Different effect of statins on platelet oxidized-LDL receptor (CD36 and LOX-1) expression in hypercholesterolemic subjects.

Hydroxymethyl-glutaryl-CoA-reductase inhibitors (statins) reduce cardiovascular mortality by decreasing cholesterol as well as by non-lipid-related actions. Oxidized low-density lipoproteins (ox-LDL) are pro-atherogenic molecules and potent platelet agonists. CD36 and lectin-like ox-LDL receptor-1 (LOX-1) are specific ox-LDL receptors also expressed in platelets. This study was planned to address whether treatment with atorvastatin 10 mg/day, pravastatin 40 mg/day or simvastatin 20 mg/day could affect platelet CD36 and LOX-1 expression. Twenty-four patients for each treatment were evaluated after 3, 6, and 9 days and at 6 weeks for complete lipid profile (chromogenic), ox-LDL (ELISA), platelet P-selectin (P-sel), CD36, LOX-1 (FACS), and intracellular citrullin recovery (iCit) (HPLC). Data show hyperactivated platelets (P-sel absolute values, percent variation in activated cells, all p < 0.001), and CD36 and LOX-1 overexpression (all p < 0.001) in patients at baseline. P-sel, CD36, and LOX-1 were significantly decreased by atorvastatin and simvastatin (all p < 0.01) and related with iCit increase (r = 0.58, p < 0.001) and platelet-associated ox-LDL (r = 0.51, p < 0.01) at 9 days. Pravastatin reduced LOX-1 and P-sel (p < 0.05) at 6 weeks in relation with decreased LDL and ox-LDL (r = 0.39, p < 0.01 and r = 0.37, p < 0.01, respectively). These data suggest that atorvastatin and simvastatin reduce platelet activity by exposure of CD36 and LOX-1 before significant LDL reduction, whereas pravastatin action is detected later and in relation with LDL and ox-LDL lowering. Rapid and consistent reduction of CD36 and LOX-1 could be considered a direct anti-atherothrombotic mechanism related to the role of ox-LDL in platelet activation, platelet-endothelium interactions, and NO synthase activity.

Platelet hyperactivity after statin treatment discontinuation.

Hydroxymethyl-glutaryl-CoA-reductase inhibitors (statins) reduce cardiovascular events by cholesterol lowering as well as by non-lipid related actions. Among them, the modulation of platelet activity could play a relevant role in vascular protection. Furthermore withdrawal of statins has been associated with increased cardiovascular event rate. The aim of our study was to evaluate platelet activity after cerivastatin discontinuation in eighteen subjects that did not accept other drugs and in sixteen subjects continuing treatment with simvastatin. Fourteen subjects at the end of the discontinuation period decided to receive other drugs (simvastatin) and they were evaluted six weeks later. We measured complete lipid profile by the chromogenic method (LDL-C was calculated); oxidized-LDL (ox-LDL; ELISA), platelet P-selectin (P-sel) expression (flow cytometry detection), platelet aggregation (% change of transmitted light), intracellular citrullin production (iCit; HPLC) as an indicator of intracellular NO synthase activity at baseline and 7, 14, 28, 60 days after statin discontinuation. P-sel expression and platelet aggregation were increased at 14 days (p < 0.001 and p < 0.05) in association with raised ox-LDL (r = 0.30, p < 0.05) and decreased iCit (r = 0.53, p < 0.01). Increased LDL-C was related to P-sel and platelet aggregation at 28 days (r = 0.30, p < 0.05). Subjects continuing statin treatment had no significant changes of P-sel at 28 (p = 0.221) and 60 days (p = 0.238). Subjects treated with simvastatin after 60 days of diet showed a significant reduction of P-sel and platelet aggregation after six weeks of treatment (p < 0.01). Our data suggest a platelet hyperactivation state in the second week after statin discontinuation which is partially related to raised LDL-C. Such a finding could participate in the increased cardiovascular event rate after statin discontinuation.

Dyslipidemias and fibrinolysis.

BACKGROUND: The relation between fibrinolysis and cardiovascular disease is an open debate. Fibrinolysis is related to endothelial function and presents many molecular links with platelet and coagulation activity. Furthermore, reduced fibrinolysis has been reported in several dysmetabolic conditions. METHODS: To detect mechanisms linking dyslipidemias and fibrinolysis we evaluated 75 subjects (42 males, 33 females, 20 hypercholesterolemic, 20 hypertriglyceridemic or 20 with mixed hyperlipoproteinemia, 15 with isolated low HDL-cholesterol). Plasminogen activator inhibitor (PAI)-1, tissue-type plasminogen activator activity and plasmin-antiplasmin complexes (PAP) were determined at baseline and after the venous occlusion test. We also measured D-dimer, lipid pattern, soluble E-selectin, platelet surface P-selectin, prothrombin fragments 1 + 2 (F1 + 2), lipoprotein(a), factor VII, von Willebrand factor, plasma insulin, fibrinogen, homocysteine, thrombin activable fibrinolysis inhibitor (TAFI) activity, thrombomodulin, factor XIII, urokinase-type plasminogen activator. RESULTS: Hypertriglyceridemic patients were found to have lower PAP and D-dimer and higher PAI-1 serum levels (baseline and venous occlusion test, p < 0.001 and p < 0.01) compared to hypercholesterolemic and control subjects (p < 0.01, p < 0.001). P-selectin, F1 + 2 and TAFI were significantly increased only in hypercholesterolemic subjects (p < 0.001) and associated with reduced PAP and D-dimer, showing a linear relation with LDL-cholesterol levels (p < 0.01, r = -0.62 and p < 0.01, r = -0.59). PAI-1 activity was not different with respect to controls (baseline p = 0.59, venous occlusion test p = 0.42). Serum levels of von Willebrand factor were significantly increased in hypertriglyceridemic/low HDL subjects compared to hypercholesterolemics (p < 0.01). CONCLUSIONS: Impaired fibrinolysis in subjects with hypertriglyceridemia/low HDL-cholesterol is associated with increased serum levels of PAI-1 whereas enhanced thrombin generation and TAFI hyperactivity are the main findings in hypercholesterolemia. Such data may suggest the opportunity of evaluating several fibrinolytic factors when studied as prognostic factors in diverse dyslipidemias.