Comparison between activated clotting time and anti-activated factor X activity for the monitoring of unfractionated heparin therapy in patients with aortic aneurysm undergoing an endovascular procedure.

OBJECTIVE: Current guidelines recommend administration of unfractionated heparin (UFH) and measurement of activated clotting time (ACT) during endovascular procedures. The aim of this study was to compare ACT and anti-activated factor X (anti-Xa) measurements for monitoring of UFH therapy during an aortic endograft procedure and to assess the association of peak ACT and peak anti-Xa activity with periprocedural bleeding. METHODS: We retrospectively studied 104 patients with aortic aneurysm undergoing endovascular procedures with repeated coagulation measurements. After a UFH bolus, further UFH doses were given according to ACT (target range, ≥250 seconds) in clinical routine, and in parallel to each ACT (Hemochron; Accriva Diagnostics, Newport Beach, Calif) measurement, we determined anti-Xa activity (HemosIL Liquid anti-Xa; Instrumentation Laboratory, Bedford, Mass). UFH redosing was solely based on the ACT measurements. We defined periprocedural bleeding as a drop in hemoglobin level ≥3 g/dL or red blood cell transfusion within 24 hours. RESULTS: After the initial UFH bolus (median, 67 IU/kg body weight), ACT and anti-Xa measurements showed a weak correlation (rs, 0.46; P < .001). Median ACT was 233 seconds (range, 127-374 seconds; interquartile range [IQR], 204-257 seconds); median anti-Xa activity was 1.0 IU/mL (range, 0.5-2.0 IU/mL; IQR, 0.9-1.2 IU/mL). Only 31% of the patients had an ACT value ≥250 seconds, whereas all patients had an anti-Xa activity ≥0.5 IU/mL. Accordingly, ACT triggered redosing of UFH frequently. Consequently, we saw a median total UFH use of 90 IU/kg during the procedure, a median peak ACT of 255 seconds (IQR, 234-273 seconds), and a median peak anti-Xa activity of 1.2 IU/mL (IQR, 1.0-1.4 IU/mL). Periprocedural bleeding occurred in 40 (38%) patients. Peak ACT ≥250 seconds was not associated with bleeding (odds ratio, 1.05; 95% confidence interval, 0.41-2.70; P = .952), whereas peak anti-Xa activity ≥1.2 IU/mL was independently associated with bleeding (odds ratio, 4.95; 95% confidence interval, 1.82-13.48; P = .002). Moreover, no periprocedural thromboembolic event occurred. CONCLUSIONS: In this retrospective study of patients with aortic aneurysm undergoing an endovascular procedure, ACT and anti-Xa measurements showed poor correlation; only increased peak anti-Xa activity was independently associated with periprocedural bleeding, not increased ACT. Our findings also suggest that monitoring of UFH therapy with anti-Xa during aortic endograft procedures may reduce total UFH use. We further speculate that this approach could reduce periprocedural bleeding.

Prognostic Value of Inflammatory and Cardiovascular Biomarkers for Prediction of 90-Day All-Cause Mortality after Acute Ischemic Stroke-Results from the Linz Stroke Unit Study.

BACKGROUND: Early outcome prediction after acute ischemic stroke is of great interest. The aim of our study was to evaluate the prognostic value of blood biomarkers in patients with acute ischemic stroke. METHODS: We measured interleukin-6 (IL-6), d-dimer, amino-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T, and soluble ST2 plasma concentrations within 24 h after admission to our stroke unit in 721 consecutive acute ischemic stroke patients. End point was 90-day all-cause mortality. RESULTS: During follow-up 81 patients died (11%). In univariate Cox proportional hazards regression analyses with the biochemical markers dichotomized according to median values, all baseline blood biomarkers were strong prognostic markers. However, in the multivariate analysis after adjustment for several clinical variables and the NIH Stroke Scale (NIHSS), only NIHSS >3 [risk ratio (RR) 7.87, 95% CI, 3.61-17.16; P < 0.001], IL-6 > 7 pg/mL (RR 4.09, 95% CI, 2.02-8.29; P < 0.001), and NT-proBNP >447 ng/L (RR 4.88, 95% CI, 2.41-9.88; P < 0.001) remained independent predictors. Using a simple multimarker approach combining these 3 complementary markers, we demonstrated that patients with increased NIHSS, IL-6, and NT-proBNP had the poorest outcome with a mortality rate of 38%, whereas no patient with negative readings for all 3 markers died during follow-up. CONCLUSIONS: In this large cohort of patients with acute ischemic stroke, IL-6 and NT-proBNP at admission were strong and independent prognostic markers for 90-day all-cause mortality, and provided complementary prognostic information to the routinely used stroke severity score NIHSS.

