A groundbreaking new hypothesis connecting visceral adiposity and adipokines to heart failure with preserved ejection fraction (HFpEF) is poised to reshape how clinicians understand and treat the increasingly common condition. The theory, detailed in a 105-page paper published in the Journal of the American College of Cardiology (JACC) in October 2025, is the culmination of a year-long effort by cardiologist Milton Packer, MD, FACC, who dedicated fourteen hours a day to its development.
The “adipokine hypothesis” proposes that HFpEF isn’t primarily a disease of the heart muscle itself, or driven by other co-existing health problems, but rather a result of dysfunctional visceral adipose tissue – the fat that accumulates around internal organs. This tissue, long considered simply a storage depot for triglycerides, is now understood to be a metabolically active endocrine organ, secreting signaling molecules called adipokines that influence other parts of the body.
“HFpEF results from an adiposity-driven imbalance that promotes domain III adipokines but suppresses domain I adipokines, with domain II adipokines unable to completely counter this imbalance,” Packer writes in the paper. He categorizes adipokines into three domains: Domain I, which are cardioprotective but diminished in those with excess fat; Domain II, which increase as a compensatory response to adiposity; and Domain III, which become heightened in obesity and contribute to inflammation, heart muscle thickening, and fluid retention.
The hypothesis builds on decades of research and is supported by twelve key lines of evidence, including the strong parallels between obesity and HFpEF in terms of molecular and clinical features. Studies have shown that changes in visceral adiposity and circulating adipokines can be detected years before a HFpEF diagnosis, and that the condition is present in 85-95% of patients with HFpEF. Bariatric surgery and treatments that reduce visceral fat have been shown to improve adipokine profiles.
Experimental studies provide particularly compelling evidence. Researchers have demonstrated that artificially inducing high levels of proinflammatory adipokines in animal models is sufficient to cause HFpEF. Crucially, silencing the secretion of a single adipokine specifically in adipose tissue – without affecting other organs – prevented the development of the condition in these models, providing causal proof of the link.
The adipokine hypothesis as well offers a potential explanation for why current HFpEF therapies, such as SGLT2 inhibitors, mineralocorticoid receptor antagonists, and incretin-based therapies, appear to be effective. Packer suggests these drugs may function, at least in part, by reducing visceral fat mass and normalizing the dysfunctional state of adipose tissue.
The theory also addresses the prevalence of HFpEF in older adults and women. Packer notes that age-related redistribution of subcutaneous fat to visceral depots, particularly pronounced in women after menopause, contributes to the increased risk. He also suggests that many obese individuals may have undiagnosed HFpEF, as their breathing difficulties are often attributed solely to their weight.
The JACC publication has spurred further investigation, with a special focus issue dedicated to interrogating and validating the adipokine hypothesis. Experts have called for more research into the mechanisms underlying the connection, targeted clinical trials, and the development of more precise methods for assessing adiposity beyond body mass index (BMI), such as waist circumference, visceral fat quantification, and biomarker profiles. Researchers are also prioritizing studies to understand sex-based differences in adipokine signaling and to identify “responder” phenotypes for personalized therapy.
New pharmacological modulators targeting specific adipokines are currently in development, with early results showing promise, particularly with drugs that antagonize activin A, a key proinflammatory adipokine. Packer stated that if targeting adipokines, rather than body weight, proves effective in treating HFpEF, it would validate the hypothesis.
