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

Background and PurposeHeart 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 ApproachMulticellular 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 ResultsAt 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 ImplicationsMavacamten 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.