Mortality rates at 10 years are higher in diabetic than in non-diabetic patients with chronic lower extremity peripheral arterial disease.

Patients with lower extremity peripheral artery disease (PAD) have a substantially increased risk for mortality as compared to healthy individuals. We aimed to evaluate the risk for all-cause mortality in PAD patients and in healthy controls during a 10-year follow-up period. Our hypothesis was that the mortality rates at 10 years would differ in diabetic and non-diabetic PAD patients. Our study group consisted of 331 consecutive patients with symptomatic PAD <75 years of age admitted to a tertiary care hospital, including 216 patients without diabetes and 115 with diabetes. Control subjects without atherosclerotic disease were matched to the patients in a 1:1 design by sex, age, and diabetes mellitus status. The outcome measure was all-cause mortality at 10 years. Mortality rates at 10 years were 29% in non-diabetic PAD patients versus 14% in age- and sex-matched non-diabetic controls (risk ratio (RR), 2.31; 95% confidence interval (CI), 1.54-3.47; p<0.001), and 58% in diabetic PAD patients versus 19% in age- and sex-matched diabetic controls (RR, 4.06; 95% CI, 2.67-6.18; p<0.001). Further, PAD patients with diabetes had a significantly increased risk for death within 10 years than did the non-diabetic PAD patients (RR, 2.51; 95% CI, 1.72-3.66; p<0.001). Diabetes was independently associated with outcome, and was the strongest predictor of death in multivariate Cox proportional hazards regression. We conclude that mortality rates at 10 years differ in PAD patients <75 years old with and without diabetes. Our findings suggest that future studies should apply distinct risk assessment strategies in the two PAD subgroups.

Increased soluble ST2 predicts long-term mortality in patients with stable coronary artery disease: results from the Ludwigshafen risk and cardiovascular health study.

BACKGROUND: Soluble suppression of tumorigenicity 2 (sST2) has emerged as a strong prognostic biomarker in patients with heart failure and myocardial infarction. The aim of this study was to evaluate the long-term prognostic value of sST2 in patients with stable coronary artery disease (CAD). METHODS: sST2 plasma concentrations were measured in 1345 patients with stable CAD referred for coronary angiography at a single tertiary care center. The primary endpoint was all-cause mortality. RESULTS: During a median follow-up time of 9.8 years, 477 (36%) patients died. The median sST2 plasma concentration at baseline was significantly higher among decedents than survivors (21.4 vs 18.5 ng/mL; P < 0.001). In multivariate Cox proportional hazards regression analysis, sST2 was an independent predictor of all-cause mortality (risk ratio 1.16 per 1-SD increase in log-transformed values; 95% CI 1.05-1.29; P = 0.004). In the same multivariate analysis, amino-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) were also independent predictors, whereas galectin-3 was not. Patients with sST2 in the highest quartile (>24.6 ng/mL) displayed a 2-fold increased risk of death in univariate analysis, which was attenuated but remained significant in a fully adjusted model (risk ratio 1.39; 95% CI 1.10-1.76; P = 0.006). Further analysis showed that the prognostic impact of sST2 was additive to NT-proBNP and hs-cTnT. Using a multibiomarker approach combining these 3 complementary makers, we demonstrated that patients with all 3 biomarkers in the highest quartiles had the poorest outcome. CONCLUSIONS: In this cohort of patients with stable CAD, increased sST2 was an independent predictor of long-term all-cause mortality and provided complementary prognostic information to hs-cTnT and NT-proBNP.

Mortality rates and mortality predictors in patients with symptomatic peripheral artery disease stratified according to age and diabetes.

