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

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.

Association of Silent Myocardial Infarction and Sudden Cardiac Death.

Importance: Myocardial infarction in the absence of major or unrecognized symptoms are characterized as silent (SMI). The prevalence of SMI among individuals who experience sudden cardiac death (SCD), with or without concomitant electrocardiographic (ECG) changes, has not previously been described in detail from large studies to our knowledge. Objective: To determine the prevalence of SMI in individuals who experience SCD without a prior diagnosis of coronary artery disease (CAD) and to detect ECG abnormalities associated with SMI-associated SCD. Design, Setting, and Participants: This case-control study compared autopsy findings, clinical characteristics, and ECG markers associated with SMI in a consecutive cohort of individuals in the Finnish Genetic Study of Arrhythmic Events (Fingesture) study population who were verified to have had SCD. The Fingesture study consists of individuals who had autopsy-verified SCD in Northern Finland between 1998 and 2017. Individuals who had SCD with CAD and evidence of SMI were regarded as having had cases; those who had SCD with CAD without SMI were considered control participants. Analyses of ECG tests were carried out by investigators blinded to the SMI data. Data analysis was completed from October 2018 through November 2018. Main Outcomes and Measures: Silent MI was defined as a scar detected by macroscopic and microscopic evaluation of myocardium without previously diagnosed CAD. Clinical history was obtained from medical records, previously recorded ECGs, and a standardized questionnaire provided to the next of kin. The hypothesis tested was that SMI would be prevalent in the population who had had SCD with CAD, and it might be detected or suspected from findings on ECGs prior to death in many individuals. Results: A total of 5869 individuals were included (2459 males [78.8%]; mean [SD] age, 64.9 [12.4] years). The cause of SCD was CAD in 4392 individuals (74.8%), among whom 3122 had no history of previously diagnosed CAD. Two individuals were excluded owing to incomplete autopsy information. An ECG recorded prior to SCD was available in 438 individuals. Silent MI was detected in 1322 individuals (42.4%) who experienced SCD without a clinical history of CAD. The participants with SMI were older than participants without MI scarring (mean [SD] age, 66.9 [11.1] years; 65.5 [11.6] years; P < .001) and were more often men (1102 of 1322 [83.4%] vs 1357 of 1798 [75.5%]; P < .001). Heart weight was higher in participants with SMI (mean [SD] weight, 483 [109] g vs 438 [106] g; P < .001). In participants with SMI, SCD occurred more often during physical activity (241 of 1322 [18.2%] vs 223 of 1798 [12.4%]; P < .001). A prior ECG was abnormal in 125 of the 187 individuals (66.8%) who had SCD after SMI compared with 139 of 251 (55.4%) of those who had SCD without SMI (P = .02). Conclusions and Relevance: Many individuals who experienced SCD associated with CAD had a previously undetected MI at autopsy. Previous SMI was associated with myocardial hypertrophy and SCD during physical activity. Premortem ECGs in a subset with available data were abnormal in 67% of the individuals who had had a SCD after an SMI.