Long-term mavacamten exposure reduces force and sarcomere density in a hiPSC model of hypertrophic cardiomyopathy

BackgroundMavacamten, a first-in-class allosteric myosin inhibitor, has demonstrated efficacy and safety in obstructive hypertrophic cardiomyopathy (oHCM), notably reducing symptoms, left ventricular outflow obstruction, and wall thickness over 30 weeks. We recently reported that the MYBPC3:c.772G>A variant causes HCM through cMyBP-C haploinsufficiency, leading to accelerated sarcomere kinetics and higher energy consumption in patient myocardium and hiPSC- derived cardiomyocytes (hiPSC-CMs). These effects are counterbalanced by prolonged action potentials and slower Ca{superscript 2} transients, which preserve twitch duration but may increase arrhythmic risk. Mavacamten may reduce myocardial energetic defects in HCM. ObjectivesTo investigate the long-term effects of Mavacamten on sarcomere structure, contractility, and transcriptional remodeling using patient-specific and CRISPR-corrected isogenic hiPSC-derived cardiomyocyte models of HCM. MethodsHiPSC-CMs and engineered heart tissues (EHTs) derived from a MYBPC3:c.772G>A patient and its CRISPR-corrected line were first exposed to increasing concentrations of Mavacamten to assess acute dose-response relationships and determine IC50 values. Based on these data, chronic treatments (0.3- 0.75 M for 20 days) were performed mechanical, structural, electrophysiological, and transcriptomic adaptations. ResultsAcute exposure produced a rapid and fully reversible reduction in active force, while chronic treatment for 20 days induced a sustained decrease in contractility with incomplete recovery after 4 days of washout, indicating a two-phase mechanism of action. Long-term force reduction was paralleled by decreased cell area and sarcomere density, indicating that structural disassembly contributes to sustained functional depression and re-assembly after washout. Electrophysiological analysis confirmed the specific alterations of the MYBPC3:c.772G>A mutation previously observed, with no detectable effects following treatment with Mavacamten. In addition, transcriptome analysis was used to study the molecular mechanisms underlying the long-term effect. ConclusionsMavacamten induces a biphasic, persistent-to-reversible, reduction of sarcomeric force associated with structural remodeling, providing mechanistic insight into its capacity to promote favorable cardiac remodeling in oHCM.