11-dehydro-thromboxane-b2 and Hypercholesterolemia

Laropiprant, an antagonist of the PGD(2) receptor, DP1, is effective in reducing the flushing symptoms associated with extended-release (ER) niacin and thereby improves the tolerability of niacin therapy for dyslipidemia. Because PGD(2) has been reported to inhibit platelet aggregation in vitro, it has been speculated that antagonism of DP1 may enhance platelet reactivity. Three clinical studies evaluated the potential effect of laropiprant, with or without coadministration of ER niacin, on in vivo platelet function in healthy subjects and hypercholesterolemic or diabetic subjects by measuring urinary levels of 11-dehydrothromboxane B(2) (11-dTxB(2)), a marker of in vivo platelet activation. Following 7 days of multiple-dose administration, coadministration of laropiprant with ER niacin did not increase urinary 11-dTxB(2) levels compared to ER niacin alone in healthy, hypercholesterolemic, or diabetic subjects. In hypercholesterolemic and diabetic subjects, laropiprant did not increase urinary 11-dTxB(2) levels compared to placebo. These results demonstrate that laropiprant does not enhance in vivo platelet reactivity, either alone or in combination with niacin.

Topics: Adolescent; Adult; Aged; Biomarkers; Blood Platelets; Cross-Over Studies; Delayed-Action Preparations; Diabetes Mellitus; Double-Blind Method; Epoprostenol; Female; Humans; Hypercholesterolemia; Indoles; Male; Middle Aged; Niacin; Platelet Activation; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin; Thromboxane B2; Young Adult

Hypercholesterolemia is associated with inflammation and the prothrombotic state. CD40-CD40 ligand (CD40L) interactions promote a prothrombotic response in nucleated cells. The aim of this study was to characterize the in vivo expression of soluble CD40L (sCD40L) in hypercholesterolemia, to correlate it with the extent of the prothrombotic state, and to investigate whether it may be modified by statins.. We studied 80 hypercholesterolemic patients and 80 matched healthy subjects. Hypercholesterolemic subjects had enhanced levels of sCD40L, factor VIIa (FVIIa), and prothrombin fragment 1+2 (F1+2) compared with healthy subjects. sCD40L correlated with total cholesterol and LDL cholesterol. Moreover, sCD40L was positively associated with in vivo platelet activation, as reflected by plasma P-selectin and urinary 11-dehydro-thromboxane B2, and with procoagulant state, as reflected by FVIIa and F1+2. Inhibition of cholesterol biosynthesis by pravastatin or cerivastatin was associated with comparable, significant reductions in sCD40L, FVIIa, and F1+2.. This study suggests that sCD40L may represent the molecular link between hypercholesterolemia and the prothrombotic state and demonstrates that statin therapy may significantly reduce sCD40L and the prothrombotic state.

Topics: CD40 Ligand; Double-Blind Method; Factor VIIa; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Inflammation; Male; Middle Aged; P-Selectin; Peptide Fragments; Platelet Activation; Protein Precursors; Prothrombin; Thromboxane B2

Lipid-lowering therapy with 3-hydroxy-3-methylglutaryl-coenzymeA (HMG-CoA) reductase inhibitors reduces the incidence of atherosclerosis-related cardiovascular events. Adhesion molecules, regulating interactions between vascular and circulating cells, may play a central role in the pathogenesis of atherosclerosis and related complications. In the present report we examined the impact of the HMG-CoA reductase inhibitor fluvastatin on plasma levels of P-selectin and ICAM-1.. Plasma levels of P-selectin and ICAM-1 were determined using an enzyme immunoassay in 26 patients with type IIa hypercholesterolemia randomized to treatment with either fluvastatin (80 mg/d) or placebo in a double blind fashion for 12 weeks.. Fluvastatin administration reduced either P-selectin (118 +/- 63 vs 81 +/- 36 ng/mL [-31%], P = 0.0015) or ICAM-1 (264 +/- 75 vs 228 +/- 68 ng/mL [-13.7%], P = 0.0033) levels. Fluvastatin also lowered urinary 11-dehydro-TXB2 (1396 +/- 536 vs 1009 +/- 378 pg/mg creatinine [-27%], P = 0.0015) and von Willebrand Factor levels (1456 +/- 716 vs 1203 +/- 527 U/L [-17.4%], P = 0.0275), and a direct correlation was observed between P-selectin and 11-dehydro-TXB2 levels (r = 0.588, P = 0.0033). Patients treated with fluvastatin displayed an increase in nitric oxide (NO) generation, evaluated with measurements of serum NO2-/NO3-, (4.7 +/- 1 vs 8.9 +/- 3.1) mumol/L [98%], P = 0.0046). Moreover, an inverse correlation was observed between NO2-/NO3- and P-selectin (r = -0.420; P = 0.0343), 11-dehydro-TXB2 (r = -0.511; P = 0.0106), or LDL (r = -0.742; P = 0.0002) levels.. These results may provide novel biochemical basis for the beneficial clinical effects of HMG-CoA reductase inhibitors in hypercholesterolemia.

