The Adipokine Hypothesis: A Novel Understanding of Heart Failure with Preserved Ejection Fraction

For decades, heart failure with preserved ejection fraction (HFpEF) remained a puzzling condition, lacking a clear unifying explanation. Now, a groundbreaking hypothesis proposed by Milton Packer, MD, FACC, is poised to revolutionize how clinicians conceptualize and treat this increasingly common form of heart failure. After nearly a year of dedicated research – approximately fourteen hours a day, every day – Packer unveiled the “adipokine hypothesis,” detailed in a 105-page paper published in the Journal of the American College of Cardiology (JACC) in October 2025.¹

Challenging Conventional Wisdom

Traditionally, HFpEF was considered a disorder of the heart muscle (cardiomyocytes) or a consequence of other underlying health conditions. The adipokine hypothesis challenges this view, positing that HFpEF is fundamentally a disease of dysfunctional visceral adipose tissue – the fat that surrounds internal organs. This tissue, once thought of solely as a storage depot for triglycerides, is now recognized as a metabolically active endocrine organ. It secretes signaling molecules called adipokines, which act as messengers, communicating the state of the adipose tissue to other organs throughout the body.

The Role of Adipokines

In a lean, healthy individual, visceral adipose tissue releases adipokines with cardioprotective, anti-inflammatory, and antifibrotic effects. However, as visceral fat accumulates, the biological function shifts. The tissue becomes proinflammatory, promoting hypertrophy (enlargement of the heart), fibrosis (scarring), and hindering the body’s ability to regulate sodium levels.¹ Higher levels of proinflammatory adipokines are directly linked to increased risk and severity of HFpEF, and a poorer prognosis for patients.

Understanding the Three Domains of Adipokines

Packer categorizes adipokines into three distinct domains:

• Domain I Adipokines: These are cardioprotective molecules, such as adiponectin, that actively combat inflammation and fibrosis.
• Domain II Adipokines: Also cardioprotective, these molecules are upregulated by adiposity as a compensatory mechanism – the body’s attempt to counteract the damage caused by excess visceral fat.
• Domain III Adipokines: These proteins promote inflammation, hypertrophy, fibrosis, and sodium retention. Their secretion increases with adiposity.

HFpEF, according to the hypothesis, arises from an imbalance driven by excess adiposity. This imbalance favors Domain III adipokines while suppressing Domain I adipokines, with Domain II adipokines proving insufficient to restore equilibrium.²

Evidence Supporting the Hypothesis

The adipokine hypothesis is supported by a wealth of evidence, including:

• Strong parallels between obesity and HFpEF in molecular, pathophysiological, and clinical features.
• Mendelian randomization studies establishing a link between visceral adiposity and HFpEF.
• Observable changes in visceral adiposity and circulating adipokines occurring years before HFpEF diagnosis, and predicting its development.
• The presence of central obesity or excess visceral adiposity in over 85-95% of HFpEF patients.
• Demonstrated effects of adipokines on cardiac structure and function that can lead to HFpEF.
• Evidence that bariatric surgery or HFpEF treatments that reduce visceral fat also increase Domain I adipokines and decrease Domain III adipokines.

Crucially, experimental studies have shown that signaling molecules secreted from adipose tissue directly cause HFpEF in animal models. Silencing the secretion of even a single adipokine specifically in adipose tissue – without affecting other organs – prevented the development of HFpEF in these models.¹

Implications for Treatment

The adipokine hypothesis offers a new lens through which to view existing HFpEF therapies. Drugs like SGLT2 inhibitors, mineralocorticoid receptor antagonists, and incretin-based therapies appear to work, in part, by reducing visceral fat mass and normalizing the dysfunctional state of adipose tissue.¹

the hypothesis may explain why HFpEF predominantly affects older individuals and women, due to age-related fat redistribution and hormonal changes after menopause.¹

The Road Ahead

Packer emphasizes that the adipokine hypothesis is falsifiable, a hallmark of a robust scientific framework. Ongoing research is focused on developing new drugs – adipokine modulators – that specifically target adipokine signaling pathways. Early results with drugs that antagonize activin A, a key proinflammatory adipokine, are promising.¹

The future of HFpEF research lies in rigorous testing of the adipokine hypothesis, including clinical trials and a shift towards more comprehensive assessments of adiposity beyond simple BMI measurements, incorporating factors like waist circumference, visceral fat quantification, and biomarker profiles.¹

As Packer concludes, “If we learn that targeting adipokines, rather than body weight, has an impact on HFpEF, then the adipokine hypothesis will have been fulfilled.”¹

References

1. Packer M. The adipokine hypothesis of heart failure with a preserved ejection fraction: a novel framework to explain pathogenesis and guide treatment. JACC. 2025 Oct, 86 (16) 1269-1373. https://doi.org/10.1016/j.jacc.2025.06.055
2. Packer, M. The neurohormonal hypothesis: A theory to explain the mechanism of disease progression in heart failure. JACC. 1992 Jul, 20 (1) 248–254.