Genetic Variants Associated With Sudden Cardiac Death in Victims With Single Vessel Coronary Artery Disease and Left Ventricular Hypertrophy With or Without Fibrosis

Juha H Vähätalo,Lasse Pakanen,Risto Kerkelä,Robert J Myerburg,M Juhani Junttila,Katri Pylkäs,Juha S Perkiömäki,Katja Porvari,Lauri T A Holmström,Sini Skarp,Heikki V Huikuri,Kari S Kaikkonen

doi:10.3389/fcvm.2021.755062

Abstract

Objective: Cardiac hypertrophy with varying degrees of myocardial fibrosis is commonly associated with coronary artery disease (CAD) related sudden cardiac death (SCD), especially in young victims among whom patterns of coronary artery lesions do not entirely appear to explain the cause of SCD. Our aim was to study the genetic background of hypertrophy, with or without fibrosis, among ischemic SCD victims with single vessel CAD.Methods: The study population was derived from the Fingesture study, consisting of all autopsy-verified SCDs in Northern Finland between the years 1998 and 2017 (n = 5,869). 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 age 63.6 ± 10.3 years; 88.4% males) with single-vessel CAD in the absence of previously diagnosed CAD and cardiac hypertrophy with or without myocardial fibrosis at autopsy.Results: A total of 42 rare variants were detected in 43 subjects (45.3% of the study subjects). Five variants in eight subjects (8.4%) were classified as pathogenic or likely pathogenic. We observed 37 variants of uncertain significance in 39 subjects (40.6%). Variants were detected in myocardial structure protein coding genes, associated with arrhythmogenic right ventricular, dilated, hypertrophic and left ventricular non-compaction cardiomyopathies. Also, variants were detected in ryanodine receptor 2 (RYR2), a gene associated with both cardiomyopathies and catecholaminergic polymorphic ventricular tachycardias.Conclusions: Rare variants associated with cardiomyopathies, in the absence of anatomic evidence of the specific inherited 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 SCD in ischemic disease.

Highlights

80% of sudden cardiac deaths (SCDs) are due to coronary artery disease (CAD) and up to one-half occur in the absence of previously diagnosed cardiac disease [1]
Single-vessel CAD, determined by evidence of either acute or prior myocardial infarction due to critical stenosis or occlusion of a single epicardial coronary artery, and cardiac hypertrophy were present in 244 individuals
We carried out genetic studies in 95 SCD victims with single-vessel CAD and cardiac hypertrophy in the absence of previously diagnosed CAD, whose DNA passed the quality control for further analysis

Summary

Introduction

80% of sudden cardiac deaths (SCDs) are due to coronary artery disease (CAD) and up to one-half occur in the absence of previously diagnosed cardiac disease [1]. Regardless of the cause, cardiac hypertrophy, associated with varying degrees of myocardial fibrosis, is a risk factor for SCD and is associated with increased risk for SCD in patients with or without CAD [2]. Left ventricular hypertrophy (LVH) is a common finding in both ischemic and non-ischemic SCD victims at autopsy [3, 4]. Myocardial weight often increases along with the severity of CAD [4]. Three-vessel CAD and cardiac hypertrophy increase the vulnerability to fatal arrhythmias and SCD [4]. Some SCDs occur in victims with only single-vessel CAD and cardiac hypertrophy found at autopsy [6]

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Discussion

Conclusion