Ratios of One-Carbon Metabolites Are Functional Markers of B-Vitamin Status in a Norwegian Coronary Angiography Screening Cohort.

Background: Functional (metabolic) markers of B-vitamin status, including plasma total homocysteine (tHcy) for folate and plasma methylmalonic acid (MMA) for vitamin B-12, suffer from moderate sensitivity and poor specificity. Ratios of metabolites belonging to the same pathway may have better performance characteristics.Objective: We evaluated the ratios of tHcy to total cysteine (tCys; Hcy:Cys), tHcy to creatinine (Hcy:Cre), and tHcy to tCys to creatinine (Hcy:Cys:Cre) as functional markers of B-vitamin status represented by a summary score composed of folate, cobalamin, betaine, pyridoxal 5'-phosphate (PLP), and riboflavin concentrations measured in plasma.Methods: Cross-sectional data were obtained from a cohort of patients with stable angina pectoris (2994 men and 1167 women) aged 21-88 y. The relative contribution of the B-vitamin score, age, sex, smoking, body mass index, and markers of renal function and inflammation to the variance of the functional B-vitamin markers was calculated by using multiple linear regression.Results: Compared with tHcy alone, Hcy:Cys, Hcy:Cre, and Hcy:Cys:Cre all showed improved sensitivity and specificity for detecting plasma B-vitamin status. Improvements in overall performance ranged from 4-fold for Hcy:Cys to ∼8-fold for Hcy:Cys:Cre and were particularly strong in subjects with the common 5,10-methylenetetrahydrofolate reductase (MTHFR) 677CC genotype.Conclusions: Ratios of tHcy to tCys and/or creatinine showed a severalfold improvement over tHcy alone as functional markers of B-vitamin status in Norwegian coronary angiography screenees. The biological rationale for these ratios is discussed in terms of known properties of enzymes involved in the catabolism of homocysteine and synthesis of creatine and creatinine.

Variant Aldehyde Dehydrogenase 2 (ALDH2*2) in East Asians Interactively Exacerbates Tobacco Smoking Risk for Coronary Spasm　- Possible Role of Reactive Aldehydes.

BACKGROUND: Coronary spastic angina (CSA) is common among East Asians and tobacco smoking (TS) is an established risk factor for CSA. Aldehyde dehydrogenase 2 (ALDH2) plays a key role in removing reactive toxic aldehydes and a deficient variant ALDH2 genotype (ALDH2*2) is prevalent among East Asians. We examined the interaction between TS andALDH2*2as a risk factor for CSA to better understand the disease pathogenesis.Methods and Results:The study subjects comprised 410 patients (258 men, 152 women; mean age, 66.3±11.5) in whom intracoronary injection of acetylcholine was performed on suspicion of CSA.ALDH2genotyping was performed by direct application of the Taqman polymerase chain reaction system. Of the study subjects, 244 had CSA proven and 166 were non-CSA. The frequencies of male sex,ALDH2*2, alcohol flushing syndrome, TS, coronary organic stenosis, and plasma levels of uric acid were higher (P<0.001, P<0.001, P<0.001, P<0.001, P<0.001, and P=0.015, respectively) and that of high-density lipoprotein cholesterol lower (P=0.002) in the CSA than non-CSA group. Multivariable logistic regression analysis revealed thatALDH2*2and TS were significant risk factors for CSA (P<0.001 and P=0.002, respectively).ALDH2*2exacerbated TS risk for CSA more than the multiplicative effects of each. CONCLUSIONS: ALDH2*2synergistically exacerbates TS risk for CSA, probably through aldehydes.

KORVITIN REDUCES THE HIGH MAINTENANCE OF MYELOPEROXIDASE IN PLASMA OF BLOOD OF PATIENTS WITH THE ACUTE INFARCT OF MYOCARDIUM.

