Inherited and acquired predictors of sudden cardiac death.

1. Inherited and acquired predictors of sudden cardiac death Prof. Dr. Arthur A.M. Wilde M.D. Ph.D. Prof. Dr. Marc A. Vos Ph.D

2. Amsterdam (AMC) *Arthur A.M. Wilde MD PhD Hanno L. Tan MD PhD Connie R. Bezzina PhD *Ruben Coronel MD PhD Consortium Groningen (UMCG) J. Peter van Tintelen MD PhD Rotterdam (Erasmus MC) Miriam C.J.M. Sturkenboom PhD Utrecht (UMC, UU) *Marc A. Vos PhD *Albert J.R. Heck PhD Richard Hauer MD PhD Toon A.B. van Veen PhD Cardiology (Wilde, Tan, Hauer) Electrophysiology (Vos, Coronel) Genetics (Bezzina, van Tintelen) Proteomics (Heck) Molecular Biology (Bezzina, van Veen) Epidemiology (Sturkenboom) DISCIPLINES * added as P.I.s following suggestion of CVON P.I.s encompass all the expertise in the Netherlands relating to the focus of the application and disciplines. P.I.s

3. Health Care problem Progress in preventing SCD is hindered by the large gap in our knowledge regarding the molecular determinants of SCD and those acquired factors that conspire in increasing risk of SCD in the general population.

4. Research questions Hypothesis-free approach: 1. Which genetic factors modulate risk of SCD in the general population ? 2. Which acquired factors modulate risk of SCD in the general population ? 3. What are the genetic / molecular / electrophysiological mechanisms whereby these genetic and acquired factors modulate risk? 4. How do genetic and acquired factors interact in modulating risk of SCD? Hypothesis-based approach: 5. Which intercalated disk components modulate conduction of the cardiac electrical impulse (an important intermediate phenotype of arrhythmia)?

5. Research plan WP1 Genetics, Community-Based Samples WP4 Epidemiology, Community-Based Samples WP2 Genetics, Founder Mutations ARVC WP7 Proteomics, Intercalated Disk WP3 Genetic mechanisms of identified loci WP5 & WP6 Electrophysiology, Functional Studies

6. Innovation 1. Focus on sudden cardiac death in the general population (i.e. complex disease e.g. SCD due to ischemic heart disease). 2. Employment of state-of-the-art genomic (exome/genome sequencing, eQTL, Chip- seq) and proteomic approaches (innovative chemical proteomics methodology) . 3. Investigation of the role of acquired causes in susceptibility to SCD. 4. Availability of unique (world-wide) and highly annotated (acquired factors) commuinity-based samples of SCD with available documented ventricular fibrillation and DNA.

7. Translation 1. Prediction of SCD 2. Individualized preventive strategies 3. New therapeutic targets

8. Focus areas Dutch Heart Foundation - The epidemiology component of the application will inform us on the role of gender and acquired factors (e.g. metabolic syndrome, drugs), either in isolation or in combination with specific genetic factors, in determination of risk of SCD => hypotheses generating. - Specific hypothesis for role of gender and acquired factors +/- specific genetic factors will be tested in functional studies. - Our community-based studies have been designed with the specific aim of obtaining a vast amount of information on acquired factors to enable such studies.