine, particularly stringent recommendations would potentially (and unnecessarily) exclude a large proportion of patients with GCVD and in the process create a sedentary cardiac population deprived of the many benefits afforded by exercise for cardiovascular health.32–35,43,44 Mutational analysis, for the purpose of risk stratification for sudden death1-4,7-12,16,53,54 has limited practical impact on the present considerations. Therefore, the recommendations for exercise are presented here independent of information from genetic testing.

25.5 Other Specific Considerations and Potential Limitations There are difficulties inherent in formulating arbitrary exercise recommendations, considering the many ambiguities or “gray areas” that are unavoidably involved, particularly for this diverse group of diseases. For example, there is marked heterogeneity in phenotypic expression among these diseases as well as variable gene expression that undoubtedly influence individual patients. For example, HCM is not invariably associated with particularly marked left ventricular hypertrophy or outflow obstruction.26,54 Conversely, LQTS and Brugada syndromes show no evidence of structural heart disease or abnormalities on gross and histopathologic examination.7,25,35,39,40 Consequently, it is not possible to tailor precise exercise recommendations for each of the many phenotypic and genetic patient subsets with varying levels of risk that have been defined within the broad spectrum of each disease state.35 For example, although data are scarce, there is presently little evidence to suggest that the vast majority of genetically affected phenotypically normal family members with HCM are at substantially increased risk for sudden death. Indeed, such individuals are probably at low risk. However, should the phenotype in HCM convert morphologically from non-thickened to hypertrophied,54,55 the risk level may increase. Therefore, there is insufficient formal scientific evidence for restricting such phenotypically negative individuals with HCM54 from most modest

B. J. Maron

recreational sports activities. However, this recommendation is perhaps less compelling for LQTS, for which heightened risk has been reported in some phenotypenegative family members requiring assessment on a case-by-case basis.3 In addition to the phenotypic and genetic variability among patients with GCVD, individual responses may differ within the context of the same sporting activities – i.e., a recreational activity for one patient may be equivalent to a competitive sport for another.35 Also, the effect of exercise on a given patient with GCVD is dependent on several variables, including the intensity of the sporting activity, its physiological characteristics, (e.g., dynamic vs. static), duration (continuous vs. intermittent), environment conditions, and individual degree of hydration, or use of medications. Although the impact that emotional and psychological investment in a recreational sports activity has on the underlying disease substrate and myocardial electrophysiologic stability is not quantifiable, psychological stress is undoubtedly an important trigger influencing the likelihood of a sudden cardiac event in some vulnerable athletes. Therefore, the implementation of exercise recommendations ultimately depends in large measure on the interaction between physician and patient. It may often be necessary for clinicians to individualize exercise ­recommendations for particular patients, the specific GCVD involved, and the physical activity under consideration. These clinical decisions regarding the structure of exercise programs are also unavoidably influenced by liability issues and concerns, the possibility that physician recommendations may be ignored by some patients, and the variable tolerance for sudden death risk among patients and their families. Finally, the AHA panel35 found it difficult to design recommendations that rely on obtaining truly quantitative measurements through monitoring during exercise, such as maximum heart rate or metabolic equivalents, given the diverse sporting disciplines involved, the multitude of variables that impact these activities, and the impracticality of making accurate assessments during intense physical activity.

25.6 Recommendations General Principles: Conveying exercise and lifestyle recommendations to young patients with GCVD requires substantial physician–patient interaction to ensure that

25  Participation in Recreational Sports for Young Patients with Genetic Cardiovascular Diseases

the recommendations are translated accurately and in sufficient detail. On the other hand, arbitrary and rigid directives are impractical and likely ineffective. In communicating with patients, it is useful to define informal recreational sports by contrasting such activities with competitive sports. Because of the unique structure and pressures of organized sports, athletes with heart disease engaged in competition may not always use proper judgment to prudently extricate themselves immediately from vigorous exercise, even if they recognize the potential medical need to eliminate the activity. For example, dizziness, palpitations, fatigue, excessive dyspnea, or chest discomfort (or any other potential warning sign of cardiovascular disease) experienced during competitive sports may be difficult for the athlete to distinguish reliably from those benign and innocent sensations that can normally accompany extreme exercise and which mimic symptoms of cardiac disease. However, such considerations are not generally part of truly recreational sports activities, constituting a clear distinction on which exercise recommendations can be effectively conveyed to patients with GCVD. Participants in recreational physical activities have greater opportunity to exert reasonable control over their level of exercise, and therefore are more likely to reliably detect cardiac symptoms and willfully terminate physical activity. On the other hand, some recreational sports (e.g., soccer, tennis, squash, and racquetball) can become truly competitive even within a recreational format, largely owing to the style of play and attitudes of the participants. Not included within the definition of recreational sports are those neighborhood and elementary school activities for young children, which involve lesser degrees of physical intensity and are daily activities which are permitted in individuals with GCVD. Of note, some symptomatic patients with HCM may be under the misconception that their functional limitation can be overcome by physical training, rather than regarding such symptoms provoked by exercise as “warning signs” triggered by their underlying disease. Patient recommendations: Sports activities have been categorized with regard to the high, moderate, and low levels of physical intensity required35 (Table  25.1). These 3 partitions relate to the generally expected degree of physiological exertion expected in a sporting discipline. Patients with GCVD can safely participate in most forms of recreational

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exercise judged to be of moderate or low intensity (Table 25.1). Eligibility for exercise in specific recreational sports activities was assessed on a graded scale (from 0 to 5), with 0–1 designating activities generally not advised or strongly discouraged, with 4–5 indicating activities probably permitted, and with 2–3 indicating intermediate activities, which should be assessed on an individual basis. The assigned grades represent only estimates, which assume the usual level of physical exertion for a given recreational activity. However, in large measure, this grading system cannot take into account other potentially important variables such as the psychological burden and physical intensity uniquely brought to a sport by a particular participant, or the potential effects of cardioactive drugs, environmental conditions, and the precise clinical profile. Therefore, these recommendations are, to a certain extent, necessarily subjective and represent only a starting point for clinical judgments in individual asymptomatic (or only minimally symptomatic) patients with clinically evident GCVD. Consequently, their application requires substantial reliance on the “practice and art of medicine” and the weighing of the perceived risk against the benefit for each patient. Furthermore, these recommendations are not intended for individuals with the following clinical features: History of important cardiac symptoms including syncope or other episodes of impaired consciousness, prior cardiac operation including surgical septal myectomy; obstructive HCM; and aortic root reconstruction for Marfan syndrome; heart transplantation; presence of an implanted cardioverter-defibrillator or pacemaker; and clinically overt and potentially life-threatening arrhythmias or other evidence of highrisk status. The presence of any of these features requires individual clinical judgment in adapting the present exercise recommendations. It is also useful to express specific exercise recommendations in terms of those activities which should be avoided by patients with clinically diagnosed GCVD: • “Burst” exertion (or sprinting), characterized by rapid acceleration and deceleration over short distances. Such exercise is encountered in a variety of sports, such as basketball (particularly full-court play), soccer, and tennis. Therefore, preference is given to recreational sporting activities such as

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B. J. Maron

Table 25.1  Recommendations for recreational (noncompetitive) sports activities and exercise in patients with GCVDsa Intensity level HCMb LQTSb Marfan ARVC Brugada syndromec syndrome High Basketball   Fullcourt   Halfcourt Body buildingd Gymnastics Ice hockeyd Racquetball/squash Rock climbingd Running (sprinting) Skiing (downhill)d Skiing (cross-country) Soccer Tennis (singles) Touch (flag) football Windsurfinge

0 0 1 1 0 0 1 0 2 2 0 0 1 1

0 0 1 1 0 2 1 0 2 3 0 0 1 0

2 2 0 1 1 2 1 2 2 2 2 3 3 1

1 1 1 1 0 0 1 0 1 1 0 0 1 1

2 2 1 2 0 2 1 2 1 4 2 2 3 1

Moderate Baseball/softball Biking Modest hiking Motorcyclingd Jogging Sailinge Surfinge Swimming (lap)e Tennis (doubles) Treadmill/stationary bicycle Weightlifting (free weights)d Hiking

2 4 4 3 3 3 2 5 4 5 1 3

2 4 5 1 3 3 0 0 4 5 1 3

2 3 5 2 3 2 1 3 4 4 0 3

2 2 2 2 2 2 1 3 3 3 1 2

4 5 4 2 5 4 1 4 4 5 1 4

Low Bowling 5 5 5 4 5 Golf 5 5 5 4 5 Horseback ridingd 3 3 3 3 3 Scuba divinge 0 0 0 0 0 Skatingf 5 5 5 4 5 Snorkelinge 5 0 5 4 4 Weights (nonfree weights) 4 4 0 4 4 Brisk walking 5 5 5 5 5 Recommendations generally differ from those for weight-training machines (nonfree weights), based largely on the potential risks of traumatic injury associated with episodes of impaired consciousness during bench-press maneuvers; otherwise, the physiological effects of all weight-training activities are regarded as similar with respect to the present recommendations a Recreational sports are categorized with regard to high, moderate, and low levels of exercise and graded on a relative scale (from 0 to 5) for eligibility with 0 to 1 indicating generally not advised or strongly discouraged; 4 to 5 indicating probably permitted; and 2 to 3 indicating intermediate (and to be assessed clinically on an individual basis). The designations of high, moderate, and low levels of exercise are equivalent to an estimated >6, 4 to 6, and <4 metabolic equivalents, respectively b Assumes absence of laboratory DNA genotyping data; therefore, limited to clinical diagnosis c Assumes no or only mild aortic dilatation d These sports involve the potential for traumatic injury, which should be taken into consideration for individuals with a risk of impaired consciousness e The possibility of impaired consciousness occurring during water-related activities should be taken into account with respect to the clinical profile of the individual patient. Barotrauma is a primary risk factor associated with use of the scuba apparatus in Marfan syndrome f Individual sporting activity not associated with the team sport of ice hockey

