Background
Major depressive disorder (MDD) has been linked to inflammation, but this association may be due to common precursors to both depression and inflammation. Myeloperoxidase (MPO) is an inflammatory enzyme produced by activated leukocytes that predicts risk of coronary heart disease. We sought to examine whether MPO and other markers of inflammation are associated with MDD and whether the association is confounded by genetic or other shared familial factors.
Methods
We examined 178 monozygotic and dizygotic middle-aged male twin pairs. We assessed MDD with the Structured Clinical Interview for DSM-IV. Blood markers of inflammation included MPO, interleukin-6, white blood cell count, C-reactive protein, necrosis factor (TNF)-α, the TNF-α soluble receptor II, and fibrinogen. Analyses were conducted in the overall sample and among 67 twin pairs discordant for MDD using mixed effects regression.
Results
Twins with a history of MDD had 32% higher levels of MPO (p < .0001); this difference persisted after adjusting for other risk factors. Among dizygotic MDD-discordant twin pairs, twins with MDD had 77% higher MPO than their brothers without MDD, after adjusting for other factors (p < .0001). In contrast, no significant association was found in monozygotic twins (p = .13). Similar, but weaker, associations were found between MDD and other inflammatory biomarkers.
Conclusions
Myeloperoxidase is a useful biomarker of immune activation in MDD. However, the association between inflammation and MDD is largely due to common genetic liability. Our results are consistent with the hypothesis that genes promoting inflammation are involved in the pathogenesis of MDD.
Plasma levels of myeloperoxidase are not elevated in patients with stable coronary artery disease
Background
Plasma and serum levels of myeloperoxidase (MPO), a redox-active hemoprotein released by polymorphonuclear neutrophils (PMN) upon activation, is now recognized as a powerful prognostic determinant of myocardial infarction in patients suffering acute coronary syndromes. However, there is limited information on whether systemic MPO levels are also elevated and of discriminating value in patients with stable coronary artery disease (CAD) representing different ethnic groups.
Methods
Plasma levels of MPO and traditional CAD risk factors were quantified in African American and Caucasian patients (n = 557) undergoing elective coronary angiography.
Results
MPO levels did not differ significantly between patients with or without CAD [421 pM (321, 533) vs. 412 pM (326, 500), p > 0.05]. MPO levels were similar across ethnicity and gender, and correlated positively with CRP and fibrinogen levels (r = 0.132, p = 0.002 and r = 0.106, p = 0.011, respectively).
Conclusion
In conclusion, plasma MPO levels were not elevated in patients with stable CAD, suggesting that systemic release of MPO is not a characteristic feature of asymptomatic CAD.
Lukas Kubalaa, d , Guijing Lub, Stephan Balduse, Lars Berglundb, f and Jason P. Eiserich
ARTICLE
Plasma and serum levels of myeloperoxidase (MPO), a redox-active hemoprotein released by polymorphonuclear neutrophils (PMN) upon activation, is now recognized as a powerful prognostic determinant of myocardial infarction in patients suffering acute coronary syndromes. However, there is limited information on whether systemic MPO levels are also elevated and of discriminating value in patients with stable coronary artery disease (CAD) representing different ethnic groups.
Methods
Plasma levels of MPO and traditional CAD risk factors were quantified in African American and Caucasian patients (n = 557) undergoing elective coronary angiography.
Results
MPO levels did not differ significantly between patients with or without CAD [421 pM (321, 533) vs. 412 pM (326, 500), p > 0.05]. MPO levels were similar across ethnicity and gender, and correlated positively with CRP and fibrinogen levels (r = 0.132, p = 0.002 and r = 0.106, p = 0.011, respectively).
Conclusion
In conclusion, plasma MPO levels were not elevated in patients with stable CAD, suggesting that systemic release of MPO is not a characteristic feature of asymptomatic CAD.
