The HCM related MYBPC c.772G>A mutation: a model dependency study

Fazeelat Mazhar1, Alan Fabbri2, Eugenio Ricci2, Chiara Bartolucci2, Stefano Severi2
1University of California, 2University of Bologna


Abstract

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 c772G>A variant, that affects the myosin binding protein C (MYBPC), 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 c772G$>$A mutation using the electrophysiology ventricular models from O'Hara-Rudy, Tomek-Rodriguez and Bartolucci integrated with the contractile model from Land. 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 used averaged values from the previous calibration. Finally we compared SA under HCM to control conditions. \\ SA pointed out that $I_{Ca,L}$, $I_{Kr}$, $I_{NCX}$, $J_{up}$ and $J_{rel}$ show high correlations with AP duration (APD90), Calcium amplitude (CaTamp) and Active Tension (AT). The comparison between the HCM remodelings highlighted the importance of calibrating the parameters depending on the model in use. Indeed,the results obtained with the parameter set adopted from literature shows AP90 prolongation larger that experiental data (+76.7%,+97.6,+89.1 respectively for ORd, ToROR and BPS against exp +70.2%) and high increase in ATpeak (67.5%,59.5%,109.3%) not in agreement with experimental data (-12.6%). The calibration brings the simulation closer to experimental data, with APD90 and ATpeak changes in line with experimental data. A new sensitivity analysis let on HCM remodelled cells, highlighted similarities and differences between physiological and pathological conditions.