leukotriene-b4 and Acute-Coronary-Syndrome

Leukotriene B4 (LTB4) and extracellular matrix metalloproteinase (EMMPRIN) have been suggested as modulators of atherosclerotic plaque instability. This study sought to evaluate the potential diagnostic implication of LTB4 and EMMPRIN in patients with acute coronary syndrome (ACS).. Patients (n=153) who underwent coronary angiography, including 105 patients diagnosed with ACS, were divided into four groups: stable angina pectoris (SAP, n=19), unstable angina pectoris (UAP, n=39), acute myocardial infarction (AMI, n=66) and control (with normal coronary angiography, n=29). EMMPRIN expression in peripheral blood mononuclear cells was determined by flow cytometry and serum LTB4 levels were measured by ELISA. To examine whether LTB4 can regulate the expression of EMMPRIN and matrix metalloproteinases (MMPs) in macrophages, differentiated THP-1 macrophages were stimulated with different concentrations of LTB4 (10-10-10-7mmol/L). Expression of EMMPRIN was evaluated by Western blotting. MMP-9 mRNA expression and enzymatic activity were determined by RT-PCR and SDS-PAGE gelatin zymography.. Serum LTB4 concentration was significantly higher in AMI and UAP groups, compared with control and SAP groups (p < 0.01). Subgroups analysis showed that LTB4 was significantly higher in the AMI < 24h group, compared with the AMI > 24h group. Expression of EMMPRIN on circulating monocytes was significantly higher in patients with UAP and AMI (> 24h), compared with control, SAP and AMI (< 24h) groups (p < 0.05). In vitro study showed LTB4 up-regulated the expression of EMMPRIN, as well as the expression and activity of MMP-9, in cultured THP-1-derived macrophages (p < 0.05).. LTB4 and EMMPRIN are associated with the pathogenesis of ACS and may be potential biomarkers for patients with ACS.

Topics: Acute Coronary Syndrome; Aged; Aged, 80 and over; Basigin; Cell Line; Female; Gene Expression Regulation; Humans; Leukotriene B4; Macrophages; Male; Matrix Metalloproteinase 9; Middle Aged

Production of leukotrienes by 5-lipoxygenase (5-LO) has been linked to unstable atherosclerotic plaques and cardiovascular events. VIA-2291 is a potent 5-LO inhibitor.. In a double-blinded study, 191 patients were randomly assigned 3 weeks after an acute coronary syndrome to receive 25, 50, or 100 mg VIA-2291 or placebo daily for 12 weeks. The primary study end point, whole blood stimulated leukotriene LTB4 at trough drug level, was reduced in all VIA-2291 groups (P<0.0001) in a dose-dependent fashion, with approximately 80% inhibition in >90% of patients in the 100-mg group. A significant reduction of urine leukotriene LTE4 was obtained in all dose groups. No serious adverse events were considered related to study drug. A subset of 93 patients who had undergone a 64-slice coronary CT examination at baseline continued on study medication for a total of 24 weeks and underwent a repeat scan. Five of these patients withdrew or were noncompliant and 28 had nonevaluable scans. Among the 60 remaining patients, new coronary plaques were observed in 5 of 18 (27.8%) placebo-treated patients and in 2 of 42 (4.8%) VIA-2291-treated patients (P=0.01). A reduction in noncalcified plaque volume at 24 weeks versus placebo was observed in VIA-2291-treated groups in the 34 of these 60 patients in whom this end point was analyzable (P<0.01).. VIA-2291 reduces leukotriene production at 12 weeks after an acute coronary syndrome. Preliminary data from the CT substudy suggest that such a reduction in leukotriene production may influence atherosclerosis; however, this requires confirmation in a larger study. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00358826.

