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.

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.

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.

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.

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.

Interleukin 6, galectin 3, growth differentiation factor 15, and soluble ST2 for mortality prediction in critically ill patients.

PURPOSE: The aim of this study was to compare the prognostic value of interleukin 6 (IL-6), galectin 3, growth differentiation factor 15 (GDF-15), and soluble ST2 (sST2) in an unselected cohort of critically ill patients. METHODS: During a study period of 1 year, we recruited 530 consecutive patients admitted to a medical intensive care unit of a tertiary care hospital. We examined a combination of inflammatory, renal, and cardiac biomarkers for the prediction of 90-day all-cause mortality. RESULTS: During follow-up, 118 patients died (22%). In univariate analyses, increased IL-6, galectin 3, GDF-15, and sST2 plasma concentrations at baseline were strong prognostic markers. However, in the multivariate models, only IL-6 and sST2 remained independent biomarkers adding additional prognostic information to the routinely used Simplified Acute Physiology Score (SAPS) II. Using a simple multimarker approach, patients with increased SAPS II, IL-6, and sST2 (ie, SAPS II >35, IL-6 >32.3pg/mL, and sST2 >103ng/mL) had the poorest outcome. CONCLUSIONS: In this heterogeneous group of critically ill patients, only SAPS II, IL-6, and sST2 remained independent and additive prognostic markers for 90-day all-cause mortality. A combination of the SAPS II with the 2 complementary biomarkers might provide a valuable tool for risk stratification of critically ill patients.

Plasma B-type natriuretic peptide in patients with pleural effusions: preliminary observations.

STUDY OBJECTIVES: To address the value of plasma B-type natriuretic peptide (BNP) concentrations as a diagnostic tool for determining the cardiac etiology of pleural effusions, and to determine possible differences of plasma BNP concentrations before and after pleurocentesis in patients with congestive heart failure (CHF). DESIGN: Observational study. SETTING: Tertiary care hospital. PATIENTS: Consecutive series of 64 patients with indications for diagnostic pleurocentesis. The final diagnosis of the underlying disease was assessed by clinical criteria. Seven patients were excluded due to pleural effusions of equivocal origin or due to obvious hemothorax secondary to trauma. INTERVENTION: Pleurocentesis attempting to drain effusions dry. Plasma BNP concentrations were measured directly before pleurocentesis and 24 h after the intervention. During these 24 h, the dosages of patients' medications were held constant. MEASUREMENTS AND RESULTS: In distinguishing between patients with pleural effusions caused by CHF (n = 31) and patients with pleural effusions attributable to other causes (n = 26), the area under the curve was 0.974 (SE, 0.021; 95% confidence interval, 0.892 to 0.997) for plasma BNP. A BNP cutoff concentration of 2,201 ng/L had a sensitivity of 77% and a specificity of 100% in the diagnosis of CHF. The median plasma BNP concentrations in patients with pleural effusions caused by CHF (n = 31) did not change within 24 h after pleurocentesis compared with the concentrations obtained before the procedure (before pleurocentesis, 3,227 ng/L; 24 h after pleurocentesis, 2,759 ng/L; p = 0.189), despite a median removal of 1,100 mL pleural fluid. CONCLUSIONS: Plasma BNP concentrations of patients with pleural effusions of unknown origin may be an aid in the diagnosis of CHF as the underlying cause. If plasma BNP is used as a surrogate marker of global cardiac function, there is no indication of hemodynamic improvement caused by pleurocentesis alone in patients with CHF and pleural effusions.

Head-to-head comparison of the diagnostic utility of BNP and NT-proBNP in symptomatic and asymptomatic structural heart disease.

BACKGROUND: B-type natriuretic peptide (BNP) and the amino-terminal fragment of the BNP prohormone (NT-proBNP) are markers for functional cardiac impairment and are elevated in heart failure (HF). Aim of the present study was to perform a head-to-head comparison of the diagnostic utility of BNP and NT-proBNP in symptomatic and asymptomatic structural heart disease. METHODS: We prospectively classified 180 consecutive subjects according to ACC/AHA guidelines. Blood concentrations of BNP and NT-proBNP were determined by two fully automated chemiluminescent assays (Bayer and Roche method). Diagnostic utilities were tested by ROC analyses and logistic regression. RESULTS: ROC curves of BNP and NT-proBNP in patients with symptomatic HF (n=43) and asymptomatic subjects (n=137) did not differ significantly (AUC 0.930 vs. 0.918, p=0.650), but comparison of patients with asymptomatic structural heart disease (n=56) and subjects without structural disorder of the heart (n=81) revealed different AUCs for the respective assays (0.735 vs. 0.839, p=0.009). In the population studied, age, sex and renal function had no impact on the diagnostic performance of both tests when compared by logistic regression models. CONCLUSIONS: Both assays facilitate diagnosis of symptomatic and asymptomatic structural heart disease. BNP and NT-proBNP may be equally useful as an aid in the differential diagnosis of probable signs or symptoms of HF. In contrast, NT-proBNP might be a more discerning marker of early cardiac dysfunction than BNP.

