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. Author manuscript; available in PMC: 2009 Sep 27.
Published in final edited form as: Vasc Med. 2009 Aug;14(3):215–220. doi: 10.1177/1358863X08101999

Association of Serum Myeloperoxidase with Peripheral Arterial Disease

Zeenat Ali 1, Paul Sarcia 2, Thomas H Mosley Jr 3, Iftikhar J Kullo 1
PMCID: PMC2752685  NIHMSID: NIHMS125748  PMID: 19651670

Abstract

Myeloperoxidase (MPO) is an enzymatic mediator of several inflammatory cascades and higher serum levels have been associated with increased risk of adverse cardiovascular events. We investigated the association of serum MPO with the ankle-brachial index (ABI) and peripheral arterial disease (PAD), in a bi-ethnic cohort of African-Americans and non-Hispanic whites. Participants included 1324 African-Americans (64 y, 71% women) and 1237 non- Hispanic whites (59 y, 57% women) belonging to hypertensive sibships. Plasma levels of MPO were measured by solid phase sandwich immunoassay. ABI was measured using a standard protocol and PAD defined as ABI <0.90. Multivariable regression analysis using generalized estimating equations (GEE) were performed to assess whether serum MPO levels were associated with ABI and the presence of PAD. After adjustment for age and sex, higher MPO levels were significantly associated with lower ABI and presence of PAD in African-Americans (P=0.004 and P=0.005, respectively) and in non-Hispanic whites (P=0.001and P=0.021, respectively). After additional adjustment for conventional risk factors (diabetes, smoking status, total and HDL cholesterol, waist circumference, hypertension), prior history of myocardial infarction or stroke, and medication use (statins, aspirin, estrogen), higher MPO levels remained significantly associated with lower ABI and presence of PAD in both African- Americans (P=0.008 and P=0.012, respectively) and non-Hispanic whites (P=0.001and P=0.029, respectively). We conclude that higher MPO levels are associated with lower ABI and the presence of PAD in African-Americans and non-Hispanic whites.

Keywords: peripheral arterial disease, inflammation, ankle-brachial index, myeloperoxidase

Introduction

Inflammation plays a key role in the development and evolution of atherosclerotic plaque.1 Myeloperoxidase (MPO), an enzyme secreted by activated neutrophils, participates in various inflammatory processes involved in atherosclerosis.2,3 MPO has been implicated in the initiation and progression of atherosclerotic lesions through mechanisms related to its role in low-density lipoprotein (LDL) oxidation,2 consumption of nitric oxide leading to endothelial dysfunction4,5 and generation of numerous oxidative reactants and diffusible free radical species.6 Using immunohistochemistry and mass spectrometry, atherosclerotic plaques have been shown to be abundant in oxidation products generated by MPO.3,7–9 MPO levels are associated with the risk of coronary artery disease in apparently healthy individuals,10 with the presence and severity of coronary artery disease,11,12 and are predictive of adverse outcomes in patients presenting with chest pain13 or an acute coronary syndrome.14

Peripheral arterial disease (PAD) is a manifestation of atherosclerosis and affects ~ 8 million people in United States.15,16 Prior reports indicate that inflammation plays an important role in the development,17 progression18 and severity19 of PAD. Whether MPO is associated with systemic atherosclerotic burden is not known. We therefore investigated whether serum MPO is associated with ankle-brachial index (ABI) and the presence of PAD, as defined by ABI <0.90. Furthermore we investigated whether any association is independent of plasma C-reactive protein (CRP), a marker of systemic inflammation.

Methods

The study was part of the Proteomic Markers of Arteriosclerosis Study which is investigating the association of markers in various etiologic pathway of vascular disease with several phenotypes of arteriosclerosis. Participants belonged to the Genetic Epidemiology Network of Arteriopathy (GENOA) Study, a multicenter, community-based study that aims to identify genetic variants influencing blood pressure (BP) levels and the development of target organ damage due to hypertension.20 The study was approved by the Institutional Review Boards of the University of Mississippi Medical Center, Jackson, MS and Mayo Clinic, Rochester, MN. Written informed consent was obtained from each participant. Recruitment and participant characteristics in the initial phase of this study have been previously described.21 The present study included 2561 participants (1324 African Americans and 1237 non-Hispanic whites).