Topics: Acute Coronary Syndrome; Adult; Aged; Aged, 80 and over; Analysis of Variance; Arachidonate 5-Lipoxygenase; Biomarkers; C-Reactive Protein; Contrast Media; Coronary Angiography; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Hydroxyurea; Leukotriene B4; Leukotriene E4; Lipoxygenase Inhibitors; Male; Middle Aged; Observer Variation; Prospective Studies; Radiographic Image Enhancement; Tomography, X-Ray Computed; Treatment Outcome; Triiodobenzoic Acids

Inflammation plays a pivotal role in the pathophysiology of non-ST elevation acute coronary syndromes (NSTEACS). Intensive statin therapy reduces the recurrence of cardiovascular events after acute coronary syndromes. The aim of this study was to examine nuclear factor-kappa B activity in peripheral blood mononuclear cells, prostaglandin E2 (PGE2) and leukotriene B4 levels, and matrix metalloproteinase-9 (MMP-9) activity in plasma from patients with NSTEACS (at 0 days, 4 days, 2 months, and 6 months), patients with stable coronary artery disease, and healthy controls. On day 4, patients with NSTEACS were randomized to receive atorvastatin 80 mg/day (n = 14) or standard treatment (n = 16) during 2 months to study its effect on these parameters. Nuclear factor-kappa B activity (by electrophoretic mobility shift assay), PGE2 levels (by enzyme-linked immunosorbent assay), and MMP-9 activity (by gelatin zymography) in the plasma of patients with NSTEACS were significantly increased compared with patients with coronary artery disease and healthy controls. At 6 months, MMP-9 activity was normalized, whereas nuclear factor-kappa B activity and PGE2 levels were still increased. Leukotriene B4 plasma levels (by enzyme-linked immunosorbent assay) were similar in patients with NSTEACS and those with coronary artery disease but were significantly higher than those of healthy subjects. There was a significant correlation between plasma PGE2 levels and MMP-9 activity in patients with NSTEACS (r = 0.754, p <0.01). Atorvastatin 80 mg/day reduced circulating PGE2 levels (median 222.4 [interquartile range 157.4 to 253.5] vs 550.8 [276.9 to 613.0] pg/ml, p = 0.006) and MMP-9 activity (0.0025 [0.0017 to 0.0035] vs 0.0280 [0.0057 to 0.0712] arbitrary units, p = 0.03). In conclusion, nuclear factor-kappa B activity in peripheral blood mononuclear cells, and plasma PGE2 levels and MMP-9 activity, increase during NSTEACS. Atorvastatin 80 mg/day normalizes PGE2 levels and MMP-9 activity, providing additional mechanisms by which intensive atorvastatin therapy may reduce the incidence of cardiovascular events.

Topics: Acute Coronary Syndrome; Adult; Aged; Aged, 80 and over; Atorvastatin; Dinoprostone; Electrocardiography; Female; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Leukotriene B4; Male; Matrix Metalloproteinase 9; Middle Aged; NF-kappa B; Pyrroles; Treatment Outcome

An imbalance between inflammation-resolving lipid mediators and proinflammatory leukotrienes with the instability of atherosclerotic plaques in experimental models has been reported. However, the contribution of the balance of Resolvin D1 (RvD1) to Leukotriene B4 (LTB4) in predicting acute coronary syndrome (ACS) remains unknown. This study investigated the association of RvD1-to-LTB4 ratio with ACS.Eighty-one patients with ACS and 90 stable coronary artery disease (SCAD) patients were included in this study. Plasma RvD1 and LTB4 levels were measured with commercial kits.Patients with ACS had higher LTB4 levels, lower RvD1 levels, and a lower RvD1-to-LTB4 ratio than patients with SCAD. History of diabetes mellitus, elevated Troponin I, LTB4, and decreased RvD1-to-LTB4 ratio (odds ratio [OR]: 1.025; 95% confidence interval [CI]: 1.014-1.040; P < 0.001) were independently correlated with ACS. Receiver operating characteristic curve analysis demonstrated that RvD1-to-LTB4 ratio was a potential biomarker for the risk of ACS.A circulating proinflammatory lipid profile, characterized by a low RvD1-to-LTB4 ratio may be associated with ACS in patients with ischemic heart disease.

