A genome polygenic score for coronary artery disease (CAD) patients (GPSCAD) may predict sudden arrhythmic death (SAD) and identify people who might benefit from defibrillator therapy, according to a to a new multicenter prospective study. Roopinder K. Sandhu, MD, MPH, of Cedars-Sinai Medical Center, Los Angeles, and the University of Alberta, Jacqueline S. Dron, PhD, of the Broad Institute of MIT and Harvard, Cambridge, Massachusetts, and colleagues reported these findings from the PRE-DETERMINE database in a paper published online Monday and in the Aug. 30 issue of the Journal of the American College of Cardiology. There is a familial predisposition to SAD in the setting of CAD. Genetic markers, which can be easily measured at scale and at relatively low cost, represent a potential feasible option for SAD risk stratification. The study, therefore, investigated the utility of a validated GPSCAD for SAD risk stratification in an intermediate-risk European-descended population with established CAD but without severe systolic dysfunction and/or indication for a primary prevention implantable cardioverter-defibrillator (ICD) and assessed the absolute and relative associations of the GPSCAD with SAD risk over 8 years of follow-up. Data were based on 4,698 European-descended patients with CAD and with a left ventricular function (LVEF) >35% or an LVEF of 30% to 35% with New York Heart Association functional class I. Exclusion criteria included history of heart transplant, cardiac arrest not associated with myocardial infarction, current or planned ICD, or life expectancy. Genotyping of the PRE-DETERMINE participants was performed using the Illumina GSAv1 genotyping array. The primary endpoint was SAD. In age- and sex-adjusted Fine-Gray models, participants in the top GPSCAD decile were at 1.76-fold (95% confidence interval [CI]: 1.23- to 2.53-fold; P = 0.002) increased risk for SAD compared with the remainder of the cohort. Results were also similar if ICD therapies for ventricular tachycardia/ ventricular fibrillation were included in the SAD outcome (hazard ratio: 1.69; 95% CI: 1.20-2.38; P = 0.003). There was no association between top GPSCAD decile and non-SAD, even when limited to cardiac causes, suggesting that the GPSCAD specifically predicts SAD and no other forms of cardiac mortality in patients with CAD. The authors noted several limitations to the study. The most prominent one is that ancestry has a significant influence over allele frequencies, linkage disequilibrium patterns, and effect sizes of common polymorphisms and the predictive power of the GPSCAD score and SAD needs further investigation in diverse populations. Also, only 13.8% of the patients were classified at baseline as high-risk individuals by their propensity for CAD, and 21% of all sudden deaths observed in the study occurred in this subset of patients. Thus, most of the population at risk would still be unaccounted for. Further validation of the score is required before it can be implemented in clinical practice. The authors concluded that the study showed that among a large population with established CAD without severe systolic dysfunction, a polygenic risk score for CAD was strongly and specifically associated with increased risk of SAD. These findings suggest that the GPSCAD is a promising method to improve SAD risk stratification in CAD patients who do not currently qualify for an ICD. In an accompanying editorial, Jussi A. Hernesniemi, MD, PhD, of Tampere University and Tays Heart Hospital, Tampere, Finland, called the study “intriguing,” although he lamented that it shows “no silver bullet is in sight yet for the prevention” of SADs. Still, if future studies replicate those shown by Sandhu, Dron and colleagues, the editorialist wrote, “This translates directly into high clinical applicability, … especially if the genetic propensity can be measured more extensively in the future.” The study also calls into question “whether more stringent medical secondary prevention aims should be directed toward slowing the progression of CAD among high-risk patients,” he wrote. “Slowing the progression of the disease itself by more aggressive lipid and blood pressure–lowering therapies and preventing thrombotic events by continued use of low-dose antiplatelet or low-dose anticoagulation could also prove beneficial even without ICD therapy,” Hernesniemi wrote. Sources: Sandhu RK, Dron JS, Liu Y, et al. Polygenic Risk Score Predicts Sudden Death in Patients With Coronary Disease and Preserved Systolic Function. J Am Coll Cardiol 2022;80:873–883. Hernesniemi JA. Dawn of the Era of Individualized Genetic Profiling in the Prevention of Sudden Cardiac Death. J Am Coll Cardiol 2022;80:884–886. Image Credit: Betastock – stock.adobe.com