Height was measured by stadiometer, weight by electronic balance, and body mass index (BMI) was calculated as weight in kilograms divided by the square of height in meters. Resting systolic BP and diastolic BP were measured in the supine position by random zero sphygmomanometer. The diagnosis of hypertension was established based on BP levels measured at the study visit (≥140/90 mm Hg) or a prior diagnosis of hypertension and current treatment with antihypertensive medications. Diabetes was considered present if the subject was being treated with insulin or oral agents or had a fasting glucose level ≥126 mg/dl. ‘Ever’ smoking was defined as having smoked ≥100 cigarettes. Information about the use of BP medications and statins was obtained from the participants at the time of the study visit. Blood was drawn by venipuncture after an overnight fast. Serum total cholesterol and high-density lipoprotein (HDL) cholesterol were measured by standard enzymatic methods.

Serum myeloperoxidase (MPO) and C-reactive protein (CRP) assays

Serum MPO levels were measured by a solid phase sandwich ELISA (ALPCO Diagnostics, Salem, NH). Intra-assay coefficients of variation (CVs) were 7.4, 53.8, and 7.4% at 4.1, 53.8, and 165.6 ng/mL, respectively, and inter-assay CVs were 10.7 and 12.4% at 2.8 and 52.2 ng/mL. Plasma CRP levels were measured by a highly sensitive immunoturbidimetric assay. Inter-assay CVs were: 14%, 3.2%, 3.4%, and 3.6% at 0.33, 1.05, 9.07, and 23.8 mg/dL, respectively.

Ankle-brachial index (ABI)

At each center examiners who underwent training in Mayo Clinic’s non-invasive vascular laboratory in Rochester MN measured the ABI. This identical, standardized protocol was used at both centers. ABI was measured as follows: After a 5-min rest, subjects were evaluated in the supine position. Appropriately sized BP cuffs were placed on each arm and ankle, and a Doppler ultrasonic instrument (Medisonics, Minneapolis MN) was used to detect arterial signals. The cuff was inflated to 10 mm Hg above SBP and deflated at 2 mm Hg/s. The first reappearance of the arterial signal was taken as the SBP. To calculate the ABI, the SBP at each ankle site (posterior tibial and dorsalis pedis arteries) was divided by the higher of the two brachial pressures. The lower of the average ABIs from the two legs was used in the analyses. ABI <0.90 was used to indicate presence of PAD. Subjects with ABI >1.4 (n = 28) were excluded from the analyses as they may have non-compressible arteries due to medial arterial calcification.22

Statistical Methods

Continuous data were summarized as either mean ± SD or median and quartiles and categorical data were expressed as percentages (%). Due to significant differences in age and the proportion of women in the two ethnic groups, differences in characteristics between the two ethnic groups were assessed after adjustment for age and sex. Plasma triglycerides, serum MPO and plasma CRP were log transformed to reduce skewness. Spearman correlations between serum MPO and plasma CRP were calculated in each ethnic group.

Analyses to assess whether serum MPO is independently associated with ABI and PAD were performed separately in each ethnic group. In each ethnic group, multiple regression models were constructed to include age, sex, waist circumference (as a measure of adiposity), history of smoking, diabetes, hypertension, total cholesterol, HDL cholesterol, medication (statin, aspirin, estrogen) use, and previous history of myocardial infarction or stroke. Backward elimination was performed to identify variables independently associated with ABI. Age and sex were forced into all multivariable regression models. Because of the presence of sibships in the sample, regression analyses were performed using generalized estimating equations (GEE).23 We also assessed whether MPO contributed to the prediction of presence of PAD. Models before and after the additionof MPO were compared by calculating the c-statistic from receiver operating characteristic (ROC) curve analyses.

A two-sided P-value of <0.05 was deemed statistically significant. Statistical analyses were carried out using SAS v 8.2 (SAS Institute, Cary NC) software package.

Results

Table 1 shows baseline characteristics of the two ethnic groups. African- Americans were significantly older and had higher risk factor burden compared to non–Hispanic whites. The proportion of women was higher in both ethnic groups and the majority of participants were hypertensive. Use of statins, estrogen and aspirin was less frequent in African Americans than their non-Hispanic white counterparts. ABI was lower in African Americans as compared to non-Hispanic whites (P<0.001). Serum MPO levels were higher in African-Americans than in non-Hispanic whites (P<0.0001). MPO levels were significantly correlated with CRP levels in African-American (ρ=0.260, P<0.0001) and a weaker correlation was noted in non-Hispanic whites (ρ=0.128, P<0.0001).

Table 1.