Comparison of the automated AxSYM and ADVIA centaur immunoassays for homocysteine determination.

A new fully automated chemiluminescence assay for total homocysteine (tHcy) determination (ADVIA Centaur homocysteine, Bayer) was evaluated in comparison with a previously established fluorescence polarization assay (AxSYM homocysteine, Abbott). Linearity could be demonstrated in a concentration range up to 50 micromol/l for both methods. The detection limit was 0.92 micromol/l for the AxSYM and 0.61 micromol/l for the ADVIA Centaur analyzer. Within-run coefficients of variation (%CV) ranged from 1.7% to 1.8% for the AxSYM, and from 2.2% to 2.7% for the ADVIA Centaur analyzer, total CV ranged from 2.5% to 3.5% for the AxSYM, and from 3.6% to 4.5% for the ADVIA Centaur analyzer. Passing and Bablock regression analysis of 180 samples with the AxSYM assay as reference method revealed an intercept of -0.41 micromol/l (95% CI -1.17 to 0.20 micromol/l) and a slope of 1.11 (95% CI 1.05 to 1.18), the Bland-Altman difference plot showed a mean difference of -0.9 micromol/l between tHcy measurements with wide 95% limits of agreement (-3.6 to 1.7 micromol/l). At thresholds of 10 and 15 micromol/l there was a considerable proportion of discordant classifications of study subjects by the AxSYM and ADVIA Centaur method. When evaluating case-control status for vascular disease both assays showed similar characteristics (i.e., significant difference of tHcy in 71 CAD patients and 109 control subjects, and non-significant odds ratios for tHcy in the multivariate model). In conclusion, both methods are reliable for routine tHcy determination in clinical laboratories, as they are fast and completely automated systems with good accuracy and precision allowing sample random access, automatic dilution and stored calibration capabilities. However, results of both assays may not be used interchangeably since the ADVIA Centaur method tends to overestimate tHcy values compared to the AxSYM method.

Monitoring aspirin 100 mg and clopidogrel 75 mg therapy with the PFA-100 device in patients with peripheral arterial disease.

A tool to identify vascular patients who receive antiplatelet therapy nd to distinguish between responders and non-responders to antiplatelet therapy could be of clinical importance. The present observational study was designed to investigate whether the PFA-100 device (Dade Behring) is suitable to detect long-term therapy of aspirin (100 mg/d) and/or clopidogrel (75 mg/d) in a cohort of patients with peripheral arterial disease (PAD). A total of 150 consecutive patients with PAD were studied; 34 patients were excluded from the study due to irregular intake of antiplatelet therapy or due to method limitations. Of the remaining 116 patients, 42 had no antiplatelet therapy, 47 had daily aspirin (100 mg) intake, 19 were administered clopidogrel 75 mg daily, and 10 received a medication with 100 mg aspirin plus clopidogrel 75 mg daily, all for at least 10 days. Nonparametric Kruskal-Wallis test with post hoc comparisons showed that collagen plus epinephrine (CEPI) closure times of the patient group receiving aspirin and the group receiving aspirin plus clopidogrel were similar (p>0.05). In contrast, both patient groups exhibited prolonged CEPI values compared to patients without antiplatelet therapy and patients taking clopidogrel (p<0.001). Finally, both patients without antiplatelet therapy and patients with clopidogrel did not show marked differences with respect to their CEPI values (p>0.05). However, Kruskal-Wallis test results revealed that collagen plus adenosine-5'-diphosphate closure times were not significantly different in all four patient groups (p=0.257). In conclusion, the PFA-100 device may be a suitable tool for monitoring aspirin 100 mg therapy, but it is not appropriate for the detection of clopidogrel administration in its current setup. Although it appears plausible that patients with PAD could benefit from monitoring platelet inhibition, clear evidence for this concept is still lacking.

Analytical characterization and clinical evaluation of an enzyme-linked immunosorbent assay for measurement of afamin in human plasma.

BACKGROUND: Comparative proteomics has recently identified afamin, the newest member of the albumin gene family, as a potential biomarker for ovarian cancer. The aim of this study was the analytical and clinical evaluation of a sandwich enzyme-linked immunosorbent assay for the determination of afamin in human plasma. METHODS: We evaluated precision, linearity, and detection limit of the assay, analyte stability and biological variability, determined reference values and quantified afamin concentrations in various diseases. RESULTS: Within-run and total coefficients of variation were <10%. The method was linear across the tested measurement range. Detection limit was 7 mg/L for the assay. The analyte was stable for 24 h at room temperature, for 48 h at 4°C, and for at least one year at -20°C and -80°C. The reference change value for healthy individuals was 24%. Age- and sex-independent reference values in healthy blood donors were 45-99 mg/L (median 68 mg/L). In the clinical assay evaluation afamin plasma concentrations were modestly decreased in patients with heart failure. Patients with pneumonia or sepsis exhibited markedly decreased afamin plasma concentrations. However, patients with chronic renal disease or chronic obstructive pulmonary disease showed no difference in afamin plasma concentrations as compared to healthy individuals. Correlation analyses revealed an inverse association between afamin and inflammatory biomarkers. CONCLUSIONS: The afamin assay meets quality specifications for laboratory medicine. The results of the clinical assay evaluation revealed novel insights with respect to afamin as a potential negative acute phase protein and should encourage further studies.

