The Apelin-APJ Axis in Heart Failure: Mechanistic Insights, Clinical Evidence, and Translational Challenges

Heart failure remains a major cause of morbidity and mortality despite contemporary guideline-directed therapy, highlighting the need for additional therapeutic strategies, particularly across heterogeneous heart failure phenotypes. The apelin-Elabela-APJ axis has emerged as a biologically relevant pathway because it influences cardiac contractility, vascular tone, endothelial signalling, metabolism, and remodelling through mechanisms distinct from conventional neurohormonal targets. In this review, we examine the molecular biology of apelin, Elabela, and APJ, and critically appraise the preclinical and clinical evidence across heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, pulmonary arterial hypertension, and related cardiomyopathic states. Although experimental data and early haemodynamic studies support potential therapeutic relevance, recent setbacks with orally active APJ agonists highlight important translational challenges, including pharmacokinetic constraints, altered receptor biology in advanced disease, signalling complexity, and limited phenotypic stratification. We also discuss key research gaps and future directions, including biomarker standardisation, more human-relevant translational models, and endotype-informed trial design, that may help clarify whether apelin-targeted strategies have value in selected heart failure settings.