Heart failure with preserved ejection fraction (HFpEF), a challenging form of heart disease, may have a new treatment avenue according to a recent study by Duke-NUS Medical School and collaborators. The research, published in Circulation Research, reveals that increased glucagon activity in diseased heart cells contributes to HFpEF, and blocking this activity with a drug significantly improves heart function in pre-clinical models.
Unveiling the Role of Glucagon in HFpEF
HFpEF affects millions worldwide, characterized by the heart's inability to properly relax and refill with blood despite normal pumping function. This condition is often associated with older adults and those with hypertension, obesity, and diabetes. The study addresses a critical gap in understanding how these combined stressors contribute to HFpEF progression.
Professor Wang Yibin, Director of the Cardiovascular & Metabolic Disorders Programme at Duke-NUS and senior author of the study, explained, "Under stress conditions such as high blood pressure and metabolic disorders like obesity and diabetes, we found that glucagon signalling becomes excessively active in heart cells. This heightened activity contributes to the development of heart failure with preserved ejection fraction (HFpEF) by increasing heart stiffness and impairing its ability to relax and fill with blood."
The research team employed advanced single-cell RNA-sequencing to analyze gene expression in heart cells, revealing that genes driving glucagon activity were highly active in obese models of HFpEF.
Glucagon Receptor Blockers: A Potential Therapy
Based on these findings, the team tested a glucagon receptor blocker in a pre-clinical HFpEF model. The results showed significant improvements in heart function, including reduced stiffness, enhanced relaxation, improved blood filling capacity, and overall better heart performance.
Assistant Professor Chen Gao from the University of Cincinnati College of Medicine, the study’s first author, noted, "Our study shows strong evidence that a glucagon receptor blocker could work well to treat HFpEF. Repurposing this drug, which is already being tested in clinical trials for diabetes, could bypass the lengthy drug development process and provide quicker and more effective relief to millions of heart patients."
Implications and Future Directions
HFpEF accounts for approximately half of all heart failure cases, affecting an estimated 64 million people globally. Current treatments are limited, making the discovery of a new therapeutic target and potential drug repurposing a significant advancement.
Professor Patrick Tan, Senior Vice-Dean for Research at Duke-NUS, commented, "With our ageing population, there will likely be more patients with multiple conditions, including heart failure, diabetes and hypertension, presenting a significant challenge to health systems. 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."
The researchers are now planning clinical trials to evaluate the glucagon receptor blocker in HFpEF patients, potentially offering a new and effective treatment for this debilitating condition.
