Relation of Elevated Levels of Plasma Myeloperoxidase to Impaired Myocardial Microcirculation After Reperfusion in Patients With Acute Myocardial Infarction

doi:10.1016/j.amjcard.2009.11.013

The American Journal of Cardiology

Volume 105, Issue 7, 1 April 2010, Pages 922-929

https://doi.org/10.1016/j.amjcard.2009.11.013 Get rights and content

Previous studies have shown that oxidative stress and endothelial dysfunction are related to impaired myocardial microcirculation after reperfusion. Moreover, elevated myeloperoxidase (MPO) levels are associated with endothelial dysfunction. Plasma MPO levels were measured in patients with ST-segment elevation acute myocardial infarction (n = 160) who had undergone percutaneous coronary stenting within 12 hours of symptom onset. We investigated whether the plasma MPO level at admission was associated with impaired myocardial microcirculation, as indicated by ST-segment resolution and myocardial blush grade after reperfusion, and left ventricular ejection fraction and remodeling at 6 months. The patients were divided into 2 groups according to the median MPO value for the entire cohort (low-MPO group ≤50 ng/ml, n = 80; high-MPO group >50 ng/ml, n = 80). ST-segment resolution and the myocardial blush grade were significantly lower in the high-MPO than in the low-MPO group (48 ± 27% vs 61 ± 24%, p <0.005; and 2.1 ± 0.8 vs 2.4 ± 0.7, p <0.01; respectively). Moreover, the percentage of increase in the left ventricular end-diastolic volume index was significantly greater and the left ventricular ejection fraction at 6 months was significantly lower in the high-MPO group than in the low-MPO group (8.2 ± 24.7% vs −1.9 ± 23.5%, p <0.05; and 46 ± 9% vs 54 ± 9%, p <0.0001, respectively). Multiple regression analysis showed that the plasma MPO level was an independent predictor of incomplete ST-segment resolution (odds ratio 6.94, 95% confidence interval 2.10 to 22.9, p = 0.0015). In conclusion, elevated plasma MPO levels at admission were associated with impaired myocardial microcirculation after reperfusion in patients with acute myocardial infarction.

Section snippets

Methods

The study included 240 consecutive patients with AMI who had undergone primary coronary stenting from July 2002 to June 2006. The inclusion criteria were symptoms consistent with AMI lasting >30 minutes, arrival at our hospital within 12 hours of the onset of chest pain, ST-segment elevation >2 mm in ≥2 contiguous precordial leads, and successful angioplasty, with no additional >50% stenosis of the infarct-related artery. Successful angioplasty was defined as correct stent deployment, stable

Results

The baseline patient characteristics among those with AMI, those with stable angina pectoris, and the control subjects are listed in Table 1. The mean plasma MPO level in the patients with AMI was 62.6 ± 43.7 ng/ml, significantly greater than that in those with stable angina pectoris (31.6 ± 26.1 ng/ml, p <0.0001) or the control subjects (17.0 ± 3.4 ng/ml, p <0.0001; Figure 1).

Of the 160 patients with AMI, 2 died in the hospital from pneumonia and acute renal failure; all other patients were

Discussion

To the best of our knowledge, this is the first study to demonstrate a strong relation between elevated plasma MPO levels and impaired myocardial microcirculation, as indicated by STR and myocardial blush grade, after reperfusion in patients with AMI. Moreover, the plasma MPO levels on admission were associated with left ventricular remodeling and dysfunction after reperfusion in patients with AMI.

Several studies using a Doppler guidewire,⁷ angiographic blush grade,⁸ or myocardial contrast

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Cited by (22)

