July 9, 2007 We've all wondered how a seemingly healthy person can actually be at high risk for heart disease or a heart attack. Now researchers have uncovered a new clue to this mystery. The culprit: myeloperoxidase (MPO), a protein secreted by white blood cells that both signals inflammation and releases a bleach-like substance that damages the cardiovascular system.
Although MPO is intended to kill harmful bacteria, it may instead inflame the body's arteries and cripple protective substances in the blood, according to a study published in the July 10, 2007, issue of the Journal of the American College of Cardiology (JACC). As a result, long before conventional risk factors set off alarms, elevated MPO levels signal that harmful plaque has been building up.
"We were surprised to find that many years before a cardiovascular event actually occurs, MPO is increased," said Matthijs Boekholdt, M.D., Ph.D., a resident in cardiology at Academic Medical Center in Amsterdam, the Netherlands. "This could open up completely new areas of research and diagnosis. As we learn more about these processes, we hope to be able to identify 'vulnerable blood' as a reliable tool for detecting vulnerable patients."
Not only does MPO change low-density-lipoprotein (LDL) cholesterol into a harmful oxidized form that can cause atherosclerosis, the "bleach" produced by MPO damages the arteries directly, causing cell death and erosion of the arterial lining, a process that can create unstable plaques. MPO also hampers the protective effects of high-density-lipoprotein (HDL) cholesterol and reduces the availability of nitric oxide, a natural chemical that relaxes the blood vessels.
Earlier studies in patients with chest pain and heart disease have shown that elevated levels of MPO identify those at highest risk for a heart attack. "The novelty of the present study is that it is the first large-scale study to examine the relationship of MPO to cardiovascular risk in apparently healthy individuals," Dr. Boekholdt said.
For the study Dr. Boekholdt and colleagues recruited healthy people living in Norfolk, United Kingdom, between 1993 and 1997, as part of a larger community-based research program known as the European Prospective Investigation Into Cancer and Nutrition (EPIC). They took baseline blood samples from each participant and froze the samples for future analysis.
After an average of eight years, 1,138 EPIC-Norfolk participants had been admitted to the hospital or died from the effects of coronary artery disease (CAD), including heart attack. The researchers matched these patients with study participants who remained healthy throughout the follow-up period, selecting those of the same gender and similar ages and enrollment times.
The average blood levels of MPO were significantly higher in those who developed heart disease than in those who remained healthy. In fact, when MPO levels were divided into four groups, patients in the highest fourth were 1.49 times as likely as those in the lowest fourth to develop CAD or have a heart attack. When traditional risk factors--blood pressure, LDL and HDL cholesterol levels, body mass index, smoking and diabetes--were taken into account, an MPO level in the highest fourth increased the risk of heart disease by 1.36 times.
Equally important, elevated MPO levels signaled increased risk even in those with acceptable levels of LDL cholesterol, HDL cholesterol or C-reactive protein, a widely acknowledged marker of inflammation.
"MPO levels help to identify individuals at increased risk for CAD when traditional risk screening fails," Dr. Boekholdt said.
The search for blood tests to help identify patients at risk for heart attack is a very important one, said Christopher Cannon, M.D., F.A.C.C., who did not participate in the study and is an associate professor of medicine at Harvard Medical School, Boston, MA. "One fascinating aspect of this study is that this marker of inflammation precedes by nearly a decade the development of clinical coronary disease," he said. "This suggests MPO could be used to catch the disease in a very early stage and help in true prevention of CAD.
"Another interesting aspect of MPO is that it may be a marker for unstable plaque. Even more than the number or severity of coronary plaques, we want to know the risk of plaque rupture, and this evolving new marker may help in that regard. More study is needed, but among the hundreds of markers tested to date, MPO looks like a "keeper" that will one day become part of clinical care," Dr. Cannon said.
Researchers are continuing to assess the value of MPO in different patient groups as well as in relation to other biomarkers, Dr. Boekholdt said. Key questions include whether, and under what circumstances, MPO should be added to the laboratory tests used to screen for cardiovascular disease, and whether blocking MPO could prevent cardiovascular disease.
The EPIC-Norfolk study is supported by program grants from the Medical Research Council UK and Cancer Research UK, with additional support from the European Union, Stroke Association, British Heart Foundation, and the Wellcome Trust. Some of the measurements in this study were supported by Wyeth. One of the study's authors, Stanley L. Hazen, M.D., Ph.D., is named as a co-inventor on pending patents filed by the Cleveland Clinic Foundation relating to the use of myeloperoxidase as a biomarker for cardiovascular disease.
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