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European Heart Journal Advance Access originally published online on December 21, 2007
European Heart Journal 2008 29(2):224-230; doi:10.1093/eurheartj/ehm587
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2007. For permissions please email: journals.permissions@oxfordjournals.org

Myeloperoxidase, but not C-reactive protein, predicts cardiovascular risk in peripheral arterial disease

Gregorio Brevetti1,*, Vittorio Schiano1, Eugenio Laurenzano1, Giuseppe Giugliano1, Mario Petretta1, Francesco Scopacasa2 and Massimo Chiariello1

1 Department of Clinical Medicine and Cardiovascular and Immunological Sciences, University of Naples ‘Federico II’, Via Pansini 5, Naples, Italy
2 Department of Laboratory Medicine, University of Naples ‘Federico II’, Via Pansini 5, Naples, Italy

Received 3 May 2007; revised 14 November 2007; accepted 22 November 2007; online publish-ahead-of-print 21 December 2007.

* Corresponding author: Via G. Iannelli 45/A, 80131 Napoli, Italy. Tel/Fax: +39 081 7462240, Email: brevetti{at}unina.it

See page 150 for the editorial comment on this article (doi:10.1093/eurheartj/ehm535)


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Aims: The prognostic role of inflammation in peripheral arterial disease (PAD) remains to be conclusively established. Accordingly, in these patients we investigated the impact of myeloperoxidase (MPOx) and C-reactive protein on the incidence of myocardial infarction and stroke.

Methods and results: Of 156 PAD patients, 10 had a myocardial infarction and seven a stroke, during follow-up. We used the receiver operating characteristic curve analysis and the bootstrap approach to identify the MPOx, C-reactive protein, and ankle brachial index (ABI) threshold levels that provided the best cut-off to predict the outcome. For MPOx a cut-off ≥183.7 pM was independently associated with a poor outcome (HR = 6.80, 95% CI 1.20–38.69, P = 0.031). The result remained unmodified when MPOx was used as a continuous variable (HR = 1.03, 95% CI 1.01–1.05, P = 0.031). Conversely, C-reactive protein was not a prognostic determinant in our series (HR = 0.88, 95% CI 0.60–1.29, P = 0.514). Kaplan–Meier curves for the four groups of patients delineated according to ABI and MPOx values identified using the bootstrap approach showed that the addition of MPOx measurement to ABI improved the ability to identify patients at risk for myocardial infarction and stroke.

Conclusion: In PAD, MPOx, but not C-reactive protein, predicts an increased risk of major cardiovascular events, and adds to the prognostic value of ABI, currently the most powerful prognostic indicator in these patients.

Key Words: Peripheral arterial disease • Inflammation • C-reactive protein • Myeloperoxidase • Prognosis • Cardiovascular diseases


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Because atherothrombosis is an inflammatory response to injury, circulating factors related to inflammation may be markers of this process. Elevated levels of C-reactive protein, the biomarker most extensively investigated in relation to atherosclerosis, exert proatherogenic effects1–3 and are associated with the presence,4,5 severity,5,6 progression,7 and natural history of coronary artery disease (CAD).8,9 However, some investigators have disputed the magnitude of risk prediction.10–12

The leukocyte enzyme myeloperoxidase (MPOx) is another proinflammatory molecule implicated in the promotion and/or propagation of atherosclerosis. Indeed, when secreted by activated leukocytes at sites of inflammation, MPOx converts low-density lipoprotein into an atherogenic form,13 generates numerous reactive oxidants and diffusible radical species,14 and reduces nitric oxide availability, thereby contributing to endothelial dysfunction.15,16 Increased levels of MPOx are associated with a high prevalence of ≥50% coronary stenosis,17 are related to the severity of CAD,18 and entail a worse prognosis in patients presenting with chest pain19 or acute coronary syndromes.11

Peripheral artery disease (PAD) is another major manifestation of atherosclerosis. It affects ~20% of the population aged 55 and older,20 and carries a high risk of fatal and non-fatal ischaemic events.21,22 Cross-sectional studies indicate that inflammation is associated with the presence,23 progression,24 and severity of PAD.25 Differently from CAD, however, few studies have examined the prognostic impact of inflammation in PAD patients and many presented limitations.26–29

