Predictors of leptin concentration and association with cardiovascular risk in patients with coronary artery disease: results from the AtheroGene study.

CONTEXT: Leptin is produced in white adipose tissue, but also in human coronary atherosclerotic lesions. OBJECTIVE: The aim of this study is to assess the prognostic value of leptin in patients with proven coronary artery disease (CAD) (N = 1907). METHODS: AtheroGene is a contemporary CAD cohort study (N = 3229). Median follow-up time was 3.8 (Quartile 1/3 with 2.8/4.9) years. RESULTS: Leptin concentration was associated with a hazard ratio (HR) for the fully adjusted model of HR = 1.32 in women but was not significant in men. The endpoint cardiovascular death and non-fatal myocardial infarction was observed in 167 patients. CONCLUSION: In women with known CAD, increased leptin concentration is useful for predicting cardiovascular death and non-fatal myocardial infarction.

Cardiovascular Mortality in Chest Pain Patients: Comparison of Natriuretic Peptides With Novel Biomarkers of Cardiovascular Stress.

BACKGROUND: Natriuretic peptides are the standard biomarker for risk stratification in cardiovascular disease. Novel biomarkers of cardiovascular stress might allow refinement in risk stratification for patients with acute coronary syndrome (ACS). We tested the performance of these novel biomarkers for cardiovascular risk stratification in patients who presented with ACS. METHODS: In the AtheroGene study, 873 patients presented with ACS in the emergency department. Biomarkers measured were: B-type natriuretic peptide (BNP), N-terminal pro BNP (NT-proBNP), midregional proatrial natriuretic peptide, midregional proadrenomedullin (MR-proADM), copeptin, and troponin I. The median follow-up time was 4 years and during this time 50 patients died from cardiac causes. RESULTS: Cox regression analysis for the continuous variables NT-proBNP and BNP showed a hazard ratio (HR) of 1.9 and 1.8, respectively, for 1 SD increase (P < 0.001 and P = 0.003) in the fully adjusted model. Novel biomarkers with MR-proADM had an HR of 3.2, followed by midregional proatrial natriuretic peptide with an HR of 1.9 (both P < 0.001), and copeptin with an HR of 1.6 (P < 0.001). C-index revealed MR-proADM as the best discriminator for identifying patients with the outcome with a C-index = 0.8, and C-index was 0.72 for NT-proBNP (P for comparison = 0.017). Integrated discrimination improvement for MR-proADM was 0.059 compared with NT-proBNP (P = 0.016), thus providing background that MR-proADM was better to identify persons with the outcome. Troponin I levels at the time of admission were not significant for risk stratification. CONCLUSIONS: In patients who present with ACS the novel biomarker, MR-proADM was the best predictor for outcome. MR-proADM adds modest information and is useful for risk prediction in ACS patients.

Prognostic use of soluble fms-like tyrosine kinase-1 and placental growth factor in patients with coronary artery disease.

BACKGROUND: Intention of the study is to assess the cardiovascular mortality of patients with coronary artery disease (CAD) with the biomarkers of angiogenesis PlGF and its endogenous inhibitor sFlt-1. METHODS: The cohort included n = 1848 patients with CAD and 282 subjects without CAD. In 85 patients cardiovascular mortality, as combination of fatal myocardial infarction or any cardiac death, during a median follow-up duration of 3.9 years was reported. RESULTS: In Kaplan-Meier curve analysis PlGF in rising thirds was not predictive regarding outcome (p = 0.54), the same was shown for sFlt-1 (p = 0.44). Cox regression for the fully adjusted model provided a hazard ratio (HR) of 0.8 (p = 0.18) for PlGF and for sFlt-1 a HR = 1.0 (p = 0.8). CONCLUSION: Our results point out that these biomarkers reflecting angiogenesis might not be suited to establish prognosis in CAD.

The utility of pregnancy-associated plasma protein A for determination of prognosis in a cohort of patients with coronary artery disease.