We studied the content of myeloperoxidase in plasma of blood, which is a new additional marker of the metabolic activity of phagocytes and the activity of inflammation in patientes with the acute infarct of myocardium and possibility of its correction of Korvitin. We inspected 15 practically healthy persons in which the content of myeloperoxidase was 74,5±16,3 ng/ml, 13 patients with a stable stenocardia (the conent of myeloperoxidase was 218,4±30,9 ng/ml) and 60 patients with acute infarct of myocardium (the content of myeloperoxidase was 606,0±59,3 ng/ml at the beginning of therapy) in the dynamics of treatment. In patients accepting standard treatment (without application of Korvitin), the content of myeloperoxidase was unchanged during 7 days of treatment. It patients administered korvitin, the action of this preparation depended on the initial level of myeloperoxidase. In Patients with the initial normal plasma content of myeloperoxidase (16,7%), its content insignificantly increased during the time course of the treatment, while in patients with the high initial level of myeloperoxidase (83,3%), its level declined during treatment.

Exogenous nitric oxide inhibits Rho-associated kinase activity in patients with angina pectoris: a randomized controlled trial.

The RhoA/Rho-associated kinase (ROCK) pathway has a key physiological role in the pathogenesis of atherosclerosis. Increased ROCK activity is associated with cardiovascular diseases. Endogenous nitric oxide (NO) has an anti-atherosclerotic effect, whereas the exogenous NO-mediated cardiovascular effect still remains controversial. The purpose of this study was to evaluate the effect of exogenous NO on ROCK activity in patients with angina pectoris. This is a prospective, open-label, randomized, controlled study. A total of 30 patients with angina pectoris were randomly assigned to receive 40 mg day(-1) of isosorbide mononitrate (n=15, 12 men and 3 women, mean age of 63±12 years, isosorbide mononitrate group) or conventional treatment (n=15, 13 men and 2 women, mean age of 64±13 years, control group) for 12 weeks. ROCK activity in peripheral leukocytes was measured by western blot analysis. ROCK activities at 4 and 12 weeks after treatment were decreased in the isosorbide mononitrate group (0.82±0.33 at 0 week, 0.62±0.20 at 4 weeks, 0.61±0.19 at 12 weeks, n=15 in each group, P<0.05, respectively) but not altered in the control group. ROCK1 and ROCK2 expression levels were similar in all treatment periods in the two groups. These findings suggest that the administration of exogenous NO can inhibit ROCK activity, indicating that the usage of exogenous NO could have a protective effect in patients with angina pectoris.

Post receptor determinants of acute platelet response to clopidogrel in patients with symptomatic myocardial ischemia.

BACKGROUND: Clopidogrel resistance is more common in patients with loss-of-function CYP2C19 genotypes. Since adenylate cyclase (AC) and soluble guanylate cyclase (sGC) pathways are variably impaired in patients with ischaemic heart disease, we tested the relevance of these determinants in patients undergoing acute loading with clopidogrel (600 mg) prior to non-emergent coronary stenting. METHODS: Inhibitory effects of prostaglandin E1 (PGE1, an AC activator) and sodium nitroprusside (NP, a sGC activator) on platelet aggregation were determined at baseline and compared with platelet responses to clopidogrel (4 h after administration) assessed as ∆ADP, and Platelet Reactivity Index (∆PRI). Data were analysed according to CYP2C19 genotype. RESULTS: In patients without loss of function mutations (n=18), ∆ADP but not ∆PRI, was directly correlated with baseline PGE1 responsiveness (rs=0.62, p=0.005)). NP responsiveness did not predict ∆ADP. However there was no relationship between clopidogrel responses and either PGE1 or NP responsiveness in patients with loss of function mutations. Multivariate correlates of clopidogrel response were both the genotype status (ß=-0.609, p<0.001) and the baseline response to PGE1 (ß=0.303, p=0.03). CONCLUSIONS: While genetically impaired bio-activation markedly limits acute (4 h) clopidogrel response, impaired AC signalling provides an additional cause for clopidogrel resistance.

Treatment with the 3-ketoacyl-CoA thiolase inhibitor trimetazidine does not exacerbate whole-body insulin resistance in obese mice.

