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Murr C.,Innsbruck Medical University | Pilz S.,Medical University of Graz | Grammer T.B.,University of Heidelberg | Kleber M.E.,University of Heidelberg | And 6 more authors.
Clinical Chemistry and Laboratory Medicine | Year: 2012

Background: Low vitamin D concentrations are detected in patients suffering from various clinical conditions which are characterized also by inflammation and immune activation. We investigated whether vitamin D levels in patients with coronary artery disease (CAD) are related to markers of immune activation. Methods: Serum concentrations of 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] and the immune activation markers neopterin and high sensitivity C-reactive protein (hsCRP) were measured in 2015 patients derived from the LUdwigshafen RIsk and Cardiovascular Health (LURIC) study, a cohort study among patients referred for coronary angiography. Results: Serum concentrations of 25(OH)D and 1,25(OH)2D did not differ between patients with CAD [mean±SD: 25(OH)D: 17.4±9.4 μg/L; 1,25(OH)2D: 34.4±13.3 ng/L] and controls [25(OH)D: 18.4±11.7 μg/L; 1,25(OH)2D: 35.3±12.7 ng/L; Welch's t-test: p=n.s.] but CAD patients had higher neopterin (8.6±7.4 nmol/L) and hsCRP (9.6±19.6 mg/L) concentrations compared to controls (neopterin: 7.5±4.8 nmol/L; p=0.0004; hsCRP: 5.4±10.0 mg/L; p<0.0001). There was an inverse correlation between serum 25(OH)D or 1,25(OH)2D concentrations and serum neopterin [Spearman's rank correlation: 25(OH)D: r s=-0.183; 1,25(OH)2D: rs=-0.230] and hsCRP [25(OH)D: rs=-0.142; 1,25(OH)2D: rs=-0.130; all p<0.0001] concentrations. Conclusions: Our results indicate increased inflammatory processes in patients with low vitamin D status. Further studies should clarify the underlying mechanisms for the observed associations of vitamin D status and inflammatory parameters. Copyright © 2012 by Walter de Gruyter.


Kleber M.E.,LURIC Study nonprofit LLC | Renner W.,Medical University of Graz | Marz W.,University of Heidelberg
BMC Medical Genetics | Year: 2010

Background: C-reactive protein is a well established marker of inflammation and has been used to predict future cardiovascular disease. It is still controversial if it plays an active role in the development of cardiovascular disease. Recently, polymorphisms in the gene for HNF1α have been linked to the levels of C-reactive protein and coronary artery disease.Methods: We investigated the association of the rs2259816 polymorphism in the HNF1A gene with the circulating level of C-reactive protein and the hazard of coronary artery disease in the LURIC Study cohort.Results: Compared to CC homozygotes, the level of C-reactive protein was decreased in carriers of at least one A-allele. Each A-allele decreased CRP by approximately 15%. The odds ratio for coronary artery disease was only very slightly increased in carriers of the A-allele and this association did not reach statistical significance.Conclusions: In the LURIC Study cohort the A-allele of rs2259816 is associated with decreased CRP but not with coronary artery disease. © 2010 Kleber et al; licensee BioMed Central Ltd.


Lepper P.M.,University of Ulm | Lepper P.M.,Saarland University | Kleber M.E.,LURIC Study nonprofit LLC | Kleber M.E.,University of Heidelberg | And 5 more authors.
Atherosclerosis | Year: 2011

Background: Atherosclerosis of coronary arteries is hallmarked by non-specific local inflammatory processes accompanied by a systemic response. Lipopolysaccharide-binding protein (LBP) has been suggested to be associated with coronary artery disease (CAD) in a previous study without follow-up. Patients and methods: LBP plasma levels were measured in 2959 participants of the Ludwigshafen Risk and Cardiovascular Health (LURIC) cohort study referred to coronary angiography at baseline between 1997 and 2000. Median follow-up time was 8.0 years. Primary and secondary end points were cardiovascular and all-cause mortality, respectively. Multivariable adjusted logistic regression analyses were conducted to investigate the role of LBP. Results: Serum LBP concentration was significantly increased in 2298 patients with angiographically confirmed CAD compared to 661 individuals without coronary atherosclerosis (6.78 μg/mL (5.46-8.84) vs. 6.13 μg/mL (5.05-7.74), respectively; p< 0.001). Moreover in multivariable logistic regression analyses, adjusted for established cardiovascular risk factors and markers of systemic inflammation, LBP was a significant and independent predictor of total and cardiovascular mortality (hazard ratio (HR) for all cause mortality: 1.43, 95% CI: 1.06-1.94, p= 0.024; HR for cardiovascular mortality in the 4th quartile of LBP: 1.55, 95% CI: 1.06-2.27, p= 0.025). Conclusion: The present results add information on LBP in CAD. The data underscore the potential importance of innate immune mechanisms for atherosclerosis. Further studies are needed to clarify the pathways between innate immune system activation and atherosclerosis. © 2011 Elsevier Ireland Ltd.


