PRE-DETERMINE: Polygenic score predicts risk for sudden cardiac death in CAD
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A validated genome-wide polygenic risk score predicted clinically meaningful absolute risk for sudden arrhythmic death in a cohort of patients with CAD without severe left ventricular dysfunction, researchers reported.
The data, from participants of the ongoing prospective PRE-DETERMINE cohort, show the polygenic risk score could potentially improve risk stratification for patients with CAD who do not meet the current guideline indications for an implantable cardioverter defibrillator but experience the most sudden deaths, Roopinder K. Sandhu, MD, MPH, a cardiac electrophysiologist and associate professor of cardiology at the Smidt Heart Institute at Cedars-Sinai, and colleagues wrote in the Journal of the American College of Cardiology.
“In order to better predict and prevent sudden cardiac death, we must first understand the genetic connection between it and CAD,” Sandhu said in a press release. “We found incorporating information from this genetic risk score improved our ability to predict sudden death beyond the contributions of other known risk markers. Most exciting, the genetics were able to identify patients where sudden death was more likely to limit their life expectancy.”
Genetic data and risk
Sandhu and colleagues generated a genome-wide polygenic score for CAD utilizing genome-wide genotyping for 4,698 PRE-DETERMINE participants of European ancestry with CAD and left ventricular ejection fraction between 30% and 35%. Researchers stratified participants by polygenic score decile, defined by the general population. The primary endpoint was sudden arrhythmic death, classified according to timing (sudden vs. non-sudden) and mechanism (arrhythmic vs. non-arrhythmic). Absolute, proportional and relative risks for sudden arrhythmic death and non-sudden arrhythmic death were estimated using competing risk analyses.
“We do not have any good methods to predict sudden cardiac death in patients who have an EF greater than 35%, and most sudden deaths occur in that population,” Christine M. Albert, MD, MPH, FHRS, chair of the department of cardiology and the Lee and Harold Kapelovitz Distinguished Chair in Cardiology at the Smidt Heart Institute at Cedars-Sinai, told Healio. “There is an unmet need. We know patients with coronary disease have a higher risk for sudden cardiac death, but we do not know if it is high enough to warrant consideration of an implantable cardioverter defibrillator.”
Within the cohort, 13.8% were in the top general population-based decile of the polygenic risk scire for CAD. Compared with the rest of the cohort, participants in the top decile were younger (mean age, 63 years vs. 66 years) and were more likely to be women (27% vs. 23%), to have more severe CAD, to have a history of CABG and to have a parental history of sudden arrhythmic death.
During a median follow-up of 8.05 years, there were 176 sudden arrhythmic death events, including 22 cardiac arrests and 154 sudden cardiac deaths, and 833 non-sudden arrhythmic death events.
Researchers found participants in the top decile of the polygenic risk score for CAD were at elevated absolute risk for sudden arrhythmic death compared with all other deciles (8%; 95% CI, 5.1-12.4; vs. 4.8%; 95% CI, 3.3-7; P = .005) and had greater proportional risk for sudden arrhythmic death (29% vs. 16%; P = .0003).
Additionally, participants in the top decile were more likely to experience sudden arrhythmic death (subdistribution HR = 1.77; 95% CI, 1.23-2.54; P = .002) but not non-sudden arrhythmic death (subdistribution HR = 1; 95% CI, 0.8-1.25; P = .98) compared with all other groups. Results persisted after adjustment for LVEF, clinical factors and ECG parameters.
“We were surprised that we saw such a specific risk for sudden cardiac death,” Albert said in an interview. “Even when compared with cardiac death due to non-sudden causes ... the polygenic risk score predicted just the sudden deaths. This is unusual since established risk markers, such as left ventricular EF and HF class, equally predict all forms of death from cardiac disease.”
Albert said more work is needed to determine what the score is predicting with respect to sudden cardiac death.
“People die from sudden death, though not always due to arrhythmias,” Albert said. “Is it predicting recurrent ischemia? Is it predicting the ventricular fibrillation that often occurs with sudden cardiac death? If it is the latter, then this could be very useful for risk-stratifying patients for a defibrillator. Often the only way to figure that out is to conduct a randomized trial.”
Sandhu, who called the polygenic risk score for CAD a promising screening tool, said more research is needed with other known risk factors for sudden death and that the work must be replicated in other diverse populations.
“We need to figure out the number needed to treat to save one life with a defibrillator,” Sandhu said in an interview. “In exploratory analyses, we demonstrate how the polygenic risk score for CAD in concert with the ECG might be used to design an achievable randomized controlled trial demonstrating meaningful mortality reductions and potentially clinically relevant numbers needed to treat to save one life with a defibrillator.”
‘Clear benefit’ for risk stratification
In a related editorial, Jussi A. Hernesniemi, MD, PHD, of Tampere University and Tays Heart Hospital in Finland, noted that the genetic propensity for CAD was predominantly seen to predict sudden arrhythmic deaths but not deaths from other causes.
“This is a clear benefit of clinical risk stratification because genetic propensity could be used to identify those at high risk of sudden arrhythmic death but not at an elevated risk of death for other causes,” Hernesniemi wrote. “Successful primary prevention of sudden deaths in this population could thus yield high gains in quality-assessed life years.”
Hernesniemi, who called the findings intriguing, added that the results call for independent replication efforts.
“More importantly, they also question whether more stringent medical secondary prevention aims should be directed toward slowing the progression of CAD among high-risk patients,” Hernesniemi 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 therapy or low-dose anticoagulation could also prove beneficial even without ICD therapy.”
Reference:
Hernesniemi JA. J Am Coll Cardiol. 2022;doi:10.1016/j.jacc.2022.06.016.
For more information:
Christine M. Albert, MD, MPH, FHRS, can be reached at christine.albert@cshs.org; Twitter: @CMAlbertEP. Roopinder K. Sandhu, MD, MPH, can be reached at roopinder.sandhu@cshs.org.
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