OBJECTIVE: Atherosclerotic peripheral arterial disease (PAD) is one of the most prevalent, morbid, and mortal diseases. The aim of this study was to evaluate mortality rates of patients with atherosclerotic PAD stratified according to age and diabetes and to determine predictors of death. METHODS: We studied 487 patients with symptomatic PAD consecutively admitted to the hospital. This cohort included the following four patient subgroups: (1) 216 patients with PAD <75 years of age without diabetes mellitus; (2) 115 patients with PAD < 75 years of age with diabetes mellitus; (3) 102 patients with PAD ≥ 75 years of age without diabetes mellitus; and (4) 54 patients with PAD ≥ 75 years of age with diabetes mellitus. Control subjects without atherosclerotic disease were matched to the patients with PAD in a 1:1 design by sex, age (± 2 years), and diabetes mellitus status. Outcome measure was all-cause mortality at 5 years. RESULTS: Mortality rates at 5 years were 10% in nondiabetic patients with PAD < 75 years of age (vs 5% in control subjects; risk ratio [RR], 2.15; 95% confidence interval [CI], 1.60-4.34); 23% in diabetic patients with PAD < 75 years of age (vs 7% in control subjects; RR, 3.53; 95% CI, 1.80-6.91); 38% in nondiabetic patients with PAD ≥ 75 years of age (vs 22% in control subjects; RR, 2.08; 95% CI, 1.26-3.44); and 52% in diabetic patients with PAD ≥ 75 years of age. Applying multivariate Cox proportional hazards regression analyses (with cardiovascular risk factors, coexisting atherosclerotic disease, clinical stage of PAD, and several biochemical markers as predictor variables), we found the following independent predictors of outcome: in the 216 nondiabetic patients with PAD < 75 years of age, high-sensitivity C-reactive protein (hs-CRP) (RR, 3.04; 95% CI, 1.48-6.26); in the 115 diabetic patients with PAD < 75 years of age, amino-terminal pro-B-type natriuretic peptide (NT-proBNP) (RR, 2.63; 95% CI, 1.65-4.19); in the 102 nondiabetic patients with PAD ≥ 75 years of age, critical limb ischemia (RR, 3.70; 95% CI, 1.82-7.52) and NT-proBNP (RR, 1.93; 95% CI, 1.32-2.82); and in the 54 diabetic patients with PAD ≥ 75 years of age, hs-CRP (RR, 2.61; 95% CI, 1.45-4.67) and NT-proBNP (RR, 3.31; 95% CI, 1.96-5.60). CONCLUSIONS: Mortality rates at 5 years varied considerably among patients with PAD stratified according to age and diabetes. Predictors of death differed among the four patient subgroups in this study and included critical limb ischemia, hs-CRP, and NT-proBNP. Our results might help to develop future strategies for optimized treatment of hospitalized patients with symptomatic PAD.

A variant associated with nicotine dependence, lung cancer and peripheral arterial disease.

Smoking is a leading cause of preventable death, causing about 5 million premature deaths worldwide each year. Evidence for genetic influence on smoking behaviour and nicotine dependence (ND) has prompted a search for susceptibility genes. Furthermore, assessing the impact of sequence variants on smoking-related diseases is important to public health. Smoking is the major risk factor for lung cancer (LC) and is one of the main risk factors for peripheral arterial disease (PAD). Here we identify a common variant in the nicotinic acetylcholine receptor gene cluster on chromosome 15q24 with an effect on smoking quantity, ND and the risk of two smoking-related diseases in populations of European descent. The variant has an effect on the number of cigarettes smoked per day in our sample of smokers. The same variant was associated with ND in a previous genome-wide association study that used low-quantity smokers as controls, and with a similar approach we observe a highly significant association with ND. A comparison of cases of LC and PAD with population controls each showed that the variant confers risk of LC and PAD. The findings provide a case study of a gene-environment interaction, highlighting the role of nicotine addiction in the pathology of other serious diseases.

Soluble ST2 is not independently associated with androgen and estrogen status in healthy males and females.

BACKGROUND: Soluble ST2 (sST2) plasma concentrations are significantly higher in healthy men than in healthy women. The reason for the sex-specific difference of sST2 plasma concentrations is not established. The aim of this study was to evaluate the association of sST2 with sex-hormones in healthy males and females separately. METHODS: We recruited 528 consecutive blood donors and measured plasma concentrations of sST2 and several sex-hormones (i.e., total testosterone, estradiol, sex hormone-binding globulin, follicle-stimulating hormone, and luteinizing hormone). Of the 528 blood donors, 338 were male and 190 were female. For data analysis, we further divided the group of females into the subgroups of pre- and postmenopausal women using the age of 50 years as a proxy for menopause. RESULTS: In non-parametric Spearman's correlation analyses, we found a weak association between sST2 and total testosterone (r(s)+0.126, p=0.021) and also between sST2 and estradiol (r(s)+0.117, p=0.032) in males. In females <50 years of age (n=158) and ≥50 years of age (n=32), respectively, we did not detect any significant association between sST2 and sex-hormones. As a result of multiple linear regression analyses (calculated with log sST2 as dependent variable and log of age and all sex-hormones as explanatory variables), there was no independent association between sST2 and any of the sex-hormones neither in males nor in females. CONCLUSIONS: In the present study cohort we did not find an independent association of sST2 with sex-hormones in healthy males and females. Therefore, the reason for the sex-specific difference of sST2 plasma concentrations still remains unclear.

