Lymphatic Matters in Heart Disease: Systemic and Cardiac Perspectives

The lymphatic system plays a fundamental role in cardiovascular physiology by maintaining whole-body fluid balance, facilitating immune trafficking, and enabling lipid transport. Through these functions, lymphatic performance is tightly coupled to cardiovascular health, and disturbances in lymphatic flow, pumping, or lympho-venous return can directly influence the development and progression of heart disease. This review examines the relationship between the lymphatic and cardiovascular systems with an emphasis on systemic lymphatic function and its relevance to cardiovascular pathology. We describe the structure and physiology of the human lymphatic vasculature, including mechanisms governing lymph formation, transport, and return to the venous circulation, and discuss how these processes are challenged in conditions such as heart failure, venous congestion, and altered hemodynamics. Clinical and experimental evidence linking lymphatic dysfunction to edema, inflammation, and impaired organ function across multiple cardiovascular disease states - including heart failure, atherosclerosis, congenital heart disease, and heart transplantation - is considered. In addition, comparative and translational perspectives are presented illustrating how diverse vertebrate lymphatic strategies inform fundamental principles of lymphatic regulation and translational cardiovascular research. Finally, emerging imaging modalities and therapeutic approaches targeting lymphatic structure and function are discussed as potential avenues for improving the diagnosis and treatment of cardiovascular disease. Together, this review positions the lymphatic system as an integral, system-level contributor to cardiovascular physiology and disease, underscoring the need to consider lymphatic function alongside the blood circulation in both research and clinical practice.