Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Sep 7;144(10):759-762.
doi: 10.1161/CIRCULATIONAHA.121.056324. Epub 2021 Sep 7.

Myosin Modulation in Hypertrophic Cardiomyopathy and Systolic Heart Failure: Getting Inside the Engine

Matthew J Daniels  1   2   3 , Luca Fusi  4 , Christopher Semsarian  5 , Srihari S Naidu  6
Affiliations
Review

Myosin Modulation in Hypertrophic Cardiomyopathy and Systolic Heart Failure: Getting Inside the Engine

Matthew J Daniels et al. Circulation. .
No abstract available

Keywords: MYK-461; cardiomyopathy, hypertrophic; heart failure, systolic; myosins.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: LF, CS report no disclosures. MJD reports advisory board fees from Bristol Myers Squibb. SSN reports consultancy fees from Bristol Myers Squibb, and Cytokinetics. SSN is a member of the executive committee of the VALOR trial for Mavacamten (sponsored by Bristol Myers Squibb).

Figures

Figure 1
Figure 1. Myofilament activation and modulation.
(A) Contractility of the whole heart, in this case a heart with hypertrophic cardiomyopathy and massive septal thickening, arises from the coordinated activation of myosin motors organised into regular sarcomere arrays in single cardiomyocytes. (B) Force production is controlled by regulating myosin activity. Actin stimulates the myosin ATPase. Actin availability is controlled by fluctuating calcium levels which via the troponin complex in the thin filament regulate a molecular clutch shielding actin (purple balls) from myosin in low diastolic calcium (Ca++) and exposing it in high systolic Ca++. Myosin is bundled, forming the thick filament. The exposed head contains the motor domain which cycles between “super-relaxed” OFF (red), “relaxed” ON (pink) and “Active” force producing states (green). In diastole the OFF state predominates. In systole as the myofilament activates, an intrinsic thick filament mechanism facilitates the transition between OFF and ON (①). Peak contractility occurs with 1:10 myosin heads active. Small molecule modulators of this system are in clinical evaluation. Omecamtiv mecarbil, a Myosin ATPase activator, increases force production by stimulating transition ②. Mavacamten, a myosin ATPase inhibitor, stabilises the super-relaxed OFF state ③. (C) Hypertrophic cardiomyopathy-causing variants typically reduce myosin locked in the OFF state. With more myosin active, force production in systole and diastole increases (more green, fewer red myosin heads). (D) Restoring the balance of myosin activation in HCM, using myosin ATPase inhibitors like mavacamten, reduces force production (and ATP consumption) in systole and diastole (more red, less green).
See this image and copyright information in PMC

References

    1. Brunello E, Fusi L, Ghisleni A, Park-Holohan SJ, Ovejero JG, Narayanan T, Irving M. Myosin filament-based regulation of the dynamics of contraction in heart muscle. Proc Natl Acad Sci U S A. 2020;117:8177–8186. - PMC - PubMed
    1. Sarkar S, Trivedi DV, Morck MM, Adhikari AS, Pasha SN, Ruppel KM, Spudich JA. The hypertrophic cardiomyopathy mutations R403Q and R663H increase the number of myosin heads available to interact with actin. Sci Adv. 2020;6:eaax0069. - PMC - PubMed
    1. Sparrow AJ, Sievert K, Patel S, Chang YF, Broyles CN, Brook FA, Watkins H, Geeves MA, Redwood C, Robinson P, Daniels MJ. Measurement of myofilament-localised calcium dynamics in adult cardiomyocytes and the effect of hypertrophic cardiomyopathy mutations. Circ Res. 2019;124:1228–1239. - PMC - PubMed
    1. Teerlink JR, Diaz R, Felker GM, McMurray JJV, Metra M, Solomon SD, Adams KF, Anand I, Arias-Mendoza A, Biering-Sørensen T, et al. GALACTIC-HF Investigators. Cardiac Myosin Activation with Omecamtiv Mecarbil in Systolic Heart Failure. N Engl J Med. 2021;384:105–116. 2020. - PubMed
    1. Olivotto I, Oreziak A, Barriales-Villa R, Abraham TP, Masri A, Garcia-Pavia P, Saberi S, Lakdawala NK, Wheeler MT, Owens A, et al. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2020;396:759–769. - PubMed

Publication types

MeSH terms