Blocking Activity of Glucagon Hormone Could Treat Common and Challenging Type of Heart Failure

Globally, approximately 64 million people suffer from heart failure, which has become a global pandemic. Heart failure with preserved ejection fraction (HFpEF), a particularly challenging form of heart failure to treat, accounts for about half of these cases. In heart failure, the heart is unable to pump blood effectively. In HFpEF, the heart can pump normally, but its muscles are too stiff to relax and properly fill the chambers with blood. HFpEF often affects older adults and individuals with multiple risk factors such as high blood pressure, obesity, and diabetes. Patients with HFpEF typically experience symptoms like shortness of breath, fatigue, and reduced exercise capacity. This differs from heart failure with reduced ejection fraction (HFrEF), where the heart muscle is weakened and cannot pump with sufficient force, leading to a reduced amount of blood being circulated. Although there have been studies on how hypertension and obesity-related metabolic diseases, such as diabetes, stress the heart, these conditions have generally been studied in isolation.

Now, scientists at Duke-NUS Medical School (Singapore) and their collaborators have now identified a potential new treatment for HFpEF. The team discovered elevated levels of glucagon activity—a hormone produced by the pancreas that raises blood sugar—in the diseased heart cells. Building on this insight, they demonstrated that a drug capable of blocking this hormone could significantly improve heart function. This groundbreaking study, published in Circulation Research, considered both hypertension and obesity-associated metabolic diseases and revealed, for the first time, a molecular pathway contributing to HFpEF progression. In preclinical studies, the researchers examined the effects of hypertension on lean and diabetic/obese hearts. They found that hypertension led to HFrEF in lean models, a condition typically observed in hypertensive patients. However, obese models developed HFpEF, suggesting that a combination of stressors triggers the disease, providing a useful model for further research.

Using advanced single-cell RNA sequencing, the scientists were able to analyze the expression of every gene detected in individual heart cells, uncovering specific genetic variations linked to HFpEF. They discovered that in obese models, the most active genes were those driving glucagon activity. Under conditions of high blood pressure and metabolic disorders like obesity and diabetes, glucagon signaling in heart cells becomes excessively active. This overactivity contributes to HFpEF by increasing heart stiffness and reducing its ability to relax and fill with blood.

The team then tested a drug that blocks the glucagon receptor in a pre-clinical HFpEF model and observed significant improvements in heart function. These improvements included reduced heart stiffness, enhanced relaxation, better blood-filling capacity, and overall improved heart performance. The researchers now aim to collaborate with clinical partners to conduct trials testing the glucagon receptor blocker in humans with HFpEF. If successful, this treatment could become one of the first effective therapies for this difficult condition, improving the quality of life for millions worldwide.

“With our aging population, there will likely be more patients with multiple conditions, including heart failure, diabetes, and hypertension, presenting a significant challenge to health systems,” said Professor Patrick Tan, Senior Vice-Dean for Research at Duke-NUS. “Uncovering the synergistic impact of such illnesses and their underlying mechanisms is key to better understanding the complex process of heart failure and developing an effective treatment for the disease.”

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