Transcriptomic Profiling of Human Myocardium at Sudden Death to DefineVulnerable Substrate for LethalArrhythmias.

Abstract

While some chronic pathological substrates for sudden cardiac death (SCD) are well known (eg, coronary artery disease and left ventricular [LV] dysfunction), the acute vulnerable myocardial state predisposing to fatal arrhythmia remains a critical barrier to near-term SCD prevention. This study sought to define the distinct myocardial transcriptomic profile of autopsy-defined arrhythmic sudden deaths, compared to nonarrhythmic sudden deaths and trauma deaths, to determine the acute vulnerable state in the hours to days before SCD. We used autopsy to adjudicate arrhythmic from nonarrhythmic causes in 1,265 sudden deaths in San Francisco County from 2011 to 2018. We performed a degradation-tolerant transcriptomic evaluation of LVs sampled at the time of SCD from 245 consented cases using a curated panel of 448 gene probes with known or hypothesized association with SCD. The targeted transcriptome of arrhythmic (n = 129) vs nonarrhythmic (n=90 nonarrhythmic sudden deaths+ 26 trauma deaths) LV samples revealed 31 differentially up-regulated and 36 down-regulated genes (adjusted P< 0.05) related to the collagen-containing extracellular matrix (up-regulation of FAP, FMOD, and LTBP2), regulation of ion transport (up-regulation of KCNA5 and KCNN3 and down-regulation of KCNJ8, KCNK1, and KCNJ5), and contraction (down-regulation of MYH6). Fibrosis-related genes showed the highest magnitude increased expression in arrhythmic vs nonarrhythmic deaths and vs published transcriptomes from end-stage heart failure. After molecular stratification by known markers for mature (COL1A1, COL1A2, COL3A1) and active (POSTN, MEOX1) fibrosis, cases with the highest expression of both had the largest proportion of arrhythmic cause of death (n=27 of 36 [75%]) vs cases with low expression of both markers (n=87 of 181 [38%]) (P = 0.006) or vs mature only (n=10 of 14 [71%]) or active only (n=5 of 14 [36%]). Activated fibroblast gene expression signature was enriched in arrhythmic female vs arrhythmic male cases, among other sex-specific differences in ion-channel and myosin (up-regulation of SCN4B, SCN8A, and KCNAB1 in females and KCNJ4 and MYH7B in males) expression. RNA profiling of the myocardium at SCD identifies active fibrosis, undetectable by conventional clinical methods, in the presence of fixed scar and selected ion-channel dysregulation (more pronounced among female cases) as an acute vulnerable substrate for fatal arrhythmias. These findings may represent novel directions to identify patients at elevated near-term risk for SCD and critical pathways for intervention to reduce acute lethal arrhythmias.