There is a growing need to understand the underlying mechanisms involved in the progression of cardiovascular disease during obesity and diabetes. Although inhibition of fatty acid oxidation has been proposed as a novel approach to treat ischemic heart disease and heart failure, reduced muscle fatty acid oxidation rates may contribute to the development of obesity-associated insulin resistance. Our aim was to determine whether treatment with the antianginal agent trimetazidine, which inhibits fatty acid oxidation in the heart secondary to inhibition of 3-ketoacyl-CoA thiolase (3-KAT), may have off-target effects on glycemic control in obesity. We fed C57BL/6NCrl mice a high-fat diet (HFD) for 10 weeks before a 22-day treatment with the 3-KAT inhibitor trimetazidine (15 mg/kg per day). Insulin resistance was assessed via glucose/insulin tolerance testing, and lipid metabolite content was assessed in gastrocnemius muscle. Trimetazidine-treatment led to a mild shift in substrate preference toward carbohydrates as an oxidative fuel source in obese mice, evidenced by an increase in the respiratory exchange ratio. This shift in metabolism was accompanied by an accumulation of long-chain acyl-CoA and a trend to an increase in triacylglycerol content in gastrocnemius muscle, but did not exacerbate HFD-induced insulin resistance compared with control-treated mice. It is noteworthy that trimetazidine treatment reduced palmitate oxidation rates in the isolated working mouse heart and neonatal cardiomyocytes but not C2C12 skeletal myotubes. Our findings demonstrate that trimetazidine therapy does not adversely affect HFD-induced insulin resistance, suggesting that treatment with trimetazidine would not worsen glycemic control in obese patients with angina.

Circadian variation of Rho-kinase activity in circulating leukocytes of patients with vasospastic angina.

BACKGROUND: Vasospastic angina (VSA) is known to exhibit circadian variation with an early morning peak. We examined whether Rho-kinase activity in circulating leukocytes, which is a useful biomarker for disease activity assessment of VSA, exhibits circadian variation in patients with VSA. METHODS AND RESULTS: In consecutive 31 VSA patients (M/F 23/8, 57±13 [SD] years) and 18 non-VSA patients (M/F 8/10, 57±14 years), we measured Rho-kinase activity in circulating leukocytes at 6:00, 12:00 and 21:00. We also examined the relationship between the Rho-kinase activity and coronary vasomotor responses during provocation test. Rho-kinase activity was significantly higher in VSA patients than in non-VSA patients at 6:00 (1.17±0.17 vs. 0.92±0.22, P<0.001), and showed a significant circadian variation with a peak at 6:00 (1.00±0.15 at 21:00, 1.17±0.17 at 6:00 and 1.12±0.22 at 12:00, P<0.001) in VSA patients, whereas no such variation was noted in non-VSA patients. Importantly, Rho-kinase activity at spasm provocation test was significantly correlated with basal coronary tone defined by vasodilating responses to intracoronary nitrate (r=0.40, P<0.05) and coronary vasoconstricting responses to acetylcholine (r=0.44, P<0.05) in VSA patients. Furthermore, their Rho-kinase activity at 6:00 was positively correlated with nocturnal parasympathetic activity as evaluated by heart rate variability in Holter monitoring (r=0.48, P<0.05). CONCLUSIONS: Rho-kinase activity exhibits distinct circadian variation associated with alterations in coronary vasomotor responses and autonomic activity in VSA patients.

Alcohol flushing and positive ethanol patch test in patients with coronary spastic angina: possible role of aldehyde dehydrogenase 2 polymorphisms.

OBJECTIVE: Coronary spasm plays an important role in the pathogenesis of coronary heart disease (CHD) and angina pectoris caused by coronary spasm or coronary spastic angina (CSA) is prevalent in Japan. However, the precise mechanisms underlying coronary spasm are unclear. Alcohol intolerance is prevalent among East Asians, and we previously reported that coronary spasm could be induced by alcohol intake in CSA patients. We herein examined whether CSA is associated with alcohol intolerance in Japanese subjects. METHODS: The study subjects consisted of 80 CSA patients (57 men/ 23 women, mean age 62 ± 12) and 52 non-CSA patients (25 men/27 women, mean age 63 ± 10). The ethanol patch test (EPT) and questionnaire which evaluates flushing after ethanol intake, along with an examination of clinical features and laboratory chemistry data for CHD risk factors were done. Gender (male) and smoking were higher (p=0.007, and p=0.019, respectively) and plasma HDL cholesterol level was lower (p=0.035) in the CSA patients than in the non-CSA patients. Multivariable logistic regression analysis including age, EPT, smoking, and plasma HDL cholesterol level as independent variables revealed that positive EPT and smoking were significant predictors of CSA (p=0.011 and p=0.016, respectively). CONCLUSION: Positive EPT and alcohol flushing following alcohol intake, as well as smoking and plasma levels of HDL cholesterol, were significantly associated with CSA in Japanese patients. Therefore, alcohol ingestion as well as smoking is a significant risk factor for CSA in Japanese.

