Titin truncating variants, cardiovascular risk factors and the risk of atrial fibrillation and heart failure.

High-proportion spliced-in (hiPSI) titin truncating variant (TTNtv) carriers have a higher risk of atrial fibrillation and heart failure 1 . However, the role of cardiovascular risk factors in modifying the risk of atrial fibrillation and heart failure attributed to hiPSI TTNtv carriers is unknown. Here, we investigate the role of cardiovascular risk, quantified using the pooled cohort equations (PCEs), in influencing the hazard of outcomes attributed to hiPSI TTNtvs among UK Biobank participants without baseline cardiovascular disease. The cohort was stratified based on hiPSI TTNtv carrier status and cardiovascular risk (low: <5%, intermediate: 5.0-7.5% and high: >7.5%). The primary outcome was a composite of atrial fibrillation, heart failure or death. TTNtv noncarriers with low cardiovascular risk were used as the reference group for all analyses. Among 179,752 participants (median age: 56 (49, 62) years; 57.5% female), the risk of the primary outcome was lower in hiPSI TTNtv carriers with low cardiovascular risk (adjusted hazard ratio: 2.23 (95% confidence interval: 1.62-3.07)) than those with high cardiovascular risk (adjusted hazard ratio: 8.21 (95% confidence interval: 6.63-10.18)). A favorable cardiovascular risk factor profile may partially offset the risk of clinical outcomes among hiPSI TTNtv carriers.