Adipose Tissue, Natriuretic Peptides, and HFpEF: Clinical Implications of the Obesity Paradox

Introduction: Adipose tissue (AT) is increasingly recognized as an active endocrine and immunological organ involved in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). Dysfunctional AT, particularly visceral, promotes chronic low-grade inflammation, endothelial dysfunction, and microvascular damage. At the same time, higher body mass is associated with paradoxically lower natriuretic peptide (NP) levels, which may impact diagnostic accuracy in HFpEF. Methods: This narrative review summarizes the current evidence on the interplay between adipose tissue, NPs, and HFpEF, focusing on pathophysiological mechanisms, AT distribution, and clinical implications. Results: Adipokine-mediated inflammation contributes to the myocardial stiffness, fibrosis, and cardiac remodeling characteristic of HFpEF. Visceral adipose tissue, including epicardial fat, exhibits a more proinflammatory profile than subcutaneous fat. Obesity is associated with decreased NP levels due to increased clearance and decreased production. Consequently, lower NP levels may lead to underdiagnosis or misclassification of HFpEF, particularly in diagnostic algorithms such as HFA-PEFF and H2FPEF. Patients with low BMI or cachexia exhibit elevated NP levels, reflecting advanced disease and catabolic states. Conclusions: The obesity-natriuretic paradox poses a key diagnostic challenge in HFpEF. Interpretation of natriuretic peptide levels should take body composition into account, and refinement of biomarker cutoff values may improve diagnostic accuracy.