Mitochondrial dysfunction in refractory angina: therapeutic rationale for cardiolipin stabilization with elamipretide

Abstract

Refractory angina remains a significant clinical challenge despite advances in pharmacological therapy and coronary revascularization. Conventional anti-anginal agents primarily target myocardial oxygen demand or coronary blood flow; however, a substantial proportion of patients continue to experience persistent symptoms, particularly those with coronary microvascular dysfunction or ischemia in the absence of obstructive coronary artery disease. Increasing evidence suggests that impaired myocardial energetics and mitochondrial dysfunction play a central role in ischemic symptom generation. Cardiolipin, a key phospholipid of the inner mitochondrial membrane, is essential for maintaining electron transport chain integrity and efficient oxidative phosphorylation. Disruption of cardiolipin structure during ischemia contributes to mitochondrial dysfunction, reduced adenosine triphosphate (ATP) production, and increased susceptibility to ischemia. Elamipretide is a novel mitochondria-targeted peptide designed to stabilize cardiolipin and improve mitochondrial function under ischemic conditions without significant hemodynamic effects. This review examines the pathophysiological basis of refractory angina with a focus on mitochondrial dysfunction, outlines the pharmacological rationale for targeting cardiolipin, and critically appraises the preclinical and emerging clinical evidence supporting elamipretide as a potential therapeutic strategy. Targeting myocardial bioenergetics represents a mechanistically distinct and promising approach for selected patients with refractory angina.