BACKGROUND: Pregnancy-associated plasma protein-A (PAPP-A) is discussed as a biomarker representing unstable plaques in coronary artery disease (CAD). METHODS: In this study 927 patients with CAD (534 with stable angina and 393 with acute coronary syndrome [ACS]) and 217 patients without CAD and measured PAPP-A levels were included. Follow-up for a median of 5 years was documented. RESULTS: Rising quartiles of PAPP-A concentration had a higher cardiovascular mortality in the overall cohort of patients with CAD (p = 0.002) and the cohort with ACS (p = 0.01). Patients with suspected ACS below the LOD for troponin I but elevated PAPP-A levels had an increased cardiovascular mortality. A cut-off of 11.4 IU/l identified patients with a higher mortality during follow-up. CONCLUSION: Rising PAPP-A levels are prognostic in patients with CAD. PAPP-A levels were especially predictive in ACS patients with troponin below 10% CV of the 99 th percentile for cardiovascular mortality.

Risk Factors of Coronary Artery Disease in Secondary Prevention--Results from the AtheroGene--Study.

BACKGROUND: Risk factors are important in cardiovascular (CV) medicine for risk stratification of patients. We aimed to compare the traditional risk factors to clinical variables for the prediction of secondary cardiovascular events. METHODS AND RESULTS: For this study, 3229 patients with known coronary artery disease (CAD) were included. We calculated whether the traditional risk factors, diabetes mellitus, increased LDL/HDL ratio, arterial hypertension and smoking alone and in combination with the clinical variables, ejection fraction, creatinine clearance, multi-vessel disease and CRP concentration predict the outcome cardiovascular death or non-fatal myocardial infarction (N = 432) during the mean follow-up time of 4.2 ± 2.0 years. In this cohort diabetes mellitus was the risk factor with the strongest influence regarding occurrence of secondary events (hazard ratio; HR:1.70, confidence interval; CI 95%: 1.36-2.11; P<0.0001), followed by LDL/HDL ratio and smoking. However, risk stratification is further improved by using additional clinical variables like ejection fraction (HR:3.30 CI 95%:2.51-4.33; P>0.0001) or calculated creatinine clearence (Cockroft-Gault formula) (HR:2.26 CI 95%:1.78-2.89; P<0.0001). Further ameliorating risk stratification from the clinical variables were CRP and multi-vessel disease. The most precise risk prediction was achieved when all clinical variables were added to the CV risk factors. CONCLUSION: Diabetes mellitus has the strongest influence to predict secondary cardiovascular events in patients with known CAD. Risk stratification can further be improved by adding CV risk factors and clinical variables together. Control of risk factors is of paramount importance in patients with known CAD, while clinical variables can further enhance prediction of events.

Activity of superoxide dismutase copper/zinc type and prognosis in a cohort of patients with coronary artery disease.

AIM: Superoxide dismutase (SOD) is important to control reactive oxygen species, but the relevance to human disease like coronary artery disease (CAD) and underlying ischemia/reperfusion injury is not clarified. METHODS: For this study, 2239 patients with known CAD were prospectively followed with a median follow-up time period of 3.6 years and a maximum of 6.9 years. During follow-up cardiovascular death was reported in 103 cases. RESULTS: SOD activity (log-transformed) was investigated as continuous and categorical variable, showing a significant influence on outcome in the fully adjusted model (p = 0.045). CONCLUSION: Increased SOD activity beyond the normal range in the human physiology is related to an adverse outcome in patients with CAD.

Association of soluble endothelial protein C receptor plasma levels and PROCR rs867186 with cardiovascular risk factors and cardiovascular events in coronary artery disease patients: the Athero Gene study.