Pregnancy-associated plasma protein-A as a marker for long-term mortality in patients with peripheral atherosclerosis: inconclusive findings from the Linz Peripheral Arterial Disease (LIPAD) study.

BACKGROUND: Pregnancy-associated plasma protein-A (PAPP-A) has been associated with peripheral artery disease (PAD). The aim of this study was to evaluate the utility of PAPP-A as a marker for long-term mortality in patients with atherosclerotic PAD. METHODS: PAPP-A serum concentrations were measured using an enzymatically amplified two-step sandwich-type immunoassay in 487 consecutive patients admitted to a tertiary care hospital with symptomatic PAD. The main outcome measure was all-cause mortality at 5 years. RESULTS: During follow-up, 114 patients died and 373 survived. The median PAPP-A concentration was higher among decedents compared with survivors (0.96 vs. 0.78 mU/L, p=0.024). The area under the receiver operating characteristic curve for the prediction of 5-year mortality by PAPP-A was 0.57 [95% confidence interval (CI), 0.53-0.61; p=0.026]. Survival probability was not significantly associated with PAPP-A concentrations using Kaplan-Meier curve analysis. However, univariate Cox proportional-hazards regression analysis revealed that PAPP-A was associated with 5-year mortality [risk ratio 1.25; 95% CI, 1.05-1.50; p=0.013 per one standard deviation (SD) increase in log transformed values]. In the multivariate model using a bootstrapping method, the predictive value of PAPP-A remained significant (risk ratio 1.31; 95% CI, 1.01-1.73; p=0.024 per 1 SD increase in log transformed values), even after adjustment for clinical confounders and other biomarkers, such as high-sensitivity C-reactive protein and amino terminal pro-B-type natriuretic peptide. CONCLUSIONS: In this study, PAPP-A was an independent predictor of 5-year all-cause mortality in patients with symptomatic PAD. However, based on the weak association between PAPP-A and outcome in our cohort, we consider PAPP-A measurements to not be useful in clinical practice for prognostic purposes in patients with PAD.

Genetic determinants of acenocoumarol and phenprocoumon maintenance dose requirements.

OBJECTIVE: The variability in warfarin dose requirement is attributable to genetic and environmental factors. Acenocoumarol (AC) and phenprocoumon (PC) are coumarin derivates widely prescribed in European countries for the prevention and treatment of thromboembolic events. The aim of our study was to investigate the contribution of genes involved in the vitamin K cycle to AC and PC maintenance doses. METHODS: Common single nucleotide polymorphisms (SNPs) in the genes encoding cytochrome P450 family member 2C9 (CYP2C9), vitamin K epoxide reductase complex subunit 1 (VKORC1), gamma-glutamyl carboxylase (GGCX), calumenin (CALU) and apolipoprotein E (APOE) were studied in 206 patients receiving AC or PC. RESULTS: Compared to patients with the VKORC1 C1173C genotype, maintenance doses for AC or PC were reduced to 74.6 or 70.2% in heterozygous C1173T subjects and to 48.6 or 48.1% in homozygous T1173T subjects (P < 0.0001). Furthermore maintenance doses for AC and PC were significantly lower in heterozygous CYP2C9*1*3, CYP2C9*2*3, and in CYP2C9*3*3 homozygote individuals compared to homozygous CYP2C9*1*1 subjects (P = 0.0004 and P = 0.0017, respectively). A multiple regression model including age, sex, last INR, VKORC1, and CYP2C9 genotypes explained ~50% of the variability in AC/PC dose requirements. CALU genotype combinations showed minor effects on PC dose requirements. No associations with AC or PC dose requirements were observed for sequence substitutions in the GGCX or APOE genes. CONCLUSION: These results reveal that interindividual variability in weekly AC and PC maintenance dose requirement is mainly dependent on the VKORC1 1173C>T and the CYP2C9*3 alleles. VKORC1 and CYP2C9 genotyping might provide helpful information to prevent serious bleeding events in subjects receiving AC or PC.

