TY - JOUR AB - Temperature extremes are one facet of global warming caused by climate change. They have a broad impact on population health globally. Due to specific individual- and area-level factors, some subgroups of the population are at particular risk. Observational data has demonstrated that the association between temperature and mortality and cardiovascular mortality is U- or J-shaped. This means that beyond an optimal temperature, both low and high temperatures increase cardiovascular risk. In addition, there is emerging epidemiological data showing that climate change-related temperature fluctuations may be particularly challenging for cardiovascular health. Biological plausibility for these observations comes from the effect of cold, heat, and temperature fluctuations on risk factors for cardiovascular disease. Shared mechanisms of heat and cold adaptation include sympathetic activation, changes in vascular tone, increased cardiac strain, and inflammatory and prothrombotic stimuli. The confluence of these mechanisms can result in demand ischemia and/or atherosclerotic plaque rupture. In conclusion, public health and individual-level measures should be taken to protect susceptible populations, such as patients with risk factors and/or pre-existing cardiovascular disease, from the adverse effects of non-optimal temperatures. This review aims to provide an overview of the association between temperature extremes and cardiovascular disease through the lens of pathophysiology and observational data. It also highlights some specific meteorological aspects, gives insight to the interplay of air temperature and air pollution, touches upon social dimensions of climate change, and tries to give a brief outlook into what to expect from the future. AU - Ni, W.* AU - Areal, A.T.* AU - Lechner, K. AU - Breitner-Busch, S. AU - Zhang, S.* AU - Woeckel, M. AU - Slesinski, S.C. AU - Nikolaou, N. AU - Dallavalle, M. AU - Schikowski, T.* AU - Schneider, A.E. C1 - 74601 C2 - 57552 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland TI - Low and high air temperature and cardiovascular risk. JO - Atherosclerosis VL - 406 PB - Elsevier Ireland Ltd PY - 2025 SN - 0021-9150 ER - TY - JOUR AB - Due to their remarkable plasticity, macrophages can adapt to diverse environments and challenges therein, thereby exerting tissue-specific and context-specific functions. Macrophages are the most frequent immune cell population present in the heart and contribute substantially to cardiac homeostasis and function. Moreover, macrophages are key regulators throughout all stages of heart injury, acquiring diverse phenotypes that can either ameliorate or exacerbate cardiac pathology in a context-dependent manner. The contribution of macrophages to both tissue damage as well as to recovery/tissue repair during heart injury provides avenues for therapeutic modulation of their functions to beneficially influence heart injury progression and hence prevent heart failure. However, to effectively fine-tune macrophage function, a deep understanding of their heterogeneity is required. The present review focuses on the phenotypic diversity and different roles of macrophages in cardiac homeostasis as well as in ischemic and non-ischemic heart disease, and discusses macrophages as potential therapeutic targets in the settings of heart injury. AU - Trimaglio, G.* AU - Mirtschink, P.* AU - El-Armouche, A.* AU - Chavakis, T. C1 - 75473 C2 - 58167 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland TI - Cardiac macrophages and their functions in homeostasis and injury. JO - Atherosclerosis VL - 409 PB - Elsevier Ireland Ltd PY - 2025 SN - 0021-9150 ER - TY - JOUR AB - BACKGROUND AND AIMS: Understanding molecular processes of the early phase of atherosclerotic cardiovascular disease conditions is of utmost importance for early prediction and intervention measures. METHODS: We measured 92 cardiovascular-disease-related proteins (Olink, Cardiovascular III) in 2024 elderly participants of the population-based LIFE-Adult study. We analysed the impact of 27 covariables on these proteins including blood counts, cardiovascular risk factors and life-style-related parameters. We also analysed protein associations with 13 subclinical cardiovascular traits comprising carotid intima media thickness, plaque burden, three modes of Vicorder-based pulse-wave velocities, ankle-brachial index and ECLIA-based N-terminal prohormone of brain natriuretic peptide (NT-proBNP). RESULTS: Estimated glomerular filtration rate, triglycerides and sex where the most relevant covariables explaining more than 1 % variance of 49, 22 and 20 proteins, respectively. A total of 43 proteins were significantly associated with at least one of the analysed subclinical cardiovascular traits. NT-pro-BNP, brachial-ankle pulse-wave velocity (baPWV) and parameters of carotid plaque burden accounted for the largest number of associations. Association overlaps were relatively sparse. Only growth/differentiation factor 15, low density lipoprotein receptor and interleukin-1 receptor type 2 are associated with these three different cardiovascular traits. We confirmed several literature findings and found yet unreported associations for carotid plaque presence (von-Willebrand factor, galectin 4), carotid intima-media thickness (carboxypeptidase A1 andB1), baPWV (cathepsin D) and NT-proBNP (cathepsin Z, low density lipoprotein receptor, neurogenic locus homolog protein 3, trem-like transcript 2). Sex-interaction effects were observed, e.g. for spondin-1 and growth/differentiation factor 15 likely regulated by androgen response elements. CONCLUSIONS: We extend the catalogue of proteome biomarkers possibly involved in early stages of cardiovascular disease pathologies providing targets for early risk prediction or intervention strategies. AU - Garcia, T.* AU - Petrera, A. AU - Hauck, S.M. AU - Baber, R.* AU - Wirkner, K.* AU - Kirsten, H.* AU - Pott, J.* AU - Tönjes, A.* AU - Henger, S.* AU - Loeffler, M.* AU - Peters, A. AU - Scholz, M.* C1 - 71867 C2 - 56392 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland TI - Relationship of proteins and subclinical cardiovascular traits in the population-based LIFE-Adult study. JO - Atherosclerosis VL - 398 PB - Elsevier Ireland Ltd PY - 2024 SN - 0021-9150 ER - TY - JOUR AB - BACKGROUND AND AIMS: Endothelial dysfunction (ED) is considered to be a major driver of the increased incidence of cardiovascular disease in primary aldosteronism (PA). The functionality of the epoxyeicosatrienoic acid (EET) pathway, involving the release of beneficial endothelium-derived lipid mediators, in PA is unknown. Evidence suggests this pathway to be disturbed in various models of experimental hypertension. We therefore assessed EET production in primary human coronary artery endothelial cells exposed to aldosterone excess and measured circulating EET in patients with PA. METHODS: We used qPCR to investigate changes in the expression levels of essential genes for the synthesis and degradation of EET, calcium imaging to address the functional impact on overall endothelial function, as well as mass spectrometry to determine endothelial synthetic capacity to release EET upon stimulation. RNA-seq was performed to gain further mechanistic insights. Eicosanoid concentrations in patient's plasma were also determined by mass spectrometry. RESULTS: Aldosterone, while eliciting proinflammatory VCAM1 expression and disturbed calcium response to acetylcholine, did not negatively affect stimulated release of endothelial EET. Likewise, no differences were observed in eicosanoid concentrations in plasma from patients with PA when compared to essential hypertensive controls. However, an inhibitor of soluble epoxide hydrolase abrogated aldosterone-mediated VCAM1 induction and led to a normalized endothelial calcium response probably by restoring expression of CHRNE. CONCLUSION: EET release appears intact despite aldosterone excess. Epoxide hydrolase inhibition may revert aldosterone-induced functional changes in endothelial cells. These findings indicate a potential new therapeutic principle to address ED, which should be explored in future preclinical and clinical trials. AU - Meng, Y.* AU - Bilyal, A.* AU - Chen, L.* AU - Mederos Y Schnitzler, M.* AU - Kocabiyik, J.* AU - Gudermann, T.* AU - Riols, F. AU - Haid, M. AU - Marques, J.G.* AU - Horak, J.* AU - Koletzko, B.* AU - Sun, J.* AU - Beuschlein, F.* AU - Heinrich, D.A.* AU - Adolf, C.* AU - Reincke, M.* AU - Schneider, H.* C1 - 71726 C2 - 56390 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland TI - Endothelial epoxyeicosatrienoic acid release is intact in aldosterone excess. JO - Atherosclerosis VL - 398 PB - Elsevier Ireland Ltd PY - 2024 SN - 0021-9150 ER - TY - JOUR AB - The authors regret that there are two errors regarding citation and reference list in the above-mentioned article. 1. An incorrect reference number was used for in-text citation. The correction is as follows:Page 8: Incorrect: Luther et al. [20] further reported that Aldo infusion over 3 days resulted in increased sEH expression in adipose tissue of mice. Correct: Luther et al. [17] further reported that Aldo infusion over 3 days resulted in increased sEH expression in adipose tissue of mice. 2. Additionally, we observed an error in the reference list.Reference 24: The title of the article was cited incorrectly. Incorrect: K. Node, Y. Huo, X. Ruan, B. Yang, M. Spiecker, K. Ley, D.C. Zeldin, J.K. Liao, Anti-inflammatory properties of derived eicosanoids, Science 285 (1999) 1276–1280. Correct: K. Node, Y. Huo, X. Ruan, B. Yang, M. Spiecker, K. Ley, D.C. Zeldin, J.K. Liao, Anti-inflammatory properties of cytochrome P450 epoxygenase-derived eicosanoids, Science 285 (1999) 1276–1280. The authors apologize for any inconvenience these errors may have caused. The online version of the article has been corrected to reflect these changes. AU - Meng, Y.* AU - Bilyal, A.* AU - Chen, L.* AU - Mederos Y Schnitzler, M.* AU - Kocabiyik, J.* AU - Gudermann, T.* AU - Riols, F. AU - Haid, M. AU - Marques, J.G.* AU - Horak, J.* AU - Koletzko, B.* AU - Sun, J.* AU - Beuschlein, F.* AU - Heinrich, D.A.* AU - Adolf, C.* AU - Reincke, M.* AU - Schneider, H.* C1 - 72690 C2 - 56674 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland TI - Corrigendum to "Endothelial epoxyeicosatrienoic acid release is intact in aldosterone excess" [Atherosclerosis 398 (2024) 118591]. JO - Atherosclerosis VL - 401 PB - Elsevier Ireland Ltd PY - 2024 SN - 0021-9150 ER - TY - JOUR AB - Background and aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of lipid homeostasis. A few earlier genome-wide association studies (GWAS) investigated genetic variants associated with circulating PCSK9 concentrations. However, uncertainty remains about some of the genetic loci discovered beyond the PCSK9 locus. By conducting the largest PCSK9 meta-analysis of GWAS (meta-GWAS) so far, we aimed to identify novel loci and validate the previously reported loci that regulate PCSK9 concentrations. Methods: We performed GWAS for PCSK9 concentrations in two large cohorts (GCKD (n = 4,963) and KORA F3 (n = 2,895)). These were meta-analyzed with previously published data encompassing together 20,579 individuals. We further conducted a second meta-analysis in statin-naïve individuals (n = 15,390). A genetic risk score (GRS) was constructed on PCSK9-increasing SNPs and assessed its impact on the risk for coronary artery disease (CAD) in 394,943 statin-naïve participants (17,077 with events) of the UK Biobank by performing CAD-free survival analysis. Results: Nine loci were genome-wide significantly associated with PCSK9 concentrations. These included the previously described PCSK9, APOB, KCNA1/KCNA5, and TM6SF2/SUGP1 loci. All imputed SNPs in the PCSK9 locus account for ∼15% of variance of PCSK9 concentrations. We further identified FADS2 as a novel locus that was also found in statin-naïve participants. All imputed SNPs within the FADS2 locus explain ∼1.2% of variance of PCSK9 concentrations. Additionally, four further loci (a region on chromosome 5, SDK1, SPATA16 and HPR) were genome-wide significant in either the main model or the statin-naïve subset. The linear increase in a PCSK9 genetic risk score was associated with 1.41-fold (95%CI 1.16–1.72, p < 0.001) higher risk for incident CAD. Conclusions: We identified five novel loci (FADS2, SPATA16, SDK1, HPR and a region on chromosome 5) for PCSK9 concentrations that would require further research. Additionally, we confirm the genome-wide significant loci that were previously detected. AU - Kheirkhah, A.