Lukas Kubalaa, d , Guijing Lub, Stephan Balduse, Lars Berglundb, f and Jason P. Eiserich
ARTICLE
MPO-ANCA Induces IL-17 Production by Activated Neutrophils in Vitro Via its Fc Region- and Complement-Dependent Manner
The elevation of serum anti-neutrophil cytoplasmic autoantibodies (ANCA) is significantly associated with the progression of some patients with systemic vasculitis. Especially, myeloperoxidase-specific ANCA (MPO-ANCA) play a pivotal role in the progression of systemic vasculitis including crescentic glomerulonephritis. Here we demonstrated that MPO-ANCA-activated neutrophils allow the local environment to differentiate Th17 cells through IL-6, IL-17A, and IL-23 production. We found a variety of elevated serum cytokines, especially IL-17A, in ANCA-mediated systemic vasculitis mice. Furthermore, activated peritoneal neutrophils in vitro also produced IL-17A and IL-23 in response to MPO-ANCA. Co-stimulation of fungal mannoprotein and complements significantly enhanced the MPO-ANCA-mediated IL-17A expression, but F(ab)′2 fragments of MPO-ANCA diminished the cytokine response. These results suggest that the activated neutrophils produce IL-17A and IL-23 in response to MPO-ANCA via their Fc-region and classical complement pathway, which initiate the first steps of chronic autoimmune inflammation by allowing the local environment to develop Th17-mediated autoimmunity.
Akiyoshi Hoshinoa, b, c, Tomokazu Nagaoc, d, Noriko Nagi-Miurae, Naohito Ohnoe, Masato Yasuharab, Kenji Yamamotoa, b, Toshinori Nakayamad and Kazuo Suzuki
Akiyoshi Hoshinoa, b, c, Tomokazu Nagaoc, d, Noriko Nagi-Miurae, Naohito Ohnoe, Masato Yasuharab, Kenji Yamamotoa, b, Toshinori Nakayamad and Kazuo Suzuki
A novel assay system for myeloperoxidase activity in whole saliva.
OBJECTIVES: The application of a novel assay system for the direct measurement of MPO (myeloperoxidase) activity in whole saliva .
DESIGN AND METHODS: The assay system employs a novel sensitive substrate from 3,3'-diaminobenzidine (DAB) and guaiacol in the presence of dapsone (4,4'-diaminodiphenylsulfone) to determine MPO activity in whole saliva using an original "sandwich" test-disk (DEAE-cellulose paper and cellulose chromatography paper). The saliva (0.1 mL) was directly applied to the sandwich test-disk, and then 0.1 mL of the substrate solution containing 1 mM dapsone in 0.3 M Tris-HCl buffer (pH 7.5) was added. After incubation for 30 min at room temperature, absorbance on the test-disk was measured at 460 nm with an optical analyzer.
RESULTS: The assay system was shown to distinguish MPO from salivary peroxidase in whole mixed saliva and was sensitive, easy and cheap. The assays revealed that MPO activity in whole saliva from subjects with periodontal disease was significantly higher than in saliva from healthy subjects. There was also a significant positive correlation between MPO activity and the probing depth of subgingival pockets (r=0.736, p<0.001).
CONCLUSIONS: These results indicate that this novel assay system for measurement of MPO is a useful technique for predicting the progression of periodontal disease.
Sakamoto W, Fujii Y, Kanehira T, Asano K, Izumi H.
Institute of Well Being, Fuji Women's University , 061-3204 Ishikari, Hokkaido, Japan; Serotec Laboratory, 069-0822 Ebetsu, Hokkaido, Japan. Clin Biochem. 2008 Jan 15
DESIGN AND METHODS: The assay system employs a novel sensitive substrate from 3,3'-diaminobenzidine (DAB) and guaiacol in the presence of dapsone (4,4'-diaminodiphenylsulfone) to determine MPO activity in whole saliva using an original "sandwich" test-disk (DEAE-cellulose paper and cellulose chromatography paper). The saliva (0.1 mL) was directly applied to the sandwich test-disk, and then 0.1 mL of the substrate solution containing 1 mM dapsone in 0.3 M Tris-HCl buffer (pH 7.5) was added. After incubation for 30 min at room temperature, absorbance on the test-disk was measured at 460 nm with an optical analyzer.
