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Johannes P Schwaiger,
Yoshinobu Nakada,
Ramona Berberich,
Katsunori Ikewaki, Benjamin Dieplinger,
Emanuel Zitt,
Ulrich Neyer,
Hermann Salmhofer,
Florian Kronenberg,
Paul Koenig,
Hans Dieplinger
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ABSTRACT: BACKGROUND AND OBJECTIVES: In vivo metabolism of atherogenic apolipoprotein B (apoB)-containing lipoproteins is severely impaired in patients undergoing hemodialysis (HD), resulting in markedly prolonged residence times of these particles. It is unclear whether treatment with statins improves LDL kinetics in HD patients as is known for the general population. Therefore, this kinetic study assessed apoB-containing lipoproteins in these patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Kinetic measures were analyzed with stable-isotope technology in six men undergoing HD before and after 3 months of daily administration of 10 mg of atorvastatin. Patients were 18-65 years of age, had LDL cholesterol levels between 90 and 200 mg/dl, and had been treated with HD for >6 months. They consumed a standardized isocaloric diet for 3 days before analysis. Fractional catabolic rates (FCRs) and production rates of very-low-density lipoprotein (VLDL)-apoB, intermediate-density lipoprotein-apoB, and LDL-apoB were determined using multicompartment modeling after plasma lipoprotein separation, precipitation of apoB, and determination of tracer-to-tracee ratios using mass spectrometry. RESULTS: Plasma concentrations of VLDL- and LDL-apoB were significantly lower (mean ± SD, 7.77±2.62 versus 11.27±6.15 mg/dl, P<0.05; 56.9±23.9 versus 84.0±21.1 mg/dl, P=0.03) and their FCRs were significantly higher (7.20±3.08 versus 5.20±2.98 days(-1), P<0.05; 0.851±0.772 versus 0.446±0.232 days(-1), P<0.05) after 3 months of atorvastatin treatment. Accordingly, the residence times in plasma of VLDL- and LDL-apoB were significantly lower after treatment (0.14 versus 0.19 day and 1.2 versus 2.2 days, respectively). CONCLUSION: Lower plasma concentrations and improved kinetics of atherogenic lipoproteins were observed in HD patients after administration of low-dose atorvastatin.
Clinical Journal of the American Society of Nephrology 04/2013; · 5.23 Impact Factor
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ABSTRACT: The Presage(®) ST2 Assay (Critical Diagnostics, CA, USA) is an in vitro diagnostic device that quantitatively measures soluble suppression of tumorigenicity 2 (sST2) in serum and plasma by ELISA. This assay is US FDA approved and is indicated to be used in conjunction with clinical evaluation as an aid in assessing the prognosis of patients diagnosed with chronic heart failure. sST2 binds to IL-33 and functions as a 'decoy' receptor for IL-33, thereby attenuating the systemic effects of IL-33. Due to the role of IL-33/transmembrane isoform of suppression of tumorigenicity 2 signaling in cardiac remodeling, sST2 has emerged as a novel cardiovascular biomarker. In recent studies, it was shown that sST2 is a valuable predictor of several end points in heart failure, in acute coronary syndromes and in critically ill patients. In this review, analytical considerations and clinical applications of the Presage ST2 Assay will be discussed, as well as probable future concepts for adoption of sST2 measurements into clinical practice.
Expert Review of Molecular Diagnostics 01/2013; 13(1):13-30. · 4.86 Impact Factor
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ABSTRACT: According to a proposed concept of a gastrointestinal-renal natriuretic signaling axis, natriuretic peptides are released from the intestine into the circulation in response to oral salt intake and act on the kidneys as hormones to increase sodium excretion. The peptides guanylin and uroguanylin and their precursors proguanylin and prouroguanylin, respectively, have been suggested to be the mediators of this axis. A study by Preston and co-workers, however, provides important data not supporting this putative concept.
