# The Adipokine Hypothesis of HFpEF

Faiez Zannad

► To cite this version:

Faiez Zannad. The Adipokine Hypothesis of HFpEF. JACC. Advances, 2025, 86 (16), pp.1249-1251. 10.1016/j.jacc.2025.09.005. hal-05321960

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Submitted on 20 Oct 2025

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The Adipokine Hypothesis of HFpEF: A Bold Unifying Framework in Need of Translational

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Faiez Zannad, MD, PhD<fnref n="1" />

**Address for correspondence:**

Faiez Zannad

3 rue de l'éperon

75006 Paris, France

Email: f.zannad@chru-nancy.fr

**Word Count:** 930 words.

**Disclosures:** F. Zannad reports personal fees from 89bio, Applied Therapeutics, Bayer, Betagenon, Bioeutics, Boehringer, Cambrian, Cardior, Cellprothera, Cereno Pharmaceutical, Corteria, CVRx, Lupin, Merck, Northsea, Otsuka, Owkin, Ribocure, Salubris, Viatris; having stock options or equities at Cereno pharmaceutical; and being the founder of Cardiovascular Clinical Trialists.

<footnote n="1">¹ Université de Lorraine, Inserm Clinical Investigation Center at Institut Lorrain du Cœur et des Vaisseaux, CHRU, Nancy, France.</footnote>
## Abbreviations

BMI: Body mass index.

CKLM: cardiovascular, kidney, liver, and metabolic.

HF: Heart failure.

HFpEF: Heart failure with preserved ejection fraction.

GLP-1/GIP RAs: glucagon like peptide 1/glucose dependent insulinotropic polypeptide receptor antagonists.

SGLT2i: Sodium glucose co-transporter 2 inhibitors.
Efforts to define a unified pathophysiology for heart failure (HF) with preserved ejection fraction (HFpEF) have focused on inflammation, fibrosis, microvascular dysfunction, and ventricular stiffening (1,2), but none fully explains the syndrome's complexity as to guide effective therapy (2,3). An alternative framework, the adipokine hypothesis, integrates these established mechanisms by proposing that visceral adiposity and its maladaptive secretome are the primary origin of the disease (1,2). This framework does not negate what is already known but instead elevates a common causal pathway above familiar observations. The critical challenge now is to establish causality and demonstrate that adipokine signaling drives HFpEF pathophysiology.

Dr Packer offers a disruptive, unifying conceptual model in which expansion and biological transformation of visceral adipose tissue initiate systemic changes that culminate in HFpEF (1). According to this hypothesis, hypertrophied adipocytes acquire a pro-secretory phenotype, releasing a suite of signaling molecules—collectively termed adipokines—that exert endocrine and paracrine effects on the heart, kidneys, vasculature, and other organs, such as the liver. These effects include sodium retention, plasma volume expansion, and most importantly systemic inflammation, microvascular dysfunction, and multi-organ fibrosis—features that collectively define the HFpEF phenotype (1-3).

A strength is the classification of adipokines into three domains: Protective (adiponectin, CTRP9, omentin-1), suppressed by visceral adiposity (1,2), compensatory (FGF21, GDF-15) upregulated but inadequate; iii) maladaptive (leptin, chemerin, resistin) promoting hypertrophy, fibrosis, and inflammation.
Evidence supports the adipokine hypothesis: i) Epidemiology: Central adiposity, best assessed by waist-to-height ratio or imaging, is present in >95% of HFpEF patients, and severity tracks with disease burden (2). ii) Temporality: Visceral adiposity and adipokine changes precede HFpEF and predict development, iii) Experimental: Animal models show genetic or diet-induced obesity induces HFpEF features, reversible by adipose-targeted interventions (4,5), iv) Clinical: Bariatric surgery and drugs reducing visceral fat (glucagon like peptide 1/glucose dependent insulinotropic polypeptide receptor antagonists, GLP-1/GIP RAs, sodium glucose co-transporter 2 inhibitors (SGLT2i) improve cardiac function and reduce HF events, especially in obese HFpEF (2,6).

The hypothesis reconciles HFpEF comorbidities within a coherent mechanistic framework. By positioning visceral adiposity as primary instigator, it integrates systemic inflammation, fibrosis, endothelial dysfunction, and neurohormonal activation, under a single upstream driver. Visceral adiposity also links HFpEF with multimorbidity - chronic kidney disease, metabolic steatotic liver disease - and contributes to breaking the increasingly multispecialty siloed practice of medicine (7). It also aligns with sex differences, as women show greater epicardial fat expansion (2). The model supports therapies targeting adipose biology rather than cardiac load or remodeling alone, consistent with benefits from GLP-1/GIP RAs, SGLT2i, mineralocorticoid receptor antagonists, or angiotensin receptor neprilysin inhibition, reducing visceral mass, and favorably shifting the balance of cytoprotective and proinflammatory adipokines.

Caveats remain. First, evidence is largely associative. Visceral adiposity and HFpEF correlate strongly, but causality in humans is inferential. Observational studies cannot exclude residual confounding by age, hypertension, and physical inactivity—ubiquitous in obesity and HFpEF.
Mendelian randomization shows visceral fat causally related to cardiovascular outcomes (8), but not yet to HFpEF. Animal models support plausibility, but translation to the heterogeneous human phenotype is incomplete (4).

Second, HFpEF is heterogeneous. Lean HFpEF, common in Asia, challenges an adipocentric model (9). Epicardial fat may contribute in non-obese patients, but data are sparse.

