Background and Purpose: Heart failure can reflect impaired contractile function at the myofilament level. In healthy hearts, myofilaments become more sensitive to Ca2+ as cells are stretched. This represents a fundamental property of the myocardium that contributes to the Frank–Starling response, although the molecular mechanisms underlying the effect remain unclear. Mavacamten, which binds to myosin, is under investigation as a potential therapy for heart disease. We investigated how mavacamten affects the sarcomere-length dependence of Ca2+-sensitive isometric contraction to determine how mavacamten might modulate the Frank–Starling mechanism. Experimental Approach: Multicellular preparations from the left ventricular-free wall of hearts from organ donors were chemically permeabilized and Ca2+ activated in the presence or absence of 0.5-μM mavacamten at 1.9 or 2.3-μm sarcomere length (37°C). Isometric force and frequency-dependent viscoelastic myocardial stiffness measurements were made. Key Results: At both sarcomere lengths, mavacamten reduced maximal force and Ca2+ sensitivity of contraction. In the presence and absence of mavacamten, Ca2+ sensitivity of force increased as sarcomere length increased. This suggests that the length-dependent activation response was maintained in human myocardium, even though mavacamten reduced Ca2+ sensitivity. There were subtle effects of mavacamten reducing force values under relaxed conditions (pCa 8.0), as well as slowing myosin cross-bridge recruitment and speeding cross-bridge detachment under maximally activated conditions (pCa 4.5). Conclusion and Implications: Mavacamten did not eliminate sarcomere length-dependent increases in the Ca2+ sensitivity of contraction in myocardial strips from organ donors at physiological temperature. Drugs that modulate myofilament function may be useful therapies for cardiomyopathies.
|Number of pages||13|
|Journal||British Journal of Pharmacology|
|State||Published - Dec 2020|
Bibliographical noteFunding Information:
This work was supported by the American Heart Association (17SDG33370153 to B.C.W.T., 19TPA34860008 to B.C.W.T. and K.S.C. and GRNT25460003 to K.S.C.); the National Science Foundation (1656450 to B.C.W.T.); and the National Institutes of Health (R01HL149164 to B.C.W.T. and K.S.C. and TR001988, HL144664 and HL133358 to K.S.C.).
American Heart Association, Grant/Award Numbers: 17SDG33370153, 19TPA34860008, GRNT25460003; National Institutes of Health, Grant/Award Numbers: HL133358, HL144664, TR001988, R01HL149164; National Science Foundation, Grant/Award Number: 1656450 Funding information 10 2+ F pas F act 2+ 50 2+ 2+ n H
© 2020 The British Pharmacological Society
- cardiac muscle mechanics
- human myosin
- sarcomere length
ASJC Scopus subject areas