No study has yet investigated the prognostic role of MPOx in PAD. In an attempt to find an indicator that could improve the cardiovascular risk prediction in PAD, we evaluated the prognostic impact of C-reactive protein and MPOx on myocardial infarction and stroke in a homogeneous, relatively large group of PAD patients.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
From July 2003 to October 2005, 224 subjects consecutively referred to our vascular laboratory for suspected PAD. The diagnosis of PAD was based primarily on the presence of an ankle brachial index, ABI < 0.90. According to this criterion, 43 patients were classified as not having PAD. Those (n = 6) with ABI > 1.40 were excluded as these values may be falsely elevated due to severe vascular calcification. Seven were excluded because of the presence of critical limb ischaemia. Therefore, the diagnosis of intermittent claudication was confirmed in 168 subjects with an ABI < 0.90. Of these 168 subjects, 12 were excluded for one of the following reasons: recent surgical interventions for CAD or PAD (<6 months), recent (<3 months) unstable angina, myocardial infarction or stroke, decompensated heart failure, malignant neoplasia, and significant hepatic, renal, or inflammatory disease. Therefore the study was conducted in 156 patients with documented intermittent claudication. All women were postmenopausal, and none was receiving hormone-replacement therapy. All participants gave written informed consent to the study, which was approved by our institutional ethics committee.

Clinical history and risk factors were assessed at the first evaluation. Smokers included current or former smokers. Hypertension was diagnosed if systolic arterial pressure exceeded 140 mmHg and/or diastolic arterial pressure exceeded 90 mmHg, or if the patient used antihypertensive drugs. Hypercholesterolaemia was diagnosed if plasma total cholesterol exceeded 200 mg/dL, plasma low-density lipoprotein cholesterol exceeded 130 mg/dL, plasma high-density lipoprotein cholesterol was lower than 35 mg/dL, or if the patient used lipid-lowering drugs. Diabetes mellitus was diagnosed if plasma fasting glucose exceeded 126 mg/dL or if the patient used hypoglycemic agents. After participants had rested supine for 5 min, a Doppler probe was used to measure the systolic pressure in the right and left posterior tibial arteries, and in the right brachial artery. Pressures were measured twice, and the average of the two measurements was used to calculate the ABI. The lower ABI of the two legs was used as a predictor for future cardiovascular events.

Blood samples and laboratory assay
Venous blood was obtained after non-traumatic venipuncture of an antecubital vein, within 4 days of the baseline examination, after an overnight fast. All drugs were discontinued for at least 18 h and all subjects abstained from smoking and intake of caffeine-containing food or beverages for at least 12 h before the blood sample was taken. Serum samples were stored at –70°. MPOx was measured by ELISA according to procedures recommended by the manufacturer (Calbiochem). C-reactive protein was determined using a high sensitivity (hs) assay (Dade Behring Diagnostics). After blind assessment of the inflammatory markers, test results were merged with the database.

Assessment of cardiovascular events
Patients were contacted for a follow-up examination at intervals of 3 months. Eleven patients did not regularly attend our outpatient clinic and, thus, follow-up data were obtained by periodic telephone interviews. Medical records and death certificates of all patients who had an event were obtained and validated by a cardiologist unaware of the clinical and laboratory results. The minimum follow-up period was 6 months. The occurrence of fatal and non-fatal acute myocardial infarction and stroke was prospectively assessed. Myocardial infarction was defined by an increase of at least two-fold in creatine kinase-MB with typical ECG changes. Ischaemic stroke was defined by clinical evidence of stroke without intracranial haemorrhage. For patients who had more than one event, only the first was considered in the analysis.