Enhanced Rho-kinase activity in patients with vasospastic angina after the Great East Japan Earthquake.

BACKGROUND: It remains unclear whether disease activity of vasospastic angina (VSA) is altered during a disaster. METHODS AND RESULTS: Before and after the Great East Japan Earthquake, we examined Rho-kinase activity in circulating neutrophils of 11 VSA patients and their mental stress with the post-traumatic stress disorder (PTSD) questionnaire. Rho-kinase activity was significantly increased at 6 months after the Earthquake, and was returned to baseline level at 12 months. Importantly, percent change in Rho-kinase activity was significantly correlated with the PTSD score. CONCLUSIONS: These results indicate that the Rho-kinase activity of VSA patients was transiently enhanced associated with disaster-related mental stress.

Potential role of plasma myeloperoxidase level in predicting long-term outcome of acute myocardial infarction.

We investigated the prognostic importance of plasma myeloperoxidase levels in patients with ST-elevation myocardial infarction (STEMI) at long-term follow-up, and we analyzed the correlations between plasma myeloperoxidase levels and other biochemical values. We evaluated 73 consecutive patients (56 men; mean age, 56 ± 11 yr) diagnosed with acute STEMI and 46 age- and sex-matched healthy control participants. Patients were divided into 2 groups according to the median myeloperoxidase level (Group 1: plasma myeloperoxidase ≤ 68 ng/mL; and Group 2: plasma myeloperoxidase > 68 ng/mL). Patients were monitored for the occurrence of major adverse cardiovascular events (MACE), which were defined as cardiac death; reinfarction; new hospital admission for angina; heart failure; and revascularization procedures. The mean follow-up period was 25 ± 16 months. Plasma myeloperoxidase levels were higher in STEMI patients than in control participants (82 ± 34 vs 20 ± 12 ng/mL; P = 0.001). Composite MACE occurred in 12 patients with high myeloperoxidase levels (33%) and in 4 patients with low myeloperoxidase levels (11%) (P = 0.02). The incidences of nonfatal recurrent myocardial infarction and verified cardiac death were higher in the high-myeloperoxidase group. In multivariate analysis, high plasma myeloperoxidase levels were independent predictors of MACE (odds ratio = 3.843; <95% confidence interval, 1.625-6.563; P = 0.003). High plasma myeloperoxidase levels identify patients with a worse prognosis after acute STEMI at 2-year follow-up. Evaluation of plasma myeloperoxidase levels might be useful in determining patients at high risk of death and MACE who can benefit from further aggressive treatment and closer follow-up.

Increased leukocyte Rho-associated coiled-coil containing protein kinase activity predicts the presence and severity of coronary vasospastic angina.

OBJECTIVE: Although inhibition of Rho-associated coiled-coil containing protein kinase (ROCK) has been shown to prevent coronary vasospastic angina (CVA), direct evidence linking ROCK activity and CVA is lacking. Accordingly, we investigated whether ROCK activity is an independent marker for CVA and is altered after treatment with antispastic medications. METHODS AND RESULTS: We prospectively studied 31 Taiwanese patients who were diagnosed with CVA and 33 control subjects. Subject demographics were recorded, and blood samples were obtained at baseline in all participants and in CVA patients after 3 months of antispastic treatment. Compared with control subjects, leukocyte ROCK activity was greater in CVA patients (136% versus 91%, P<0.001). A cutoff value for leukocyte ROCK activity of 104% predicted the presence of CVA with specificity and sensitivity rates of 88% and 84%, respectively. ROCK activity increased with the severity of CVA (P for trend<0.001). Following 3-month treatment of antispastic agents, leukocyte ROCK activity, high-sensitivity C-reactive protein, and interleukin-6 levels were reduced by 43%, 42% and 27%, respectively (P<0.05 for all). CONCLUSIONS: Increased levels of leukocyte ROCK activity independently predicted the presence of CVA and correlated with CVA severity. Treatment with antispastic agents substantially reduced the level of leukocyte ROCK activity.