25  Participation in Recreational Sports for Young Patients with Genetic Cardiovascular Diseases

•

•

•

•

informal jogging without a training regimen, biking on level terrain or lap swimming, in which energy expenditure is largely stable and consistent even over relatively long distances or periods of time. Extremely adverse environmental conditions, may promote alternations in blood volume, electrolytes, and hydration and thereby increase risk. These include elevated or particularly cold temperatures disproportionate to that which the athlete is accustomed to (i.e., >80°F [27°C] and <32°F [0°C]), high humidity, or substantial altitude. Exercise programs (even if recreational in nature) that require systematic and progressive levels of exertion and are focused on achieving higher levels of conditioning and excellence, as in road running, cycling, and rowing. Patients with GCVDs such as HCM, in which limiting dyspnea may occur with exercise, should be discouraged from levels of exertion which provoke these symptoms. These individuals are also advised against systematic training during which they are extended beyond the physical limits imposed by their underlying disease and the average aerobic state expected at that age. Excessive participation in sporting events that otherwise would be regarded as recreational when performed in moderation – e.g., downhill skiing continuously over an entire day vs. more limited and selective skiing. Exercise-related and adrenergic-type activities or stress that conveys a risk for cardiac events, specific to certain disease states. For example, in LQTS, swimming, abrupt loud noises (such as from a race starter’s pistol), and diving have been implicated as triggers for sudden death, particularly with certain mutations (i.e., KCNQ1 [or LQTS] for swimming and KCNH2/HERG [or LQT2] for auditory triggers). However, such laboratory-based molecular information may not be available clinically to allow prospective exercise recommendations.

Patients with rare conditions such as CPVT,13,15 in which many forms of exercise have been associated with catecholamine release triggering ventricular tachycardia, should be cautioned against virtually all forms of vigorous physical activity. The same restriction should be adopted for that subgroup of ARVC patients that shares with CPVT, both effort-induced polymorphic ventricular tachycardia and a ryanodine receptor mutation. It is also of note that a temperature-

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dependent dysfunction of the SCN5A gene for cardiac sodium has been reported in patients with Brugada syndrome.56 This increased temperature sensitivity could predispose some Brugada patients to life-threatening arrhythmias either during a febrile state or when body temperature increases during intense physical exertion. • In HCM, intense static (isometric) exertion, such as lifting free weights, may prove to be adverse by inducing a Valsalva maneuver and dynamic left ventricular outflow obstruction (as well as the risk for traumatic injury in the event of impaired consciousness; or in Marfan syndrome by increasing wall stress and weakening the aortic media).57 • Other patients with GCVD associated with impaired consciousness (e.g., syncope and near-syncope) are subject to considerably higher risk for traumatic injury while engaged in certain sports such as free weight and bench-pressing maneuvers, downhill skiing, diving, ice hockey, rock climbing, motorcycle, and horseback riding. • It is reasonable to caution patients with GCVD, particularly those with catecholamine-sensitive or auditory-triggered arrhythmia syndromes (e.g., LQTS and CPVT) against roller coasters and other thrill-related amusement park rides which are associated with intense stress and surges of emotion due to sudden acceleration in heart rate and abrupt alterations in centrifugal or centripetal forces. • Paired athletic activities in which a second party may be at risk should an individual with GCVD suddenly incur bodily injury or impairment of consciousness and incapacitation – e.g., in recreational sports such as scuba diving or rock/mountain climbing. Diving from platforms into water would seem generally unacceptable by virtue of the exposure of patients with GCVD (in whom syncope is a common symptom) to the risk of underwater drowning. • Extreme sports (such as hang-gliding and bungeejumping) are activities that should be avoided because they require the expenditure of particularly substantial physical energy and incur psychological demands that are exceedingly unpredictable, placing individuals with GCVD in compromised circumstances in which the likelihood of injury is substantial and the possibility of rescue from a traumatic or cardiovascular event is reduced.

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• Use of substances or compounds that promote enhanced physical performance, but also the potential for adverse effects, particularly when associated with disease states or extreme environmental conditions – i.e., cocaine, anabolic steroids, or dietary and nutritional supplements such as ma huang, an herbal source of ephedrine (i.e., elemental ephedra) and cardiac stimulants that are potentially arrhythmogenic.58-61

25.7 Implantable CardioverterDefibrillators An increasing number of young patients with GCVDs are receiving implantable defibrillators for primary or secondary prevention of sudden death.49,50 Such patients may participate in a wide variety of non-competitive and non-contact recreational activities in concert with the exercise recommendations of their electrophysiologist. However, the defibrillator may itself create some activity restrictions, particularly considering that bodily trauma may disrupt the lead system, or certain levels of physical exertion may trigger an inappropriate shock due to rapid sinus tachycardia. Participation in intense exercise (including competitive athletics) should not be predicated on the presence of an implantable defibrillator and the potential for antiarrhythmic protection afforded by the device.30,31,62

References   1. Maron BJ, Moller JH, Seidman CE, et al. Impact of laboratory molecular diagnosis on contemporary diagnostic criteria for genetically transmitted cardiovascular diseases: hypertrophic cardiomyopathy, long-QT syndrome, and Marfan syndrome: a statement for healthcare professionals from the councils on clinical cardiology, cardiovascular disease in the young, and basic science, American Heart Association. Circulation. 1998;98:1460–1471   2. Alcalai R, Seidman JG, Seidman CE. Genetic basis of hypertrophic cardiomyopathy: from bench to the clinics. J Cardiovasc Electrophysiol. 2008;19:104–110   3. Priori SG, Schwartz PJ, Napolitano C, et al. Risk stratification in the long-QT syndrome. N Engl J Med. 2003;348: 1866–1874   4. Priori SG, Barhanin J, Hauer RN, et al. Genetic and molecular basis of cardiac arrhythmias: impact on clinical management, parts I and II. Circulation. 1999;99:518–528

B. J. Maron   5. Vincent GM, Timothy KW, Leppert M, et al. The spectrum of symptoms and QT intervals in carriers of the gene for the long-QT syndrome. N Engl J Med. 1992;327:846–852   6. Thiene G, Nava A, Corrado D, et al. Right ventricular cardiomyopathy and sudden death in young people. N Engl J Med. 1988;318:129–133   7. Antzelevitch C, Brugada P, Brugada J, et al. Brugada syndrome: 1992–2002: a historical perspective. J Am Coll Cardiol. 2003;41:1665–1671   8. Towbin JA. Molecular genetic basis of sudden cardiac death. Cardiovasc Pathol. 2001;10:283–295   9. Rampazzo A, Nava A, Malacrida S, et al. Mutation in human desmoplakin domain binding to plakoglobin causes adominant form of arrhythmogenic Right ventricular cardiomyopathy. Am J Hum Genet. 2002;71:1200–1206 10. Tiso N, Stephan DA, Nava A, et al. Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic Right ventricular cardiomyopathy type 2 (ARVD2). Hum Mol Genet. 2001;10:189–194 11. Dietz HC, Cutting GR, Pyeritz RE, et al. Marfan syndrome caused by a recurrent de  novo missense mutation in the fibrillin gene. Nature. 1991;352:337–339 12. Dietz HC, Pyritz RE. Mutations in the human gene for fibrillin-1 (FBN1) in the Marfan syndrome and related disorders. Hum Mol Genet. 1995;4:1799–1809 13. Leenhardt A, Lucet V, Denjoy I, Grau F, Ngoc DD, Coumel P. Catecholaminergic polymorphic ventricular tachycardia in children. A 7-year follow-up of 21 patients. Circulation. 1995;91:1512–1519 14. Ackerman MJ, Clapham DE. Ion channels: basic science and clinical disease. N Engl J Med. 1997;336:1575–1586 15. Priori SG, Napolitano C, Memmi M, et  al. Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia. Circulation. 2002; 106:69–74 16. Myerburg RJ. Scientific gaps in the prediction and prevention of sudden cardiac death. J Cardiovasc Electrophysiol. 2002;13:709–723 17. Maron BJ, Shirani J, Poliac LC, et al. Sudden death in young competitive athletes: clinical, demographic and pathologic profiles. JAMA. 1996;276:199–204 18. Yetman AT, Bornemeier RA, McCrindle BW. Long-term outcome in patients with Marfan syndrome: is aortic dissection the only cause of Sudden death? J Am Coll Cardiol. 2003;41:329–332 19. Maron BJ, Carney KP, Lever HM, et al. Relationship of race to sudden cardiac death in competitive athletes with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2003;41:974–980 20. VanCamp SP, Bloor CM, Mueller FO, et  al. Nontraumatic sports death in high school and college athletes. Med Sci Sports Exerc. 1995;27:641–647 21. Liberthson RR. Sudden death from cardiac causes in children and young adults. N Engl J Med. 1996;334:1039–1044 22. Burke AP, Farb A, Virmani R, et al. Sports-related and nonsports-related sudden cardiac death in young adults. Am Heart J. 1991;121(pt1):568–575 23. Maron BJ. Cardiovascular risks to young persons on the athletic field. Ann Intern Med. 1998;129:379–386 24. Corrado D, Thiene G, Nava A, et al. Sudden death in young competitive athletes: clinicopathologic correlations in 22 cases. Am J Med. 1990;89:588–596

