In a preclinical study, researchers at the University of Miami Miller School of Medicine and at the Miami VA Hospital have shown that growth hormone-releasing hormone agonist (GHRH-A) could potentially help patients suffering from heart failure with preserved ejection fraction (HFpEF), which currently has few treatments. The research was published this month in the journal PNAS.
“We had two important findings in this study,” said Joshua Hare, M.D., principal investigator on the study and director of the Miller School’s Interdisciplinary Stem Cell Institute. “First, we showed that GHRH-A could help patients with this particular type of heart failure. But equally important, we developed an animal model that will allow us to test GHRH-A and other HFpEF therapies.”
For many years, heart failure was mostly associated with reduced ejection fraction (HFrEF), which measures the amount of blood that leaves the heart as it contracts. More recently, researchers and clinicians have learned that HFpEF is an equally serious condition and may affect more people. In HFpEF (also called diastolic heart failure), the heart’s left ventricle fails to pump blood properly. Unfortunately, medications designed for HFrEF patients fail to help people with HFpEF.
Preclinical model was needed
This recognition has driven new research to find HFpEF treatments, and GHRH-A has shown great potential. However, before they could adequately test it, the researchers needed to develop a good HFpEF large animal model. A dearth of good preclinical HFpEF models had been holding researchers back.
To test GHRH-A in the new model, Dr. Hare worked closely with Andrew Schally, Ph.D., M.D.H.C., D.Sc.H.C., who was awarded the Nobel Prize for Physiology or Medicine in 1977 for his work unraveling key endocrine pathways. Over his career, Dr. Schally showed that GHRH, traditionally thought to work only in the brain, also can play an important role as a molecular signaling protein throughout the body.
“In 2010, we started studying GHRH and synthetic agonist versions of GHRH discovered by the Schally lab in the heart,” Dr. Hare said. “Working with a group in Italy, we and other research groups found there are GHRH receptors in the heart, and we've been working ever since to understand what happens when we stimulate those receptors.”
In the blinded, randomized study, animals that received the synthetic versions of GHRH showed restored diastolic function in the left ventricle. The therapy reduced inflammation, inhibited programmed cell death, reduced fibrosis and stimulated cardiac progenitor cells — immature heart cells that can differentiate into and replace damaged tissue.
Targeting human trials
These are encouraging results, and the research team plans to continue their work on GHRH-A, starting with additional preclinical work and eventually moving into human trials.
“The next step would be more studies in animal models to better understand the actual molecular pathways,” said Angela Rieger, M.D., M.Sc., the study’s first author, “and then we want to take this into humans. There are many people suffering with HFpEF, and nothing works for them. It’s a huge unmet medical need.”
Other Miller School authors of the study include Luiza L. Bagno, Ph.D., Alessandro Salerno, Ph.D., Victoria Florea, M.D., Jose Rodriguez, M.D., Marcos Rosado, Darren Turner, Raul A. Dulce, Ph.D., Lauro M.Takeuchi, Rosemeire M. Kanashiro-Takeuchi, D.V.M., Peter Buchwald, Ph.D., Amarylis C.B.A.Wanschel, Ph.D., Wayne Balkan, Ph.D., and Ivonne H. Schulman, M.D.
This study was funded by NIH Grants 1R01 HL107110, 1R01 HL13735 and by The Lipson Family (to J.M.H.). J.M.H. is also supported by NIH Grants 5UM1 HL113460, 1R01 HL134558, 5R01429 CA136387, and HHSN268201600012I; Department of Defense Grant W81XWH-19-PRMRP-CTA; and The Soffer Family and Starr Foundations.