Estimating the Effect of Danicamtiv on Human Cardiac Function

Dilated cardiomyopathy (DCM) is a condition characterized by impaired cardiac contractility and enlargement of the heart chambers, leading to systolic dysfunction. Danicamtiv, a novel myosin activator, shows potential in restoring cardiac function by modulating crossbridge cycling affecting positively on increasing force and calcium sensitivity. While promising results have been observed in mouse and porcine models, the translational gap to human cardiac function remains. To address this, we used the MUSICO computational platform, which models sarcomere dynamics and crossbridge behavior, to simulate the effects of Danicamtiv on human trabeculae affected by DCM. MUSICO simulations were performed using experimental data from mouse and porcine cardiac tissues, incorporating physiological differences such as heart rates and myosin isoforms. The simulations demonstrated that Danicamtiv enhances tension at high calcium concentrations (pCa=4), increases calcium sensitivity, and prolongs muscle relaxation during twitch contractions. These effects are achieved by increasing [Ca<sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2+</sup>] sensitivity of the transition rate from the crossbridge “OFF” state to “ON” state and by decreasing ADP release rate, leading to prolonged tension development. Our findings suggest that Danicamtiv has the potential to improve cardiac function in human DCM, providing a valuable tool for predicting drug efficacy in silico. Further validation using human cardiac tissue is needed to confirm its therapeutic impact.