Genetic risk-enhanced CHA2DS2-VASc score predicts ischemic stroke after atrial fibrillation catheter ablation

Backgroud and Aims Although atrial fibrillation catheter ablation (AFCA) can reduce the risk of ischemic stroke (IS), patients remain at residual risk. The genetic basis of post-AFCA IS is unclear. We investigated single-nucleotide polymorphisms (SNPs) associated with post-AFCA IS and evaluated whether incorporating a genetic risk score (GRS) provides incremental predictive value beyond CHA2DS2-VASc scores in two independent cohorts. Methods We developed and validated a GRS-enhanced CHA2DS2-VASc model for predicting post-AFCA IS using the UK Biobank (UKB) cohort (n=2,063) and the independent Yonsei Atrial Fibrillation Ablation (YAF) cohort (n=2,897), excluding procedure-related IS (<14 days post-ablation). We created a CHA2DS2-VASc-G score by adding one point to the CHA2DS2-VASc score in patients with high genetic risk (defined as GRS ≥ 1.025, derived from the Youden index). We evaluated the performance and clinical utility of the CHA2DS2-VASc+GRS model. Results Over a mean follow-up of 5.5 years in the UKB cohort and 5.1 years in the YAF cohort, 46 and 48 patients experienced post-AFCA IS, corresponding to incidence rates of 0.40 and 0.33 per 100 person-years, respectively. Five genomic loci (SMARCC1, FGF10, RUNX1T1, HEMGN, VAC14) were significantly associated with post-AFCA IS and replicated in both cohorts. The GRS was higher in patients with IS (1.9±2.2 vs. 0.3±0.7, p<0.001; hazard ratio 1.80 per 1 SD, [95% CI, 1.63-1.99]). The CHA2DS2-VASc+GRS model demonstrated superior discrimination (C statistic, 0.754 vs. 0.599; p < 0.001) and improved net reclassification (net reclassification index, 21%; 95% CI, 3.3%–37.5%) compared with the CHA2DS2-VASc model alone. During long-term follow-up, the incidence of post-AFCA IS remained high in high-risk patients classified by the CHA2DS2-VASc-G score (≥2; log-rank p < 0.001) compared with low-risk patients, in contrast to patients classified by the CHA2DS2-VASc score alone. Among patients with a CHA2DS2-VASc score <2, the incidence rate of post-AFCA ischemic stroke was higher in those classified as having genetic risk by the CHA2DS2-VASc-G score than in those without genetic risk (0.59 vs. 0.14 per 100 person-years; incidence rate ratio, 4.28; p<0.001). Conclusions Incorporating GRS into the CHA2DS2-VASc score significantly improved the prediction of IS after AFCA compared with the CHA2DS2-VASc score alone. The CHA2DS2-VASc-G score identified high-risk patients for post-AFCA IS among those with a CHA2DS2-VASc score <2.Performance of modelsCumulative incidence of post-AFCA IS