25  Participation in Recreational Sports for Young Patients with Genetic Cardiovascular Diseases 25. Maron BJ. Sudden death in young athletes. N Engl J Med. 2003;349:1064–1075 26. Maron BJ. Hypertrophic cardiomyopathy: a systematic review. JAMA. 2002;287:1308–1320 27. Estes NA, Link MS, Cannom D, et al. Report of the NASPE Policy conference on arrhythmias and the athlete. J Cardiovasc Electrophysiol. 2001;12:1208–1219 28. Mitchell JH, Maron BJ, Epstein SE.16th Bethesda conference: cardiovascular abnormalities in the athlete: recommendations regarding eligibility for competition. J Am Coll Cardiol. 1985;6:1186–1232 29. Maron BJ, Mitchell JH. 26th Bethesda conference: recommendations for determining eligibility for competition in athletes with cardiovascular abnormalities. J Am Coll Cardiol. 1994;24:845–899 30. Maron JB, Zipes DP. 36th Bethesda conference. Eligibility recommendations for competitive athletes with cardiovascular abnormalities. J Am Coll Cardiol. 2005;45:1313–1368 31. Pelliccia A, Zipes DP, Maron BJ. Bethesda conference #36 and the European Society of Cardiology Consensus Recommendations revisited a comparison of U.S. and European criteria for eligibility and disqualification of competitive athletes with cardiovascular abnormalities. J Am Coll Cardiol. 2008;52:1990–1996 32. Balady GJ, Chaitman B, Driscoll D, et al. Recommendations for cardiovascular screening, staffing, and emergency policies at health/fitness facilities. Circulation. 1998;97:2283–2293 33. Albert CM, Mittleman MA, Chae CU, et al. Triggering of sudden death by vigorous exertion. N Engl J Med. 2000;343: 1355–1361 34. Maron BJ, Araújo CG, Thompson PD, Fletcher GF, de Luna AB, Fleg JL, Pelliccia A, Balady GJ, Furlanello F, Van Camp SP, Elosua R, Chaitman BR, Bazzarre TL; World Heart Federation; International Federation of Sports Medicine; American Heart Association Committee on Exercise, Cardiac Rehabilitation, and Prevention. Recommendations for preparticipation screening and the assessment of cardiovascular disease in masters athletes: an advisory for healthcare professionals from the working groups of the World Heart Federation, the International Federation of Sports Medicine, and the American Heart Association Committee on Exercise, Cardiac Rehabilitation, and Prevention. Circulation. 2001;103:327–334 35. Maron BJ, Chaitman BR, Ackerman MJ, Bayés de Luna A, Corrado D, Crosson JE, Deal BJ, Driscoll DJ, Estes NAM III, Araújo CG, Liang DH, Mitten MJ, Myerburg RJ, Pelliccia A, Thompson PD, Towbin JA, Van Camp SP. American Heart Association Scientific Statement: Recommendations for Physical Activity and Recreational Sports Participation for Young Patients with Genetic Cardiovascular Diseases. Circulation. 2004;109:2807–2816 36. Basso C, Thiene G, Corrado D, et al. Hypertrophic cardiomyopathy and sudden death in the young: pathologic evidence of myocardial ischemia. Hum Pathol. 2000;31: 988–998 37. Corrado D, Basso C, Thiene G, et al. Spectrum of clinicopathologic manifestations of arrhythmogenic right ventricular cardiomyopathy/dysplasia: a multicenter study. J Am Coll Cardiol. 1997;30:1512–1520 38. Pyeritz RE. The Marfan syndrome. Annu Rev Med. 2000; 51:481–510

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39. Matsuo K, Kurita T, Inagaki M, et al. The circadian pattern of the development of ventricular fibrillation in patients with Brugada syndrome. Eur Heart J. 1999;20:465–470 40. Maron BJ, Doerer JJ, Haas TS, Tierney DM, Mueller FO. Sudden deaths in young competitive athletes: analysis of 1,866 deaths in the U.S., 1980–2006. Circulation. 119:1085–1092 41. Basso C, Maron BJ, Corrado D, et al. Clinical profile of congenital coronary artery anomalies with origin from the wrong aortic sinus leading to sudden death in young competitive athletes. J Am Coll Cardiol. 2000;35:1493–1501 42. Corrado D, Basso C, Poletti A, Angelini A, Valente M, Thiene G. Sudden death in the young. Is acute coronary thrombosis the major precipitating factor? Circulation. 1994;90:2315–2323 43. Fletcher GF, Blair SN, Blumenthal J, Caspersen C, Chaitman B, Epstein S, Falls H, Froelicher ES, Froelicher VF, Pina IL. Statement on exercise. Benefits and recommendations for physical activity programs for all Americans. A statement for health professionals by the Committee on Exercise and Cardiac Rehabilitation of the Council on Clinical Cardiology, American Heart association. Circulation. 1992;86:340–344 44. NIH Consensus Development Panel on Physical Activity and Cardiovascular Health. Physical activity and cardiovascular health. JAMA. 1996;276:241–246 45. Wing RR, Hill JO. Successful weight loss maintenance. Annu Rev Nutr. 2001;21:323–341 46. Maron BJ. The paradox of exercise. N Engl J Med. 2000; 343:1409–1411 47. Maron BJ, Thompson PD, Puffer JC, McGrew CA, Strong WB, Douglas PS, Clark LT, Mitten MJ, Crawford MH, Atkins DL, Driscoll DJ, Epstein AE. Cardiovascular preparticipation screening of competitive athletes. A statement for health professionals from the Sudden Death Committee (clinical cardiology) and Congenital Cardiac Defects Committee (cardiovascular disease in the young), American Heart Association. Circulation. 1996;94:850–856 48. Corrado D, Basso C, Schiavon M, et al. Screening for hypertrophic cardiomyopathy in young athletes. N Engl J Med. 1998;339:364–369 49. Maron BJ, Spirito P, Shen W-K, et al. Implantable cardioverter-defibrillators and prevention of sudden cardiac death in hypertrophic cardiomyopathy. JAMA. 2007;298:405–412 50. Chatrath R, Porter CB, Ackerman MJ. Role of transvenous implantable cardioverter defibrillators in preventing sudden cardiac death in children, adolescents, and young adults. Mayo Clin Proc. 2002;77:226–231 51. Corrado D, Leoni L, Link MS, et  al. Implantable cardioverter-defibrillator therapy for prevention of sudden death in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia. Circulation. 2003;108:3084–3091 52. Moss AJ, Daubert JP. Images in clinical medicine: internal ventricular defibrillation. N Engl J Med. 2000;342:398 53. Maron BJ, McKenna WJ, Danielson GK, Kappenberger LJ, Kuhn HJ, Seidman CE, Shah PM, Spencer WH, Spirito P, ten Cate FJ, Wigle ED. American College of Cardiology/ European Society of Cardiology Clinical Expert Consensus Document on Hypertrophic Cardiomyopathy. A report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines Committee to Develop an Expert Consensus Document on Hypertrophic

326 Cardiomyopathy. J Am Coll Cardiol. 2003;42:1687–1713 and Eur Heart J. 2003;24:1965–1991 54. Maron BJ, Niimura H, Casey SA, et al. Development of left ventricular hypertrophy in adults with hypertrophic cardiomyopathy caused by cardiac myosin-binding protein C mutations. J Am Coll Cardiol. 2001;38:315–321 55. Maron BJ, Spirito P, Wesley YE, Arce J. Development and progression of left ventricular hypertrophy in children with hypertrophic cardiomyopathy. N Engl J Med. 1986;315:610–614 56. Dumaine R, Towbin JA, Brugada P, et al. Ionic mechanisms responsible for the electrocardiographic phenotype of the Brugada syndrome are temperature dependent. Circ Res. 1999;85:803–809 57. Kinoshita N, Mimura J, Obayashi C, et al. Aortic root dilatation among young competitive athletes: echocardiographic screening of 1929 athletes between 15 and 34 years of age. Am Heart J. 2000;139:723–728

B. J. Maron 58. Lange RA, Hillis LD. Cardiovascular complications of cocaine use [published erratum appears in N Engl J Med 2001;345:1432]. N Engl J Med.. 2001;345:351–358 59. Samenuk D, Link MS, Homoud MK, et al. Adverse cardiovascular events temporally associated with mahuang, an herbal source of ephedrine [published erratum appears in Mayo Clin Proc 2003;78:1055]. Mayo Clin Proc. 2002;77: 12–16 60. Valli G, Giardina EG. Benefits, adverse effects and drug interactions of herbal therapies with cardiovascular effects. J Am Coll Cardiol. 2002;39:1083–1095 61. Shen W-K, Edwards WD, Hammill SC, et al. Sudden unexpected nontraumatic death in 54 young adults: a 30-year population-based study. Am J Cardiol. 1995;76:148–152 62. Maron BJ, Zipes DP. Heart Rhythm Controversy: it is not prudent to allow all athletes with ICDs to participate in all sports (editorial). Heart Rhythm. 2008;5:864–866

