The role of the cardiac lymphatic system in heart failure “reverse remodeling”: from developmental signals to druggable targets

Despite advances in therapies targeting hemodynamic and neurohormonal axes in heart failure (HF), incomplete reverse remodeling (RR) characterized by persistent myocardial edema and fibrosis remains a major clinical challenge. This review posits that dysfunction of the cardiac lymphatic system, a critical but understudied pathway for interstitial fluid and immune cell clearance, constitutes a fundamental barrier to complete myocardial recovery. We synthesize current evidence outlining the anatomy, developmental biology, and physiological role of cardiac lymphatics in maintaining myocardial fluid homeostasis and immune surveillance. In the context of HF, the lymphatic system undergoes a dynamic evolution: an initial compensatory lymphangiogenic response in the acute phase facilitates the clearance of edema and inflammatory cells, while its subsequent exhaustion or impairment in chronic HF perpetuates a vicious cycle of inflammation, fibrosis, and adverse remodeling. Central molecular pathways, including the VEGF-C/VEGFR-3 axis and transcriptional regulators like PROX1/FOXC2, govern lymphatic growth, integrity, and function. Furthermore, lymphatics actively modulate post-injury immune responses via specialized mechanisms such as CCL21/CCR7-guided cell trafficking. Therapeutically, augmenting cardiac lymphangiogenesis presents a promising strategy to enhance fluid drainage, resolve maladaptive inflammation, and directly support cardiomyocyte survival, thereby creating a conducive milieu for RR. However, translating this potential requires overcoming translational hurdles related to intervention timing, comorbidity-specific lymphatic dysfunction, and the development of targeted delivery systems. This review concludes that harnessing the cardiac lymphatic system represents a paradigm-shifting therapeutic avenue, complementary to existing regimens, with the potential to promote more complete and sustainable reverse remodeling in heart failure.