* AU - Schachtl-Riess, J.F.* AU - Lamina, C.* AU - Di Maio, S.* AU - Koller, A.* AU - Schönherr, S.* AU - Coassin, S.* AU - Forer, L.* AU - Sekula, P.* AU - Gieger, C. AU - Peters, A. AU - Köttgen, A.* AU - Eckardt, K.U.* AU - Kronenberg, F.* C1 - 68784 C2 - 55026 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland TI - Meta-GWAS on PCSK9 concentrations reveals associations of novel loci outside the PCSK9 locus in White populations. JO - Atherosclerosis VL - 386 PB - Elsevier Ireland Ltd PY - 2023 SN - 0021-9150 ER - TY - JOUR AB - Background and aims: High lipoprotein(a) [Lp(a)] concentrations are associated with increased coronary artery disease (CAD) risk. Lp(a) is regulated mainly genetically by the LPA gene but involved genetic variants have not been fully elucidated. Improved understanding of the entanglements of genetic Lp(a) regulation may enhance genetic prediction of Lp(a) and CAD risk. We investigated an interaction between the well-known LPA missense SNP rs41272110 (known as Thr3888Pro) and the frequent LPA splicing mutation KIV-2 4925G>A. Methods: Effects on Lp(a) concentrations were investigated by multiple quantile regression in the German Chronic Kidney Disease (GCKD) study, KORA-F3 and KORA-F4 (ntotal = 10,405) as well as in the UK Biobank (UKB) 200k exome dataset (n = 173,878). The impact of the interaction on CAD risk was assessed by survival analysis in UKB. Results: We observed a significant SNP-SNP interaction in all studies (p = 1.26e-05 to 3.03e-04). In quantile regression analysis, rs41272110 as a predictor shows no impact on Lp(a) (β = −0.06 [-0.79; 0.68], p = 0.879), but in a joint model including both SNPs as predictors, rs41272110 is associated with markedly higher Lp(a) (β = +9.40 mg/dL [6.45; 12.34], p = 4.07e-10). Similarly, rs41272110 shows no effect on CAD in UKB (HR = 1.01 [0.97; 1.04], p = 0.731), while rs41272110 carriers not carrying 4925G>A show an increased CAD risk (HR = 1.10 [1.04; 1.16], p = 6.9e-04). This group corresponds to 4% of the population. Adjustment for apolipoprotein(a) isoforms further modified the effect estimates markedly. Conclusions: This work emphasizes the complexity of the genetic regulation of Lp(a) and the importance to account for genetic subgroups in Lp(a) association studies and when interpreting genetic cardiovascular risk profiles. AU - Grüneis, R.* AU - Lamina, C.* AU - Di Maio, S.* AU - Schönherr, S.* AU - Zoescher, P.* AU - Forer, L.* AU - Streiter, G.* AU - Peters, A. AU - Gieger, C. AU - Köttgen, A.* AU - Kronenberg, F.* AU - Coassin, S.* C1 - 64982 C2 - 52355 SP - 151-159 TI - The effect of LPA Thr3888Pro on lipoprotein(a) and coronary artery disease is modified by the LPA KIV-2 variant 4925G>A. JO - Atherosclerosis VL - 349 PY - 2022 SN - 0021-9150 ER - TY - JOUR AB - Background and aims: Genetic risk scores for common diseases as myocardial infarction (MI) gain increasing attention for individual's risk prediction. One might wonder if assessing family history becomes redundant. It was the aim of this study to evaluate the amount of shared information between family history and genetic risk scores and to assess their independent and combined effects on prevalent and incident MI risk. Methods: A genome wide polygenic risk score (PGS) and one family risk score (FamRS) were calculated in a population-based study from Southern Germany (n = 3071) with up to 11 years of follow-up. Logistic and Cox Regression models were used adjusting for lifestyle and classical risk factors. Results: A right shift in MI risk for increasing values of PGS was found, with. considerably increasing ORs along the top quantiles of PGS (OR = 3.03 for top 10%; OR = 5.55 for top 2.5%). The PGS was not associated with incident MI cases, though. The FamRS was significantly associated with both prevalent and incident MI cases with an OR of 2.9 for participants with a strong positive family history compared to average. ORs and HRs did hardly change in a combined model including both measures, indicating independent contribution to MI risk. The simultaneous addition of PGS and FamRS to a model including classical risk factors significantly enhanced prediction for prevalent cases and non-cases (p = 3.28 × 10−5). Conclusions: These findings emphasize that both genetic information and family history are relevant for the determination of MI risk and that neither of them can replace the other. AU - Schnitzer, F.* AU - Forer, L.* AU - Schönherr, S.* AU - Gieger, C. AU - Grallert, H. AU - Kronenberg, F.* AU - Peters, A. AU - Lamina, C.* C1 - 65356 C2 - 52119 SP - 10-17 TI - Association between a polygenic and family risk score on the prevalence and incidence of myocardial infarction in the KORA-F3 study. JO - Atherosclerosis VL - 352 PY - 2022 SN - 0021-9150 ER - TY - JOUR AB - Background and aims: Risk assessment studies on the impact of carotid intima-media thickness (CIMT) on cardiovascular events (CVEs) often apply a linear relationship in Cox models of proportional hazards. However, CVEs are mostly induced through rupture of plaques driven by nonlinear mechanical properties of the arterial wall. Hence, the risk response might be nonlinear as well and should be detectable in CVE incidence data when associated with CIMT as surrogate variable for atherosclerotic wall degeneration.Methods: To test this hypothesis, we investigate the KORA F4 study comprising 2580 participants with CIMT measurements and 153 first CVEs (86 strokes and 67 myocardial infarctions). CIMT is only a moderate predictor of CVE risk due to confounding by attained age. Biological evidence suggests that age-related CIMT growth is not entirely connected with atherosclerosis. To explore the complex relations between age, CIMT and CVE risk, we apply linear and nonlinear models of both CIMT and dnCIMT, defined as deviation from a sex and age-adjusted normal value.Results: Based on goodness-of-fit and biological plausibility, threshold and logistic step models clearly reveal nonlinear risk response relations for vascular covariables CIMT and dnCIMT. The effect is more pronounced for models involving dnCIMT as novel risk factor, which is not correlated with age.Conclusions: Compared to the standard approach of risk assessment with linear models involving CIMT, the application of excess dnCIMT with nonlinear risk responses leads to a more precise identification of asymptomatic high risk patients, especially at younger age. AU - Simonetto, C. AU - Heier, M. AU - Rospleszcz, S. AU - Meisinger, C. AU - Seissler, J. AU - Peters, A. AU - Kaiser, J.C. C1 - 57977 C2 - 48090 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - 32-39 TI - Risk for cardiovascular events responds nonlinearly to carotid intima-media thickness in the KORA F4 study. JO - Atherosclerosis VL - 296 PB - Elsevier Ireland Ltd PY - 2020 SN - 0021-9150 ER - TY - JOUR AB - Background and aims: Serum uromodulin, a novel biomarker of kidney function and tubular integrity, has been linked to cardiovascular events and total mortality in patients at high cardiovascular risk. Here, we analyze the association of serum uromodulin with cardiovascular morbidity and cardiovascular as well as total mortality in the population-based KORA F4 study stratified by sex.Methods: Baseline serum uromodulin was measured in 1079 participants of the KORA F4 study (age 62-81 years). Using multivariable adjusted Cox proportional hazards models, the associations of serum uromodulin with total mortality and cardiovascular mortality were analyzed after a median follow-up period of 8.6 years, and with non-fatal and fatal stroke and myocardial infarction/coronary death after a median follow-up time of 8.4 years.Results: Serum uromodulin was significantly inversely associated with total mortality (HR 0.65; 95% CI 0.53-0.79 per standard deviation of logarithmized serum uromodulin; p < 0.001) and cardiovascular mortality (HR 0.70; 95% CI 0.52-0.93) in men, but not in women (HR for all-cause mortality in women 0.98; 95% CI 0.77-1.25, HR for cardiovascular mortality 0.78; 95% CI 0.56-1.11) after adjustment for age, BMI, diabetes and eGFR. In addition, serum uromodulin was significantly inversely associated with incident stroke in men (HR 0.68; 95% CI 0.50-0.92), but not in women (HR 0.96; 95% CI 0.68-1.38) after multivariable adjustment. The association of serum uromodulin with incident myocardial infarction was attenuated and lost significance after multivariable adjustment in both sexes.Conclusions: Serum uromodulin is an independent biomarker for total and cardiovascular mortality in men from the general community aged 62 years or older. AU - Then, C. AU - Then, H.L.* AU - Lechner, A.* AU - Thorand, B. AU - Meisinger, C. AU - Heier, M. AU - Peters, A. AU - Koenig, W.* AU - Rathmann, W.* AU - Scherberich, J.* AU - Seissler, J. C1 - 58205 C2 - 48185 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - 1-7 TI - Serum uromodulin and risk for cardiovascular morbidity and mortality in the community-based KORA F4 study. JO - Atherosclerosis VL - 297 PB - Elsevier Ireland Ltd PY - 2020 SN - 0021-9150 ER - TY - JOUR AB - BACKGROUND AND AIMS: Dyslipidemia is a major risk factor for cardiovascular disease, the leading cause of preventable death worldwide. As a result, a full understanding of the factors influencing dyslipidemia is urgently necessary. Bile acids have been recognized as regulators of lipid metabolism, and neutral sterols may influence serum lipid levels. Therefore, this analysis was conducted to better understand the relationship between bile acids, neutral sterols, and dyslipidemia. METHODS: We examined cross-sectional associations between selected fecal metabolites and serum lipids or markers of dyslipidemia in 1387 participants of the KORA FF4 study using linear and logistic regression models. RESULTS: We found positive associations between fecal bile acids and serum high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-c), total cholesterol, triglycerides and markers of dyslipidemia, though associations were seen most consistently with triglycerides and hypertriglyceridemia. We also found positive associations between fecal cholesterol and serum LDL-c, total cholesterol, triglycerides, hypertriglyceridemia and high serum total cholesterol, though only associations with triglycerides or hypertriglyceridemia remained significant after applying the Bonferroni correction. Unexpectedly, several fecal plant sterols were positively associated with serum lipids and the associated markers of dyslipidemia. However, many of these associations were no longer statistically significant after adjusting for multiple testing. CONCLUSIONS: Our results provide insight into the role that bile acids may play in the development or progression of dyslipidemia. However, further confirmation of these results is warranted. Longitudinal and experimental studies are necessary to clarify the mechanisms behind these associations and to determine causality. AU - Breuninger, T. AU - Wawro, N. AU - Meisinger, C. AU - Artati, A. AU - Adamski, J. AU - Peters, A. AU - Grallert, H. AU - Linseisen, J. C1 - 56548 C2 - 47103 SP - 1-8 TI - Associations between fecal bile acids, neutral sterols, and serum lipids in the KORA FF4 study. JO - Atherosclerosis VL - 288 PY - 2019 SN - 0021-9150 ER - TY - JOUR AU - Coassin, S.* AU - Schoenherr, S.* AU - Weissensteiner, H.* AU - Erhart, G.* AU - Di Maio, S.* AU - Forer, L.* AU - Lamina, C.* AU - Peters, A. AU - Thorand, B. AU - Eckardt, K.U.* AU - Koettgen, A.* AU - Utermann, G.* AU - Specht, G.* AU - Kronenberg, F.