Abstract Body: Background: The risks for atrial and ventricular arrhythmias are increased with cardiomyopathy. Currently, left ventricular dysfunction is the major determinate of implantable cardioverter-defibrillator (ICD) placement despite left ventricular ejection fraction only having an odds ratio of 2.9 for subjects with an LVEF <35% with sensitivity and specificity that suggests many patients are inappropriately receiving or not receiving a device. Additional testable variables would aid in arrhythmia risk stratification. There is growing evidence that atrial dysfunction is both a cause and consequence of ventricular disease. Atrial fibrillation (AFib) is the most common atrial arrhythmia and is highly heritable suggesting a strong genetic basis, and AFib occurs at increased frequency with cardiomyopathies. Genome-wide association studies (GWAS) identify >100 loci that contribute to AFib, and signals from GWAS can be used to develop polygenic risk scores (PRS). Subjects in the top 3% of one AFib PRS were found to have ~2 fold greater risk for AFib (OR 1.7-4.6).

Hypothesis: The genetic pathways represented in an AFib PRS account for a portion of arrhythmia risk associated with cardiomyopathy and can be exploited to predict ventricular arrhythmia risk.

Approach: As part of an AHA Arrhythmia and Sudden Death Strategically Funded Research Network, we assembled a cohort with varying risk for sudden cardiac death ranging from low-risk individuals with non-ischemic cardiomyopathy without arrhythmia to higher risk individuals who underwent ICD placement for aborted sudden death and sudden death. Whole genome sequencing was completed 1043 individuals across the arrhythmia risk spectrum.

Results: We examined an AFib PRS to define ventricular outcomes in the cohort. Of the 440 participants with disease, 81% had cardiomyopathy, 8% channelopathy and 7% idiopathic arrest. We found the AFib PRS stratified subjects without significant ventricular arrhythmia risk from subjects with known ventricular arrhythmia (p=0.03), indicating that the AFib PRS includes components that are important markers of ventricular dysfunction.

Conclusions: The AFib PRS is a useful tool to stratify ventricular arrhythmia risk.