BACKGROUND: Blood coagulation is an essential determinant of coronary artery disease (CAD). Soluble Endothelial Protein C Receptor (sEPCR) may be a biomarker of a hypercoagulable state. We prospectively investigated the relationship between plasma sEPCR levels and the risk of cardiovascular events (CVE). METHODS: We measured baseline sEPCR levels in 1673 individuals with CAD (521 with acute coronary syndrome [ACS] and 1152 with stable angina pectoris [SAP]) from the AtheroGene cohort. During a median follow up of 3.7 years, 136 individuals had a CVE. In addition, 891 of these CAD patients were genotyped for the PROCR rs867186 (Ser219Gly) variant. RESULTS: At baseline, sEPCR levels were similar in individuals with ACS and SAP (median: 111 vs. 115 ng/mL respectively; p=0.20). Increased sEPCR levels were found to be associated with several cardiovascular risk factors including gender (p=0.006), soluble Tissue Factor levels (p=0.0001), diabetes (p=0.0005), and factors reflecting impaired renal function such as creatinine and cystatin C (p<0.0001). sEPCR levels were not significantly associated with the risk of CVE (median: 110 and 114 ng/mL in individuals with and without future CVE respectively; p=0.68). The rs867186 variant was found to explain 59% of sEPCR levels variability (p<10-200) but did not associate with CVE risk. CONCLUSION: Our findings show that in patients with CAD, circulating sEPCR levels are related to classical cardiovascular risk factors and renal impairment but are not related to long-term incidence of CVE.

Midregional proadrenomedullin for prediction of cardiovascular events in coronary artery disease: results from the AtheroGene study.

BACKGROUND: Midregional proadrenomedullin (MR-proADM) is a newly identified prognostic marker in heart failure. We evaluated the prognostic impact of MR-proADM in a cohort of patients with symptomatic coronary artery disease according to their clinical presentation. METHODS: We measured baseline MR-proADM concentrations in 2240 individuals from the prospective AtheroGene study and evaluated the prognostic impact on future fatal and nonfatal cardiovascular events during a follow-up period of 3.6 (1.6) years. RESULTS: The sample comprised 1355 individuals with stable angina pectoris (SAP) and 885 with acute coronary syndrome (ACS). A cardiovascular event occurred in 192 people. Individuals presenting with SAP had only slightly lower plasma MR-proADM concentrations than those with ACS (0.53 vs 0.55 nmol/L, P=0.006). MR-proADM showed a moderate association with age, serum N-terminal pro-B-type natriuretic peptide (NT-proBNP), glomerular filtration rate, serum C-reactive protein, hypertension, diabetes, and prevalent multivessel disease (all P<0.0005). Individuals suffering from a cardiovascular event had higher MR-proADM concentrations at baseline in both groups (SAP 0.63 vs 0.53 nmol/L and ACS 0.65 nmol/L vs 0.55 nmol/L, both P<0.0005). Cox regression analysis incorporating various variables of cardiovascular risk and NT-proBNP revealed a hazard ratio of 1.4 (95% CI 1.2-1.6; P<0.0005) per increment of MR-proADM by 1SD. In risk models for secondary prevention, MR-proADM provided information comparable to that of NT-proBNP. CONCLUSIONS: MR-proADM is an independent predictor for future cardiovascular events in patients with symptomatic coronary artery disease, providing information comparable to NT-proBNP for secondary risk stratification.

A genome-wide association study identifies LIPA as a susceptibility gene for coronary artery disease.

BACKGROUND: eQTL analyses are important to improve the understanding of genetic association results. We performed a genome-wide association and global gene expression study to identify functionally relevant variants affecting the risk of coronary artery disease (CAD). METHODS AND RESULTS: In a genome-wide association analysis of 2078 CAD cases and 2953 control subjects, we identified 950 single-nucleotide polymorphisms (SNPs) that were associated with CAD at P<10(-3). Subsequent in silico and wet-laboratory replication stages and a final meta-analysis of 21 428 CAD cases and 38 361 control subjects revealed a novel association signal at chromosome 10q23.31 within the LIPA (lysosomal acid lipase A) gene (P=3.7×10(-8); odds ratio, 1.1; 95% confidence interval, 1.07 to 1.14). The association of this locus with global gene expression was assessed by genome-wide expression analyses in the monocyte transcriptome of 1494 individuals. The results showed a strong association of this locus with expression of the LIPA transcript (P=1.3×10(-96)). An assessment of LIPA SNPs and transcript with cardiovascular phenotypes revealed an association of LIPA transcript levels with impaired endothelial function (P=4.4×10(-3)). CONCLUSIONS: The use of data on genetic variants and the addition of data on global monocytic gene expression led to the identification of the novel functional CAD susceptibility locus LIPA, located on chromosome 10q23.31. The respective eSNPs associated with CAD strongly affect LIPA gene expression level, which was related to endothelial dysfunction, a precursor of CAD.

