Impaired contractility in mutation-specific hypertrophic cardiomyopathy: a mechano-energetic in silico study with pharmacological insights

Abstract: Introduction: Mavacamten (MAVA), Blebbistatin (BS), and Omecamtiv mecarbil (OM) are promising drugs directly targeting sarcomere dynamics, with demonstrated efficacy against hypertrophic cardiomyopathy (HCM) in clinical trials. However, the molecular mechanism by which they affect the cardiac contractility regulation, and the diseased cell mechano-energetics are yet to be fully understood. Methods: We present a metabolic-sensitive computational model of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) electromechanics to investigate the pathology of R403Q HCM mutation and the effect of MAVA, BS, and OM on the cell mechano-energetics. Results: The added thermodynamic formulations to the contractile element capture the prolonged contractile relaxation due to R403Q mutation (~33%) without assuming any further modifications such as an additional Ca2+ flux to the thin filaments. Our HCM model variant correctly predicts the insignificant alteration in ATPase activity in R403Q HCM condition compared to normal hiPSC-CMs. The simulated inotropic effects of MAVA, OM, and BS, along with the ATPase activities in the control and HCM model variant agree with in vitro results from different labs. The proposed model recapitulates the tension-Ca2+ relationship and action potential duration change due to 1uM OM and 5uM BS consistent with in vitro data. Finally, our model replicates experimental dose-dependent effect of OM and BS on the normalised isometric tension. Conclusion: This work introduces a mechanistic in silico method, extending the well-established ion channel blocking formalism, to simulate the effect of compounds that predominantly affect the metabolic-sensitive interfilament kinetics accelerating the development of future HCM therapeutics.