HYPOTHESIS The paper proposes a novel unifying hypothesis—that heart failure with preserved ejection fraction (HFpEF) arises primarily from the expansion and dysfunctional transformation of visceral adipose tissue, leading to the secretion of altered suite of signaling molecules (adipokines), which causes systemic inflammation, plasma volume expansion, and cardiac hypertrophy and fibrosis.
ELEMENTS OF THE FRAMEWORK The framework groups adipokines into 3 domains. Domain I adipokines are cardioprotective molecules but are suppressed in patients with excess adiposity. Domain II adipokines are cardioprotective molecules that are up-regulated by adiposity as a compensatory response mechanism. Domain III adipokines, whose secretion is heightened in adiposity, have proinflammatory, prohypertrophic, profibrotic, and antinatriuretic effects. HFpEF results from an adiposity-driven imbalance that promotes Domain III adipokines but suppresses Domain I adipokines, with Domain II adipokines representing an inadequate counter-regulatory response.
KEY LINES OF EVIDENCE 1) Obesity and dietary nutrient excess are the major drivers of experimental HFpEF; 2) changes in visceral adiposity and circulating adipokines are observed years before and predict the diagnosis of HFpEF (but not heart failure with a reduced ejection fraction) in the general community; 3) central obesity or visceral adiposity is present in >95% of patients with HFpEF and tracks with disease severity; 4) obesity and HFpEF exhibit striking parallelism in their molecular, pathophysiological, and clinical features; 5) characteristic changes in the adipokine profile occur in parallel in central obesity and heart failure and are correlated with disease severity; 6) adipokines have established effects on cardiac structure and function that can lead to HFpEF; 7) bariatric surgery or drug treatments for HFpEF cause shrinkage of visceral fat depots (disproportionate to changes in body weight), while simultaneously increasing Domain I adipokines and decreasing Domain III adipokines; 8) excess adiposity appears to identify patients most likely to respond to current treatments for HFpEF; and 9) experimental interventions that target only adipose tissue to selectively increase or decrease its secretion of specific adipokines cause distant effects on the heart to modulate cardiac structure and the evolution of cardiomyopathy.
CONCLUSIONS The totality of evidence suggests that HFpEF evolves—not as a heterogenous disorder related to diverse comorbidities and not as a primary disorder of cardiomyocytes—but as an adipose-driven derangement that is disseminated (through endocrine-paracrine signaling) to the heart.
Editors
Editor-in-Chief
Harlan M. Krumholz, MD, SM, FACC
CME Editor
Ragavendra R. Baliga, MD
Author
Milton Packer, MD
Important Dates
Date of Release: October 13, 2025
Term of Approval/Date of CME/MOC Expiration: October 12, 2026