Modeling incomplete penetrance in long QT syndrome type 3 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 "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 ΔKPQ), 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 afterdepolarization (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.

Optimization of a Cardiomyocyte Model Illuminates Role of Increased INaLin Repolarization Reserve

“…They further show that this relationship is not demonstrated in models of reduced repolarization reserve (i.e., heart failure rabbit and pig cardiomyocytes). Lastly, a study by Miller et al (Miller et al, 2023) found that susceptibility to arrhythmia is decreased with a higher I Kr -to-I Na ratio in a LQT3 model. Therefore, in a model of increased I Kr , and high RRC size, increases in I NaL could be important in preventing pathophysiology.…”

“…There have been studies that provide a more global view on repolarization reserve (Sarkar and Sobie, 2011; Britton et al, 2017; Miller et al, 2023). Sarkar and Sobie (2011) used multivariable regression to quantify repolarization reserve after 75% I Kr block; Britton et al (2017) used a population of models approach to study repolarization abnormalities upon multichannel ionic block of I Kr , I Ks , I K1 , and I CaL ; and Miller et al (2023) published a population of models study that provided insight to ion-channel conductance correlations that play a role in LQT3 susceptibility. All these studies provide valuable insights to arrhythmia resistance in the case of decreased repolarization reserve by using ion-channel block or disease mutation models.…”

“…Extremes in levels of some conductances due to congenital disease or drugs can lead to repolarization failure or early afterdepolarization (EAD) development, and susceptibility to arrhythmia (Fenichel et al, 2004; Kannankeril et al, 2010; Hancox et al, 2008). Even two seemingly healthy cardiomyocytes can differ in their robustness against arrhythmia when under the influence of a perturbation (Weiss et al, 2012; Ballouz et al, 2021; Miller et al, 2023). Unfortunately, a mechanistic understanding of repolarization abnormality development, and improvement of pharmacological mitigation strategies, is complicated by the many different ion-channel conductance profiles that can define a cardiomyocyte (Behr and Ensam, 2016).…”

“…However, such studies do not consider the values or correlations between other ion-channel conductances in a given cell’s profile. Research using a more comprehensive approach has been completed using methods such as a population of models (Britton et al, 2017; Miller et al, 2023) and multivariable regression (Sarkar and Sobie, 2011). These studies make conclusions about ion-channel variability and proarrythmic susceptibility, but only in a reduced repolarization reserve environment.…”