Sarcomere dynamics simulations to uncover mechanisms in hypertrophic cardiomyopathy

Mutations in the beta myosin heavy chain (MYH7) can cause hypercontractility and cardiac remodeling in hypertrophic cardiomyopathy (HCM), but the mechanisms of specific mutations can be difficult to predict. Many mutations change intrinsic rates of myosin activity and their force sensitivity, which can dynamically alter chemo-mechanical cycle events and resultant force generation during cardiac contraction. Our team's multiscale approach enables measurement of the kinetics and force generation in purified myosin proteins, isolated myofibrils, and single and multicellular human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) platforms. Computational modeling can integrate results across these scales and provide additional insights into the individual and combinatorial effects of different changes in myosin kinetics. We have previously used a continuum model to highlight the significance of dysregulation of the super relaxed state of myosin driving hypercontractility in hiPSC-CMs with the P710R mutation. Sensitivity analysis also supported variable myofibril density and sarcomeric organization as a source of population heterogeneity in the force generating capacity of individual hiPSC-CMs. In our ongoing studies, we are leveraging computational modeling to compare the predicted and measured effects of HCM mutations in our different experiments. We have incorporated the measured changes in unloaded myosin to predict force generation after isometric maximal calcium activation (myofibril measurements) and twitch stimulation in single hiPSC-CMs on gels of physiologic stiffness. Additional simulations with spatially explicit models enable more direct prediction of the impact of heterogeneous mixtures of myosins with different molecular profiles and on cooperativity effects associated with the transmission of tension along the length of a sarcomere. Finally, we have visualized the strain profiles of individual sarcomeres in contracting myofibrils in live cells and are correlating these measurements to our simulations. These studies will give new insights into the key biophysical drivers of HCM.