A prospective, single-blind, multicenter, dose escalation study of intracoronary iNOS lipoplex (CAR-MP583) gene therapy for the prevention of restenosis in patients with de novo or restenotic coronary artery lesion (REGENT I extension).

Neointimal hyperplasia causing recurrent stenosis is a limitation of the clinical utility of percutaneous transluminal coronary interventions (PCI). Nitric oxide (NO) inhibits smooth muscle cell proliferation, platelet activation, and inflammatory responses, all of which have been implicated in the pathogenesis of restenosis. In animals, neointimal proliferation after balloon injury has been shown to be effectively reduced by gene transfer of the inducible NO synthase (iNOS). The primary objective of this first multicenter, prospective, single-blind, dose escalation study was to obtain safety and tolerability information of the iNOS lipoplex (CAR-MP583) gene therapy for reducing restenosis following PCI. Local coronary intramural CAR-MP583 delivery was achieved using the Infiltrator balloon catheter. A total of 30 patients were treated in the study (six patients, 0.5 µg; six patients, 2.0 µg; six patients, 5.0 µg; and 12 patients, 10 µg). There were no complications related to local application of CAR-MP583. In one patient, PCI procedure-related transient vessel occlusion occurred with consecutive troponin elevation. There were no signs of inflammatory responses or hepatic or renal toxicity. No dose relationship was seen with regard to adverse events across the dose groups. Thus, coronary intramural lipoplex-enhanced iNOS gene therapy during PCI is feasible and appears to be safe. These initial clinical results are encouraging to support further clinical research, in particular in conjunction with new local drug delivery technologies.

Multiple marker approach to risk stratification in patients with stable coronary artery disease.

AIMS: multimarker approaches for risk prediction in coronary artery disease have remained inconsistent. We assessed multiple biomarkers representing distinct pathophysiological pathways in relation to cardiovascular events in stable angina. METHODS AND RESULTS: we investigated 12 biomarkers reflecting inflammation [C-reactive protein, growth-differentiation factor (GDF)-15, neopterin], lipid metabolism (apolipoproteins AI, B100), renal function (cystatin C, serum creatinine), and cardiovascular function and remodelling [copeptin, C-terminal-pro-endothelin-1, mid-regional-pro-adrenomedullin (MR-proADM), mid-regional-pro-atrial natriuretic peptide (MR-proANP), N-terminal-pro-B-type natriuretic peptide (Nt-proBNP)] in 1781 stable angina patients in relation to non-fatal myocardial infarction and cardiovascular death (n = 137) over 3.6 years. Using Cox proportional hazards models and C-indices, the strongest association with outcome for log-transformed biomarkers in multivariable-adjusted analyses was observed for Nt-proBNP [hazard ratio (HR) for one standard deviation increase 1.65, 95% confidence interval (CI) 1.28-2.13, C-index 0.686], GDF-15 (HR 1.59, 95% CI 1.25-2.02, C-index 0.681), MR-proANP (HR 1.46, 95% CI 1.14-1.87, C-index 0.673), cystatin C (HR 1.39, 95% CI 1.10-1.75, C-index 0.671), and MR-proADM (HR 1.63, 95% CI 1.21-2.20, C-index 0.668). Each of these top single markers and their combination (C-index 0.690) added predictive information beyond the baseline model consisting of the classical risk factors assessed by C-index and led to substantial reclassification (P-integrated discrimination improvement <0.05). CONCLUSION: comparative analysis of 12 biomarkers revealed Nt-proBNP, GDF-15, MR-proANP, cystatin C, and MR-proADM as the strongest predictors of cardiovascular outcome in stable angina. All five biomarkers taken separately offered incremental predictive ability over established risk factors. Combination of the single markers slightly improved model fit but did not enhance risk prediction from a clinical perspective.

