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

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 (SCD_CAD) through autopsy data and genetic screening with a particular emphasis on rare variants (minor allele frequency < 0.01). We included 241 SCD_CAD 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. SCD_CAD 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, <i>p</i> < 0.001), winter (AOR = 2.06, 95% CI: 1.33-3.20, <i>p</i> = 0.001), multiple vessel occlusion (AOR = 1.79, 95% CI: 1.16-2.77, <i>p</i> = 0.009), right coronary artery stenosis (AOR = 2.38, 95% CI: 1.54-3.68, <i>p</i> < 0.001) and unstable plaque (AOR = 2.17, 95% CI: 1.46-3.23, <i>p</i> < 0.001) were identified as risk factors of SCD_CAD. The PRS score was associated with a 60% increased risk of SCD_CAD (OR = 1.632 per SD, 95%CI: 1.631-1.633, <i>p</i> < 0.001). Genetic analysis identified MUC19 and CGN as being associated with SCD_CAD. 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.