Populations of Models Show Increased Arrhythmogenicity of the Hypertrophic Cardiomyopathy MYBPC3-c.772G>A Mutation

Several mutations can lead to hypertrophic cardiomyopathy (HCM), making it the most common genetic heart disease. Given the large heterogeneity of phenotypes shown by mutation carriers, robust patient stratification is still lacking, limiting treatment efficacy. In this work, we adopt a population of models approach to investigate the arrhythmic potential of the recently discovered MYBPC3-c.772G>A mutation, to provide an additional risk assessment tool. According to this objective, we built control and mutated populations of 10000 electro-mechanical models of single adult ventricular myocytes, randomizing 19 parameters (maximal conductances, kinetics and contractile element parameters) and calibrating them according to experimental data ranges. The mutation was modeled by applying ionic and contractile remodeling measured on patients myectomy samples. Different stimulation protocols were implemented to assess the influence on delayed after depolarizations and early-after depolarizations (EADs) inducibility. The results highlight a higher propensity of mutated cells in showing an arrhythmic behavior, with Ca2+related and K+ currents parameters driving EADs susceptibility. In conclusion, this work provides detailed insights on HCM arrhythmia mechanisms, potentially aiding risk stratification of patients.