Pro-A-type natriuretic peptide and pro-adrenomedullin predict progression of chronic kidney disease: the MMKD Study.

A-type natriuretic peptide (ANP) and adrenomedullin (ADM) are potent hypotensive, diuretic, and natriuretic peptides involved in maintaining cardiovascular and renal homeostasis. We conducted a prospective 7-year study of 177 nondiabetic patients with primary chronic kidney disease to see if ANP and ADM plasma concentrations predict the progression of their disease, using novel sandwich immunoassays covering the midregional epitopes of the stable prohormones (MRproANP and MR-proADM). Progression of chronic kidney disease was defined as doubling of baseline serum creatinine and/or terminal renal failure, which occurred in 65 patients. Analysis of the receiver operating characteristic curve for the prediction of renal endpoints showed similar areas under the curve for the glomerular filtration rate (GFR) (0.838), MR-proANP (0.810), and MRproADM (0.876), respectively, as did the Kaplan-Meier curve analyses of the patients stratified according to the median of the respective markers. In separate multiple Cox-proportional hazard regression analyses, increased plasma concentrations of both peptides were each strongly predictive of the progression of chronic kidney disease after adjustments for age, gender, GFR, proteinuria and amino-terminal pro-B-type natriuretic peptide. Our study suggests that MR-proANP and MR-proADM are useful new markers of progression of primary nondiabetic chronic kidney disease.

Amino-terminal pro-B-type natriuretic peptide as predictor of mortality in patients with symptomatic peripheral arterial disease: 5-year follow-up data from the Linz Peripheral Arterial Disease Study.

BACKGROUND: Amino-terminal pro-B-type natriuretic peptide (NT-proBNP) has emerged as predictor of mortality endpoints in cardiac disease. In contrast, the prognostic value of NT-proBNP in patients with peripheral arterial disease (PAD) is unclear. Therefore, we aimed to evaluate the capability of NT-proBNP as a marker for long-term prognosis in atherosclerotic PAD. METHODS: We obtained NT-proBNP serum concentrations in 487 consecutive patients with symptomatic PAD admitted to a tertiary-care hospital. The endpoint was defined as all-cause mortality, and the study participants were followed for 5 years. RESULTS: Of the 487 patients enrolled, 114 died and 373 survived during follow-up. The median NT-proBNP concentration was higher among decedents than survivors (692 vs 143 ng/L; P < 0.001). Using the median NT-proBNP concentration of the entire cohort (213 ng/L) as threshold level, Kaplan-Meier curve analysis demonstrated that the survival probability was lower in patients with NT-proBNP above the median (log-rank test, P < 0.001). In the fully adjusted Cox proportional-hazards regression analysis, NT-proBNP >213 ng/L had a risk ratio of 2.27 (95% CI 1.27-4.03; P = 0.005) independent of age, sex, glomerular filtration rate, clinical stage of PAD, cardiovascular comorbidity, and other potential confounders. Further analyses showed that NT-proBNP added significantly to the value of established and emerging outcome predictors of PAD. CONCLUSIONS: In this study, a NT-proBNP serum concentration >213 ng/L was a robust and independent predictor of 5-year all-cause mortality in patients with symptomatic PAD. Thus, NT-proBNP measurements can be considered a valuable tool for risk stratification in these patients.

Comparative evaluation of B-type natriuretic peptide, mid-regional pro-A-type natriuretic peptide, mid-regional pro-adrenomedullin, and Copeptin to predict 1-year mortality in patients with acute destabilized heart failure.

BACKGROUND: The aim of the present study was to evaluate the capability B-type natriuretic peptide (BNP) as a prognostic marker in patients with acute destabilized heart failure in comparison with mid-regional pro-A-type natriuretic peptide (MR-proANP), mid-regional pro-adrenomedullin (MR-proADM), and the C-terminal part of the arginine vasopressin prohormone (Copeptin). METHODS AND RESULTS: BNP, MR-proANP, MR-proADM, and Copeptin plasma concentrations were obtained in 137 patients with acute destabilized heart failure attending a tertiary care hospital. The end point was defined as all-cause mortality, and the study participants were followed for 365 days. Of the 137 patients enrolled, 41 died and 96 survived during follow-up. ROC curve analysis showed that the areas under curve for the prediction of 1-year mortality were similar for BNP (0.716; 95% CI 0.633-0.790), MR-proANP (0.725; 95% CI 0.642-0.798), MR-proADM (0.708; 95% CI 0.624-0.782), and Copeptin (0.688; 95% CI 0.603-0.764). Using tercile approaches, Kaplan-Meier curve analyses demonstrated that the predictive value of all four analytes for survival probability was comparable (log-rank test for trend, P < .001 for each). In multivariable Cox proportional-hazards regression analyses, increased BNP, MR-proANP, MR-proADM, and Copeptin plasma concentrations were the strongest predictors of mortality. CONCLUSION: BNP is considered an established prognostic marker for heart failure patients. The present study provides evidence that MR-proANP, MR-proADM, and Copeptin measurements might have similar predictive properties compared with BNP determinations for one-year all-cause mortality in acute destabilized heart failure.