RESULTS: The assay system was shown to distinguish MPO from salivary peroxidase in whole mixed saliva and was sensitive, easy and cheap. The assays revealed that MPO activity in whole saliva from subjects with periodontal disease was significantly higher than in saliva from healthy subjects. There was also a significant positive correlation between MPO activity and the probing depth of subgingival pockets (r=0.736, p<0.001).
CONCLUSIONS: These results indicate that this novel assay system for measurement of MPO is a useful technique for predicting the progression of periodontal disease.
Sakamoto W, Fujii Y, Kanehira T, Asano K, Izumi H.
Institute of Well Being, Fuji Women's University , 061-3204 Ishikari, Hokkaido, Japan; Serotec Laboratory, 069-0822 Ebetsu, Hokkaido, Japan. Clin Biochem. 2008 Jan 15
Prognostic value of plasma myeloperoxidase concentration in patients with stable coronary artery disease
BACKGROUND: There are no studies yet on the usefulness of myeloperoxidase (MPO) as a prognostic tool in patients with stable coronary artery disease (CAD).
METHODS: The study included 382 patients with clinical and angiographic confirmation of stable CAD. Blood samples for MPO measurement were taken before angiography. Myeloperoxidase was determined using an enzyme immunoassay. The primary end point of the study was all-cause mortality.
RESULTS: Patients were categorized into 2 groups: the high-MPO group included patients in the third tertile of MPO levels (>75.0 microg/L; 127 patients), and the low-MPO group included patients in the first (<52.6 microg/L) and second tertiles (52.6-75.0 microg/L) of MPO levels (255 patients). The median follow-up was 3.5 [3.3-4.8] years. There were 35 deaths (9.2%) during the follow-up. The MPO concentration was 60.1 [47.0; 83.8] microg/L in survivors and 72.7 [54.8; 105.1] microg/L in nonsurvivors (P = .06). There were 17 deaths in the high-MPO level and 18 deaths in the low-MPO group: Kaplan-Meier estimates of mortality were 18.3% and 10.5% with an odds ratio of 1.96 (95% confidence interval [1.02-3.76], P = .04). The Cox proportional hazards model adjusting for correlates of mortality showed that plasma MPO was not an independent correlate of mortality (hazard ratio 1.06, 95% confidence interval [0.71-1.59], P = .77 for 1 SD increase in the log variable).
CONCLUSION: Although elevated plasma MPO concentration is associated with a more advanced cardiovascular risk profile, plasma MPO does not predict mortality independent of other cardiovascular risk factors in patients with stable CAD.
Am Heart J. 2008 Feb;155(2):356-60. Epub 2007 Dec 19,Faculty of Medicine, McGill University, Montreal, Quebec, Canada
METHODS: The study included 382 patients with clinical and angiographic confirmation of stable CAD. Blood samples for MPO measurement were taken before angiography. Myeloperoxidase was determined using an enzyme immunoassay. The primary end point of the study was all-cause mortality.
RESULTS: Patients were categorized into 2 groups: the high-MPO group included patients in the third tertile of MPO levels (>75.0 microg/L; 127 patients), and the low-MPO group included patients in the first (<52.6 microg/L) and second tertiles (52.6-75.0 microg/L) of MPO levels (255 patients). The median follow-up was 3.5 [3.3-4.8] years. There were 35 deaths (9.2%) during the follow-up. The MPO concentration was 60.1 [47.0; 83.8] microg/L in survivors and 72.7 [54.8; 105.1] microg/L in nonsurvivors (P = .06). There were 17 deaths in the high-MPO level and 18 deaths in the low-MPO group: Kaplan-Meier estimates of mortality were 18.3% and 10.5% with an odds ratio of 1.96 (95% confidence interval [1.02-3.76], P = .04). The Cox proportional hazards model adjusting for correlates of mortality showed that plasma MPO was not an independent correlate of mortality (hazard ratio 1.06, 95% confidence interval [0.71-1.59], P = .77 for 1 SD increase in the log variable).
CONCLUSION: Although elevated plasma MPO concentration is associated with a more advanced cardiovascular risk profile, plasma MPO does not predict mortality independent of other cardiovascular risk factors in patients with stable CAD.
