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Mannheim, Germany

Synlab Academy

Mannheim, Germany
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Delgado G.E.,University of Heidelberg | Kleber M.E.,University of Heidelberg | Kleber M.E.,Competence Cluster of Nutrition and Cardiovascular Health | Kleber M.E.,Friedrich - Schiller University of Jena | And 6 more authors.
Journal of the American Society of Nephrology | Year: 2017

The mucoprotein uromodulin is the most abundant protein in mammalian urine and has important roles in ion transport, maintenance of water and electrolyte balance, and clearance of bacteria fromthe urinary tract. Low urinary uromodulin concentrations have been associated with increased mortality risk. However, measuring uromodulin in urine has several preanalytic drawbacks, and sensitive assays for the detection of uromodulin in blood have becomeavailable. In this study, we investigated the association of serum uromodulin concentration with cardiovascular biomarkers and mortality risk in a large cohort of patients referred for coronary angiography. Uromodulin concentrations were available in 3057 of 3316 participants of the Ludwigshafen Risk and Cardiovascular Health Study. Higher serum uromodulin concentration associated with a favorable metabolic profile, lower prevalence rates of comorbidities (arterial hypertension, diabetes mellitus, and heart failure), and a lower risk for 10-year mortality, with hazard ratios (95% confidence intervals) of 0.65 (0.54 to 0.78), 0.71 (0.58 to 0.88), and 0.57 (0.45 to 0.73) in the second, third, and fourth quartiles, respectively, compared with the first quartile. The association with reduced mortality was independent of other cardiovascular risk factors, including eGFR, and stronger after adjustment for the genotype of the rs12917707 polymorphism at the UMOD locus. Adding serum uromodulin concentration to established cardiovascular risk prediction scores improved risk prediction. Uromodulin may, therefore, be a useful marker for cardiovascular and renal health. © 2017 by the American Society of Nephrology.

Wang L.,Brigham and Women's Hospital | Song Y.,Brigham and Women's Hospital | Manson J.E.,Brigham and Women's Hospital | Manson J.E.,Harvard University | And 14 more authors.
Circulation: Cardiovascular Quality and Outcomes | Year: 2012

Background-Vitamin D status has been linked to the risk of cardiovascular disease (CVD). However, the optimal 25-hydroxy-vitamin D (25[OH]-vitamin D) levels for potential cardiovascular health benefits remain unclear. Methods and Results-We searched MEDLINE and EMBASE from 1966 through February 2012 for prospective studies that assessed the association of 25(OH)-vitamin D concentrations with CVD risk. A total of 24 articles met our inclusion criteria, from which 19 independent studies with 6123 CVD cases in 65 994 participants were included for a meta-analysis. In a comparison of the lowest with the highest 25(OH)-vitamin D categories, the pooled relative risk was 1.52 (95% confidence interval, 1.30-1.77) for total CVD, 1.42 (95% confidence interval, 1.19-1.71) for CVD mortality, 1.38 (95% confidence interval, 1.21-1.57) for coronary heart disease, and 1.64 (95% confidence interval, 1.27-2.10) for stroke. These associations remained strong and significant when analyses were limited to studies that excluded participants with baseline CVD and were better controlled for season and confounding. We used a fractional polynomial spline regression analysis to assess the linearity of dose-response association between continuous 25(OH)-vitamin D and CVD risk. The CVD risk increased monotonically across decreasing 25(OH)-vitamin D below ̃60 nmol/L, with a relative risk of 1.03 (95% confidence interval, 1.00-1.06) per 25-nmol/L decrement in 25(OH)-vitamin D. Conclusions-This meta-analysis demonstrated a generally linear, inverse association between circulating 25(OH)-vitamin D ranging from 20 to 60 nmol/L and risk of CVD. Further research is needed to clarify the association of 25(OH)-vitamin D higher than 60 nmol/L with CVD risk and assess causality of the observed associations. © 2012 American Heart Association, Inc.

Kostner K.M.,University of Queensland | Marz W.,University of Heidelberg | Marz W.,Medical University of Graz | Marz W.,Synlab Academy | Kostner G.M.,Medical University of Graz
European Heart Journal | Year: 2013

