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Rescuing injured hearts by enhancing regeneration

eart function, as measured on echocardiograms: their hearts pumped almost as well as the hearts of uninjured rats. They also had reduced thinning of the cardiac wall and the least amount of scarring.

Rats receiving only the p38 MAP kinase inhibitor had increased proliferation of cardiomyocytes, but no longer had improved heart function at three months. Those receiving only FGF1 maintained their functional improvement, but did not show as much cell proliferation as those receiving the p38 MAP kinase inhibitor. Rats receiving both agents had the greatest improvements in both cell proliferation and heart function.

The findings suggest that getting cardiomyocytes to replicate is not enough to rescue heart function, but that angiogenesis is also needed, Engel says.

"Regeneration is not just making more cardiomyocytes," he says. "Cardiomyocytes need a blood supply and oxygen to survive. FGF1 did not have a great effect on cell proliferation, but we found it was providing a new blood supply. If you just inhibit p38 MAP kinase, you don't get blood vessels."

Two important steps are needed to turn these findings into a treatment, Engel says. First is to show that the treatment works when not given immediately after the heart attack, since many people sustain progressive damage to their hearts from repeated minor infarctions. In this study, rats were treated soon after injury.

Second is the need to develop a safe delivery method. Because FGF1 stimulates angiogenesis, it has the potential for serious side effects if it goes to places other than the heart, possibly promoting tumor growth, for example. And the p38 MAP kinase inhibitor has been shown to damage the liver.

"Every treatment trying to induce proliferation of cardiomyocytes also carries a risk of inducing tumor growth, and thus you have to limit the time and location of treatment," Engel adds.

One possibility is to inject smaller doses of th
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Contact: Anna Gonski
anna.gonski@childrens.harvard.edu
617-355-6420
Children's Hospital Boston
9-Oct-2006


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