Not Blood Pressure, But Fat? New Hypothesis Changes Perspective on HFpEF Causes

Excess visceral fat, rather than hypertension itself, may be the primary culprit in heart failure with preserved ejection fraction (HFpEF). This thesis—dubbed the adipokine hypothesis—has been put forward by Dr. Milton Packer of Baylor University Medical Center. The article was published in JACC and will be discussed at the 2025 ESC Congress.

HFpEF is the most common form of heart failure, affecting approximately 4 million people in the United States and 32 million worldwide. The heart becomes stiff, does not fill with blood properly, and patients experience shortness of breath and fluid buildup.

For years, hypertension was believed to be the primary cause. However, Dr. Milton Packer argues that the fatty tissue surrounding the organs plays a crucial role.

Adipokines are proteins released by adipose tissue that, in a healthy body, protect the heart and kidneys, reduce inflammation, and regulate fluid balance. The problem begins when visceral fat accumulates too much, altering the adipokine profile and promoting inflammation, stress, and cardiac fibrosis.

Experimental studies show that the effectiveness of some medications in HFpEF involves affecting adipose tissue and modifying the adipokine profile. This includes GLP-1 receptor agonists such as semaglutide and tirzepatide, which may improve adipokine balance.

Packer notes that drugs that reduce fat tissue and restore its normal function are already approved by the FDA, although they are still not standard treatment for HFpEF.

The author points out that BMI does not reflect actual excess visceral fat. A better indicator is the ratio of waist circumference to height.

If the result is above 0.5 (waist greater than half the height), you should be vigilant.

This isn't the first theory proposed by the American cardiologist. Thirty-three years ago, Packer described the neurohormonal hypothesis for heart failure with reduced ejection fraction, which revolutionized the clinical approach.

Now, his "adipokine hypothesis" may similarly transform the understanding and treatment of HFpEF. Concurrently, two companion articles have been published in JACC: Heart Failure that examine the role of eicosanoids and adipokine-related microRNAs in this disease.