Statistical analysis
All statistical analyses were performed using SPSS version 12.0 (SPSS, Inc., Chicago, IL, USA) and Stata version 7.0 (Stata Corp., College Station, TX, USA). Serum levels of MPOx and hs-C-reactive protein are expressed as median, and 25th and 75th percentiles because of their skewed distribution. Other variables are expressed as mean ± SD or n (%). In the statistical analyses, MPOx, C-reactive protein, and ABI were first treated as continuous variables and then as categorical variables. To identify the MPOx, C-reactive protein, and ABI threshold levels that provided the best cut-off to predict the outcome, we chose the value in which the sum of the specificity and sensitivity was the highest. This value was obtained by time-dependent receiver operating characteristic (ROC) curve analysis.30 To test the robustness of the results, we used the bootstrap approach.31 After randomly sampling the study population, drawn with a replacement 200 times, the mean and the 95% confidence interval (CI) of the 200 bootstrapped cut-off estimates were calculated. This mean value was used as the best cut-off. Cumulative event rates were estimated with Kaplan–Meier survival curves, and probability values were calculated with the log-rank test. Cox proportional hazard modelling was performed to test the association between MPOx levels and cardiovascular events. The following covariates known to be potential contributors to the occurrence of myocardial infarction or stroke were included in the model: age, sex, smoking, body mass index (BMI), diabetes mellitus, hypercholesterolaemia, hypertension, ABI, C-reactive protein, and presence of concomitant coronary and cerebrovascular diseases. The proportional hazards assumption was confirmed by testing whether the hazard ratio changed with time. This was done by testing the interaction of the variable with time using this multiplicative term as a time-dependent covariate. There was no evidence to suggest that the assumption was invalid. The linearity assumption for continuous measures was evaluated using restricted cubic spline transformations and comparing the –2 log likelihood {chi}2 of models with the linear vs. transformed variable. All statistical tests were two-sided. For all tests, a P-value <0.05 was considered statistically significant.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Table 1 shows baseline characteristics of the study population. The median follow-up in our 156 patients was 17.5 (12.0–24.0) months. During this time, 17 had an event: 10 had an acute myocardial infarction (five were fatal) and seven a stroke (one was fatal).


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  		Table 1 Baseline characteristics of the study population

 
MPOx serum levels and prognosis
Considered as a continuous variable, MPOx was significantly associated with an increased risk also after adjustment for factors that are known to be important predictors of outcome. Actually, in a Cox proportional hazard model that included age, sex, smoking, BMI, diabetes mellitus, hypercholesterolaemia, hypertension, ABI, concomitant coronary and cerebrovascular diseases, and C-reactive protein, MPOx was an independent predictor of myocardial infarction and stroke (HR = 1.03, 95% CI 1.01–1.05, P = 0.031). ROC curve analysis showed that the MPOx cut-off value that provided the maximum sum of the specificity and sensitivity in predicting the outcome was 179.4 pM. The c-statistic (area under the curve) for this MPOx value was 0.69 (95% CI 0.61–0.75, P = 0.015). The bootstrapped cut-off value estimate for MPOx was 183.7 (95% CI 173.9–193.4) pM. Table 2 shows the baseline characteristics after categorization of the study population using a threshold MPOx level of 183.7 pM. The only difference in baseline characteristics between the groups with low and high MPOx levels was a higher hs-C-reactive protein serum level in patients with MPOx > 183.7 pM. In our 156 patients, the occurrence of cardiovascular events was 4.4% in those with MPOx levels ≤183.7 pM and 20.0% in those with MPOx levels >183.7 pM. Based on these data, we could detect a true difference in cardiovascular risk of 15.6 percentage points or larger between the two subgroups obtained using the cut-off value of 183.7 pM as statistically significant with a two-sided paired t-test at {alpha} = 0.05 and 85% power. Kaplan–Meier curves showed that the incidence of cardiovascular events was significantly higher in patients with MPOx levels >183.7 pM than in those with levels ≤183.7 pM (Figure 1). Cox analysis, adjusted for the factors indicated above, revealed that MPOx levels >183.7 pM were independently associated with cardiovascular events (HR = 6.80, 95% CI 1.20–38.69, P = 0.031).