Genetic Counseling in Cardiovascular Conditions

26

Laura Robb

26.1 Introduction The spheres of cardiology and genetics overlap when there is an episode of sudden cardiac death (SCD), because part of the investigation of the incident includes examining possible genetic causes. Inheritance may play a role in the event, and therefore, an important goal in dealing with SCD occurrences is the identification of other at-risk family members, including asymptomatic individuals, before they themselves experience a serious health event. Understanding what genetic counseling implies will elucidate the role of this health care service for families who have experienced an SCD event. The American Society of Human Genetics adopted the following definition of genetic counseling: “Genetic counseling is a communication process which deals with the human problems associated with the occurrence, or the risk of an occurrence, of a genetic disorder in the family. This process involves an attempt by one or more appropriately trained persons to help the individual or family to (1) comprehend the medical facts, including the diagnosis, probable course of the disorder, and the available management; (2) appreciate the way heredity contributes to the disorder, and the risk of recurrence in specified relatives; (3) understand the alternatives for dealing with the risk of occurrence; (4) choose the course of action which seems to them appropriate in view of their risk, their family goals, and their ethical and religious standards, to act in accordance with that decision; and (5) to make the best possible adjustment to the disorder

L. Robb Cardiovascular Genetic Centre, Montreal Heart Institute, Montreal, Quebec, Canada e-mail: [email protected]

in an affected family member and/or the risk of recurrence of that disorder.”1 As a further definition, the National Society of Genetic Counselors has indicated that genetic counseling is the “process of helping people understand and adapt to the medical, psychological and familial implications of genetic contributions to disease. This process integrates the following: (a) Interpretation of family and medical histories to assess the chance of disease occurrence or recurrence. (b) Education about inheritance, testing, management, prevention, resources and research. (c) Counseling to promote informed choices and adaptation to the risk or condition.”2 SCD can be a difficult and heartbreaking event for families. Their needs following the incident revolve around obtaining information, appropriate health care and psychosocial support from health care providers. Genetic counseling, as part of the health care pathway, can significantly contribute in addressing these needs.

26.2 Sudden Cardiac Death and Genetics Although the hereditary nature of many conditions causing SCD has been recognized for a long time, the realization of specific genetic causes are a much more recent advance in medical knowledge. Essentially, the identification of the first cardiomyopathy gene, causing familial hypertrophic cardiomyopathy in 1991, can be considered the beginning of current cardio-genetic practice.3-5 The health care services, which are offered to families who have experienced a SCD event, clearly benefit from both cardiologic and genetic expertise, because a percentage of these events, especially in younger persons, may be attributed to hereditary conditions.6-11 Since the description of this first cardiac

R. Brugada et al. (eds.), Clinical Approach to Sudden Cardiac Death Syndromes, DOI: 10.1007/978-1-84882-927-5_26, © Springer-Verlag London Limited 2010

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genetic disease, the field has become an interdisciplinary collaborative arena, which includes both cardiology and genetics health care professionals.6 Important goals after a SCD incident are investigations to provide explanations, information and possibly reassurance for the patient, their family and their health care providers. The results of these investigations may have important implications for a large number of persons within a family. In concert with cardiac investigation and genetic testing, a cardio-genetic clinic can offer specialized genetic counseling, including psychosocial support,11 which can be of paramount importance in these difficult moments for families. The relevance for these interdisciplinary implications has been shown in a number of studies. Among SCD episodes in children aged 1–18 years, a relatively high proportion of 56% of these were able to be attributed to inherited heart disease by means of postmortem analysis or cardiologic and genetic investigation of surviving relatives 11. In families with at least one sudden unexplained death, an inherited cardiac disease was identified in 40–53% 9,12 of these cases, again by means of comprehensive clinical evaluation and mutation analysis. Inherited cardiac conditions have also been suggested as causes for some cases of sudden infant death syndrome 13,14 (SIDS), and one study identified genetic mutations for a specific inherited cardiac condition, long QT syndrome in 9.5% of SIDS cases.15 Additionally, there is also some evidence of long QT syndrome associated gene mutations in third trimester fetal demise.16 Albeit the small patient numbers in some of these studies, there is clear evidence of a hereditable factor in many SCD events.

26.3.1 Interpretation of Medical and Family Histories

26.3 Genetic Counseling in Sudden Cardiac Death

Table  26.1  Questions to consider in constructing a family pedigree

A description of a fictitious SCD incident will be used in this chapter to illustrate the various steps and implications of genetic counseling for a family. Mark died suddenly in his sleep at the age of 24 years Investigations into this incident revealed that Mark had been a healthy young man with no previous health problems. He had had a single reported episode of fainting while playing hockey at age 20. The autopsy did not indicate any specific cause of his sudden death with regards to structural heart abnormalities, and the possibility of a channelopathy was raised in the conclusions.

Along with possible cardiologic, pathologic and biochemical assessments following a SCD incident, part of the investigation also includes a thorough family history, which may provide evidence for a hereditary cardiac condition. The most useful tool for recording and examining this information is the family pedigree. It is generally recommended that a three-generation pedigree be documented in order to provide the most information.6,17 A three-generation pedigree will often reflect a valuable picture of family health and dynamics, as well as the limits of most families’ knowledge regarding their relatives. When a SCD incident has occurred, some questions which may be useful to include in constructing a family pedigree are included in Table 26.1. While evidence of cardiac conditions may be obvious in histories involving members with implantable cardioverterdefibrillators or heart transplants, other reported family indications can be more vague. These other reported findings, such as the history of fainting, possible epilepsy or unexplained accidental deaths, may however turn out to be quite significant. More detailed information surrounding echocardiographic and ECG features, as well as specific medications, may additionally be pertinent to verify.17 Further confirmation of specific family members who are suspected to also have the condition may be done by direct evaluation of these members or by obtaining medical records for review.6,18 These ancillary investigations are extremely important for clarifying the type of condition, which may be

Is there anyone in the family who has had: Heart problems (enlarged heart, heart transplant, etc) Implanted pacemaker or defibrillator High blood pressure Heart palpitations or irregular heart beat Fainting Dizziness Shortness of breath or asthma Epilepsy Unexplained traumatic death (such as a car accident or drowning) Death at an early age Sudden infant death syndrome Late pregnancy loss or stillbirth

26  Genetic Counseling in Cardiovascular Conditions

underlying the history and the pattern of inheritance in a particular family. Because the penetrance of many SCD conditions is not complete, meaning that persons who inherit the disease mutation will not necessarily present with the condition, these conditions often appear to not be directly transmitted from one generation to the next in the pedigrees. Persons within a family, who have the same genetic mutation, may actually express the condition very differently, with some having no symptoms, some having mild palpitations and others presenting with acute SCD. Complexities such as incomplete penetrance, variable expressivity and limitations of family knowledge often complicate the information gleaned in family histories and therefore the interpretation. When a pattern of inheritance is recognized, this can assist in identifying family members who may benefit from options of genetic testing and/or cardiac surveillance or preventative actions. Most hereditary SCD conditions are inherited in an autosomal dominant manner, meaning that a specific genetic mutation is transmitted directly from one generation to the next, with a risk of 50% that a child will have inherited the factor and a risk of 50% that they will not have inherited this mutation.6,17,19 The high heritability of autosomal dominant conditions can be valuable in that, even in the absence of available postmortem investigations on the actual patient, a diagnosis can often still be established because cardiologic and genetic investigations can be performed in surviving relatives.11 Other inheritance types such as autosomal recessive, X-linked and mitochondrial are also possible and clues may be evident in family pedigrees. While spontaneous gene mutations can occur, the proportion of persons with genetic SCD conditions caused by these de novo mutations is unknown. It is therefore additionally important to point out that if a patient has the condition due to a de novo mutation (thus truly representing the first incidence of the condition in a family), while other family members, such as their parents, are not at risk, the offspring of this patient will have significant risks. The recognition of an apparent inheritance pattern in a family can therefore support the diagnosis, the genetic testing decisions and the identification of at-risk family members. The family history indicated that Mark has a 26 year old sister and a 21  year old brother who are both in good health. His parents are both well, in their fifties, without cardiac problems.

329 On the maternal side of the family, his mother is one of 6 siblings. One maternal uncle was reported to have died suddenly 10 years ago at the age of 36 years without a clear explanation. Another maternal uncle died in a car accident at age 19  years. His mother also has 2 sisters and another brother who are alive and well. His maternal grandfather died of a heart attack at age 67 and had a strong family history of similar health problems. His grandmother is alive at age 77; she has diabetes and has had a number of episodes of syncope. On the paternal side of the family, one uncle had a myocardial infarctus at age 61 and an aunt died in infancy at age 2½ months of unknown cause. The two paternal grandparents are alive and are reported to have familial heart problems (see Fig. 26.1 for family pedigree).

26.3.2 Issues Surrounding Genetic Testing in a Patient with SCD Molecular genetic testing is possible for many hereditary SCD syndromes, and this type of analysis can be especially valuable when the cause of death cannot otherwise be determined.4,7,9

26.3.2.1 Gene Targeting Applications and Challenges Protocols that include details regarding clinical investigations, family history, and frequency of mutations may enable targeting specific genes to test for a particular patient.4,6,12,20 Gene targeting can be particularly useful in well-defined SCD cases, due to the large number of genes involved with these types of conditions and the relatively high cost of genetic analyzes. In some populations, the existence of founder mutations can also streamline testing to a certain extent. Important challenges in genetic testing for SCD syndromes include: (a) there can be multiple genes that are associated with a specific inherited cardiac condition, (b) some of the implicated genes have been associated with more than one inherited cardiac condition, (c) a proportion of affected patients actually have more than one disease-causing mutation, which may influence the severity of the condition, as well as the genetic test result implications for other family members.4,6,21 Information provided during genetic counseling for these conditions should address genetic testing

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L. Robb

MI 77

Heart

Heart

80

79

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Heart 82

76

MI x2 73

68

MI

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Bernard Betty

MI 63

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Grace

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Lionel

Stella

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died in war

syncopes

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accident Harriet

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Susan

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P

P

Fig. 26.1  Family pedigree. SUD sudden unexplained death; SIDS sudden infant death syndrome; MI myocardial infarctus; P pregnancy; Heart reported heart problems

issues regarding the type of test and the potential complexities involved.

