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Sudden Cardiac Death Risk Informed by Genome-Wide Polygenic Score for Heart Disease

NEW YORK – Together with clinical factors, an individual's genetic risk of coronary artery disease (CAD) may help in predicting sudden and/or arrhythmic death (SAD), new research suggests.

"This study indicates there is opportunity to identify patients at highest risk for sudden cardiac death, and then offer meaningful, preventative treatment solutions like a defibrillator," senior and corresponding author Christine Albert, chair of the Cedars-Sinai Medical Center's Smidt Heart Institute's cardiology department and a preventive medicine researcher with Brigham and Women's Hospital, said in a statement.

With array-based genotyping, the researchers profiled variants across the genome in almost 4,700 individuals with a history of CAD, including prior myocardial infarction, epicardial vessel stenoses, or coronary revascularization — work they reported in the Journal of the American College of Cardiology on Tuesday. The participants came from an ongoing prospective, observational study known as PRE-DETERMINE, led by investigators at Brigham and Women's Hospital.

Those data, in turn, led to a genome-wide polygenic score (GPS) for CAD. The team found that individuals at the highest risk of CAD according to the GPS also had a higher-than-usual risk of SAD over a median follow up time of eight years: the absolute risk of SAD was 8 percent higher for the 646 individuals in the top GPS-CAD group, while proportional risk of SAD went up to 29 percent compared to a risk of 16 percent for the 4,052 participants in other GPS groups.

"We found incorporating information from this genetic risk score improved our ability to predict sudden death beyond the contributions of other known risk markers," first author Roopinder Sandhu, a cardiology researcher at Cedars-Sinai, said in a statement. "Most exciting, the genetics were able to identify patients where sudden death was more likely to limit their life expectancy."

The uptick in SAD risk in the top GPS-CAD group persisted after the investigators adjusted for left ventricular ejection fraction, and in CAD patients with preserved systolic function. Individuals classified in the highest risk group by GPS-CAD appeared to have roughly 77 percent greater SAD risk compared with those classified into CAD genetic other risk tiers.

"Among CAD patients without severe systolic dysfunction, high GPS-CAD specifically predicted SAD and enriched for both absolute and proportional SAD risk, identifying a population who might benefit from defibrillator therapy," the authors reported, noting that more than 70 percent of sudden cardiac deaths currently occur in coronary heart disease patients who do not meet guidelines for preventive treatment with an implantable cardioverter-defibrillator.

"To reduce the global burden of sudden death, it will be critical to improve risk stratification in this population," they explained, noting that genetic markers "represent [a] potential feasible option for SAD risk stratification in this broad population."