Danicamtiv increases cardiac mechanical efficiency

Danicamtiv is a recently developed cardiac-specific myosin activator that directly increases actomyosin interaction and, thereby, increases force. It is currently studied pre-clinically and has entered clinical trials. In this study, we provide the first assessment of its effects on cardiac energetics. Ventricular trabeculae from rats were isolated and studied in vitro. Each trabecula was stimulated to produce twitch force over ranges of muscle lengths and afterloads, with muscle heat output simultaneously measured. Each trabecula was superfused with and without danicamtiv (5 µM). In both interventions, muscles were required to undergo both isometric and work-loop contraction protocols to quantify the components of heat output - that from muscle contraction, that from intracellular Ca²⁺ cycling and that from actomyosin cross-bridge cycling. Danicamtiv was found to increase twitch force, muscle heat and cross-bridge heat, with no effect on the energy expenditure associated with intracellular Ca²⁺ cycling. Danicamtiv slowed isometric twitch force kinetics and slowed shortening kinetics. Danicamtiv increased the extent of muscle shortening, increased muscle work output and increased mechanical efficiency, while preserving cross-bridge efficiency. In conclusion, danicamtiv increases mechanical efficiency, the mechanism of which arises from the greater increase of force and muscle shortening that increase mechanical work than the increase of heat. The relative smaller increase of heat is due to a null effect of danicamtiv on the energy for intracellular Ca²⁺ cycling. Our results provide perspective for the utility of danicamtiv as an inotropic agent not only for mechanical enhancement but also for energetic enhancement in increasing mechanical efficiency. KEY POINTS: Clinical trials are presently exploring the potential of a new myotrope, danicamtiv, to improve cardiac mechanics by increasing muscle force output. A range of active pre-clinical research is likewise uncovering the biophysical mechanism of how danicamtiv affects cardiac mechanics, increases cardiac force and slows contractile kinetics. This study provides the first energetic assessment of danicamtiv by measuring muscle heat output, and shows that danicamtiv increases cardiac energy efficiency. The mechanism of the increased efficiency resides in the increase of muscle force-length work greater than the increase of muscle heat. This study demonstrates that danicamtiv is a cardiac myotrope that not only enhances mechanics, but also exerts its enhancement effect on energetics.