Ventricular arrhythmogenesis in the genetically- susceptible heart Citation for published version (APA): ter Bekke, R. M. A. (2018). Ventricular arrhythmogenesis in the genetically-susceptible heart: time to change concepts of mechanisms and management. https://doi.org/10.26481/dis.20180622rb Document status and date: Published: 01/01/2018 DOI: 10.26481/dis.20180622rb Document Version: Publisher's PDF, also known as Version of record Please check the document version of this publication: • A submitted manuscript is the version of the article upon submission and before peer-review. There can be important differences between the submitted version and the official published version of record. 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If the publication is distributed under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license above, please follow below link for the End User Agreement: www.umlib.nl/taverne-license Take down policy If you believe that this document breaches copyright please contact us at: [email protected] providing details and we will investigate your claim. Download date: 04 Oct. 2021 Ventricular Arrhythmogenesis in the Genetically-Susceptible Heart: Time to Change Concepts of Mechanisms and Management Rachel ter Bekke VENTRICULAR ARRHYTHMOGENESIS IN THE GENETICALLY-SUSCEPTIBLE HEART: TIME TO CHANGE CONCEPTS OF MECHANISMS AND MANAGEMENT PROEFSCHRIFT ter verkrijging van de graad van doctor aan de Universiteit Maastricht, op gezag van de Rector Magnificus, Prof. dr. Rianne M. Letschert volgens het besluit van het College van Decanen, in het openbaar te verdedigen op vrijdag 22 juni 2018 om 14.00 uur door Rachel Mariet Anouk ter Bekke Promotor Prof. dr. P.G.A. Volders Beoordelingscommissie Prof. dr. H.J.G.M. Crijns (voorzitter) Prof. dr. C.R. Bezzina (Universiteit van Amsterdam) Prof. dr. F.W. Prinzen Prof. dr. P.J. Schwartz (IRCCS Istituto Auxologico Italiano, Milaan, Italië) Prof. dr. H.J.J. Wellens The research in this thesis was supported by a grant of the Dutch Heart Foundation/ The Netherlands CardioVascular Research Initiative (CVON-PREDICT). Additional research support by the Health Foundation Limburg is gratefully acknowledged. The Dutch Heart Foundation also contributed to the printing costs of this thesis. I also thank the Stichting Hartsvrienden RESCAR for a financial contribution the publication of this thesis. © Rachel M.A. ter Bekke, 2018 ISBN 978-94-6159-821-9 Cover art and design: Claudia Volders and Rachel ter Bekke For all families including mine: Jade, Myrthe, Inez, Marga, Frans, and Esther | VII CONTENTS CHAPTER 1 1 Introduction. CHAPTER 2 21 Arrhythmogenic Mechano-Electric Heterogeneity in the Long-QT Syndrome. Rachel M.A. ter Bekke, Paul G.A. Volders Prog Biophys Mol Biol 2012;110:347-358 CHAPTER 3 41 Electromechanical Window Negativity in Genotyped Long-QT Syndrome Patients: Relation to Arrhythmia Risk. Rachel M.A. ter Bekke, Kristina H. Haugaa, Arthur van den Wijngaard, J. Martijn Bos, Michael J. Ackerman, Thor Edvardsen, Paul G.A. Volders Eur Heart J 2015;36:179-186 Editorial 59 Vox Clamantis in Deserto. We Spoke but Nobody was Listening: Echocardiography can help Risk Stratification of the Long-QT Syndrome. Gaetano M. De Ferrari, Peter J. Schwartz Eur Heart J 2015;36:148-150 CHAPTER 4 65 Proarrhythmic Proclivity of Left-Stellate Ganglion Stimulation in a Canine Model of Drug-Induced Long-QT Syndrome Type 1. Manuscript submitted, 2018 CHAPTER 5 83 Heritability in a SCN5A-Mutation Founder Population with Female Susceptibility to Non-Nocturnal Ventricular Tachyarrhythmia and Sudden Cardiac Death. Rachel M.A. ter Bekke, Aaron Isaacs, Andrei Barysenka, Marije B. Hoos, Jan D.H. Jongbloed, Jan C.A. Hoorntje, Alfons S.M. Patelski, Apollonia T.J.M. Helderman-van den Enden, Arthur van den Wijngaard, Monika Stoll, Paul G.A. Volders Heart Rhythm 2017;14:1873-1881 VIII | Editorial 103 Founder Populations with Channelopathies and Church Records Reveal All Sorts of Interesting Secrets: Some are Scientifically Relevant. Peter J. Schwartz and Lia Crotti Heart Rhythm 2017;14:1882-1883 CHAPTER 6 107 Beauty and the Beat: A Complicated Case of Multifocal Ectopic Purkinje-Related Premature Contractions. Manuscript accepted for publication in Heart Rhythm Case Reports CHAPTER 7 119 