A gender-specific analysis of association between hyperuricaemia and cardiovascular events in patients with coronary artery disease.

BACKGROUND AND AIMS: Gender-related differences in the association between hyperuricaemia and cardiovascular events remain poorly understood. The objective of this study was to assess gender-related differences in the association between hyperuricaemia and cardiovascular events in patients with coronary artery disease (CAD). METHODS AND RESULTS: This study included 13,273 patients with CAD. Hyperuricaemia was defined as a plasma uric acid >7.0mgdl(-1) in men and >5.7mgdl(-1) in women. The primary outcome was 1-year all-cause mortality. Hyperuricaemia was found in 3745 men (36.5%) and 1562 women (50.3%); odds ratio (OR)=1.76, 95% confidence interval (CI) 1.62-1.91; P<0.001. Women with hyperuricaemia were older, had higher proportions of patients with diabetes and arterial hypertension and had reduced renal function and higher C-reactive protein levels compared with men with hyperuricaemia. One-year all-cause mortality was 9.3% (n=143) in women with hyperuricaemia versus 6.9% (n = 252) in men with hyperuricaemia (P=0.002). After adjustment in multivariable Cox proportional hazards model, uric acid predicted 1-year mortality with an adjusted hazard ratio (HR)=1.17, 95% CI (1.03-1.31), P=0.012 in men and HR=1.25, 95% CI (1.06-1.48), P=0.007 in women, for each standard deviation increase in the natural logarithm. Uric acid predicted 1-year mortality with an area under the receiver-operating characteristic curve=0.625, 95% CI (0.594-0.656) in men and 0.676, 95% CI (0.635-0.717) in women (P=0.044, for women versus men). CONCLUSION: Hyperuricaemia predicts an increased risk of 1-year mortality in both genders with a stronger association in women. Differences in cardiovascular risk profile may explain the stronger association between hyperuricaemia and cardiovascular events in women.

Erythropoietin-induced progenitor cell mobilisation in patients with acute ST-segment-elevation myocardial infarction and restenosis.

Erythropoietin improves myocardial function and enhances re-endothelialisation. Aim of this study was to analyse progenitor cell mobilisation and restenosis in patients from the Regeneration of Vital Myocardium in ST-Segment Elevation Myocardial Infarction by Erythropoietin (REVIVAL-3) study. Patients with STEMI undergoing percutaneous coronary intervention (PCI) were randomly assigned to Epoetin beta (EPO) (n=68) or placebo (n=70). Drug-eluting stents (DES) were utilised in 93% of patients receiving EPO and in 95% of patients receiving placebo (p=0.83). Serial venous blood samples were drawn; CD133+ progenitor cells were quantified by four-colour flow cytometry and cytokines interleukin (IL)-1ß, IL-6, IL-8, IL-10, IL-12 and tumour necrosis factor (TNF) alpha were analysed by cytometric bead array. Forty-eight hours after PCI a significant increase in CD133+ progenitor cells was observed in the EPO group. Yet, no differences in plasma cytokines were found. Quantitative coronary angiography after six months revealed an increase in segment diameter stenosis in the EPO group (32 ± 19% vs. 26 ± 14%, p=0.046). However, this increase in neointima generation was not associated with progenitor cell mobilisation. EPO in patients with STEMI treated with PCI is associated with an increase in diameter stenosis that is not associated with circulating progenitor cells.

Tissue Factor-Factor VIIa complex induces cytokine expression in coronary artery smooth muscle cells.

OBJECTIVE: Within atherosclerotic lesions Tissue Factor (TF)-Factor VIIa (FVIIa) not only contributes to thrombotic events but also alters vascular remodeling through enhancement of migration. Moreover, the TF-FVIIa-FXa complex activates protease-activated receptors (PAR). TF/FVIIa/PAR-2 signaling has also been shown to promote proliferation and metastasis of tumor cells. Since coagulation factors promote inflammation which plays a major role during atherosclerosis as well as tumor metastasis this study sought to investigate the effects of FVIIa on the inflammatory response in vascular cells. METHODS/RESULTS: FVIIa induces interleukin-8 (IL-8) and IL-6 in primary smooth muscle cells (SMC), which was correlated to the expression of TF and PAR-2 as shown by immunoassay and qRT-PCR. The effect was dose-dependent and required TF, the proteolytic activity of FVIIa and PAR-2. Secondary effects of downstream coagulation factors were excluded. No proinflammatory FVIIa effect was observed in endothelial cells (EC) and mononuclear cells (MNC), expressing either TF or PAR-2. In atherosclerotic lesions mRNA expression of PAR-1, PAR-2 and IL-8 was elevated compared to healthy vessels indicating a role for PAR-1 and PAR-2 signaling in atherosclerosis. CONCLUSION: In addition to the procoagulant and promigratory role of the TF-FVIIa complex we identify a proinflammatory role of FVIIa in human SMC dependent on expression of TF and PAR-2 that provides yet another link between coagulation and inflammation.