Subject characteristics. (n = 2561)*

African Americans (n = 1324) Non-Hispanic whites (n = 1237) P
Age, years 63.6 ± 9.3 58.9 ± 10.2 <0.0001
Men, n (%) 388 (29.3) 535 (43.2) <0.0001
BMI, kg/m2 31.6 ± 6.6 30.8 ± 6.3 0.0021
Waist circumference, cm 103.6 ± 14.5 100.7 ± 15.9 <0.0001
Total cholesterol, mg/dL 201.8 ± 41.5 197.2 ± 34.6 0.0028
HDL cholesterol, mg/dL 57.6 ± 18.2 51.8 ± 15.2 <0.0001
Systolic BP, mm Hg 138.5 ± 20.9 131.1 ± 17.1 <0.0001
Diastolic BP, mm Hg 79.1 ± 10.8 73.9 ± 9.2 <0.0001
Previous history of MI or stroke 131 (9.9) 92 (7.4) 0.0275
Smoking, n (%) 539 (40.7) 610 (49.3) <0.0001
Diabetes, n (%) 391 (29.5) 185 (15.0) <0.0001
Hypertension, n (%) 1058 (79.9) 902 (72.9) <0.0001
Triglyceride, mg/dL 119.1 ± 68.7 156.5 ± 94.2 <0.0001
Statin use, n (%) 246 (18.6) 362 (29.3) <0.0001
Aspirin, n (%) 436 (32.9) 510 (41.2) <0.0001
Estrogen, n (%) 222 (16.8) 277 (22.4) 0.0003
MPO, ng/mL 43.3 ± 29.4 35.8 ± 30.5 <0.0001
PAD, n ( %) 151 (11.7) 74 (6.3) <0.0001
Ankle-brachial index 1.0 ± 0.1 1.1 ± 0.1 <0.0001
C-reactive protein, mg/dL 5.9 ± 6.5 4.2 ± 5.1 <0.0001
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*

Data are presented as mean ± SD or percentage of study participants.

*

BMI, body mass index; HDL, high-density lipoprotein; MPO, myeloperoxidase

*

In African- Americans, n for MPO, PAD and ABI is 1164, 1294 and 1294 respectively; in NHW, n for MPO, PAD and ABI is 1215, 1177and 1177 respectively.

In African-Americans, after adjustment for age and sex in linear regression models, higher MPO levels were significantly associated with lower ABI (P=0.004). These associations remained significant after further adjustment for conventional risk factors (P=0.008). However, after additional adjustment for plasma CRP, the association of higher MPO levels with lower ABI was of borderline significance (P=0.094) (Table 2). The results of multivariable logistic regression models were consistent with those of linear regression models. After adjustment for age and sex, higher MPO levels were significantly associated with presence of PAD (P=0.005). After additional adjustment for conventional risk factors, higher MPO levels remained significantly associated with presence of PAD (P=0.012). However the association was not statistically significant after additional adjustment for plasma CRP (P=0.209) (Table 3). In ROC curve analysis, the c-statistic for predicting PAD was 0.784 using age, sex and conventional risk factors. After addition of MPO, the c-statistic was essentially unchanged (0.785).

Table 2.

Association of MPO with ABI: Linear Regression Models

African Americans Non-Hispanic whites
β ± SE P β ± SE P
Unadjusted model −0.014 ± 0.006 0.019 −0.021 ± 0.006 0.0001
Model 1 −0.017 ± 0.006 0.004 −0.017 ± 0.005 0.001
Model 2 −0.015 ± 0.006 0.008 −0.018 ± 0.005 0.001
Model 3 −0.010 ± 0.006 0.094 −0.017 ± 0.005 0.001
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Model 1: Adjusted for age and sex

Model 2: Adjusted for age, sex, history of myocardial infarction or stroke, smoking, diabetes, estrogen use, waist circumference, total and HDL cholesterol.

Model 3: Adjusted for age, sex, history of myocardial infarction or stroke, smoking, diabetes, estrogen use, waist circumference, total and HDL cholesterol, and C-reactive protein.

Table 3.

Association of MPO with PAD: Logistic Regression Models

African Americans Non-Hispanic whites
β ± SE P β ± SE P
Unadjusted model 0.242 ± 0.132 0.067 0.532 ± 0.185 0.004
Model 1 0.399 ± 0.143 0.005 0.427 ± 0.186 0.021
Model 2 0.372 ± 0.149 0.012 0.455 ± 0.208 0.029
Model 3 0.193 ± 0.154 0.209 0.445 ± 0.209 0.033
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Model 1: Adjusted for age and sex

Model 2: Adjusted for age, sex, history of myocardial infarction or stroke, smoking, diabetes, estrogen use, waist circumference, total and HDL cholesterol.

Model 3: Adjusted for age, sex, history of myocardial infarction or stroke, smoking, diabetes, estrogen use, waist circumference, total and HDL cholesterol, and C-reactive protein.

