For Information Contact:
Dr. Paul Wolf
(858) 347-1882 (pager)
Cindy Butler
(858) 552-8585, ext. 7821
[email protected]
HEART ATTACK RESPONSE FINDINGS OFFER HOPE FOR NEW TREATMENTS
SAN DIEGO -- Reporting in the March 2 issue of the New England Journal of Medicine, researchers from the Department of Veterans Affairs (VA) and the University of California at San Diego (UCSD) have discovered new information about the body's molecular response to hypoxia. They successfully mapped the basic response period to these cardiac events, starting with the release of a protein (HIF-1) which stimulates the activation of blood-vessel-developing genes, and the progress of those genes in reparation of damaged tissue. The findings may lead to the development of new therapeutics that could diminish the severity of heart attacks.
"This is a dramatic finding in the heart," said study co-author and director of autopsy and hematology laboratory Paul L. Wolf, M.D, of the VA San Diego Health Care System. "Possible therapeutic implications include the development of new treatments in emergency cardiac care." Dr. Wolf is also a clinical professor of pathology at UCSD.
Hypoxia is a condition characterized by decreased oxygen levels in blood or tissue resulting from heart attack or closing of cardiac blood vessels. The focus of this study was hypoxia-inducible factor 1 (HIF-1), a protein that is expressed in response to decreased cellular oxygen levels.
When oxygen levels drop to dangerous levels, HIF-1 activates genes, such as VEGF (vascular endothelial growth factor), involved in blood vessel development. By stimulating an increase in the vascularization of an area, HIF-1 increases the flow of oxygen to that region, eliminating or diminishing the hypoxic conditions which can result in tissue death.
In order to evaluate the role of HIF-1, researchers examined heart tissue biopsies collected from 37 patients during coronary bypass surgery. Both emergency and scheduled surgery patients participated in the study. Scientists used samples taken from the damaged region of the heart and compared them to samples taken from healthy cardiac areas in the same patients.
The VA/UCSD team performed chemical studies on the heart biopsies to identify increased levels of HIF-1 and VEGF, and examined the samples for evidence of damage caused by ischemia or heart attack.
Patients who had suffered a heart attack less than 24 hours before the surgery had detectable levels of HIF-1 in their tissue, but no VEGF. Patients undergoing surgery 24 to 120 hours after heart attack tested positive for both factors. Patients who had suffered acute ischemia less than 48 hours before surgery also tested positive for both HIF-1 and VEGF. The remaining 12 patients who had no sign of heart attack or ischemia tested negative for both factors.
These findings suggest that HIF-1 is an early molecular marker for ischemia or heart attack and is initiated quickly after the onset of these conditions. VEGF activation occurs later in the response period and has a longer duration, which is necessary to ensure preservation of the heart tissue and limit the damage caused by hypoxic destruction.
The researchers are now planning to evaluate whether doctors can decrease heart attack severity and the damage done to heart tissue by increasing HIF-1 levels in cardiac patients, either pharmacologically or by gene therapy. Other researchers are investigating the effect of decreasing HIF-1 levels in cancer patients, with the intention of diminishing oxygen supply to cancer cells thereby prohibiting their growth and proliferation.
In addition to Wolf, other authors of the study include Sang H. Lee, M.D., a resident in surgery at the VA San Diego Health Care System and UCSD, Patricia A. Thistlethwaite, M.D., Ph.D., assistant professor of cardiothoracic surgery, Stuart W. Jamieson, M.B., FRCS, chief of cardiothoracic surgery at UCSD, and Ryan Escudero, B.S., and Reena Deutsch, Ph.D.
This study was funded by VA, the Nina Braunwald Career Development Award from the Thoracic Surgery Foundation, and the National Institutes of Health. VA research provides improved medical care for veterans, as well as the general population. Through its unique affiliation with medical schools, VA plays a crucial role in educating future physicians in research and clinically oriented areas.
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SPECIAL NOTE FOR REPORTERS: Paul Wolf, M.D, of the VA San Diego Health Care System and co-author of the hypoxia study is available for press interviews. He can be reached via pager at (858) 347-1882. For additional assistance, please contact Cindy Butler at (858) 552-8585, ext. 7821.
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