* C1 - 56869 C2 - 47298 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - E58-E58 TI - A comprehensive map of the variability in the lipoprotein (A) KIV 2 repeat region and follow-up of the KIV-2 ARG20TER mutation in 11,000 individuals. JO - Atherosclerosis VL - 287 PB - Elsevier Ireland Ltd PY - 2019 SN - 0021-9150 ER - TY - JOUR AB - Background and aims Preclinical experiments on animal models are essential to understand the mechanisms of cardiovascular disease (CVD). Metabolomics allows access to the metabolic perturbations associated with CVD in heart and vessels. Here we assessed which potential animal CVD model most closely mimics the serum metabolite signature of increased carotid intima-media thickness (cIMT) in humans, a clinical parameter widely accepted as a surrogate of CVD. Methods A targeted mass spectrometry assay was used to quantify and compare a series of blood metabolites between 1362 individuals (KORA F4 cohort) and 5 animal CVD models: ApoE−/−, Ldlr−/−, and klotho-hypomorphic mice (kl/kl) and SHRSP rats with or without salt feeding. The metabolite signatures were obtained using linear regressions adjusted for various co-variates. Results In human, increased cIMT [quartile Q4 vs. Q1] was associated with 26 metabolites (9 acylcarnitines, 2 lysophosphatidylcholines, 9 phosphatidylcholines and 6 sphingomyelins). Acylcarnitines correlated preferentially with serum glucose and creatinine. Phospholipids correlated preferentially with cholesterol (total and LDL). The human signature correlated positively and significantly with Ldlr−/− and ApoE−/− mice, while correlation with kl/kl mice and SHRP rats was either negative and non-significant. Human and Ldlr−/− mice shared 11 significant metabolites displaying the same direction of regulation: 5 phosphatidylcholines, 1 lysophosphatidylcholines, 5 sphingomyelins; ApoE−/− mice shared 10. Conclusions The human cIMT signature was partially mimicked by Ldlr−/− and ApoE−/− mice. These animal models might help better understand the biochemical and molecular mechanisms involved in the vessel metabolic perturbations associated with, and contributing to metabolic disorders in CVD.   AU - Saulnier-Blache, J.S.* AU - Wilson, R. AU - Klavins, K.* AU - Graham, D.* AU - Alesutan, I.* AU - Kastenmüller, G. AU - Wang-Sattler, R. AU - Adamski, J. AU - Roden, M.* AU - Rathmann, W.* AU - Seissler, J. AU - Meisinger, C. AU - Koenig, W.* AU - Thiery, J.* AU - Suhre, K.* AU - Peters, A. AU - Kuro-O, M.* AU - Lang, F.* AU - Dallmann, G.* AU - Delles, C.* AU - Voelkl, J.* AU - Waldenberger, M. AU - Bascands, J.-L.* AU - Klein, J.* AU - Schanstra, J.P.* C1 - 54239 C2 - 45322 SP - 140-147 TI - Ldlr-/- and ApoE-/- mice better mimic the human metabolite signature of increased carotid intima media thickness compared to other animal models of cardiovascular disease. JO - Atherosclerosis VL - 276 PY - 2018 SN - 0021-9150 ER - TY - JOUR AU - Sulkava, M.* AU - Levula, M.* AU - Lyytikäinen, L.-P.* AU - Pashupati, P.M.* AU - Klopp, N. AU - Illig, T. AU - Seppälä, I.* AU - Kholova, I.* AU - Laaksonen, R.* AU - Järvinen, O.* AU - Mennander, A.* AU - Kahonen, M.* AU - Miettinen, M.* AU - Lehtimäki, T.* AU - Oksala, N.* AU - Raitoharju, E.* C1 - 54416 C2 - 45521 CY - Elsevier House, Brookvale Plaza, East Park Shannon, Co, Clare, 00000, Ireland SP - E104-E105 TI - Formyl peptide receptors 1-3 and annexin 1 in atherosclerotic plaques  - tampere vascular study. JO - Atherosclerosis VL - 275 PB - Elsevier Ireland Ltd PY - 2018 SN - 0021-9150 ER - TY - JOUR AB - Background and aims: Depressed mood and exhaustion (DEEX) have gained attention as a risk predictor for cardiovascular disease (CVD). Studies to estimate its ranking in prediction models are sparse. Methods: The study included 3428 men aged 45-74 years who participated in one of three population-based MONICA/KORA Augsburg surveys conducted between 1984 and 1995. Within a follow-up time of 10 years (31,791 person-years), 557 cases of all-cause mortality and 269 fatal CVD events were observed. Adjusted Cox proportional hazards models were used to assess mortality risks for DEEX and five classical cardiovascular risk factors. The predictive ability was evaluated by the area under the receiver-operating characteristic curve, the integrated discrimination improvement statistics and the net classification improvement. Results: The (crude) absolute mortality risk for DEEX was 23.1 cases per 1000 person-years for all-cause and 11.2 for CVD mortality. The adjusted hazard ratios of 1.52 for all-cause and 1.52 for CVD mortality (p < 0.01) were higher than those for hypercholesterolemia and obesity, but lower than for hypertension, smoking and diabetes. The improvements in risk prediction from DEEX were comparable to those of hypercholesterolemia and obesity, but substantially lower than those of hypertension, smoking and diabetes. The adjusted population-attributable risk (PAR) for DEEX accounted for about 15% for all-cause and CVD mortality, which gives DEEX a middle ranking amongst the classical risk factors. Conclusions: DEEX is a strong predictor of mortality risk, ranking in a medium position amongst classical somatic risk factors. AU - Ladwig, K.-H. AU - Baumert, J.J. AU - Marten-Mittag, B.* AU - Lukaschek, K. AU - Johar, H. AU - Fang, X. AU - Ronel, J.* AU - Meisinger, C. AU - Peters, A. C1 - 50410 C2 - 42270 CY - Clare SP - 224-231 TI - Room for depressed and exhausted mood as a risk predictor for all-cause and cardiovascular mortality beyond the contribution of the classical somatic risk factors in men. JO - Atherosclerosis VL - 257 PB - Elsevier Ireland Ltd PY - 2017 SN - 0021-9150 ER - TY - JOUR AU - Braenne, I.* AU - Willenborg, C.* AU - Reiz, B.* AU - Zeng, L.* AU - do O, V.T.* AU - Meitinger, T. AU - Samani, N.J.* AU - Kessler, T.* AU - Asselbergs, F.W.* AU - Erdmann, J.* AU - Schunkert, H.* C1 - 50197 C2 - 42118 CY - Clare SP - E252-E253 TI - Pleiotropic molecular targets of coxibs reveals novel genomic loci conferring coronary artery disease risk. JO - Atherosclerosis VL - 252 PB - Elsevier Ireland Ltd PY - 2016 SN - 0021-9150 ER - TY - JOUR AB - BACKGROUND AND AIMS: Subclinical atherosclerosis assessed by sonographic intima-media-thickness measurement of the carotid artery (cIMT) is considered to be an early precursor of cardiovascular disease already in childhood. Structural analysis of the carotid intimal layer (carotid intima-media-roughness, cIMR) improves cardiovascular risk profiling for the adult patient and has been shown to be increased also in paediatric patients with elevated cardiovascular risk. To date, normal values for the paediatric age are lacking. Thus, we present normative data for a paediatric age group. METHODS: 602 healthy German school children (age 8-18 y) were studied, and cIMT and cIMR calculated; reference values were given for three age groups (group 1: 8-10.99 years; group 2: 11-13.99 years; group 3: 14-17.99 years). RESULTS: cIMT values were: 0.48 ± 0.03 mm for girls and boys in age group 1, 0.49 ± 0.03 mm for girls and boys in age group 2; and 0.45 ± 0.03 mm for girls and 0.49 ± 0.03 mm for boys in age group 3; cIMR was 0.04 ± 0.01 mm for both sexes in age group 1 and 3; while in age group 2, both sexes showed a cIMR of 0.03 ± 0.01 mm. Physical fitness was significantly negatively correlated with cIMR (r = - 0.212, p < 0.0001) and a strong predictor for cIMR increase. CONCLUSIONS: The normative data of cIMR for a paediatric age group presented here allow for the identification of patients at elevated cardiovascular risk. By including cIMR as surface analysis of the arterial wall, the individual risk stratification may be improved compared to thickness-analysis of the Intima-Media-Layer (cIMT) also at a paediatric age. AU - Dalla Pozza, R.* AU - Pirzer, R.* AU - Beyerlein, A. AU - Weberruß, H.* AU - Oberhoffer, R.* AU - Schmidt-Trucksäss, A.* AU - Netz, H.* AU - Haas, N.* C1 - 48882 C2 - 41481 CY - Clare SP - 164-169 TI - Beyond intima-media-thickness: Analysis of the carotid intima-media-roughness in a paediatric population. JO - Atherosclerosis VL - 251 PB - Elsevier Ireland Ltd PY - 2016 SN - 0021-9150 ER - TY - JOUR AU - Kollerits, B.* AU - Huth, C. AU - Kiechl, S.* AU - Lamina, C.* AU - Meisinger, C. AU - Herder, C.* AU - Kedenko, L.* AU - Willeit, J.* AU - Thorand, B. AU - Daehnhardt, D.* AU - Stöckl, D. AU - Roden, M.* AU - Rathmann, W.G.* AU - Paulweber, B.* AU - Peters, A. AU - Dieplinger, H.* AU - Kronenberg, F.* C1 - 50200 C2 - 42121 CY - Clare SP - E217-E218 TI - Plasma concentrations of afamin are associated with the prevalence and incidence of type 2 diabetes mellitus. JO - Atherosclerosis VL - 252 PB - Elsevier Ireland Ltd PY - 2016 SN - 0021-9150 ER - TY - JOUR AU - Pfeiffer, L. AU - Wilson, R. AU - Grallert, H. AU - Reischl, E. AU - Peters, A. AU - Gieger, C. AU - Wahl, S. AU - Waldenberger, M. C1 - 50198 C2 - 42119 CY - Clare SP - E263-E263 TI - Associations between lipoprotein subfractions and genome-wide DNA methylation in KORA F4. JO - Atherosclerosis VL - 252 PB - Elsevier Ireland Ltd PY - 2016 SN - 0021-9150 ER - TY - JOUR AU - Schratter, G.* AU - Karbiener, M.* AU - Almer, G.* AU - Mangge, H.* AU - Scheideler, M. AU - Prassl, R.* C1 - 50201 C2 - 42122 CY - Clare SP - E131-E131 TI - Liposomes for microRNA delivery to human adipocytes. JO - Atherosclerosis VL - 252 PB - Elsevier Ireland Ltd PY - 2016 SN - 0021-9150 ER - TY - JOUR AB - BACKGROUND AND AIMS: The exact mechanism of premature atherosclerosis in diabetes is still unclear. Inappropriate activation of the renin-aldosterone-angiotensin system may be an important risk factor for cardiovascular disease. We investigated whether renin and aldosterone are associated with vasoactive peptides midregional-pro atrial natriuretic peptide (MR-proANP) and midregional-pro adrenomedullin (MR-proADM), or with intima media thickness (IMT) as a marker for early atherosclerotic alterations in the general community and in subjects with type 2 diabetes. METHODS: In 1261 participants in the KORA F4 study, the associations of renin, aldosterone and aldosterone to renin ratio with MR-proANP, MR-proADM and IMT were assessed using linear regression models stratified for the presence of prediabetes and type 2 diabetes. RESULTS: After adjustment for confounding factors, an inverse association of MR-proANP with renin (p = 0.002) and aldosterone (p = 0.021) and a direct association of MR-proADM with renin (p < 0.001) and aldosterone (p = 0.019) were seen in nondiabetic individuals. In diabetic subjects, there was no significant correlation of MR-proANP or MR-proADM with renin or aldosterone. Renin and aldosterone were not directly associated with IMT in non-diabetic subjects and the total cohort, whereas aldosterone was associated with IMT in diabetic participants (p = 0.005). CONCLUSIONS: This study shows associations between renin, aldosterone and MR-proANP/MR-proADM plasma levels that are altered in type 2 diabetes. Plasma renin and aldosterone are not independent biomarkers for early atherosclerotic damages of the carotid arteries in the general community. AU - Then, C. AU - Rottenkolber, M.* AU - Lechner, A. AU - Meisinger, C. AU - Heier, M. AU - Koenig, W.* AU - Peters, A. AU - Rathmann, W.* AU - Bidlingmaier, M.* AU - Reincke, M.* AU - Seissler, J. C1 - 49253 C2 - 41780 CY - Clare SP - 88-96 TI - Altered relation of the renin-aldosterone system and vasoactive peptides in type 2 diabetes: The KORA F4 study. JO - Atherosclerosis VL - 252 PB - Elsevier Ireland Ltd PY - 2016 SN - 0021-9150 ER - TY - JOUR AU - Tomas, L.* AU - Bjoerkbacka, H.* AU - Edsfeldt, A.* AU - Danielsson, A.* AU - Wigren, M.* AU - Grufman, H.* AU - Persson, A.* AU - Prehn, C. AU - Adamski, J. AU - Nilsson, J.* AU - Gonçalves, I.