University of Florida Researchers Study Possible Genetic Link to Dysfunctional Coronary Arteries in Women

March 21, 2001

GAINESVILLE, Fla. — Cardiologists have spent decades puzzling over what causes chest pain in many of their female patients. That’s because the majority of women who complain of severe discomfort actually have coronary arteries that appear relatively normal in X-ray images of the heart.

Now University of Florida researchers report that many of these women have a genetic variation that could influence their blood vessels’ ability to function properly — a theoretical cause of their distress. They released their findings Tuesday at the American College of Cardiology’s 50th Annual Scientific Session in Orlando.

“One goal of our research is to try to determine whether there are factors in the lining of the coronary arteries that may be contributing to this chest pain syndrome,” said Dr. Daniel Pauly, an assistant professor in the division of cardiovascular medicine at UF’s College of Medicine. “These women might not have any visible narrowing of the large coronary arteries by angiography, but we’re trying to determine whether their vessels are functioning abnormally.

“This type of chest pain is a significant cause of women seeking medical attention,” he added. “And because many seek medical attention or even seek emergency room attention, it is a significant cost burden for the health-care system.”

Of those who visit a doctor for symptoms that suggest heart disease, women are much more likely than men to have coronary arteries free of obvious fatty obstructions that might account for their chest pain, Pauly said. In fact, only 30 percent or so of the women who undergo heart catheterization each year have atherosclerosis, compared with 85 percent of men who have the same procedure.

In the early 1970s, physicians labeled this condition “syndrome X.” These women often are disabled by their recurrent symptoms. Today, doctors are still not sure how best to treat them — or even diagnose their condition. A further complication: Some women who actually do have arterial blockages may never be referred for testing and treatment. That’s because some physicians may be reluctant to give the referral, knowing that angiography doesn’t always reveal any explanation for chest pain in women, said Dr. Carl Pepine, a professor and chief of cardiovascular medicine at UF.

UF researchers studied 150 women whose symptoms were so frequent and severe they were referred for heart catheterization. This procedure involves placing a catheter into the heart’s vessels to check for blockages or anatomic abnormalities that indicate heart disease. The women were participating in the $7 million federally funded Women’s Ischemic Syndrome Evaluation study, known as WISE. The multicenter trial includes collaborators from the University of Pittsburgh, the University of Alabama, the Allegheny Health Science Center and the National Institutes of Health.

During the catheterization procedure, researchers took an added step: They infused a hormone called acetylcholine through a small catheter placed in a coronary artery. Normally, the coronary vessels dilate in response to acetylcholine. A vessel that responds abnormally to acetylcholine fails to enlarge or actually constricts and is considered dysfunctional. This reaction alone is a predictor of worse cardiovascular outcomes, including death, Pauly said.

Researchers suspected that some women with dysfunctional arteries might have a genetic variation that plays a role in the abnormal response to certain naturally occurring hormones, regardless of whether they had severe obstructions characteristic of heart disease — or none at all. (In fact, 63 women had no visual evidence of heart disease at all, while 55 had only mild disease.) So the researchers drew blood samples, isolated genetic material from white blood cells and analyzed the specific sequence of DNA that codes for one site where the hormone angiotensin acts. This hormone is important for vascular tone and plays a role in hypertension.

Forty-four percent of the women who had no signs of heart disease or only mild disease had arteries that still responded abnormally to acetylcholine. And 43 percent of all participants had the genetic variation.

“What we found was that women who carried the genetic variation were much more likely to have vessels that responded abnormally to acetylcholine than women without the variation,” Pauly said. “On average, in those with the variation the artery narrowed about 8 percent when acetylcholine was introduced. But in the women without the genetic variation, the artery enlarged by about 10 percent. Our data suggest there may be a genetic reason why the coronary arteries react in the way that they do.”

The findings were particularly striking for women without obvious heart disease but who had the genetic variation. On average, their vessels constricted about 5 percent, compared with their counterparts without the genetic variation, whose arteries dilated by 16.5 percent, Pauly said.

“Dysfunctional vessels may help explain the chest pain that occurs in approximately 70 percent of women who don’t have occlusive coronary disease,” Pauly said. “And the genetic variation may help explain why some women are prone to endothelial dysfunction.”

Researchers have only recently begun to debate the effects of gender, age, hormones and other factors on heart disease. In fact, for years it was not recognized that heart disease was the leading cause of death and disability in women, who have been notoriously underrepresented in clinical trials of the condition.

“Our future research will be directed at how this genetic variation influences changes in the function of the vessels’ lining,” Pauly said. “We know it’s associated, but we don’t quite understand yet how that’s happening.”

A genetic test could someday be used as a marker for abnormal coronary artery reactivity, and this information could provide new therapeutic targets to better manage this debilitating disorder in women, Pepine said.

“This is the beginning of a line of inquiry that may ultimately determine whether this finding is useful in a clinical sense,” said Dr. Pamela Ouyang, an associate professor of medicine at the Johns Hopkins University School of Medicine. “It is too early to tell whether determining the genetics will help identify women such as these or provide any information on prognosis for these women, or whether they will respond differently to medical treatments.”