Altered contractility in mutation-specific hypertrophic cardiomyopathy: A mechano-energetic in silico study with pharmacological insights

Abstract

Introduction: Mavacamten (MAVA), Blebbistatin (BLEB), and Omecamtiv mecarbil (OM) are promising drugs directly targeting sarcomere dynamics, with demonstrated efficacy against hypertrophic cardiomyopathy (HCM) in (pre)clinical trials. However, the molecular mechanism affecting cardiac contractility regulation, and the diseased cell mechano-energetics are not fully understood yet. Methods: We present a new metabolite-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, BLEB, and OM on the cell mechano-energetics. Results: We offer a mechano-energetic HCM calibration of the model, capturing the prolonged contractile relaxation due to R403Q mutation (∼33%), without assuming any further modifications such as an additional Ca²⁺ flux to the thin filaments. The HCM model variant correctly predicts the negligible alteration in ATPase activity in R403Q HCM condition compared to normal hiPSC-CMs. The simulated inotropic effects of MAVA, OM, and BLEB, 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 1 µM OM and 5 µM BLEB, consistently with in vitro data. Finally, our model replicates the experimental dose-dependent effect of OM and BLEB on the normalized isometric tension. Conclusion: This work is a step toward deep-phenotyping the mutation-specific HCM pathophysiology, manifesting as altered interfilament kinetics. Accordingly, the modeling efforts lend original insights into the MAVA, BLEB, and OM contributions to a new interfilament balance resulting in a cardioprotective effect.

Keywords: action potential; cardiac metabolism; human stem cell-derived cardiomyocyte; hypertrophic cardiomyopathy; immature cardiomyocytes; in silico modeling; pharmacology.

FIGURE 1

Schematics of the interfilament coupling in cardiac force generation (A) the modelled crossbridge (XB) cycling used in hiMCE model (B), and the schematic of hiPSC-CM cell main functional components (C). DRX: Disturbed relax state. SRX: Super relaxed state. T: troponin, TCa: Ca²⁺ bound troponin, N_XB: non-permissive state preventing XB formation, P_XB: permissive state of XB formation, XB_preR: strongly bound XB before isomerised rotation, XB_pstR: XB in strongly bound post isomerised rotation state, AM1 and AM2 are strongly-bound rapid equilibrium substates contributing equally to the force generation and we assumed MgADP binds to AM1 (Tran et al., 2010).

FIGURE 2

Standard results of the model in spontaneous beating: Action Potentials (A), Ca²⁺ Transients (B), Active Tensions (C), ATPase rate (D), Flux of Ca²⁺ towards the contractile element (E), Fractional cell shortening at 1 Hz pacing (F). Cited works: (Ruan et al., 2016; Pioner et al., 2020; Forouzandehmehr et al., 2021).

FIGURE 3

Simulated action potential (A), Calcium transients (B), active tensions (C), ATPase rate (D), Flux of Ca²⁺ towards the myofilament (E), and fractional cell shortenings (F) in R403Q hypertrophic cardiomyopathy and Mavacamten modes (All simulations were done at 1 Hz pacing). The percents of prolonged tension relaxation in R403Q mode (C), the reduction in tension relaxation due to MAVA (C), the reduction in fractional shortening in R403Q mode due to MAVA (F), and the reduction in ATPase rate due to MAVA (D) agree with the experimental data (Toepfer et al., 2020; Gollapudi et al., 2021).

FIGURE 4

Calcium-tension relationships in control and drug-induced modes in isometric condition (A), ap2 coefficients found for different BLEB and OM concentrations (B,C), and dose-dependent tension-Ca²⁺ relationships of BLEB (D) and OM (E) in isometric conditions. OM: Omecamtive mecarbil. BLEB: Blebbistatin. Experimental data from (Kampourakis et al., 2018). T₀: isometric force in the absence of drugs.

FIGURE 5

Predicted effect of 1 µM OM by hiMCE on action potentials (A), Ca²⁺ flux towards the myofilament (B), L-type Ca²⁺ current (C), Na⁺/Ca²⁺ exchanger I_NCX (D) Ca²⁺ transients (E), sarcolemmal Ca²⁺ pump current (F), Na⁺/K⁺ pump (G), and ATPase rates (H). The change of APD has been considered calculating APD₉₀ in agreement with experimental data reported in (Szentandrassy et al., 2016). OM: Omecamtiv mecarbil.