Individuals With A Common Gene Variant Appear More Likely To Have Blockages In Artery "Stents"

June 25, 1997

DALLAS, July 1 -- Doctors may have a way to identify people with heart disease whose coronary arteries will become obstructed again after they have been propped open with tiny metal tubes called stents. The clue may be found, French scientists say, not in the individuals' diseased blood vessel but in their genes, according to a report in today's American Heart Association journal Circulation.

Stents are implanted after balloon angioplasty, which is used to restore blood flow to the heart in people whose blood vessels have been blocked by cholesterol-laden plaque. Stents have reduced the number of relapses following angioplasty, but blockages still occur after up to 20 percent of implantations of the "Slinky"-type coils, researchers say. When relapses occur, coronary bypass or angioplasty may be needed to prevent heart attack and death.

The researchers found that patients with one readily identifiable variant of what's known as the "ACE gene" are up to four times more susceptible to the vessel-reclogging problem, called restenosis, after a stent installation, compared to other individuals having the least active form of the gene. An expert in genetics research calls the report a "remarkable account of gene-environment interaction." If confirmed, writes Klaus Lindpaintner, M.D., in a Circulation commentary, "These developments herald a new and coming era of disease management where drugs are custom-tailored to the genetic profile of individual patients, resulting in a higher rate of treatment success and a lower incidence of side effects.

"And the findings are likely to attain direct practical importance in clinical medicine by providing a tool for risk assessment and prognostication."

But these "intriguing" results first need to be validated in larger trials, cautions Lindpainter, a cardiologist at Brigham and Women's Hospital, Boston, and a geneticist and director of cardiovascular research at F. Hoffman-La Roche Pharmaceuticals in Basel, Switzerland.

The scientists, whose report appears in Circulation, are from the Institut Pasteur and Hôpital Cardiologique in Lille, France. They studied 146 consecutive individuals who had the flexible metal scaffolds placed in heart vessels after balloon angioplasty. In a six-month follow-up, 31 of the patients had recurring blockages, defined as obstruction of more than 50 percent of treated vessel's opening through which blood flows. Genetic testing showed that a disproportionately large number of the 31 carried the "DD" variant of the ACE gene, compared to the number with "ID" and "II" forms.

The investigators, led by Carole Amant and Michel E. Bertrand, M.D., say the relative risk of restenosis after stenting appears to be proportional to the number of D variants (one or two) carried by an individual. The researchers say their results show that the ACE gene pattern "is an independent predictor of the degree of late [vessel diameter] narrowing after coronary stenting."

Everyone has one of the ACE gene combinations -- DD, ID or II (pronounced "eye-eye") -- scientists explain. The gene encodes for angiotensin converting enzyme, or ACE.

The enzyme "turns on" angiotensin, a protein that in its activated state plays a role in the disease process such as high blood pressure and other disorders including heart and kidney failure. Drugs called ACE-inhibitors, which reduce the enzyme's activity, are effective in treating these disorders.

Earlier studies have shown that individuals with the DD form of the ACE gene have higher circulating levels of ACE. Amant, Bertrand and their co-workers speculate that increased activity of ACE may account for the higher degree of blood vessel wall thickening seen in those who have the DD variant.

But results of research testing this concept have been mixed, the French scientists and Lindpaintner agree. Animal studies that suggested ACE-inhibitors could control the frothy buildup of blockages after an artery is damaged by a balloon did not pan out in clinical trials in humans.

Investigators believe there may be a biological link between the specific type of cellular accumulation that clogs arteries following stent placement and the activity of angiotensin converting enzyme. This process of reacting to a "foreign body"-- the metal stent -- may differ, the scientists think, from the cellular changes in the artery wall (called "remodeling") that result in wall thickening and vessel narrowing after conventional balloon angioplasty, which doesn't include implanting a stent.

While many questions remain to be resolved by additional studies, advances in DNA analysis and gene-mapping make future developments in the field highly promising, Lindpaintner says. Techniques allowing direct testing of DNA have caused a "paradigm shift," he notes.

One result of the most recent research findings, Lindpaintner says, is that doctors may soon be able to identify individuals with the genetic tendency toward clotting inside coronary stents, then take additional preventive steps to help them remain free of blockages, such as through the use of "radioactive" stents. These experimental coils have been pre-treated with a low-grade radioactive material that in early tests has shown promise in keeping stents free of new blockages while remaining otherwise harmless.

Co-authors of the study with Amant and Bertrand are Christophe Bauters, M.D.; Jean-Christophe Bodart, M.D.; Jean-Marc Lablanche, M.D.; Gilles Grollier, M.D.; Nicolas Danchin, M.D.; Martial Hamon, M.D.; Florence Richard, M.D.; Nicole Helbecque, Ph.D.; Eugene P. McFadden, M.R.C.P.I.; and Philippe Amouyel, M.D., Ph.D.

Circulation is one of five journals published in Dallas by the American Heart Association.

Media advisory: Dr. Bertrand can be reached by calling 33-3-20-44-5302. Dr. Lindpaintner can be reached in Boston at (617) 732-8173 or in Basel, Switzerland, at 011-41-61-688-0254. Dr. Amouyel can be reached by calling 33-320-87710. Reporters may call (214) 706-1173 for copies of the journal report and editorial.

American Heart Association

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