Pharmacological Management of Heart Failure: A Review of Recent Progress

Abstract Heart failure (HF) remains a leading cause of morbidity and mortality despite advances in guideline-directed medical therapy. Established pharmacological pillars—including angiotensin receptor-neprilysin inhibitors, beta blockers, aldosterone antagonists, and sodium-glucose cotransporter-2 inhibitors—have substantially improved outcomes in HF with reduced ejection fraction. However, significant therapeutic gaps persist, particularly in HF with preserved ejection fraction and HF with mid-range ejection fraction, with 30%–40% of patients with HF with reduced ejection fraction remaining symptomatic despite optimal therapy. This comprehensive review summarizes recent evidence on emerging HF therapeutics, examining 7 distinct therapeutic domains: myosin/sarcomere activators; mitochondrial-metabolic modulators; phosphodiesterase-9 inhibitors; anti-inflammatory/immunomodulatory agents; gene/RNA-based therapeutics; anti-fibrotic matrix modulators; and natriuretic receptor agonists. For each domain, a systematic analysis was performed of the mechanistic rationale, preclinical validation, clinical trial evidence, developmental stage, and translational barriers. Integration of these emerging therapies into precision medicine frameworks targeting specific pathophysiological phenotypes offers potential to further reduce morbidity and mortality associated with HF. This review emphasizes both scientific promise and practical barriers to clinical translation, providing a critical perspective on drug development trajectories and realistic prospects for clinical implementation in this rapidly evolving therapeutic landscape.