EDITORIAL COMMENT
Appraisal of Myeloperoxidase for Evaluation of Patients With Suspected Acute Coronary Syndromes*
David A. Morrow, MD, MPH, FACC*
TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts.
* Reprint requests and correspondence: Dr. David A. Morrow, TIMI Study Group, 350 Longwood Avenue, 1st Floor, Boston, Massachusetts 02115. (Email: dmorrow{at}partners.org).
Recognition of inflammation as a critical contributor to atherothrombosis has led to the pursuit of new approaches for diagnosis and treatment of patients with coronary heart disease (1). As the intricate relationships between cellular and noncellular participants in the inflammatory aspects of atherogenesis, plaque destabilization, and thrombosis have been defined, specific constituents have emerged as potential noninvasive indicators of these processes (2). Myeloperoxidase (MPO) is a protein released during degranulation of neutrophils and monocytes that has shown promise as a biomarker of inflammatory activation in acute coronary syndromes (ACS) (3). In 2005, an assay for MPO was approved by the U.S. Food and Drug Administration for risk assessment in patients presenting with chest pain. In this issue of the Journal, Mocatta et al. (4) report an association between MPO, measured after an acute myocardial infarction (MI), and mortality during 5 years of follow-up. In addition, to gain mechanistic insight into this relationship, Mocatta et al. (4) examined proposed mediators of the risk associated with MPO. Their important findings provide an opportunity to assess the available experimental and clinical evidence supporting a possible role for MPO in the clinical evaluation and management of patients with suspected ACS.
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Experimental Evidence
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Myeloperoxidase is a member of the heme peroxidase superfamily and is an abundant component of the azurophilic granules of leukocytes. Release of these granules by activated leukocytes enables the participation of MPO in host defense by its elaboration of numerous potent reactive oxidant species, including hypochlorous acid (HOCl). Myeloperoxidase is found predominantly in neutrophils and monocytes and has been shown to be enriched, along with its oxidation products, within human atheroma (5). Specifically, chlorotyrosine, a marker of protein modification by HOCl, has been localized within atherosclerotic lesions. Moreover, increased amounts of chlorotyrosine and other oxidation products have been found in low-density lipoprotein (LDL) cholesterol isolated from human atheroma, suggesting that HOCl, as well as other MPO-derived reactive species, may participate in the oxidation of LDL within the arterial wall (5). These histopathologic findings, in conjunction with in vitro studies of the interaction between HOCl and LDL, have pointed toward a role of MPO in the generation of proatherogenic oxidized LDL (6).
In addition to its hypothesized promotion of atherogenesis through modification of lipids and initiation of endothelial dysfunction, MPO may have destabilizing effects on atheromatous plaque through the activation of metalloproteinases, induction of endothelial apoptosis, and stimulation of tissue factor expression (6,7). At the same time, MPO may limit the protective vascular response through consumption of nitric oxide as a vasodilator (8). As such, MPO has plausibly been proposed to contribute to several phases of atherothrombosis, from the initial insult to the vascular endothelium, to development of the atheroma, to rupture of the vulnerable atherosclerotic plaque and its clinical manifestation as an ACS (5). Therefore, 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. However, the possibility of diminished specificity in patients with active infectious or inflammatory conditions also must be recognized.
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Clinical Evidence
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Pre-analytical and analytical evaluation.
To be clinically useful, accurate and reproducible analytical methods must be available. In addition, the influence of pre-analytical factors such as the specimen type and sample handling must be thoroughly evaluated. The currently available assay for MPO is a sandwich immunoassay for measurement in plasma, and published reports of pre-analytical sources of variability are incomplete. The administration of heparin increases the plasma concentration of MPO in human plasma and should be considered as a potential confounder in observational studies (9). In addition, there is a need for an independent, peer-reviewed evaluation of the analytical performance of MPO assays proposed for clinical use.
Observational studies.
The plasma concentration of MPO is increased among patients with stable coronary artery disease (10) and those presenting with ACS, including those without myonecrosis evident at initial presentation (3). In addition, at least 2 studies have shown that an increased concentration of MPO measured early after presentation with suspected ACS is associated with a greater risk of death or ischemic events (3,11). Specifically, when evaluated in 604 patients with chest pain (78.5% with a final diagnosis of ACS) at a mean of 4 h from the onset of symptoms, plasma MPO at presentation showed a graded association with the risk of death, MI (including the presenting syndrome), or revascularization with a >5-fold greater adjusted relative odds in patients in the highest versus lowest quartile (3). Moreover, among 547 patients with definite ACS, a concentration of MPO 
350 µg/l in serum was associated with a >2-fold higher adjusted odds of death or new MI at 6 months (11). Together, these 2 studies provided strong preliminary evidence for the complementary prognostic value of MPO, in conjunction with cardiac troponin, in patients with suspected ACS.
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New Evidence
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Mocatta et al. (4) have provided interesting new mechanistic as well as clinical data regarding MPO in ACS. They demonstrated greater concentrations of protein carbonyls, a marker of protein oxidation, measured 1 to 4 days and 4 months after MI compared with control patients. However, intriguingly, the concentration of chlorotyrosine did not differ between patients with MI and control patients, suggesting that the predominant mechanisms of protein oxidation did not include MPO-derived HOCl. In addition, a systemic index of protein oxidation was not associated with survival. These findings do not exclude the possibility of a local role of HOCl with a contribution that is biologically important without manifesting substantial change in a systemic index of protein oxidation. Nevertheless, the observation should prompt continued investigation of the pathobiology of MPO in atherothrombosis.
