Heart failure with preserved ejection fraction (known as HFpEF), is the most common kind of heart failure, affecting millions globally. The heart still pumps, it just can't relax and fill appropriately. Think of it like a stiff balloon that won't stretch, blood backs up, pressure builds, and breathing becomes a struggle. Fluid can even pool in the lungs, belly, or legs.
For years, high blood pressure was blamed. But research now points to a sneakier culprit: internal fat. Nearly every HFpEF patient tracked in a new study had extra fat wrapped around vital organs, including the heart. And scientists are now thinking it might be quietly sabotaging the heart from the outside in.
A new study introduces the Adipokine Hypothesis, which suggests that HFpEF may stem from biological changes in internal fat. This fat isn't just sitting there; it's sending out chemical signals (called adipokines) that can stir up inflammation, raise pressure, and mess with how the heart relaxes.
"Up to now, there has been no unifying hypothesis to explain HFpEF," said Milton Packer from Imperial College in London. "That has resulted in significant misunderstanding and a lack of direction in both diagnosis and therapy. 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."
In healthy bodies, adipokines are like peacekeepers. They soothe inflammation, protect the heart and kidneys, and keep sodium and fluid in balance. But when internal fat builds up, especially around organs, it transforms. It starts releasing a cast of rogue adipokines that promote stress, inflammation, and scarring in the heart. It is now hypothesized that this biochemical rebellion is what leads to HFpEF.
Certain drugs could reverse the damage, not by fixing the heart directly, but by retraining the fat. These treatments are designed to tweak the adipokine profile, turning the chemical tide back toward healing.
The Adipokine Hypothesis emphasizes the therapeutic potential of targeting dysfunctional fat tissue, not just to reduce its volume, but to restore its beneficial signaling profile. Several FDA-approved drugs for heart failure with preserved ejection fraction (HFpEF) already act on this pathway, yet remain underutilized in clinical practice.
Notably, GLP-1 receptor agonists such as semaglutide and tirzepatide have shown promise in modulating adipokine release, shifting the balance toward anti-inflammatory and cardioprotective profiles.
The paper argues that "obesity" isn't the best way to identify people with too much internal fat. A better method is measuring the waist-to-height ratio.
Ideally, your waist should be less than half your height (a ratio under 0.5). Most people with HFpEF have a ratio above 0.5, and often over 0.6, even if their BMI doesn't classify them as obese. This makes the waist-to-height ratio a more useful clinical marker for this.
"In patients with an elevated waist-to-height ratio, clinicians should be very vigilant to ask patients about potential symptoms of HFpEF," Packer said. "Many people who are short of breath with walking attribute their symptoms to obesity, when in fact, these symptoms are related to HFpEF and can be effectively treated."
The paper was published in JACC and is being presented at ESC Congress 2025.
Source: American College of Cardiology