* C1 - 50199 C2 - 42120 CY - Clare SP - E260-E260 TI - A lipid metabolite profile in atherosclerotic plaques associated with increased inflammation and cardiovascular. JO - Atherosclerosis VL - 252 PB - Elsevier Ireland Ltd PY - 2016 SN - 0021-9150 ER - TY - JOUR AB - Background and aims Focal adhesions (FA) play an important role in the tissue remodeling and in the maintenance of tissue integrity and homeostasis. Talin and vinculin proteins are among the major constituents of FAs contributing to cellular well-being and intercellular communication. Methods Microarray analysis (MA) and qRT-PCR low-density array were implemented to analyze talin-1, talin-2, meta-vinculin and vinculin gene expression in circulating blood and arterial plaque. Results All analyzed genes were significantly and consistently downregulated in plaques (carotid, abdominal aortic and femoral regions) compared to left internal thoracic artery (LITA) control. The use of LITA samples as controls for arterial plaque samples was validated using immunohistochemistry by comparing LITA samples with healthy arterial samples from a cadaver. Even though the differences in expression levels between stable and unstable plaques were not statistically significant, we observed further negative tendency in the expression in unstable atherosclerotic plaques. The confocal tissue imaging revealed gradient of talin-1 expression in plaque with reduction close to the vessel lumen. Similar gradient was observed for talin-2 expression in LITA controls but was not detected in plaques. This suggests that impaired tissue mechanostability affects the tissue remodeling and healing capabilities leading to development of unstable plaques. Conclusions The central role of talin and vinculin in cell adhesions suggests that the disintegration of the tissue in atherosclerosis could be partially driven by downregulation of these genes, leading to loosening of cell-ECM interactions and remodeling of the tissue. AU - von Essen, M.* AU - Rahikainen, R.* AU - Oksala, N.* AU - Raitoharju, E.* AU - Seppälä, I.* AU - Mennander, A.* AU - Sioris, T.* AU - Kholova, I.* AU - Klopp, N.* AU - Illig, T. AU - Karhunen, P.J.* AU - Kähönen, M.* AU - Lehtimäki, T.* AU - Hytönen, V.P.* C1 - 49925 C2 - 41901 CY - Clare SP - 43-53 TI - Talin and vinculin are downregulated in atherosclerotic plaque; Tampere Vascular Study. JO - Atherosclerosis VL - 255 PB - Elsevier Ireland Ltd PY - 2016 SN - 0021-9150 ER - TY - JOUR AB - BACKGROUND AND AIMS: We aimed at studying the association of three major human monocyte subsets after percutaneous transluminal angioplasty (PTA) in patients with femoropopliteal disease. METHODS: We prospectively studied 67 sequential patients (40 male, 27 female; mean age 71 ± 11 years) treated with femoropopliteal angioplasty. Multi-color flow cytometry characterized monocyte subsets from venous blood for expression of CD14 and CD16 and intracellular myeloperoxidase (MPO) prior to, and 3, 6 and 12 months post PTA. Analyses tested associations between monocyte subsets and risk for restenosis. RESULTS: 16/67 patients (24%) developed restenosis within 12 months after PTA. Patients with hyperlipidemia had increased risk for restenosis (HR = 1.7, 95% CI 0.7-2.9, p = 0.001). Increased baseline monocytes associated with an increased risk of late restenosis (HR = 4.9, 95% CI: 1.3-18.6, p = 0.047). CD14(++)CD16(++) 'intermediate' monocytes assessed at baseline, and after 3, 6, and 12 months significantly associated with the risk for subsequent restenosis: HR = 3.9 (95% CI: 2.4-6.5, p = 0.029), HR = 5.7 (95% CI = 0.7-44.7, p = 0.013), HR = 6.5 (95% CI: 2.5-16.9, p = 0.001) and HR = 1.5 (95% CI = 1.4-15.5 p = 0.001), respectively. Moreover, the probability for freedom of restenosis decreased with increased levels of intermediate subsets at 12 months after PTA. Additionally, intracellular MPO expression in CD14(++)CD16(++) measured at 3, 6 and 12 months associated with an increased restenosis risk (HR = 1.5, 95% CI: 0.8-2.1, p = 0.214, HR = 1.9, 95% CI: 1.0-2.3 p = 0.051 and HR = 1.4, 95% CI: 1.0-1.8, p = 0.052). CONCLUSIONS: Our results imply altered innate immunity after angioplasty. Elevated CD14(++)CD16(++) intermediate monocyte frequencies and increased MPO expression may identify individuals at heightened risk for restenosis. AU - Wildgruber, M.* AU - Czubba, M.* AU - Aschenbrenner, T.* AU - Wendorff, H.* AU - Hapfelmeier, A.* AU - Glinzer, A.* AU - Schiemann, M. AU - Zimmermann, A.* AU - Eckstein, H.H.* AU - Berger, H.* AU - Wohlgemuth, W.A.* AU - Meier, R.* AU - Libby, P.* AU - Zernecke, A.* C1 - 49469 C2 - 31974 CY - Clare SP - 128-134 TI - Increased intermediate CD14++CD16++ monocyte subset levels associate with restenosis after peripheral percutaneous transluminal angioplasty. JO - Atherosclerosis VL - 253 PB - Elsevier Ireland Ltd PY - 2016 SN - 0021-9150 ER - TY - JOUR AB - BACKGROUND: The mechanisms underlying the association between diabetes and coronary artery disease (CAD) risk are unclear. We aimed to assess this association by studying genetic variants that have been shown to associate with type 2 diabetes (T2DM). If the association between diabetes and CAD is causal, we expected to observe an association of these variants with CAD as well. METHODS AND RESULTS: We studied all genetic variants currently known to be associated with T2DM at a genome-wide significant level (p < 5*10(-8)) in CARDIoGRAM, a genome-wide data-set of CAD including 22,233 CAD cases and 64,762 controls. Out of the 44 published T2DM SNPs 10 were significantly associated with CAD in CARDIoGRAM (OR>1, p < 0.05), more than expected by chance (p = 5.0*10(-5)). Considering all 44 SNPs, the average CAD risk observed per individual T2DM risk allele was 1.0076 (95% confidence interval (CI), 0.9973-1.0180). Such average risk increase was significantly lower than the increase expected based on i) the published effects of the SNPs on T2DM risk and ii) the effect of T2DM on CAD risk as observed in the Framingham Heart Study, which suggested a risk of 1.067 per allele (p = 7.2*10(-10) vs. the observed effect). Studying two risk scores based on risk alleles of the diabetes SNPs, one score using individual level data in 9856 subjects, and the second score on average effects of reported beta-coefficients from the entire CARDIoGRAM data-set, we again observed a significant - yet smaller than expected - association with CAD. CONCLUSIONS: Our data indicate that an association between type 2 diabetes related SNPs and CAD exists. However, the effects on CAD risk appear to be by far lower than what would be expected based on the effects of risk alleles on T2DM and the effect of T2DM on CAD in the epidemiological setting. AU - Jansen, H.* AU - Loley, C.* AU - Lieb, W.* AU - Pencina, M.J.* AU - Nelson, C.P.* AU - Kathiresan, S.* AU - Peloso, G.M.* AU - Voight, B.F.* AU - Reilly, M.P.* AU - Assimes, T.L.* AU - Boerwinkle, E.* AU - Hengstenberg, C.* AU - Laaksonen, R.* AU - McPherson, R.* AU - Roberts, R.* AU - Thorsteinsdottir, U.* AU - Peters, A. AU - Gieger, C. AU - Rawal, R. AU - CARDIoGRAM Consortium (Döring, A. AU - Meisinger, C. AU - Schunkert, H. AU - Meitinger, T.) AU - Thompson, J.R.* AU - König, I.R.* AU - Vasan, R.S.* AU - Erdmann, J.* AU - Samani, N.J.* C1 - 45244 C2 - 37274 CY - Clare SP - 419-426 TI - Genetic variants primarily associated with type 2 diabetes are related to coronary artery disease risk. JO - Atherosclerosis VL - 241 IS - 2 PB - Elsevier Ireland Ltd PY - 2015 SN - 0021-9150 ER - TY - JOUR AB - BACKGROUND: Kindlins (FERMT) are cytoplasmic proteins required for integrin (ITG) activation, leukocyte transmigration, platelet aggregation and thrombosis. Characterization of kindlins and their association with atherosclerotic plaques in human(s) is lacking. METHODS AND RESULTS: Exploratory microarray (MA) was first performed followed by selective quantitative validation of robustly expressed genes with qRT-PCR low-density array (LDA). In LDA, ITGA1 (1.30-fold, p = 0.041) and ITGB3 (1.37-fold, p = 0.036) were upregulated in whole blood samples of patients with coronary artery disease (CAD) compared to healthy controls. In arterial plaques, both robustly expressed transcript variants of FERMT3 (MA: 5.90- and 3.4-fold; LDA: 3.99-fold, p < 0.0001 for all) and ITGB2 (MA: 4.81- and 4.92-fold; LDA: 5.29-fold, p < 0.0001 for all) were upregulated while FERMT2 was downregulated (MA: -1.61-fold; LDA: -2.88-fold, p < 0.0001 for both). The other integrins (ITGA1, ITGAV, ITGB3, ITGB5) were downregulated. All these results were replicated in at least one arterial bed. The latter FERMT3 transcript variant associated with unstable plaques (p = 0.0004). FERMT3 correlated with M2 macrophage markers and in hierarchical cluster analysis clustered with inflammatory and macrophage markers, while FERMT2 correlated with SMC-rich plaque markers and clustered with SMC markers. In confocal immunofluorescence analysis, FERMT3 protein colocalized with abundant CD68-positive cells of monocytic origin in the atherosclerotic plaques, while co-localization of FERMT3 with HHF35 indicative of smooth muscle cells was low. CONCLUSIONS: Kindlin-3 (FERMT3) is upregulated in atherosclerotic, especially unstable plaques, mainly in cells of monocytic origin and of M2 type. Simultaneous upregulation of ITGB2 suggests a synergistic effect on leukocyte adherence and transmigration into the vessel wall. AU - Oksala, N.* AU - Pärssinen, J.* AU - Seppälä, I.* AU - Klopp, N. AU - Illig, T. AU - Laaksonen, R.* AU - Levula, M.* AU - Raitoharju, E.* AU - Kholova, I.* AU - Sioris, T.* AU - Kähönen, M.* AU - Lehtimäki, T.* AU - Hytönen, V.P.* C1 - 46382 C2 - 37553 CY - Clare SP - 145-154 TI - Kindlin 3 (FERMT3) is associated with unstable atherosclerotic plaques, anti-inflammatory type II macrophages and upregulation of beta-2 integrins in all major arterial beds. JO - Atherosclerosis VL - 242 IS - 1 PB - Elsevier Ireland Ltd PY - 2015 SN - 0021-9150 ER - TY - JOUR AB - BACKGROUND: Supplementation of calcium (Ca) and vitamin D for the prevention of osteoporosis is frequently found in Western countries. Recent re-analyses of clinical trials observed a higher risk of myocardial infarction and stroke in subjects taking Ca (+vitamin D) supplements, although the underlying mechanisms are not clear. OBJECTIVE: Thus, we analyzed the associations between Ca and vitamin D supplementation as well as serum concentrations of Ca and 25-hydroxyvitamin D (25(OH)D) and subclinical cardiovascular disease (CVD) phenotypes, namely intima-media thickness, ankle-brachial-index (ABI), intermittent claudication, and atrial fibrillation (AF). DESIGN: Data of 1601 participants aged 50-81 years of the population-based cross-sectional Cooperative Health Research in the Region of Augsburg (KORA) F4 study in Germany were analyzed. Logistic and linear regression models were used to estimate odds ratios (OR) (95% confidence intervals (CI)) and β-estimates (p-values), respectively. RESULTS: Regular Ca supplementation showed a significant positive association with the presence of AF after multivariable adjustment (OR = 3.89; 95% CI 1.28-11.81). Higher serum 25(OH)D concentrations were independently associated with a lower prevalence of asymptomatic peripheral arterial disease as assessed by ABI measurements (β = 0.007; p = 0.01). No other significant associations between supplementation or serum concentrations of Ca or vitamin D and CVD phenotypes were identified. CONCLUSIONS: Although based on few cases the finding of a significant higher prevalence of AF in Ca supplement users hints at one possible mechanism that may contribute to an increased risk of myocardial infarction and stroke. The observed association between serum 25(OH)D and ABI supports results from other studies. AU - Thiele, I. AU - Linseisen, J. AU - Meisinger, C. AU - Schwab, S. AU - Huth, C. AU - Peters, A. AU - Perz, S. AU - Meitinger, T. AU - Kronenberg, F.* AU - Lamina, C.* AU - Thiery, J.* AU - Koenig, W.* AU - Rathmann, W.* AU - Kääb, S.* AU - Then, C. AU - Seissler, J. AU - Thorand, B. C1 - 45682 C2 - 37420 CY - Clare SP - 743-751 TI - Associations between calcium and vitamin D supplement use as well as their serum concentrations and subclinical cardiovascular disease phenotypes. JO - Atherosclerosis VL - 241 IS - 2 PB - Elsevier Ireland Ltd PY - 2015 SN - 0021-9150 ER - TY - JOUR AU - Dieplinger, H.* AU - Kollerits, B.* AU - Lamina, C.* AU - Kiechl, S.* AU - Willeit, J.* AU - Meisinger, C. AU - Thorand, B. AU - Wietzorrek, G.* AU - Paulweber, B.