Recently published epidemiological and genetic studies strongly suggest a causal relationship of elevated concentrations of lipoprotein (a) [Lp(a)] with cardiovascular disease (CVD), independent of low-density lipoproteins (LDLs), reduced high density lipoproteins (HDL), and other traditional CVD risk factors. The atherogenicity of Lp(a) at a molecular and cellular level is caused by interference with the fibrinolytic system, the affinity to secretory phospholipase A2, the interaction with extracellular matrix glycoproteins, and the binding to scavenger receptors on macrophages. Lipoprotein (a) plasma concentrations correlate significantly with the synthetic rate of apo(a) and recent studies demonstrate that apo(a) expression is inhibited by ligands for farnesoid X receptor. Numerous gaps in our knowledge on Lp(a) function, biosynthesis, and the site of catabolism still exist. Nevertheless, new classes of therapeutic agents that have a significant Lp(a)-lowering effect such as apoB antisense oligonucleotides, microsomal triglyceride transfer protein inhibitors, cholesterol ester transfer protein inhibitors, and PCSK-9 inhibitors are currently in trials. Consensus reports of scientific societies are still prudent in recommending the measurement of Lp(a) routinely for assessing CVD risk. This is mainly caused by the lack of definite intervention studies demonstrating that lowering Lp(a) reduces hard CVD endpoints, a lack of effective medications for lowering Lp(a), the highly variable Lp(a) concentrations among different ethnic groups and the challenges associated with Lp(a) measurement. Here, we present our view on when to measure Lp(a) and how to deal with elevated Lp(a) levels in moderate and high-risk individuals. © The Author 2013.

Kleber M.E.,University of Heidelberg | Delgado G.,University of Heidelberg | Grammer T.B.,University of Heidelberg | Silbernagel G.,University of Bern | And 6 more authors.
Journal of the American Society of Nephrology | Year: 2015

Obesity and diets rich in uric acid-raising components appear to account for the increased prevalence of hyperuricemia in Westernized populations. Prevalence rates of hypertension, diabetes mellitus, CKD, and cardiovascular disease are also increasing.We used Mendelian randomization to examine whether uric acid is an independent and causal cardiovascular risk factor. Serum uric acid was measured in 3315 patients of the Ludwigshafen Risk and Cardiovascular Health Study. We calculated a weighted genetic risk score (GRS) for uric acid concentration based on eight uric acid-regulating single nucleotide polymorphisms. Causal odds ratios and causal hazardratios (HRs)were calculatedusing a two-stage regression estimatewith theGRS as the instrumental variable to examine associations with cardiometabolic phenotypes (cross-sectional) and mortality (prospectively) by logistic regression and Cox regression, respectively. Our GRS was not consistently associated with any biochemical marker except for uric acid, arguing against pleiotropy. Uric acid was associated with a range of prevalent diseases, including coronary artery disease. Uric acid and the GRS were both associated with cardiovascular death and sudden cardiac death. In a multivariate model adjusted for factors including medication, causal HRs corresponding to each 1-mg/dl increase in genetically predicted uric acid concentration were significant for cardiovascular death (HR, 1.77; 95% confidence interval, 1.12 to 2.81) and sudden cardiac death (HR, 2.41; 95% confidence interval, 1.16 to 5.00). These results suggest that high uric acid is causally related to adverse cardiovascular outcomes, especially sudden cardiac death. Copyright © 2015 by the American Society of Nephrology.

Pilz S.,Medical University of Graz | Pilz S.,VU University Amsterdam | Gaksch M.,Medical University of Graz | O'Hartaigh B.,Yale University | And 4 more authors.
Archives of Toxicology | Year: 2013

The high worldwide prevalence of vitamin D deficiency is largely the result of low sunlight exposure with subsequently limited cutaneous vitamin D production. Classic manifestations of vitamin D deficiency are linked to disturbances in bone and mineral metabolism, but the identification of the vitamin D receptor in almost every human cell suggests a broader role of vitamin D for overall and cardiovascular health. The various cardiovascular protective actions of vitamin D such as anti-diabetic and anti-hypertensive effects including renin suppression as well as protection against atherosclerosis and heart diseases are well defined in previous experimental studies. In line with this, large epidemiological studies have highlighted vitamin D deficiency as a marker of cardiovascular risk. However, randomized controlled trials (RCTs) on vitamin D have largely failed to show its beneficial effects on cardiovascular diseases and its conventional risk factors. While most prior vitamin D RCTs were not designed to assess cardiovascular outcomes, some large RCTs have been initiated to evaluate the efficacy of vitamin D supplementation on cardiovascular events in the general population. When considering the history of previous disappointing vitamin RCTs in general populations, more emphasis should be placed on RCTs among severely vitamin D-deficient populations who would most likely benefit from vitamin D treatment. At present, vitamin D deficiency can only be considered a cardiovascular risk marker, as vitamin D supplementation with doses recommended for osteoporosis treatment is neither proven to be beneficial nor harmful in cardiovascular diseases. © 2013 Springer-Verlag Berlin Heidelberg.