Am Heart J. 2008 Feb;155(2):356-60. Epub 2007 Dec 19,Faculty of Medicine, McGill University, Montreal, Quebec, Canada
Myeloperoxidase, but not C-reactive protein, predicts cardiovascular risk in peripheral arterial disease
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 myeloperoxidase , C-reactive protein , and ankle brachial index (ABI) threshold levels that provided the best cut-off to predict the outcome. For MPO 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, Myeloperoxidase MPO , 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.
Brevetti G, Schiano V, Laurenzano E, Giugliano G, Petretta M, Scopacasa F, Chiariello M. Department of Clinical Medicine and Cardiovascular and Immunological Sciences, University of Naples,Eur Heart J. 2007 Dec 21
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 myeloperoxidase , C-reactive protein , and ankle brachial index (ABI) threshold levels that provided the best cut-off to predict the outcome. For MPO 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, Myeloperoxidase MPO , 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.
Brevetti G, Schiano V, Laurenzano E, Giugliano G, Petretta M, Scopacasa F, Chiariello M. Department of Clinical Medicine and Cardiovascular and Immunological Sciences, University of Naples,Eur Heart J. 2007 Dec 21
Usefulness of Baseline Plasma Myeloperoxidase Levels as an Independent Predictor of Myocardial Infarction at Two Years in Patients Presenting With Acu
Baseline plasma myeloperoxidase (MPO) levels have been shown to independently predict the early risk of myocardial infarction (MI) in patients presenting with chest pain. In addition, baseline MPO levels have been demonstrated to predict the development of adverse cardiac events up to 6 months after an acute coronary syndrome (ACS). However, in contrast to other biomarkers, there are no data about the long-term independent predictive value of baseline MPO values in patients with ACS.
The present study investigated the long-term prognostic significance of baseline Myeloperoxidase MPO levels in a well-characterized cohort of 193 men with ACS who were referred for coronary angiography at a Veterans Administration Medical Center. All patients were followed prospectively for the development of death and MI , and follow-up data were available for all patients at 24 months. After controlling for different baseline clinical, laboratory, and angiographic variables, baseline plasma MPO values were a strong and independent predictor of MI at 24 months by multivariate analysis.
Using the median MPO value of the entire cohort of patients (i.e., 20.34 ng/ml) as a prespecified cutoff, the MI-free survival at 24 months for the group whose baseline MPO values were ≤20.34 ng/ml was 88% compared with 74% in those whose values were >20.34 ng/ml (p = 0.0249 by log-rank test).
In conclusion, these data demonstrate that baseline MPO levels independently predict MI at 2 years in patients with ACS.
The American Journal of Cardiology
Volume 99, Issue 10, 15 May 2007, Pages 1364-1368
cDivision of Cardiovascular Medicine, Department of Medicine, University of Michigan , Ann Arbor, Michigan.
doi:10.1016/j.amjcard.2006.12.060
The present study investigated the long-term prognostic significance of baseline Myeloperoxidase MPO levels in a well-characterized cohort of 193 men with ACS who were referred for coronary angiography at a Veterans Administration Medical Center. All patients were followed prospectively for the development of death and MI , and follow-up data were available for all patients at 24 months. After controlling for different baseline clinical, laboratory, and angiographic variables, baseline plasma MPO values were a strong and independent predictor of MI at 24 months by multivariate analysis.
Using the median MPO value of the entire cohort of patients (i.e., 20.34 ng/ml) as a prespecified cutoff, the MI-free survival at 24 months for the group whose baseline MPO values were ≤20.34 ng/ml was 88% compared with 74% in those whose values were >20.34 ng/ml (p = 0.0249 by log-rank test).
In conclusion, these data demonstrate that baseline MPO levels independently predict MI at 2 years in patients with ACS.
The American Journal of Cardiology
Volume 99, Issue 10, 15 May 2007, Pages 1364-1368
cDivision of Cardiovascular Medicine, Department of Medicine, University of Michigan , Ann Arbor, Michigan.
doi:10.1016/j.amjcard.2006.12.060
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