26.3.2.2 Implications and Limitations of Results Possible results for an individual suspected to be affected may be either positive (revealing a known mutation for a particular condition) or inconclusive (where testing reveals no mutations for a particular condition or reveals a sequence variant, which is not previously known to be associated with a particular condition). Inconclusive results, without an identified mutation, cannot confirm the genetic nature of the condition, and therefore, no definitive testing can be offered to unaffected family members. Inconclusive results, in which a sequence variant of unknown significance is identified, may lead to testing in some other family members, in order to ascertain whether the mutation is, in fact, associated with the particular condition. Confirmation of a sequence variant in other family members, who are also affected, will support the implication of the variant in the pathology. While various genes have been associated with SCD-associated conditions, current molecular testing is only able to detect a percentage of families with

these conditions. The detection rates are likely to increase, however, with further scientific and technological advances. It is possible that there are other mutations in these known genes, which are undetectable by current testing methods, and that there are other, yet unidentified, genes involved. For these reasons, a molecular result, which shows no mutations detected cannot be interpreted as the condition being absent. If this type of negative result is found in a patient suspected of having a condition at risk for SCD, it is therefore recommended that this individual continues close follow-up with his or her physician. Because there may well be potential risks for the family members of this patient, cardiac examination, treatment or prevention options may be available for these persons as well. It is important to underline that the key person in a family for whom to initiate testing is someone who actually has the condition in question. Unfortunately, in a number of families in which there has been a SCD incident, this one person may be the only family member known to be affected and may be deceased, with no retained tissue from which analyzable DNA can be obtained. Appropriate sampling of patients with SCD should be encouraged for hospitalized patients or during the process of autopsy in order not to lose the opportunity to explain an incident of SCD and

26  Genetic Counseling in Cardiovascular Conditions

therefore, to provide information to the family. In a number of jurisdictions, coroners have worked closely with pathology and cardio-genetic specialists to ensure that DNA is banked in all cases, which might warrant possible genetic investigation. In the absence of retained samples from a deceased patient, testing of unaffected family members, as an initial step, may be completely uninformative. In cases where no sample is available from the patient, family cardiac investigations following the incident may identify other members with potential inherited cardiac conditions for whom genetic testing might be informative for the family. The identification of the appropriate patient on whom to consider testing is essential for accurately determining the cause of SCD in a family. Genetic testing results on tissue obtained during Mark’s autopsy revealed the presence of a known mutation in the KCNH2 gene, which is associated with the Long QT syndrome phenotype (LQT2).

If the genetic nature of a SCD incident can be confirmed with a positive molecular genetic result, this will provide information regarding why SCD occurred, what risks there are for other family members, and what testing, treatment, or prevention options there are for at-risk family members. In cases where multiple disease causing mutations have been identified in a single patient, the meaning for family members may not be completely clear and decisions regarding medical management may need to be weighed for individual family members. The benefits and limitations regarding the option of genetic testing should therefore be explained to families where single or multiple mutations have been identified.

26.4 Implications for the Immediate Family with a Known Mutation When genetic testing does identify the genetic mutation that caused SCD in the family, other at-risk family members can be tested to see if they also carry the mutation and are at risk for the SCD condition. Genetic counseling prior to testing is important to address what the results will or will not mean. A negative test in another family member is generally reassuring regarding this person’s health and recommended routine medical follow-up regarding similar cardiac incidents.

331

A positive result, on the other hand, will indicate an increased risk for this person to have the cardiac condition, but does not generally indicate a certainty of manifesting the condition because of incomplete penetrance. Persons who are identified with a known family mutation should be offered cardiac surveillance in order to judge whether and when medical interventions might be recommended. The genetic results can additionally clarify who is at risk or not at risk to possibly transmit the genetic factors to their children, but cannot identify if the factors have necessarily been passed on to one’s offspring. Cascade testing by means of testing parents prior to children is the most effective method of family testing, however this may not be possible in all families due to members who are deceased or not interested in genetic testing themselves. When the KCNH2 mutation was identified in Mark’s autopsy tissue, the immediate family was contacted for a genetic counseling session in order to discuss the results and implications for themselves. His parents, brother and sister were informed that they each had a 50% risk to have the mutation. After reviewing the information, they all decided to proceed with testing. The results indicated that Mark’s brother, Max, and his mother, Stella, also had the same mutation, but that his sister and father did not. ECG had been normal in all four family members. Cardiological surveillance and management was then arranged for both brother and mother. Genetic testing could now be offered to other members of the maternal family.

Choices regarding genetic testing are, and should be, personal. Genetic counseling can assist individuals to weigh the pros and cons of testing such that they are able to make the right decisions for themselves. Table 26.2 indicates some reasons that individuals may or may not choose to pursue genetic testing. Possible psychosocial consequences of genetic testing may include changes in lifestyle, anxiety levels and family relationships. It has been noted that many of these issues apply not only to genetic testing, but also to cardiologic investigations of family members;5 however possible outcomes should be discussed with patients prior to proceeding to genetic testing, such that they make a decision with which they are comfortable. A number of these issues may be also similar for both diagnostic and predisposition testing, although they may be more acute in the latter for asymptomatic persons. Because of the numerous individual issues

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L. Robb

Table 26.2  Considerations in choosing for or against genetic testing Pros Cons May provide an explanation for the condition occurring in family

May not provide conclusive results

May give reassurance or reduce May increase anxiety with a positive result anxiety associated with uncertainty Can result in information, which enables targeting of appropriate surveillance and prevention options

Result cannot necessarily predict clinical outcome

Can enable planning for future

Testing may not prevent the condition from occurring

Can result in information, which may benefit other family members

There may be a possibility that results will not remain confidential

May advance research and understanding of the condition

There may be a possibility of discrimination from third parties, such as employers or insurance companies

May have a positive effect on family relationships

May have a negative effect on family relationships

surrounding testing and the possibility of inconclusive results, families and their healthcare providers need to comprehend the complexity of genetic testing.

26.4.1 Informed Consent Informed consent for genetic testing should include the following information:22,23 1. Details surrounding how testing is done. 2. What options are available, if a patient decides against having genetic testing? 3. What results may indicate and not indicate? 4. What the implications are for the family? 5. What possible psychosocial implications of results might be? 6. Issues surrounding confidentiality. 7. Various options of medical management and their limitations. 8. Discussion of how result disclosure may be addressed for at-risk relatives.

Depending on the actual patient presenting for cardiogenetic care and on the condition in question, the options available regarding genetic testing may include: (a) A genetic counseling consultation to review information regarding genetic tests in order to make an informed decision whether or not to proceed to testing. (b) DNA banking, in cases where the family may not be ready for genetic counseling due to medical or personal reasons. The purpose of this option is to keep all options available to a family, should they decide that they wish to proceed with genetic testing in the future. (c) An informed patient decision to decline genetic counseling or DNA banking. Health care professionals dealing with these families must be able to communicate the risks and benefits of these alternatives and to act upon patient decisions in order to arrange the services desired. There is a recognized evolving role for genetic testing in cardio-genetic clinical practice with regards to diagnosis, to presymptomatic or predisposition identification of at-risk persons, to possible consideration of prenatal diagnosis options, to potential risk stratification and to therapeutic selections.3,4,7,19,24 The purpose of genetic counseling for family members of a patient who has experienced SCD is to provide them with information and support regarding how testing is done, what the implications of the results might be, and medical management options that are available should they choose to proceed with genetic testing or not.

26.4.2 Psychosocial Implications for the Family Because of the shared, rather than purely individual, nature of genetic testing results, communication of genetic information within a family is essential, if medical issues are to be addressed for other at-risk members. Studies have shown that, while generally information about an inherited condition does get disseminated to close relatives, barriers such as the complexity of genetic information, established family communication patterns, feelings of guilt or anxiety, social or geographical closeness and existing illness or

26  Genetic Counseling in Cardiovascular Conditions

pregnancy may inhibit this communication.25,26 Needs for strategies, which enhance and support patients in their communication with both close and more distant relatives have been acknowledged.25,27,28 Some valuable communication strategies include the offer of appointments for family groups and informative letters for family members, prepared by the health care professionals. Both the information and the support provided in the course of genetic counseling have been shown to favorably influence communication within families and therefore, the number of at-risk family members who seek information for themselves.26 When patients decline to inform their family, in cases where a potential benefit of the relatives having this knowledge is evident, the health care provider may be in the difficult position of weighing the duty of confidentiality regarding their patient versus the duty to warn at-risk family members. Although various policy approaches to this complicated issue have been addressed,25,29,30 professional judgment on a case-bycase basis is warranted.31,32 Genetic counseling can be considered to be family centered care, with one main goal being assuring appropriate health care for as many at-risk persons as possible in a particular family. The extended family was advised of the results of Stella’s genetic testing by means of an informative family letter and personal contact with Stella. Because the results confirm a hereditary condition in their family, with risks for other persons, the option of genetic counseling and possible genetic testing was proposed to other members of the maternal family. Stella has 5 siblings.

