Heart failure with preserved ejection fraction may be driven primarily by dysfunctional visceral fat and harmful adipokines—shifting screening toward waist‑to‑height ratio and treatment toward fat‑targeting therapies, including GLP‑1 agents.
✨ 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.
❓ 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.
