Effects of mavacamten on myocardial viscoelasticity under maximal Ca2+-activated conditions
Sinusoidal length-perturbation analysis was used to measure the myocardium’s viscoelastic characteristics and the effects of mavacamten on cross-bridge recruitment and detachment rates at maximally activated conditions (pCa 4.5). For both sarcomere lengths mavacamten reduced elastic moduli values across a wide range of frequencies (Fig. 5A-B), indicating less cross-bridge binding in mavacamten-treated strips under maximally activated conditions. These decreases in cross-bridge binding also underlie the lower force values observed for mavacamten-treated strips (Fig. 2), as changes in elastic moduli and isometric tension typically mirror each other.
Frequency shifts in the viscoelastic system response follow from changes in the enzymatic cross-bridge cycling kinetics under Ca2+-activated conditions. These frequency shifts are most easily observed in the characteristic dips and peaks of the viscous modulus vs. frequency relationship (Fig. 5C-D). Negative viscous moduli represent frequencies where the muscle produces work, and positive viscous moduli represent frequencies where the muscle absorbs work. For both sarcomere lengths mavacamten decreased the magnitude of negative viscous moduli, indicating less work production in mavacamten-treated strips than control strips. In addition, the frequencies where mavacamten-treated strips generated work was shifted towards lower frequencies. These shifts were quantified via the frequency of minimum viscous modulus for each strip (p<0.001 for main effect of mavacamten; Fig. 6A), indicating that cross-bridge recruitment rate slowed in mavacamten-treated strips (Mulieri et al., 2002; Campbell et al., 2004). Mavacamten also increased the frequency of maximum viscous modulus (p=0.029 for main effect of mavacamten; Fig. 6B), indicating that cross-bridge detachment rate increased in mavacamten-treated strips at physiological temperature.