Now, scientists at the University of Pennsylvania Medical Center have shown that free-radical injury also likely occurs following heart bypass surgery or treatment for a heart attack during the critical period of reperfusion, when blood flow is restored to the heart muscle. Paradoxically, serious dysfunction or failure of the heart often occurs in this period of renewed blood supply, a fact that has frustrated doctors and surgeons caring for these patients. The findings appear in the June 3 issue of Circulation.
Using a new noninvasive, quantitative test developed at Penn and first reported last year, the researchers precisely documented sharp spikes in free-radical activity following reperfusion, suggesting oxidant stress as a cause for the heart's negative response during this phase of cardiac treatment. Such a link has been long been suspected, but has never before been conclusively demonstrated. The same test will allow the investigators to develop specific pre- operative therapies with antioxidant vitamins or drugs to see if these mitigate the process.
"Using this approach, we can rationally evaluate precise doses of antioxidant vitamins or drugs with the aim of suppressing the free-radical mechanism during reperfusion and then seeing whether there are benefits for patients," explains Garret A. FitzGerald, MD, chairman of the department of pharmacology and senior author on the study. "Once we've defined the appropriate doses, we will be able to assess whether giving these compounds before surgery leads to improved outcomes."
The test developed by FitzGerald and his colleagues use gas chromatography and mass spectrometry to measure urinary levels of a biochemical called 8-epi PGF2-alpha, which is a stable end product resulting from free-radical-catalyzed attack on arachidonic acid. Arachidonic acid is a fatty acid, a kind of specialized lipid, that is a normal constituent of cell membranes throughout the body.
Several experiments are described in the current paper, including a set of three clinical studies conducted at Mater Hospital in Dublin, Ireland, during FitzGerald's time there, and at the Hospital of the University of Pennsylvania. In the first, urinary levels of 8-epi PGF2-alpha were characterized in groups of normal volunteers. In the second, 20 healthy volunteers and 20 patients with stable angina were compared with 12 patients presenting with acute myocardial infarction who were then treated with the clot- busting drug streptokinase. In the heart-attack patients, urinary levels of 8-epi PGF2-alpha jumped immediately following this thrombolysis treatment -- i.e., during the period of reperfusion -- to more than 2-1/2 times those of the other two groups, whose levels were similar to each other. In the third clinical study, urinary levels of 8-epi PGF2- alpha were assessed in five patients prior to, during, and after elective coronary artery bypass graft surgery. During reperfusion, levels of 8-epi PGF2-alpha nearly tripled over the preoperative baseline. Twenty-four hours after surgery, levels had returned to normal.
"What we found is that, in clinical settings of reperfusion, specifically in people undergoing bypass surgery and in people given thrombylitic drugs to treat myocardial infarction, we see a pronounced elevation of this biochemical marker of oxidant stress," FitzGerald says.
Funding for the study was provided by the Wellcome Trust, the Health Research Board of Ireland, the Irish Heart Foundation, and the National Institutes of Health.
The University of Pennsylvania Medical Center's sponsored
research ranks fifth in the United States, based on grant
support from the National Institutes of Health, the primary
funder of biomedical research in the nation -- $149 million
in federal fiscal year 1996. In addition, for the second
consecutive year, the institution posted the highest growth
rate in its research activity -- 9.1 percent -- of the top
ten U.S. academic medical centers during the same period.
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