Dec. 28, 2001 Transplantation of embryonic stem cells can help repair injured heart muscle and improve cardiac function following heart attacks and the development of congestive heart failure (CHF), according to the results of an animal study conducted at Beth Israel Deaconess Medical Center.
The findings raise the possibility of a future treatment option for CHF, which diminishes the heart's pumping ability, leaving patients fatigued, often to the point of debilitation. Nearly 5 million people in the U.S. suffer from CHF. "Congestive heart failure is the last major area of cardiac medicine that remains without a readily available effective treatment," explains BIDMC cardiologist James Morgan, M.D., Ph.D., Herman Dana Distinguished Professor of Medicine at Harvard Medical School and co-author of the study, which appears in the January issue of the Journal of Applied Physiology. "The statistics on this condition are troubling – even with optimal medical treatment, a person’s chances of surviving for five years with heart failure is only around 50 percent."
Heart failure develops when the heart stops pumping effectively due to the destruction of muscle cells, known as cardiomyocytes. Damage inflicted during a heart attack – or myocardial infarction – causes massive loss of cardiomyocytes, resulting in ventricular dysfunction. Although heart transplantation has proven very successful in the treatment of CHF, notes Morgan, only a small fraction of organs – about 2,000 – are actually available for transplant.
Heart disease has been a focus of stem cell research for a number of years, with promising results shown in mice which were treated with adult stem cells. However, previous research utilized fully differentiated muscle cells and had not tested embryonic stem cells in heart muscle that had already been damaged. Morgan, together with the study's lead author Yong Fu Xiao, M.D., Ph.D., of the Department of Cardiology at BIDMC and colleagues, designed this study to determine whether implanted ES cells, derived from early embryos, could survive in injured heart muscle and improve cardiac function following heart attack. ES cells are pluripotent, meaning they have the ability to differentiate into many cell types.
To answer these questions, the researchers surgically induced myocardial infarctions in two groups of rats, one which was treated with a culture of ES mouse cells, and one treated with a "sham" culture. Prior to transplantation, the cultured ES cells were "marked" with green fluorescent protein and suspended in a medium. ES cell transplantation was then performed within 30 minutes of the MI induction; injections were made at three separate sites in the heart, one directly where the MI took place, and two in the heart muscle bordering this area. The control group of rats received an equivalent amount of medium – free of ES cells – at the same three sites as in the damaged heart.
Six weeks after transplantation, the researchers examined both groups of rats and found that MI damage was reduced in the animals that had been implanted with ES cells. The ES group also showed significant improvement in left ventricular function, or pumping ability. The animals in the control group did not show any improvement.
"Our results demonstrate that the engrafted ES cells survived in damaged heart muscle," says Xiao, who is Assistant Professor of Medicine at Harvard Medical School. Calculations showed that the number of "marked" cells had successfully replicated, with 7.3 percent growth of the total number of enzymatically isolated single cardiomyocytes. Most important, these cells were now rod-shaped with clear striations that mimicked heart muscle cells.
"These data strongly suggest that cardiogenesis – growth of new cardiomyocytes – occurred in the damaged heart muscle following ES cell transplantation," says Xiao. Measurements of the heart's left ventricular systolic pressure and diastolic pressure – which reflect the heart's pumping ability – also demonstrated improved cardiac function in the rats with ES cell transplantation. The control group showed no such positive results.
"The results were a dramatic improvement," adds Morgan. To illustrate his point, he explains that CHF patients are typically divided into four classes of severity, with "one" meaning no symptoms except under extremely strenuous conditions and "four" being out of breath just crossing a room. "If this procedure had been performed in human patients, I would expect the improvement would be such that they would move from one class to another."
One of the advantages of using ES cells over other types of stem cells is to reduce immunoreactivity. "Because ES cells have fewer surface antigens, they're unlikely to trigger immunoreaction, in which the body rejects the foreign ‘intruder,’" Morgan explains. This is particularly important to heart failure patients, the majority of whom are too sick to receive immunosuppressive drugs.
"There's a 1 percent incidence of CHF among the population at large, and that figure rises to 10 percent among elderly patients," says Morgan, adding that approximately half of these cases result from heart attacks. "A new therapy that could replace the unwieldy multiple medications currently prescribed for CHF patients could produce a dramatic improvement in patients' quality of life."
Study co-authors include Jiang-Yong Min, M.D., Yinke Yong, M.D., Ph.D., Kimber L. Converso, RDCS, and Lixin Liu, M.D., of Beth Israel Deaconess Medical Center, and Qin Huang, M.D., Ph.D., of Holy Family Hospital and Medical Center, Methuen, Mass.
The study was funded with support from the National Institutes of Health and the American Heart Association.
Beth Israel Deaconess Medical Center is a major patient care, research and teaching affiliate of Harvard Medical School and founding member of CareGroup Healthcare System. Beth Israel Deaconess is the fourth largest recipient of National Institutes of Health research funding.
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