Systemic Interactions in HFpEF: A Multiorgan Perspective on Pathways and Therapeutic Targets

Heart failure with preserved ejection fraction (HFpEF) is a complex multisystem syndrome with increasing prevalence in aging and metabolically compromised populations. In addition to diastolic dysfunction, HFpEF involves metabolic abnormalities, chronic inflammation, and oxidative stress across kidney, lung, liver, adipose tissue, and skeletal muscle. Interorgan crosstalk plays a key role in disease progression. Current treatments including SGLT2 inhibitors, GLP-1 receptor agonists, combined with lifestyle interventions like exercise and diet, offer potential benefits for specific subgroups, but broader efficacy remains limited. In this review, we summarized the pathophysiological characteristics of HFpEF from a multi-organ perspective, encompassing intrinsic cardiac mechanisms, cardio-renal and cardio-hepatic interactions, pulmonary and skeletal muscle abnormalities, regional adiposity, and endothelial dysfunction. Future strategies emphasizing multi-organ integration to develop individualized, mechanism-based therapies for the precision treatment and comprehensive management of HFpEF were further discussed.