Cardiac Myosin Activators in Heart Failure: Experimental Advances Amid Clinical Uncertainty

Heart failure remains a leading cause of morbidity and mortality despite advances in neurohormonal and device-based therapies, and conventional inotropes are constrained by pro-arrhythmic and energetically costly mechanisms. Cardiac myosin activators (CMAs) offer a conceptually distinct approach by directly modulating the actin-myosin cross-bridge cycle within the sarcomere, but their clinical trajectory has been more nuanced than initially anticipated. Omecamtiv mecarbil(OM) and danicamtiv are the most advanced CMAs to enter human trials; both show reproducible, dose-dependent improvements in systolic function and chamber mechanics in preclinical and early-phase studies, yet a narrow exposure window, signals of diastolic and energetic trade-offs at higher doses, and largely modest or heterogeneous effects on clinical outcomes have tempered expectations and no agent has yet achieved regulatory approval. In this review, we critically appraise the mechanistic rationale, translational evidence and pivotal clinical trials of these agents, integrating emerging work on myocardial energetics and diastolic function. We also compare myosin activation with myosin inhibition and outline future research priorities-including optimisation of dosing strategies, phenotype-guided patient selection, rigorous evaluation of long-term safety and exploration of next-generation myosin-targeting strategies-that must be addressed before CMAs can be credibly positioned within routine heart-failure management.