Gamma-glutamyltransferase in acute coronary syndrome patients without ST elevation and its association with stenotic lesion and cardiac events.

BACKGROUND: There are limited data on prognostic value of gamma-glutamyltransferase (GGT) in acute coronary syndromes (ACS) with non-ST-segment elevation (NSTE-ACS). We investigated GGT levels and their association with significant stenosis and major cardiac events (MACE) in NSTE-ACS patients. METHODS AND RESULTS: This study included 237 patients with NSTE-ACS (ACS group), and age-matched and sex-matched controls with normal coronary arteries (control group). ACS group was divided into subgroups with and without significant stenosis. Serum creatine kinase-MB, troponin T and GGT levels were measured. ACS patients were followed up for MACE (composite of cardiac death, myocardial infarction, recurrent angina, and hospitalization) during 12 months. Median GGT level was higher in ACS group than control group (32 vs. 16 U/l, P=0.001). NSTE-ACS was independently associated with hypertension [odds ratio (OR): 2.83, P=0.001], smoking (OR: 2.19, P=0.015), GGT [OR: 1.16, 95% confidence interval (CI): 1.11-1.21, P=0.001] and ejection fraction (OR: 0.92, P=0.01). GGT level was also higher in patients with significant stenosis than those without significant stenosis (37 vs. 22 U/l, P=0.001). Presence of significant stenosis was independently associated with GGT level (OR: 1.17, 95% CI: 1.12-1.23, P=0.001). At 12 months, MACE-free survival was slightly poor in ACS patients with upper GGT tertile compared with those with lower GGT tertile (77 vs. 97%, P=0.06). CONCLUSION: In NSTE-ACS patients, increased GGT levels can be associated with significant stenosis and MACE.

Lipocalin-type prostaglandin D synthase is associated with coronary vasospasm and vasomotor reactivity in response to acetylcholine.

BACKGROUND: Lipocalin-type prostaglandin D synthase (L-PGDS) catalyzes the biosynthesis of PGD(2), which acts as an anticoagulant, vasodilator, and inflammatory mediator. We examined the serum L-PGDS level, coronary macro- and microvasomotor functions, and their relationship in patients with chest pain and angiographically normal coronary arteries. METHODS AND RESULTS: The study included 96 patients who underwent diagnostic coronary angiography and had angiographically normal coronary arteries. Blood flow of the left anterior descending coronary artery (LAD) was analyzed by Doppler guidewire examination. Serum L-PGDS level was determined by ELISA. Infusion of acetylcholine (ACh) induced vasospasm of the LAD in all patients with vasospastic angina (VSA) (n=45), but in none of the patients without VSA (n=51). There were no significant differences in the baseline clinical characteristics of the nonVSA and VSA groups, except for the frequency of smoking. Serum L-PGDS level in the VSA group was significantly higher than that in the nonVSA group (77.1±4.4 vs. 63.9±2.5 µg/dl, P<0.01). Significant negative correlations were observed between the degree of LAD vasomotion in response to ACh and serum L-PGDS level (3 µg/min: r=-0.33; 10 µg/min: r=-0.35; 30 µg/min: r=-0.33, P<0.01). CONCLUSIONS: The L-PGDS level was elevated in patients with VSA and was associated with epicardial coronary vasomotion in response to ACh.

Association of matrix metalloproteinase-1, matrix metalloproteinase-9, tissue inhibitor of matrix metalloproteinase-1, and interleukin-6 with epicardial and myocardial perfusion.

