Fluvastatin reduces soluble P-selectin and ICAM-1 levels in hypercholesterolemic patients: role of nitric oxide.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: These results may provide novel biochemical basis for the beneficial clinical effects of HMG-CoA reductase inhibitors in hypercholesterolemia.

Determinants of enhanced thromboxane biosynthesis in patients with systemic lupus erythematosus.

OBJECTIVE: To evaluate the rate of thromboxane biosynthesis in patients with systemic lupus erythematosus (SLE), exploring the interplay between antiphospholipid antibodies (aPL) and 2 markers of endothelial perturbation: thrombin generation and platelet activation. METHODS: A comparison of 11-dehydrothromboxane B2 (TXB2) excretion, which is a marker of in vivo platelet activation, aPL, von Willebrand factor (vWF) and tissue plasminogen activator (tPA), which are 2 circulating markers of endothelial perturbation, and plasma levels of the prothrombin fragment F1+2, which is a marker of thrombin generation, was performed in 40 SLE patients and 40 healthy subjects. Thromboxane metabolite excretion was also measured in 8 SLE patients before and after treatment with low-dose aspirin. RESULTS: SLE patients had significantly higher 11-dehydro-TXB2 excretion, plasma F1+2, vWF, and tPA levels than controls. A statistically significant correlation was found between plasma levels of vWF and tPA and excretion of thromboxane metabolite. Moreover, significantly higher 11-dehydro-TXB2 was found in patients with aPL positivity and endothelial perturbation. Low-dose aspirin suppressed 11-dehydro-TXB2 by 80%, suggesting a predominant platelet source of enhanced thromboxane biosynthesis. After a median followup of 48 months, all SLE patients who experienced major cardiovascular events had thromboxane metabolite excretion, aPL positivity, and signs of endothelial perturbation. CONCLUSION: We have characterized a sensitive marker of platelet activation, which is abnormal in SLE patients who were positive for aPL and endothelial perturbation. This analytical approach may help identify those patients at increased risk of thrombosis as potential candidates for antiplatelet therapy.

Influence of metabolic control on thromboxane biosynthesis and plasma plasminogen activator inhibitor type-1 in non-insulin-dependent diabetes mellitus.

We have previously shown that tight metabolic control by insulin therapy reduced thromboxane-dependent platelet activation in non-insulin-dependent diabetes mellitus (NIDDM) patients. The present study was undertaken to determine whether a similar effect could be obtained without switching diabetics in secondary failure to insulin treatment. For this purpose, we gave strict diet and exercise advise program and adjusted on a weekly basis the oral antidiabetic therapy (glipizide) that 26 patients with NIDDM had been given over the previous months. Basal measurements of urinary 11-dehydro-TXB2 and PAI-1 confirmed previous findings of enhanced levels of these parameters in NIDDM patients with macrovascular disease in comparison to age- and sex-matched controls. After 2-6 weeks, 16 patients achieved tight metabolic control associated with significant reduction of both thromboxane biosynthesis and PAI-1 levels; 10 patients remained in poor control and no significant decrease of both parameters was observed. We conclude that reduction of in-vivo platelet activation and PAI-1 antigen levels after metabolic improvement obtained by frequent reassessment of sulphonylurea therapy together with strict diet and exercise programs may have beneficial effects on the progression of diabetic micro- and macrovascular disease.