* AU - Kedenko, L.* AU - Peters, A. AU - Huth, C. AU - Adham, I.* AU - Kronenberg, F.* C1 - 32625 C2 - 35175 SP - E70-E71 TI - Plasma concentrations of afamin are associated with the prevalence and developement of metabolic syndrome. JO - Atherosclerosis VL - 235 IS - 2 PY - 2014 SN - 0021-9150 ER - TY - JOUR AB - OBJECTIVE: Deletion of inducible nitric oxide synthase (iNOS) in apolipoprotein E knockout mice was shown to mitigate the extent of arteriosclerosis. Oxidized low density lipoprotein (oxLDL) inhibits macrophage migration and traps foam cells, possibly through a mechanism involving oxidative stress. Here, we addressed whether a reduction of iNOS-mediated oxidative stress remobilizes macrophage-derived foam cells and may reverse plaque formation. METHODS: Migration of RAW264.7 cells and bone marrow cells was quantified using a modified Boyden chamber. iNOS expression, phalloidin staining, focal adhesion kinase phosphorylation, lipid peroxides, nitric oxide (NO) and reactive oxygen species (ROS) production were assessed. RESULTS: oxLDL treatment significantly reduced cell migration compared to unstimulated cells (p < 0.05). This migratory arrest was reversed by co-incubation with a pharmacologic iNOS inhibitor 1400W (p < 0.05) and iNOS-siRNA (p > 0.05). Furthermore, apoE/iNOS double knockout macrophages do not show migratory arrest in response to oxLDL uptake, compared to apoE knockout controls (p > 0.05). We documented significantly increased iNOS expression following oxLDL treatment and downregulation using 1400W and small inhibitory RNA (siRNA). iNOS inhibition was associated with a reduction in NO and peroxynitrite (ONOO-)- and increased superoxide generation. Trolox treatment of RAW264.7 cells restored migration indicating that peroxynitrite mediated lipid peroxide formation is involved in the signaling pathway mediating cell arrest.. CONCLUSIONS: Here, we provide pharmacologic and genetic evidence that oxLDL induced iNOS expression inhibits macrophage-derived foam cell migration. Therefore, reduction of peroxynitrite and possibly lipid hydroperoxide levels in plaques represents a valuable therapeutic approach to reverse migratory arrest of macrophage-derived foam cells and to impair plaque formation. AU - Huang, H.* AU - Koelle, P.* AU - Fendler, M.* AU - Schröttle, A.* AU - Czihal, M.* AU - Hoffmann, U.* AU - Conrad, M. AU - Kuhlencordt, P.J.* C1 - 31476 C2 - 34519 CY - Clare SP - 213-222 TI - Induction of inducible Nitric Oxide Synthase (iNOS) expression by oxLDL inhibits macrophage derived foam cell migration. JO - Atherosclerosis VL - 235 IS - 1 PB - Elsevier Ireland Ltd PY - 2014 SN - 0021-9150 ER - TY - JOUR AB - OBJECTIVE: To evaluate the association between a family history of cardiovascular and metabolic diseases or risk factors and the presence of peripheral artery disease (PAD). METHODS: Participants were recruited within one PAD case-control study (CAVASIC, n = 481) and two population-based studies (KORA-F3, n = 3118; KORA-F4, n = 1325). In the KORA studies, an ankle-brachial-index <0.9 and/or symptomatic claudication was defined as PAD. For myocardial infarction, stroke, diabetes mellitus, hypertension, PAD, and obesity, family risk scores (FamRS) were calculated taking into account the number and age of diseased parents and siblings and regressed on prevalent PAD or ankle-brachial-index. RESULTS: A significant association with PAD was found for family history of myocardial infarction and hypertension in a combined analysis of all studies and for family history of PAD in the case-control study. A combined family history score was derived from FamRS myocardial infarction, stroke, diabetes mellitus, hypertension and PAD. A positive family history of at least two and/or a strong positive family history of at least one of these diseases was found to be associated with increased risk of prevalent PAD in all three studies, even after adjustment for classical risk factors (OR = 1.93, 95%CI = [1.53-2.44], p = 2.6 × 10(-8)). CONCLUSION: The presence of a positive family history for cardiovascular and metabolic diseases or risk factors was shown to be associated with the presence of PAD. A FamRS calculation tool that considers age and family size can guide a physician to perform extended examinations to prevent complications and progression of PAD. AU - Lamina, C.* AU - Linsenmeyer, J.* AU - Weissensteiner, H.* AU - Kollerits, B.* AU - Meisinger, C. AU - Rantner, B.* AU - Stöckl, D. AU - Stadler, M.* AU - Klein-Weigel, P.* AU - Peters, A. AU - Fraedrich, G.* AU - Kronenberg, F.* C1 - 32384 C2 - 35030 SP - 243-250 TI - Correlation between a positive family risk score and peripheral artery disease in one case-control and two population-based studies. JO - Atherosclerosis VL - 237 IS - 1 PY - 2014 SN - 0021-9150 ER - TY - JOUR AB - OBJECTIVE: A large body of epidemiologic data strongly suggests an association between excess adiposity and coronary artery disease (CAD). Low adiponectin levels, a hormone secreted only from adipocytes, have been associated with an increased risk of CAD in observational studies. However, these associations cannot clarify whether this relationship is causal or due to a shared set of causal factors or even confounding. Genome-wide association studies have identified common variants that influence adiponectin levels, providing valuable tools to examine the genetic relationship between adiponectin and CAD. METHODS: Using 145 genome wide significant SNPs for adiponectin from the ADIPOGen consortium (n = 49,891), we tested whether adiponectin-decreasing alleles influenced risk of CAD in the CARDIoGRAM consortium (n = 85,274). RESULTS: In single-SNP analysis, 5 variants among 145 SNPs were associated with increased risk of CAD after correcting for multiple testing (P < 4.4 × 10(-4)). Using a multi-SNP genotypic risk score to test whether adiponectin levels and CAD have a shared genetic etiology, we found that adiponectin-decreasing alleles increased risk of CAD (P = 5.4 × 10(-7)). CONCLUSION: These findings demonstrate that adiponectin levels and CAD have a shared allelic architecture and provide rationale to undertake a Mendelian randomization studies to understand if this relationship is causal. AU - Dastani, Z.* AU - Johnson, T.* AU - Kronenberg, F.* AU - Nelson, C.P.* AU - Assimes, T.L.* AU - Marz, W.* AU - CARDIoGRAM Consortium (Wichmann, H.-E. AU - Döring, A. AU - Illig, T. AU - Klopp, N. AU - Peters, A. AU - Meisinger, C. AU - Meitinger, T.) AU - ADIPOGen Consortium (*) AU - Richards, J.B.* C1 - 28183 C2 - 32996 SP - 145-148 TI - The shared allelic architecture of adiponectin levels and coronary artery disease. JO - Atherosclerosis VL - 229 IS - 1 PB - Elsevier Ireland PY - 2013 SN - 0021-9150 ER - TY - JOUR AB - Aims: This study was set up to compare the accuracy, sensitivity and specificity of gene expression results between the Illumina HumanHT-12 v3 Expression BeadChip (GWE) and the TaqMan qRT-PCR low-density array (LDA) in atherosclerotic plaques. Methods: Gene expression levels of 196 genes were determined from 22 atherosclerotic samples and 6 controls with both the GWE and the LDA. Results: The accuracies of GWE in comparison to that of qRT-PCR for absolute fold changes (FC) 1.2,1.6, 2.0 and 3.0 between cases and controls were 73.5%, 79.1%, 72.4% and 60.7%, respectively. The correlation of expression measurements between these methods was good (r = 0.87, y = 0.151 + 0.586x), and the Bland-Altman plot showed that for highly up-or down-regulated transcripts, GWE yields lower absolute FC values than LDA. Conclusion: Gene expression results obtained with the GWE are replicated with high accuracy in LDA, even for technically demanding atherosclerotic samples. AU - Raitoharju, E.* AU - Seppälä, I.* AU - Lyytikäinen, L.-P.* AU - Levula, M.* AU - Oksala, N.* AU - Klopp, N. AU - Illig, T. AU - Laaksonen, R.* AU - Kähönen, M.* AU - Lehtimäki, T.* C1 - 11868 C2 - 30889 SP - 149-152 TI - A comparison of the accuracy of Illumina HumanHT-12 v3 Expression BeadChip and TaqMan qRT-PCR gene expression results in patient samples from the Tampere Vascular Study. JO - Atherosclerosis VL - 226 IS - 1 PB - Elsevier PY - 2013 SN - 0021-9150 ER - TY - JOUR AB - Objective: Sex differences in the onset of cardiovascular disease disappear in the postmenopause, suggesting that reproductive factors could be influential. The aim of the present study was to examine the possible association between reproductive parameters and peripheral arterial disease (PAD) in a female population-based sample. Methods: In this cross-sectional study data of 887 women aged 52-81 years participating in the population-based KORA F4 study (conducted in 2006-2008) was analyzed. Reproductive parameters were obtained by standardized interviews. PAD was assessed by measuring noninvasively the ankle-brachial index and using a cut-off value of 0.9 and by assessing the presence of claudication by the Edinburgh questionnaire. Results: In multivariable logistic regression analyses later age at menarche (>15 years) compared to age at menarche between 12 and 15 years was significantly associated with about half the probability for PAD (OR = 0.48; 95%CI 0.24-0.98). The presence of hot flashes was positively associated with PAD (OR = 2.09; 95%CI 1.11-3.92). Further reproductive parameters, such as parity, age at menopause, time since menopause, duration of fertility, ever use or current use of hormone replacement therapy, ever use of oral contraceptives, history of hysterectomy, bilateral oophorectomy and depressive mood in relation to menopausal transition showed no significant association with PAD. Conclusions: Later age at menarche was inversely related to PAD and the presence of hot flashes was associated with an increased presence of PAD. Prospective population-based studies in women are needed to assess the impact of reproductive parameters on the development of PAD and subsequently cardiovascular disease. AU - Stöckl, D. AU - Döring, A. AU - Thorand, B. AU - Heier, M. AU - Peters, A. AU - Lamina, C.* AU - Kronenberg, F.* AU - Meisinger, C. C1 - 24808 C2 - 31688 SP - 224-229 TI - Reproductive factors and its association with peripheral arterial disease in women aged 52-81 years: The KORA F4 study. JO - Atherosclerosis VL - 228 IS - 1 PB - Elsevier Ireland PY - 2013 SN - 0021-9150 ER - TY - JOUR AB - OBJECTIVE: Subjects with metabolic syndrome (MetS) and individuals with type 2 diabetes are at high risk for vascular complications. Hormones acting on vascular endothelium may be involved in the atherogenic process associated with metabolic disorders. The objective of this study was to determine the correlation of pro-atrial natriuretic hormone (proANP) with the presence of subclinical atherosclerosis. METHODS: In 1272 subjects participating in the KORA F4 study, we determined plasma levels of mid-regional proANP (MR-proANP) and the intima-media thickness (IMT) of the carotid artery. We used logistic regression models to investigate the relation of MR-proANP with components of MetS and IMT. RESULTS: In multiple adjusted regression models, MR-proANP levels were inversely associated with MetS (OR = 0.66, 95% CI 0.47-0.93), central obesity (OR = 0.67, 95% CI 0.46-0.96), raised triglyceride levels (OR = 0.53, 95% CI 0.37-0.77), prediabetes (OR = 0.62, 95%, CI 0.44-0.87) and type 2 diabetes (OR = 0.55, 95% CI 0.35-0.88) when comparing the top quartile vs. the lower three quartiles. Furthermore, there was an inverse relationship between MR-proANP and IMT. After adjustment for traditional cardiovascular risk markers, individuals with high MR-proANP plasma levels in the top quartile (Q4) had significantly lower IMT values (Q4 vs. Q1-Q3: β -0.0178, 95% CI -0.0344; -0.0013). CONCLUSIONS: In this population-based study, high plasma concentrations of MR-proANP were significantly associated with a lower incidence of MetS components and lower measures of early atherosclerosis. The data suggest a link between MR-proANP levels and the development of vascular complications. AU - Then, C. AU - Kowall, B.* AU - Lechner, A. AU - Meisinger, C. AU - Heier, M. AU - Koenig, W.