Serum selenium and prognosis in cardiovascular disease: results from the AtheroGene study.

OBJECTIVE: Experimental data suggest a protective role of the essential trace element selenium against cardiovascular disease (CVD), whereas epidemiological data remains controversial. We aimed to investigate the impact of serum selenium concentration in patients presenting with stable angina pectoris (SAP) or acute coronary syndrome (ACS) on long term prognosis. METHODS: Baseline selenium concentration was measured in 1731 individuals (852 with SAP, and 879 with ACS). During a median follow-up of 6.1 years, 190 individuals died from cardiovascular causes. RESULTS: In those ACS patients who subsequently died of cardiac causes, selenium levels were lower compared to survivors (61.0microg/L versus 71.5microg/L; P<0.0001). In a fully adjusted model, patients in the highest tertile of selenium concentration had a hazard ratio of 0.38 (95% CI: 0.16-0.91; P=0.03) as compared with those in the lowest. No association between selenium levels and cardiovascular outcome was observed in SAP. CONCLUSIONS: Low selenium concentration was associated with future cardiovascular death in patients with ACS.

Growth-differentiation factor-15 for risk stratification in patients with stable and unstable coronary heart disease: results from the AtheroGene study.

BACKGROUND: Growth-differentiation factor-15 (GDF-15) is a stress-responsive transforming growth factor-beta-related cytokine that has emerged as a prognostic biomarker in acute coronary syndrome trial populations. Its predictive role in stable coronary heart disease (CHD) has never been assessed. METHODS AND RESULTS: The circulating levels of GDF-15 were measured by immunoradiometric assay in patients with stable angina pectoris (n=1352) or acute coronary syndrome (n=877) who were followed up for a median of 3.6 years. Stable angina pectoris patients presenting with normal (<1200 ng/L), moderately elevated (1200 to 1800 ng/L), or markedly elevated (>1800 ng/L) GDF-15 levels had 3.6-year CHD mortality rates of 1.4%, 2.7%, and 15.0%, respectively (P<0.001). By backward stepwise Cox-regression analysis, which adjusted for age and gender, clinical variables, the number of diseased vessels, renal function, the levels of C-reactive protein, cardiac troponin I, and N-terminal pro-B-type natriuretic peptide, GDF-15 remained an independent predictor of CHD mortality (P<0.001). Addition of GDF-15 improved the prognostic accuracy of a clinical risk prediction model concerning CHD mortality (c-statistic, 0.84 versus 0.74; P=0.005). Analysis of the acute coronary syndrome part of the study population confirmed GDF-15 as an independent predictor of CHD mortality (P<0.001). The circulating levels of GDF-15 did not predict the future risk of nonfatal myocardial infarction in patients with stable angina pectoris or acute coronary syndrome. CONCLUSIONS: This study identifies GDF-15 as a strong and independent predictor of CHD mortality across the broad spectrum of patients with stable and unstable CHD.

Cystatin C and cardiovascular mortality in patients with coronary artery disease and normal or mildly reduced kidney function: results from the AtheroGene study.