Scavenger receptor class B type I polymorphisms and peripheral arterial disease.

Genetic variations of the scavenger receptor class B type I (SR-BI) have been demonstrated to be associated with plasma lipid parameters, anthropomorphic parameters, and coronary artery disease. We determined the frequency of 3 single-nucleotide polymorphisms within the SR-BI gene (SCARB1) in 354 patients with peripheral arterial disease (PAD) and 354 controls matched for age, sex, and diabetes and related to lipids and disease state, that is, PAD. SCARB1 combined genotype exon 1/intron 5/exon 8 were found to be associated with plasma total and low-density lipoprotein cholesterol levels, respectively. In terms of disease, a significant risk for PAD was observed in female subjects carrying the common allele of exon 8 (odds ratio, 2.623; 95% confidence interval, 1.321-5.208; P=.003). The variant allele of intron 5 was found to be a risk factor for PAD in men (odds ratio, 2.182; 95% confidence interval, 1.288-3.698; P=.005). Furthermore, the SCARB1 combined genotype intron 5/exon 8 proved predictive for PAD in the whole population (P=.006), which remained significant after correction for traditional risk factors. In conclusion, in the present study population, SCARB1 polymorphisms not only show associations with plasma levels of total and low-density lipoprotein cholesterol, respectively, but also with the risk for PAD.

Utility of whole blood impedance aggregometry for the assessment of clopidogrel action using the novel Multiplate analyzer--comparison with two flow cytometric methods.

BACKGROUND: Non-responsiveness to anti-platelet therapy has been reported and has been linked to the occurrence of adverse events. No standard method to monitor clopidogrel efficacy is available at present. We aimed at comparing the utility of whole blood impedance aggregometry for the assessment of clopidogrel action using the novel Multiplate analyzer with two flow cytometric methods. METHODS: Platelet function was determined before and after the initiation of clopidogrel therapy (300 mg loading dose, followed by 75 mg qd) in 40 patients (observational study). Furthermore, 77 patients and 77 referents with and without clopidogrel treatment (75 mg qd) were evaluated (case control study). Platelet function was assessed by Multiplate ADP and ADP+PG tests, by P-selectin (CD62P) expression, and by vasodilator stimulated phosphoprotein (VASP) phosphorylation status. RESULTS: The observational study revealed that platelet reactivity decreased significantly after clopidogrel administration with all 4 methods (p<0.001 for each). In the case control study the median values of all 4 tests were significantly higher in the referents without clopidogrel treatment than in the patients on clopidogrel therapy (p<0.001 for each). Applying test specific lower reference limits as criterion for the differentiation between responders and non-responders to clopidogrel treatment, 57% of the patients on clopidogrel therapy were classified as non-responders with the Multiplate ADP test, 38% with the Multiplate ADP+PG test, 55% with the P-selectin assay, 9% with the PLT VASP/P2Y12 assay. CONCLUSIONS: The VASP phosphorylation assay appeared to be advantageous for the assessment of clopidogrel action compared to the Multiplate ADP+PG test, the P-selectin assay, and the Multiplate ADP test (listed in descending order). However, our method comparison study underscores the critical nature of the dependence of results on the techniques used in specific studies, and it remains to be elucidated which method correlates best with the occurrence of adverse events.

Association of adiponectin and amino terminal proBNP in peripheral arterial disease.