Kidney International 12/2012; 82(12):1253-5. · 6.61 Impact Factor
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Michael E Frischmann,
Katsunori Ikewaki,
Evi Trenkwalder,
Claudia Lamina, Benjamin Dieplinger,
Muhidien Soufi,
Horst Schweer,
Juergen R Schaefer,
Paul König,
Florian Kronenberg,
Hans Dieplinger
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ABSTRACT: OBJECTIVE: Lipoprotein(a) [Lp(a)] consists of apolipoprotein B-100 (apoB-100) as part of an LDL-like particle and the covalently linked glycoprotein apolipoprotein(a) [apo(a)]. Detailed mechanisms of its biosynthesis, assembly, secretion and catabolism are still poorly understood. To address the Lp(a) assembly mechanism, we studied the in vivo kinetics of apo(a) and apoB-100 from Lp(a) and LDL apoB-100 in nine healthy probands using stable-isotope methodology. METHODS: The level of isotope enrichment was used to calculate the fractional synthesis rate (FSR), production rate (PR) and retention time (RT) using SAAMII software and multicompartmental modeling. RESULTS: We observed a similar mean PR for apo(a) (1.15 nmol/kg/d) and apoB-100 (1.31 nmol/kg/d) from Lp(a), which differed significantly from the PR for apoB-100 from LDL (32.6 nmol/kg/d). Accordingly, mean FSR and RT values for Lp(a)-apo(a) were similar to those of Lp(a)-apoB and different from those for LDL-apoB. CONCLUSION: Two different kinetic apoB pools within Lp(a) and LDL suggest intracellular Lp(a) assembly from apo(a) and newly synthesized LDL.
Atherosclerosis 10/2012; · 3.79 Impact Factor
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Clinica chimica acta; international journal of clinical chemistry 06/2012; 413(19-20):1493-4. · 2.54 Impact Factor
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Christina L Wassel,
Claudia Lamina,
Vijay Nambi,
Stefan Coassin,
Kenneth J Mukamal,
Santhi K Ganesh,
David R Jacobs,
Nora Franceschini,
George J Papanicolaou,
Quince Gibson, [......],
John P Cooke,
Devin M Absher,
Jeffrey W Olin,
Braxton D Mitchell,
Muredach P Reilly,
Emile R Mohler,
Kari E North,
Alexander P Reiner,
Florian Kronenberg,
Joanne M Murabito
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ABSTRACT: Candidate gene association studies for peripheral artery disease (PAD), including subclinical disease assessed with the ankle-brachial index (ABI), have been limited by the modest number of genes examined. We conducted a two stage meta-analysis of ∼50,000 SNPs across ∼2100 candidate genes to identify genetic variants for ABI.
We studied subjects of European ancestry from 8 studies (n=21,547, 55% women, mean age 44-73 years) and African American ancestry from 5 studies (n=7267, 60% women, mean age 41-73 years) involved in the candidate gene association resource (CARe) consortium. In each ethnic group, additive genetic models were used (with each additional copy of the minor allele corresponding to the given beta) to test each SNP for association with continuous ABI (excluding ABI>1.40) and PAD (defined as ABI<0.90) using linear or logistic regression with adjustment for known PAD risk factors and population stratification. We then conducted a fixed-effects inverse-variance weighted meta-analyses considering a p<2×10(-6) to denote statistical significance.
In the European ancestry discovery meta-analyses, rs2171209 in SYTL3 (β=-0.007, p=6.02×10(-7)) and rs290481 in TCF7L2 (β=-0.008, p=7.01×10(-7)) were significantly associated with ABI. None of the SNP associations for PAD were significant, though a SNP in CYP2B6 (p=4.99×10(-5)) was among the strongest associations. These 3 genes are linked to key PAD risk factors (lipoprotein(a), type 2 diabetes, and smoking behavior, respectively). We sought replication in 6 population-based and 3 clinical samples (n=15,440) for rs290481 and rs2171209. However, in the replication stage (rs2171209, p=0.75; rs290481, p=0.19) and in the combined discovery and replication analysis the SNP-ABI associations were no longer significant (rs2171209, p=1.14×10(-3); rs290481, p=8.88×10(-5)). In African Americans, none of the SNP associations for ABI or PAD achieved an experiment-wide level of significance.