Kleber M.E.,LURIC Study Nonprofit LLC | Renner W.,Medical University of Graz | Linsel-Nitschke P.,University of Lübeck | Boehm B.O.,University of Ulm | And 4 more authors.
Atherosclerosis | Year: 2010

Objective: The rs599839 polymorphism A/G in the vicinity of the sortilin 1 gene has been reported to be associated with low density lipoprotein cholesterol (LDL-C) and coronary artery disease (CAD). The objective of this study was to further characterize the protective effect of the minor allele by analyzing the association with a variety of quantitative traits. Methods: Association of rs599839 with plasma levels of different parameters of LDL and triglyceride (TRIG) metabolism as well as the risk of CAD was tested in the LURIC study cohort. Results: Compared to AA homozygotes, the levels of LDL-C, low density lipoprotein triglycerides (LDL-TRIG) and apolipoprotein B were decreased in carriers of at least one G-allele. The G-allele was also associated with an increasing radius of the LDL particles. Regarding TRIG metabolism we observed a significant decrease in the level of triglycerides for homozygous carriers of the G-allele as well as decreased levels of free fatty acids (FFA), free glycerol and free cholesterol. With each G-allele the prevalence of CAD (multivariate OR 0.806; 95% CI: 0.692. -0.940, P=0.006) decreased significantly whereas we observed only a marginal decrease for MI which did not reach significance.For GG homozygotes, the OR for CAD was 0.588 (95% CI: 0.394. -0.877; P=0.009) and the OR for previous myocardial infarction (MI) was 0.693 (95% CI: 0.490. -0.980; P=0.038). These associations were independent of cardiovascular risk factors. Conclusion: In the LURIC Study the G-allele of rs599839 is associated with LDL and TRIG metabolism and the risk of coronary artery disease and myocardial infarction. © 2009 Elsevier Ireland Ltd.


Janis M.T.,Zora Biosciences | Tarasov K.,Zora Biosciences | Ta H.X.,Zora Biosciences | Suoniemi M.,Zora Biosciences | And 13 more authors.
Atherosclerosis | Year: 2013

Objectives: Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has been proposed to be a potential new therapeutic target for treatment of hypercholesterolaemia. However, little is known about the effects of PCSK9 inhibition on the lipidome. Methods: We performed molecular lipidomic analyses of plasma samples obtained from PCSK9-deficient mice, and serum of human carriers of a loss-of-function variant in the PCSK9 gene (R46L). Results: In both mouse and man, PCSK9 deficiency caused a decrease in several cholesteryl esters (CE) and short fatty acid chain containing sphingolipid species such as CE 16:0, glucosyl/galactosylceramide (Glc/GalCer) d18:1/16:0, and lactosylceramide (LacCer) d18:1/16:0. In mice, the changes in lipid concentrations were most prominent when animals were given regular chow diet. In man, a number of molecular lipid species was shown to decrease significantly even when LDL-cholesterol was non-significantly reduced by 10% only. Western diet attenuated the lipid lowering potency of PCSK9 deficiency in mice. Conclusions: Plasma molecular lipid species may be utilized for characterizing novel compounds inhibiting PCSK9 and as sensitive efficacy markers of the PCSK9 inhibition. © 2013 Elsevier Ireland Ltd.