Prognostic value of soluble ST2 in an unselected cohort of patients admitted to an intensive care unit - The Linz Intensive Care Unit (LICU) study.

BACKGROUND: Soluble ST2 (sST2) has emerged as a prognostic biomarker in patients with heart disease. We tested the hypothesis that sST2 is an independent predictor of mortality in patients admitted to an intensive care unit (ICU). METHODS: We performed measurements of sST2 plasma concentrations in 530 consecutive patients admitted to a medical ICU of a tertiary care hospital during a study period of one year. The patients recruited during the first six months were used for the derivation cohort (n=274) and the patients recruited during the second six months were used for the validation cohort (n=256). The endpoint was defined as 90-day all-cause mortality. RESULTS: In the derivation cohort, sST2 was higher among decedents (n=56; median, 146 U/mL) than survivors (n=218; median 42 U/mL, p<0.001). In multivariate Cox proportional-hazard regression analysis (offering age, sex, BMI, APACHE II score, SAPS II, CRP, IL-6, PCT, creatinine, total cholesterol, albumin, hs-cTnT, BNP and sST2 as independent variables), sST2 was a significant predictor of mortality (risk ratio 1.48, 95% CI 1.15-1.90; p=0.002 per 1 SD increase in log transformed values). In this statistical model, only sST2 and SAPS II contributed independently to mortality prediction. We further observed an additive effect of an sST2 plasma concentration of >84 U/mL and an increased SAPS II for mortality prediction. The findings from the derivation cohort were confirmed in the independent validation cohort. In those patients with a length of stay of >48 h at the ICU (n=225), sST2 obtained two days after baseline measurement had a better capability than baseline sST2 to predict mortality. CONCLUSIONS: In an unselected cohort of patients admitted to the ICU, sST2 was an independent predictor of 90-day all-cause mortality and added prognostic information to the SAPS II.

Long-term stability of soluble ST2 in frozen plasma samples.

OBJECTIVE: The aim of this study was to investigate the long-term in vitro stability of soluble ST2 (sST2). DESIGN AND METHODS: EDTA plasma samples were drawn from 15 individuals with various diseases. The Presage ST2 assay was used for measurement of sST2 concentrations directly after blood collection and after storing plasma samples for 18 months at -20 degrees C and -80 degrees C. The default criterion for analyte stability was set at 95%. RESULTS: sST2 concentrations in the 15 individuals ranged from 12 U/mL to 140 U/mL. Directly after blood collection, the mean (+/-SD) sST2 concentration was 51+/-37 U/mL, and absolute analyte recoveries were 50+/-35 U/mL and 51+/-34 U/mL after storage of samples for 18 months at -20 degrees C and -80 degrees C, respectively. Relative analyte recoveries after 18 months of storage at -20 degrees C and -80 degrees C were 99+/-5% and 101+/-7%. CONCLUSION: sST2 is stable for at least 1.5 years in plasma samples stored at -20 degrees C and -80 degrees C.

Prognostic value of established and novel biomarkers in patients with shortness of breath attending an emergency department.

OBJECTIVES: Acute dyspnea is a common cause for emergency department visits. The aim of this study was to evaluate the prognostic value of established and novel biomarkers in patients with acute dyspnea. DESIGN AND METHODS: We measured 10 biomarkers [B-type natriuretic peptide (BNP), midregional pro-A-type natriuretic peptide (MR-proANP), midregional-proadrenomedullin (MR-proADM), copeptin, C-terminal endothelin-1 precursor fragment (CT-proET-1), soluble ST2 (sST2), chromogranin A (CgA), adiponectin, proguanylin, and prouroguanylin] in 251 consecutive patients with acute dyspnea presenting to the emergency department of a tertiary care hospital. Outcome measure was all-cause mortality at 1 year. RESULTS: At baseline decedents (n=62) had significantly higher median plasma concentrations of all 10 biomarkers than survivors (n=189). Applying univariate Cox proportional-hazard regression analyses, all biomarkers were significant outcome predictors displaying risk ratios (RR) from 1.4 to 2.4 (per 1 SD increase in log transformed values). In multivariate Cox proportional-hazard regression analysis, however, only MR-proANP (RR 1.6; 95% CI, 1.1-2.2; p=0.008), sST2 (RR 1.7; 95% CI, 1.3-2.3; p<0.001), and CgA (RR 1.5; 95% CI, 1.2-1.9, p<0.001) were independently associated with 1-year mortality. We provide a possible explanation for the complementary prognostic value of those three biomarkers in our cohort, where coincidence of heart failure and inflammatory pulmonary disease was common and also related to worse outcome. CONCLUSIONS: Our evaluation of biomarkers in patients with acute dyspnea suggests that MR-proANP, sST2, and CgA are strong, independent and complementary outcome predictors. MR-proANP is considered a specific marker of cardiac stretch, sST2 might reflect both inflammation and cardiac stretch, and CgA obviously indicates neuroendocrine activation in various diseases.