leukotriene-e4 and Myocardial-Infarction

Myocardial infarction (MI) is the leading cause of death in the world. Variants in the 5-lipoxygenase-activating protein (FLAP) gene are associated with risk of MI.. To determine the effect of an inhibitor of FLAP on levels of biomarkers associated with MI risk.. A randomized, prospective, placebo-controlled, crossover trial of an inhibitor of FLAP (DG-031) in MI patients who carry at-risk variants in the FLAP gene or in the leukotriene A4 hydrolase gene. Of 268 patients screened, 191 were carriers of at-risk variants in FLAP (87%) or leukotriene A4 hydrolase (13%). Individuals were enrolled in April 2004 and were followed up by designated cardiologists from a university hospital in Iceland until September 2004.. Patients were first randomized to receive 250 mg/d of DG-031, 500 mg/d of DG-031, 750 mg/d of DG-031, or placebo. After a 2-week washout period, patients received DG-031 if they had received placebo first or placebo if they had received DG-031 first. Treatment periods lasted for 4 weeks.. Changes in levels of biomarkers associated with risk of MI.. In response to 750 mg/d of DG-031, production of leukotriene B4 was significantly reduced by 26% (95% confidence interval [CI], 10%-39%; P = .003) and myeloperoxidase was significantly reduced by 12% (95% CI, 2%-21%; P = .02). The higher 2 doses of DG-031 produced a nonsignificant reduction in C-reactive protein (16%; 95% CI, -2% to 31%; P = .07) at 2 weeks. However, there was a more pronounced reduction (25%; 95% CI, 5%-40%; P = .02) in C-reactive protein at the end of the washout period that persisted for another 4 weeks thereafter. The FLAP inhibitor DG-031 was well tolerated and was not associated with any serious adverse events.. In patients with specific at-risk variants of 2 genes in the leukotriene pathway, DG-031 led to significant and dose-dependent suppression of biomarkers that are associated with increased risk of MI events.

Topics: 5-Lipoxygenase-Activating Proteins; Aged; Biomarkers; Carrier Proteins; Coronary Artery Disease; Cross-Over Studies; Epoxide Hydrolases; Female; Humans; Leukotriene B4; Leukotriene E4; Lipoxygenase Inhibitors; Male; Membrane Proteins; Middle Aged; Myocardial Infarction; Peroxidase; Polymorphism, Single Nucleotide; Prospective Studies; Quinolines; Risk Factors

INTRODUCTION Leukotrienes (LTs) may be involved in atherosclerosis and may contribute to cardiovascular outcomes in CAD. OBJECTIVES    We aimed to compare the baseline LT production in patients with stable CAD (sCAD) and myocardial infarction (MI), and to assess whether an increased LT production is associated with major adverse cardiovascular events (MACEs) at 1 year after MI. PATIENTS AND METHODS    LTIMI (Leukotrienes and Thromboxane In Myocardial Infarction) was a single‑center, prospective, observational study of patients with stable sCAD and MI. Urinary leukotriene E4 (LTE4) levels were measured on admission, at 1 month, and at 1 year, using high‑performance liquid chromatography tandem mass spectrometry. RESULTS    Of the 404 patients screened, 289 were enrolled (110 with sCAD and 179 with MI; mean [SD] age, 63.9 [10.9] years). Patients with MI had higher median (interquartile range [IQR]) levels of log‑transformed LTE4 (logLTE4) than those with sCAD (4.74 pg/mg creatinine [4-5.45] vs 4.51 pg/mg creatinine [3.99 4.86], respectively; P <0.001). Median (IQR) logLTE4 levels in patients with MI significantly decreased at 1 month to 4.37 pg/mg creatinine (3.81-4.95), and at 1 year to 4.16 pg/mg creatinine (3.55-4.85). The baseline urinary logLTE4 levels were similar in patients with MACEs and those without MACEs (median [IQR], 4.78 pg/mg creatinine [4.01-5.56]) and 4.68 pg/mg creatinine [3.97-5.28], respectively; P >0.05). Multiple regression showed no relation between LTE4 levels and the incidence of MACEs. CONCLUSIONS    LT production assessed by urinary LTE4 excretion is higher in patients with MI than in those with sCAD; however, LTE4 levels at baseline do not differ between patients with and without MACEs at 1 year after MI.

