Venous vascular pharmacology: how does it contribute to heart failure with preserved ejection fraction?

Heart failure with preserved ejection fraction (HFpEF) is a major cause of cardiovascular morbidity and mortality globally. Despite significant research, the pathophysiological mechanisms underlying this complex condition remain poorly defined. Recently, the venous system has emerged as an underrecognized yet critical contributor to HFpEF pathogenesis, functioning as the primary capacitance system and a determinant of central venous pressure. Evidence suggests an imbalance between endothelial-derived relaxing and contractile factors (EDRF/EDCF), leading to venous endothelial dysfunction, elevated venous tone, and increased mean circulatory filling pressure, all factors that contribute to ventricular–vascular mismatch. This review synthesizes current literature on the vasoactive effects of EDRF and EDCF in the venous vs. arterial systems, in both preclinical and clinical models, and examines how HFpEF therapies may target these pathways. While preclinical models demonstrate the vasoactivity of these mediators in veins of healthy and hypertensive animals, studies investigating its effects in validated HFpEF models are lacking, prompting further research. Furthermore, clinical studies should also prioritize functional assessments and venous-specific endpoints, including direct measures of venous compliance, to better guide therapeutic strategies for HFpEF.