OBJECTIVES: Matrix metalloproteinases (MMPs), which are important regulators of extracellular matrix degradation, are known to induce atherosclerotic plaque rupture because of the degradation of collagen fibers in the fibrous cap. We aimed to investigate the possible association between these enzymes and objective coronary angiographic parameters of epicardial or myocardial perfusion. METHODS: A total of 140 patients with acute coronary syndromes or stable angina pectoris, who were advised to undergo coronary angiography, were included. The correlation between the serum levels of MMP-1, MMP-9, tissue inhibitor of matrix metalloproteinase-1, interleukin-6 (IL-6), and Thrombolysis in Myocardial Infarction frame count (TFC), myocardial blush grade, and the magnitude of change in these parameters after percutaneous intervention was investigated in addition to the association between MMPs and the need for revascularization. RESULTS: TFC and corrected TFC scores were found to be higher in patients with higher MMP-1 levels (R: 0.706, P < 0.001; R: 0.867, P < 0.001). The absolute amount of decrease in TFC/corrected TFC after percutaneous intervention in the patients, who were advised to undergo revascularization, was correlated with higher MMP-1 and MMP-9 levels. MMP-1, MMP-9, and IL-6 were negatively correlated with myocardial blush grade although this association was weaker for MMP-9 and IL-6 compared with MMP-1 (R: -0.574, -0.367, and -0.496, P < 0.001). The mean serum levels of MMP-1, MMP-9, and IL-6 were higher in the patients who were advised to undergo revascularization compared with the patients who did not need revascularization. Odds ratios of MMP-1 and IL-6 for predicting revascularization need were calculated as 1.7 (95% confidence interval: 1.4-2.1; P < 0.001) and 6.5 (95% confidence interval: 2.5-16; P < 0.001), respectively. CONCLUSION: Higher levels of serum MMP-1, MMP-9, and IL-6 can be used to predict worse coronary angiographic findings and may be further targets of active investigation for wide use as risk predictors.

Myeloperoxidase is not associated with scintigraphic myocardial perfusion abnormalities in type 2 diabetic patients with mild stable anginal complaints.

BACKGROUND: MPO, an enzyme of the innate immune system, exhibits pro-atherogenic effects. These include oxidative damage to LDL- and HDL-cholesterol, and promotion of endothelial dysfunction. Recent studies revealed that MPO independently predicts adverse outcomes in patients with chest pain or suspected acute coronary syndrome. We evaluated whether plasma myeloperoxidase (MPO) levels are associated with scintigraphic myocardial perfusion abnormalities, in type 2 diabetic patients with mild anginal complaints. METHODS: MPO was measured in plasma samples of 267 patients with diabetes mellitus type 2 and stable angina pectoris complaints (Canadian Cardiovascular Society class I-II/IV) prior to myocardial perfusion scintigraphy (MPS). RESULTS: The median plasma level of MPO was 141 pmol/L (IQR 115-171 pmol/L). One-hundred-ninety patients (71%) had perfusion abnormalities on MPS and of these, 138 patients had myocardial ischemia. No relation was found between plasma MPO levels and the scintigraphic myocardial perfusion abnormalities. Even in combination with known other cardiovascular risk factors MPO failed to predict scintigraphic myocardial perfusion abnormalities. CONCLUSIONS: MPO levels are not associated with scintigraphic myocardial perfusion abnormalities in type 2 diabetic patients with mild anginal complaints. Therefore, in type 2 diabetic patients MPO is not a useful biomarker to predict hemodynamically significant coronary artery disease.

[Gelatinases A and B activities in the serum of patients with various coronary artery disease stages].

