Late Sodium Current Inhibition Counteracts Pro−arrhythmic Mechanisms in Human Hypertrophic Cardiomyopathy

Abstract

Hypertrophic cardiomyopathy (HCM) is a genetic disorder characterised by increased arrhythmic risk. The causes are still unclear, but potential pro-arrhythmic mechanisms may include increased temporal and spatial variability in action potential duration (APD) as well as repolarisation abnormalities, such as early afterdepolarisations (EADs) and APD alternans. We performed investigations of these pro-arrhythmic mechanisms and their modulation by late sodium current (I\textlessinf\textgreaterNaL\textless/inf\textgreater) inhibition, in two populations of healthy (CTRL) and HCM human endocardial action potential (AP) models, calibrated against human experimental recordings of AP and Ca\textlesssup\textgreater2+\textless/sup\textgreater transient (CaT) in single cells. The simulated HCM phenotype was in agreement with the experimental observations, showing prolonged AP and CaT, together with an increase in their variability. In addition, simulation results show that HCM promotes EADs and APD alternans at rapid pacing rates. Their occurrence is counteracted by I\textlessinf\textgreaterNaL\textless/inf\textgreater inhibition, suggesting this as a good therapeutic target in HCM.