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  		Table 2 Baseline characteristics of PAD patients according to the MPOx status

 

Figure 1
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  		Figure 1 Kaplan–Meier analysis of event-free survival curves in patients with myeloperoxidase serum levels below and above 183.7 pM

 
The ABI value that provided the highest sum of sensitivity and specificity in predicting the outcome was 0.56 (the c-statistic for this value =0.64, 95% CI 0.56–0.72, P = 0.029). The bootstrapped cut-off value estimate for ABI was 0.58 (95% CI 0.55–0.60). Survival curves for the four groups of patients delineated according to the values of ABI and MPOx identified using the bootstrap approach (0.58 for ABI and 183.7 pM for MPOx) are shown in Figure 2. Notably, the addition of MPOx measurement to ABI improved the ability to identify patients at risk for myocardial infarction and stroke.


Figure 2
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  		Figure 2 Kaplan–Meier analysis of event-free survival curves refers to the four subgroups of patients delineated according to the cut-off values of ankle brachial index and MPOx identified using the bootstrap approach (0.58 for ankle brachial index and 183.7 pM for MPOx). Combination of ankle brachial index ≤0.58 and MPOx > 183.7 pM was associated with the highest cardiovascular event incidence

 
High-sensitivity C-reactive protein serum levels and prognosis
Cox analysis corrected for classic risk factors, BMI, ABI, concomitant coronary and cerebrovascular diseases, and MPOx levels revealed that hs-C-reactive protein, used as a continuous variable, was not an independent predictor of the outcome (HR = 0.88, 95% CI 0.60–1.29, P = 0.514). Furthermore, the ROC analysis revealed no significant contribution of hs-C-reactive protein in predicting the outcome. Actually the c-statistic was 0.53 (95% CI 0.41–0.65, P = 0.670). Finally, hs-C-reactive protein failed to predict the outcome also when patients were stratified into three subgroups according to American Heart Association guidelines32 (Figure 3). Even when we pooled patients with hs-C-reactive protein >1 mg/L (i.e. those at medium and high risk), adjusted Cox analysis did not show a significant association between C-reactive protein and the outcome (HR = 0.76, 95% CI 0.08–7.41, P = 0.810).


Figure 3
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  		Figure 3 Kaplan–Meier analysis of event-free survival curves in patients with <1, 1–3, and >3 mg/L hs-C-reactive protein serum levels

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The results of this study indicate that MPOx has a strong prognostic impact on the risk of major cardiovascular events in PAD patients. Indeed, patients with MPOx serum concentrations >183.7 pM (a cut-off identified using the bootstrap approach) had a much greater risk of developing myocardial infarction or stroke than patients with MPOx ≤ 183.7 pM. The increased risk was unrelated to classic risk factors and to the use of cardiovascular drugs, which were similar in patients with and without an event. Notably, the higher risk was also unrelated to previous cardiovascular events and severity of PAD, evaluated by ABI.

MPOx plays a role in a range of events involving the initiation, propagation, and clinical complications of atherosclerosis. In addition to the generation of atherogenic lipoproteins13 and nitric oxide consumption leading to endothelial dysfunction,15,16 MPOx promotes destabilization and rupture of the plaque surface by activating protease cascades that affect the stability and thrombogenicity of plaques.33,34 Furthermore, MPOx levels are elevated within culprit lesions prone to rupture.35 Notably in this regard, MPOx identifies patients at risk of myocardial infarction who have low baseline troponin T serum levels.11,19 Therefore, increased serum levels of MPOx seem to precede myocardial injury and thus may be considered a predictor of vulnerable plaques. This could be particularly important in PAD patients in whom the first manifestation of CAD is often acute coronary syndromes.36 The addition of MPOx measurement to initial risk stratification in PAD subjects with stable CAD may help to identify individuals at increased risk who should undergo further non-invasive and, if necessary, invasive diagnostic evaluation. In this context, it is noteworthy that MPOx serum levels >183.7 improve the risk stratification provided by ABI alone which, to date, is the most powerful prognostic indicator in PAD.37

Consistent with the finding that MPOx has a strong predictive value in acute coronary syndromes,11 although its serum levels did not correlate with other important markers of coronary risk, we found that MPOx levels did not correlate with ABI. The lack of a relationship between MPOx levels and ABI, which reflects the atherosclerotic burden of the affected limb on duplex scanning,38 suggests that it is the quality rather than the quantity of the atherosclerotic lesions that contributes to increase MPOx levels. In other words, in PAD patients, neutrophils may be activated by inflamed plaques, which are common in the affected leg arteries,39,40 that provide a large surface for the release of inflammatory molecules. However, we cannot exclude that neutrophils activated by unstable carotid or coronary plaques may have contributed to increase MPOx levels in subjects with an event at the follow-up.