Trummer O.,Medical University of Graz | Pilz S.,Medical University of Graz | Hoffmann M.M.,Albert Ludwigs University of Freiburg | Winkelmann B.R.,Cardiology Group Sachsenhausen | And 7 more authors.
Clinical Chemistry | Year: 2013

BACKGROUND: Decreased circulating 25-hydroxy-vitamin D (25-OH-vitamin D) concentrations have been associated with mortality rates, but it is unclear whether this association is causal. We performed a Mendelian randomization study and analyzed whether 3 common single-nucleotide polymorphisms (SNPs) associated with 25-OH-vitamin D concentrations are causal for mortality rates. METHODS: Genotypes of SNPs in the group-specific component gene ( GC , rs2282679), 7-dehydrocholesterol reductase gene (DHCR7, rs12785878), and cytochrome P450 IIR-1 gene (CYP2R1, rs10741657) were determined in a prospective cohort study of 3316 male and female participants [mean age 62.6 (10.6) years] scheduled for coronary angiography between 1997 and 2000. 25-OH-vitamin D concentrations were determined by RIA. The main outcome measures were all-cause deaths, cardiovascular deaths, and noncardiovascular deaths. RESULTS: In a linear regression model adjusting for month of blood sampling, age, and sex, vitamin D concentrations were predicted by GC genotype (P < 0.001), CYP2R1 genotype (P = 0.068), and DHCR7 genotype (P < 0.001), with a coefficient of determination (r2) of 0.175. During a median follow-up time of 9.9 years, 955 persons (30.0%) died, including 619 deaths from cardiovascular causes. In a multivariate Cox regression adjusted for classical risk factors, GC, CYP2R1, and DHCR7 genotypes were not associated with all-cause mortality, cardiovascular mortality, or noncardiovascular mortality. CONCLUSIONS: Genetic variants associated with 25-OH-vitamin D concentrations do not predict mortality. This suggests that low 25-OH-vitamin D concentrations are associated with, but unlikely to be causal for, higher mortality rates. © 2012 American Association for Clinical Chemistry.

Zewinger S.,Saarland University | Speer T.,Saarland University | Kleber M.E.,Saarland University | Scharnagl H.,University of Heidelberg | And 10 more authors.
Journal of the American Society of Nephrology | Year: 2014

In the general population, HDL cholesterol (HDL-C) is associated with reduced cardiovascular events. However, recent experimental data suggest that the vascular effects of HDL can be heterogeneous. We examined the association of HDL-C with all-cause and cardiovascular mortality in the Ludwigshafen Risk and Cardiovascular Health study comprising 3307 patients undergoing coronary angiography. Patients were followed for a median of 9.9 years. Estimated GFR (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration eGFR creatinine-cystatin C (eGFRcreat-cys) equation. The effect of increasing HDL-C serum levels was assessed using Cox proportional hazard models. In participants with normal kidney function (eGFR>90 ml/min per 1.73 m2), higher HDL-C was associated with reduced risk of all-cause and cardiovascular mortality and coronary artery disease severity (hazard ratio [HR], 0.51, 95% confidence interval [95% CI], 0.26-0.92 [P=0.03]; HR, 0.30, 95% CI, 0.13-0.73 [P=0.01]). Conversely, in patients with mild (eGFR=60-89 ml/min per 1.73 m2) and more advanced reduced kidney function (eGFR,60 ml/min per 1.73 m2), higher HDL-C did not associate with lower risk for mortality (eGFR=60-89 ml/min per 1.73 m2: HR, 0.68, 95% CI, 0.45-1.04 [P=0.07]; HR, 0.84, 95% CI, 0.50-1.40 [P=0.50]; eGFR,60 ml/min per 1.73 m2: HR, 1.18, 95% CI, 0.60-1.81 [P=0.88]; HR, 0.82, 95% CI, 0.40-1.69 [P=0.60]).Moreover,Cox regression analyses revealed interaction betweenHDL-Cand eGFR in predicting all-cause and cardiovascular mortality (P=0.04 and P=0.02, respectively). We confirmed a lack of association between higher HDL-C and lower mortality in an independent cohort of patients with definite CKD (P=0.63). In summary, higher HDL-C levels did not associate with reduced mortality risk and coronary artery disease severity in patients with reduced kidney function. Indeed, abnormal HDL function might confound the outcome of HDL-targeted therapies in these patients. Copyright © 2014 by the American Society of Nephrology.