Despite the mechanistic question raised by this study, the epidemiologic observations add to the existing evidence for an association between MPO and prognosis in patients with ACS. Novel in its long-term follow-up, these investigators followed 512 patients with MI for a period of 5 years and observed a 1.8-fold greater adjusted risk of death in patients with MPO >55 µg/l in plasma (4). Appropriate to the sample size, the number of clinical factors adjusted for by the investigators was constrained and, thus, the incremental discriminatory capacity of MPO above the full set of traditional clinical tools for risk assessment after MI was not directly addressed. Nevertheless, the relationship of MPO with long-term mortality was significant after adjustment for several of the strongest predictors of mortality, including age, left ventricular function, and N-terminal pro-B-type natriuretic peptide. These findings are thus persuasive with respect to the association of MPO with survival after MI.
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Summary and Future Directions
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The available experimental and epidemiologic evidence provide compelling evidence to sustain strong interest in MPO as a candidate for clinical application. Nevertheless, additional investigation will be important to fully evaluate MPO as a clinical tool in ACS. First, the number of studies in this setting remains few compared with that for most cardiovascular biomarkers supported by clinical guidelines and/or integrated into routine practice (12). In addition, the cut points applied in these studies are disparate, perhaps because of different sample types and handling, leaving optimal decision limits uncertain and highlighting the need for studies of pre-analytical and analytical performance. Second, the additional prognostic information conferred by MPO beyond the clinician’s established tools and other novel biomarkers remains incompletely characterized. Third, the role of MPO in directing specific therapeutic interventions is not yet defined. These 3 major areas define needs for future investigation of this promising biomarker.
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Footnotes
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The TIMI Study Group has received significant research grant support from Bayer Healthcare, Beckman-Coulter, Biosite, Dade-Behring, Ortho-Clinical Diagnostics, and Roche Diagnostics. Dr. Morrow has received honoraria for educational presentations/materials from Bayer Diagnostics, Beckman-Coulter, Dade-Behring, and Roche Diagnostics and has served on advisory boards for Critical Diagnostics, Ortho-Clinical Diagnostics, and Beckman-Coulter.
* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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- Libby P, Aikawa M. Stabilization of atherosclerotic plaques: new mechanisms and clinical targets Nat Med 2002;8:1257-1262.[CrossRef][ISI][Medline]
- Morrow DA, Braunwald E. Future of biomarkers in acute coronary syndromes: moving toward a multimarker strategy Circulation 2003;108:250-252.[Free Full Text]
- Brennan ML, Penn MS, Van Lente F, et al. Prognostic value of myeloperoxidase in patients with chest pain N Engl J Med 2003;349:1595-1604.[Abstract/Free Full Text]
- Mocatta TJ, Pilbrow AP, Cameron VA, et al. Plasma concentrations of myeloperoxidase predict mortality after myocardial infarction J Am Coll Cardiol 2007;49:1993-2000.[Abstract/Free Full Text]
- Hazen SL, Heinecke JW. 3-Chlorotyrosine, a specific marker of myeloperoxidase-catalyzed oxidation, is markedly elevated in low density lipoprotein isolated from human atherosclerotic intima J Clin Invest 1997;99:2075-2081.[ISI][Medline]
- Nicholls SJ, Hazen SL. Myeloperoxidase and cardiovascular disease Arterioscler Thromb Vasc Biol 2005;25:1102-1111.[Abstract/Free Full Text]
- Sugiyama S, Kugiyama K, Aikawa M, Nakamura S, Ogawa H, Libby P. Hypochlorous acid, a macrophage product, induces endothelial apoptosis and tissue factor expression: involvement of myeloperoxidase-mediated oxidant in plaque erosion and thrombogenesis Arterioscler Thromb Vasc Biol 2004;24:1309-1314.[Abstract/Free Full Text]
- Abu-Soud HM, Hazen SL. Nitric oxide is a physiological substrate for mammalian peroxidases J Biol Chem 2000;275:37524-37532.[Abstract/Free Full Text]
- Baldus S, Rudolph V, Roiss M, et al. Heparins increase endothelial nitric oxide bioavailability by liberating vessel-immobilized myeloperoxidase Circulation 2006;113:1871-1878.[Abstract/Free Full Text]
- Zhang R, Brennan ML, Fu X, et al. Association between myeloperoxidase levels and risk of coronary artery disease JAMA 2001;286:2136-2142.[Abstract/Free Full Text]
- Baldus S, Heeschen C, Meinertz T, et al. Myeloperoxidase serum levels predict risk in patients with acute coronary syndromes Circulation 2003;108:1440-1445.[Abstract/Free Full Text]
- Morrow DA, Cannon CP, Jesse RL, et al. National Academy of Clinical Biochemistry Laboratory Medicine practice guidelines: clinical characteristics & utilization of biochemical markers in acute coronary syndromes Circulation 2007;115:e356-e375.[Free Full Text]
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D. A. Morrow, M. S. Sabatine, M.-L. Brennan, J. A. de Lemos, S. A. Murphy, C. T. Ruff, N. Rifai, C. P. Cannon, and S. L. Hazen
Concurrent evaluation of novel cardiac biomarkers in acute coronary syndrome: myeloperoxidase and soluble CD40 ligand and the risk of recurrent ischaemic events in TACTICS-TIMI 18
Eur. Heart J.,
May 1, 2008;
29(9):
1096 - 1102.
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