Isolated and interactive impact of common CYP2C19 genetic variants on the antiplatelet effect of chronic clopidogrel therapy.

BACKGROUND: With the cytochrome P450 CYP2C19*2 (*2) allelic variant resulting in complete loss of enzyme function and the CYP2C19*17 (*17) variant being linked to increased transcriptional activity with extensive metabolism of CYP2C19 substrates, two common variants of the CYP2C19 gene have been explored recently. Currently, the isolated and interactive impacts of both variants on the antiplatelet effects of chronic clopidogrel therapy are unknown. OBJECTIVES: The aim of this study was to assess the isolated and interactive impacts of *2 and *17 on clopidogrel responsiveness in patients under clopidogrel maintenance treatment. METHODS: Patients (n=986) eligible for this study were under therapy with coronary stent-related chronic treatment with aspirin and clopidogrel. The ADP-induced platelet aggregation was measured on a Multiplate analyzer (in AU*min), and genotypes were determined with a TaqMan assay. RESULTS: Platelet aggregation values were significantly higher in carriers of at least one *2 allele than in homozygous wild-type allele carriers (P<0.001). For *17, platelet aggregation values were significantly lower in carriers of at least one *17 allele than in homozygous wild-type patients (P=0.01). A gene-dose effect was observed for both variants, with a pronounced effect of the mutant allele (*2 or *17) in homozygous patients being seen. For the interactive effect of both variants on platelet aggregation values, a gradual increase in platelet aggregation values was observed from (+)*17/(-)*2 patients, who exhibited the lowest values (median of 207 AU*min) to (-)*17/(-)*2, (+)*17/(+)*2 and (-)*17/(+)*2 patients, who exhibited the highest values (median of 309 AU*min) (P<0.001). CONCLUSIONS: *2 and *17 allele carriage are independent predictors for the antiplatelet effect of chronic clopidogrel therapy.

Antiplatelet effects of clopidogrel and bleeding in patients undergoing coronary stent placement.

BACKGROUND: In patients undergoing percutaneous coronary intervention (PCI), a link between bleeding and excess mortality has been demonstrated. A potential association of platelet response to clopidogrel and bleeding has not been well established yet. OBJECTIVES: The aim of the present study was to assess the impact of clopidogrel responsiveness on the risk of bleeding in clopidogrel-treated patients undergoing PCI. METHODS: Patients (n=2533) undergoing PCI after pretreatment with 600 mg of clopidogrel were enrolled in this study. Blood was obtained directly before PCI. Adenosine-diphosphate (ADP)-induced platelet aggregation was assessed on a Multiplate analyzer. The primary endpoint was the incidence of in-hospital Thrombolysis in Myocardial Infarction (TIMI) major bleeding and the secondary endpoint was in-hospital TIMI minor bleeding. Receiver-operator curve (ROC) analysis was used to derive the optimal platelet aggregation value defining enhanced clopidogrel responders for the association of measurements with major bleeding. RESULTS: Thirty-four (1.3%) major bleeding events and 137 (5.4%) minor bleeding events were observed. The risk of a major bleeding was significantly higher in patients (n=975) with an enhanced response to clopidogrel as compared with the remaining patients (n=1558) (2.2 vs. 0.8%, unadjusted odds ratio (OR) 2.6, 95% confidence interval (CI) 1.3-5.2, P=0.005; adjusted OR 3.5, 95% CI 1.6-7.3, P=0.001). No significant differences between both groups were observed for the occurrence of minor bleeding events (P=0.68). CONCLUSIONS: Enhanced clopidogrel responsiveness is associated with a higher risk of major bleeding. Whether guidance of antiplatelet treatment based on platelet function testing proves useful for avoiding bleeding events warrants further investigation.

