The Senescent Heart’s Hidden Drain: Senescence-Associated Secretory Phenotype–Mediated Cardiac Lymphatic Dysfunction as a Novel Mechanistic Axis in Heart Failure With Preserved Ejection Fraction: A Narrative Review

Abstract

Heart failure with preserved ejection fraction (HFpEF) represents the dominant and most therapeutically recalcitrant phenotype of heart failure in the contemporary era, yet its pathophysiology remains incompletely delineated. This narrative review advances a novel mechanistic framework proposing that cellular senescence and, specifically, its principal paracrine effector, the senescence-associated secretory phenotype, orchestrate a progressive impairment of cardiac lymphatic function that critically amplifies the myocardial interstitial edema, chronic inflammation, and fibrotic remodeling that define HFpEF. We critically synthesize emerging evidence from molecular geroscience, lymphatic biology, and cardiac physiology to argue that senescence-associated secretory phenotype-driven lymphatic endothelial dysfunction constitutes a previously underappreciated but mechanistically compelling axis in HFpEF pathobiology. We further discuss the translational implications of this paradigm, including the therapeutic potential of senolytic and senomorphic interventions, the obstacles inherent in cardiac lymphatic imaging and targeted drug delivery, and the ethical considerations surrounding the application of antiaging strategies in a predominantly elderly and comorbid patient population. This synthesis is intended to stimulate interdisciplinary investigation and provide a conceptual scaffold for future clinical trials targeting the senescence-lymphatic interface in HFpEF.