Association of F11 Gene Variants With Cardiovascular Events and Cardiac Function

Background FXI (Factor XI) inhibitors have emerged as a promising antithrombotic strategy. However, a recent study linked decreased FXI levels with increased risk of heart failure (HF) and atrial fibrillation (AF), particularly in older adults. This study aims to investigate the associations of genetic FXI inhibition with cardiovascular events and cardiac function. Methods This prospective study included 408 642 UK Biobank participants of European ancestry. Two F11 ‐based genetic scores were constructed, weighted separately by their associations with activated partial thromboplastin time or circulating FXI levels. Adjusted Cox or linear regression models were built to predict incident HF, AF, and cardiac magnetic resonance measures. Interactions with age and age‐related cardiometabolic traits were tested. Results Over 14.6 years median follow‐up, 14 451 participants developed incident HF, and 29 243 developed incident AF. The FXI activated partial thromboplastin time score was not associated with HF, AF, or cardiac magnetic resonance measures overall. In exploratory interaction analyses, baseline hemoglobin A1c (HbA1c) modified its association with HF ( P <0.001) and AF ( P =0.027), with higher HF risk observed among participants with HbA1c≥7% (hazard ratio per 10% genetically predicted increase in activated partial thromboplastin time, 1.65 [95% CI, 1.13–2.40]) but not in those with HbA1c<7%. No association was observed with AF across HbA1c strata. Similar patterns were observed for the FXI level score. Conclusions Genetically proxied FXI inhibition was not associated with HF, AF, or cardiac magnetic resonance–derived cardiac measures overall, but its associations with HF and AF may be modified by HbA1c. Future studies are needed to verify these exploratory findings.