Distribution of angiographic measures of restenosis after drug-eluting stent implantation.

BACKGROUND: A bimodal distribution of measures of restenosis has been demonstrated at 6-8 months after bare metal stent implantation. Drug-eluting stent (DES) treatment has attenuated the impact of certain factors (eg, diabetes) on restenosis but its effect on the distribution of indices of restenosis is not known. OBJECTIVE: To perform a detailed analysis of the metrics of restenosis indices after DES implantation. Design, settings, PATIENTS: Prospective observational study of patients undergoing DES implantation (Cypher, sirolimus-eluting stent; or Taxus, paclitaxel-eluting stent) at two German centres, with repeat angiography scheduled at 6-8 months after coronary stenting. MAIN OUTCOME MEASURES: In-stent late luminal loss (LLL) and in-segment percentage diameter stenosis (%DS) as determined by quantitative coronary angiography at recatheterisation. RESULTS: Paired cineangiograms were available for 2057 patients. Overall mean (SD) LLL was 0.31 (0.50) mm; mean (SD) %DS was 30.3 (15.7)%. Distribution of both LLL and %DS differed significantly from normal (Kolmogorov-Smirnov test; p<0.001 for each). For both parameters a mixed distribution model better described the data (likelihood ratio test with 3df; p<0.001 for each). This consisted of two normally distributed subpopulations with means (SD) of 0.10 (0.25) mm and 0.69 (0.60) mm for LLL, and means (SD) of 22.2 (8.6)% and 40.1 (16.6)% for %DS. The results were consistent across subgroups of DES type, "on-label" versus "off-label" indication, and presence or absence of diabetes. CONCLUSIONS: LLL and %DS at follow-up angiography after DES implantation have a complex mixed distribution that may be accurately represented by a bimodal distribution model. The introduction of DES treatment has not resulted in elimination of a variable propensity to restenosis among subpopulations of patients with stented lesions.

Pre-procedural C-reactive protein levels and clinical outcomes after percutaneous coronary interventions with and without abciximab: pooled analysis of four ISAR trials.

OBJECTIVE: To assess the prognostic value of the baseline C-reactive protein (CRP) level in patients undergoing percutaneous coronary intervention (PCI) after pre-treatment with 600 mg of clopidogrel and whether there is an interaction between CRP level and abciximab in terms of outcome. DESIGN: Pooled analysis from the ISAR-SWEET, SMART-2, ISAR-REACT and REACT-2 trials. SETTING, METHODS: The study included 4847 patients with coronary artery disease (CAD) undergoing PCI after pre-treatment with 600 mg of clopidogrel. The primary outcome was one-year mortality. The combined incidence of death, myocardial infarction and target lesion revascularisation was the secondary outcome. RESULTS: Based on the median value of CRP (2.3 mg/l), patients were divided into two groups: the high-CRP group (n = 2448) and the low-CRP group (n = 2399). During one year, there were 141 deaths (5.8%) in the high-CRP group compared with 51 deaths (2.1%) in the low-CRP group (OR = 2.77, 95% CI 2.04 to 3.77; p<0.001). The incidence of major adverse cardiac events (MACE) was 28% in the high-CRP group compared with 25% in the low-CRP group (OR = 1.13, 95% CI 1.01 to 1.26; p = 0.034). The Cox proportional hazards model showed that high CRP was an independent predictor of one-year mortality (hazard ratio 2.20, 95% CI 1.54 to 3.15; p<0.001 for CRP level >2.3 mg/l vs CRP level < or =2.3 mg/l). No significant interaction was observed between CRP level and abciximab regarding one-year mortality (p = 0.08) or MACE (p = 0.68). CONCLUSION: In patients with CAD undergoing PCI after pretreatment with 600 mg of clopidogrel, baseline CRP level predicts one-year mortality and MACE. Abciximab therapy did not confer any particular beneficial effect in patients with a higher inflammatory burden.

P27 and P53 gene polymorphisms and restenosis following coronary implantation of drug-eluting stents.