Third, anthropometrics require refinement. Body mass index (BMI) inadequately reflects visceral fat, focusing on subcutaneous and skeletal mass. Waist circumference and waist-to-height ratio improve prognostic accuracy, but clinical adoption lacks standardization. Imaging (dual-energy X-ray absorptiometry, magnetic resonance imaging) offers precision but is impractical for routine use (2,7). Most studies involve White Western cohorts; Lean-fat Asian patients with diabetes and kidney disease remain under-characterized (9).

Fourth, phenotypic characterization of the overarching adiposity-adipokine pathophysiology must integrate imaging and biomarkers. Adipokine biomarkers profiles, ideally ratios of protective versus maladaptive signals, may enable risk stratification, early diagnosis, and personalized interventions.

Fifth, alternative or synergistic mechanisms warrant consideration. Hypertension is nearly universal in HFpEF and contributes substantially to ventricular remodeling. Blood pressure reduction generally lowers HF risk, suggesting a persistent role for arterial load, but its effect in obese phenotypes remains unclear. Contributions of aging biology, microvascular dysfunction, and atrial myopathy are incompletely addressed (3).

Finally, therapeutic implications, while promising, remain preliminary. GLP-1 RA, SGLT2i, or bariatric surgery improve outcomes, but benefits may extend beyond adipokine modulation,
given their pleiotropic metabolic effects (2,6,7). Whether selective adipokine targeting
improves outcomes remains unknown.

Where to go from here?

The adipokine hypothesis represents a bold step toward mechanistic clarity in HFpEF. Its validation, however, requires rigorous translational studies. Future directions include, i) Mendelian randomization to test adiposity causality ii) Phenotypic stratification with, anthropometry and imaging (2,3,8), iii) Biomarker identification of adipokine signatures predictive of HFpEF and drug targets, iv) Interventional trials of adipokine targeted therapies beyond weight loss (2), v) Epidemiologic studies of lean HFpEF and diverse ethnic groups (2,9).

Clinically, waist circumference and visceral adiposity should be included in risk assessment, now. Precision medicine may replace the “one-size-fits-all” approach, integrating adiposity phenotypic-targeted strategies with established hemodynamic and neurohormonal therapies. Prevention is the next frontier, tested either in dedicated trials or embedded within broader weight loss and cardiovascular, kidney, liver, and metabolic (CKLM) trials (7,10). Proof-of-concept show obesity-targeted therapies improve symptoms and outcomes in HFpEF (6). Trials should test whether visceral fat reduction delays HFpEF onset using enrichment strategies with discrete adiposity-adipokine phenotypes. Multi-organ endpoint studies should aim simultaneously at CKLM outcomes and potentially support multiple approval claims. And master protocols should compare multiple therapies efficiently (7).
By reframing HFpEF as an adipose-driven disorder, the adipokine hypothesis provides a coherent, testable paradigm. Its promise is substantial, but definitive evidence is required to link conceptual elegance with clinical reality (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. *J Am Coll Cardiol.* 2025;xx:xx-xx. https://doi.org/XX

2. Borlaug BA, Jensen MD, Kitzman DW, Lam CSP, Obokata M, Rider OJ. Obesity and heart failure with preserved ejection fraction: new insights and pathophysiological targets. *Cardiovasc Res.* 2023;118:3434-3450. https://doi.org/10.1093/cvr/cvac120

3. Samson R, Jaiswal A, Ennezat PV, Cassidy M, Le Jemtel TH. Clinical phenotypes in heart failure with preserved ejection fraction. *J Am Heart Assoc.* 2016;5:e002477.
https://doi.org/10.1161/JAHA.115.002477

4. de Moura E Dias M, Dos Reis SA, da Conceição LL, et al. Diet-induced obesity in animal models: points to consider and influence on metabolic markers. *Diabetol Metab Syndr.* 2021;13:32. https://doi.org/10.1186/s13098-021-00647-2

5. Berger JH, Shi Y, Matsuura TR, et al. Two-hit mouse model of heart failure with preserved ejection fraction combining diet-induced obesity and renin-mediated hypertension. *Sci Rep.* 2025;15:422. https://doi.org/10.1038/s41598-024-84515-9

6. Costa TA, Harrington JL. Advances in the management of obesity and heart failure: latest evidence from clinical trials. *Curr Opin Cardiol.* 2025;40:164-171.
https://doi.org/10.1097/HCO.0000000000001214
7. Lee CJM, Kosyakovsky LB, Khan MS, et al. Cardiovascular, kidney, liver, and metabolic interactions in heart failure: breaking down silos. *Circ Res*. 2025;136:1170-1207.

https://doi.org/10.1161/CIRCRESAHA.125.325602

8. Huang Y, Liu Y, Ma Y, et al. Associations of visceral adipose tissue, circulating protein biomarkers, and risk of cardiovascular diseases: a mendelian randomization analysis. *Front Cell Dev Biol*. 2022;10:840866. https://doi.org/10.3389/fcell.2022.840866

9. Chandramouli C, Tay WT, Bamadhaj NS, et al. Association of obesity with heart failure outcomes in 11 Asian regions: a cohort study. *PLoS Med*. 2019;16:e1002916.

https://doi.org/10.1371/journal.pmed.1002916

10. Upadhya B, Hegde S, Tannu M, Stacey RB, Kalogeropoulos A, Schocken DD. Preventing new-onset heart failure: Intervening at stage A. *Am J Prev Cardiol*. 2023;16:100609.

Published 2023 Oct 2. https://doi.org/10.1016/j.ajpc.2023.100609