AIMS: Chronic kidney disease is associated with increased risk of cardiovascular disease. Cystatin C is a promising marker to reliably mirror renal function. The role of cystatin C in patients with coronary artery disease (CAD) and normal or mildly reduced kidney function is the subject of current investigation. METHODS AND RESULTS: In 2162 patients, over the whole spectrum of CAD, baseline cystatin C concentrations were measured. Patients with an estimated glomerular filtration rate of < or =60 mL/min per 1.73 m(2) (n = 295) were excluded. In patients with complete follow-up information (n = 1827), 66 cardiovascular deaths were registered during a median follow-up of 3.65 years. Logarithmically transformed, standardized cystatin C was associated with cardiovascular death [hazard ratio: 1.94, 95% confidence interval (CI): 1.59-2.37, P < 0.001]. A potential threshold effect was observed; patients in the upper quartile had a 3.87-fold (95% CI: 2.33-6.42; P < 0.001) risk of mortality compared with the pooled lower quartiles. This risk association remained robust after adjustment for potential confounders including classical risk factors and N-terminal pro B-type natriuretic peptide. Serum creatinine was not associated with the outcome in this group of patients with normal renal function. CONCLUSION: Results of this prospective study show that cystatin C is a potent predictor of cardiovascular mortality beyond classical risk factors in patients with CAD and normal or mildly reduced kidney function.

PLTP activity is a risk factor for subsequent cardiovascular events in CAD patients under statin therapy: the AtheroGene study.

Phospholipid transferprotein (PLTP) mediates both net transfer and exchange of phospholipids between different lipoproteins. Although many studies have investigated the role of PLTP in atherogenesis, the role of PLTP in atherosclerotic diseases is unclear. We investigated the association of serum PLTP activity with the incidence of a combined endpoint (myocardial infarction and cardiovascular death) and its relation to other markers of atherosclerosis in 1,085 patients with angiographically documented coronary artery disease (CAD). In the median follow-up of 5.1 years, 156 patients had suffered from the combined endpoint of myocardial infarction or cardiovascular death including 47 of 395 patients who were on statins at baseline. In Kaplan-Meyer analyses serum PLTP activity was not associated with the combined endpoint in all patients. However, in the subgroup of patients receiving statins at baseline, PLTP was shown to be a significant predictor of cardiovascular outcome (P = 0.019), and this also remained stable in univariate (P = 0.027) and multivariate cox regression analyses (P = 0.041) including potential confounders (classical risk factors, HDL cholesterol (HDL-C), and others). We showed in our study that, under statin treatment, high plasma PLTP activity was related to fatal and nonfatal cardiovascular events in CAD patients.

Different calculations of ankle-brachial index and their impact on cardiovascular risk prediction.

BACKGROUND: An ankle-brachial index (ABI; ratio of ankle and brachial systolic blood pressure) <0.9 indicates peripheral arterial disease (PAD) and is a strong predictor of cardiovascular events. The aim of the present study was to address the prognostic value of different methods of ABI calculation. METHODS AND RESULTS: In 831 patients admitted with chest pain for diagnostic heart catheterization, blood pressure of both anterior and posterior tibial arteries was measured. ABI was calculated for each leg with the higher of the 2 ankle pressures (current definition of the American Heart Association) or with the lower of the 2 ankle pressures (modified definition) in relation to the higher of the left or right brachial systolic blood pressure. For each patient, the lower ABI from both legs was used for further evaluation. Fifteen patients (1.8%) with ABI >1.5 were excluded. We compared patients with ABI <0.9 according to the current definition (with PAD, n=204 [25.0%]), those with ABI >or=0.9 according to the modified definition (without PAD, n=524 [64.2%]), and those with ABI <0.9 according to the modified definition and >or=0.9 according to the current definition (suspected PAD, n=88 [10.8%]). Follow-up data (median 6.6 years) were available for 812 patients (99.5%); 157 patients (19.3%) experienced cardiovascular events (cardiovascular death, myocardial infarction, or stroke). Patients without PAD had the lowest cardiovascular event rate, whereas event rates were comparable for patients with PAD and those with suspected PAD (14.8% versus 28.4% versus 25.0%, respectively). In a fully adjusted Cox regression analysis that included patients without PAD as the reference group, the hazard ratio (95% CI) was 1.56 (0.97 to 2.53) for patients with suspected PAD and 1.67 (1.16 to 2.40) for patients with PAD. CONCLUSIONS: When the higher ankle pressure is used for ABI calculation, a group of patients at high risk for cardiovascular events is overlooked. With a simple modification of ABI (use of the lower instead of the higher ankle pressure), more patients at risk could be identified.

