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.