BACKGROUND: The aim of the present study was to investigate the relationship of adiponectin, a novel adipocytokine, and amino terminal proBNP (NT-proBNP) in patients with peripheral arterial disease (PAD). METHODS: Serum concentrations of adiponectin and NT-proBNP were measured in 487 patients with symptomatic PAD from the Linz Peripheral Arterial Disease (LIPAD) study. RESULTS: Correlation analysis revealed an association of adiponectin and NT-proBNP (r, +0.47; p<0.001). Even after adjustment for age, sex, body mass index, diabetes mellitus, smoking, arterial hypertension, estimated glomerular filtration rate (eGFR), fasting glucose, LDL-cholesterol, HDL-cholesterol, triglycerides, high-sensitivity C-reactive protein, and total homocysteine the relationship of adiponectin and NT-proBNP remained significant (r, +0.35; p<0.001). Furthermore, a subgroup analysis of patients with first manifestation of symptomatic PAD (n=287) demonstrated that disease severity (classified by Fontaine stages) was positively related to adiponectin (r, +0.13; p=0.003) and NT-proBNP (r, +0.28; p<0.001). CONCLUSION: Adiponectin was positively associated with NT-proBNP in symptomatic atherosclerotic PAD, independent of traditional and non-traditional risk factors. Moreover, adiponectin and NT-proBNP were related to disease severity, indicating a possible role for assessment of future morbidity and mortality in patients with PAD.

The heart matters in diabetes: 10-Year outcomes of peripheral artery disease.

OBJECTIVES: Mortality rates at 10 years are higher in diabetic patients with chronic lower extremity peripheral arterial disease than in non-diabetic peripheral arterial disease patients. We tested the hypothesis that the predictors of mortality differ between diabetic and non-diabetic peripheral arterial disease patients. METHODS: We studied 331 consecutive patients who were <75 years of age, symptomatic for peripheral arterial disease, and admitted to a tertiary care hospital. Our cohort included 216 patients without diabetes mellitus and 115 with diabetes mellitus. The outcome measure was all-cause mortality at 10 years post-admission. RESULTS: Mortality rates at 10 years were 29% among non-diabetic peripheral arterial disease patients and 58% among diabetic peripheral arterial disease patients. We identified the following independent predictors of death in the 216 peripheral arterial disease patients without diabetes: age ≥65 years (risk ratio: 2.15; 95% confidence interval: 1.28-3.59), ankle brachial index <0.60 mmHg/mmHg (risk ratio: 1.88; 95% confidence interval: 1.14-3.08), history of peripheral arterial disease-specific intervention (risk ratio: 1.81; 95% confidence interval: 1.10-2.97), and high-sensitivity C-reactive protein ≥5.0 mg/L (risk ratio: 2.11; 95% confidence interval: 1.28-3.47). For the 115 peripheral arterial disease patients with diabetes, independent predictors of mortality were as follows: age ≥65 years (risk ratio: 1.72; 95% confidence interval: 1.05-2.83) and amino-terminal pro-B-type natriuretic peptide ≥125 ng/L (risk ratio: 2.10; 95% confidence interval: 1.22-3.60). CONCLUSION: In this study, the predictors of death at 10 years differed between peripheral arterial disease patients with and without diabetes. Among the biomarkers tested, high-sensitivity C-reactive protein was independently associated with outcomes in non-diabetic patients, whereas amino-terminal pro-B-type natriuretic peptide was an independent predictor of death in patients with diabetes. Our findings suggest that in future studies, risk assessment and treatment strategies should be differentially applied to the two peripheral arterial disease subgroups.

B-type natriuretic peptide and amino terminal proBNP predict one-year mortality in short of breath patients independently of the baseline diagnosis of acute destabilized heart failure.

BACKGROUND: The aim of the present study was to demonstrate the capability of B-type natriuretic peptide (BNP) and amino terminal proBNP (NT-proBNP) as prognostic markers in patients with dyspnoea as a chief complaint. METHODS: BNP and NT-proBNP plasma concentrations were obtained from 251 short of breath patients presenting to the emergency department of a tertiary care hospital. Patients with acute coronary syndromes or trauma were excluded. The endpoint was defined as all-cause mortality, and the study participants were followed up for 365 days from the time they attended the emergency department. RESULTS: Of the 251 patients, 62 died and 189 stayed alive during follow-up. In the present study, optimal cut off levels for the prediction of survival were 454 ng/L for BNP, and 2060 ng/L for NT-proBNP. Mortality was higher in patients with baseline BNP and NT-proBNP concentrations above these cut off levels (log rank p<0.001; hazard ratios, 0.325 and 0.357, respectively). In multivariate Cox proportional-hazards regression analyses, elevated BNP/NT-proBNP, low systolic blood pressure, and renal dysfunction were predictors of mortality even when the baseline diagnosis of acute destabilized heart failure was factored into the model. CONCLUSIONS: Both BNP and NT-proBNP measures obtained from short of breath patients presenting to an emergency department may be predictive of one-year all-cause mortality independently of the baseline diagnosis of acute destabilized heart failure.

