June 14, 2007

Expanding the Role of MPO Testing

Marker Shows Prognostic Potential for Mortality after AMI

By Julie McDowell

When PrognostiX’s (Cleveland, Ohio) CardioMPO assay was cleared by the FDA in 2005, clinicians and laboratorians were given yet another diagnostic tool for the risk assessment of major adverse cardiac events in patients presenting with chest pain. Since then, there have been numerous studies done on other applications for the myeloperoxidase (MPO) marker, and recently, research has suggested that the marker has prognostic potential. This issue of Strategies examines a recent study indicating that high levels of MPO are a risk factor for long-term mortality, and what this might foretell about future applications of this marker.

In addition to its approved use as adverse event predictor in patients presenting with chest pain, studies show that high levels of the marker MPO are linked to many phases of atherothrombosis, according to David Morrow, MD, MPH, Assistant Professor of Medicine at Harvard Medical School and an Associate Physician in the Division of Cardiovascular Medicine at Brigham and Women’s Hospital (Boston, Mass.). This encompasses early development of cardiac inflammation, accumulation of atherosclerotic plaque, and eventually, clinical manifestation of acute coronary syndrome (ACS).

“From a pathobiologic perspective, MPO is of great interest to researchers because it reflects processes that are distinct from those detected by traditional tools for risk stratification, including biomarkers of necrosis,” he wrote in a recent editorial in the Journal of the American College of Cardiology (JACC, 2007; 49: 2001-2002).

This same issue of JACC also featured findings on MPO related to patients’ clinical outcomes after acute myocardial infarction (2007; 49: 1993-2000).The study, conducted by researchers with the Christchurch School of Medicine and Health Sciences’ Department of Pathology and Medicine in New Zealand, looked at patients admitted to the hospital after having a heart attack and followed their survival over the next five years. The researchers also looked at MPO levels of these patients in combination with levels of NT-proBNP and left ventricular ejection fraction (LVEF). The researchers concluded that high levels of MPO were independently predictive of mortality, and that MPO also adds prognostic value to these two measurements in attempting to predict mortality after a myocardial infarction.

“We found MPO to be a risk factor independent of either NT-proBNP or LVEF, and the greatest discrimination when both markers were considered,” explained one of the study’s co-authors, Christine Winterbourn, PhD, a Professor with the University of Otago’s Department of Pathology in Christchurch. “For example, above median NT-proBNP and MPO were associated with a six-fold great risk [of mortality] than if both were below median.” Overall, the researchers concluded that MPO is a potentially useful prognostic marker in patients who have had a heart attack, but it is likely to be most useful when measured in combination with NT-proBNP.

Moving forward, Winterbourn said that these findings need validation in a comparable patient group, and further investigation is needed to determine if there is a threshold MPO level above which risk increases. “Our study also looked only at death as an outcome,” she said. “Further studies should include other adverse events.”

Further Validation, Research Needed

These findings regarding MPO as a prognostic marker are significant because they provide validation of previous research, which also showed a relationship between MPO and long-term mortality, said Morrow, who is studying biomarkers of cardiovascular disease as an investigator with the Thrombolysis in Myocardial Infarction (TIMI) Study Group at Brigham and Women’s Hospital in Boston.

“This study reinforces MPO as a candidate to add to our present tools for risk stratification,” he explained. “However, we need additional support and validation in larger population groups in which we can adequately control for all of our available present day tools. We also need to have better insight in to how MPO should direct our therapy.”

In order to further use of MPO in both clinical and research pathways, Morrow also believes that the influence of pre-analytical and analytical factors, including specimen type and sample handling, must be thoroughly evaluated. For example, the anticoagulant drug heparin could be one pre-analytical influence, as it increases the concentration of MPO in human plasma. In terms of analytical performance, Morrow believes that an independent, peer-reviewed evaluation of MPO assays proposed for clinical use is needed.

“I think there’s still more that we can learn, as MPO evaluations and assays are applied more broadly, especially if they are going to be used in research and clinical applications that require us to have additional information beyond the application that received FDA approval and that is on the assay label,” he explained.

Dr. Morrow and the TIMI Study Group have received research grant support and honoraria from numerous IVD companies, including Beckman-Coulter (Fullerton, Calif.), Biosite (San Diego, Calif.), and Roche Diagnostics (Indianapolis, Ind.).

Dr. Winterbourn’s laboratory has a commercial interest in developing protein carbonyl assay kits.

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