Cardiology Group

Frankfurt am Main, Germany

Cardiology Group

Frankfurt am Main, Germany
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Meinitzer A.,Medical University of Graz | Kielstein J.T.,Hannover Medical School | Pilz S.,Medical University of Graz | Pilz S.,VU University Amsterdam | And 5 more authors.
Clinical Chemistry | Year: 2011

BACKGROUND: Asymmetrical dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, has been linked to cardiovascular risk. The clinical role of its structural isomer symmetrical dimethylarginine (SDMA) remains largely unclear. METHODS: We measured SDMA and ADMA in 3229 patients undergoing coronary angiography at baseline (1997-2000) and recorded total and cardiovascular mortality during a median follow-up time of 7.7 years. We investigated associations of SDMA with cardiovascular risk factors and mortality and compared its role as a cardiovascular risk factor with ADMA, which predicted mortality in previous analyses of our study. RESULTS: In linear regression analyses including common cardiovascular risk factors as covariates, SDMA and ADMA were significantly associated with cystatin C, N-terminal pro-B-type natriuretic peptide, New York Heart Association classification, and homocysteine. The regression coefficients were higher for SDMA than for ADMA. In Cox proportional-hazards models adjusted for cardiovascular risk factors, the hazard ratios (HRs) (with 95% CI) in the second, third, and fourth SDMA quartile compared to the lowest quartile were 0.77 (0.60-0.99), 0.99 (0.78 -1.25), and 1.51 (1.20 -1.91) for total mortality and 0.92 (0.68- 1.25), 0.93 (0.68 -1.26), and 1.54 (1.14 -2.01) for cardiovascular mortality. The same calculations for ADMAquartiles revealed HRs of 1.05 (0.83-1.32), 1.19 (0.95-1.50), and 1.61 (1.30 -1.99) for total mortality and HR of 1.00 (0.74 -1.34), 1.26 (0.95-1.68), and 1.54 (1.18 -2.02) for cardiovascular mortality. CONCLUSIONS: Serum concentrations of SDMA are independently associated with increased cardiovascular and all-cause mortality in patients undergoing coronary angiography. The pattern of risk linked to SDMA is different from that linked to ADMA, suggesting different pathophysiological roles of these 2methylarginine metabolites. © 2010 American Association for Clinical Chemistry.

Kleber M.E.,LURIC Study Nonprofit LLC | Wolfert R.L.,diaDexus | De Moissl G.D.,University of Heidelberg | Winkelmann B.R.,Cardiology Group | And 2 more authors.
Clinical Laboratory | Year: 2011

Background: Lipoprotein-associated phospholipase A2 (LpPLA2) is a lipoprotein-bound enzyme involved in inflammation and atherosclerosis. This cohort study investigates LpPLA2 concentration to predict cardiovascular and total mortality in patients scheduled for coronary angiography. Methods: LpPLA2 concentration was determined in 2298 patients with and in 661 patients without angiographically confirmed coronary artery disease (CAD). During the median observation period of 8.0 years 686 patients died. Results: In patients with tertiles of LpPLA2 of 307-475 ng/mL, or ≥475 ng/mL unadjusted hazard ratios (HR) for total mortality were 1.47 (95% CI 1.21-1.80; p <0.001), and 1.63 (95% CI 135-1.97; p <0.001), respectively, compared to patients with LpPLA2 ≤307 ng/mL. HRs for cardiovascular death were 1.33 (95% CI 1.04-1.71; p = 0.026), and 1.59 (95% CI 1.26-2.02; p <0.001), respectively. After accounting for established risk factors and including angiographic CAD status and high sensitivity C-reactive protein (hsCRP), the 3 rd tertile of LpPLA2 concentration predicted death from all causes with a HR of 1.40 (95% CI 1.15-1.71; p = 0.001) and cardiovascular death with a HR of 135 (95% CI 1.05-1.73; p = 0.018). LpPLA2 increased the risk of cardiovascular death significantly even in individuals with high hsCRP. In patients with hsCRP >33 mg/L and LpPLA2 >392 ng/mL the risk of cardiovascular death was almost two-fold higher compared to patients with low hsCRP and low LpPLA2 with a HR of 1.98 (95% CI 150-2.62; p <0.001). Conclusions: LpPLA2 concentration predicts risk for total and cardiovascular mortality independently from established risk factors and indicates risk for cardiovascular death even in patients with high hsCRP levels.