OBJECTIVE: Drug-eluting stents (DES) have reduced restenosis rates compared with bare-metal stents. P27 and P53 play important roles in the signal transduction leading to neointimal growth inhibition and induction of apoptosis of smooth muscle cells due to rapamycin and paclitaxel. We hypothesized that genetic variants of P27 and P53 influence the development of restenosis and the clinical outcome of patients receiving DES. METHODS: Polymorphisms in the genes encoding for P27 and P53 were tested for their association with restenosis and major adverse cardiac events. P27 C-79T and P53 G72C polymorphism genotypes were determined in a series of 433 consecutive patients receiving DES. Follow-up angiography after 6 months was performed in 87% of the patients. Genotyping was performed with PCR-based methods. RESULTS: For patients with the respective P27 C-79T and P53 G72C genotypes, the angiographic restenosis rates were between 5.0 and 22.0%, and the clinical restenosis rates were between 0.0 and 16.3%, without significant differences for the studied genotypes (p > 0.19). There was no association of the studied genotypes with the 1-year incidences of death and myocardial infarction. CONCLUSION: This study could not demonstrate a clinically relevant role of P27 and P53 polymorphisms in the processes leading to in-stent restenosis.

Aspirin and clopidogrel with or without phenprocoumon after drug eluting coronary stent placement in patients on chronic oral anticoagulation.

OBJECTIVES: Optimal antithrombotic/anticoagulation therapy in patients on chronic oral anticoagulation (OAC) undergoing drug-eluting stent (DES) implantation is unknown. We investigated the efficacy and safety of two regimens of antithrombotic/anticoagulation therapy in patients who present for DES implantation whilst on OAC. METHODS: We included a series of 515 patients on OAC who underwent DES implantation between 2002 and 2007. Based on predefined clinical and echocardiographic criteria, 306 patients continued OAC (triple therapy) and 209 patients discontinued OAC (dual therapy) for the time they received antiplatelet therapy with clopidogrel and aspirin [stent-related antithrombotic treatment (SRAT)]. The primary end point was a composite of death, myocardial infarction, stent thrombosis or stroke. RESULTS: During SRAT the primary endpoint was observed in 13 patients in the group with triple therapy versus 15 patients in the group with dual therapy [Kaplan-Meier estimates 4.2% and 7.2%, odds ratio (OR) = 0.61, 95% confidence interval (CI) 0.29-1.28; P = 0.19]. At 2 years of follow-up, the primary endpoint was observed in 35 patients in the group with triple therapy versus 36 patients in the group with dual therapy (Kaplan-Meier estimates 14.1% and 18.0%, OR = 0.76, 95% CI: 0.48-1.21; P = 0.25). Two-year incidence of major bleeding was 1.4% (n = 4, triple therapy) versus 3.1% (n = 6, dual therapy) (P = 0.34). CONCLUSIONS: In patients on chronic OAC undergoing DES implantation, clinical and echocardiographic criteria help to define postprocedural antithrombotic/anticoagulation therapy. Based on these criteria, both a double antiplatelet therapy (clopidogrel plus aspirin) and a triple therapy (OAC plus clopidogrel plus aspirin) are associated with favourable safety and efficacy.

Myeloperoxidase level in patients with stable coronary artery disease and acute coronary syndromes.

BACKGROUND: No studies have measured plasma myeloperoxidase (MPO) across the entire spectrum of patients with coronary artery disease (CAD). The aim of the study was to compare MPO level across the entire spectrum of CAD, to assess the accuracy of MPO in predicting acute coronary syndromes and to define independent correlates of MPO level. DESIGN: This case-control study included 874 patients with angiographically proven CAD. Cases included 680 patients with CAD (382 patients with stable CAD, 107 patients with non-ST-segment elevation acute coronary syndromes and 191 patients with ST-segment elevation acute myocardial infarction). Controls included 194 subjects with normal coronary angiograms. MPO was measured using an enzyme immunoassay before angiography and heparin administration. RESULTS: MPO level [median (25th-75th percentiles)] was 74.5 (52.5-135.3) microg L(-1) in cases vs. 61.2 (44.6-80.9), microg L(-1) in controls (P < 0.001). MPO level was 61.2 (47.5-85.8), microg L(-1) in patients with stable CAD, 99.2 (62.2-154.9), microg L(-1) in patients with non-ST-segment elevation acute coronary syndromes and 129.5 (72.2-216.0) microg L(-1) in patients with acute myocardial infarction (P < 0.001). Elevated MPO level was associated with acute coronary syndromes with an area under receiver operating characteristic (ROC) curve of 0.731 (95% confidence interval 0.692-0.770; P < 0.001). Independent correlates of MPO level were acute coronary syndrome (P < 0.001), high-sensitivity C-reactive protein (P = 0.007), creatinine (P = 0.026), left ventricular ejection fraction (P = 0.027, negative association) and smoking (P = 0.028). CONCLUSIONS: MPO level is elevated in patients with CAD and higher levels of MPO were found with progression of CAD from stable CAD to non-ST-segment elevation acute coronary syndromes and to acute myocardial infarction.