−− Her brother Stephen died at age 19 years in a car accident and had no children.

−− Her brother Scott died suddenly in his garden 10 years ago at the age of 36 without any clear explanation. He had two children, now aged 11 and 14. His widow Harriet is very anxious about her children and therefore interested in considering genetic testing for them. −− Her sister Susan has been informed about the family testing and has indicated that she is too scared to test for herself and unsure if she will speak to her 3 children about testing as 2 of them have pregnancies underway. Susan is worried that her children will become overly concerned and, because she herself has no health problems, does not want to even bring up the subject with them. As it turns out, one of Susan’s daughters who is pregnant, has already informed herself through conversations with her cousin Melanie and would very much like to have testing done for herself. −− Her brother Sam has told the family that testing is completely unnecessary as he is in perfect health and would only consider testing if he presented symptoms. Stella is

333 unsure if he has spoken to his 2 sons, one of whom is training to be a pilot. −− Her sister Sally has 4 children and is interested in testing for herself, however she has brought up concerns about the issue of life insurance for her children −− Stella’s father passed away due to a heart attack at age 67 and her mother, Grace, at age 77, has indicated that she is not interested in testing and sees no reason to obtain this information at this point in her life. “At any rate, it probably comes from their father’s family.”, she has said.

Some of the psychosocial and ethical issues brought up in this particular family, (such as the anxiety produced in raising the subject of hereditary conditions with options of genetic testing, the genetic testing of children, how and if information is disseminated within family, the genetic status of a parent possibly revealed in testing a child, potential occupational hazards of not disclosing a familial condition and the possibility of insurance discrimination) underline the importance of communicating, during the genetic counseling process, what testing results may reveal and what implications these might have, such that patient decisions about proceeding or not proceeding to genetic testing are fully informed.

26.5 Conclusion Genetic counseling for cardiovascular conditions associated with SCD should be an integral part of the care provided to patients and their families. Generally, the counseling related to genetic testing is performed by a genetic health care professional such as a medical geneticist, genetic counselor or genetic nurse, and many cardio-genetic teams comprise such professionals. In some situations, however, various aspects of genetic counseling can be performed by another appropriately trained professional.33 The application of genetic knowledge has extended into many health care settings, and therefore, the use of genetic and genomics in health care requires that diverse health professionals develop expertise in order to enable them to practice appropriately.34 Complementarily, patients have indicated that they desire to have genetic information communicated to them by their own health care professionals, including general practitioners and specialists; however they do expect that such information will be received from a wide range of health care professionals.35 While genetic knowledge may currently be insufficient among cardiology specialists, improvements in education, clinical

334

structure and interdisciplinary collaboration will enable optimizing cardio-genetic care.36 Components of genetic counseling include education, regarding inheritance and genetic testing, and counseling, regarding medical options and adjustment to a family condition. The need for information is one of the major desires expressed by families confronted by hereditary conditions, such as those associated with SCD.35 It may be important to state that genetic counseling can be useful, even when genetic testing is not possible or not desired by families, as the information provided may still alert the family as to who else may be at risk.6 The difficulty of communicating genetic information, given the incomplete penetrance and variable expressivity of numerous conditions, means that genetic expertise is essential for professionals providing these services. The complexity of genetic testing underlines the need for genetic counseling, such that patients and their healthcare providers understand both the implications and limitations of the results for both individuals and their extended families.4,6,9 An occurrence of SCD may instigate personal and familial crises with various ramifications. The value of psychosocial counseling and decision-making support, as components of the genetic testing process, is therefore significant. The process of genetic counseling can promote intrafamilial sharing of information and therefore, increase the proportion of family members who consult cardio-genetic services.26 Finally, the evolving nature of our comprehension of genetics and of our technological abilities means that cardio-genetic professionals, who provide information for both patients and their health care providers, must be aware of pertinent advances related to the conditions diagnosed.6 The integration of genetic counseling into cardiogenetic health care can support the goal of decreasing SCD incidents by providing appropriate health care management, which is congruent with personal beliefs and choices.

References   1. Fraser FC. Genetic counseling. Am J Hum Genet. 1974; 26(5):636–661   2. Resta R, Biesecker BB, Bennett RL, et al. A new definition of genetic counseling: National Society of Genetic Counselors’ Task Force Report. J Genet Couns. 2006;15(2):77–83

L. Robb   3. Marian AJ, Roberts R. To screen or not is not the question–it is when and how to screen. Circulation. 2003;107(17): 2171–2174   4. Priori SG, Cerrone M. Molecular genetics: is it making an impact in the management of inherited arrhythmogenic syndromes? Hellenic J Cardiol. 2005;46(2):83–87   5. Kodde J, Hofman N, Reichert CL, et  al. Cardio-genetic counseling in a non-university hospital. Neth Heart J. 2007; 15(12):412–414   6. Ingles J, Semsarian C. Sudden cardiac death in the young: a clinical genetic approach. Internal Med. 2007;37:32–37   7. Arking DE, Chugh SS, Chakravarti A, et  al. Genomics in sudden cardiac death. Circ Res. 2004;94(6):712–723   8. Doolan A, Langlois N, Semsarian C. Causes of sudden cardiac death in young Australians. Med J Aust. 2004;180(3): 110–112   9. Tan HL, Hofman N, van Langen IM, et  al. Sudden unexplained death: heritability and diagnostic yield of cardiological and genetic examination in surviving relatives. Circulation. 2005;112(2):207–213 10. Wren C. Screening children with a family history of sudden cardiac death. Heart. 2006;92(7):1001–1006 11. Hofman N, Tan HL, Clur SA, et al. Contribution of inherited heart disease to sudden cardiac death in childhood. Pediatrics. 2007;120(4):e967-e973 12. Behr ER, Dalageorgou C, Christiansen M, et  al. Sudden arrhythmic death syndrome: familial evaluation identifies inheritable heart disease in the majority of families. Eur Heart J. 2008;29(13):1670–1680 13. Tester DJ, Ackerman MJ. Sudden infant death syndrome: how significant are the cardiac channelopathies? Cardiovasc Res. 2005;67(3):388–396 14. Weese-Mayer DE, Ackerman MJ, Marazita ML, et  al. Sudden infant death syndrome: review of implicated genetic factors. Am J Med Genet A. 2007;143A(8):771–788 15. Arnestad M, Crotti L, Rognum TO, et al. Prevalence of long QT syndrome gene variants in sudden infant death syndrome. Circulation. 2007;115(3):361–367 16. Miller TE, Estrella E, Myerburg RJ, et al. Recurrent thirdtrimester fetal loss and maternal mosaicism for long-QT syndrome. Circulation. 2004;109(24):3029–3034 17. Morales A, Cowan J, Dagua J, Hershberger RE. Family history: an essential tool for cardiovascular genetic medicine. Congest Heart Fail. 2008;14(1):37–45 18. Taylor MR, Carniel E, Mestroni L. Cardiomyopathy, familial dilated. Orphanet J Rare Dis. 2006;1:27 19. Robin NH, Tabereaux PB, Benza R, et al. Genetic testing in cardiovascular disease. J Am Coll Cardiol. 2007;50(8):727–737 20. Napolitano C, Priori SG, Schwartz PJ, et al. Genetic testing in the long QT syndrome: development and validation of an efficient approach to genotyping in clinical practice. JAMA. 2005;294(23):2975–2980 21. Ingles J, Doolan A, Chiu C, et  al. Compound and double mutations in patients with hypertrophic cardiomyopathy: implications for genetic testing and counseling. J Med Genet. 2005;42(10):e59 22. Cowan J, Morales A, Dagua J, Hershberger RE. Genetic testing and genetic counseling in cardiovascular genetic medicine: overview and preliminary recommendations, Congest Heart Fail. 2008;14(2):97–105

26  Genetic Counseling in Cardiovascular Conditions 23. American Society of Clinical Oncology Policy Statement Update. Genetic testing for cancer susceptibility. J Clin Onco. 2003;21(12):2397–2406 24. Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death – executive summary: a report of the American College of Cardiology/ American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing committee to develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death). Circulation. 2006;114(10):1088–1132 25. Sermijn E, Goelen G, Teugels E, et al. The impact of proband mediated information dissemination in families with a BRCA1/2 gene mutation. J Med Genet. 2004;41(3):e23 26. Forrest LE, Burke J, Bacic S, et al. Increased genetic counseling support improves communication of genetic information in families. Genet Med. 2008;10(3):167–172 27. McGivern B, Everett J, Yager GG, et al. Family communication about positive BRCA1 and BRCA2 genetic test results. Genet Med. 2004;6(6):503–509 28. DeMarco TA, McKinnon WC. Life after BRCA1/2 testing: family communication and support issues. Breast Dis. 2006–2007;27:127–136 29. Hallowell N, Foster C, Eeles R, et al. Balancing autonomy and responsibility: the ethics of generating and disclosing genetic information. J Med Ethics. 2003;29(2):74–79; discussion 80–83