Although hs-C-reactive protein was significantly higher in patients with MPOx > 183.7 pM, consistent with previous findings,11 MPOx levels were not correlated with C-reactive protein levels. Moreover, hs-C-reactive protein was not a prognostic determinant in our series, unlike previous PAD studies.26–28 This discrepancy may be due to several factors, namely patient selection, number of patients studied, and study endpoints. One study26 showed that, in 51 PAD patients, serum C-reactive protein levels >9 mg/L were significantly associated with the risk of myocardial infarction. However, this result, obtained in a heterogeneous group of patients who were undergoing lower limb revascularization, was not corrected for the ABI. This limitation applies to the study by Vainas et al.,27 who found a significant association between increased levels of C-reactive protein and the occurrence of cardiovascular events in a population that included patients with critical limb ischaemia. Our population consisted of a homogeneous group of 156 patients with intermittent claudication. Furthermore, in the study by Vainas and coworkers and in the small series reported by Beckman et al.,28 patients were assessed also for the occurrence of peripheral artery events and revascularizations, which were the most frequent events observed at the follow-up. Conversely, we assessed only major cardiovascular events. Our finding that hs-C-reactive protein is unrelated to cardiovascular risk in PAD patients is in line with reappraisals of the prognostic role of C-reactive protein. Indeed, in many studies only a moderate association was identified between C-reactive protein and cardiovascular risk.10,11,19,40–42 In another study, C-reactive protein failed to predict the risk of death and cardiovascular events in older adults.41 Furthermore, other biomarkers were reported to be more closely associated with cardiovascular risk than C-reactive protein.42,43 In particular, MPOx, but not C-reactive protein, significantly predicted myocardial infarction in patients with chest pain and negative troponin T.11,19

Conclusions
Our study demonstrates that serum levels of MPOx, but not of hs-C-reactive protein, are strong predictors of myocardial infarction and stroke in patients with symptomatic PAD. It is noteworthy that the prognostic value of MPOx was independent of ABI, which is the most powerful marker of cardiovascular risk in PAD. More importantly, our data show that combined measurement of MPOx and ABI provides a better risk stratification than ABI alone. This finding may have important implications. First, it suggests that MPOx measurement could be used in PAD patients to identify those for further diagnostic evaluation of the carotid and coronary districts. Furthermore, it may serve to select PAD patients who need more aggressive and specific therapy. In this context, although further studies are needed to verify the predictive value of MPOx in PAD, we hope that our findings, coupled with those of previous reports,11,17,19 encourage the development of interventions able to modulate the catalytic activity of MPOx.

