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Effects of mavacamten on Ca2+-sensitivity of contraction as sarcomere length varied in human myocardium
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  • Peter Awinda,
  • Yemeserach Bishaw,
  • Marissa Watanabe,
  • Maya Guglin,
  • Kenneth Campbell,
  • Bertrand Tanner
Peter Awinda
Washington State University
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Yemeserach Bishaw
Washington State University
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Marissa Watanabe
Washington State University
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Maya Guglin
University of Kentucky
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Kenneth Campbell
University of Kentucky
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Bertrand Tanner
Washington State University
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Abstract

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 myocardium that contributes to the Frank-Starling response, although the molecular mechanisms underlying the effect remain unclear. Mavacamten is a drug that binds to myosin, which is under investigation as a potential therapy for cardiovascular disease. We tested 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 procured 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. Pharmaceuticals that modulate myofilament function may be useful therapies for cardiovascular disease.

Peer review status:ACCEPTED

04 May 2020Submitted to British Journal of Pharmacology
06 May 2020Submission Checks Completed
06 May 2020Assigned to Editor
07 May 2020Reviewer(s) Assigned
11 Jun 2020Editorial Decision: Revise Minor
18 Aug 20201st Revision Received
21 Aug 2020Submission Checks Completed
21 Aug 2020Assigned to Editor
21 Aug 2020Reviewer(s) Assigned
01 Sep 2020Review(s) Completed, Editorial Evaluation Pending
07 Sep 2020Editorial Decision: Revise Minor
08 Sep 20202nd Revision Received
08 Sep 2020Submission Checks Completed
08 Sep 2020Assigned to Editor
09 Sep 2020Reviewer(s) Assigned
10 Sep 2020Review(s) Completed, Editorial Evaluation Pending
11 Sep 2020Editorial Decision: Accept