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Assessment of the Incidence, Etiology, Circumstances and Familial Risk for Sudden Cardiac Death and Aborted Sudden Cardiac Death in Young Individuals

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Assessment of the Incidence, Etiology, Circumstances and Familial Risk for Sudden Cardiac Death and Aborted Sudden Cardiac Death in Young Individuals The Family Study: Assessment of the Incidence, Etiology, Circumstances and Familial Risk for Sudden Cardiac Death and Aborted Sudden Cardiac Death in Young Individuals by Katherine Sarah Allan A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Institute of Medical Science University of Toronto © Copyright by Katherine Allan 2016 The Family Study: Assessment of the Incidence, Etiology, Circumstances and Familial Risk for Sudden Cardiac Death and Aborted Sudden Cardiac Death in Young Individuals Katherine Allan Doctor of Philosophy Institute of Medical Science University of Toronto 2016 Abstract Background: Recent reviews have highlighted our lack of information on the incidence etiology and circumstances of sudden death (SD) in the young, particularly the distribution of underlying disorders, preventable triggers, and identifiable familial predisposition to fatal arrhythmias. Methods: This study had 3 parts: (1) the development and (2) implementation of a novel, comprehensive methodology to capture all SDs and aborted SDs (both cardiac and non-cardiac) in a defined geographic area, (3) followed by a feasibility study with a case control design. We utilized a prospectively collected, population-based registry of all out-of-hospital cardiac arrests (OHCAs) in the Greater Toronto Area, to identify patients from 2009-2012. The retrospective study included cases that were OHCAs ages 2-45, treated or untreated, died or survived and we reviewed all available data for each case and adjudicated an etiology. In the feasibility study, included cases were presumed cardiac, treated OHCAs ages 18-65. Two relatives per patient were ii interviewed regarding symptoms prior to the arrest, cardiac history, and family history of sudden cardiac death (SCD). Two sets of control patients were administered the same questionnaire as cases. Results: We identified 656 SCDs ages 2-45 over a 4 year period, with an overall annual incidence rate of 3.97 per 100,000 persons. We report a high autopsy rate, with a shift towards ischemic heart disease as the predominant underlying etiology in adults ages 35-45, from structural heart disease and sudden unexplained deaths in children. Adults experienced their SCDs more frequently at home and at rest than did children, and most reported new symptoms in the day preceding their event. Our feasibility studies demonstrated that it is viable to obtain a reliable family history of SCD and major cardiac risk factors from both cases and controls using a self-developed survey. Conclusions: By using a validated comprehensive population based registry of consecutive cases to identify all eligible patients, in combination with a novel classification methodology, large sample size, and multiple sources of data, we were able to better describe the nature and scope of the problem of sudden cardiac death within a young, urban Canadian population. iii Acknowledgments This thesis could not have been accomplished without the input from a great number of people, whose contribution in varying ways deserves special mention. First and foremost I would like to thank all of the sudden cardiac death and aborted sudden cardiac death patients and their families, without which this thesis would not have been possible. Their kindness and openness to participating in research after experiencing such a traumatic event deeply touched and inspired me. I hope that the results from my thesis will promote discussion and systematic change in the way that these families receive their follow-up and clinical care. Secondly, to my supervisor Paul Dorian – my deepest thanks for being such a wonderful mentor to me, in both my work and as a graduate student. I have learned and grown so much under your supervision and I aspire to become an outstanding, successful researcher and supervisor like yourself. I am eternally grateful for your endless support and patience, especially with regards to my family, without which I would not have survived this intense process. I hope that our collaboration (and friendship) will be lifelong. To my committee Dr. Laurie Morrison, Dr. Jack Tu and Dr. Bart Harvey – my deepest thanks also for your superb scientific guidance and endless support and patience. Thank you for having my back when I needed it most and for encouraging and challenging me to always better myself. Your endless questions and suggestions guided and challenged my thinking, and I hope, substantially improving the finished product. iv To the wonderful staff at Rescu without whom this thesis would not be possible: Katie Dainty for excellent advice