What’s New

• Cardiologist Milton Packer proposes the Adipokine Hypothesis: HFpEF arises when internal fat (visceral adipose tissue) expands and undergoes a pathological shift in adipokine signaling that promotes inflammation, volume expansion, and fibrosis.
• Published in JACC and presented at ESC 2025, the framework is described by JACC editors as “bold” and “generative,” inviting validation and challenge through rigorous studies.

Fat Biology Over Pressure

• In health, adipokines protect the heart and kidneys by damping stress and inflammation and maintaining sodium/fluid balance; with excess visceral fat, this profile flips to pro-inflammatory, pro-fibrotic, volume-expanding signaling implicated in HFpEF.
• The model organizes adipokine “domains” whose imbalance explains hallmark HFpEF findings—systemic congestion, myocardial stiffness, and exercise intolerance—beyond a hypertension-centric view.

Who’s at Risk (Beyond BMI)

• BMI can miss visceral adiposity; the waist-to-height ratio (WHtR) better flags risk, with concern above 0.5 and many HFpEF patients exceeding 0.6 in cohorts cited by the framework.
• This aligns with public guidance encouraging waists under half of height, enabling earlier recognition when dyspnea is mislabeled as “just obesity.”

Treatment Implications

• Prioritize therapies that reduce fat mass and normalize adipokines; several approved HFpEF treatments may work partly via adipose biology but are underused in appropriate phenotypes.
• GLP-1 receptor agonists (e.g., semaglutide, tirzepatide) favorably influence adipokine release and have shown substantial reductions in HF hospitalization and all-cause death in contemporary analyses—mechanistically consistent with the hypothesis.

How to Measure (Simple and Scalable)

• Use WHtR at the point of care to stratify risk and phenotype candidates for adipose-targeted therapy; consider serial WHtR to track response alongside standard HFpEF metrics.
• Pair WHtR with clinical profiling (congestion, exercise capacity) to identify those most likely driven by adipokine imbalance.

Why This Matters

• Provides a testable, unified pathobiology to guide screening and therapy in a heterogeneous syndrome long lacking a single explanatory model.
• Sets the stage for trials stratified by visceral adiposity and adipokine signatures to optimize therapy selection and timing.

Historical Parallel

• Packer’s 1992 neurohormonal hypothesis transformed HFrEF management by shifting focus from mechanics to neurohormonal drivers; the adipokine framework aims to catalyze a similar shift for HFpEF.
• Editors published the new hypothesis because it “invites rigorous challenge,” signaling a field-level call to test and refine the model.

Information Gain: Adipokine Domains and Clinical Consequences

FAQ

• What is the Adipokine Hypothesis?
  A model positing HFpEF results from expansion and dysfunction of visceral fat that shifts adipokine signaling toward inflammation, volume expansion, and fibrosis.
• Why not rely on BMI?
  BMI misses visceral fat burden; WHtR > 0.5—and often > 0.6 in HFpEF—better reflects risk tied to adipokine dysfunction.
• How might treatment change?
  Greater emphasis on fat-targeting strategies and drugs that restore healthy adipokines (including GLP-1 RAs), alongside guideline-directed HFpEF care.
• Is it proven?
  It’s a generative framework; prospective trials by adiposity/adipokine phenotype are needed for validation and clinical algorithms.