A small-molecule inhibitor of sarcomere contractility suppresses hypertrophic cardiomyopathy in mice

Abstract

Hypertrophic cardiomyopathy (HCM) is an inherited disease of heart muscle that can be caused by mutations in sarcomere proteins. Clinical diagnosis depends on an abnormal thickening of the heart, but the earliest signs of disease are hyperdynamic contraction and impaired relaxation. Whereas some in vitro studies of power generation by mutant and wild-type sarcomere proteins are consistent with mutant sarcomeres exhibiting enhanced contractile power, others are not. We identified a small molecule, MYK-461, that reduces contractility by decreasing the adenosine triphosphatase activity of the cardiac myosin heavy chain. Here we demonstrate that early, chronic administration of MYK-461 suppresses the development of ventricular hypertrophy, cardiomyocyte disarray, and myocardial fibrosis and attenuates hypertrophic and profibrotic gene expression in mice harboring heterozygous human mutations in the myosin heavy chain. These data indicate that hyperdynamic contraction is essential for HCM pathobiology and that inhibitors of sarcomere contraction may be a valuable therapeutic approach for HCM.

Impact of the Myosin Modulator Mavacamten on Force Generation and Cross‐Bridge Behavior in a Murine Model of Hypercontractility

“…This result can be explained by the cMyBPC ablation‐induced displacement of XBs towards thin filaments and possibly reduced repression of XB movement, such that acto‐myosin interactions are increased, thereby resulting in enhanced XB‐mediated XB recruitment and force generation at submaximal Ca 2+ ‐activations 31, 47. Previous findings show that Myk461 inhibits myosin ATPase activity, decreases force generation, and prevents adverse cardiac remodeling in hypercontractile mouse hearts expressing HCM‐causing MHC missense mutations 21. It has been shown that myocardial samples isolated from HCM patients expressing cMyBPC mutations often display reduced total cMyBPC expression7, 25 and accelerated XB kinetics27; therefore, we sought to investigate the effects of Myk461 on the contractile function of myocardium lacking cMyBPC.…”

“…Previous studies have shown that the myosin modulator mavacamten (Myk461) has a potential role in attenuating cardiac hypercontractility caused by β‐MHC mutations by decreasing myosin ATPase activity and XB transitions to force‐generating states 21, 22. However, the effects of Myk461 on cardiac hypercontractility resulting from decreased cMyBPC expression have not been investigated until now.…”

“…It has been proposed that Myk461 binds directly to myosin and prolongs the overall duration of the ATPase cycle by decreasing the number of XBs transitioning from the weakly bound to the strongly bound state and the rate of phosphate release, which together reduces the total number of XBs that are in a force‐generating state at a given time 21, 22. Thus, in our study, it is apparent that Myk461 reduces force generation more at low Ca 2+ levels than at high Ca 2+ levels in detergent‐skinned mouse myocardium.…”

“…Thus, recent studies have attempted to normalize HCM‐related hypercontractility by directly targeting the myosin motor rather than using β‐blockers and calmodulin antagonists, which may trigger the activation of unwanted signaling pathways 19, 20. Specifically, the myosin modulator mavacamten (Myk461) has been recently shown to decrease both myosin ATPase activity and the transition of XB's from their weakly to strongly bound conformations 21, 22. Notably, transgenic mice expressing missense mutations in MHC that were treated with Myk461 displayed significant reductions in systolic function indicated by reduced fractional shortening, and resulted in regression of pathological remodeling as evidenced by reduced left ventricular wall thickness, myocyte disarray and fibrosis, such that overall cardiac function was improved 21.…”

“…Specifically, the myosin modulator mavacamten (Myk461) has been recently shown to decrease both myosin ATPase activity and the transition of XB's from their weakly to strongly bound conformations 21, 22. Notably, transgenic mice expressing missense mutations in MHC that were treated with Myk461 displayed significant reductions in systolic function indicated by reduced fractional shortening, and resulted in regression of pathological remodeling as evidenced by reduced left ventricular wall thickness, myocyte disarray and fibrosis, such that overall cardiac function was improved 21. Similarly, acute MyK461 infusion in a feline model of HCM led to reduced left ventricular outflow obstruction and improved systolic function 23…”