Emerging therapeutic directions for inotropic therapy in heart failure

Heart failure (HF) remains a major global health burden despite advances in pharmacological and device-based therapies. Current guideline-directed medical therapy (GDMT) slows disease progression through neurohormonal modulation but does not address the fundamental deficit in contractile function, particularly in patients with advanced HF with reduced ejection fraction (HFrEF). Conventional inotropes improve contractility but worsen outcomes. Recent advances have identified novel therapeutic approaches that enhance cardiac contractility without the deleterious effects of conventional inotropes. This review examines pathophysiologic mechanisms compromising contractility in HFrEF and therapeutic strategies that enhance contractility, spanning both traditional calcium-dependent inotropes and emerging classes of small molecules. Their mechanisms of action, along with supporting preclinical and clinical data, are discussed to highlight their future therapeutic potential. These novel strategies reflect a paradigm shift from indirect neurohormonal modulation toward direct myocardial modulation, potentially reshaping the therapeutic landscape for both acute and chronic HF with targeted, efficacious, and safer interventions.