Silbernagel G.,LURIC Study Nonprofit LLC | Silbernagel G.,University of Tübingen | Rosinger S.,University of Ulm | Grammer T.B.,University of Heidelberg | And 6 more authors.
Atherosclerosis | Year: 2012

Objective: Type 2 diabetes represents a major cardiovascular risk factor. However, few studies have addressed the impact of the disease duration on mortality. Thus, we aimed to investigate the predictive value of diabetes duration for all-cause and cardiovascular mortality in subjects undergoing coronary angiography. Methods: We studied 2455 participants of the LUdwigshafen RIsk and Cardiovascular health study (1768 males/687 females). They had a mean±standard deviation (SD) age of 63.1±9.0 years (range: 40.0-79.9) and a mean±SD body mass index of 27.7±4.0kg/m 2. 704 subjects were newly diagnosed with type 2 diabetes according to the 2010 criteria of the American Diabetes Association and 446 subjects had a known history of type 2 diabetes. The mean±SD duration of the follow-up for all-cause and cardiovascular mortality was 7.4±2.3 years. Results: A total of 543 deaths occurred during the follow-up. Among these, 343 were accounted for by cardiovascular diseases. The duration of type 2 diabetes was strongly and positively correlated with all-cause and cardiovascular mortality (both P<. 0.001). The multivariate adjusted hazard ratios (95% confidence intervals) for cardiovascular mortality compared to subjects without diabetes were 1.76 (1.34-2.32), 2.86 (2.00-4.08), 2.96 (1.85-4.74), and 4.55 (3.24-6.39) for subjects with new onset type 2 diabetes and subjects with known type 2 diabetes (duration ≤5, >5 and ≤10, >10 years), respectively. Conclusions: The data emphasise the need to consider the diabetes duration for the prediction of mortality in subjects at intermediate to high cardiovascular risk. © 2012 Elsevier Ireland Ltd.


Marx N.,RWTH Aachen | Silbernagel G.,University of Tübingen | Brandenburg V.,RWTH Aachen | Burgmaier M.,RWTH Aachen | And 8 more authors.
Diabetes Care | Year: 2013

OBJECTIVEdC-peptide is a proinsulin cleavage product released from the pancreas in amounts equimolar to insulin, and elevated levels of C-peptide have been found in patients with insulin resistance and early type 2 diabetes mellitus. Recent data suggest that C-peptide could play a causal role in the pathophysiology of vascular disease, but nothing is known about the prognostic value of C-peptide concentrations in the circulation. RESEARCH DESIGNANDMETHODSdWe examined whether C-peptide is associated with cardiovascular and total mortality in 2,306 patients from the Ludwigshafen Risk and Cardiovascular Health Study who underwent coronary angiography at baseline (1997-2000). RESULTSdDuring amean follow-up of 7.6 years, 440 deaths (19.1%) occurred, 252 (10.9%) of which were due to cardiovascular causes. Age-and sex-adjusted hazard ratios (HRs) in the third compared with the first tertile of C-peptide were 1.46 (95%CI 1.15-1.85; P = 0.002) for all cause and 1.58 (1.15-2.18; P = 0.005) for cardiovascular mortality. After further adjustment for common risk factors as well as markers of glucosemetabolism, these HRs remained significant at 1.46 (1.10-1.93; P = 0.008) and 1.55 (1.07-2.24; P = 0.022), respectively. Moreover, patients in higher tertiles of C-peptide exhibited higher levels of markers of endothelial dysfunction and atherosclerosis as well as a more severe extent of coronary lesions. CONCLUSIONSdIn patients undergoing coronary angiography, C-peptide levels are independently associated with all cause and cardiovascular mortality as well as presence and severity of coronary artery disease. Further studies are needed to examine a potential causal role of Cpeptide in atherogenesis in humans. Copyright © 2013 by the American Diabetes Association.


Silbernagel G.,LURIC Study Nonprofit LLC | Silbernagel G.,University of Tübingen | Sourij H.,Medical University of Graz | Grammer T.B.,University of Heidelberg | And 8 more authors.
Atherosclerosis | Year: 2012

