The HCM Related MYBPC3 c.772G>A Mutation: A Model Dependency Study

Hypertrophic cardiomyopathy (HCM) is responsible for the thickening of left ventricle walls due to genetic mutations that affect the sarcomere, with prevalence of 1 out 500 in the general population. Even if HCM may be a silent disease, diastolic dysfunction, heart failure and sudden cardiac death are reported as adverse events. Recent studies described the HCM-related c.772G>A variant, that affects the myosin binding protein C (MYBPC3), both from the clinical and the cellular perspective, thanks to the enrollment of HCM patients who underwent left ventricle septum myectomy. Our aim is to simulate the effects of the HCM c.772G>A mutation using the electrophysiology ventricular models by O’Hara-Rudy (ORd), Tomek-Rodriguez (ToRORd) and Bartolucci (BPS) integrated with the Land contractile model. The results are analyzed from a model dependency point of view. First, we identified the most influential parameters thanks to sensitivity analysis (SA) under control conditions. Then we compared three different HCM remodelings: the first using values from previous works, the second through model specific calibration; the third one used averaged values from the previous calibration. The comparison between HCM remodelings and experimental data highlighted the importance of calibrating the parameters depending on the model in use.