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Weill Cornell Researchers Discover Growth Factor Boosts Heart Cell Production in Damaged Hearts

Finding May One Day Help Patients Recover from Heart Attacks

New York, NY (Feb 12, 2004)

Weill Cornell Medical College researchers have discovered that injecting a growth factor called PDGF-AB along with bone marrow cells into the heart can cause new heart cells to grow in scar tissue. The research, conducted in an animal model, has just been published in the Online First section of Circulation Research (March 19 print and online issue).

The finding may one day lead to better treatments for heart attack, which can cause portions of the heart to die and form scar tissue. Many researchers are trying to use stem cells which are immature cells found in bone marrow to replace cells that are dead or damaged after a heart attack.

Dr. Jay Edelberg and colleagues report that they added PDGF-AB (platelet-derived growth factor-AB) to mouse bone marrow cells in the laboratory and doubled the number of heart cells produced by the marrow.

And the growth factor dramatically boosted the number of heart cells, known as cardiac myocytes, in rats with heart damage similar to that seen in human heart-attack patients. Myocytes are cells that can beat on their own, and when they connect with each other correctly in the heart, they beat as one unit.

When saline solution (as a control) was injected into the heart, no new myocytes formed in the scar tissue. Adding a combination of PDGF-AB and bone marrow cells doubled or quadrupled the number of cardiac myocytes in the heart compared with injection of bone marrow cells or PDGF-AB alone.

The most important thing is that we now have a new way of being able toenhance the generation of cardiac myocytes, and we can do it both in tissue cultureand in the heart, and that offers us great promise, said Dr. Edelberg,Assistant Professor of Medicine in the Greenberg Division of Cardiology at WeillCornell Medical College, and Assistant Attending Physician at NewYork-PresbyterianHospital/Weill Cornell Medical Center.

In the past 4-5 years, a number of studies have shown that, in the laboratory, stem cells in bone marrow can produce heart cells. And other studies have suggested that delivering bone marrow cells to the heart of heart attack patients may improve their outcome.

But no one has actually been able to link the two of those things together, saidDr. Edelberg.

We found that when we injected the bone marrow cells straight up into thehearts of the rats, we got a lot of blood vessel cells and a couple of cardiacmyocytes, and that was similar to what others have found, he said. Whenwe mixed bone marrow cells with the extra growth factor, we suddenly got a lotmore cardiac myocytes.

However, more study is needed before such a treatment can be tried in patients. Although the PDGF-AB boosted heart cell production, the cells seemed to grow in a disorganized fashion and did not hook up correctly with neighboring heart cells.

The bone marrow-derived cells made a lot of cardiac myocytes and that's great. The problem is we made so many of them, so quickly, they did not make all the functional connections they should have made, said Dr. Edelberg. We may be able to correct this by giving them more time or directing their growth. We have to make sure they go in all the right places at the right time.

A disorganized cluster of heart cells could contribute to heart arrhythmias, so the researchers are working on a way to get cells to grow in a specific pattern.

We think the blood vessels will give us the natural patterning, so we arefocusing a lot on that and pushing in that direction, he said.

What's more, PDGF-AB is not yet appropriate for use in patients because it can boost the growth of smooth muscle cells, a type of cell that could block arteries. This could pose a problem if given directly to heart disease patients who already have clogging of the arteries.

We are trying to develop approaches that are more specific so that it willinduce just cardiac myocytes, said Dr. Edelberg.

The researchers ultimately hope to find an oral drug that could enhance the body's natural ability to mobilize bone marrow stem cells and produce cardiac myocytes. Injecting growth factors and bone marrow cells directly into the heart is impractical for treating most heart attack patients.

The most important thing we found is that there are molecular pathwaysthat target the body's own ability to make myocytes. While you might form a fewof these cells after a heart attack, we hope to be able to make more, saidDr. Edelberg. The real goal at the end of the day is to have a way to ticklethe body's own way of doing this, so you don't have to inject cells with a needle that would be really nice.

The study's co-authors include Weill Cornell's Dr. Munira Xaymardan (lead author), Dr. Lilong Tang, Leze Zagreda, Dr. Benedetta Pallante, Dr. Jingang Zheng, Joseph Chazen, Andrew Chin, Inga Duignan, Dr. Patrick Nahirney, Dr. Shahin Rafii, and Dr. Takashi Mikawa.

The study was funded by grants from the National Institutes of Health, the Rockefeller Brothers Charles E. Culpeper Scholarship Program, American Heart Association, and the Atrovastatin Research Awards Program.2453048pubkebloom&&16:22-11- 5-2004kebloom10:53- 8-23-200402_12b_04

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