Correspondence

Prognostic Value of Myeloperoxidase in Patients with Chest Pain

N Engl J Med 2004; 350:516-518January 29, 2004

Article

To the Editor:

Brennan et al. (Oct. 23 issue)1 report an intriguing study of myeloperoxidase in the evaluation of patients with acute chest pain. However, the use of a test for clinical prediction also requires decisions about the sensitivity and specificity of any selected cutoff point.2 The only information of this type provided in the article is the evaluation of the creatine kinase MB isoform (CK-MB), C-reactive protein, and myeloperoxidase for the prediction of major cardiac events within 30 days in patients with chest pain and normal troponin T levels. When the sensitivities and specificities are combined into likelihood ratios, which are more helpful for determining how much a test result increases or decreases the likelihood of a bad outcome in an individual patient,3 they indicate that a positive result for CK-MB is actually much more predictive of an adverse cardiac outcome at 30 days than is an elevated myeloperoxidase level and that a negative result for myeloperoxidase does not decrease the likelihood of an adverse outcome much more than does a negative result for CK-MB (Table 1Table 1Sensitivities, Specificities, and Likelihood Ratios for the Prediction of Major Cardiac Events at 30 Days.). Although myeloperoxidase levels are correlated with risk, they do not yet appear to provide additional prognostic information for the evaluation of individual patients.

William E. Cayley, Jr., M.D.
University of Wisconsin Medical School, Eau Claire, WI 54701
bcayley@yahoo.com

3 References

1. 1

   Brennan M-L, Penn MS, Van Lente F, et al. Prognostic value of myeloperoxidase in patients with chest pain. N Engl J Med 2003;349:1595-1604
   Full Text | Web of Science | Medline

2. 2

   Manolio T. Novel risk markers and clinical practice. N Engl J Med 2003;349:1587-1589
   Full Text | Web of Science | Medline

3. 3

   Greenhalgh T. How to read a paper: papers that report diagnostic or screening tests. BMJ 1997;315:540-543[Erratum, BMJ 1997;315:942, 1998;316:225.]
   CrossRef | Web of Science | Medline

To the Editor:

In their report on myeloperoxidase, Brennan et al. state that plasma myeloperoxidase levels independently predicted the risk of cardiac events in patients in whom unstable angina was suspected. We would like to support their data with those from our study of the –463G/A myeloperoxidase-promoter polymorphism in patients with stable angina. The GG genotype is present in 60 to 66 percent of the Western population and is associated with higher myeloperoxidase levels than either the AG or AA genotype.1 Our study population consisted of 270 patients referred for a first coronary angiographic study for the evaluation of stable angina. The GG genotype was related to an increased risk of a cardiovascular event during long-term follow-up (Figure 1Figure 1Kaplan–Meier Analysis of the Relation between the Myeloperoxidase Genotype and the Risk of Cardiovascular Events.). This relation between the GG genotype and cardiovascular events was independent of the presence or absence of traditional cardiovascular risk factors and coronary artery disease. Our findings suggest that assessment of the myeloperoxidase-promoter polymorphism may be of value for risk assessment in all patients in whom angina is suspected. It would be interesting to know whether the myeloperoxidase levels in the patients studied by Brennan et al. were related to the presence of the promoter polymorphism.

Folkert W. Asselbergs, M.D.
University Hospital Groningen, 9713GZ Groningen, the Netherlands

Jan-Willem Cohen Tervaert, M.D., Ph.D.
University Hospital Maastricht, 6229HX Maastricht, the Netherlands

René A. Tio, M.D., Ph.D.
University Hospital Groningen, 9713GZ Groningen, the Netherlands
r.a.tio@thorax.azg.nl

1 References

1. 1

   Reynolds WF, Chang E, Douer D, Ball ED, Kanda V. An allelic association implicates myeloperoxidase in the etiology of acute promyelocytic leukemia. Blood 1997;90:2730-2737
   Web of Science | Medline

Author/Editor Response

We thank Dr. Asselbergs and colleagues for sharing their unpublished data linking a polymorphism in the promoter region of the myeloperoxidase gene (–463G/A) with the risk of major cardiac events. Their genetic studies suggest a cardioprotective effect in persons carrying an A allele and argue that myeloperoxidase not only is a marker of cardiovascular disease, but also has a potential pathogenic role in it. Although molecular studies examining the functional significance of –463G/A strongly support a functional role for this single-nucleotide polymorphism (i.e., decreased transcription of myeloperoxidase is seen in reporter constructs due to ablation of an Sp1 transcription initiation site1), these in vitro findings have not been confirmed in human clinical studies, and further work on these exciting data is needed.

