Modeling incomplete penetrance in long QT syndrome type 3 (LQT3) through ion channel heterogeneity: An in silico population study.

Abstract

Many cardiac diseases are characterized by an increased late sodium current, including heart failure, hypertrophic cardiomyopathy, and inherited long QT syndrome type 3 (LQT3). The late sodium current in LQT3 is caused by a gain-of-function mutation in the voltage-gated sodium channel Nav1.5. Despite a well-defined genetic cause of LQT3, treatment remains inconsistent due to incomplete penetrance of the mutation and variability of anti-arrhythmic efficacy. Here, we investigate the relationship between LQT3-associated mutation incomplete penetrance and variability in ion channel expression, simulating a population of 1,000 single-cell “individuals” using the O’Hara-Rudy model of the human ventricular myocyte. We first simulate healthy electrical activity (i.e., in the absence of a mutation), then incorporate heterozygous expression for three LQT3-associated mutations (Y1795C, I1768V, and ∆KPQ), to directly compare the effects of each mutation on individuals across a diverse population. For all mutations, we find that susceptibility, defined either by the presence of an early after depolarization (EAD) or prolonged action potential duration (APD), primarily depends on the balance between the conductance of IKr and INa, for which individuals with a higher IKr-INa ratio are less susceptible. Further, we find distinct differences across the population, observing individuals susceptible to zero, one, two, or all three mutations. Individuals tend to be less susceptible with an appropriate balance of repolarizing currents, typically via increased IKs or IK1. Interestingly, the more critical repolarizing current is mutation specific. We conclude that balance between key currents plays a significant role in mutant-specific presentation of the disease phenotype in LQT3.