Monica Nguyen

Introduction: Familial Hypertrophic Cardiomyopathy (HCM) is an increasingly common chronic heart condition affecting 1 in 500 individuals and can lead to heart failure, arrhythmias, stroke and sudden cardiac death.^1,2 It is characterized by left ventricular myocardial hypertrophy with histological changes including cardiac myocyte disarray, cardiac myocyte enlargement and myocardial fibrosis. ² Over 450 mutations have been identified with the most common mutations affecting β-Myosin Heavy Chain (MYH), and Cardiac Myosin Binding Protein C (MYBPC). ^2-4 These mutations have been shown to destabilize the Super-Relax-State, an important myosin confirmation that allows for regulation of sarcomeric contractility and force output. ^3,4 Although current treatment of HCM focuses on symptom management, regulation of cardiac contractility and the Super-Relax-State is a promising emerging therapeutic strategy.^2,4,5 Mavacamten is a novel allosteric myosin ATPase inhibitor which may prevent and reverse HCM progression. ^2,4,5 Methods HCM mouse models with murine α–cardiac myosin heavy chain mutations were treated orally with MYK-416 (Mavacamten) and evaluated by echocardiogram, histological sampling, and RNA sequencing.² Furthermore, myosin head ATPase activity was measured by NADH-coupled assay and steady-state fluorescence detection.⁶ To measure population of the Super Relaxed State and its effect on cardiac contractility; mouse models and human cardiomyocytes derived from induced pluripotent stem cells were assayed for myosin ATPase and analyzed with Florence detection.^4,5 In a randomized, double-blind, placebo-controlled clinical trial of Mavacamten, patients were evaluated using EKGs, Echocardiograms, and NYHA functional class.⁷ Results: Mavacamten was reported to significantly inhibit the release of phosphate from the myosin head, slowing ATP turnover. ² Notably, treatment of Mavacamten significantly decreased cardiac myocyte disarray and cardiac fibrosis and suppressed hypertrophic and profibrotic gene expression.² It also stabilizes myosin head to head affinity and myosin head interaction with the thick filament promoting the Super Relaxed state.⁶ Further studies showed that treatment of Mavacamten repopulated the Super-Relaxed state while decreasing sarcomeric shortening and relaxation duration time in both cases of MYH and MYBPC mutations.^4,5 Mavacamten is currently being evaluated in Phase 3 clinical trials and has shown to be effective in improving left ventricular ejection fraction and NYHA functional class in patients with HCM.⁷ Conclusions: Mutations in sarcomeric genes alter the Super-Relaxed State of cardiac myosin, leading to characteristic HCM hypercontractility and cardiac remodeling. Mavacamten is a very promising therapeutic agent because it is able to reverse multiple pathological changes through a dual mechanism of decreasing contractility while promoting efficient relaxation and is a promising therapeutic for future treatment of HCM.

1. Maron BJ, Gardin JM, Flack JM, Gidding SS, Kurosaki TT, Bild DE. Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA Study. Coronary Artery Risk Development in (Young) Adults. Circulation. 1995;92(4):785-789. doi:10.1161/01.cir.92.4.785
2. Green EM, Wakimoto H, Anderson RL, et al. A small-molecule inhibitor of sarcomere contractility suppresses hypertrophic cardiomyopathy in mice. Science. 2016;351(6273):617-621. doi:10.1126/science.aad3456
3. Sarkar SS, Trivedi DV, Morck MM, et al. The hypertrophic cardiomyopathy mutations R403Q and R663H increase the number of myosin heads available to interact with actin. Sci Adv. 2020;6(14):eaax0069. Published 2020 Apr 3. doi:10.1126/sciadv.aax0069
4. Toepfer CN, Wakimoto H, Garfinkel AC, et al. Hypertrophic cardiomyopathy mutations in MYBPC3 dysregulate myosin. Sci Transl Med. 2019;11(476):eaat1199. doi:10.1126/scitranslmed.aat1199
5. Toepfer CN, Garfinkel AC, Venturini G, et al. Myosin Sequestration Regulates Sarcomere Function, Cardiomyocyte Energetics, and Metabolism, Informing the Pathogenesis of Hypertrophic Cardiomyopathy [published correction appears in Circulation. 2020 Mar 10;141(10):e645]. Circulation. 2020;141(10):828-842. doi:10.1161/CIRCULATIONAHA.119.042339
6. Rohde JA, Roopnarine O, Thomas DD, Muretta JM. Mavacamten stabilizes an autoinhibited state of two-headed cardiac myosin. Proc Natl Acad Sci U S A. 2018;115(32):E7486-E7494. doi:10.1073/pnas.1720342115
7. Olivotto I, Oreziak A, Barriales-Villa R, et al. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2020;396(10253):759-769. doi:10.1016/S0140-6736(20)31792-X