Conflict of interest: There are no potential conflicts of interest or funding sources to disclose.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Torzewski M, Rist C, Mortensen RF, Zwaka TP, Bienek M, Waltenberger J, Koenig W, Schmitz G, Hombach V, Torzewski J. C-reactive protein in the arterial intima: role of C-reactive protein receptor-dependent monocyte recruitment in atherogenesis. Arterioscler Thromb Vasc Biol (2000) 20:2094–2099.[Abstract/Free Full Text]
  2. Pasceri V, Cheng JS, Willerson JT, Yeh ET. Modulation of C-reactive protein-mediated monocyte chemoattractant protein-1 induction in human endothelial cells by anti-atherosclerosis drugs. Circulation (2001) 103:2531–2534.[Abstract/Free Full Text]
  3. Verma S, Wang CH, Li SH, Dumont AS, Fedak PW, Badiwala MV, Dhillon B, Weisel RD, Li RK, Mickle DA, Stewart DJ. A self-fulfilling prophecy: C-reactive protein attenuates nitric oxide production and inhibits angiogenesis. Circulation (2002) 106:913–919.[Abstract/Free Full Text]
  4. Brevetti G, Piscione F, Silvestro A, Galasso G, Di Donato A, Oliva G, Scopacasa F, Chiariello M. Increased inflammatory status and higher prevalence of three-vessel coronary artery disease in patients with concomitant coronary and peripheral atherosclerosis. Thromb Haemost (2003) 89:1058–1063.[Web of Science][Medline]
  5. Tataru MC, Heinrich J, Junker R, Schulte H, von Eckardstein A, Assmann G, Koehler E. C-reactive protein and the severity of atherosclerosis in myocardial infarction patients with stable angina pectoris. Eur Heart (2000) 21:1000–1008.[CrossRef]
  6. Erren M, Reinecke H, Junker R, Fobker M, Schulte H, Schurek JO, Kropf J, Kerber S, Breithardt G, Assmann G, Cullen P. Systemic inflammatory parameters in patients with atherosclerosis of the coronary and peripheral arteries. Arterioscler Thromb Vasc Biol (1999) 19:2355–2363.[Abstract/Free Full Text]
  7. Zouridakis E, Avanzas P, Arroyo-Espliguero R, Fredericks S, Kaski JC. Markers of inflammation and rapid coronary artery disease progression in patients with stable angina pectoris. Circulation (2004) 110:1747–1753.[Abstract/Free Full Text]
  8. Haverkate F, Thompson SG, Pyke SD, Gallimore JR, Pepys MB. Production of C-reactive protein and risk of coronary events in stable and unstable angina. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. Lancet (1997) 349:462–466.[CrossRef][Web of Science][Medline]
  9. Speidl WS, Graf S, Hornykewycz S, Nikfardjam M, Niessner A, Zorn G, Wojta J, Huber K. High-sensitivity C-reactive protein in the prediction of coronary events in patients with premature coronary artery disease. Am Heart J (2002) 144:449–455.[CrossRef][Web of Science][Medline]
  10. Danesh J, Wheeler JG, Hirschfield GM, Eda S, Eiriksdottir G, Rumley A, Lowe GD, Pepys MB, Gudnason V. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med (2004) 350:1387–1397.[Abstract/Free Full Text]
  11. Baldus S, Heeschen C, Meinertz T, Zeiher AM, Eiserich JP, Munzel T, Simoons ML, Hamm CW, CAPTURE Investigators. Myeloperoxidase serum levels predict risk in patients with acute coronary syndromes. Circulation (2003) 108:1440–1445.[Abstract/Free Full Text]
  12. Folsom AR, Chambless LE, Ballantyne CM, Coresh J, Heiss G, Wu KK, Boerwinkle E, Mosley TH Jr, Sorlie P, Diao G, Sharrett AR. An assessment of incremental coronary risk prediction using C-reactive protein and other novel risk markers: the atherosclerosis risk in communities study. Arch Intern Med (2006) 166:1368–1373.[Abstract/Free Full Text]
  13. Podrez EA, Schmitt D, Hoff HF, Hazen SL. Myeloperoxidase-generated reactive nitrogen species convert LDL into an atherogenic form in vitro. J Clin Invest (1999) 103:1547–1560.[Web of Science][Medline]
  14. Klebanoff SJ. Oxygen metabolism and the toxic properties of phagocytes. Ann Intern Med (1980) 93:480–489.[Abstract/Free Full Text]
