Platelet reactivity and a proinflammatory chemokine were reduced more by the higher atorvastatin dose than by ezetimibe plus low-dose atorvastatin. In patients with coronary artery disease, it might be important to combine ezetimibe with higher statin dosages to benefit from cholesterol-independent pleiotropic effects.
BackgroundAlthough antiplatelet therapy involving clopidogrel is a standard treatment for preventing cardiovascular events after coronary stent implantation, patients can display differential responses. Here, we assessed the effectiveness of clopidogrel on platelet function inhibition in subjects with and without type-2 diabetes and stable coronary artery disease. In addition, we investigated the correlation between platelet function and routine clinical parameters.MethodsA total of 64 patients with stable coronary heart disease were enrolled in the study. Among these, 32 had known type-2 diabetes, whereas the remaining 32 subjects were non-diabetics (control group). A loading dose of 300 mg clopidogrel was given to clopidogrel-naïve patients (13 patients in the diabetes group and 14 control patients). All patients were given a daily maintenance dose of 75 mg clopidogrel. In addition, all patients received 100 mg ASA per day. Agonist-induced platelet aggregation measurements were performed on hirudin-anticoagulated blood using an impedance aggregometer (Multiple Platelet Function Analyzer, Dynabyte, Munich, Germany). Blood samples were drawn from the antecubital vein 24 h after coronary angiography with percutaneous coronary intervention. The platelets were then stimulated with ADP alone or ADP and prostaglandin-E (ADP and ADP-PGE tests, respectively) in order to evaluate clopidogrel-mediated inhibition of platelet function. The effectiveness of ASA was measured by stimulation with arachidonic acid (ASPI test). In addition, maximal platelet aggregation was assessed via stimulation with thrombin receptor-activating peptide (TRAP test).ResultsPatients with diabetes exhibited significantly less inhibition of platelet function than patients without diabetes (ADP-PGE test p = 0.003; ASPI test p = 0.022). Administering a clopidogrel loading dose of 300 mg did not result in a lower level of ADP-PGE-induced platelet reactivity in comparison to the use of a 75 mg maintenance dose. Moreover, we observed that ADP-PGE-induced platelet inhibition was positively correlated with fasting blood glucose and HbA1c (p < 0.01).ConclusionsPatients with type-2 diabetes exhibited increased platelet reactivity compared to patients without diabetes despite combined treatment with clopidogrel and ASA. Using a loading dose of clopidogrel rather than small daily doses was not sufficient for adequately overcoming increased platelet reactivity in patients with type-2 diabetes, highlighting the need for more effective anti-platelet drugs for such patients.
Summary. Background: Myocardial inflammation is associated with an increase in circulating microparticles (MPs) and procoagulability. Objectives: We determined whether acute inflammation was associated with altered full‐length tissue factor (flTF) expression and increased procoagulability in cardiomyocytic cells. Methods: This study examined the transcriptional regulation of flTF expression in murine cardiomyocytic (HL‐1) cells. Also, the generation of MPs by HL‐1 cells and their ability to diffuse through an artificial endothelium was evaluated. Results: Constitutive and tumor necrosis factor‐α (TNF‐α)‐induced flTF expression of HL‐1 was reduced when c‐Jun N‐terminal kinase (JNK) was inhibited. Tissue factor (TF)‐positive procoagulant MPs were released from HL‐1 cells in response to TNF‐α. JNK inhibition potentiated the release of MPs from HL‐1 cells without affecting MP‐associated TF activity. MP generation was dependent on RhoA activation and associated with a reorganization of the actin cytoskeleton. Increased diffusion of HL‐1‐derived MPs through an endothelial monolayer was found after TNF‐α treatment. The increased diffusion was dependent not only on TNF‐α but also on HL‐1‐released mediators. Conclusions: Full‐length TF expression in HL‐1 cells was regulated through JNK. The TNF‐α‐induced increase in procoagulability was mediated through RhoA‐dependent release of flTF‐bearing MPs. These MPs were able to diffuse through an endothelial barrier adjacent to HL‐1 cells and increased the procoagulability of the extracellular endothelial space. Cardiomyocytes seem to be a likely source of flTF‐bearing procoagulant MPs.
Dual antiplatelet medication with acetylsalicylic acid (ASA) and clopidogrel is the main therapy for patients with stable coronary vessel disease (CVD) after percutaneous coronary intervention (PCI). Despite platelet inhibition subgroups of patients have been shown to exhibit an increase of risk for adverse cardiovascular events. The aim of our study was to elucidate the influence of sex on platelet reactivity in patients with CVD under medication with ASA and clopidogrel. Two hundred and thirty patients with CVD on combined therapy with ASA (100 mg/day) and clopidogrel (75 mg/day) were included into our study. These patients were divided into a male (n = 128) and female (n = 102) group. Platelet reactivity was assessed by impedance aggregometry. Women demonstrated a significantly higher thrombin receptor-activating peptide (TRAP)-induced platelet reactivity than men (male 79.43 ± 28.55 U vs. female 89.3 ± 30.69 U; P < 0.05). The ADP-induced (male 19.81 ± 15.51 U vs. female 23.73 ± 17.68 U; P > 0.05) or arachidonic acid-induced (male 10.3 ± 12.87 U vs. female 12.76 ± 14.44 U; P > 0.05) platelet aggregation did not differ significantly between women and men. A multivariate linear regression model revealed female sex to be a significant prognostic marker for an increased TRAP-induced platelet reactivity, independent of the ASA and clopidogrel-associated platelet function inhibition. Sex differences did not influence the effectiveness of ASA or clopidogrel-mediated platelet function inhibition. Nevertheless, women had a significantly increased maximal platelet reactivity compared to men despite antiplatelet therapy.
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