Internal fat may be the leading cause of heart failure, study finds

Heart failure with preserved ejection fraction, or HFpEF, has puzzled doctors for years. Nearly four million Americans and more than 30 million people worldwide live with this condition, yet treatment options remain limited.

Unlike traditional heart failure, where the heart muscle weakens and struggles to pump, HFpEF looks normal on scans. The heart still pushes blood forward, but it cannot relax and fill properly between beats. That stiffness makes you feel short of breath, drained of energy, and sometimes swollen in the legs, belly, or lungs.

For decades, high blood pressure was thought to be the primary culprit. But a new idea challenges that view. According to Milton Packer, MD, Distinguished Scholar in Cardiovascular Science at Baylor University Medical Center and Visiting Professor at Imperial College London, the real driver may not be the heart at all.

His team suggests that signals coming from fat tissue could be behind much of the disease. Their theory, called the Adipokine Hypothesis, was published in JACC and presented at the 2025 European Society of Cardiology Congress.

Many people picture fat as little more than stored calories. In reality, fat is a living organ that sends out chemical messages across the body. These messengers, called adipokines, are proteins and hormones that can influence your heart, blood vessels, metabolism, and immune system.

When fat is healthy, adipokines protect organs, reduce inflammation, and help control fluid balance. But when fat becomes excessive and unhealthy, the signals change. Harmful adipokines are released in higher amounts while the protective ones decline.

This shift in fat biology, Packer explains, transforms fat into an organ that drives stress, inflammation, and scarring inside the heart. “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,” he said. “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.”

The new framework outlines several ways that adipokines from unhealthy fat might set HFpEF in motion. One route is inflammation. When fat tissue becomes stressed, it attracts immune cells that release even more inflammatory chemicals.

These molecules damage blood vessel linings and heart muscle cells. Another pathway is vascular stiffness. Arteries lose flexibility, making it harder for blood to move and raising pressure inside the heart. Over time, scarring—or fibrosis—sets in. That scar-like tissue prevents the heart from relaxing and filling properly. Add in metabolic stress from conditions like diabetes or high blood pressure, and the cycle accelerates.

The result is a heart that seems to pump normally but fails to deliver enough blood to meet the body’s needs during exertion. Climbing a flight of stairs may suddenly feel exhausting, not because the heart cannot squeeze, but because it cannot fill.

The Adipokine Hypothesis pulls together findings from many different fields. Patients with HFpEF almost always show extra fat stored deep inside the body, often wrapping around organs like the heart. Laboratory experiments in animals and cells demonstrate that adipokines can directly impair relaxation of heart muscle.

Blood vessel studies confirm that harmful adipokines limit dilation, which forces blood pressure up. And clinical data reveal that HFpEF commonly strikes those with metabolic syndrome—a cluster of obesity, high blood sugar, and high blood pressure—pointing again to fat’s central role.

What makes this idea powerful is that it unites these scattered observations under one roof. Instead of viewing obesity, diabetes, and hypertension as separate risks, it links them through the signals fat tissue sends.

If Packer is correct, HFpEF is not only a heart problem but a systemic disease. The heart shows the symptoms, but the roots spread across the body, starting with fat. This perspective changes how doctors might diagnose and treat patients. Rather than focusing only on cardiac function, physicians could measure inflammation markers, study fat distribution, and check waist-to-height ratios.

Packer stresses that body mass index, or BMI, is a poor guide because it is influenced by muscle and bone. Instead, the waist-to-height ratio is more telling. A healthy ratio is less than 0.5, meaning your waist is less than half your height.

Most HFpEF patients have a ratio above 0.5, and often above 0.6, even if they do not meet obesity criteria by BMI. “In patients with an elevated waist-to-height ratio, clinicians should be very vigilant to ask about potential symptoms of HFpEF,” he noted. Shortness of breath, often blamed on weight alone, may signal a treatable heart problem.

One striking implication of the hypothesis is that drugs may help by changing fat biology rather than directly targeting the heart. Several medications already approved for other uses appear to reshape adipokine profiles. GLP-1 receptor agonists such as semaglutide and tirzepatide, originally designed for diabetes and weight loss, have shown encouraging effects.

By shrinking unhealthy fat and restoring healthier signaling, these drugs may reduce inflammation and scarring that drive HFpEF. Experimental studies support the idea, and more clinical trials are underway.

Lifestyle measures that reduce harmful fat—like diet, exercise, or surgery—could also prove essential. If confirmed, this approach would offer a range of new strategies for the millions struggling with the disease.

The Adipokine Hypothesis is still a theory, not a proven fact. Much of the current evidence comes from models and associations. Scientists need more large-scale clinical studies to pinpoint which adipokines matter most, how they interact with other risk factors, and whether altering them truly improves outcomes. Still, experts see promise. Packer himself notes that 33 years ago he proposed the neurohormonal hypothesis for another type of heart failure, and that theory transformed treatment. The hope is that this new one could spark a similar revolution for HFpEF.

If confirmed, the Adipokine Hypothesis could shift both prevention and treatment of heart failure. Doctors may screen patients using waist-to-height ratios, giving earlier warning of risk. Patients with high ratios could receive therapies aimed at reducing harmful fat signals.

Already approved drugs like semaglutide may gain new roles in managing HFpEF. For patients, this means that shortness of breath and fatigue often brushed aside as “just weight issues” might be recognized as treatable heart symptoms.

At a public health level, the findings highlight the urgent need to address rising obesity rates, since HFpEF cases are expected to rise sharply in coming decades. By tackling fat as an active organ, science may open new doors for prevention and care.

Note: The article above provided above by The Brighter Side of News.

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