Topics: Aged; Coronary Artery Disease; Female; Humans; Leukotriene E4; Male; Middle Aged; Myocardial Infarction; Prospective Studies

Urinary excretion of leukotriene (LT) E(4) is an index of LTC(4) biosynthesis and platelet-neutrophil interactions, which may occur in coronary heart disease and contribute to myocardial ischaemia. Enhanced LTC(4) biosynthesis may be a consequence of myocardial ischaemia or be linked to its pathogenetic substrate.. Overnight urine collections were obtained from 17 patients with chronic stable angina, three patients with Prinzmetal's angina, 16 patients with non ST-elevation acute coronary syndromes (NSTE-ACS) and six patients with acute ST-elevation myocardial infarction (STEMI). LTE(4) excretion was measured by enzyme immunoassay after HPLC separation. Compared with healthy controls (51.1 +/- 21.3 pg mg(-1) creatinine, mean +/- SD, n = 11) and with non-coronary cardiac controls (36.6 +/- 9.8 pg mg(-1) creatinine, n = 9), LTE(4) excretion was unchanged in stable angina (40.5 +/- 25.8 pg mg(-1) creatinine), but significantly (P < 0.01) increased in NSTE-ACS (122.7 +/- 137.2 pg mg(-1) creatinine) and STEMI (213.4 +/- 172.4 pg mg(-1) creatinine). In these patients, LTE(4) excretion rapidly dropped after day 1, consistent with effective coronary reperfusion. In patients with NSTE-ACS, the increase in LTE(4) excretion was entirely restricted to patients with recent (< 48 h) spontaneous anginal episodes. Myocardial ischaemia elicited by a positive exercise stress test was not accompanied by any detectable increase in LTE(4) excretion, while a significant (P < 0.01) increase was detected after a single-vessel percutaneous coronary interventions (PCI) procedure (n = 10), as compared with diagnostic angiography (n = 9).. In coronary heart disease, increased LTC(4) biosynthesis is restricted to ACS and not linked to myocardial ischaemia per se, but likely to the occurrence of plaque disruption.

Topics: Acute Coronary Syndrome; Adult; Aged; Angina Pectoris; Biomarkers; Chromatography, High Pressure Liquid; Cross-Sectional Studies; Female; Humans; Immunoenzyme Techniques; Leukotriene E4; Male; Middle Aged; Myocardial Infarction

Experimental cardiac ischemia in some animal models results in the activation of the enzyme 5-lipoxygenase and the subsequent production of leukotrienes, potent proinflammatory lipid mediators, by the affected myocardium. Furthermore, prototype antileukotriene drugs can show some beneficial effects on infarct size and cardiac function in these models. Accordingly, urinary excretion of leukotriene E4 (LTE4), the major urinary metabolite of peptide leukotrienes in humans, was measured in patients admitted to the hospital with evidence of acute myocardial ischemia to assess in vivo release of 5-lipoxygenase products during and after the ischemic episode.. Urinary leukotriene excretion was measured by reversed-phase high-performance liquid chromatography and specific radioimmunoassay on admission with acute chest pain and again on day 3 in the following patient groups: acute myocardial infarction (AMI), AMI and clinical evidence of early reperfusion after treatment with recombinant tissue-type plasminogen activator (rt-PA), diagnosis of unstable angina (UA) based on clinical history and coronary arteriography, controls with nonischemic chest pain who underwent coronary arteriography, and age-matched controls and normal hospital employees. In 16 patients with diagnosis of AMI, LTE4 excretion on admission (331 +/- 99 pg/mg creatinine sulfate; mean +/- SEM) was considerably higher than that measured on day 3 (195 +/- 59 pg/mg creatinine sulfate). In a subgroup of seven subjects treated with rt-PA resulting in early reperfusion, day 1 excretion was similar (215 +/- 50 pg/mg) but had significantly declined by day 3 (65 +/- 16 pg/mg; p less than 0.01). Urinary LTE4 excretion at admission for chest pain was also elevated in 14 patients having unstable angina (UA; 370 +/- 125 pg LTE4/mg creatinine sulfate). This had declined significantly (p less than 0.05) by day 3 (at which time chest pain had resolved) to 94 +/- 31 pg/mg creatinine sulfate, an excretion rate comparable with that measured in eight similarly aged subjects (64 +/- 12 pg/mg creatinine).. This study suggests that peptide leukotrienes are released during episodes of myocardial ischemia and provides clinical evidence for involvement of their biosynthetic enzyme, 5-lipoxygenase, during and after acute myocardial infarction and unstable angina attacks. Thus, potent and specific orally active leukotriene biosynthesis inhibitors may have therapeutic potential in limiting myocardial damage and functional abnormalities after acute ischemia.

Topics: Angina, Unstable; Arachidonate 5-Lipoxygenase; Chest Pain; Coronary Disease; Creatinine; Enzyme Activation; Female; Humans; Leukotriene E4; Leukotrienes; Male; Middle Aged; Myocardial Infarction; Myocardial Reperfusion; Reference Values; SRS-A; Tissue Plasminogen Activator