Inflammation-Related Enzyme May Predict CAD Risk in Healthy Individuals

AMSTERDAM, July 3 -- Measuring the proinflammatory enzyme myeloperoxidase (MPO) might help identify healthy individuals at risk for coronary artery disease, possibly years before onset, investigators found.

Elevated levels of myeloperoxidase in otherwise healthy men and women increased the likelihood of overt coronary artery disease by 50% over 8 years compared with patients who had the lowest levels of the enzyme (P<0.001), according to a report published online in the Journal of the American College of Cardiology, in advance of its July 10 issue.

The enzyme remained an independent predictor of coronary artery disease after adjustment for traditional risk factors. Elevated levels of the enzyme also predicted disease risk in patients who had lower-risk features at baseline, said S. Matthijs Boekholdt, M.D., of the Academic Medical Center here, and colleagues.

MPO, traditionally considered to be a bactericidal enzyme, has recently gained attention for its role in promoting plaque buildup in coronary arteries. In patients with overt coronary artery disease, MPO is elevated and predicts the risk of future cardiovascular events.

To determine the significance of the enzyme in healthy individuals, the investigators performed a nested, case-control analysis of participants in an ongoing, community-based population study of cancer and nutrition in nine European countries. The analysis involved 3,375 men and women who were free of coronary artery disease at study entry.

Serum MPO was measured by means of a commercially available assay. The serum came from frozen samples collected as far back as 1994, when the cancer-nutrition study began.

During follow up, 1,138 participants developed fatal (N=342) or nonfatal coronary artery disease. The 2,237 who did not served as the study controls.

Those who developed coronary artery disease had a significantly higher median baseline MPO level compared with controls (704 pmol/L versus 638 pmol/L, P<0.001).

MPO levels were also significantly higher in men than in women (680 pmol/L versus 619, P<0.001) and in fatal cases of coronary artery disease than in nonfatal cases (789 pmol/L versus 681, P<0.001).

Comparison of MPO levels and traditional coronary artery disease risk factors revealed a strong, positive linear relationship with CRP and white blood cell count, a negative association with baseline HDL, and an association with smoking status.

Stratification of MPO data into quartiles showed that risk for coronary artery disease increased with MPO levels. Patients in the top quartile had a CAD odds ratio of 1.49 compared with patients in the bottom quartile (P=0.001). After adjustment for conventional risk factors, the difference between the top and bottom quartile remained significant (OR 1.36, P<0.001).

Among patients who died of coronary artery disease, baseline MPO had an even stronger association (OR 1.82, P<0.025). The enzyme's association with nonfatal disease translated into an odds ratio of 1.35 (P=0.013).

The association between MPO and coronary artery disease was more pronounced in men (OR 1.61, P=0.003) than in women (OR 1.17, NS).

In the current study, the enzyme's association with future risk of coronary artery disease was weaker than had been reported in studies involving patients with acute coronary syndrome (ACS), Dr. Boekholdt and colleagues noted.

The difference suggests that MPO might be a more potent marker of plaque instability than of coronary artery disease risk or atheroma burden, they said. MPO is derived predominantly from activated neutrophils and monocytes, and elevated levels of MPO seen in acute coronary syndrome could reflect the influx and migration of the cells toward unstable plaque.

They pointed out that "the association of MPO with future coronary artery disease among apparently healthy individuals was weaker than that of [previously reported] traditional cardiovascular risk factors and CRP.

The unadjusted OR (top vs. bottom quartile) of the traditional risk factors in the EPIC study vary between 1.7 for LDL-cholesterol to 3.9 for diabetes. The OR for CRP was 2.4, 1.66 after adjustment for traditional risk factors," they noted.

The authors also noted several limitations to their findings. Deaths from coronary artery disease were determined by death certificates and hospital admission data, which could have introduced errors. Also, a single measurement of MPO might not accurately reflect the enzyme's relationship with disease.

Plus, they noted, storage of serum samples for as long as 12 years might have affected the concentration of MPO.

However, the investigators concluded, "It is clear that elevation of inflammatory markers, such as MPO and CRP [C-reactive protein], and their interactions precede the onset of CAD by years. This underscores the potential relevance of exploration of anti-inflammatory strategies."