Mavacamten Efficacy in Mutation-specific Hypertrophic Cardiomyopathy: an In Silico Approach to Inform Precision Medicine

Hypertrophic cardiomyopathy (HCM) is a common genetic heart disease characterised by hyperdynamic contraction and slowed relaxation. It has been proposed that cellular hypercontractility can derive from mutations that destabilise the energy-conserving myosin super relaxed state, SRX. A new drug, Mavacamten, has been shown to re-stabilise myosin SRX. Here we develop a human-based in-silico model to investigate how disease and drug-induced SRX changes alter cardiac contractility. We do this to mechanistically investigate how Mavacamten restores function in a HCM causing mutation. Our simulations show that hypercontractility is accounted for by an increased availability of crossbridges due to a reduced abundance of myosin SRX, but cellular diastolic dysfunction is only recapitulated if there is a direct crossbridge contribution to thin filament activation. Our model replicates reduced cellular contractility with Mavacamten treatment, which also rescues the hypercontractile phenotype in HCM Our model demonstrates that Mavacamten is effective in correcting HCM abnormalities caused by mutations that destabilise SRX. However, genotypes that cause HCM via other molecular pathways may be incompletely salvaged by Mavacamten.