Topics: Adult; Aged; Creatinine; Double-Blind Method; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Indoles; Intercellular Adhesion Molecule-1; Male; Middle Aged; Nitric Oxide; Nitrogen Dioxide; P-Selectin; Thromboxane B2; von Willebrand Factor

Hypercholesterolemia is associated with platelet activation. Reduction of plasma cholesterol levels by the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor simvastatin has been found to improve certain aspects of platelet function in vitro and in vivo, but controlled trials are largely lacking. The present randomized, double-blind, crossover study was performed to evaluate whether 10- to 12-week treatment with simvastatin or placebo affects platelet function in vivo in 23 hypercholesterolemic men. Measurements were performed at rest and during mental stress. Simvastatin treatment reduced plasma total cholesterol levels by 18 +/- 2% and low density lipoprotein cholesterol levels by 26 +/- 2% (P < .001 for both), whereas high density lipoprotein cholesterol levels increased slightly (6 +/- 2%, P < .05). Platelet aggregability as assessed by filtragometry ex vivo was unaffected by simvastatin treatment both at rest and during mental stress. Plasma beta-thromboglobulin levels, which reflect platelet secretion, were also unaltered by simvastatin treatment both at rest (antilog of the mean: 20.2 versus 20.0 ng/mL during placebo) and during mental stress. Moreover, nocturnal excretion of 11-dehydrothromboxane B2 in urine did not differ between placebo and active treatment: 218 versus 216 ng/mmol creatinine, respectively. The corresponding values for urinary excretion of high-molecular-weight beta-thromboglobulin were 1.78 versus 1.92 ng/mmol creatinine. Thus, simvastatin treatment had no clear-cut effect on platelet function, as assessed by four different in vivo related platelet function variables, in hypercholesterolemic men.

Topics: Blood Platelets; Cross-Over Studies; Double-Blind Method; Enzyme Inhibitors; Humans; Hypercholesterolemia; Lipids; Lovastatin; Male; Platelet Aggregation; Rest; Simvastatin; Stress, Psychological; Thromboxane B2; Thyroglobulin

The aim of this study was to assess the effects of fluvastatin and pravastatin on lipid profiles and urinary thromboxane (TX) A2 metabolites (11-dehydro TXB2 and 2,3-dinor TXB2) in patients with type IIa hypercholesterolemia. A total of 20 patients (13 men, 7 women; mean age 53 +/- 9 years) with primary type IIa hypercholesterolemia (Fredrickson's classification) in a 4-week, double-blind, parallel-group study were randomized to fluvastatin or pravastatin, both at 40 mg once daily (at bedtime), after a single-blind, 4-week, placebo run-in period. Total cholesterol, low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and triglycerides were measured after placebo (baseline) and after 4 weeks of double-blind treatment. Thromboxane metabolites were measured at the same time points, using an enzyme immunoassay kit, in 12 hr urine samples. At baseline, the mean +/- SD levels of total cholesterol, LDL-C, triglycerides, and HDL-C were: 292 +/- 23, 213 +/- 47, 186 +/- 119 and 41 +/- 17 mg/dL with fluvastatin; and 301 +/- 40, 212 +/- 40, 150 +/- 124 and 43 +/- 10 mg/dL with pravastatin, respectively. Baseline thromboxane-metabolite levels were positively and significantly (p < 0.04) correlated with levels of total cholesterol, but not LDL-C. Compared with baseline, total cholesterol and LDL-C were significantly (p < 0.01) decreased by 27% and 30% with fluvastatin, and by 23% and 31% with pravastatin, respectively. HDL-C increased from 41 +/- 17 to 59 +/- 25 mg/dL with fluvastatin, and from 43 +/- 10 to 46 +/- 12 mg/dL with pravastatin.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Anticholesteremic Agents; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Double-Blind Method; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Indoles; Lipids; Male; Middle Aged; Placebos; Pravastatin; Single-Blind Method; Thromboxane A2; Thromboxane B2; Thromboxanes; Triglycerides

