P481The genetic background of sudden cardiac deaths caused by single vessel coronary artery disease and myocardial hypertrophy with fibrosis

Abstract

Abstract Funding Acknowledgements Sigrid Juselius Foundation, Finnish Foundation for Cardiovascular Research, Aarne Koskelo Foundation, The Finnish Medical Foundation Background Coronary artery disease (CAD) is the most common underlying cause of sudden cardiac death (SCD). Cardiac hypertrophy with varying amount of myocardial fibrosis is a common risk factor for CAD related SCD especially in young SCD victims where severity of CAD seems not to entirely explain the cause of SCD. Purpose The aim was to study the genetic background of hypertrophy and fibrosis among young, ischemic SCD victims with single vessel CAD. Methods The study population was derived from the Fingesture study consisting of all autopsy-verified sudden cardiac deaths in Northern Finland between years 1998-2017 (n = 5,869). CAD was determined to be the cause of SCD in 4,392 victims (74.8%). We carried out targeted next-generation sequencing using a panel of 174 genes associated with myocardial structure and ion channel function in 95 ischemic-SCD victims (mean [standard error] age, 63.6 [1.06] years; 88.4% males) with single-vessel CAD and cardiac hypertrophy in the absence of previously diagnosed CAD, and whose DNA passed the quality control for further analysis. Assessment for pathogenicity of detected variants was based on American College of Medical Genetics consensus guidelines. Results A total of 43 variants were detected in 43 of the study subjects (45.3 %). Five variants in eight subjects (8.4%) were classified as pathogenic or likely pathogenic. We observed 38 variants of uncertain significance in 39 victims (40.6 %). Variants were detected in myocardial structure protein coding genes, associated with arrhythmogenic right ventricular cardiomyopathy (13 variants), dilated cardiomyopathy (16 variants), hypertrophic cardiomyopathy (6 variants) and left ventricular non-compaction cardiomyopathy (3 variants). Five variants were detected in RYR2 associated with both cardiomyopathies and catecholaminergic polymorphic ventricular tachycardias. Seven variants were detected in multiple unrelated subjects. None of the subjects presented characteristic autopsy findings related to cardiomyopathies. Conclusions Variants associated with cardiomyopathies were common findings among CAD related SCD victims with single vessel disease and myocardial hypertrophy found at autopsies, suggesting that these variants may modulate the risk for fatal arrhythmias and sudden death in ischemic disease.