Prognostic value of myeloperoxidase concentration in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention
2016, International Journal of Cardiology
Citation Excerpt :
MPO exerts its adverse effects even after the occurrence of complications of atherosclerosis. Studies by Yunoki et al. [25] showed that a high concentration of MPO in patients with ST-segment elevation myocardial infarction (STEMI) was associated with significantly worse reperfusion at the tissue level after successful primary percutaneous coronary intervention (pPCI) and with greater postinfarction cardiac remodeling. The role of MPO as a potential prognostic factor in patients with acute coronary syndromes (ACS) began after the publication of Brennan et al. in 2003.
Inflammation plays an important role on every stage of atherosclerosis. Myeloperoxidase (MPO), a leukocyte-derived enzyme that participates in the innate immunity, probably is involved in many stages of atherothrombosis. According to the recent studies, MPO is related with unfavorable outcome in patients with chest pain and acute coronary syndromes. Its role in prediction of outcomes after ST-segment elevation myocardial infarction (STEMI) remains unclear.
The aim of the study was to assess if elevated MPO level is a predictor of long-term adverse cardiac events in patients with STEMI treated with primary percutaneous coronary intervention (pPCI).
We evaluated data of 127 patients with STEMI. Plasma levels of MPO collected on admission and the 3rd–4th day of hospitalization were measured by ELISA method. C-reactive protein (CRP) and N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) were also determined. All patients were followed-up prospectively for the occurrence of major adverse cardiovascular events (MACE) defined as unscheduled coronary revascularization procedure, stroke, reinfarction or all-cause death.
After 14 months of follow-up 20% of patients developed MACE. Elevated MPO levels collected on the 3rd–4th day of STEMI were the predictor of death, reinfarction, the need for coronary revascularization and all adverse events taken together. In multivariate analysis, MPO and CRP levels assessed on the 3rd–4th day of hospitalization revealed to be significant predictors of MACE. MPO demonstrated to be significantly better predictor of MACE than NT-proBNP level.
Myeloperoxidase is a prognostic marker in patients with STEMI treated with pPCI.
Gender-specific correlation between plasma myeloperoxidase levels and serum high-density lipoprotein-associated paraoxonase-1 levels in patients with stable and unstable coronary artery disease
2013, Atherosclerosis
Citation Excerpt :
Therefore, these findings suggest that increased MPO levels may be a marker of plaque vulnerability and instability. Indeed, our previous data and the present study showed that circulating MPO concentrations are significantly higher in ACS patients than in SAP patients [7,8]. Hence, one could hypothesize that neutrophil infiltration and activation and MPO release at sites of inflammatory reactions and thrombosis in unstable plaques could contribute to an increase in MPO levels in the blood of UAP patients.
Low high-density lipoprotein (HDL) cholesterol is well-established as a negative risk factor for coronary artery disease (CAD) and its anti-oxidant property has been attributed mainly to the HDL-bound enzyme paraoxonase-1 (PON-1). Recently, myeloperoxidase (MPO), a pro-oxidant enzyme released from activated neutrophils, has been shown to alter the atheroprotective function of HDL to a dysfunctional form. This study investigated the relationship between plasma MPO and serum PON-1 levels in patients with stable (SAP) and unstable angina pectoris (UAP).
Plasma MPO levels and serum PON-1 concentration/activity were measured in patients with SAP (n = 226), UAP (n = 151) and in control subjects (n = 99).
Plasma MPO levels in UAP patients were significantly higher than those in SAP patients or in control subjects (UAP, 21.6[16.7–44.6]; SAP, 19.3[15.7–29.1]; control, 15.9[14.7–18.7] ng/mL; P < 0.0001). Serum PON-1 concentrations in UAP and SAP patients were significantly lower than those in control subjects (UAP, 55.6[45.9–69.7]; SAP, 55.0[46.9–64.9]; control, 62.5[51.1–78.8] μg/mL; P = 0.0002). Plasma MPO levels showed a weak inverse correlation with serum PON-1 concentrations in all subjects (R = −0.163, P < 0.0005). Moreover, in women, plasma MPO levels showed a significant inverse correlation with serum PON-1 concentrations and PON-arylesterase activity in SAP (concentration: R = −0.537, P < 0.0001; arylesterase-activity: R = −0.469, P < 0.001) and UAP (concentration: R = −0.340, P < 0.05; arylesterase-activity: R = −0.350, P < 0.05) patients, but not in men.
This study demonstrates that plasma MPO levels have a significant inverse correlation with PON-1 levels, especially in women, in SAP and UAP patients, and suggests that an imbalance between pro-oxidants and anti-oxidants may contribute to the progression of coronary plaque instability.
N-acetyl lysyltyrosylcysteine amide inhibits myeloperoxidase, a novel tripeptide inhibitor
2013, Journal of Lipid Research
Myeloperoxidase (MPO) plays important roles in disease by increasing oxidative and nitrosative stress and oxidizing lipoproteins. Here we report N-acetyl lysyltyrosylcysteine amide (KYC) is an effective inhibitor of MPO activity. We show KYC inhibits MPO-mediated hypochlorous acid (HOCl) formation and nitration/oxidation of LDL. Disulfide is the major product of MPO-mediated KYC oxidation. KYC (⩽4,000 μM) does not induce cytotoxicity in bovine aortic endothelial cells (BAECs). KYC inhibits HOCl generation by phorbol myristate acetate (PMA)-stimulated neutrophils and human promyelocytic leukemia (HL-60) cells but not superoxide generation by PMA-stimulated HL-60 cells. KYC inhibits MPO-mediated HOCl formation in BAEC culture and protects BAECs from MPO-induced injury. KYC inhibits MPO-mediated lipid peroxidation of LDL whereas tyrosine (Tyr) and tryptophan (Trp) enhance oxidation. KYC is unique as its isomers do not inhibit MPO activity, or are much less effective. Ultraviolet-visible spectral studies indicate KYC binds to the active site of MPO and reacts with compounds I and II. Docking studies show the Tyr of KYC rests just above the heme of MPO. Interestingly, KYC increases MPO-dependent H₂O₂ consumption. These data indicate KYC is a novel and specific inhibitor of MPO activity that is nontoxic to endothelial cell cultures. Accordingly, KYC may be useful for treating MPO-mediated vascular disease.
Myeloperoxidase in Cardiovascular Disease
2013, Advances in Clinical Chemistry
Myeloperoxidase (MPO) plays a central role in the innate immune system by generating leukocyte-derived oxidants to combat invading pathogens. These reactive intermediates have been increasingly recognized to be potentially deleterious, causing oxidative injury in inflammatory disease states such as cardiovascular disease. Recent evidence now suggests that circulating MPO can act as a clinical prognostic indicator for patients with cardiovascular disease.
Usefulness of circulating biomarkers for the prediction of left ventricular remodeling after myocardial infarction
2012, American Journal of Cardiology
Citation Excerpt :
We included studies that reported LV volumes or LV diameters as indicators of LV remodeling. Because variability of the data reported (morphologic and biological variables on their original continuous scales or dichotomized into 2 groups) precluded a formal meta-analysis, relations between biomarkers and LV remodeling are presented in Table 1 as positive if a high level of the biomarker was significantly associated (p <0.05) with increased LV remodeling, negative if a low level of the biomarker was significantly associated (p <0.05) with increased LV remodeling, and none in the absence of any significant association.1–59 To visualize the association of a given biomarker with LV remodeling, data were grouped by biomarker; thus, publications that assessed >1 biomarker appear >1 time in Table 1.
Left ventricular (LV) remodeling after myocardial infarction (MI) indicates a high risk of heart failure and death, but LV remodeling remains difficult to predict. Biomarkers may help to refine risk stratification for a more personalized medical approach. They may also shed light on the pathophysiologic processes involved. We performed a systematic review of the published evidence about the association of circulating biomarkers with LV remodeling after MI. We selected 59 publications. Overall, these studies examined 112 relations between 52 different biomarkers and LV remodeling. The biomarkers most consistently associated with LV remodeling were involved in extracellular matrix turnover or neurohormonal activation: matrix metalloproteinase-9, collagen peptides, and B-type natriuretic peptide. This review underscores the vitality of the research on LV remodeling but concludes that the ideal biomarker has not yet been identified. To reach this goal, future studies will have to be larger, have standardized imaging end points, and include replication populations to define optimal cutoffs for LV remodeling prediction. Cardiovascular magnetic resonance appears to be the best technique for LV remodeling assessment but its current availability may be a concern for recruitment for multicenter studies. Recent technologic advances will probably yield new candidate biomarkers of LV remodeling. Tests are necessary to determine whether a multimarker approach would significantly improve risk prediction.
Time-dependent changes of myeloperoxidase in relation to in-hospital mortality in patients with the first anterior ST-segment elevation myocardial infarction treated by primary percutaneous coronary intervention
2012, Clinical Biochemistry
Citation Excerpt :
The degree of MPO increase is influenced by various factors such as myocyte necrosis and reperfusion [20–22], as well as time of sampling after the presentation [23]. Single MPO measurement before pPCI [18,19] raises the possibility that MPO does not reflect several aspects of the patient's post procedural condition [22,24–26]. Accordingly, we have evaluated the optimal MPO sampling to stratify the risk in STEMI treated by pPCI.
To analyze the prognostic value of myeloperoxidase (MPO) in relation to in-hospital mortality and to identify the optimum time point for sampling in patients with the first anterior ST-segment elevation myocardial infarction (STEMI) treated by primary percutaneous coronary intervention (pPCI).
A total of 100 consecutive patients with the first anterior STEMI undergoing pPCI were included. Blood samples were collected at baseline, 4, 8, 12, 18, 24, 48 and 168 hours (h) after pPCI.
MPO concentrations have showed a biphasic pattern over time; the highest MPO levels were at4 h and 24 h after pPCI. In-hospital mortality was 6%. MPO at 24 h significantly correlated with troponin I as well as heart failure. After multivariate adjustment, MPO at 24 h was an independent predictor of the in-hospital mortality (OR 3.34, 95% CI 1.13–9.86, P = 0.029).
In patients with the first anterior STEMI treated by pPCI, MPO at 24 h after procedure was an independent predictor of the in-hospital mortality.