* AU - Peters, A. AU - Thiery, J.* AU - Rathmann, W.* AU - Seissler, J. C1 - 27660 C2 - 32790 SP - 235-241 TI - Plasma MR-proANP levels are associated with carotid intima-media thickness in the general community: The KORA F4 study. JO - Atherosclerosis VL - 230 IS - 2 PB - Elsevier Ireland PY - 2013 SN - 0021-9150 ER - TY - JOUR AB - Objective: Effect modification by obesity or obesity-related phenotypes (e.g. physical activity and diet) was observed in some candidate gene studies on lipids. We aimed to evaluate gene-obesity interaction effects on HDL (HDL-C), LDL (LDL-C) and total cholesterol (TC) levels using genetic predisposition scores. Methods: We derived imputed genotypes for 104 SNPs in 84 lipid-associated loci in the population-based studies KORA F3 (n = 1406) and KORA F4 (n = 1515). We inferred specific unbiased weights for each SNP from linear regression estimates in KORA F4. Weighted genotypic predisposition SNP-scores were then calculated for each lipid trait in KORA F3. Interaction terms of SNP-scores with each of the obesity parameters (BMI, waist-hip-ratio, waist circumference) were included in age-and sex-adjusted linear regression models on HDL-C, LDL-C and TC. Results: All three SNP-scores were shown to be highly associated with their respective lipid levels (p = 1.11 x 10(-47) for HDL-C, p = 3.25 x 10(-19) for LDL-C and 1.53 x 10(-13) for TC). BMI, WHR and waist circumference modified the effect of the weighted HDL-C SNP-score on HDL-C significantly (all interaction p-values < 0.0062). No interaction term was significant for LDL-C or TC. Accounting for gene-obesity interaction substantially increased the proportion of HDL-C variance explained by 3-3.5%. Conclusion: Our investigation revealed a significant interaction effect between obesity parameters and a SNP-score on HDL-C: the combined effect of HDL-C-increasing alleles on HDL-C is attenuated with increasing levels of obesity-relevant parameters. Future studies aiming to detect new genetic variants or to model genetic predictions of HDL-C levels should take obesity or obesity associated parameters into account. AU - Lamina, C.* AU - Forer, L.* AU - Schönherr, S.* AU - Kollerits, B.* AU - Ried, J.S. AU - Gieger, C. AU - Peters, A. AU - Wichmann, H.-E. AU - Kronenberg, F.* C1 - 11483 C2 - 30754 SP - 363-369 TI - Evaluation of gene-obesity interaction effects on cholesterol levels: A genetic predisposition score on HDL-cholesterol is modified by obesity. JO - Atherosclerosis VL - 225 IS - 2 PB - Elsevier PY - 2012 SN - 0021-9150 ER - TY - JOUR AB - Background: 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 similar to 50,000 SNPs across similar to 2100 candidate genes to identify genetic variants for ABI. Methods and results: 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 x 10(-6) to denote statistical significance. Results: In the European ancestry discovery meta-analyses, rs2171209 in SYTL3 (beta = -0.007, p = 6.02 x 10(-7)) and rs290481 in TCF7L2 (beta = -0.008, p = 7.01 x 10(-7)) were significantly associated with ABI. None of the SNP associations for PAD were significant, though a SNP in CYP2B6 (p = 4.99 x 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 x 10(-3); rs290481, p = 8.88 x 10(-5)). In African Americans, none of the SNP associations for ABI or PAD achieved an experiment-wide level of significance. Conclusions: 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. AU - Wassel, C.L.* AU - Lamina, C.* AU - Nambi, V.* AU - Coassin, S.* AU - Mukamal, K.J.* AU - Ganesh, S.K.* AU - Jacobs, D.R.* AU - Franceschini, N.* AU - Papanicolau, G.J.* AU - Gibson, Q.* AU - Yanek, L.R.* AU - van der Harst, P.* AU - Ferguson, J.F.* AU - Crawford, D.C.* AU - Waite, L.L.* AU - Allison, M.A.* AU - Criqui, M.H.* AU - McDermott, M.M.* AU - Mehra, R.* AU - Cupples, L.A.* AU - Hwang, S.J.* AU - Redline, S.* AU - Kaplan, R.C.* AU - Heiss, G.* AU - Rotter, J.I.* AU - Boerwinkle, E.* AU - Taylor, H.A.* AU - Eraso, L.H.* AU - Haun, M.* AU - Li, M.Y* AU - Meisinger, C. AU - O'Connell, J.R.* AU - Shuldineri, A.R.* AU - Tybjaerg-Hansen, A.* AU - Frikke-Schmidt, R.* AU - Kollerits, B.* AU - Rantner, B.* AU - Dieplinger, B.* AU - Stadler, M.* AU - Mueller, T.* AU - Haltmayer, M.* AU - Klein-Weigel, P.* AU - Summerer, M.* AU - Wichmann, H.-E. AU - Asselbergs, F.W.* AU - Navis, G.* AU - Leach, I.M.* AU - Brown-Gentry, K.* AU - Goodloe, R.* AU - Assimes, T.L.* AU - Becker, D.M.* AU - Cooke, J.P.* AU - Absher, D.M.* AU - Olin, J.W.* AU - Mitchell, B.D.* AU - Reilly, M.P.* AU - Mohler, E.R.* AU - North, K.E.* AU - Reiner, A.P.* AU - Kronenberg, F.* AU - Murabito, J.M.* C1 - 7974 C2 - 29941 SP - 138-147 TI - Genetic determinants of the ankle-brachial index: A meta-analysis of a cardiovascular candidate gene 50K SNP panel in the Candidate gene Association Resource (CARe) consortium. JO - Atherosclerosis VL - 222 IS - 1 PB - Elsevier PY - 2012 SN - 0021-9150 ER - TY - JOUR AB - OBJECTIVE: Oxidative stress-induced cell damage contributes to several chronic conditions such as cardiovascular disease, but only very few population-based studies have examined the influence of regular physical activity (PA) on oxidative stress. METHODS: 1820 men and women aged 35-74 years were randomly drawn from three population-based MONICA/KORA Augsburg Studies conducted between 1984 and 1995. Geometric means of the oxidative stress markers myeloperoxidase (MPO) and oxidized LDL (ox-LDL) were calculated and multiple linear regression was performed to assess their associations with three self-reported PA domains, namely work, leisure-time or walking. RESULTS: Mean MPO concentrations were lower for participants engaged in high leisure-time PA (124.2μg/ml; 95%-CI, 116.8-132.0) compared to the inactive reference group (133.5μg/ml; 95%-CI, 127.6-139.6) (P(trend) across PA levels: 0.007). No significant association between ox-LDL and PA domains was observed (P(trend) between 0.162 and 0.803). CONCLUSION: These data indicate that regular leisure-time PA may reduce MPO concentrations. AU - Autenrieth, C.S. AU - Emeny, R.T. AU - Herder, C.* AU - Döring, A. AU - Peters, A. AU - Koenig, W.* AU - Thorand, B. C1 - 6782 C2 - 29266 SP - 774-777 TI - Myeloperoxidase, but not oxidized LDL, is associated with leisure-time physical activity: Results from the MONICA/KORA Augsburg Studies 1984-1995. JO - Atherosclerosis VL - 219 IS - 2 PB - Elsevier PY - 2011 SN - 0021-9150 ER - TY - JOUR AB - Background: Recent genome-wide association studies (GWAS) have identified associations with myocardial infarction and coronary artery disease (CAD), but the mechanisms underlying these associations remain largely unclear. Carotid intima-media thickness (IMT) is a measure of early arterial remodeling and arteriosclerosis. Therefore, if CAD associated SNPs are also associated with carotid IMT; it suggests that they are acting via the early stages of the atherosclerotic process. Methods: In three large community based independent populations (CAPS, KORA and Young Finns) of European ancestry in which common carotid IMT had been measured (total 4961 individuals), we determined whether SNPs that have been associated with CAD in GWAS studies are also associated with carotid IMT. Associations with plaque were not examined. Results We identified 11 SNPs and one haplotype previously associated with CAD. None of these were associated with common carotid IMT. Conclusions: We found no evidence that SNPs associated with CAD on GWAS are also associated with carotid IMT. This suggests these genetic associations are not acting via early vessel remodeling or early arteriosclerosis. AU - Conde, L.* AU - Bevan, S.* AU - Sitzer, M.* AU - Klopp, N. AU - Illig, T. AU - Thiery, J.* AU - Seissler, J.* AU - Baumert, J.J. AU - Raitakari, O.* AU - Kähönen, M.* AU - Lyytikäinen, L.-P.* AU - Laaksonen, R.* AU - Viikari, J.* AU - Lehtimäki, T.* AU - Koernig, W.* AU - Halperin, E.* AU - Markus, H.S.* C1 - 6706 C2 - 29143 SP - 684-689 TI - Novel associations for coronary artery disease derived from genome wide association studies are not associated with increased carotid intima-media thickness, suggesting they do not act via early atherosclerosis or vessel remodeling. JO - Atherosclerosis VL - 219 IS - 2 PB - Elsevier PY - 2011 SN - 0021-9150 ER - TY - JOUR AB - OBJECTIVE: Sequence variation at Ch9p21 is a predisposing genetic factor for a number of diseases, including myocardial infarction (MI) and diabetes. We determined the risk of MI associated with various alleles and haplotypes, established and compared the predictive values of risk alleles, tested for the independence of associations between different risk alleles and MI, and sought to provide evidence for dual association of alleles with MI and diabetes. METHODS: With the use of 35 single nucleotide polymorphisms, together capturing common variation seen in the associated interval, we genotyped 3657 MI cases and 1211 controls prospectively sampled in a European population. RESULTS: Polymorphisms rs10757278 and rs1333049 both exhibited the strongest individual risk signal (OR, 1.45; 95% CI, 1.32-1.59). Two haplotype blocks were established, each of which was mainly represented by a pair of a risk-conferring and a protective haplotype, but none of the risk-associated haplotypes exhibited stronger effects than rs10757278 or rs1333049 alone. Specific polymorphisms (rs7865618, rs1537378, rs7857345, rs1333049) were identified as independent predictors of MI in multivariable models adjusted for conventional cardiovascular risk factors. In specific instances, the presence of two or three polymorphisms in a model, instead of only one, improved the discriminating power. Finally, evidence was provided to suggest dual association of rs7865618 with MI and diabetes. CONCLUSION: In keeping with published results, this work was consistent with the association of alleles and haplotypes at Ch9p21 with MI and extended prior knowledge by also showing independence of associations among different risk alleles and an association of a specific polymorphism with both MI and diabetes. AU - Koch, W.* AU - Türk, S.* AU - Erl, A.* AU - Hoppmann, P.* AU - Pfeufer, A. AU - King, L.* AU - Schömig, A.* AU - Kastrati, A.* C1 - 6751 C2 - 29207 SP - 220-226 TI - The chromosome 9p21 region and myocardial infarction in a European population. JO - Atherosclerosis VL - 217 IS - 1 PB - Elsevier PY - 2011 SN - 0021-9150 ER - TY - JOUR AB - OBJECTIVE: GATA4iKO mice exhibit impeded triglyceride absorption from intestine and decreased plasma triglyceride levels. Data in humans are lacking. We hypothesized that triglyceride levels might also be regulated by polymorphisms in the GATA4 gene in humans. We used publicly available data from different sources to evaluate this hypothesis. Our approach is a more often applicable advance to uncover associations and their functional implications which would have been otherwise missed by standard genome-wide association studies (GWAS). METHODS: We used the publicly available GWAS results from 137 SNPs in the GATA4 region for triglyceride levels. We embedded these results into the comprehensive functional genomics data provided in the UCSC Genome Browser including among others information on regulatory elements and interspecies conservation. A concise graphical presentation is proposed together with an R function for automatic data preparation. This process is presented in an educational manner using a screencast to become most useful for other researchers. RESULTS: We observed several polymorphisms in and around the GATA4 gene which have a significant influence on plasma triglyceride levels with the lowest p-value at SNP rs1466785 (Bonferroni-corrected p-value = 1.76e-5). The bioinformatic evaluation of this locus in publicly available functional genomics data provided converging evidence for the presence of a transcriptional regulator downstream of GATA4. CONCLUSION: The combination of different sources of data has revealed an association of GATA4 with triglyceride levels in humans. Our evaluation exemplifies how an integrative analysis including both statistical and biological perspectives can shed new light on available association data and reveals novel candidate genes, which are otherwise hidden in the noisy region below genome-wide significance. AU - Lamina, C.