Finding Could One Day Be Used To Halt Heart Attack Damage in Patients
Mar 23, 2004
Injecting a combination of growth factors can protect the heart during a heart attack, NewYork-Presbyterian Hospital/Weill Cornell Medical Center researchers report in this month's issue of the Journal of Experimental Medicine.
The finding, in an animal model, may one day help keep heart cell damage to a minimum after a heart attack.
We think this has promise in terms of being able to arrest cell death around the time of heart attack, said Dr. Jay Edelberg, Assistant Professor of Medicine in the Greenberg Division of Cardiology at Weill Cornell Medical College, and Assistant Attending Physician at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. This is a whole new way of suppressing cell death after a heart attack.
Dr. Edelberg and his colleagues specifically set out to study a growth factor known as PDGF-AB, or platelet-derived growth factor. It was known that injecting the growth factor into the hearts of young rats can help protect against heart attack-like damage, but that this protective effect wanes as rats age.
We asked what exactly does PDGF do? How is it cardioprotective? said Dr. Edelberg. We knew that the young heart got more benefit than the older heart, so we decided to deliver it to the hearts of both young and old rats there must be something that is different.
In a series of experiments, they found that PDGF-AB triggers the production of two other proteins, vascular endothelial growth factor (VEGF) and angiopoietin (Ang)-2, in the heart cells of young rats. This did not occur in heart cells from 2-year-old rats, which would be in old age, given the 2-to-5-year lifespan of the average rat.
PDGF-AB, VEGF, and Ang-2 are thought to work together to promote the growth of new blood vessels (angiogenesis) after a heart attack, and possibly stimulate immature heart cells to replace dead and dying cells.
Additional experiments showed that PDGF-AB boosted heart cell receptors that bind to VEGF and Ang-2. The receptors were twice as common in young hearts versus old hearts treated with PDGF-AB.
What was very exciting was that PDGF was not just able to induce these growth factors, but could also induce the receptors for these growth factors, said Dr. Edelberg.
Injecting all three factors into the heart during a heart attack drastically reduced the area of dead and dying tissue in the heart. The combination cut the area of cell damage by 40% in young rats and 24% in old rats. Adding VEGF and Ang-2 to the mix helped older rats get the same benefit from PDGF-AB as younger animals.
We've commonly thought of these growth factor pathways as pro-angiogenic -- basically they have the ability to produce blood vessels quickly. But what we also found is that they have an important action in terms of suppressing cell death, said Dr. Edelberg. When we gave these factors in combination right at the time of a myocardial infarction a heart attack with no time to form new blood vessels, they markedly suppressed the death of the treated tissue.
We don't envision people being injected with these compounds in an ambulance ride on the way to the hospital, he said. Obviously what we need is something we can give orally or in an IV, as opposed to right into the heart.
The real goal is to be able to identify novel compounds that can do this that would be cardiac-specific, he said. PDGF has other actions and may increase smooth muscle cells, which is just what you don't want in the patient who's had a heart attack, emphasized Dr. Edelberg.
People have tried to inhibit apoptosis, or programmed cell death, which occurs after a heart attack, and that's an exciting avenue of research, he said. What our study shows is that some of the body's natural growth factor pathways act along those lines. What we are doing is just increasing their delivery to a much higher level to suppress that death, which hopefully allows the body to repair the cells and possibly create new heart cells.
The co-authors of the study include Munira Xaymardan (lead author), Jingang Zheng, Inga Duignan, Andrew Chin, Jacquelyne Holm, and Victoria Ballard.
The study was funded by the National Institutes of Health, and an American Federation for Aging Research-Paul Beeson Physician Faculty Scholar in Aging Research Award.
Cornell University has filed for patent protection on these findings and is actively seeking partners with which to develop new medicines based on them.