Impact of inflammatory markers on cardiovascular mortality in patients with metabolic syndrome.

BACKGROUND: Recent investigations suggest the inclusion of inflammatory markers in the definition of the metabolic syndrome (MS). The aim of this study was to address the role of C-reactive protein, fibrinogen, interleukin-6 (IL-6) and IL-18 (IL-18) on cardiovascular prognosis in accordance to MS. METHODS: A total of 1263 patients with documented coronary artery disease were prospectively included. We defined MS (MS yes: N=533, 42.2%) as the presence of at least three of the following criteria: triglycerides>or=150 mg/dl; low high-density lipoprotein cholesterol (men: <40 mg/dl women: <50 mg/dl); body mass index greater than 30 kg/m; blood pressure>or=130/85 mmHg; fasting glucose>or=100 mg/dl. In addition, we determined C-reactive protein, fibrinogen, IL-6 and IL-18 levels. RESULTS: Follow-up data (median 6.1 years) were available for 1257 patients (99.5%). 139 patients (11.1%) died from cardiovascular causes. Cardiovascular mortality was related to MS (MS yes: 15.1% versus MS no: 8.1%, P<0.0001) and was further increased by elevation of each inflammatory marker. To address whether elevation of inflammatory markers provides additional prognostic information, a subgroup analysis was performed including patients with MS. In a multivariate-adjusted model including all four inflammatory markers, only IL-18 could be identified as an independent predictor of cardiovascular mortality. CONCLUSION: The measurement of inflammatory markers, especially IL-18, adds important prognostic information with regard to the long-term prognosis of patients with MS.

In-vitro comparison of fondaparinux, unfractionated heparin, and enoxaparin in preventing cardiac catheter-associated thrombus.

BACKGROUND: The Organization to Assess Strategies in Acute Ischemic Syndromes trials showed that fondaparinux (fonda) is at least as effective and safe as unfractionated heparin (UFH) and enoxaparin (enoxa) in acute coronary syndromes. Unexpectedly, there was an increase in catheter-related thrombus formation during percutaneous coronary interventions in fonda-treated patients. METHODS: Ten healthy male volunteers were pretreated with aspirin 500 mg 2 h before venesection of 50 ml of blood. Eight groups of anticoagulant (combinations) were tested and volunteers donated blood eight times, thus, acting as their own controls. The groups were UFH, UFH+eptifibatide, enoxa, enoxa+eptifibatide, fonda, fonda+eptifibatide, fonda+(half-therapeutic) UFH, and fonda+eptifibatide+(half-therapeutic) UFH. The blood/anticoagulant mix was kept at 37 degrees C and continuously circulated through a guiding catheter for 60 min or until the catheter became blocked with thrombus. Thrombus development was assessed by weighing each catheter before and after the procedure. Electron microscopy of the catheter lining was used to quantify the degree of erythrocyte and fibrin deposition. RESULTS: Despite fonda anticoagulation, catheters were invariably occluded by thrombus before the 60 min perfusion period had elapsed. Thrombotic catheter occlusion occurred even with higher fonda concentrations and combined fonda/eptifibatide use. All other combinations (including fonda and half-therapeutic UFH) ensured catheter patency for 60 min. Furthermore, thrombus weight and the cell/fibrinogen counts were significantly increased in fonda and fonda+eptifibatide compared with other treatment groups. CONCLUSION: Treatment with fonda, even in combination with eptifibatide, was not sufficient to prevent cardiac catheter thrombus development in our in-vitro study. However, the combination of fonda with 'half' therapeutic dosages of UFH were as efficient as other treatment strategies in preventing thrombus formation.