  15. Eiserich JP, Baldus S, Brennan ML, Ma W, Zhang C, Tousson A, Castro L, Lusis AJ, Nauseef WM, White CR, Freeman BA. Myeloperoxidase, a leukocyte-derived vascular NO oxidase. Science (2002) 296:2391–2394.[Abstract/Free Full Text]
  16. Vita JA, Brennan ML, Gokce N, Mann SA, Goormastic M, Shishehbor MH, Penn MS, Keaney JF Jr, Hazen SL. Serum myeloperoxidase levels independently predict endothelial dysfunction in humans. Circulation (2004) 110:1134–1139.[Abstract/Free Full Text]
  17. Zhang R, Brennan ML, Fu X, Aviles RJ, Pearce GL, Penn MS, Topol EJ, Sprecher DL, Hazen SL. Association between myeloperoxidase levels and risk of coronary artery disease. JAMA (2001) 286:2136–2142.[Abstract/Free Full Text]
  18. Buffon A, Biasucci LM, Liuzzo G, D'Onofrio G, Crea F, Maseri A. Widespread coronary inflammation in unstable angina. N Engl J Med (2002) 347:5–12.[Abstract/Free Full Text]
  19. Brennan ML, Penn MS, Van Lente F, Nambi V, Shishehbor MH, Aviles RJ, Goormastic M, Pepoy ML, McErlean ES, Topol EJ, Nissen SE, Hazen SL. Prognostic value of myeloperoxidase in patients with chest pain. N Engl J Med (2003) 349:1595–1604.[Abstract/Free Full Text]
  20. Meijer WT, Hoes AW, Rutgers D, Bots ML, Hofman A, Grobbee DE. Peripheral arterial disease in the elderly: The Rotterdam Study. Arterioscler Thromb Vasc Biol (1998) 18:185–192.[Abstract/Free Full Text]
  21. Criqui MH, Langer RD, Fronek A, Feigelson HS, Klauber MR, McCann TJ, Browner D. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med (1992) 326:381–386.[Abstract]
  22. Brevetti G, Martone VD, Perna S, Cacciatore F, Corrado S, Di Donato A, Di Iorio A. Intermittent claudication and risk of cardiovascular events. Angiology (1998) 49:843–848.[Web of Science][Medline]
  23. Wildman RP, Muntner P, Chen J, Sutton-Tyrrell K, He J. Relation of inflammation to peripheral arterial disease in the national health and nutrition examination survey, 1999–2002. Am J Cardiol (2005) 96:1579–1583.[CrossRef][Web of Science][Medline]
  24. Tzoulaki I, Murray GD, Lee AJ, Rumley A, Lowe GD, Fowkes FG. C-reactive protein, interleukin-6, and soluble adhesion molecules as predictors of progressive peripheral atherosclerosis in the general population: Edinburgh Artery Study. Circulation (2005) 112:976–983.[Abstract/Free Full Text]
  25. Silvestro A, Scopacasa F, Ruocco A, Oliva G, Schiano V, Zincarelli C, Brevetti G. Inflammatory status and endothelial function in asymptomatic and symptomatic peripheral arterial disease. Vasc Med (2003) 8:225–232.[Abstract/Free Full Text]
  26. Rossi E, Biasucci LM, Citterio F, Pelliccioni S, Monaco C, Ginnetti F, Angiolillo DJ, Grieco G, Liuzzo G, Maseri A. Risk of myocardial infarction and angina in patients with severe peripheral vascular disease: predictive role of C-reactive protein. Circulation (2002) 105:800–803.[Abstract/Free Full Text]
  27. Vainas T, Stassen FR, de Graaf R, Twiss EL, Herngreen SB, Welten RJ, van den Akker LH, van Dieijen-Visser MP, Bruggeman CA, Kitslaar PJ. C-reactive protein in peripheral arterial disease: relation to severity of the disease and to future cardiovascular events. J Vasc Surg (2005) 42:243–251.[CrossRef][Web of Science][Medline]
  28. Beckman JA, Preis O, Ridker PM, Gerhard-Herman M. Comparison of usefulness of inflammatory markers in patients with versus without peripheral arterial disease in predicting adverse cardiovascular outcomes (myocardial infarction, stroke, and death). Am J Cardiol (2005) 96:1374–1378.[CrossRef][Web of Science][Medline]
  29. Silvestro A, Brevetti G, Schiano V, Scopacasa F, Chiariello M. Adhesion molecules and cardiovascular risk in peripheral arterial disease Soluble vascular cell adhesion molecule-1 improves risk stratification. Thromb Haemost (2005) 93:559–563.[Web of Science][Medline]