Genetic determinants of ABI and PAD remain elusive. Follow-up of these preliminary findings may uncover important biology given the known gene-risk factor associations. New and more powerful approaches to PAD gene discovery are warranted.
Atherosclerosis 02/2012; 222(1):138-47. · 3.79 Impact Factor
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Joanne M Murabito,
Charles C White,
Maryam Kavousi,
Yan V Sun,
Mary F Feitosa,
Vijay Nambi,
Claudia Lamina,
Arne Schillert,
Stefan Coassin,
Joshua C Bis, [......],
H-Erich Wichmann,
James F Wilson,
Jacqueline C M Witteman,
Yongmei Liu,
Caroline Hayward,
Ingrid B Borecki,
Andreas Ziegler,
Kari E North,
L Adrienne Cupples,
Florian Kronenberg
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ABSTRACT: Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts.
Continuous ABI and PAD (ABI ≤0.9) phenotypes adjusted for age and sex were examined. Each study conducted genotyping and imputed data to the ≈2.5 million single nucleotide polymorphisms (SNPs) in HapMap. Linear and logistic regression models were used to test each SNP for association with ABI and PAD using additive genetic models. Study-specific data were combined using fixed effects inverse variance weighted meta-analyses. There were a total of 41 692 participants of European ancestry (≈60% women, mean ABI 1.02 to 1.19), including 3409 participants with PAD and with genome-wide association study data available. In the discovery meta-analysis, rs10757269 on chromosome 9 near CDKN2B had the strongest association with ABI (β=-0.006, P=2.46×10(-8)). We sought replication of the 6 strongest SNP associations in 5 population-based studies and 3 clinical samples (n=16 717). The association for rs10757269 strengthened in the combined discovery and replication analysis (P=2.65×10(-9)). No other SNP associations for ABI or PAD achieved genome-wide significance. However, 2 previously reported candidate genes for PAD and 1 SNP associated with coronary artery disease were associated with ABI: DAB21P (rs13290547, P=3.6×10(-5)), CYBA (rs3794624, P=6.3×10(-5)), and rs1122608 (LDLR, P=0.0026).
Genome-wide association studies in more than 40 000 individuals identified 1 genome wide significant association on chromosome 9p21 with ABI. Two candidate genes for PAD and 1 SNP for coronary artery disease are associated with ABI.
Circulation Cardiovascular Genetics 12/2011; 5(1):100-12. · 6.11 Impact Factor
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ABSTRACT: 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).
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.
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.
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.
Clinica chimica acta; international journal of clinical chemistry 12/2011; 413(5-6):587-93. · 2.54 Impact Factor
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ABSTRACT: The biomarkers proguanylin and prouroguanylin are members of the natriuretic peptide family. The aim of this study was to evaluate two commercially available assays for proguanylin and prouroguanylin and to further characterize both analytes in terms of important clinical features.
We evaluated precision and linearity of the BioVendor human proguanylin and prouroguanylin ELISAs. In order to characterize both analytes, we tested in vitro analyte stabilities at -80 °C, and determined biological variability and reference values for proguanylin and prouroguanylin.
Within-run and total coefficients of variation were <10% for the BioVendor proguanylin and prouroguanylin assays. Both methods were linear across the tested measurement ranges. The analytes proguanylin and prouroguanylin were stable for at least 2 months at -80 °C. With respect to biological variability, the reference change values (RCV) were 27% and 59% for proguanylin and prouroguanylin, respectively. For proguanylin, age-independent reference values were 4.0-13.4 ng/mL in males and 4.6-16.3 ng/mL in females. For prouroguanylin, age- and sex-independent reference values were 2.1-11.2 ng/mL.
