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Transcriptomic Profiling of Human Myocardium at Sudden Death to Define Vulnerable Substrate for Lethal Arrhythmias
Arianne Caudal1, Yu Liu1, Paul D Pang1
1Stanford Cardiovascular Institute, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA; Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
Insights
Sudden cardiac death (SCD) transcriptomics reveal active fibrosis and ion channel dysregulation as key factors. These findings offer new ways to identify individuals at high risk for SCD and develop interventions.
Area of Science:
- Cardiovascular Science
- Molecular Biology
- Genomics
Background:
- Chronic substrates like coronary artery disease and left ventricular dysfunction are known causes of sudden cardiac death (SCD).
- The acute myocardial state predisposing to fatal arrhythmias remains a critical, yet poorly understood, barrier to SCD prevention.
Purpose of the Study:
- To define the distinct myocardial transcriptomic profile of autopsy-defined arrhythmic sudden deaths.
- To compare this profile with nonarrhythmic sudden deaths and trauma deaths.
- To elucidate the acute vulnerable myocardial state preceding SCD.
Main Methods:
- Autopsy data from 1,265 sudden deaths (2011-2018) were used to classify causes.
- Degradation-tolerant transcriptomic evaluation was performed on left ventricular (LV) samples from 245 consented SCD cases.
- A panel of 448 gene probes with known or hypothesized association with SCD was utilized.
Main Results:
- Transcriptomic analysis revealed 31 up-regulated and 36 down-regulated genes in arrhythmic vs. nonarrhythmic LV samples.
- Key gene expression changes were observed in extracellular matrix (fibrosis), ion transport, and myocardial contraction pathways.
- Active fibrosis markers (e.g., POSTN, MEOX1) were significantly elevated in arrhythmic deaths, particularly in females, alongside ion channel and myosin gene dysregulation.
Conclusions:
- RNA profiling at SCD identifies active fibrosis and ion channel dysregulation as an acute vulnerable substrate for fatal arrhythmias.
- This active fibrosis is undetectable by conventional clinical methods, even in the presence of fixed scar.
- Findings suggest novel strategies for identifying patients at elevated near-term SCD risk and developing targeted interventions.
Background:
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.
Objectives:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
