Revolutionary Insights: Changes in Internal Fat Biology as a Key Driver of Heart Failure

Recent research suggests that alterations in the biology of internal fat tissue could be the primary cause of a common form of heart failure known as Heart Failure with Preserved Ejection Fraction (HFpEF). This emerging theory, called the Adipokine Hypothesis, offers a new perspective on how internal fat influences cardiac health.

Published in the Journal of the American College of Cardiology (JACC) and presented at ESC Congress 2025, the hypothesis was developed by renowned cardiologist Dr. Milton Packer. Historically, high blood pressure was regarded as the main contributor to HFpEF; however, new findings indicate that excess internal fat surrounding vital organs, including the heart, plays a crucial role.

HFpEF affects nearly 4 million Americans and 32 million globally, characterized by a stiff heart muscle that can't stretch properly to accommodate incoming blood. This leads to increased internal pressure, causing symptoms like shortness of breath, fluid buildup in the lungs, abdomen, or legs.

The key insight from the Adipokine Hypothesis is that fat tissue operates differently when it accumulates excessively within the body. Fat tissue releases signaling molecules called adipokines, which normally help protect organs and maintain balance. But when internal fat stores expand abnormally, the biology of fat tissue shifts, causing it to produce maladaptive adipokines that promote stress, inflammation, and scarring in the heart.

Experimental studies reveal that treating HFpEF may be more effective by targeting fat tissue directly rather than the heart itself. Drugs that shrink internal fat and restore healthy adipokine profiles—some already approved by the FDA—show promise. Notably, GLP-1 receptor agonists such as semaglutide and tirzepatide could have beneficial effects on adipokine release.

A practical way to identify individuals at risk is by measuring the waist-to-height ratio—ideally less than 0.5—since most HFpEF patients exhibit ratios above this threshold, regardless of body mass index (BMI). This emphasizes the importance of evaluating internal fat rather than just overall body weight.

Dr. Packer emphasizes that many breathless individuals may mistake symptoms for obesity, when in fact, HFpEF related to internal fat may be the underlying cause. Recognizing this could lead to more targeted and effective treatments.

This new framework builds on Packer's previous work on heart failure, shifting the focus from traditional neurohormonal explanations towards a deeper understanding of fat biology's role in cardiac disease. Further insights are expected from connecting adipokines in inflammation and microRNA research.

In conclusion, the Adipokine Hypothesis underscores the importance of addressing internal fat health to combat HFpEF. It advocates for the use of existing medications that modulate fat tissue and encourages clinicians to measure waist-to-height ratio for early detection of at-risk populations.