335 30. Godard B, Hurlimann T, Letendre M, et al. Guidelines for disclosing genetic information to family members: from development to use. Fam Cancer. 2006;5:103–116 31. Lucassen A, Parker M. Confidentiality and serious harm in genetics - preserving the confidentiality of one patient and preventing harm to relatives. Eur J Hum Genet. 2004;12(2): 93–97 32. Lacroix M, Godard B, Knoppers BM. Warning patients’ relatives of genetic risks: policy approaches. GenEdit 2005; 3:1–8. Available at: www.humgen.umontreal.ca/int/GE/ en/2005–3.pdf, Accessed 07–01-08 33. Recommendations for genetic counseling related to genetic testing (Draft 2) 2007, Available at: http://www.eurogentest. org/web/info/public/unit3/draft_recommendations_genetic_ counselling.xhtml, Accessed 12–06-08 34. Skirton H, Lewis C, Kent A, et  al. Core competences in genetics for health professionals in Europe, 2008, Available at: http://www.eurogentest.org/web/info/public/unit6/core_ competences.xhtml, Accessed 12–06-08 35. Burke S, Bennet C, Bedward J, et al. The experiences and preferences of people receiving genetic information from health care professionals, NHS National Genetics Education and Development Centre, 2007, Available at: http://www. geneticseducation.nhs.uk/downloads/genetics_experiences_ report.pdf, Accessed 12.06.08 36. van Langen IM, Birnie E, Leschot NJ, et al. Genetic knowledge and counselling skills of Dutch cardiologists: sufficient for the genomics era? Eur Heart J. 2003;24(6):560–566

Index

A Abetalipoproteinemia, 218–220, 222 Acetyl-CoA acetyltransferase (ACAT), 211 Adenosine/ATP test, 30 Adult congenital heart disease (ACHD) arrhythmias, 37–51 sudden cardiac death, 37–51 Adverse drug reactions (ADRs), 271, 275 Alagille syndrome, 263, 265 Alcohol use, 12–13 Aldosterone antagonists, 271, 276 Ambulatory monitoring (‘’Holter’’), 29, 42, 51, 66, 86, 87, 157, 159, 185, 196, 199, 251 Aneurysm, 95, 100, 225, 226, 229–232, 249, 301 Angiotensin-converting enzyme (ACE) inhibitors, 188, 189, 232, 271, 272, 276 Angiotensin II receptor blockers (ARBs), 188, 279 Aortic atresia, 264 Aortic dilatation, 225–232 Aortic dissection, 227, 230, 261, 317 Aortic valve stenosis, 261, 264 Apo B editing complex (ApoBec), 209 Apolipoprotein (Apo), 206–213, 215, 218, 219, 221, 278, 296 Arrhythmias modifiers of, 288 polygenic studies, 287–292 risk of, 75, 78, 138, 249, 287–292 Arrhythmic disorders, 57, 310 Arrhythmogenesis, 5, 62, 134, 235–257 Arrhythmogenic right ventricular cardiopathy (ARVC), 60, 62, 63, 65, 67, 69, 164, 165, 168, 310, 311, 315–317, 321 Arrhythmogenic right ventricular dysplasia (ARVD), 60, 62, 81–83, 100, 101, 105, 159, 163–170 clinical diagnosis, 164–168 clinical presentation, 163–164 management strategies, 168–170 overt arrhythmic form of, 163 Athletes, screening, 65–66 Athlete’s heart, 57–58, 61, 63, 65, 69 ATP-binding cassette transporter A1 (ABCA1), 207, 211, 212, 219, 220, 298 ATP-binding cassette transporter G1 (ABCG1), 212 Atrial fibrillation (AF) familial, 176, 177 nonfamilial, 176–178



Atrial flutter, 64 Atrial septal anomalies, 264–265 Atrial septal defects (ASDs), 38–41, 43, 51, 261, 263–265 Atrioventricular canal defects (AVCD), 41, 42, 44, 46, 51 Atrioventricular (AV) nodal block, 37 Automated external defibrillators (AED), 68 Autonomic nervous system (ANS), 8, 10, 15–17 Autopsy procedure, 94–95 B Beta-blockers, 121, 125, 159–161, 271, 273, 277–278, 311 Bicuspid aortic valve (BAV), 230, 259, 261, 263, 264 Biochemical abnormalities, 217, 255, 256 Brugada syndrome characteristics, 131 clinical manifestations, 135, 138 diagnostic criteria, 131 genetics, 131, 133, 137, 139 prognosis, 134, 136, 140–142 risk stratification, 140–143 C Cardiac defects, decision trees for, 261–267 Cardiac lesions, 261, 262 Cardiomyopathies, secondary, 185, 186, 235–236 Cardiovascular conditions, genetic counseling, 325–332 Cardiovascular disease, 3, 57, 95, 113, 118, 205–222, 271, 279, 315–322 Catecholaminergic polymorphic ventricular tachycardia (CPVT), 9, 86–89, 91, 157–161, 315, 321 Channelopathies, 8–9, 17, 27, 61, 66, 68, 73, 91, 104, 106, 131, 133, 154, 176, 326 Child care settings, 14 Cholesterol (C), 205, 207, 209–221, 250, 271, 276, 296 Cholesteryl ester (CE), 206–212, 214, 216, 217, 219 Cholesteryl ester transfer protein (CETP), 209, 210, 212, 219 Chromosomal aberrations, 260–262 Clinical risk factors, 196 Coenzyme A (CoA), 211, 238, 242 Commotio cordis, 63 Congenital heart diseases (CHD) clinical genetics in, 259–269 genetic basis, 260–261 Congenital rubella, 263 Conotruncal defects, 265, 267 Coronary artery disease (CAD), genetic challenge, 295–303

337

338 Costello syndrome, 263 Cytochromes P450, 273–275 D Danon’s disease, 187, 188, 237, 240, 243–246 DARVIN study, 168, 169 Death circumstances, 93, 94 Diastolic function, 58, 61 DiGeorge syndrome, 113, 261, 262 Digoxin, 189, 271 Dilated cardiomyopathy (DCM) clinical diagnosis, 183–184 epidemiology, 181–182 genetic basis, 181–182 management, 188 Diuretics, 168, 188, 200, 214, 271 DNA mutation analysis, 256, 260 Double-outlet right ventricle, 267 Drug effects, complexity of, 272–273 Drug interactions, 275, 279 Drug transporters, 273, 275–276 D-transposition on the great arteries (D-TGA), 49–51, 261 Dyslipidemia, 205, 271 Dyslipoproteinemia, 205, 213, 215, 216, 220 E Ebstein’s anomaly, 43, 44, 48, 267 ECG. See Electrocardiograms Echocardiography, 58, 61, 65, 66, 69, 157, 158, 176, 183, 184, 190, 197, 199, 226, 254, 261 Edurance sport practice, 57–69 Ehlers–Danlos syndrome, 228, 229, 263, 317 EKG alterations, 28, 30, 57, 59 of the athlete, 59–60 Electrocardiograms (ECG), 17, 28–31, 33, 45, 48, 66, 73–89, 94, 95, 99, 121–123, 131–133, 135–143, 149–151, 154, 157–161, 163, 164, 167, 168, 183, 185, 197, 199, 237, 243, 246, 248–251, 253, 255, 292, 302, 326, 329 Electrophysiology study, 30, 137, 141, 142, 149, 152, 169 Ellis–van Creveld syndrome, 265 Encephalopathy, 255, 256 Endothelial lipase (EL), 209, 212 Energy production, 8, 11, 238, 239, 255 Epinephrine testing, 122 Exercise testing, 29, 66, 68, 123 F Fabry disease, 135, 194, 246–248, 257 Fatty acid oxidation disorders, 15, 240, 242–243 Fluorescence in situ hybridization (FISH), 260, 263 Fontan palliation, 46–47, 51 Fontan surgery, 51 Forensic pathology, 91–108 Free fatty acids (FFA), 206, 209, 217, 238 G Genetic cardiovascular diseases (GCVDs), 181–191, 315–322 Genetic data, 17, 118, 122, 199 Genetic determinants, 114, 125

Index Genetic investigations, psychological implications, 309–313 Genetic linkage studies, 115–116 Genetic lipoprotein disorders, 205–222 Genetic risk factors, 8–11, 15–17, 113, 116, 126, 197, 275 Genetic studies, 8–11, 17, 108, 113–119, 176, 195, 259, 260, 292, 298 Genetic testing, 5, 58, 105, 122, 143, 160, 181, 197, 221, 246, 264, 309, 318, 326 Genome-wide association studies (GWAS), 116, 299, 300, 303 for complex traits, 116–118 Ghent nosology, 226, 227, 231 Giant cell myocarditis, 102–104 Glenn surgery, 44, 51 Glycogen accumulation, 239–241, 249, 252 Glycogen storage diseases, 236, 243–253, 257 Great arteries, transposition, 38, 42–43, 49–51, 267 GWAS. See Genome-wide association studies H Heart disease, 3, 25, 37, 57, 82, 93, 113, 132, 169, 175, 184, 194, 205, 256, 259, 279, 292, 303, 315, 326 Heart failure (HF), 41, 46, 51, 103, 108, 163, 164, 168, 170, 181, 183, 184, 188–190, 235, 238, 243, 244, 251, 255, 271, 276, 277, 279, 310 Heart rate (HR), 25, 29, 58, 59, 68, 73, 77, 83, 121, 123, 125, 126, 138, 149, 151, 153, 157, 176, 184, 311, 318, 321 Hepatic lipase (HL), 207, 209, 210, 212, 213 Heterotaxy syndromes, 43–44 HHRR method, 117 High-density lipoprotein (HDL), 205–207, 209–217, 219–221 High-resolution banding karyotype, 259 His-Purkinje disease, 37 Histology, 65, 92, 93, 97, 99, 107 Holt–Oram syndrome, 113 Hormone-sensitive lipase (HSL), 208 Human gene mutation database (HGMD), 113 Hydralazine, 271, 272 Hydroxymethylglutaryl coenzyme A reductase (HMG CoA Red), 211 Hyperlipidemia, 205, 213–217, 219, 220 Hypersensitivity myocarditis, 102–103 Hypertrophic cardiomyopathy (HCM) and athlete’s heart, 61–62 characteristics, 61 clinical diagnosis, 194–195 clinical manifestations, 193–194 genetic testing in, 198–199 molecular genetics, 195–196 risk factors for SCD in, 196–198 Hypertrophy, in children, 237–238 Hypobetalioproteinemia, 218–220 Hypoplastic left heart syndrome, 261, 264 I Illicit drug use, 12–13 Implantable cardioverter-defibrillators (ICD), 30, 48, 49, 51, 68, 81, 95, 127, 134, 136, 137, 141, 143, 144, 152–155, 159, 161, 163, 167–170, 189, 245, 251, 310–313 Implantable loop recording (ILR), 31, 32