Life-Threatening Ventricular Arrhythmias in the Genetically-Susceptible Heart: Time to Change Concepts. CHAPTER 8 141 HeArt Project. Rachel M.A. ter Bekke, Claudia A.A. Volders Manuscript accepted for publication in Tijdschrift voor Gezondheidswetenschappen SUMMARY/SAMENVATTING 153 VALORIZATION 157 REFERENCES 163 GENEALOGICAL SOURCES 195 LIST OF ABBREVIATIONS 203 ACKNOWLEDGEMENTS/DANKWOORD 207 CURRICULUM VITAE 213 “Le cœur a ses raisons que la raison ne connaît pas” | 1 1 INTRODUCTION CONTENTS GENETIC PREDISPOSITION TO SUDDEN CARDIAC DEATH 2 Genetic Susceptibility to Sudden Cardiac Death 3 Infarct-Related Ventricular Fibrillation 4 Inherited Arrhythmia Syndromes 5 Drug-Induced Repolarization Prolongation 6 Genetic Modulators of Disease Variability 6 ARRHYTHMIA MECHANISMS 7 LQTS: A Purely Electrical Disease? 7 Arrhythmogenic Role of Purkinje Fibers 9 Brugada Syndrome: Depolarization or Repolarization? 10 VENTRICULAR ARRHYTHMOGENESIS AND THE AUTONOMIC NERVOUS SYSTEM 10 THERAPEUTIC AVENUES 12 Antiarrhythmic Drugs 12 Interventional Modalities 13 AIMS AND STRUCTURE OF THIS THESIS 14 2 | CHAPTER 1 GENETIC PREDISPOSITION TO SUDDEN CARDIAC DEATH One early morning in June 2017, in a home nearby Maastricht, The Netherlands, a father heard a snoring sound in the corridor while traversing to the bathroom. Startled by this peculiar noise, but still somewhat drowsy, he checked on his sleeping daughter, who was well. Two hours later his other child, the apparently healthy 29-year-old son, was found dead in his bed. A stilling “why” is what remains amongst the relatives, and a deafening call to health-care providers concerned with the topic of sudden cardiac death. As exemplified by this case, sudden death is defined as an unexpected, non-traumatic fatal event occurring within one hour of the onset of symptoms in an apparently healthy subject.1 A cardiac origin is suspected if a potentially fatal cardiac condition was known to be present, when autopsy has indicated a cardiac anomaly as the probable cause of the event or no obvious extra-cardiac causes have been identified by post-mortem examinations with fatal arrhythmia being the likely cause of death.1 Sudden cardiac death (SCD) imposes a sizable socioeconomic and psychosocial burden, claiming almost a million deaths annually in Western Europe and the United States. It accounts for 15-20% of all natural deaths and up to 50% of all cardiovascular deaths.2, 3 Out- of-hospital SCD occurs with a yearly incidence of 39-100 per 100,000 individuals aged 20-75 years in the Netherlands.4, 5 In the Dutch province of Limburg SCA affects approximately 15 individuals per week.6 Once SCA ensues, the victim’s survival rate declines at a rapid pace (8-10% per minute),7 prompting urgent attempts to rescue the subject by cardiopulmonary resuscitation, preferably with community-available automated external defibrillators (AEDs) utilized by trained volunteers. Ventricular fibrillation (VF) mostly underlies SCD and usually occurs in the setting of coronary heart disease and myocardial ischemia (~75%).3, 8, 9 However, SCD is the first manifestation of heart disease in approximately 45% of cases.4 Inherited arrhythmia syndromes predispose to VF, accounting for 5-10% of total VF victims, relatively often in the young.10 These primary electrical arrhythmia syndromes comprise of the long-QT syndrome (LQTS), Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia (CPVT), short-QT syndrome (SQTS), short-coupled torsades de pointes (TdP), early-repolarization syndrome (ERS), and other rare conditions. In <5% of VF cases no cardiac structural or electrical abnormalities can be ascertained; this is referred to as “idiopathic VF”. In this thesis, I will focus on life-threatening ventricular tachyarrhythmias, including VF, in the structurally-normal, but electrically-compromised heart. I will investigate genotype- phenotype relations, assess novel SCD risk indicators, evaluate triggers of arrhythmia, and discuss antiarrhythmic treatment. Special emphasis will be put on electromechanical interrelations and the influence of the autonomic nervous system. These aspects are examined mainly in the long-QT syndrome, Brugada syndrome, and multifocal ectopic Purkinje-related ectopy. The gained insights into ventricular arrhythmogenesis