Leveraging a genetic proxy to investigate the effects of lifelong cardiac sodium channel blockade

Atrial fibrillation (AFib) and other cardiac arrhythmias pose a major public health burden but prevention remains difficult. Here, we investigated a genetic variant which we found to act like a natural lifelong cardiac sodium channel blockade.

We studied the impact of the Finnish-enriched SCN5A missense variant (rs45620037 [T220I]) on cardiac arrhythmias, associated mortality and electrocardiographic (ECG) phenotypes in > 1M individuals across three cohorts (FinnGen, UK biobank, Health 2000). We identified protective effects of T220I on multiple common cardiac arrhythmias, most notably atrial fibrillation (AFib) (hazard ratio [HR] 0.60, 95% confidence interval [CI] 0.55 – 0.66, p = 3.13×10 ^-25 ), but also ventricular premature depolarization or ventricular tachycardia, yet increasing susceptibility to conduction-slowing conditions such as sick sinus syndrome (mostly in older age groups). Overall, T220I conveyed a protection from mortality due to cardiac arrhythmia (HR = 0.65, 0.47 – 0.98, p = 0.015) without a significant effect on overall mortality (HR=0.98, p = 0.78). T220I heterozygotes had similar electrophysiological effects as sodium channel blockers such as significantly shortening QT intervals (−7.49 ms 95% CI −10.07 – [−4.91] ms, p = 0.0037, n=6,048) in the H2000 cohort, which we replicated in the UK Biobank (n=81,195). In addition, T220I protected from (left) heart failure and dilated cardiomyopathy. Early post–myocardial infarction, we found that T220I increased mortality in agreement with known sodium channel blocker effects which however continuously normalised to baseline 10-15 years post myocardial infarction. Finally, we found that T220I could lower a high genetic burden (a high polygenic score) for AFib to population average.

The SCN5A T220I variant, consistent with a previously described weak loss-of-function effect, acted like a genetic proxy for cardiac sodium channel blockade. This enabled us to gain new potentially clinically relevant insights for pharmacological sodium channel blockade such as after myocardial infarction which would be too risky to investigate with clinical trials. Our findings may also inspire redesign of cardiac sodium channel blockers.