The Adipokine Hypothesis of Heart Failure With a Preserved Ejection Fraction: A Novel Framework to Explain Pathogenesis and Guide Treatment (JACC October 2025-1)-Article: The Adipokine Hypothesis of Heart Failure With a Preserved Ejection Fraction: A Novel Framework to Explain Pathogenesis and Guide Treatment

Article: The Adipokine Hypothesis of Heart Failure With a Preserved Ejection Fraction: A Novel Framework to Explain Pathogenesis and Guide Treatment

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The "Adipokine Hypothesis of Heart Failure with Preserved Ejection Fraction (HFpEF)," proposed by Dr. Milton Packer, presents a novel unifying framework attributing HFpEF primarily to the expansion and dysfunction of visceral adipose tissue. This altered fat depot secretes a maladaptive profile of signaling molecules, termed adipokines, which instigate systemic inflammation, plasma volume expansion, and cardiac pathological remodeling—including hypertrophy and fibrosis—culminating in diastolic dysfunction characteristic of HFpEF.<br /><br />The hypothesis categorizes adipokines into three functional domains: Domain I adipokines are cardioprotective and suppressed in obesity; Domain II adipokines are cardioprotective but upregulated as a compensatory, yet often inadequate, response in obesity; Domain III adipokines, elevated in obesity, are proinflammatory, profibrotic, and promote adverse cardiac and vascular effects. HFpEF arises from an adipokine imbalance favoring Domain III and deficient Domain I signaling.<br /><br />Key evidence supporting this framework includes: (1) Obesity and dietary excess are major drivers of experimental HFpEF; (2) Visceral adiposity and altered adipokines precede and predict HFpEF onset; (3) Nearly all patients with HFpEF exhibit central obesity correlating with disease severity; (4) Obesity and HFpEF share molecular and clinical parallels; (5) Adipokines directly modulate cardiac structure and function, influencing HFpEF progression; (6) Bariatric surgery and pharmacological treatments (e.g., mineralocorticoid receptor antagonists, SGLT2 inhibitors, GLP-1 receptor agonists, and angiotensin receptor neprilysin inhibitors) reduce visceral fat disproportionately to body weight loss while restoring a favorable adipokine balance; (7) Experimental adipose-specific modulation of adipokines impacts cardiac remodeling and function; (8) Excess adiposity identifies patients who respond best to current HFpEF therapies.<br /><br />The hypothesis challenges the prevailing view of HFpEF as a heterogeneous syndrome without a unifying mechanism, instead attributing its pathogenesis to adipose tissue-driven endocrine and paracrine signaling to the heart. It emphasizes epicardial adipose tissue’s role as a local mediator of myocardial inflammation and fibrosis.<br /><br />Therapeutically, this framework provides guidance to existing treatments and directs future development toward agents modulating adipokine profiles, including adiponectin receptor agonists, FGF21 analogs, leptin antagonists, autotaxin inhibitors, and activin receptor antagonists. It also contextualizes why drugs like metformin and fenofibrate, affecting adipose tissue biology, may benefit HFpEF.<br /><br />In conclusion, the adipokine hypothesis offers a coherent, testable, and falsifiable model connecting obesity-driven adipose dysfunction to HFpEF, suggesting new research and therapeutic avenues to improve patient outcomes.

Keywords

Adipokine Hypothesis

Heart Failure with Preserved Ejection Fraction

HFpEF

Visceral Adipose Tissue

Adipokines

Obesity and HFpEF

Cardiac Remodeling

Systemic Inflammation

Bariatric Surgery

Adipokine-targeted Therapies