Abstract Body: Heart failure commonly presents with impaired relaxation, both in heart failure with preserved ejection fraction and in heart failure with reduced ejection fraction. Modulation of relaxation by alterations in afterload and/or calcium handling has not been able to accelerate relaxation. We have investigated Mechanical Control of Relaxation (MCR), the strain-rate dependence of relaxation, and determined that sarcomeric proteins may be a key modifier of how quickly the myocardium responds to stretch.

The goal of this study was to characterize the effect of Danicamtiv on Mechanical Control of Relaxation. Danicamtiv (MYK-491) is a myosin activator that is known to increase the myosin ATPase activity and calcium sensitivity.

Intact, excitable cardiac trabeculae were isolated from Sprague Dawley rats and mounted between a length motor and force transducer. Trabeculae were assayed under isometric and isotonic conditions to determine tension and relaxation rates. Increasing doses of Danicamtiv were added and assays were repeated.

Developed tension was not increased above DMSO control treated trabeculae when treated with Danicamtiv; this result is consistent with our findings using Omecamtiv Mercarbil and published work on rodent muscles. At high doses (10 uM), developed tension decreased rapidly. Both isometric relaxation rates and Mechanical Control of Relaxation were not different vs control until Danicamtiv concentration increased to 1 uM, when isometric relaxation rate fell but Mechanical Control of Relaxation increased. This result contrasts with our findings that Omecamtiv Mercarbil causes relaxation to slow and Mechanical Control of Relaxation to increase at clinically-relevant concentrations.

The current data support that Danicamtiv activates myosin in a process different to Omecamtiv Mercarbil and this difference may be responsible for differences in relaxation after treatment. The data also indicate that myosin activation (force generation) alone may not be sufficient to alter Mechanical Control of Relaxation, but additional mechanisms must be considered.