Objective: The American Diabetes Association (ADA) has revised the criteria for the diagnosis of diabetes in 2010. Glycated haemoglobin at a cut-point of ≥6.5% has been included in the diagnostic algorithm. We aimed to investigate whether there is still the need to perform oral glucose tolerance tests (OGTT). Methods: We studied 2002 people referred for angiography who did not have a history of diabetes. OGTT were performed in all 1772 subjects with fasting glucose <126 mg/dl. Participants were prospectively followed for all-cause and cardiovascular mortality over a mean duration (±standard deviation) of 7.7 ± 2.0 years. Results: Using the ADA 2010 criteria 618 individuals were categorised as having new-onset type 2 diabetes. Among these, 167 had isolated post-challenge hyperglycaemia. A total of 346 participants died during follow-up. Cardiovascular death occurred in 202 cases. Those with elevated fasting glucose ≥126 mg/dl and/or glycated haemoglobin ≥6.5% had increased all-cause (hazard ratio [HR]: 1.63, 95% confidence interval [95%CI]: 1.28-2.08, p < 0.001) and cardiovascular mortality (HR: 1.66, 95%CI: 1.21-2.29, p = 0.002) compared to subjects without diabetes according to the ADA 2010 definition. Isolated elevation of post-challenge glucose independently predicted increased cardiovascular mortality (HR: 1.57, 95%CI: 1.02-2.43, p = 0.041). All-cause and cardiovascular mortality were not significantly different between subjects with increased fasting glucose and/or glycated haemoglobin and those with isolated elevation of post-challenge glucose. Conclusions: Performing OGTT will identify a high risk group for cardiovascular mortality undetected by fasting glucose or glycated haemoglobin. © 2012.


Stojakovic T.,Medical University of Graz | Scharnagl H.,Medical University of Graz | Trauner M.,Medical University of Graz | Pieske B.,Medical University of Graz | And 7 more authors.
Atherosclerosis | Year: 2010

Objective: Serum gamma-glutamyl transferase (GGT) seems to be a predictor for coronary artery disease (CAD). The objective of this study was to elucidate the relationship between GGT and total as well as cardiovascular mortality. Methods: Serum levels of GGT were determined in 2556 subjects with and 699 subjects without angiographic evidence of CAD in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. Results: Serum GGT was positively associated with male gender, alcohol consumption and markers of the metabolic syndrome (triglycerides, blood pressure, waist circumference and insulin resistance). It was positively related to aspartate aminotransferase, alanine aminotransferase, C-reactive protein, interleukin-6, and negatively related to glutathione and increased age. During a mean follow-up period of 7.75 years, 754 subjects died. Compared with subjects in the lowest quartile of GGT, the unadjusted hazard ratios (95% CI) for all-cause death were 1.2 (0.9-1.5), 1.4 (1.1-1.8) and 1.9 (1.5-2.3), respectively, in other GGT quartiles. Hazard ratios (CI) for death from cardiovascular causes were 1.4 (1.0-2.0), 1.8 (1.4-2.5) and 2.2 (1.6-2.9). After adjustment for age, gender and cardiovascular risk factors GGT remained a significant predictor for total and cardiovascular mortality. In angiographic CAD the predictive value of GGT was also significant and similar to that in the entire cohort. Conclusion: Serum GGT is predictive of all-cause and cardiovascular mortality in individuals with CAD independently of other cardiovascular risk factors. © 2009 Elsevier Ireland Ltd. All rights reserved.


De Boer S.P.M.,Erasmus University Rotterdam | Cheng J.M.,Erasmus University Rotterdam | Garcia-Garcia H.M.,Erasmus University Rotterdam | Oemrawsingh R.M.,Erasmus University Rotterdam | And 10 more authors.
EuroIntervention | Year: 2014

Aims: The European Collaborative Project on Inflammation and Vascular Wall Remodeling in Atherosclerosis - Intravascular Ultrasound (ATHEROREMOIVUS) study aims to investigate the relations of genetic profile and novel circulating biomarkers with coronary plaque phenotype and vulnerability as determined by intravascular ultrasound (IVUS). Methods and results: ATHEROREMOIVUS is a prospective, observational cohort study of 846 patients with stable angina pectoris or acute coronary syndrome (ACS) who are referred for coronary angiography. Prior to the catheterisation procedure, blood samples are drawn for biomarker measurements and genetic analyses. During the catheterisation procedure, IVUS is performed in a nonculprit coronary artery. The primary endpoint is the presence of vulnerable plaque as determined by IVUS virtual histology. Secondary endpoints include the incidence of major adverse cardiac events during longterm followup. Conclusions: Results from ATHEROREMOIVUS are expected to improve our knowledge of the role of genetic profile and circulating biomarkers in relation to the development of atherosclerosis and vulnerable plaques. Assessment and early validation of the prognostic value of novel biomarkers and intracoronary imaging techniques will be performed.

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