Index Increased vagal tone, 59 Infant feeding practices, 14 Infant sleep practices, 13 Infection, 10–11 Inflammation, 10–11 Inflammatory myocardial diseases, 102–104 Inherited metabolic diseases, 237 Intermediate density lipoprotein (IDL), 207, 209, 210 Intraatrial reentrant tachycardias (IART), 37, 38, 44–47, 49–51 J Jacobsen syndrome, 264 Jesse Edwards registry of Cardiovascular Disease, 3 L Lecithin cholesterol acyltransferase (LCAT), 206, 209, 212, 214, 219–221 Left ventricular hypertrophy (LVH), 105, 240 Left ventricular noncompaction (LVNC), 102, 185, 187 Left ventricular outflow tract obstructions, 263–264 LEOPARD syndrome, 263 Life habits, 279–280 Lipoprotein disorders, 212–220 Lipoprotein (a) Lp(a), 206, 218–219 Lipoprotein metabolism, 209–212 Lipoprotein transport system, 206–208 Loeys Dietz syndrome (LDS), 228–229, 231 Long QT syndrome (LQT/LQTS) autosomal dominant, 123–125 autosomal recessive, 125 clinical manifestations, 121 diagnosis, 123 diagnostic tools, 121–123 genotype–phenotype correlation, 125 management strategies, 126–127 molecular genetics, 123 risk stratification, 125–126 score, 121–122 Low-density lipoprotein (LDL), 206, 207, 209, 210, 217, 221, 296 Low-density lipoprotein receptor (LDL-R), 210, 211, 217, 221, 296 Low-density lipoprotein receptor-related peptide (LRP), 208 L-transposition on the great arteries (L-TGA), 42–43 Lysosomal storage, 235, 256 M Marfan syndrome (MFS), 60, 65, 225–232, 315–317, 319, 321 Maternally inherited cardiomyopathy (MICM), 254–255 Mendelian traits, 114–115 Metabolism, error, 255–257 Mitochondrial diseases, 194, 242, 254–255 Monckeberg’s sling, 44 Mustard surgery, 51 Myocardial abnormalities, pathophysiology, 238–242 N Negative T waves, 59, 61, 62, 132, 246 Newborn screening. See Screening Niemann–Pick disease type C protein (NPC) like 1 (NPC1L1), 208

339 Nitrates, 271 Noonan syndrome, 238, 262–263, 265 O Oregon Sudden Unexpected Death Study, 4 P Pacifier use, 14 Parental controls, 117 Paroxysmal supraventricular tachycardia, 32, 63–64 Pharmacodynamics, 273, 275–279 Pharmacogenomics, 271–280 Phospholipid transfer protein (PLTP), 209, 210, 212 Pompe disease, 238, 243, 248–250, 255 Pregnancy-related factors, 12 Prenatal screening. See Screening Principal component analysis (PCA), 118 PR interval, 41, 73, 81, 136, 243, 246, 248, 249, 251, 255 PRKAG2 mutations, 237, 242–245, 250–252 Pulmonary artery branch stenosis, 263 Pulmonary outflow obstruction, 262–263 Pulmonary valve stenosis, 262–263 P wave, 43, 45, 73 Q QRS complex, 73–75, 78, 79, 81, 82, 88, 142, 249 QT interval, 8, 9, 29, 60, 76–80, 84–86, 88, 121–123, 125–127, 138, 149–154, 292 QT pronlongation, 78, 124, 127, 151, 153, 158, 176 QT syndrome, 5, 8, 15, 27, 68, 77–80, 83–86, 91, 115, 121–127, 134, 149–155, 158, 176, 177, 287, 288, 296, 312, 315, 326, 329 R Reduced penetrance, 261 Rennin–angiotensin–aldosterone system (RAAS) antagonists, 276–277, 279 Rhythm disorders, 67, 139, 175, 289, 291 Right ventricle (RV), 42, 43, 45, 46, 49, 58, 62, 63, 65, 97, 100, 101, 136, 163, 170, 261, 267 Right ventricle dysplasia, 62 S Sarcoidosis, 102–104 Scavenger receptor B1 (SR-B1), 207, 212 SCD. See Sudden cardiac death Screening, 5, 57, 61, 67, 69, 94, 106, 121, 136, 139, 141, 153, 160, 164, 165, 167, 168, 183, 187, 189, 190, 199, 221, 226, 230, 235, 238, 250, 259, 264, 298, 299, 302, 303, 309 athletes, 65–66 Senning surgery, 51 Serotonin transporter 5 (5-HTT), 8–10, 15, 16 Short QT syndrome (SQTS) clinical diagnosis, 149–152 diagnosis, 152 genetic basis, 153–154 prevention strategies, 155 risk stratification, 152–153 role of genetics, 154–155 therapeutic approach, 153

340 Single gene vs. polygenic disorders, 7, 296–297 Single nucleotide polymorphisms (SNPs), 113, 116–118, 178, 195, 196, 287, 288, 292, 297–301, 303 Single ventricle physiology, 44–46 Sinus rhythm (SR), 41, 49, 73, 79, 82, 84, 87, 139, 155, 246, 311 Smooth endoplasmic reticulum (sER), 211 Sociodemographic factors, 11–12 Sport eligibility, 62, 67–69 Sports activity, 166, 316, 318 Standard karyotype, 259, 260 Statins, 214, 216, 271, 276, 278–279 ST segment, changes, 59–60 Sudden cardiac death (SCD) in forensic pathology, 91–108 syndrome, 310–311, 327 Sudden death, in athletes, 57, 60 Sudden infant death syndrome (SIDS) environmental risk factors, 11–15 gene–environment interactions, 16–17 genetic risk factors, 8–11 infants, 13–14 phenotypes associated with risk for, 15 recurrence in siblings, 14–15 Sudden unexpected death in infancy (SUDI), 7–10, 16, 17 Sudden unexplained death syndrome (SUDS) diagnostic considerations, 4–5 magnitude, 3–4 relationship with gender, 4 role of the molecular autopsy, 4–5 Supravalvular stenosis, 264 Supraventricular arrhythmias, 63–65, 86, 134, 139, 143, 157, 183, 184, 189, 193, 288 Syncope in athletes, 69 definition, 25 diagnostic approach, 31–33 etiology, 25–28 pathophysiology, 25 unexplained, 25 Systolic function, 29, 58, 181, 183, 194, 254

Index T Tetralogy of Fallot, 47–49, 51, 261, 263, 265 Three-generation family history, 261 Tilt test, 29–30 Tobacco use, 12–13 Torsade(s) de pointes (TdP), 77–81, 121, 126, 127, 157, 249 Toxic myocarditis, 102, 103 Toxicology, 97–98, 107 Transient ischemic attack (TIA), 175 Transmission disequilibrium test (TDT), 117, 118 Triglyceride-rich lipoproteins (TRL), 206, 210–212, 215, 219 Triglycerides (TG), 206, 209, 210, 212–220 Trisomy 13, 259, 261 Trisomy 18, 259, 261, 265, 267 Trisomy 21, 259, 261–262 Turner syndrome, 259, 261, 264 T wave, 59, 61, 62, 66, 75, 76, 78–84, 86, 121, 125, 131, 132, 138, 142, 143, 150–154, 163, 164, 246 V Variable expressivity, 260, 327, 332 Ventricular arrhythmias, 9, 28, 41–43, 48, 60–65, 68, 76, 81, 86, 87, 98, 103, 104, 121, 126, 127, 131, 134, 138, 139, 141–143, 157, 160, 163, 164, 166–169, 183, 184, 189, 193, 197, 200, 235, 242, 288, 316 Ventricular complex arrhythmias, 63 Ventricular preexcitation, 63–64, 97, 237, 243, 244, 246, 251, 253 Ventricular premature beats, 57, 63, 67, 247 Ventricular repolarization components, 75–77 Ventricular septal abnormalities, 265 Ventricular septal defects (VSDs), 41–43, 45, 261, 265 Very-low-density lipoprotein (VLDL), 206, 207, 209, 210, 212, 213, 215, 216, 218, 219 Very-low-density lipoprotein receptor (VLDL-R), 207, 208, 210 W Warfarin, 271, 273, 274, 278–280 Williams–Beuren syndrome, 264 Wolff–Parkinson–White syndrome, 44, 187