Understanding Heart Failure wiht Preserved Ejection Fraction

More than half of all heart failure cases are now classified as Heart Failure with preserved Ejection fraction (hfpef). Unlike other forms of heart failure where the heart struggles to pump enough blood, in HFpEF the heart can pump effectively, but the heart muscle becomes stiff adn doesn’t fill properly with blood between beats. This often goes undiagnosed, and effective treatments have been elusive. HFpEF is particularly prevalent in older adults and those with conditions like hypertension,obesity,and type 2 diabetes.

The Role of CHOP in hfpef Development

Researchers, led by Nour-Eddine Rhaleb, Ph.D., FAHA, a professor of Physiology at Wayne State University School of Medicine and a senior staff scientist at Henry Ford Health, have been investigating the link between metabolic stress and heart failure. Their recent study, “Novel insights into beta cell ER stress CHOP and its role in HFpEF development,” published in Cardiovascular Diabetology, reveals a surprising connection: a stress-related protein called C/EBP Homologous Protein (CHOP) within pancreatic beta cells.

using a mouse model designed to mimic HFpEF, Dr. Rhaleb and his team, including collaborator Khalid Matrougui, Ph.D., a professor of Physiological Sciences at Old Dominion University, discovered that removing CHOP from beta cells offered meaningful protection. Mice without CHOP experienced less heart and kidney damage, lower blood pressure, and improved physical endurance, even when exposed to conditions known to trigger hfpef. This suggests that prolonged endoplasmic reticulum stress in these cells, mediated by CHOP, plays a previously unrecognized role in the development of the condition.

From Pancreas to Heart: The Cardiometabolic connection

the research highlights the “pancreas-heart axis,” demonstrating how dysfunction in the pancreas can directly impact heart health. Deleting CHOP in beta cells not only prevented heart dysfunction but also reduced inflammation, vascular problems, and metabolic stress in the mice. This suggests that targeting metabolic and inflammatory pathways originating in the pancreas could be a viable approach to preventing or treating hfpef.

Dr. Rhaleb’s team has a long history of investigating cardiometabolic disease mechanisms, building on previous work examining hypertension, endothelial dysfunction, and inflammation. This project represents an expansion of that focus, reinforcing the importance of systemic regulation in cardiovascular disease.

What’s on the Horizon?

The team is now planning several follow-up studies, including:

• Testing CHOP inhibitors and gene therapy specifically targeted to beta cells.
• Identifying the specific factors released from beta cells that contribute to heart inflammation.
• Investigating the role of CHOP in female mice, recognizing potential sex differences in HFpEF.
• translating these findings into clinical trials, particularly for patients with diabetes or prediabetes, who are at higher risk of developing HFpEF.

This research was supported in part by the National Institutes of Health award HL136456.