Ganesh S.K.,University of Michigan | Tragante V.,University Utrecht | Guo W.,Case Western Reserve University | Guo Y.,Children's Hospital of Philadelphia | And 146 more authors.
Human Molecular Genetics | Year: 2013

Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped ~50 000 single-nucleotide polymorphisms (SNPs) that capture variation in ~2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed 10 previously known loci associated with SBP, DBP, MAP or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P < 2.4 × 10-6). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention. © The Author 2013. Published by Oxford University Press. All rights reserved.

Ritsch A.,Innsbruck Medical University | Scharnagl H.,Medical University of Graz | Eller P.,Innsbruck Medical University | Tancevski I.,Innsbruck Medical University | And 8 more authors.
Circulation | Year: 2010

Background-: The role of cholesteryl ester transfer protein (CETP) in the development of atherosclerosis is still open to debate. In the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial, inhibition of CETP in patients with high cardiovascular risk was associated with increased high-density lipoprotein levels but increased risk of cardiovascular morbidity and mortality. In this report, we present a prospective observational study of patients referred to coronary angiography in which CETP was examined in relation to morbidity and mortality. Methods and Results-: CETP concentration was determined in 3256 participants of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study who were referred to coronary angiography at baseline between 1997 and 2000. Median follow-up time was 7.75 years. Primary and secondary end points were cardiovascular and all-cause mortality, respectively. CETP levels were higher in women and lower in smokers, in diabetic patients, and in patients with unstable coronary artery disease, respectively. In addition, CETP levels were correlated negatively with high-sensitivity C-reactive protein and interleukin-6. After adjustment for age, sex, medication, coronary artery disease status, cardiovascular risk factors, and diabetes mellitus, the hazard ratio for death in the lowest CETP quartile was 1.33 (1.07 to 1.65; P=0.011) compared with patients in the highest CETP quartile. Corresponding hazard ratios for death in the second and third CETP quartiles were 1.17 (0.92 to 1.48; P=0.19) and 1.10 (0.86 to 1.39; P=0.46), respectively. Conclusions-: We interpret our data to suggest that low endogenous CETP plasma levels per se are associated with increased cardiovascular and all-cause mortality, challenging the rationale of pharmacological CETP inhibition. © 2010 American Heart Association, Inc.

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.

Grammer T.B.,University of Heidelberg | Hoffmann M.M.,Albert Ludwigs University of Freiburg | Renner W.,Medical University of Graz | Kleber M.E.,LURIC Non Profit LLC | And 4 more authors.
Atherosclerosis | Year: 2011

C-reactive protein (CRP) has been implicated in the development of atherosclerosis. The genetic polymorphism of apolipoprotein (apo) E is associated with the concentration of CRP. We analyzed the association between the apo E genotype, CRP and angiographic coronary artery disease (CAD). The concentration of CRP was similar in patients with stable CAD and in controls, but increased in patients presenting with acute coronary syndromes. In models adjusting for the main confounding variables, the alleles e{open}4 and e{open}2 were associated with decreased and increased concentrations of CRP, respectively, compared to the wild-type allele e{open}3. In spite of this, the e{open}2 allele was associated with a lower prevalence of angiographic CAD, while the slight over-representation of the e{open}4 allele was statistically not significant. We conclude that the apo E genotype is associated with circulating CRP. A causal role of CRP in the development of CAD would be supported if genotypes that raise CRP in the long-term were themselves associated with CAD. As we found the opposite, we suggest that the association between CRP and cardiovascular events reflects confounding and reverse causation. © 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.

Kleber M.E.,University of Heidelberg | Siekmeier R.,University of Bonn | Delgado G.,University of Heidelberg | Grammer T.B.,University of Heidelberg | And 7 more authors.
Advances in Experimental Medicine and Biology | Year: 2014

Measurement of high sensitivity CRP (hsCRP) and lipoprotein-associated phospholipase A2 (LpPLA2) provides information on systemic inflammation and stability of atherosclerotic plaques. Data analyzing the effect of smoking on these parameters are sparse. The aim of our study was the analysis of these parameters in active smokers and never-smokers. The study included 777 smokers and 1,178 never-smokers, of whom 221 and 302 died during a follow-up, respectively. The values of LpPLA2 and hsCRP were signifi- cantly higher in smokers than in never-smokers. Mortality was highest in smokers and never-smokers with elevation of both biomarkers. Multivariate adjusted hazard ratios for patients in the highest tertile of both hsCRP and LpPLA2 compared with patients in the lowest tertile of both markers were 1.85 (1.04-3.28) in never-smokers and 1.94 (1.10-3.45) in smokers. Our data confirmed the predictive value of hsCRP and LpPLA2. However, there were a relevant number of patients with an increase of only one of these parameters. Therefore, beside other risk factors for cardiovascular disease, both parameters should be determined at least in high risk patients. © Springer International Publishing Switzerland 2014.

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