Association of adiponectin with adverse outcome in coronary artery disease patients: results from the AtheroGene study.

AIMS: In primary prevention, the adipocytokine adiponectin seems to be protective against diabetes mellitus and cardiovascular disease. Data in patients with manifest coronary artery disease (CAD) are scant stimulating the investigation of the association of adiponectin concentrations and cardiovascular outcome in a prospective CAD cohort. METHODS AND RESULTS: In 1890 consecutive patients with documented CAD [1130 with stable angina (SAP) and 760 with acute coronary syndrome (ACS)] baseline concentrations of adiponectin were measured by enzyme-linked immuno assay. During a median follow-up of 2.5 years cardiovascular events were registered (cardiovascular deaths 70; non-fatal myocardial infarction 46). Baseline adiponectin concentrations were similar in patients presenting with SAP [9.03 microg/mL (6.7, 13.45)] or ACS [9.19 microg/mL (6.72, 13.15)], P = 0.779. Kaplan-Meier survival analysis showed a stepwise decrease in event-free survival across quartiles of adiponectin baseline concentration (P log rank = 0.0188). A similar pattern was observed in both subgroups of patients (SAP P = 0.075 and ACS P = 0.254). In univariate analyses, continuous adiponectin concentration was related to event-free survival in all patients [HR 1.02 (95% confidence interval 1.0-1.04), P = 0.012] as well as in the subgroup of SAP subjects [1.03 (1.01-1.05), P = 0.012]. The relation was less strong in the subgroup presenting with ACS [1.014 (0.99-1.04), P = 0.280]. A correlation of adiponectin with high density cholesterol (r = 0.39) and a negative relation to triglyceride levels (r = -0.22) could be described. An increase of one interquartile distance in adiponectin concentration was associated with a 1.17-fold risk for future cardiovascular events (P = 0.013), in B-type natriuretic peptide (BNP) it meant a 1.13-fold risk (P < 0.001). In the overall patient group, this risk association remained robust after the adjustment for classical risk factors, clinical presentation and cardiac medication. Only after adjustment for BNP adiponectin lost its independent predictive value. CONCLUSION: In contrast to studies including initially healthy individuals, the current prospective study demonstrates that adiponectin is associated with adverse cardiovascular outcome in patients with manifest CAD.

Monocyte-derived dendritic cells of patients with coronary artery disease show an increased expression of costimulatory molecules CD40, CD80 and CD86 in vitro.

BACKGROUND: Atherosclerosis is a disease triggered by diverse exogenous stimuli and sustained by chronic inflammatory processes. Dendritic cells (DCs) are key regulatory antigen-presenting cells and play a crucial role in regulating the adaptive and innate immune system in any chronic inflammatory process. DCs are present in atherosclerotic lesions in the areas of the highest T-cell density. So far, their role in atherosclerosis has not been fully elucidated. We investigated the phenotypic properties of DCs in patients with coronary artery disease (CAD) in comparison to healthy individuals. METHODS: Peripheral blood monocytes were isolated from 50 patients with CAD and 19 healthy individuals and differentiated over 9 days to immature and mature DCs. Analysis of the distribution of important stimulatory and costimulatory molecules on the surface of immature and mature DCs was performed by flow cytometry. RESULTS: We observed no changes between the groups concerning cell numbers or expression of CD1a or HLA-DR on DCs. Patients with CAD, however, showed a significant upregulation of the costimulatory molecules CD80, CD86 and CD40 as compared with healthy controls. Expression of CD40, CD80 and CD86 on DCs partly correlated with smoking, family history of CAD, as well as with C-reactive protein levels. High-density lipoprotein cholesterol was inversely associated with the expression of CD40 and CD80 on mature DCs (P<0.05). CONCLUSION: Upregulation of important costimulatory molecules on monocyte-derived DCs of CAD patients, is influenced multifactorially. Our results show notable differences between CAD patients and healthy individuals, possibly contributing to the pathophysiological processes in atherogenesis.