Differential effects of myosin activators on myocardial contractile function in nonfailing and failing human hearts.

Abstract

The second-generation myosin activator danicamtiv (DN) has shown improved function compared with the first-generation myosin activator omecamtiv mecarbil (OM) in nonfailing myocardium by enhancing cardiac force generation but attenuating slowed relaxation. However, whether the functional improvement with DN compared with OM persists in remodeled failing myocardium remains unknown. Therefore, this study aimed to investigate the differential contractile responses to myosin activators in nonfailing and failing myocardium. Mechanical measurements were performed in detergent-skinned myocardium isolated from donor and failing human hearts. Steady-state force, stretch activation responses and loaded shortening velocity were analyzed at submaximal [Ca²⁺] in the absence or presence of 0.5 µmol/L OM or 2 µmol/L DN. The effects of DN and OM on Ca²⁺ sensitivity of force generation were determined by incubating myocardial preparations at various [Ca²⁺]. The inherent impairment in force generation and cross-bridge behavior sensitized the failing myocardium to the effects of myosin activators. Specifically, increased Ca²⁺ sensitivity of force generation, slowed rates of cross-bridge recruitment and detachment following acute stretch, slowed loaded shortening velocity, and diminished power output were more prominent following treatment with OM or DN in failing myocardium compared with donor myocardium. Although these effects were less pronounced with DN compared with OM in failing myocardium, DN impaired contractile properties in failing myocardium that were not affected in donor myocardium. Our results indicate that similar to first-generation myosin activators, the DN-induced slowing of cross-bridge kinetics may result in a prolongation of systolic ejection and delayed diastolic relaxation in the heart failure setting.NEW & NOTEWORTHY This is the first study to provide a detailed mechanistic comparison of omecamtiv mecarbil (OM) and danicamtiv (DN) in failing and nonfailing human myocardium. These findings have clinical implications and the potential to inform the clinical utility of myosin activators in the heart failure setting.