Topics: Acute Coronary Syndrome; Docosahexaenoic Acids; Humans; Inflammation; Leukotriene B4

We investigated the relationships between the ALOX5AP gene rs10507391 and rs4769874 polymorphisms, serum levels of leukotriene (LT) B4, and risk of acute coronary syndrome (ACS).. A total of 709 participants, comprising 508 ACS patients (ACS group) and 201 noncoronary artery disease patients with chest pain (control group) were recruited from the Han population of the Changwu region in China. Two polymorphic loci were genotyped using polymerase chain reaction and restriction fragment length polymorphism analysis. Serum LTB4 level was determined by enzyme-linked immunosorbent assay.. Serum LTB4 levels were significantly higher (P<0.001) in the ACS group (median/interquartile range, 470.27/316.32 pg/ml) than in the control group (233.05/226.82 pg/ml). No statistical differences were observed between genotype, allele and haplotype frequencies for the tested loci in either the ACS group or the control group, even after adjustments were made for conventional risk factors by multivariate logistic regression. This suggests there is no association between the ALOX5AP rs10507391 and rs4769874 polymorphisms and ACS risk. Elevated serum LTB4 level was closely linked to ACS risk, and may be independent of traditional risk factors as a risk factor for ACS (P<0.001). There was no significant association between serum LTB4 levels and the two variants in either the ACS group or the control group.. Rs10507391, rs4769874 and its haplotypes in ALOX5AP are unrelated to ACS risk in the Chinese Han population of Changwu, but elevated serum LTB4 level is strongly associated with ACS risk. Serum LTB4 level is not subject to the influence of either the rs10507391, rs4769874 or the haplotype.

Topics: 5-Lipoxygenase-Activating Proteins; Acute Coronary Syndrome; Aged; Alleles; Asian People; China; Female; Genetic Association Studies; Genetic Predisposition to Disease; Haplotypes; Humans; Leukotriene B4; Male; Middle Aged; Polymorphism, Single Nucleotide

To observe the expression of extracellular matrix metalloproteinase inducer (EMMPRIN) in the unstable plaque of patients with acute coronary syndrome (ACS), and the impact of leukotriene B4 (LTB4) on the EMMPRIN expression in macrophages.. The EMMPRIN expression was detected by immunohistochemistry in 11 unstable plaques from patients with ACS. Protein expression of EMMPRIN was evaluated by Western blot on macrophages differentiated from THP-1 which were stimulated with LTB4 in the absence or presence of LTB4 antagonist U75302. There are 8 study groups: 1-THP-1, 2-8-the macrophages derived from THP-1, 2-6-macrophages were stimulated by LTB4 (0, 10(-10), 10(-9), 10(-8) and 10(-7) mol/L) for 24 h, 7-8-the macrophages were pretreated by 10(-6) mol/L or 10(-7) mol/L U75302 2 h before the LTB4 (10(-7) mol/L) stimulation.. Abundant EMMPRIN expression was detected in macrophages and smooth muscle cells of unstable plaques from ACS patients. As to the THP-1 derived macrophages, EMMPRIN expression was significantly upregulated in a concentration-dependent manner in LTB4 stimulated groups, which was significantly higher in group 3-6 than in the THP-1 group (group 1) and macrophages group (group 2) (all P < 0.05) and pretreatment with U75302 significantly reduced the LTB4 induced upregulation of EMMPRIN in a dose-dependent manner (P < 0.05).. EMMPRIN expression is enhanced in macrophages and smooth muscle cells on unstable coronary artery plaques from ACS patients. LTB4 could stimulate EMMPRIN expression on THP-1 derived macrophages suggesting that LTB4 and EMMPRIN might be both involved in the formation and progression of unstable plaques, future studies are warranted to explore if LTB4 and EMMPRIN antagonists are effective or not for treating patients with ACS.

Topics: Acute Coronary Syndrome; Basigin; Cell Line; Humans; Leukotriene B4; Macrophages; Myocytes, Smooth Muscle; Plaque, Atherosclerotic