* AU - Coassin, S.* AU - Illig, T. AU - Kronenberg, F.* C1 - 6859 C2 - 29362 SP - 698-703 TI - Look beyond one's own nose: Combination of information from publicly available sources reveals an association of GATA4 polymorphisms with plasma triglycerides. JO - Atherosclerosis VL - 219 IS - 2 PB - Elsevier PY - 2011 SN - 0021-9150 ER - TY - JOUR AB - BACKGROUND: Recent revision to the Canadian Cardiovascular Society (CCS) guidelines on cardiovascular disease (CVD) risk stratification provides expanded recommendations for statin therapy. If CVD risk in the remaining individuals can further be stratified and discriminated by additional risk assessment using coronary artery calcium (CAC) scoring is unknown. METHODS AND RESULTS: In a retrospectively analyzed subgroup comprising 1934 participants from the Heinz Nixdorf Recall study, who did not meet criteria for statin therapy based on current CCS guidelines, traditional CVD risk variables and CAC were measured. Between 2000 and 2008, incident CVD events, i.e. coronary deaths, non-fatal myocardial infarction, coronary revascularization, stroke and CV death were determined. Those 43 participants who experienced 55 CVD events (5-year risk to first event: 2.2% (1.6-3.0%)) had higher CAC scores than those who did not (p<0.0001). In multiple Cox regression analysis including age, sex, total-/HDL-cholesterol ratio, and antihypertensive medication, log2(CAC+1) remained an independent predictor of CVD events (HR=1.21 (1.09-1.33), p<0.001). Measures of discrimination improved with the addition of CAC into the model: the incremental discrimination improvement was 0.0167, p=0.014. Net reclassification improvement using risk categories of 0-<3%, 3-10% and >10% was 25.1%, p=0.01, largely driven by a 32.6% correct up-classification in persons with events. Yet, only 38 (2%) of participants were identified being at high risk using CAC imaging in addition to traditional risk factor assessment. CONCLUSION: Adding CAC to traditional risk assessment in persons without indication for statin therapy improves discrimination. However, reclassification to the high risk category and overall event rates seem too low to justify liberal CAC testing in all these individuals. AU - Möhlenkamp, S.* AU - Lehmann, N.* AU - Greenland, P.* AU - Moebus, S.* AU - Kälsch, H.* AU - Schmermund, A.* AU - Dragano, N.* AU - Stang, A.* AU - Siegrist, J.* AU - Mann, K.* AU - Jöckel, K.-H.* AU - Erbel, R.* AU - Heinz Nixdorf Recall Study Investigative Group (Löwel, H.) C1 - 32354 C2 - 35000 SP - 229-236 TI - Coronary artery calcium score improves cardiovascular risk prediction in persons without indication for statin therapy. JO - Atherosclerosis VL - 215 IS - 1 PY - 2011 SN - 0021-9150 ER - TY - JOUR AB - OBJECTIVE: MicroRNAs are small non-coding RNAs that inversely regulate their target gene expression. The whole miRNA profile of human atherosclerotic plaques has not been studied previously. The aim of this study was to investigate the miRNA expression profile in human atherosclerotic plaques as compared to non-atherosclerotic left internal thoracic arteries (LITA), and to connect this expression to the processes in atherosclerosis. METHODS: The miRNA expression profiles of six LITAs and 12 atherosclerotic plaques obtained from aortic, carotid, and femoral atherosclerotic arteries from Tampere Vascular Study were analyzed. The analyses were performed with Agilent's miRNA Microarray. The expression levels of over 4-fold up-regulated miRNAs were verified with qRT-PCR from a larger population (n=50). Messenger RNA levels were analyzed with Illumina's Expression BeadChip to study miRNA target expression. RESULTS: Ten miRNAs were found to be differently expressed in atherosclerotic plaques when compared to controls (p<0.05). The expression of miR-21, -34a, -146a, -146b-5p, and -210 was verified and found to be significantly up-regulated in atherosclerotic arteries versus LITAs (p<0.001, fold changes 4.61, 2.55, 2.87, 2.82, and 3.92, respectively). Several predicted targets of these miRNAs were down-regulated, and gene set enrichment analysis showed several pathways which could be differently expressed due to this miRNA profile. CONCLUSIONS: The microRNA expression profile differs significantly between atherosclerotic plaques and control arteries. The most up-regulated miRNAs are involved in processes known to be connected to atherosclerosis. Interfering with the miRNA expression in the artery wall is a potential way to affect atherosclerotic plaque and cardiovascular disease development. AU - Raitoharju, E.* AU - Lyytikäinen, L.-P.* AU - Levula, M.* AU - Oksala, N.* AU - Mennander, A.* AU - Tarkka, M.* AU - Klopp, N. AU - Illig, T. AU - Kähönen, M.* AU - Karhunen, PJ.* AU - Laaksonen, R.* AU - Lehtimäki, T.* C1 - 5637 C2 - 29389 SP - 211-217 TI - miR-21, miR-210, miR-34a, and miR-146a/b are up-regulated in human atherosclerotic plaques in the Tampere Vascular Study. JO - Atherosclerosis VL - 219 IS - 1 PB - Elsevier PY - 2011 SN - 0021-9150 ER - TY - JOUR AB - OBJECTIVE: The single nucleotide polymorphism (SNP) rs2995300 in the metalloproteinase-disintegrin gene ADAM8 has been shown to affect the areas of complicated coronary plaques and the risk of fatal myocardial infarction (MI) in men. This study was set up to further investigate the role of ADAM8 in MI AIM: To investigate the possible association of the ADAM8 SNPs rs2995300 and rs2275725 with ADAM8 mRNA levels, serum soluble ADAM8 (sADAM8) concentrations, and MI risk METHODS: Samples from the Finnish cardiovascular study (FINCAVAS, N=2156) and the angiography and genes study (ANGES, N=1000) were genotyped. Serum sADAM8 concentrations were determined with ELISA (N=443). ADAM8 mRNA levels in atherosclerotic plaques were analysed from the tampere vascular study (TVS, N=53) samples. RESULTS: A significantly increased MI risk for carriers of the rs2995300C allele and the rs2275725 A allele was revealed in the meta-analysis of the ANGES and FINCAVAS patient data (OR=1.42, P<0.001 and OR=1.43, P<0.001). The risk increase was comparable to that caused by smoking in these cohorts. The risk allele carriers also had higher sADAM8 serum concentrations. CONCLUSIONS: The risk alleles of the investigated ADAM8 SNPs were associated with elevated sADAM8 serum levels and MI risk. The present results implicate ADAM8 in the development of CVDs and suggest its prognostic and therapeutic potential. AU - Raitoharju, E.* AU - Seppälä, I.* AU - Levula, M.* AU - Kuukasjärvi, P.* AU - Laurikka, J.* AU - Nikus, K.* AU - Huovila, A.P.* AU - Oksala, N.* AU - Klopp, N. AU - Illig, T. AU - Laaksonen, R.* AU - Karhunen, P.J.* AU - Viik, J.* AU - Lehtinen, R.* AU - Pelto-Huikko, M.* AU - Tarkka, M.* AU - Kähönen, M.* AU - Lehtimäki, T.* C1 - 6727 C2 - 29173 SP - 127-133 TI - Common variation in the ADAM8 gene affects serum sADAM8 concentrations and the risk of myocardial infarction in two independent cohorts. JO - Atherosclerosis VL - 218 IS - 1 PB - Elsevier PY - 2011 SN - 0021-9150 ER - TY - JOUR AB - OBJECTIVE: Plasma adiponectin is strongly associated with various components of metabolic syndrome, type 2 diabetes and cardiovascular outcomes. Concentrations are highly heritable and differ between men and women. We therefore aimed to investigate the genetics of plasma adiponectin in men and women. METHODS: We combined genome-wide association scans of three population-based studies including 4659 persons. For the replication stage in 13795 subjects, we selected the 20 top signals of the combined analysis, as well as the 10 top signals with p-values less than 1.0 x 10(-4) for each the men- and the women-specific analyses. We further selected 73 SNPs that were consistently associated with metabolic syndrome parameters in previous genome-wide association studies to check for their association with plasma adiponectin. RESULTS: The ADIPOQ locus showed genome-wide significant p-values in the combined (p=4.3 x 10(-24)) as well as in both women- and men-specific analyses (p=8.7 x 10(-17) and p=2.5 x 10(-11), respectively). None of the other 39 top signal SNPs showed evidence for association in the replication analysis. None of 73 SNPs from metabolic syndrome loci exhibited association with plasma adiponectin (p>0.01). CONCLUSIONS: We demonstrated the ADIPOQ gene as the only major gene for plasma adiponectin, which explains 6.7% of the phenotypic variance. We further found that neither this gene nor any of the metabolic syndrome loci explained the sex differences observed for plasma adiponectin. Larger studies are needed to identify more moderate genetic determinants of plasma adiponectin. AU - Heid, I.M. AU - Henneman, P.* AU - Hicks, A.* AU - Coassin, S.* AU - Winkler, T.* AU - Aulchenko, Y.S.* AU - Fuchsberger, C.* AU - Song, K.* AU - Hivert, M.-F.* AU - Waterworth, D.M.* AU - Timpson, N.J.* AU - Richards, J.B.* AU - Perry, J.R.B.* AU - Tanaka, T.* AU - Amin, N.* AU - Kollerits, B.* AU - Pichler, I.* AU - Oostra, B.A.* AU - Thorand, B. AU - Frants, R.* AU - Illig, T. AU - Dupuis, J.* AU - Glaser, B.* AU - Spector, T.* AU - Guralnik, J.* AU - Egan, J.M.* AU - Florez, J.C* AU - Evans, D.M* AU - Soranzo, N.* AU - Bandinelli, S.* AU - Carlson, O.D.* AU - Frayling, T.M.* AU - Burling, K.* AU - Smith, George D.* AU - Mooser, V.* AU - Ferrucci, L.* AU - Meigs, J.B.* AU - Vollenweider, P.* AU - van Dijk, K.W.* AU - Pramstaller, P.* AU - Kronenberg, F.* AU - van Duijn, C.M.* C1 - 164 C2 - 27115 SP - 412-420 TI - Clear detection of ADIPOQ locus as the major gene for plasma adiponectin: Results of genome-wide association analyses including 4659 European individuals. JO - Atherosclerosis VL - 208 IS - 2 PB - Elsevier PY - 2010 SN - 0021-9150 ER - TY - JOUR AB - OBJECTIVE: Despite modulating a number of metabolic processes linked to atherosclerosis, including glucose regulation, hematopoiesis, fatty acid catabolism and angiogenesis, the potential association of adiponectin and leptin with coronary heart disease is still a matter of controversy. METHODS: We conducted a population-based case-cohort study within the MONICA/KORA Augsburg studies. Serum levels of adipokines were measured in 333 case subjects with incident CHD and 1,728 non-case subjects selected from a source population of 9300 middle-aged men and women. Mean follow-up was 10.8+/-4.6 years. We sought to analyze the association of leptin and adiponectin and their ratio with CHD. RESULTS: After adjustment for various confounding factors the hazard ratios and 95% confidence intervals comparing tertile extremes were 0.79 (0.53-1.17) for leptin (top vs bottom tertile) and 0.87 (0. 62-1.23) for adiponectin (bottom vs top tertile), respectively. Furthermore, the ratio of leptin/adiponectin also showed no association with CHD (HR 1.01 (0.68-1.51)). CONCLUSIONS: The present study reports the association of leptin and adiponectin with incident CHD in a large population-based cohort. In contrast to fairly strong associations previously reported, our findings indicate no clinically relevant association between leptin, adiponectin and their ratio with the risk of CHD after adjustment for potential confounders. AU - Karakas, M.* AU - Zierer, A. AU - Herder, C.* AU - Baumert, J.J. AU - Meisinger, C. AU - Koenig, W.