Atrial Fibrillation Screening According to Genetic Risk: A Secondary Analysis of the Randomized LOOP Study.

Abstract

Polygenic risk scores (PRS) hold promise in risk stratification and screening for cardiovascular diseases, including atrial fibrillation (AF). This study investigated the efficacy of AF screening for stroke prevention based on a PRS for AF. This prespecified post hoc analysis of the randomized LOOP (Atrial Fibrillation Detected by Continuous ECG Monitoring Using Implantable Loop Recorder to Prevent Stroke in High-Risk Individuals) study included 5,656 AF-naive individuals aged ≥70 years with stroke risk factors and available genetic data. The participants were randomized 1:3 for screening with an implantable loop recorder (ILR) vs usual care. Genetic risk of AF was assessed using a PRS for AF (PRS_AF). The primary outcome was a composite of stroke and systemic embolism (SE). Interaction between the randomization arm and PRS_AF was assessed in cause-specific Cox regressions for the full cohort and across the observed range of polygenic risk using a continuous prediction grid. Secondary analyses included models stratified by PRS level, gene-screening interactions for major bleeding events, and associations between PRS_AF and AF burden (≥1 episode lasting ≥24 hours among participants with ILR-detected AF). Over a median follow-up period of 5.4 years, 969 participants (17.1%) received a diagnosis of AF, 296 (5.2%) had stroke/SE, and 206 (3.6%) had major bleeding. PRS_AF was associated with higher rates of AF (HR per SD increase: 1.20; 95% CI: 1.13-1.28; P < 0.001). A significant interaction was observed between ILR screening and PRS_AF for stroke/SE (P_interaction = 0.006). ILR screening was associated with lower rates of stroke/SE in individuals with PRS_AF ≥median (HR: 0.65; 95% CI: 0.43-0.97; P = 0.036) but not in those with PRS_AF <median (HR: 1.06; 95% CI: 0.72-1.57; P = 0.75). ILR screening was associated with higher rates of major bleeding at lower levels of PRS_AF (P_interaction = 0.036), corresponding to a HR of 1.71 (95% CI: 1.12-2.64; P = 0.011) in those with PRS_AF <median. A 1-SD increase in PRS_AF was associated with an OR of 1.35 (95% CI: 1.02-1.78; P = 0.037) for having ≥1 AF episode lasting ≥24 hours. ILR screening for AF was associated with a significant reduction in stroke/SE in individuals with higher genetic risk of AF but not in those with lower genetic risk. These hypothesis-generating findings indicate that genetic predisposition may aid in selecting individuals who benefit from AF screening.