Jul 18 2007
When human hearts are injured, as during a heart attack, healthy tissue normally can't regrow.
Researchers now demonstrate in rats that a sponge-like patch, soaked in a compound called periostin and placed over the injury, can not only get heart cells to begin dividing and making copies of themselves again, but also improves heart function.
Their findings appear in the July 15 online edition of Nature Medicine.
Periostin is a component of the material that surrounds cells and is derived from the skin around bone. Though the mature heart only has tiny amounts, it's abundant during fetal heart development, and increased amounts are also made after skeletal-muscle injury, bone fracture and blood vessel injury, stimulating mature, specialized cells to begin dividing again. Led by Bernhard Kuhn, MD, in the Department of Cardiology at Children's Hospital Boston, the researchers theorized that placing periostin near the site of a myocardial infarction could help restore this growth-friendly environment and get heart tissue to regenerate.
Kuhn and colleagues at Massachusetts General Hospital and the Mount Sinai School of Medicine first stimulated mature, rod-shaped heart muscle cells (known as cardiomyocytes) with periostin in a Petri dish. About 1 percent of the cells entered the mitotic cell cycle – namely, they began dividing and replicating. (One percent seems like a small proportion, but normally the percentage is close to zero.)
“We found a small subpopulation of cells that could, with proper stimulation, re-enter the cell cycle,” says Kuhn, who was awarded the Young Investigator's Award for this research by the American College of Cardiology in March. “This finding supports the idea that differentiated cardiomyocytes can proliferate.”
Using a small patch fashioned from a sponge-like material called Gelfoam, they then moved to experiments in rats with induced heart attacks. In half the rats, a patch that had been incubated with periostin was placed over the infarct site; the others received Gelfoam only.
Twelve weeks later, the treated patches were still releasing biologically-active periostin. The periostin-treated rats had improved cardiac pumping ability, as indicated by increased ejection fraction and improved ventricular remodeling on echocardiograms, and decreased left-ventricular wall stress on catheterization. They also had less scarring of heart tissue, a reduction in infarct size and a denser network of blood vessels feeding the area. In contrast, the rats receiving Gelfoam alone showed little if any improvement.
At the cellular level, the periostin-treated group had a 100-fold increase in the number of cardiomyocytes entering the cell cycle, and grew, on average, 6 million more cardiomyocytes, far exceeding the number of dying cells. (For perspective, the average rat heart has about 20 million cardiomyocytes overall.)
Kuhn, a pediatric cardiologist, envisions using a sustained-delivery periostin patch not only to treat adults with heart attack, but also to encourage cardiomyocyte proliferation in children with congenital heart disease.
“Many patients with severe congenital heart disease eventually hit a place where the heart isn't pumping adequately,” Kuhn says. He envisions inserting the patch via a catheter, directly through the skin or during heart surgery performed for other reasons.
“The most elegant approach would be systemic therapy – finding the most relevant parts of the periostin molecule and giving it by infusion,” he says.
Mark Keating, MD, then in Children's Department of Cardiology and now at the Novartis Institute for BioMedical Research, was senior investigator on the study. Last fall, a separate study from Keating's laboratory at Children's showed that a combination of two agents – FGF1 and an inhibitor of the enzyme p38 MAP kinase – also rescued heart function in a rat model.
However, both of these agents have the potential for side effects, whereas periostin appears safe and practical to administer.
The research was funded in part by grants from the National Institutes of Health.
Children's Hospital Boston is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 500 scientists, including eight members of the National Academy of Sciences, 11 members of the Institute of Medicine and 10 members of the Howard Hughes Medical Institute comprise Children's research community. Founded as a 20-bed hospital for children, Children's Hospital Boston today is a 347-bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Children's also is the primary pediatric teaching affiliate of Harvard Medical School.