Diagnostic and prognostic accuracy of galectin-3 and soluble ST2 for acute heart failure.

BACKGROUND: We aimed to compare head-to-head the diagnostic and prognostic capabilities of galectin-3, soluble ST2 (sST2) and B-type natriuretic peptide (BNP) for heart failure (HF) in an emergency setting. METHODS: We studied 251 consecutive patients with dyspnoea as a chief compliant presenting to an emergency department. The diagnosis of HF was based on the Framingham score for HF plus echocardiographic evidence of systolic or diastolic dysfunction. All-cause mortality was assessed at one year. Plasma concentrations of galectin-3 and BNP were measured with two commercially available assays from Abbott Diagnostics, plasma concentrations of sST2 were quantified with the Presage ST2 assay. The diagnostic and prognostic accuracies of galectin-3, sST2 and BNP were assessed by receiver operating characteristic (ROC) curve analysis. RESULTS: Of the 251 patients, 137 had dyspnoea attributable to acute HF and 114 had dyspnoea attributable to other reasons. BNP had a higher area under the curve (AUC) for the diagnosis of HF (0.92; 95% CI, 0.87-0.95) than galectin-3 (0.57; 95% CI, 0.51-0.64) and sST2 (0.63; 95% CI, 0.56-0.69). Of the 137 patients with acute HF, 41 died and 96 survived during follow up. The AUC of BNP for the prediction of one-year all-cause mortality in HF patients (0.72; 95% CI, 0.63-0.79) was not different from the AUCs of galectin-3 (0.70; 95% CI, 0.62-0.78) and sST2 (0.75; 95% CI, 0.67-0.82). CONCLUSIONS: In this study, galectin-3, sST2 and BNP were equally useful for the prediction of one-year all-cause mortality in patients with acute HF. However, in contrast to BNP, galectin-3 and sST2 were not useful as an aid in the diagnosis of acute HF in short of breath patients presenting to an emergency department.

Reference values of galectin-3 and cardiac troponins derived from a single cohort of healthy blood donors.

BACKGROUND: Here we describe the determination of upper reference limits (URL) for galectin-3, high-sensitivity cardiac troponin I (hs-cTnI) and high-sensitivity cardiac troponin T (hs-cTnT) in a single cohort of healthy blood donors using routine assays. METHODS: For this reference value study, we used a cohort of 402 consecutive blood donors (64% were male and 36% were female). The median individuals' age was 35.0 years (range, 18.0-64.4). Individuals of this reference population were free of cardiovascular disease, diabetes mellitus, renal disease, cancer, current infection and chronic inflammatory disease. Plasma concentrations of galectin-3 were measured with the "routine Galectin-3" assay (Abbott Diagnostics), of hs-cTnI with the "STAT High Sensitive Troponin-I" assay (Abbott Diagnostics), and of hs-cTnT with the "Troponin T hs" assay (Roche Diagnostics). URLs were calculated by using a non-parametric percentile method. RESULTS: The 97.5th percentile URL for galectin-3 was 16 ng/mL in males and 17 ng/mL in females; the 99 th percentile URL for hs-cTnI was 39 ng/L in males and 24 ng/L in females; and the 99 th percentile URL for hs-cTnT was 14 ng/L in males and 11 ng/L in females. Those individuals with hs-cTnI values ≥ 15 ng/L (n=8) were different from those individuals with hs-cTnT values ≥ 10 ng/L (n=7). Of the 402 individuals, none had galectin-3 values below the limit of detection (LOD, <1.0 ng/mL), 290 (72%) had hs-cTnI values below the LOD (i.e., 1.9 ng/L), and 359 (89%) had hs-cTnT values below the LOD (i.e., 5.0 ng/L). CONCLUSION: Plasma concentrations of galectin-3, hs-cTnI and hs-cTnT and corresponding 99 th percentile URLs were rather low in our cohort of healthy blood donors compared with previously published data. In our reference population, analyte plasma concentrations above the LOD were detectable in 100% of the individuals with the Abbott galectin-3 assay, but only in less than 50% for both the Abbott hs-cTnI assay and the Roche hs-cTnT assay.