The BioVendor human proguanylin ELISA and the BioVendor human prouroguanylin ELISA meet the needs of quality specifications of laboratory medicine. The results of the characterization of both analytes provide essential information for further clinical studies.
Clinica chimica acta; international journal of clinical chemistry 08/2011; 412(23-24):2277-83. · 2.54 Impact Factor
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ABSTRACT: 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.
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.
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.
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.
Clinical Chemistry and Laboratory Medicine 06/2011; 49(9):1515-8. · 2.15 Impact Factor
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ABSTRACT: The aim of this study was to investigate the long-term in vitro stability of soluble ST2 (sST2).
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%.
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%.
sST2 is stable for at least 1.5 years in plasma samples stored at -20 degrees C and -80 degrees C.
Clinical biochemistry 09/2010; 43(13-14):1169-70. · 2.02 Impact Factor
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Solveig Gretarsdottir,
Annette F Baas,
Gudmar Thorleifsson,
Hilma Holm,
Martin den Heijer,
Jean-Paul P M de Vries,
Steef E Kranendonk,
Clark J A M Zeebregts,
Steven M van Sterkenburg,
Robert H Geelkerken, [......],
Janet T Powell,
David J Carey,
Helena Kuivaniemi,
Jes S Lindholt,
Gregory T Jones,
Augustine Kong,
Jan D Blankensteijn,
Stefan E Matthiasson,
Unnur Thorsteinsdottir,
Kari Stefansson
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ABSTRACT: We performed a genome-wide association study on 1,292 individuals with abdominal aortic aneurysms (AAAs) and 30,503 controls from Iceland and The Netherlands, with a follow-up of top markers in up to 3,267 individuals with AAAs and 7,451 controls. The A allele of rs7025486 on 9q33 was found to associate with AAA, with an odds ratio (OR) of 1.21 and P = 4.6 x 10(-10). In tests for association with other vascular diseases, we found that rs7025486[A] is associated with early onset myocardial infarction (OR = 1.18, P = 3.1 x 10(-5)), peripheral arterial disease (OR = 1.14, P = 3.9 x 10(-5)) and pulmonary embolism (OR = 1.20, P = 0.00030), but not with intracranial aneurysm or ischemic stroke. No association was observed between rs7025486[A] and common risk factors for arterial and venous diseases-that is, smoking, lipid levels, obesity, type 2 diabetes and hypertension. Rs7025486 is located within DAB2IP, which encodes an inhibitor of cell growth and survival.
Nature Genetics 08/2010; 42(8):692-7. · 35.53 Impact Factor
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Thorgeir E Thorgeirsson,
Daniel F Gudbjartsson,
Ida Surakka,
Jacqueline M Vink,
Najaf Amin,
Frank Geller,
Patrick Sulem,
Thorunn Rafnar,
Tõnu Esko,
Stefan Walter, [......],
Ben A Oostra,
Dorret I Boomsma,
Henning Tiemeier,
Cornelia M van Duijn,
Jaakko Kaprio,
Jeffrey R Gulcher,
Mark I McCarthy,
Leena Peltonen,
Unnur Thorsteinsdottir,
Kari Stefansson
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ABSTRACT: Smoking is a common risk factor for many diseases. We conducted genome-wide association meta-analyses for the number of cigarettes smoked per day (CPD) in smokers (n = 31,266) and smoking initiation (n = 46,481) using samples from the ENGAGE Consortium. In a second stage, we tested selected SNPs with in silico replication in the Tobacco and Genetics (TAG) and Glaxo Smith Kline (Ox-GSK) consortia cohorts (n = 45,691 smokers) and assessed some of those in a third sample of European ancestry (n = 9,040). Variants in three genomic regions associated with CPD (P < 5 x 10(-8)), including previously identified SNPs at 15q25 represented by rs1051730[A] (effect size = 0.80 CPD, P = 2.4 x 10(-69)), and SNPs at 19q13 and 8p11, represented by rs4105144[C] (effect size = 0.39 CPD, P = 2.2 x 10(-12)) and rs6474412-T (effect size = 0.29 CPD, P = 1.4 x 10(-8)), respectively. Among the genes at the two newly associated loci are genes encoding nicotine-metabolizing enzymes (CYP2A6 and CYP2B6) and nicotinic acetylcholine receptor subunits (CHRNB3 and CHRNA6), all of which have been highlighted in previous studies of smoking and nicotine dependence. Nominal associations with lung cancer were observed at both 8p11 (rs6474412[T], odds ratio (OR) = 1.09, P = 0.04) and 19q13 (rs4105144[C], OR = 1.12, P = 0.0006).
