Association between digoxin use and sudden cardiac death in individuals with the rs10494366 variant of the NOS1AP gene

Abstract

Background Digoxin is one of the oldest cardiovascular medications still used to treat heart failure and atrial fibrillation. Due to its narrow therapeutic window, it is associated with life threatening intoxication and arrhythmias, and with QTc-shortening. Common genetic variation in the nitric oxide synthase-1 adaptor protein (NOS1AP) has been associated with QTc interval prolongation. Purpose We investigated whether the rs10494366 variant of the NOS1AP gene modified the risk of SCD in patients using digoxin. Methods In a prospective population-based cohort study, we included data of the three cohorts, started as of January 1st, 1991 until January 1st 2014. Digoxin current use on the date of cardiac death in cases and the same day of follow-up in the remainder of the cohort was a time-dependent exposure. The main outcome was SCD defined as sudden and unexpected death as a result of cardiac causes, according to international criteria. Identification and adjudication of SCD was performed independently, before the start of this study. We used Cox proportional hazard regression analysis to investigate the associations between NOS1AP rs10494366 variant and incident SCD among digoxin users compared to non-users. Associations were adjusted for age, sex (model 1) in addition to BMI, prevalent diabetes, myocardial infarction, baseline hypertension and smoking status (past, current, never) (model 2). Results We included 14,594 individuals, with a mean age of 65.3 (SD 10.3) years. Almost 59% were female. The cumulative incidence of SCD was 9.5% (609 cases) by the end of follow up. Among them, 98 (16%) individuals were exposed to digoxin at the time of death. In model 1, NOS1AP rs10494366 variant was not associated with SCD in the total study population. However, an interaction term of the gene with the daily dose of digoxin was significantly associated with increased risk of SCD (p-value 0.0001). In model 2, the risk of SCD in current users of digoxin was 4.2 [95% CI 1.3–13.8] for the GG genotype; 2.1 [95% CI 1.1–4.2] for the GT genotype, and 1.5 [95% CI 0.7–3.2] for the TT genotype. Conclusion NOS1AP rs10494366 variant modified the risk of sudden cardiac death in users of digoxin. Our study suggests that individuals with the homozygous minor GG allele have a fourfold increased risk of sudden cardiac death. Funding Acknowledgement Type of funding source: None