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: Dr. Yunoki was a research fellow from Okayama University Graduate School of Medicine, Okayama, Japan during the study period.

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Coronary artery diseaseRelation of Elevated Levels of Plasma Myeloperoxidase to Impaired Myocardial Microcirculation After Reperfusion in Patients With Acute Myocardial Infarction

Section snippets

Methods

Results

Discussion

J Biol Chem

J Am Coll Cardiol

Am J Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

J Biol Chem

Free Radic Biol Med

Am J Cardiol

Myeloperoxidase-generated reactive nitrogen species convert LDL into an atherogenic form in vitro

J Clin Invest

Serum myeloperoxidase levels independently predict endothelial dysfunction in humans

Circulation

Direct comparison of transcardiac difference between brain natriuretic peptide (BNP) and N-terminal pro-BNP in patients with chronic heart failure

Eur J Heart Fail

Prognostic value of myeloperoxidase in patients with chest pain

N Engl J Med

Incomplete resolution of ST-segment elevation is a marker of transient microcirculatory dysfunction after stenting for acute myocardial infarction

Circulation

Angiographic assessment of myocardial reperfusion in patients treated with primary angioplasty for acute myocardial infarction: myocardial blush grade

Circulation

Coronary artery disease
Relation of Elevated Levels of Plasma Myeloperoxidase to Impaired Myocardial Microcirculation After Reperfusion in Patients With Acute Myocardial Infarction