Nature Genetics 05/2010; 42(5):448-53. · 35.53 Impact Factor
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ABSTRACT: 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.
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.
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.
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.
Clinical Chemistry and Laboratory Medicine 02/2010; 48(4):537-42. · 2.15 Impact Factor
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ABSTRACT: 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.
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.
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.
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.
Clinical biochemistry 02/2010; 43(9):714-9. · 2.02 Impact Factor
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ABSTRACT: 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.
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.
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.
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.
European Journal of Clinical Pharmacology 12/2009; 66(3):253-60. · 2.85 Impact Factor
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ABSTRACT: The protein ST2 is a member of the interleukin-1 receptor family. Blood concentrations of the soluble isoform of ST2 (sST2) are increased in inflammatory diseases and in heart disease and are considered a prognostic marker in both. The aim of this study was the analytical and clinical evaluation of the novel Presage ST2 assay for the determination of sST2 in human plasma.
We evaluated precision and linearity of the assay, analyte stability, and biological variability, determined reference values, performed a method comparison with an established ELISA, and quantified sST2 concentrations in various diseases.
Within-run and total coefficients of variation were <2.5% and <4.0%. The method was linear across the whole measurement range of the assay. The analyte was stable for 48 h at room temperature, for 7 days at 4 degrees C, and for at least 2 months at -20 degrees C and -80 degrees C. The reference change value for healthy individuals was 30%. Age-independent reference values were 3-28 U/mL in males, and 2-16 U/mL in females. The method comparison revealed a high proportional bias. sST2 plasma concentrations were increased modestly in heart failure and moderately in pneumonia and chronic obstructive pulmonary disease. Patients with sepsis exhibited highly elevated sST2 values. In patients with chronic renal disease, however, there was no difference compared to healthy individuals.
The Presage ST2 assay meets the needs of quality specifications of laboratory medicine. The results of the clinical assay evaluation are novel with respect to sST2 in various diseases and should initiate further studies.
Clinica chimica acta; international journal of clinical chemistry 08/2009; 409(1-2):33-40. · 2.54 Impact Factor
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Carsten Gnewuch,
Gerhard Liebisch,
Thomas Langmann, Benjamin Dieplinger,
Thomas Mueller,
Meinhard Haltmayer,
Hans Dieplinger,
Alexandra Zahn,
Wolfgang Stremmel,
Gerhard Rogler,
Gerd Schmitz
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ABSTRACT: To determine free and conjugated serum bile acid (BA) levels in inflammatory bowel disease (IBD) subgroups with defined clinical manifestations.
Comprehensive serum BA profiling was performed in 358 IBD patients and 310 healthy controls by liquid chromatography coupled to electrospray ionization tandem mass spectrometry.
Serum levels of hyodeoxycholic acid, the CYP3A4-mediated detoxification product of the secondary BA lithocholic acid (LCA), was increased significantly in Crohn's disease (CD) and ulcerative colitis (UC), while most other serum BA species were decreased significantly. Total BA, total BA conjugate, and total BA glycoconjugate levels were decreased only in CD, whereas total unconjugated BA levels were decreased only in UC. In UC patients with hepatobiliary manifestations, the conjugated primary BAs glycocholic acid, taurocholic acid, and glycochenodeoxycholic acid were as significantly increased as the secondary BAs LCA, ursodeoxycholic acid, and tauroursodeoxycholic acid compared to UC patients without hepatobiliary manifestations. Finally, we found that in ileocecal resected CD patients, the unconjugated primary BAs, cholic acid and chenodeoxycholic acid, were increased significantly compared to controls and patients without surgical interventions.