and moral support and to Andrea Meeson – thank you for your kindness and patient listening; I will always treasure our discussions. Thank you also to my support network (NW, TA, SC, IF, LP, CF, VR, LDS, KC, RA, MG, AF, BZ) who listened patiently, dried my tears, provided much needed wisdom (and perspective) lifted me up, and encouraged me to keep going until the very end. You have my infinite love and gratitude. I received equally important assistance from both family and friends. My parents instilled in me, from a very early age, the desire and skills to be a perpetual student and to never give up, no matter what. Special thanks to my sister and my mother-in-law for your unwavering support. Thank you to my husband and children whose love, dedication, understanding and patience made it possible for me to finish this thesis. v Contributions To all of my ad hoc scientific advisors who gave so generously of their time and expertise, thank you also from the bottom of my heart: From the Office of the Chief Coroner of Ontario: Dr. Jim Edwards for patient recruitment, scientific advice and your endless support right from the beginning. Dr. Dan Cass and Dr. Karen Woodall for your support and scientific input regarding autopsy/coroner/toxicology protocols. Dr. Kris Cunningham for your scientific input regarding coroners and autopsy protocols, in particular the OCCO SCD protocols and for your superb teaching, Andrew Stephen and Lisa Perri for helping me navigate my way at the OCCO, for finding coroner charts and analyzing coroner data and for your wonderful support and enthusiasm. From St. Michael’s Hospital: Dr. Joel Ray and Peter Gozdyra for your excellent scientific guidance regarding incidence calculations and Canada Census data. Dr. Arnold Pinter, Dr. Paul Angaran and Dr. Iqwal Mangat for your terrific support and input on the study protocol and thesis manuscripts. Dr. Gerald Lebovic thank you for your helpful statistical advice on both analysis sections. vi From Rescu: Cathy Zhan for her outstanding analyst skills and for cheerfully helping me no matter how urgent my requests. Matthew Common for patiently running all of my data queries and for moral support; Kate Byrne for always helping me with Epistry data access Data Abstractors at St. Michael’s Hospital: They say it takes a village to raise a child, if true, then it certainly takes a city to help finish a PhD! Thank you to each and every volunteer who has helped me along the way with SOPS, patient recruitment, data abstraction and data entry starting with: Andrei Vagaon, Matthew Guttman, Natalja Tchajkova, Lindsay Cheskes, Sarah Sahheed, Christine Tenedero, Theresa Aves, Iris Fan, Suzanne Chung, Navkiran Chahal, Brian Ngyuen, Dhanisha Patel, David Dorian, Cameron Landry and Golnaz Roshanker. I am so deeply grateful to all of you for your hard work and dedication to my project, without which most of this would not be possible. Thank you also for your high energy and enthusiasm, which kept me going when times were tough. Wishing all of you the very best in your endeavours. From the Sunnybrook Osler Centre for Prehospital Care: Dr. Rick Verbeek and Dr. Sheldon Cheskes for your support and aid for my project as site primary investigators at Sunnybrook Health Sciences Centre. vii Table of Contents Abstract ii Acknowledgements iv Contributions vi Table of Contents viii List of Tables xiii List of Figures xv List of Appendices xvi List of Abbreviations xvii Chapter 1: Introduction 1 1.0 Background 2 1.1 Understanding the Methodology 2 1.2 Methods for Case Identification 2 1.2.1 Internet and Media Searches 2 1.2.2 Death Certificates and ICD Codes 3 1.2.3 Autopsy Based Registries 5 1.2.4 OHCA Data 6 1.2.5 Multisource Surveillance and Data Collections Methods 7 1.3 Definitions for Sudden Cardiac Death 9 1.4 Accurately Determining and Classifying Cause of Death 11 1.5 What will it take to solve the problem? 12 1.5.1 Methodology to Accurately Ascertain Cases 13 1.5.2 Standardized Definitions 14 1.5.3 Accurate Understanding and Classification of Etiologies 15 1.6 Causes of Sudden Death in the Young 16 1.6.1 Structural Causes of Sudden Cardiac Death 17 1.6.1.1 Cardiomyopathies 17 1.6.1.2 Hypertrophic Cardiomyopathy 18 1.6.1.3 Arrhythmogenic Right Ventricular Cardiomyopathy 19 1.6.1.4Coronary Artery Disease 20 1.6.1.5 Structural Acquired - Cocaine Induced Cardiomyopathy 21 1.6.1.6 Structural Causes Summary 22 1.6.2 Primary Arrhythmic Syndromes 22 1.6.2.1 Long QT Syndrome 23 1.6.2.2 Sudden Unexplained Death 24 1.6.2.3 Acquired (Drug Induced) Arrhythmias 25 1.6.2.4 Mechanisms Leading to Arrhythmias 26 1.6.2.5.Psychotropic Arrhythmia Inducing Drugs 26 1.6.2.6 Antipsychotics 26 1.6.2.7 Antidepressants 27 1.6.2. Acquired Arrhythmias - Cocaine Induced 28 1.6.2.9 Summary for Heritable and Acquired Arrhythmias 29 viii 1.7 Non-cardiac Causes of Sudden Death in the Young 30 1.7.1 Sudden Unexplained Death in Epilepsy 31 1.7.2 Depression
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