In non-Hispanic whites, after adjustment for age and sex in linear regression models, higher MPO levels were significantly associated with lower ABI (P=0.001). These associations were robust to additional adjustment for conventional risk factors (P=0.001) and plasma CRP (P=0.001) (Table 2). The results of multivariable logistic regression models were consistent with those of linear regression models. After adjustment for age and sex, higher MPO levels were significantly associated with presence of PAD (P=0.021). These associations remained significant after further adjustment for conventional risk factors (P=0.029) and plasma CRP (P=0.033) (Table 3). In ROC curve analysis, the c-statistic for predicting PAD was 0.856 using age, sex and conventional risk factors. After addition of MPO, the c-statistic increased modestly to 0.866.

Discussion

The results of this study demonstrate that higher serum MPO levels are associated with lower ABI and presence of PAD, independent of age, sex and conventional risk factors. Additional adjustment for plasma CRP, a marker of systemic inflammation, attenuated these associations in African-Americans but not in non-Hispanic whites. Addition of MPO to a model including age, sex and conventional risk factors led to a modest increase in the c-statistic for the presence of PAD in non-Hispanic whites but not in African-Americans.

The results of several recent studies indicate that MPO plays a key role in the evolution of atherosclerosis, through various mechanisms leading to initiation, propagation and subsequent complications of atherosclerotic plaque formation. MPO-generated reactive species promote oxidation,24,25 lipid peroxidation 26 and crosslinking of LDL,27 facilitating uptake by macrophages.2,28 MPO also plays a role in the generation of dysfunctional HDL29–31 and interferes with its capacity to promote cholesterol efflux.32 MPO leads to endothelial dysfunction by serving as an enzymatic sink for nitric oxide, limiting its bioavailability and function.33–35 MPO derived reactive species contribute to plaque destabilization and rupture by activating various protease cascades that affect the stability and thrombogenicity of plaques.36–38

Several studies have shown an association between MPO and coronary heart disease. In a prospective nested case-control study conducted among apparently healthy men and women (n=1,138 for cases and n=2,237 for controls), baseline MPO levels were significantly higher in individuals who developed coronary heart disease during 8 years of follow up than among those who did not.10 Higher serum MPO levels have been associated with the presence11 and severity12 of coronary artery disease on angiography and are predictive of adverse outcomes in patients presenting to emergency department with chest pain.13 In the CAPTURE study (a randomized placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina, n=1090), serum MPO was an independent predictor of adverse cardiac outcomes over 6 months of follow up.14 Brevetti et al39 demonstrated that in patients with PAD, higher serum MPO levels predict risk of developing myocardial infarction/stroke.

To the best of our knowledge, the present study is the first to show a cross-sectional association between MPO and presence of PAD. Adjustment for conventional risk factors did not attenuate the association, indicating that MPO is not strongly associated with such risk factors. Indeed, we confirmed that MPO was poorly correlated with age, sex, presence of hypertension/diabetes, plasma lipids and smoking status (analyses not shown). Thus MPO appears to be an ‘orthogonal’ marker that may have clinical utility in assessing risk for developing PAD. In ROC curve analyses, there was no increase in the c-statistic for predicting PAD after addition of MPO to a model that included age, sex and conventional risk factors in African Americans and only a small increase in c-statistic in non-Hispanic whites. Single markers may not yield a significant increase in the c-statistic and multiple markers may be needed to obtain predictive information that is incremental to conventional risk factors.40,41 Further investigation is needed to assess the utility of MPO in multimarker panels for predicting risk of PAD.42

A strength of the present study is the inclusion of a large bi-ethnic cohort of individuals from the community. We used uniform protocols in the two ethnic groups including questionnaires, anthropometric measurements, assessment of conventional risk factors, and the MPO assay. Limitations include the cross-sectional nature of the study making it difficult make inferences about causality. Confounding by unknown potential causal factors cannot be ruled out. The majority of the study participants were hypertensive and therefore, the findings may not be generalizable to the entire population and further studies need to be done in normotensives and younger adults.

In conclusion our study demonstrates an association between serum MPO levels and PAD, a surrogate for systemic atherosclerosis, independent of conventional risk factors. However the association, although statistically significant, was modest and not independent of plasma CRP level in African-Americans. Further investigation is needed to assess whether MPO could serve as a biomarker for future risk of PAD and to identify PAD patients at risk for adverse outcomes.

Acknowledgments

The authors would like to acknowledge Venkateswarlu Kondragunta and Guanghui Liu for help with statistical analyses. This work was funded by grants HL81331 and HL75794 from the National Institutes of Health.

Footnotes

Disclosures

No conflicts of interest to disclose

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