Comparative mechanistic analysis of danicamtiv and omecamtiv mecarbil's in vivo cardiac effects.

Danicamtiv is a second-generation myotropic sarcomere activator currently in clinical trials for treating heart failure with reduced ejection fraction. Initial clinical and preclinical studies suggest that danicamtiv improves upon the major shortcoming of the first-generation myotropic sarcomere activator, omecamtiv mecarbil (OM), which overly impaired diastolic function. However, no study has directly compared the in vivo cardiac effects of danicamtiv and OM to verify these claims. These direct comparisons are essential to understand the potential benefits of one drug over the other. Therefore, this study employed carefully controlled experiments with left ventricular pressure-volume loop and echocardiographic strain analysis to compare how danicamtiv and OM alter each phase of the cardiac cycle. Our results show that for similar increases in left ventricular stroke volume, danicamtiv reduced diastolic performance and myocardial relaxation less than OM. However, danicamtiv still significantly decreased diastolic function at higher doses, like OM. Furthermore, danicamtiv and OM elicited a qualitatively similar triphasic dose-response from the left ventricle. These similarities between danicamtiv and OM in the whole heart were surprising given recent evidence showing significant differences in the drugs' molecular effects on myosin mechanics. We therefore conclude that danicamtiv likely has a wider therapeutic window than OM, but may be limited by the same trade-off between systolic and diastolic performance, driven by similar underlying mechanisms.