Dr. Cayley raises questions regarding the additional prognostic information provided by the measurement of myeloperoxidase levels. In our data set, 58 percent of the patients who had a major cardiac event within six months of presentation would have been identified through screening strategies based solely on the measurement of troponin levels. In comparison, the addition of myeloperoxidase measurement to the screening strategy (i.e., either a high troponin T level or a high myeloperoxidase level) increased this number significantly, to 84.5 percent. Many of the issues Dr. Cayley raises will ultimately be best addressed with the use of additional data sets and examination of multiple marker approaches. In support of our data, Baldus and colleagues recently reported consistent findings in a cohort of more than 1000 patients.2 However, even when the likelihood-ratio criterion was used, patients with elevated myeloperoxidase levels were 1.6 times as likely to have an event, and the negative likelihood ratio for myeloperoxidase was similar to that with CK-MB. Likelihood ratios do not allow the adjustment of additional factors. In our study, when we used multivariate models that adjusted for other factors (including the level of CK-MB), we still found that myeloperoxidase levels served as an independent predictor of major cardiac events, even in patients with persistently negative results for troponin T.

Marie-Luise Brennan, Ph.D.
Marc S. Penn, M.D., Ph.D.
Stanley L. Hazen, M.D., Ph.D.
Cleveland Clinic Foundation, Cleveland, OH 44195
hazens@ccf.org

2 References

1. 1

   Piedrafita FJ, Molander RB, Vansant G, Orlova EA, Pfahl M, Reynolds WF. An Alu element in the myeloperoxidase promoter contains a composite SP1-thyroid hormone-retinoic acid response element. J Biol Chem 1996;271:14412-14420
   CrossRef | Web of Science | Medline

2. 2

   Baldus S, Heeschen C, Meinertz T, et al. Myeloperoxidase serum levels predict risk in patients with acute coronary syndromes. Circulation 2003;108:1440-1445
   CrossRef | Web of Science | Medline

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   J. T. Atosuo, E.-M. Lilius. (2011) The Real-Time-Based Assessment of the Microbial Killing by the Antimicrobial Compounds of Neutrophils. TheScientificWorldJOURNAL 11, 2382-2390
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   Volker Rudolph, Tanja K. Rudolph, Lukas Kubala, Navina Clauberg, Renke Maas, Michaela Pekarova, Anna Klinke, Denise Lau, Katalin Szöcs, Thomas Meinertz, Rainer H. Böger, Stephan Baldus. (2009) A myeloperoxidase promoter polymorphism is independently associated with mortality in patients with impaired left ventricular function. Free Radical Biology and Medicine 47:11, 1584-1590
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   J. W. Cohen Tervaert. (2009) Translational Mini-Review Series on Immunology of Vascular Disease: Accelerated atherosclerosis in vasculitis. Clinical & Experimental Immunology 156:3, 377-385
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   Denise Lau, Stephan Baldus. (2006) Myeloperoxidase and its contributory role in inflammatory vascular disease. Pharmacology & Therapeutics 111:1, 16-26
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   Sotirios Tsimikas, James T. Willerson, Paul M. Ridker. (2006) C-Reactive Protein and Other Emerging Blood Biomarkers to Optimize Risk Stratification of Vulnerable Patients. Journal of the American College of Cardiology 47:8, C19-C31
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   Jan K. Damås, Pål Aukrust. (2006) Systemic markers of inflammation – are they useful predictive tools in coronary artery disease?. Scandinavian Cardiovascular Journal 40:5, 262-266
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