Growth factor may determine who grows new blood vessels that protect against heart attacks

August 02, 1999

DALLAS, August 3 -- The ability of some individuals to develop new coronary arteries that help to re-route blood flow around artery blockages might be the result of their ability to produce a growth factor, a protein that helps to generate new blood vessels, according to a paper in Circulation: Journal of the American Heart Association.

Heart specialists have long been puzzled by the fact that some patients are able to form networks of new blood vessels, called coronary artery collateral beds, whereas other patients are not. A strong collateral blood supply can help reduce the severity of heart attacks, or even prevent them, experts say.

A team of Israeli researchers has identified a possible explanation for this phenomenon. They found that the ability to grow the new vessels in the heart strongly correlates with how much vascular endothelial growth factor (VEGF) a person produces when the heart muscle receives insufficient oxygen -- a condition called hypoxia.

The Israeli team studied 51 patients, all of whom had a blockage of 70 percent or greater in at least one coronary artery. The patients underwent diagnostic angiography -- an X-ray that shows where a narrowing has occurred in an artery. These angiograms also showed researchers the extent of collateral blood supply in each patient. The patients were then divided into three groups depending on the extent of their collateral beds. The levels of VEGF were also tested.

The researchers found no significant difference in the patients' ability to produce VEGF when cells received normal levels of oxygen. However, the patients differed markedly in VEGF production when the cells got insufficient oxygen. Those patients who produced the most VEGF during hypoxia also had the most extensive collateral blood supply.

This correlation of VEGF production with the number of collateral blood vessels remained even after researchers considered factors that might adversely affect the extent of collateral-vessel growth. These variables include age, gender, high blood pressure, high blood cholesterol levels, smoking, diabetes and prior efforts to increase the blood flow in the heart, through bypass surgery or balloon angioplasty.

"We are now working out the molecular mechanisms that will allow for the development of a drug that would increase VEGF production in those patients who produce low levels of it and allow them to grow their own collateral blood vessels," says the study's senior author Andrew P. Levy, M.D., Ph.D., of the Rappaport Faculty of Medicine of Technion-Israel Institute of Technology.

The team has already developed a simple laboratory test to identify whether a person produces small or large amounts of VEGF when the heart cells get insufficient oxygen.

Coronary collateral vessels were once thought to pre-exist in the heart and open only to allow blood to flow through them when needed. However, scientists have learned in recent decades that the collateral beds are actually new vessels that grow in the areas of the heart that are deprived of life-sustaining oxygen because of reduced blood flow.

The study findings shed new light on the formation of collateral beds and suggest that certain heart patients might benefit from treatments that enhance their ability to grow new blood vessels. One approach might be gene therapy or a treatment that involves giving people who produce low levels of VEGF a genetically engineered version of the growth factor, according to the researchers.

If further research confirms the study's findings, physicians could easily identify patients unlikely to grow collateral arteries on their own. Such people would be expected to do poorly with currently available medical therapies and be the most likely to benefit from gene therapy or growth factor therapy, says Levy.

"This would allow us to develop oral medications that will enable individuals who produce low levels of VEGF during hypoxia to respond better."

The findings may also have implications for treating several other diseases. Cancerous tumors, for example, do not grow unless they develop blood vessels, which 'feed' the tumor. Diabetic retinopathy, which can result in blindness, is caused by the growth of abnormal blood vessels in the eye's retina.

"One would propose that in patients with tumors, those who produce higher levels of VEGF (high responders) might have more aggressive tumors, which could spread early," Levy said. "Patients with diabetes who are high responders may develop diabetic retinopathy earlier than low responders." If so, patients with both diseases might be helped by treatments that reduce their ability to produce VEGF.

Scientists don't yet know whether the vast differences in VEGF production are due to an as-yet-unidentified molecule in the patient's blood plasma or to differences in the activity of their cells. If the answer proves to be a difference in cellular activity, it could result from several things, including environmental factors or genetic influences.

Dr. Levy and his colleagues said recent laboratory experiments using breast cancer cells lends credence to the theory that genes are the key factor in determining the degree of VEGF activity.

Co-authors include: Aylit Schultz, B.A.; Lena Lavie, D.Sc.; Irit Hochberg, B.S.; Rafael Beyar, M.D., D.Sc.; Tzachi Stone; Karl Skorecki, M.D.; Peretz Lavie, Ph.D.; and Ariel Roguin, M.D.
-end-


American Heart Association

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