F2-isoprostanes are bioactive prostaglandin (PG)-like compounds that are produced from arachidonic acid through a nonenzymatic process of lipid peroxidation catalyzed by oxygen free-radicals. 8-Epi-PGF2 alpha may amplify the platelet response to agonists, circulates in plasma, and is excreted in urine. We examined the hypothesis that the formation of 8-epi-PGF2 alpha is altered in patients with hypercholesterolemia and contributes to platelet activation in this setting. Urine samples were obtained from 40 hypercholesterolemic patients and 40 age- and sex-matched control subjects for measurement of immunoreactive 8-epi-PGF2 alpha. Urinary excretion of 11-dehydro-thromboxane (TX) B2, a major metabolite of TXA2, was measured as an in vivo index of platelet activation. Low-dose aspirin, indobufen, and vitamin E were used to investigate the mechanism of formation and effects of 8-epi-PGF2 alpha on platelet activation. Urinary 8-epi-PGF2 alpha was significantly (P = .0001) higher in hypercholesterolemic patients than in control subjects: 473 +/- 305 versus 205 +/- 95 pg/mg creatinine. Its rate of excretion was inversely related to the vitamin E content of LDL and showed a positive correlation with urinary 11-dehydro-TXB2. Urinary 8-epi-PGF2 alpha was unchanged after 2-week dosing with aspirin and indobufen despite complete suppression of TX metabolite excretion. Vitamin E supplementation was associated with dose-dependent reductions in both urinary 8-epi-PGF2 alpha and 11-dehydro-TXB2 by 34% to 36% and 47% to 58% at 100 and 600 mg daily, respectively. We conclude that the in vivo formation of the F2-isoprostane 8-epi-PGF2 alpha is enhanced in the vast majority of patients with hypercholesterolemia. This provides an aspirin-insensitive mechanism possibly linking lipid peroxidation to amplification of platelet activation in the setting of hypercholesterolemia. Dose-dependent suppression of enhanced 8-epi-PGF2 alpha formation by vitamin E supplementation may contribute to the beneficial effects of antioxidant treatment.

Topics: Antioxidants; Aspirin; Cardiovascular Diseases; Cross-Sectional Studies; Cyclooxygenase Inhibitors; Dinoprost; Female; Humans; Hypercholesterolemia; Isoindoles; Lipid Peroxidation; Lipoproteins, LDL; Male; Middle Aged; Phenylbutyrates; Platelet Activation; Platelet Aggregation Inhibitors; Reactive Oxygen Species; Thromboxane B2; Vitamin E

Thromboxane A2 biosynthesis was studied in healthy subjects, in patients in whom the extent of carotid atherosclerosis was determined, and in patients receiving chronic aspirin treatment, to determine what factors activate platelets to develop carotid atherosclerosis. Urinary 11-dehydrothromboxane B2, a major metabolite of thromboxane A2, was measured by radioimmunoassay after purification by reverse-phase HPLC. The extent of carotid atherosclerosis was determined by real-time B-mode ultrasonography. The severity of carotid atherosclerosis in each subject was evaluated by plaque score, which was computed by summing the maximum thickness of plaque measured in millimeters. Urinary excretion of 11-dehydrothromboxane B2 in healthy subjects was higher (P < 0.01) in cigarette smokers (1063 +/- 244 ng/g creatinine) than in non-smokers (815 +/- 183 ng/g creatinine). Aspirin significantly suppressed 11-dehydrothromboxane B2 excretion (266 +/- 114 ng/g creatinine). In the 24 patients in whom the plaque score was measured, multivariate analysis indicated a significant positive correlation between urinary excretion of 11-dehydrothromboxane B2 and plaque score, age, smoking and hypercholesteremia. Our results indicate that risk factors such as age, hypercholesteremia, atherosclerosis and smoking activate platelets in vivo to develop carotid atherosclerosis.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Arteriosclerosis; Aspirin; Carotid Artery Diseases; Female; Humans; Hypercholesterolemia; Male; Middle Aged; Multivariate Analysis; Platelet Activation; Risk Factors; Smoking; Thromboxane B2