Insights into the molecular mechanisms of bradycardia-triggered arrhythmias in long QT-3 syndrome

Congenital long QT syndrome is a rare disease in which the electrocardiogram QT interval is prolonged due to dysfunctional ventricular repolarization. Variant 3 (LQT-3) is associated with mutations in SCN5A, the gene coding for the heart Na+ channel a subunit. Arrhythmias in LQT-3 mutation carriers are more likely to occur at rest, when heart rate is slow. Several LQT-3 Na+ channel mutations exert their deleterious effects by promoting a mode of Na+ channel gating wherein a fraction of channels fails to inactivate. This gating mode, termed "bursting," results in sustained macroscopic inward Na+ channel current (I-sus), which can delay repolarization and prolong the QT interval. However, the mechanism of heart-rate dependence of I-sus has been unresolved at the single-channel level. We investigate an LQT-3 mutant (Y1795C) using experimental and theoretical frameworks to elucidate the molecular mechanism of I-sus rate dependence. Our results indicate that mutation-induced changes in the length of time mutant channels spend bursting, rather than how readily they burst, determines I-sus. inverse heart-rate dependence. These results link mutation-induced changes in Na+ channel gating mode transitions to heart rate-dependent changes in cellular electrical activity underlying a key LQT-3 clinical phenotype.