BACKGROUND/AIM: The main characteristic of matrix metalloproteinases (MMPs) is the degradation of extracellular matrix. Synthesis of MMPs has been reported in coronary atherosclerotic lesions in patients with coronary disease (CD) suggesting a pathogenic role of MMPs in its development. Recently there is increasing evidence that gelatinase A (pro MMP-2) and gelatinase B (proMMP-9) play a pathogenic role in the development of the atherosclerotic plaques. The aim of the study was to determine, by the use of a gel image system, a possible presence of active gelatinases in the serum of the patients with CD, as well as if their activity is higher in these patients than in healthy people. METHODS: By gelatin zymography we analyzed the activity of proMMP-2 and proMMP-9 in the serum of 50 patients with various coronary artery disease stages and in the serum of 15 healthy controls. The activity was measured by using a gel image system (Kodak Image 1D 3.6.). RESULTS: ProMMP-2 and proMMP-9 activity was significantly higher in the serum of patients with CD compared to controls. There was higher activity of MMP-2 and MMP-9 in the serum of patients with acute myocardial infarction (AMI) compared to patients with stable angina pectoris, as well as higher proMMP-9 activity in patients with unstable angina pectoris compared to patients with stable angina pectoris. CONCLUSION: ProMMP-2 and proMMP-9 participate in processes associated with destabilizing plaques and understanding the processes of MMPs activation and regulation may have significant benefits in clinical interpretation. The reported higher proMMP-2 and proMMP-9 activity in the serum of patients with CD suggests a role of proMMP-2 and proMMP-9 in prognostic stratification of these patients and in designing new drugs.

Increased expression and plasma levels of myeloperoxidase are closely related to the presence of angiographically-detected complex lesion morphology in unstable angina.

BACKGROUND: Myeloperoxidase (MPO) is a leucocyte enzyme that catalyses the formation of a number of reactive oxidant species. OBJECTIVE: The purpose of this study is to evaluate the relationship between angiographic coronary plaque morphology in patients with unstable angina pectoris (UAP) or stable angina pectoris (SAP) and MPO levels. PATIENTS AND DESIGN: Plasma MPO levels on admission were measured in 236 patients with UAP, 146 with SAP and 85 control subjects using an ELISA kit. The angiographic morphology of the culprit lesion was classified into two types, simple or complex, based on the Ambrose classification. In addition, 61 atherectomy specimens obtained from a different cohort of patients with UAP and SAP were studied immunohistochemically for MPO. RESULTS: Median (IQR) plasma MPO levels in patients with UAP with a complex lesion were significantly higher than in patients with a simple lesion (41.9 (21.7­73.7) ng/ml vs 20.5 (15.9­27.9) ng/ml, p<0.0001), but there was no significant difference between the two groups in patients with SAP. On multivariate analysis, raised plasma MPO levels and Braunwald class III were independent factors for angiographically-detected complex lesions (adjusted OR 12.49, 95% CI 3.24 to 48.17, p=0.0002). In the atherectomy specimens the number of MPO-positive cells in patients with UAP with complex lesions was significantly higher (p<0.0005) than in patients with simple lesions. Moreover, in this cohort, plasma MPO levels were positively correlated with the number of MPO-positive cells in atherectomy specimens (R=0.42, p=0.024). CONCLUSIONS: This study shows that increased expression and plasma MPO levels are closely related to the presence of angiographically-detected complex lesion morphology in patients with UAP.

Plasma haemoxygenase-1 in coronary artery disease. A comparison with angiogenin, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1 and vascular endothelial growth factor.

It was the aim of this study to determine plasma haemoxygenase-1 (HO-1) across the spectrum of health, angina but normal coronary arteries (NCA), stable coronary artery disease (CAD), and acute coronary syndromes (ACS), and relationships with angiogenin, matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1, and vascular endothelial growth factor. Plasma markers were measured (ELISA) in peripheral venous citrated plasma from 50 healthy subjects, 30 with NCA, 70 with stable CAD and 24 with an ACS, and from patient's aortic root, coronary ostium, coronary sinus and femoral artery. Human umbilical vein endothelial cells (HUVECs) were cultured with or without tumour necrosis factor (TNF), and platelets were probed. HO-1 was raised in stable CAD (p<0.05) and increased further in ACS (p<0.01) compared to healthy controls and NCA. HO-1 correlated only with MMP-9, and then only in the healthy controls. There were no major differences from cardiac or peripheral sites. HO-1 was present in HUVECs and 24-hour HUVEC supernatants but release was abolished by TNF. Platelets had no HO-1. In conclusion, HO-1 is raised in stable CAD and ACS and may arise from the endothelium but not the platelet. This may have implications for our understanding of the pathophysiology of CAD and its acute presentation as ACS.