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Mannheim, Germany

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. Source


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. Source


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. Source


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. Source


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. Source

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