Broad therapeutic benefit of myosin inhibition in hypertrophic cardiomyopathy [RNASeq_LSM]

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, mutation R502W reduces the binding affinity of cMyBP-C for myosin, increases Ca2+ sensitivity and promotes the ON structural state of myosin heads without inducing a shift towards more active myosin conformations as observed when cMyBP-C levels are reduced.