Nitric Oxide and Mitochondrial Dysfunction in Chronic Heart Failure: A Narrative Review

Abstract

Chronic heart failure (CHF) remains a leading cause of hospital admission, disability, and cardiovascular death despite major advances in guideline-directed therapy. Beyond hemodynamic impairment and neurohormonal activation, CHF is increasingly understood as a disorder of endothelial dysfunction, nitrosoredox imbalance, mitochondrial injury, energetic failure, and regulated cell death. Nitric oxide (NO) signaling and mitochondrial homeostasis are interconnected components of this broader pathophysiologic network. Under physiologic conditions, endothelial NO synthase-derived NO contributes to vascular tone, coronary microvascular regulation, and myocardial signaling. In CHF, reduced endothelial NO bioavailability may coexist with increased formation of reactive nitrogen species, particularly in inflammatory and oxidizing conditions. The resulting nitroso-redox imbalance can interact with mitochondrial respiratory dysfunction, altered calcium handling, oxidative stress, and regulated cell death, although the relative contribution of these mechanisms varies across heart failure phenotypes and disease states. Guidelinedirected therapies, including angiotensin-converting enzyme inhibitors, angiotensin receptor-neprilysin inhibitors, sodium-glucose cotransporter 2 inhibitors, evidence-based beta-blockers, and mineralocorticoid receptor antagonists, improve clinical outcomes through established neurohormonal, renal, and hemodynamic mechanisms. Experimental and translational evidence suggests that some of these therapies may also influence endothelial, redox, metabolic, or mitochondrial pathways, although the clinical contribution of these secondary effects remains incompletely defined. These mechanistic observations have also motivated investigation of therapies that more directly target endothelial, redox, or mitochondrial abnormalities. Hypertril (1-(beta-phenylethyl)-4-amino-1,2,4-triazolium bromide) is an investigational compound with reported beta-blocking, NO-related, and metabolic effects in experimental models; however, the available evidence remains predominantly preclinical and does not establish clinical efficacy in human CHF. This narrative review examines NO dysregulation and mitochondrial dysfunction as interconnected components of CHF pathophysiology, considers their relationship to contemporary pharmacotherapy, and discusses the translational limitations and research priorities associated with targeting these pathways.