Heart failure is a common cause of death globally. A significant and growing portion of those with heart failure have what is known as heart failure with preserved ejection fraction (HFpEF). HFpEF is characterized by normal ejection fraction- the amount of blood leaving the heart at each squeeze, yet profound diastolic dysfunction, cardiac hypertrophy, and fibrosis. This means that while the heart can pump normally, its muscles are too stiff to refill its chambers with blood.
The clinical manifestations of HFpEF are still poorly defined. Given its increasing prevalence, the condition is currently regarded as the most significant challenge in cardiology today.
In the current study, researchers observed how stress from hypertension affected the hearts of lean and diabetic/ obese mice. While the lean mice developed heart failure with reduced ejection fraction (HFeEF), typically seen in hypertensive patients, the obese models developed HFpRF. This revealed that a combination of stressors triggers the condition and that such mice may be a suitable model for further study.
Next, the researchers analyzed the heart cells of the mice using advanced single-cell RNA-sequencing technologies. They ultimately found that glucagon signaling became excessively active in the heart cells of obese mice.
Following this, the team tested a drug that blocks the glucagon receptor on mouse models of HFpEF. This generated significant improvements in heart function, including reduced heart stiffness, enhanced relaxation, improved blood-filling capacity, and overall better heart performance.
"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,” said first author of the study, Assistant Professor Chen Gao from the Department of Pharmacology, Physiology and Neurobiology at the University of Cincinnati College of Medicine, in a press release.
The researchers now hope to work with clinical partners to carry out clinical trials to test glucagon receptor blockers in human patients with HFpEF. If these trials prove successful, the drug could become among the first effective treatments for HFpEF.
Sources: Science Daily, Circulation Research