* AU - Thorand, B. C1 - 4662 C2 - 27472 SP - 220-225 TI - Leptin, adiponectin, their ratio and risk of Coronary Heart Disease: Results from the MONICA/KORA Augsburg Study 1984-2002. JO - Atherosclerosis VL - 209 IS - 1 PB - Elsevier PY - 2010 SN - 0021-9150 ER - TY - JOUR AB - BACKGROUND: A single nucleotide polymorphism (SNP) rs599839 located at chromosome 1p13.3 has previously been associated with risk of coronary artery disease (CAD) and with serum levels of low-density lipoprotein cholesterol (LDL-C). A functional link explaining the association of SNP rs599839 with LDL-C levels and CAD risk has not yet been elucidated. METHODS: We analyzed the association of rs599839 with LDL-C in 6605 individuals across a wide age spectrum and with CAD in four case-control studies comprising 4287 cases and 7572 controls. Genome-wide expression array data was used to assess the association of SNP rs599839 with gene expression at chromosome 1p13. Finally, we overexpressed sortilin in transfected cells to study LDL-uptake in vitro. RESULTS: Each copy of the G-allele of rs599839 associated with a decrease of serum LDL-C by 0.14mmol/L (90% confidence interval (CI) 0.09-0.17mmol/L, p=2.6x10(-11)). Moreover, each copy of the G-allele associated with a 9% decrease of CAD risk (90% CI 4-14%) in the presently studied four case-control samples and with a 13% decrease (90% CI 10-17%, p=2.18x10(-9)) in a pooled meta-analysis including recent genome-wide association studies on CAD. The same allele was associated with higher mRNA-expression levels of the multiligand receptor sortilin (log transformed mRNA AA vs. GG=8.31 vs. 8.55; p=0.01). Overexpression of SORT1 cDNA resulted in a significant increase in LDL-particle uptake (+23%, p=0.01). CONCLUSIONS: Rs599839 associates with decreased LDL-C and a lower risk of CAD. Effects appear to be mediated by increased sortilin expression and subsequently enhanced LDL-uptake into cells. AU - Linsel-Nitschke, P.* AU - Heeren, J.* AU - Aherrahrou, Z* AU - Bruse, P.* AU - Gieger, C. AU - Illig, T. AU - Prokisch, H. AU - Heim, K. AU - Döring, A. AU - Peters, A. AU - Meitinger, T. AU - Wichmann, H.-E. AU - Hinney, A.* AU - Reinehr, T.* AU - Roth, C.* AU - Ortlepp, J.R.* AU - Soufi, M.* AU - Sattler, A.M.* AU - Schaefer, J.* AU - Stark, K.* AU - Hengstenberg, C.* AU - Schaefer, A.* AU - Schreiber, S.* AU - Kronenberg, F.* AU - Samani, N.J.* AU - Schunkert, H.* AU - Erdmann, J.* C1 - 1150 C2 - 26455 SP - 183-189 TI - Genetic variation at chromosome 1p13.3 affects sortilin mRNA expression, cellular LDL-uptake and serum LDL levels which translates to the risk of coronary artery disease. JO - Atherosclerosis VL - 208 IS - 1 PB - Elsevier PY - 2010 SN - 0021-9150 ER - TY - JOUR AB - The 12/15-lipoxygenase plays a janus-role in inflammation with pro-inflammatory and anti-inflammatory effects in cell systems and even opposite effects on atherosclerosis in two different animal species. Screening of the human 15-lipoxygenase (ALOX15) gene detected a polymorphic C to T substitution at position c.-292, which led to three times higher ALOX15 activity in macrophages and showed a trend to be atheroprotective in a small case-control study for coronary artery disease (CAD). A second polymorphism at position c.1693C>T leading to an T560M exchange and an inactive enzyme was recently associated with increased CAD. We now investigated whether these polymorphisms or a certain haplotype of ALOX15 are associated with myocardial infarction (MI) in a case-control subset from the population-based MONIKA/KORA cohort S3. Six polymorphisms in ALOX15 were analyzed in 2629 participants to cover all major haplotypes with a frequency higher than 1% in the Caucasian population. None of the polymorphism was associated with MI but a rare ALOX15 haplotype showed a significant protective effect on the risk for MI (p=0.03). However, none of the polymorphisms or haplotypes was associated with CRP levels. These data suggest that ALOX15 may play a less prominent role during later stages of atherosclerosis involving atherothrombotic mechanisms than eventually during early plaque development. AU - Hersberger, M.* AU - Müller, M. AU - Marti-Jaun, J. AU - Heid, I.M.* AU - Coassin, S.* AU - Young, T.F.* AU - Waechter, V.* AU - Hengstenberg, C.* AU - Meisinger, C. AU - Peters, A. AU - König, W.* AU - Holmer, S.* AU - Schunkert, H.* AU - Klopp, N. AU - Kronenberg, F.* AU - Illig, T. C1 - 1950 C2 - 27111 SP - 192-196 TI - No association of two functional polymorphisms in human ALOX15 with myocardial infarction. JO - Atherosclerosis VL - 205 IS - 1 PB - Elsevier PY - 2009 SN - 0021-9150 ER - TY - JOUR AB - Objective: Macrophage migration inhibitory factor (MIF). a central cytokine of the innate immunity, has been reported to contribute to the development of cardiovascular disease. MIF is expressed in atherosclerotic lesions in humans, and gene deletion and antibody inhibition studies in animal models indicated that MIF may be Cause rather than consequence of atherosclerosis. We sought to assess the triangular association between MIF genotypes, circulating MIF levels and risk for incident coronary heart disease (CHD) in the large, prospective, population-based MONICA/KORA case-cohort study (Augsburg, Southern Germany). Methods: MIF genotypes, haplotypes and serum concentrations were determined in 363 individuals with incident CHD and 1908 individuals Without CHD during follow-up (mean follow-up time 10.3 years). Results: Circulation, MIF concentrations were not associated with the risk for CHD. In women, carriers of the minor alleles rs755622C and rs2070766G had a higher risk for incident CHD, and a haplotype that contained these two minor alleles was significantly associated with increased risk for CHD (HR 2.44 95% CI 1.30-4.59). Conclusion: The lack of association between serum levels and incident CHID indicates that MIF may not be a novel biomarker for CHD risk. However. the association of a haplotype containing the rs755622C allele. which has been reported before to increase the Susceptibility for various other proinflammatory conditions, with CHD points towards a role for MIF in local vascular inflammation and atherogenesis. AU - Herder, C.* AU - Illig, T. AU - Baumert, J.J. AU - Mueller, M.* AU - Klopp, N. AU - Khuseyinova, N.* AU - Meisinger, C. AU - Martin, S.* AU - Thorand, B. AU - Koenig, W.* C1 - 3381 C2 - 25840 SP - 380-388 TI - Macrophage migration inhibitory factor (MIF) and risk for coronary heart disease: Results from the MONICA/KORA Augsburg case-cohort study, 1984-2002. JO - Atherosclerosis VL - 200 IS - 2 PB - Elsevier PY - 2008 SN - 0021-9150 ER - TY - JOUR AB - AIMS: Intermittent claudication (IC) is the most common symptom of peripheral arterial disease and is associated with an increased mortality. Within the Erfurt Male Cohort (ERFORT) Study, one of the most long-lasting population-based prospective cohort studies in Europe, we investigated (i) which variables predict the development of incident IC determined by the WHO Rose questionnaire over a period of 15 years and (ii) if IC is predictive for 30 years all-cause mortality. METHODS: The baseline survey examined a random population-based sample of 1160 males aged 40-59 years with three follow-up examinations 5, 10 and 15 years after enrollment using each time the Rose questionnaire. RESULTS: An adjusted Cox regression analysis revealed smoking (HR (95% CI), 2.20 (1.24-3.92), p=0.01), diabetes mellitus (HR (95% CI), 4.68 (1.61-13.63), p=0.01) and coronary heart disease (HR (95% CI), 2.74 (1.08-6.96), p=0.03) to be significantly associated with incident IC. Participants with an IC had an significantly increased age-adjusted 30 years all-cause mortality (HR (95% CI), 1.56 (1.16-2.10), p=0.003). This association remained still significantly predictive after adjustment for other cardiovascular risk factors. CONCLUSIONS: Mainly smoking and diabetes mellitus are associated with incident IC. A positive Rose questionnaire is a strong predictor for all-cause mortality over 30 years. The simplicity of their use makes questionnaires highly attractive for identification of high-risk patients in primary health care. AU - Kollerits, B.* AU - Heinrich, J. AU - Pichler, M.* AU - Rantner, B.* AU - Klein-Weigel, P.* AU - Wölke, G. AU - Brasche, S.* AU - Strube, G.* AU - Kronenberg, F.* C1 - 3310 C2 - 25285 SP - 214-222 TI - Intermittent claudication in the Erfurt Male Cohort (ERFORT) Study: its determinants and the impact on mortality. A population-based prospective cohort study with 30 years of follow-up. JO - Atherosclerosis VL - 198 IS - 1 PB - Elsevier Science PY - 2008 SN - 0021-9150 ER - TY - JOUR AU - Meisinger, C. AU - Döring, A. AU - Schneider, B. AU - Löwel, H. C1 - 2916 C2 - 24274 SP - 297-302 TI - Serum gamma-glutamyltransferase is a predictor of incident coronary events in apparently healthy men from the general population. JO - Atherosclerosis VL - 189 PY - 2006 SN - 0021-9150 ER - TY - JOUR AU - Thorand, B. AU - Baumert, J.J. AU - Döring, A. AU - Herder, C.* AU - Kolb, H.* AU - Rathmann, W.* AU - Giani, G.* AU - Koenig, W.* C1 - 5413 C2 - 23480 SP - 216-224 TI - Sex differences in the relation of body composition to markers of inflammation. JO - Atherosclerosis VL - 184 PY - 2006 SN - 0021-9150 ER - TY - JOUR AU - Döring, A. AU - Fröhlich, M.* AU - Löwel, H. AU - Koenig, W.* C1 - 662 C2 - 22015 SP - 281-286 TI - Third generation oral contraceptive use and cardiovascular risk factors. JO - Atherosclerosis VL - 172 PY - 2004 SN - 0021-9150 ER - TY - JOUR AB - The antioxidant effects of vitamin E may protect low density lipoproteins from peroxidation and thus inhibit the development of arteriosclerosis. Inverse associations between vitamin E levels and coronary heart disease have been reported from cross-sectional and ecologic studies. In the population-based MONICA Augsburg cohort (2023 men, 1999 women, age 25–64 years at baseline in 1984, 93% of whom were reexamined in 1987/1988) we investigated the relationship between serum vitamin E concentrations and the risk of subsequent myocardial infarction (MI). Between 1984 and 1991, 46 cases of fatal and non-fatal myocardial infarction from this cohort were recruited for a nested case-control study. Four controls were sampled from the cohort for each case of MI with matching for age, sex, and total cholesterol. There were no marked differences between cases and their matched controls in the means of vitamin E concentrations (33.9 μmol/l vs. 32.8 μmol/l, P = 0.37) or in the mean vitamin E/total cholesterol ratios (4.89 μmol/mmol vs. 4.82 μmol/mmol, P = 0.75). The covariate adjusted relative risk (RR) for fatal plus non-fatal MI in the lowest tertile of vitamin E relative to the upper two tertiles was 0.72 (90% confidence interval: 0.33–1.57). Likewise, for the lowest tertile of the ratio (vitamin E/total cholesterol) the RR was 0.81 (0.42–1.56). The association was not modified by history of previous coronary heart disease, fatality of MI, temporal distance of MI onset from vitamin E determinations, or season. Although the limited statistical power of this study has to be considered, risk estimates appeared too low to be compatible with a substantial protective effect of vitamin E levels. We conclude, therefore, that serum vitamin E concentrations were not associated with the myocardial infarction risk and suggest that this is probably due to the high average levels of vitamin E in our study population. AU - Hense, H.W. AU - Stender, M. AU - Bors, W. AU - Keil, U. C1 - 20696 C2 - 13914 SP - 21-28 TI - Lack of an Association Between Serum Vitamin E and Myocardinal Infarction in a Population with high Vitamin E Levels. JO - Atherosclerosis VL - 103 IS - 1 PY - 1993 SN - 0021-9150 ER - TY - JOUR AB - When rats were fed a diet containing 0.3% clofibrate or a derivative of this drug, BM 15075, serum cholesterol was lowered within 3-7 days by 26-38%. Both drugs diminished the activity of hydroxymethylglutaryl CoA reductase, the regulatory enzyme of hepatic cholesterol biosynthesis, in rat liver microsomes by about 60% under the same conditions. The decrease in the activity of the enzyme obviously is due to changes in the amount of enzyme protein. Under in vitro conditions, microsomal hydroxymethylglutaryl CoA reductase was inhibited competitively by (1.35 mM) clofibrate acid (sodium salt) and by BM 15075 (1 mM) with respect to its substrate. These results give evidence that these drugs can affect both, the rate of synthesis and the substrate affinity of hydroxymethylglutaryl CoA reductase. AU - Berndt, J. AU - Gaumert, R. AU - Still, J.S. C1 - 41835 C2 - 0 SP - 147-152 TI - Mode of action of the lipid-lowering agents, elofibrate and BM 15075, on cholesterol biosynthesis in rat liver. JO - Atherosclerosis VL - 30 IS - 2 PY - 1978 SN - 0021-9150 ER -