Broad therapeutic benefit of myosin inhibition in hypertrophic cardiomyopathy

Myosin inhibitor mavacamten is the only targeted treatment available for hypertrophic cardiomyopathy (HCM), a disease caused by hundreds of genetic variants that affect mainly sarcomeric myosin and its negative regulator cardiac myosin-binding protein C (cMyBP-C, encoded by MYBPC3 ). Here, we have examined whether the reported limited efficacy of mavacamten in a fraction of HCM patients can result from dissimilar HCM pathomechanisms triggered by different genetic variants, a scenario particularly relevant for MYBPC3 -associated HCM. To this aim, we have generated knock-in mice including missense pathogenic variant cMyBP-C p.R502W, which, different from patients who carry truncations in the protein, develop progressive pathogenic myocardial remodeling in the absence of alterations of cMyBP-C levels and localization. Mechanistically, we find that mutation R502W reduces the binding affinity of cMyBP-C for myosin without inducing a shift towards more active myosin conformations as observed when cMyBP-C levels are reduced. Despite these diverging molecular alterations, we show that mavacamten blunts myocardial remodeling both in R502W and cMyBP-C-deficient, knock-out hearts. These beneficial effects are accompanied by improved tolerance to exercise only in R502W animals. Hence, our results indicate that myosin inhibition is effective to treat HCM caused by both truncating and missense variants in MYBPC3 regardless of the primary pathomechanisms they elicit. ### Competing Interest Statement Roberto Barriales Villa is member of advisory boards and has received speaker fees from Bristol Myers Squibb (BMS), Sanofi, Cytokinetics, Alnaylam, Chiesi, and Pfizer. Lucie Carrier is advisor and shareholder of DiNAQOR AG developing a MYBPC3-based gene therapy for HCM. James A. Spudich is cofounder and on the Scientific Advisory Board of Cytokinetics, Inc, a company developing small molecule therapeutics for treatment of hypertrophic cardiomyopathy. The laboratory of Jorge Alegre Cebollada received funding from Myokardia (now BMS) between 2020-2021 for the project Titin Allelic Discrimination to Uncover Pathophysiology Mechanisms in DCM.