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Study Shows GHRH-Agonists Can Activate Cardiac Repair After Myocardial Infarction

1/18/2010

Despite major therapeutic advances, congestive heart failure remains a leading cause of death and disability. There is currently no therapy that fully reverses heart failure and/or left ventricular (LV) dysfunction, leaving physicians with a great need for viable treatments.

A team of physician-scientists from the University of Miami Miller School of Medicine, including a Nobel Laureate, have demonstrated that growth hormone-releasing hormone agonists (GHRH-A) can stimulate major recovery of the heart injured by a heart attack. GHRH is a master regulator of growth hormone that is produced by the brain. Joshua M. Hare, M.D., Louis Lemberg Professor of Medicine in the Cardiovascular Division, was the principal investigator of the study that included fifteen researchers, among them co-senior author Andrew V. Schally, Ph.D., M.D.h.c., D.Sc.h.c., the 1977 Nobel Prize winner for Physiology or Medicine, Distinguished Medical Research Scientist of the Department of Veterans Affairs, distinguished professor in the Department of Pathology at the Miller School of Medicine. Their work is published in the January 18 online edition of the Proceedings of the National Academy of Sciences.

While there has been major interest in the role of growth hormone (GH) and insulin-like growth factor 1 (IGF-1) in the heart, only recently have scientists appreciated that the major regulator of this pathway, GHRH, has activity within the heart. This finding has major significance because GHRH avoided many side effects related with the use of GH-releasing peptides and compounds that cause the secretion of GH. “This discovery is a major step forward in harnessing a new therapeutic opportunity for heart disease that avoids unwanted side effects,” says Hare.

For the study, the team used a synthetic compound which stimulated the GHRH receptor. This compound, synthesized by the Schally team, is a highly potent analogue of GHRH itself and could be harnessed to treat patients in the future.

Rosemeire M. Kanashiro-Takeuchi, Ph.D., first author, post doctoral associate in the Cardiovascular Division, and the team of investigators tested the hypothesis that GHRH-A has a favorable cardiac effect, diminishing the size of the infarct area and improving function following myocardial infarction. Working with animal models, the scientists measured the impact of GHRH-A synthesized in Dr. Schally’s laboratory versus rat recombinant GH (rrGH) on cardiac function and structure following a myocardial infarction. Echocardiography indicated that treatment with GHRH-A reduced the left ventricular dysfunction, and increased ejection fraction that had been reduced by a heart attack.

“What we found,” says Kanashiro-Takeuchi, “is that GHRH-A has a protective role on the cardiac structure after acute myocardial infarction. There was clearly an improvement in the cardiac function and structure in animals that received GHRH-A, compared to those that received rrGH.” In addition, the study also indicated a reduction in infarct size and cardiac fibrosis, one of the main biologic determinants of poor prognosis in heart failure.

Schally, who has dedicated much of his research to studying the effects of agonists and antagonists of growth hormone-releasing hormone, said the results “indicate the possible therapeutic importance of growth hormone-releasing hormone agonists in cardiology. New, more potent GHRH agonists should be made at UM.” The Nobel Prize winner has published a number of studies detailing the role of GHRH in cancer.

For now, scientists don’t have all the answers about the mechanisms underlying the differences between GHRH and GH effects. Hare and Schally plan a major initiative to study this finding in detail so as to optimize the translation of this finding to the clinic. “We next want to focus on learning more about the precise mechanisms of GHRH and to develop a program aimed at testing this finding in patients with heart disease,” says Hare.