NHLBI Scientists Find Link Between Common Virus and Restenosis

August 29, 1996

Scientists with the National Heart, Lung, and Blood Institute (NHLBI) have found a strong link between prior infection with cytomegalovirus (CMV) and restenosis--the renarrowing of coronary arteries that commonly occurs after coronary angioplasty.

Heart disease patients whose blood showed elevated levels of antibodies to CMV prior to atherectomy--the specific angioplasty procedure used in this study--had a significantly higher rate of restenosis at six months than did patients without CMV antibodies, the investigators reported in the August 29 issue of the New England Journal of Medicine.

"This study opens up a new way of looking at the possible causes of restenosis," said NHLBI Director Dr. Claude Lenfant. "If this research is confirmed, we may be able to predict in advance which patients have the greatest risk of restenosis and, therefore, might be better served by bypass surgery rather than angioplasty," he said.

"This study also raises the possibility of new therapeutic approaches involving antiviral strategies to prevent restenosis," added Dr. Lenfant.

Infection with CMV, a member of the herpesvirus family, is common but is rarely associated with any clinical disease in people with functioning immune systems. By age 35, about half of the population has been exposed to the virus and by age 60, about 60 to 70 percent has been infected.

Of the 75 patients in the study, 49 showed evidence of prior CMV infection before undergoing an atherectomy in which artery blockages were removed by a cutting device on the end of a catheter. Six months after the atherectomy, the CMV-positive patients had a 43 percent rate of restenosis compared to an 8 percent restenosis rate in the group without prior infection. Restenosis was confirmed by coronary angiography. In this procedure, a catheter is threaded through a blood vessel to the heart. Dye injected through the catheter highlights on an x-ray any renarrowing of the artery.

Approximately 400,000 angioplasty procedures are performed each year in the U.S. Restenosis occurs in 20 to 50 percent of patients who have undergone a revascularization procedure.

The association between restenosis and CMV has been suspected for a couple of years, according to the principal investigators of the current study, Dr. Stephen Epstein, chief of the NHLBI's Cardiology Branch, and Dr. Yi Fu Zhou, visiting scientist in the Branch.

Dr. Epstein emphasized that in order to understand this association, the complex nature of restenosis must first be appreciated. Both atherectomy and balloon angioplasty procedures "injure" the vessel. The tissue responds with a healing process in which smooth muscle cells in the vessel wall are activated, proliferate, and form a type of scar tissue called "neointimal hyperplasia." In about 50 percent of patients, too much neointimal hyperplasia is produced leading to renarrowing of the artery.

In addition to hyperplasia, the artery typically "remodels" itself as a response to injury. In this process, the artery constricts--producing a narrower opening. Most cases of restenosis involve hyperplasia and remodeling and, according to Dr. Epstein, CMV may play a role in the devlopment of these responses to injury.

In a previous study conducted by Dr. Epstein, Edith Speir, and other NHLBI colleagues, CMV DNA was found in restenotic lesions. Moreover, smooth muscle cells grown from restenotic lesions expressed some of the genes of CMV indicating functional virus was present in the vessel wall. One of the gene's products -- 1E84--was able to bind to an inhibitory protein called p53. P53 prevents cells from proliferating

"By binding to p53, CMV essentially `revs' up the cell--cancelling p53's inhibitory controls so that excessive neointima (new tissue) develops," said Dr. Epstein.

Dr.Epstein and Dr. Zhou took the research a step further in a study of balloon angioplasty in rats. After angioplasties, half of the rats were infected with CMV. Rats in the CMV group had excessive neointimal hyperplasia.

"This study and the current one in heart disease patients contribute to a growing body of evidence that points to a strong association between CMV and restenosis," said Dr. Epstein. "As this research continues, we may find that cardiologists have to become virologists," he added.

To arrange an interview with Dr. Epstein, call the NHLBI Communications Office at 301-496-4236.

NIH/National Heart, Lung and Blood Institute

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