  30. Heagerty PJ, Lumley T, Pepe MS. Time-dependent ROC curves for censored survival data and a diagnostic marker. Biometrics (2000) 56:337–344.[CrossRef][Web of Science][Medline]
  31. Efron B, Tibshirani RJ. An Introduction to the Bootstrap. (1993) London, UK: Chapman & Hall.
  32. Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO, Criqui M, Fadl YY, Fortmann SP, Hong Y, Myers GL, Rifai N, Smith SC, Taubert K, Tracy RP, Vinicor F. Centers for Disease Control and Prevention; American Heart Association. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation (2003) 107:499–511.[Free Full Text]
  33. Shabani F, McNeil J, Tippett L. The oxidative inactivation of tissue inhibitor of metalloproteinase-1 (TIMP-1) by hypochlorous acid (HOCI) is suppressed by anti-rheumatic drugs. Free Radic Res (1998) 28:115–123.[Web of Science][Medline]
  34. Fu X, Kassim SY, Parks WC, Heinecke JW. Hypochlorous acid oxygenates the cysteine switch domain of pro-matrilysin (MMP-7). A mechanism for matrix metalloproteinase activation and atherosclerotic plaque rupture by myeloperoxidase. J Biol Chem (2001) 276:41279–41287.[Abstract/Free Full Text]
  35. Sugiyama S, Okada Y, Sukhova GK, Virmani R, Heinecke JW, Libby P. Macrophage myeloperoxidase regulation by granulocyte macrophage colony-stimulating factor in human atherosclerosis and implications in acute coronary syndromes. Am J Pathol (2001) 158:879–891.[Abstract/Free Full Text]
  36. Dormandy J, Mahir M, Ascady G, Balsano F, De Leeuw P, Blombery P, Bousser MG, Clement D, Coffman J, Deutshinoff A. Fate of the patient with chronic leg ischaemia. A review article. J Cardiovasc Surg (1989) 30:50–57.[Medline]
  37. Newman AB, Shemanski L, Manolio TA, Cushman M, Mittelmark M, Polak JF, Powe NR, Siscovick D. Ankle-arm index as a predictor of cardiovascular disease and mortality in the Cardiovascular Health Study. The Cardiovascular Health Study Group. Arterioscler Thromb Vasc Biol (1999) 19:538–545.[Abstract/Free Full Text]
  38. Fowkes FG, Allan PL, Tsampoulas C, Smith FB, Donnan PT. Validity of duplex scanning in the detection of peripheral arterial disease in the general population. Eur J Vasc Surg (1992) 6:31–35.[CrossRef][Web of Science][Medline]
  39. Vink A, Schoneveld AH, Richard W, de Kleijn DP, Falk E, Borst C, Pasterkamp G. Plaque burden, arterial remodeling and plaque vulnerability: determined by systemic factors? J Am Coll Cardiol (2001) 38:718–723.[Abstract/Free Full Text]
  40. Pasterkamp G, Schoneveld AH, van der Wal AC, Hijnen DJ, van Wolveren WJ, Plomp S, Teepen HL, Borst C. Inflammation of the atherosclerotic cap and shoulder of the plaque is a common and locally observed feature in unruptured plaques of femoral and coronary arteries. Arterioscler Thromb Vasc Biol (1999) 19:54–58.[Abstract/Free Full Text]
  41. Kistorp C, Raymond I, Pedersen F, Gustafsson F, Faber J, Hildebrandt P. N-terminal pro-brain natriuretic peptide, C-reactive protein, and urinary albumin levels as predictors of mortality and cardiovascular events in older adults. JAMA (2005) 293:1609–1616.[Abstract/Free Full Text]
  42. Wang TJ, Gona P, Larson MG, Tofler GH, Levy D, Newton-Cheh C, Jacques PF, Rifai N, Selhub J, Robins SJ, Benjamin EJ, D'Agostino RB, Vasan RS. Multiple biomarkers for the prediction of first major cardiovascular events and death. N Engl J Med (2006) 355:2631–2639.[Abstract/Free Full Text]
  43. Blankenberg S, McQueen MJ, Smieja M, Pogue J, Balion C, Lonn E, Rupprecht HJ, Bickel C, Tiret L, Cambien F, Gerstein H, Munzel T, Yusuf S, HOPE Study Investigators. Comparative impact of multiple biomarkers and N-Terminal pro-brain natriuretic peptide in the context of conventional risk factors for the prediction of recurrent cardiovascular events in the Heart Outcomes Prevention Evaluation (HOPE) Study. Circulation (2006) 114:201–208.[Abstract/Free Full Text]

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