Laufs U.,Universitatsklinikum des Saarlandes | Scharnagl H.,Medical University of Graz | Marz W.,Medical University of Graz | Marz W.,University of Heidelberg | Marz W.,Synlab Academy
Current Opinion in Lipidology | Year: 2015

Purpose of review: Adherence to hydroxymethylglutaryl-CoA reductase reductase inhibitor (statin) therapy correlates with cardiovascular mortality. Muscle symptoms are the most significant side-effects of statin therapy. This review article summarizes the current concepts of the diagnosis and clinical work-up of patients with statin-associated muscle symptoms (SAMS). Recent findings: SAMS represent a major barrier to maintain long-term persistence to statin treatment. SAMS reduce the quality of life and rare complications may extend to rhabdomyolysis. The molecular pathology of SAMS is heterogeneous. After exclusion of other causes of muscle symptoms the main principle of treatment is re-exposure to very low dose of statin and slow uptitration until the maximally tolerated dose is established. Using this approach the vast majority of patients can be treated with statins long term. For patients with SAMS that are not at low-density lipoproteins (LDL) goal with their maximally tolerated dose of statin combination therapy with ezetimibe and proprotein convertase subtilisin/kexin-9 inhibitors are available. Summary: Time and care is needed to address SAMS because they impair drug adherence. For most patients it is possible to continue the statin therapy. However, combination therapy is wanted if the maximally tolerated statin dose is not sufficient to reach LDL targets. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Silbernagel G.,University of Bern | Fauler G.,Medical University of Graz | Genser B.,University of Heidelberg | Genser B.,Federal University of Bahia | And 9 more authors.
Journal of the American College of Cardiology | Year: 2015

Background Hemodialysis patients are high absorbers of intestinal cholesterol; they benefit less than other patient groups from statin therapy, which inhibits cholesterol synthesis. Objectives This study sought to investigate whether the individual cholesterol absorption rate affects atorvastatin's effectiveness to reduce cardiovascular risk in hemodialysis patients. Methods This post-hoc analysis included 1,030 participants in the German Diabetes and Dialysis Study (4D) who were randomized to either 20 mg of atorvastatin (n = 519) or placebo (n = 511). The primary endpoint was a composite of major cardiovascular events. Secondary endpoints included all-cause mortality and all cardiac events. Tertiles of the cholestanol-to-cholesterol ratio, which is an established biomarker of cholesterol absorption, were used to identify high and low cholesterol absorbers. Results A total of 454 primary endpoints occurred. On multivariate time-to-event analyses, the interaction term between tertiles and treatment with atorvastatin was significantly associated with the risk of reaching the primary endpoint. Stratified analysis by cholestanol-to-cholesterol ratio tertiles confirmed this effect modification: atorvastatin reduced the risk of reaching the primary endpoint in the first tertile (hazard ratio [HR]: 0.72; p = 0.049), but not the second (HR: 0.79; p = 0.225) or third tertiles (HR: 1.21; p = 0.287). Atorvastatin consistently significantly reduced all-cause mortality and the risk of all cardiac events in only the first tertile. Conclusions Intestinal cholesterol absorption, as reflected by cholestanol-to-cholesterol ratios, predicts the effectiveness of atorvastatin to reduce cardiovascular risk in hemodialysis patients. Those with low cholesterol absorption appear to benefit from treatment with atorvastatin, whereas those with high absorption do not benefit. © 2015 American College of Cardiology Foundation Published By Elsevier Inc.

Silbernagel G.,University of Tübingen | Genser B.,University of Heidelberg | Genser B.,Federal University of Bahia | Nestel P.,Baker IDI Heart and Diabetes Institute | And 3 more authors.
Current Opinion in Lipidology | Year: 2013

PURPOSE OF REVIEW: Plant sterols as ingredients to functional foods are recommended for lowering LDL cholesterol. However, there is an ongoing discussion whether the use of plant sterols is safe. RECENT FINDINGS: Genetic analyses showed that common variants of the ATP binding cassette transporter G8 (ABCG8) and ABO genes are associated with elevated circulating plant sterols and higher risk for cardiovascular disease. However, these data do not prove a causal role for plant sterols in atherosclerosis because the risk alleles in ABCG8 and ABO are also related to elevated total and LDL cholesterol levels. The ABO locus exhibits still further pleiotropy. Moreover, analyses in the general population indicated that moderately elevated circulating plant sterols are not correlated with present or future vascular disease. In agreement, novel studies using food frequency questionnaires, studies in experimental animals, and dietary intervention studies support that ingestion of plant sterols may be beneficial to cardiovascular health. SUMMARY: Taken together, current evidence supports the recommendations for the use of plant sterols as LDL cholesterol-lowering agents. Nevertheless, a prospective, randomized, controlled, double-blinded, intervention trial conclusively showing that plant sterol supplementation will prevent hard cardiovascular endpoints is not available to date. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

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