Risk Factors and Genetic Insights into Coronary Artery Disease-Related Sudden Cardiac Death: A Molecular Analysis of Forensic Investigation

Abstract

Sudden cardiac death (SCD) is a major cause of mortality among patients with coronary artery disease (CAD). This study aimed to identify risk factors for CAD-related SCD (SCDCAD) through autopsy data and genetic screening with a particular emphasis on rare variants (minor allele frequency < 0.01). We included 241 SCDCAD cases (mean age 54.6 ± 12.8 years, 74.7% male) verified by medico-legal examination and 241 silent CAD controls (mean age 53.6 ± 15.2 years, 25.3% female) who died from severe craniocerebral trauma. Information about death characteristics was obtained from questionnaires, police reports and autopsy data. Whole-exome sequencing was performed on myocardial tissue samples. Polygenic risk score (PRS) from a previously validated model was applied and rare variant pathogenicity was predicted using in silico tools. SCDCAD victims predominantly died at night and showed higher mortality rates during summer and winter months, with more complex coronary disease. Nocturnal time (adjusted odds ratio [AOR] = 3.53, 95% CI: 2.37–5.25, p < 0.001), winter (AOR = 2.06, 95% CI: 1.33–3.20, p = 0.001), multiple vessel occlusion (AOR = 1.79, 95% CI: 1.16–2.77, p = 0.009), right coronary artery stenosis (AOR = 2.38, 95% CI: 1.54–3.68, p < 0.001) and unstable plaque (AOR = 2.17, 95% CI: 1.46–3.23, p < 0.001) were identified as risk factors of SCDCAD. The PRS score was associated with a 60% increased risk of SCDCAD (OR = 1.632 per SD, 95%CI: 1.631–1.633, p < 0.001). Genetic analysis identified MUC19 and CGN as being associated with SCDCAD. We identified both hereditary and acquired risk factors that may contribute to cardiac dysfunction and precipitate SCD in CAD patients, thereby facilitating the prevention and early recognition of high-risk individuals.