The latest issue of JACC provides further in-depth examination of the framework for understanding heart failure with preserved ejection fraction (HFpEF) and guiding treatment through the lens of adipocyte biology and secreted mediators, also known as the “adipokine hypothesis,” developed by Milton Packer, MD, FACC,.

"Up to now, there has been no unifying hypothesis to explain HFpEF. That has resulted in significant misunderstanding and a lack of direction in both diagnosis and therapy," said Packer, who presented the hypothesis at ESC Congress 2025. "This bold new framework helps to identify the true cause of HFpEF in most people. That should make an enormous difference in guiding effective treatments.”

Why the focus issue? “For too long the scientific community has miscalculated on obesity,” writes Erica S. Spatz, MD, MHS, FACC, in a JACC Editor’s Note. “With HFpEF now the fastest growing cardiovascular disease, and mortality rates from heart failure rising, there is no time to waste. … JACC is intent on providing a platform for provocative ideas that foster dialogue and drive progress.”

The JACC focus issue features the following perspectives from experts in HFpEF, obesity and adipokine biology, with the goal of charting a path forward:

Parsing the Adipokine Axis in HFpEF: In this viewpoint, Subodh Verma, MD, PhD, and Deepak L. Bhatt, MD, MPH, MBA, FACC, write: “The adipokine hypothesis of Packer represents a landmark conceptual advance in the evolving landscape of HFpEF research. […] Whether this adipose-centric model will be a reliable guidepost for therapeutic decision-making remains uncertain. What is certain is that it will shape future investigation and challenge us to reconsider longstanding assumptions about this complex syndrome.”

Obese HFpEF: From Pariah to Paradigm: In this viewpoint, Carolyn S.P. Lam, MBBS, PhD, and Dalane W. Kitzman, MD, FACC, caution against abandoning the management of hypertension or other contributors, but rather elevating attention to adiposity. They write: “Clinicians and their patients will clearly benefit from greater awareness of the importance of adiposity as a modifiable risk factor alongside advances in fat loss treatment. However, this should not be at the expense of managing non-adiposity comorbidities and treating patients regardless of measured adiposity with evidence-based therapies such as sodium-glucose cotransporter 2 inhibitors, mineralocorticoid antagonists, and exercise training. […] Although the adipokine hypothesis shines a valuable spotlight on adiposity, its value lies in complementing, not replacing, existing models.”

On the Adipokines Hypothesis Toward a Mechanism-Guided Reframing of HFpEF: In this viewpoint, Gabriele G. Schiattarella, MD, PhD, stresses the need to “let biology, not body size, lead the way.” According to Schiattarella, “the adipokine hypothesis does not eliminate the complexity of HFpEF, but it contributes to organize it. It invites a transition from treating volume to treating signal; from reacting to dysfunction to intercepting it upstream. If this vision holds, it may reorient how we approach HFpEF as well as a broader class of cardiometabolic diseases defined not by cardiac origin but by cardiac consequence. Caution is warranted, however. As with all translational frameworks, testing across human cohorts with broad geographic, genetic, and phenotypic diversity remains essential.”

The Adipokine Hypothesis of HFpEF: A Bold Unifying Framework in Need of Translational Proof: In this viewpoint, Faiez Zannad, MD, PhD, notes that “efforts to define a unified pathophysiology for [HFpEF] have focused on inflammation, fibrosis, microvascular dysfunction and ventricular stiffening, but none fully explains the syndrome’s complexity so as to guide effective therapy. According to Zannad, the adipokine hypothesis integrates these established mechanisms by proposing that visceral adiposity and its maladaptive secretome are the primary origin of the disease. “This framework does not negate what is already known, but instead elevates a common causal pathway above familiar observations,” he writes. “The critical challenge now is to establish causality and demonstrate that adipokine signaling drives HFpEF pathophysiology.”

Body Composition and Treatment Response in [HFpEF]: Interpreting the Adipokine Hypothesis: According to this viewpoint, authored by Amanda R. Vest, MBBS, MPH; Onyedika J. Ilonze, MD, MPH, FACC, et al., “current tools to assess dysfunctional adiposity, including anthropometric, imaging-based, and biomarker assessments, remain both underutilized in clinical practice and underrepresented in HFpEF research.” As such, the authors underscore an “urgent need to develop and validate multidimensional frameworks that integrate refined body composition measures, high-resolution imaging of visceral and epicardial fat, and multiplexed biomarker panels to better define adiposity-related HFpEF responsive to metabolic therapies.”

It’s About Sex, Not Just Fat: Interpreting the Adipokine Hypothesis in the Context of Sex Differences in HFpEF: In this viewpoint, Amanda L. Grundmann; Emily S. Lau, MD, MPH, FACC; and Jennifer E. Ho, MD, FACC, highlight “there is more to HFpEF than just fat alone.” They propose a “nuanced interpretation” of the adipokine hypotheses “that requires consideration of: 1) inherent differences between men and women in the way that adiposity contributes to HFpEF; 2) female-specific HFpEF risk factors beyond adipokine signaling; and 3) alternative biological pathways beyond adiposity, particularly considering evidence supporting similar therapeutic benefit of incretin-based therapies in men and women despite greater weight loss in women.”

Adipokine-Cardiomyocyte Crosstalk: A 2-Way Street in HFpEF Pathogenesis? In this viewpoint, Norbert Frey, MD, and Johannes Backs, MD, “concur that the search for new therapeutic options in HFpEF should have a focus on inhibition or activation of adipokine-dependent signaling.” However, they propose not overlooking “the potential of other systemic (e.g., liver-derived) factors as well as cardiomyocyte-autonomous molecular targets for therapeutic modulation.” They suggest that “interventions directly targeting altered cardiac energy metabolism (e.g., via EDEM2 or HDACs) or sarcomere dysfunction (e.g., via myosin inhibition) hold promise in extending our therapeutic armamentarium in HFpEF.”

HFpEF in East Asia Does the Adipokine Hypothesis Hold? In this viewpoint, Xin Du, MD; Yu Xu, MD; and Weiping Jia, MD, write: “Although the adipokine hypothesis offers a promising framework for understanding HFpEF, there is still much to be explored, particularly in East Asian populations. […] Recognizing that visceral adiposity, aging, and chronic inflammation may contribute differentially across populations, a more targeted and context-specific intervention is warranted.”

Do [HFpEF] Treatments Work by Targeting Adipose Biology? In this viewpoint, Barry A. Borlaug, MD, FACC, stresses the importance of trying harder when confronted with adversity and highlights HFpEF as a case-in-point. “Theodore Roosevelt said that ‘in any moment of decision, the best thing you can do is the right thing, the next best thing is the wrong thing, and the worst thing you can do is nothing,’” he writes. “A generation later, his cousin Franklin stated that ‘the country demands bold, persistent experimentation. It is common sense to take a method and try it: If it fails, admit it frankly and try another. But above all, try something.’”

Adipokine Signaling in [HFpEF]: A New Clinical Frontier: In this viewpoint, Robert J. Mentz, MD, FACC, and Kemi Oladuja, MSC, write: “We are not yet in a place where the data support routine measurement of adipokines to inform diagnosis or management. However, just as we are beginning to more routinely check the urine albumin-creatinine ratio to better capture the cardiorenal picture for our patients, there may be future opportunities to assess adipokine measures to guide testing of novel agents and then support future implementation.”

To accompany the focus issue, JACC also launched an interactive adipokine tool, which allows readers to explore the molecules and understand their functional roles in HFpEF. Read the full issue.

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure

Keywords: Heart Failure, Adipokines, Obesity, Adiposity, Adipose Tissue