Endocardial cushion defect in a patient with Crouzon syndrome carrying a mutation in the fibroblast growth factor receptor (FGFR)-2 gene.

Crouzon syndrome is an autosomal dominant disorder caused by mutation in the fibroblast growth factor receptor (FGFR)-2 gene. Recent findings from animal studies imply a critical role for FGFs in the regulation of cardiac development including cardiac cushion proliferation and valvulogenesis. We report on a 36-year-old woman, who required surgical closure for an atrial septal defect, a clinical feature that has not been previously reported in other patients with Crouzon syndrome. The findings suggest that cardiac investigations are warranted in patients with a diagnosis of Crouzon syndrome.

Clinical evidence on polymer-based sirolimus and paclitaxel eluting stents.

Percutaneous coronary interventions with the use of stents have become the mainstay treatment of patients with various clinical manifestations of coronary artery disease. Despite their remarkable success, restenosis has remained the major drawback and its prevention has absorbed intensive experimental and clinical research work. After the failure of multiple efforts with systemic use of various drugs, local application of antiproliferative and anti-inflammatory agents released by specially designed coated stents led to considerable suppression of neointima and opened new prospects in the prevention of restenosis. An increasing body of evidence is showing the advantages provided by drug-eluting stents (DES) in almost all subsets of patients with coronary artery disease with a drastic decrease in the need for reintervention. To date, the most commonly used and the only US Food and Drug Administration (FDA) approved DES are a sirolimus-eluting stent (Cypher) and a paclitaxel-eluting stent (Taxus), both of which are polymer-based DES and will constitute the focus of this review. Recent data demonstrate that DES are not equal in their safety and efficacy. A less optimistic aspect of DES technology are the reiterated concerns about a more prolonged risk of stent thrombosis. Although all agree on the need of a longer duration of dual antiplatelet therapy in patients treated with DES, its optimal length is still to be defined. Because polymers used for stent coating are often seen at the origin of the compromised long-term safety of DES, new technologies able to avoid permanent polymers may offer a valuable alternative.

Current drug-eluting stents in complex patients and lesions.

Drug-eluting stents (DES) are playing an increasingly important role in the treatment of coronary artery disease. These new devices work by releasing controlled amounts of pharmacological agents with anti-restenosis properties at the implantation site. Most of them use polymer coating as a drug carrier, but concerns about long-term negative effects of a permanent polymer coating have stimulated the development of non-polymer DES or DES based on bioabsorbable polymers. Several randomized studies with DES have demonstrated their superiority over bare metal stents mostly in selected patients and lesion subsets. Accumulating evidence is showing significant differences in performance between currently used DES. These differences are more pronounced in complex, high-risk subsets of patients and lesions and should be considered during the process of DES selection for the individual patient. Interventional cardiologists have learned that patients who receive DES require a more prolonged antiplatelet therapy, but the optimal length and regimen are still unclear and further investigations are needed. Major advances in interventional cardiology have caused a dramatic shift away from aorto-coronary bypass surgery and an increase in the complexity of percutaneous coronary interventions. Observational and specifically designed randomized studies are currently addressing the issue of the role of DES in complex situations including in-stent restenosis, ostial and bifurcation lesions, chronic occlusions, small vessels, long lesions, saphenous vein grafts, multivessel disease, left main disease, acute myocardial infarction and diabetes mellitus. Although definitive answers are still to come from ongoing research, available data support the use of DES in most of these situations.