Effects of mavacamten on Ca²⁺ sensitivity of contraction as sarcomere length varied in human myocardium.

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 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.

SUBMITTER: Awinda PO 

PROVIDER: S-EPMC7707091 | biostudies-literature |

REPOSITORIES: biostudies-literature