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

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

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.

Research questionsHypothesis-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)?

Research plan

WP1Genetics,

Community-Based Samples

WP4Epidemiology,

Community-Based Samples

WP2Genetics,

Founder MutationsARVC

WP7Proteomics,

Intercalated Disk

WP3Genetic

mechanisms of identified loci

WP5 & WP6Electrophysiology,Functional Studies

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.

Translation

1. Prediction of SCD

2. Individualized preventive strategies

3. New therapeutic targets

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.

PerspectiveOngoing participation in (inter)national consortia:

• CTMM-COHFAR (Utrecht, Amsterdam)

• FP7 (Amsterdam, Utrecht, Rotterdam)

• Leducq (Amsterdam. Utrecht)

• CHARGE consortium (Amsterdam, Rotterdam)

Submitted / planned grant applications:

• ERC Advanced

• ERC Starting

• Leducq

• NWO Top

• etc