The findings, which emerged from an animal study by researchers at Beth Israel Deaconess Medical Center (BIDMC) and the University of Pittsburgh School of Medicine, appear in the February issue of the journal Nature Medicine.
Restenosis – reclogging of the heart's arteries – is a vexing problem for patients who have undergone balloon angioplasty for the treatment of coronary heart disease. The condition apparently develops as a result of the angioplasty itself, in which a balloon is inserted inside the artery in order to widen the clogged vessel. If, during the procedure, the cells lining the vessel are damaged, they may become inflamed and multiply, reblocking the artery. A similar problem can occur following heart transplantation, leading to chronic graft failure, the primary reason behind organ rejection.
"These situations develop when lesions appear in between two layers of cells – the vessels' endothelial cells and smooth muscle cells," explains the study's senior author, Miguel Soares, Ph.D., of the Immunobiology Research Center at BIDMC and Instructor of Surgery at Harvard Medical School (HMS). "When this happens there is extensive proliferation of the smooth muscle cells and subsequent narrowing of the blood vessel. The net result is that blood flow is decreased – and in some cases stopped altogether – potentially leading to a heart attack or to organ rejection."
The paradoxical idea that the poisonous gas carbon monoxide (CO) might prevent this dangerous turn of events is rooted in animal studies co-authored by Soares and Fritz Bach, M.D., director of BIDMC's Immunobiology Research Center and Lewis Thomas Professor of Surgery at HMS. Their earlier findings in mice that had undergone heart transplants showed that among the animals that fared best, an enzyme called heme oxygenase-1 was producing levels of carbon monoxide that were actually protecting the heart by preventing the development of the lesions.
"We thought that if somehow we could [administer] carbon monoxide locally into the injured blood vessel then we might be able to achieve a similarly positive effect," says Soares, who together with Bach, led this study in collaboration with University of Pittsburgh School of Medicine researchers Leo Otterbein, Ph.D., Brian Zuckerbraun, M.D., and Augustine Choi, M.D.
Using an experimental mouse model, the researchers discovered that by administering very small doses of carbon monoxide one hour prior to inducing a "balloon-like injury" in the carotid vessels of the mice, the development of arteriosclerotic lesions was reduced by 60 to 80 percent, compared with the animals that were not exposed to the gas. The "injury" that the researchers created resembled one which might develop in response to an angioplasty procedure.
"Among the group of control animals, it took two to three weeks for dangerous lesions to form," says Soares. "For the animals that received carbon monoxide prior to suffering the 'injury,' the lesions were suppressed altogether."
Coronary artery disease afflicts more than 6 million individuals throughout the U.S., resulting in angina (chest pain) that often severely limits their activities and puts them at risk for heart attacks, the leading cause of mortality in the United States.
"The findings reported in this study suggest that [prophylactic use of ] carbon monoxide may prove to be useful during angioplasty or heart transplant procedures," says Soares. "However, determining the best way to make use of this potent molecule in the treatment of humans will require further study."
This study was funded by grants from the National Institutes of Health, the Roche Organ Transplantation Research Foundation, Pfizer, Inc., and the American Heart Association.
Coauthors include BIDMC researchers Manabu Haga, M.D., Ph.D., Anny Usheva, Ph.D., Christina Stachulak, Ph.D., Natalya Bodyak, Ph.D., R. Neal Smith, M.D., Ph.D., Eva Csizmadia, Shivraj Tyagi, Ph.D., and Yorihiro Akamatsu, M.D., and University of Pittsburgh School of Medicine researchers Fang Liu, Ruiping Song, Richard Flavell, Timothy Billiar, MD, and Edith Tzeng.
Beth Israel Deaconess Medical Center is a major patient care, research and teaching affiliate of Harvard Medical School and a founding member of CareGroup Healthcare System. Beth Israel Deaconess is the third largest recipient of National Institutes of Health (NIH) research funding among independent U.S. teaching hospitals.
Journal
Nature Medicine