Left ventricular systolic dysfunction is the hallmark pathology in heart failure 
with reduced ejection fraction. Increasing left ventricular contractility with 
beta-adrenergic receptor agonists, phosphodiesterase-3 inhibitors, or 
levosimendan has failed to improve clinical outcomes and, in some situations, 
increased the risk of sudden cardiac death. Beta-adrenergic receptor agonists 
and phosphodiesterase-3 inhibitors retain an important role in advanced heart 
failure. Thus, there remains an unmet need for safe and effective therapies to 
improve left ventricular systolic function. Two novel cardiac myotropes, 
omecamtiv mecarbil and danicamtiv, target cardiac myosin to increase left 
ventricular systolic performance. Neither omecamtiv mecarbil nor danicamtiv 
affects cardiomyocyte calcium handling, the proposed mechanism underlying the 
life-threatening arrhythmias associated with cardiac calcitropes and calcium 
sensitizers. Phase 2 clinical trials have demonstrated that these cardiac myosin 
activators prolong left ventricular systolic ejection time and promote left 
ventricular and atrial reverse remodeling. At higher plasma concentrations, 
these agents may be associated with myocardial ischemia and impaired diastolic 
function. An ongoing phase 3 clinical trial will estimate the clinical efficacy 
and safety of omecamtiv mecarbil. An additional study of these agents, which 
have minimal hemodynamic and renal effects, is warranted in patients with 
advanced heart failure refractory to guideline-directed neurohormonal blockers.