A rare genetic variant suggested a role for targeted sodium channel modulation in arrhythmia risk. A study published in Circulation evaluated the SCN5A T220I variant and its associations with arrhythmias, electrophysiological traits, and mortality.

The multicohort observational study included more than one million individuals from FinnGen, UK Biobank, and Health 2000. Outcomes assessed included arrhythmia incidence, mortality patterns, and electrocardiographic traits, with additional analyses in groups defined by polygenic risk scores.

T220I reduced AF risk, with a hazard ratio (HR) of 0.56 and a 95% confidence interval (CI) of 0.50 to 0.63. The variant protected against ventricular premature depolarization and ventricular tachycardia. It increased susceptibility to conduction-slowing disorders, including sick sinus syndrome in older populations. The variant lowered arrhythmia-related mortality, with an HR of 0.65, and had no effect on overall mortality. T220I shortened QT intervals by 7.49 milliseconds in Health 2000 and showed similar results in UK Biobank. It also protected against heart failure and dilated cardiomyopathy. Post–myocardial infarction mortality increased before normalizing after 10 to 15 years.

These findings indicate that T220I functions like a weak sodium channel blocker and reveal mechanistic patterns relevant to future drug development.