Serum BA profiling in IBD patients that indicates impaired intestinal barrier function and increased detoxification is suitable for advanced diagnostic characterization and differentiation of IBD subgroups with defined clinical manifestations.
World Journal of Gastroenterology 08/2009; 15(25):3134-41. · 2.47 Impact Factor
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ABSTRACT: The evaluation of novel biomarkers for the diagnosis of acute destabilised heart failure (HF).
Prospectively conducted study on diagnostic accuracy.
Emergency department of a tertiary care hospital.
251 consecutive patients presenting to the emergency department with dyspnoea as the chief complaint.
Index tests were plasma concentrations of 10 biomarkers (BNP, MR-proANP, MR-proADM, copeptin, CT-proET-1, ST2, adiponectin, chromogranin A, proguanylin and prouroguanylin). The reference standard was the diagnosis of acute destabilised HF, which was based on the Framingham score for HF plus echocardiographic evidence of systolic or diastolic dysfunction.
Median plasma concentrations of all 10 biomarkers were higher in patients with dyspnoea attributable to acute destabilised HF (n = 137) than in patients with dyspnoea attributable to other reasons (n = 114). Applying receiver operating characteristic curve (ROC) analyses, areas under the curve (AUCs) for BNP (0.92) and MR-proANP (0.88) were significantly higher than the AUCs of the other eight biomarkers (MR-proADM, 0.75; adiponectin, 0.73; CT-proET-1, 0.72; proguanylin, 0.68; ST2, 0.67; prouroguanylin, 0.62; copeptin, 0.62; and chromogranin A, 0.56). In multivariate logistic regression analysis only increased BNP and MR-proANP concentrations remained independent markers for the diagnosis of HF. Both markers alone or in combination added similar diagnostic information besides all clinical information available in the emergency department.
The data showed that BNP and MR-proANP were the only independent diagnostic markers of HF. Both markers provided similar diagnostic information and were clinically useful as an aid in the diagnosis of acute destabilised HF in an emergency setting.
Heart (British Cardiac Society) 07/2009; 95(18):1508-13. · 4.22 Impact Factor
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ABSTRACT: We have previously demonstrated that adiponectin is associated with amino terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with peripheral artery disease (PAD). Furthermore, we have shown that NT-proBNP is a strong predictor of mortality in these patients. The aim of this study was therefore to evaluate the value of adiponectin as long-term prognostic marker in patients with atherosclerotic PAD in the same cohort.
We measured adiponectin 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.
Of the 487 patients enrolled, 114 died and 373 survived during follow-up. The median adiponectin concentration was higher among decedents than survivors (11.3 vs. 9.1mg/L; p<0.001). Univariate Cox proportional-hazard regression analysis revealed that adiponectin concentrations were associated with 5-year mortality in PAD patients (risk ratio 1.05, 95% CI 1.03-1.07; p<0.001 per 1mg/L increase). Even after adjustment for age, sex, body mass index, estimated glomerular filtration rate, clinical stage of PAD, cardiovascular comorbidity, and other potential confounders, the predictive value of adiponectin serum concentrations remained statistically significant (risk ratio 1.03, 95% CI 1.00-1.05; p=0.030 per 1mg/L increase). However, adiponectin lost its independent association with mortality in symptomatic PAD after additional adjustment for NT-proBNP.
In this study, adiponectin serum concentrations predicted 5-year all-cause mortality in patients with symptomatic PAD independently of other established and emerging outcome predictors. Only after adjustment for NT-proBNP, adiponectin lost its independent predictive value.
Clinica chimica acta; international journal of clinical chemistry 07/2009; 408(1-2):87-91. · 2.54 Impact Factor
