Thomas Münzel

Publications of Thomas Münzel

• Defining a reference population to determine the 99th percentile of a contemporary sensitive cardiac troponin I assay.

  Authors: Till Keller, Francisco Ojeda, Tanja Zeller, Philipp S Wild, Stergios Tzikas, Christoph R Sinning, Dirk Peetz, Thomas Münzel, Stefan Blankenberg, Karl J Lackner

  International journal of cardiology. 05/2012;

  BACKGROUND: Diagnosis of acute myocardial infarction (AMI) according to the universal definition is based on ischemic symptoms, imaging findings and elevated myocardial necrosis markers, preferablyBACKGROUND: Diagnosis of acute myocardial infarction (AMI) according to the universal definition is based on ischemic symptoms, imaging findings and elevated myocardial necrosis markers, preferably cardiac troponin I/T with diagnostic threshold representing the 99th percentile of a reference population. It is not clearly defined if this should be an unselected population-based or a healthy cohort with respect to cardiac diseases. Aim of the current study was to describe the distribution of troponin I using a sensitive assay and to evaluate the impact of cardiac diseases and cardiovascular risk factors in apparently healthy individuals. METHODS: Troponin I was determined using a contemporary sensitive assay (TnI Ultra, Siemens) with 10% coefficient of variation (0.03ng/mL) below the published 99th percentile (0.04ng/mL) in 5000 participants (49.2% female) of the Gutenberg Health Study, a community-based, prospective, observational single-center cohort study. The calculated 99th percentile cut-offs were tested in 1818 patients with suspected AMI. RESULTS: Troponin I concentration representing the 99th percentile of the overall study population was 0.04ng/mL. Excluding individuals with prevalent cardiovascular disease lowers the 99th percentile to 0.034ng/mL. Exclusion of individuals with traditional risk factors or elevated natriuretic peptide leads to further reduction with 0.029/0.028ng/mL. These lower cut-offs detect more patients at risk in individuals with suspected AMI. Correlations of troponin I with age, gender and traditional risk factors were observed. CONCLUSIONS: Troponin I concentrations in apparently healthy individuals are dependent on prevalent cardiovascular diseases, traditional risk factors, gender and age. Application of corresponding cut-offs in diagnosis of AMI alters the group of patients potentially at risk.

• Chronic therapy with isosorbide-5-mononitrate causes endothelial dysfunction, oxidative stress, and a marked increase in vascular endothelin-1 expression.

  Authors: Matthias Oelze, Maike Knorr, Swenja Kröller-Schön, Sabine Kossmann, Anna Gottschlich, Robert Rümmler, Alexandra Schuff, Steffen Daub, Christopher Doppler, Hartmut Kleinert, Tommaso Gori, Andreas Daiber, Thomas Münzel

  European heart journal. 05/2012;

  AimsIsosorbide-5-mononitrate (ISMN) is one of the most frequently used compounds in the treatment of coronary artery disease predominantly in the USA. However, ISMN was reported to induce endothelialAimsIsosorbide-5-mononitrate (ISMN) is one of the most frequently used compounds in the treatment of coronary artery disease predominantly in the USA. However, ISMN was reported to induce endothelial dysfunction, which was corrected by vitamin C pointing to a crucial role of reactive oxygen species (ROS) in causing this phenomenon. We sought to elucidate the mechanism how ISMN causes endothelial dysfunction and oxidative stress in vascular tissue.Methods and resultsMale Wistar rats (n= 69 in total) were treated with ISMN (75 mg/kg/day) or placebo for 7 days. Endothelin (ET) expression was determined by immunohistochemistry in aortic sections. Isosorbide-5-mononitrate infusion caused significant endothelial dysfunction but no tolerance to ISMN itself, whereas ROS formation and nicotinamide adenine dinucleotidephosphate (NADPH) oxidase activity in the aorta, heart, and whole blood were increased. Isosorbide-5-mononitrate up-regulated the expression of NADPH subunits and caused uncoupling of the endothelial nitric oxide synthase (eNOS) likely due to a down-regulation of the tetrahydrobiopterin-synthesizing enzyme GTP-cyclohydrolase-1 and to S-glutathionylation of eNOS. The adverse effects of ISMN were improved in gp91phox knockout mice and normalized by bosentan in vivo/ex vivo treatment and suppressed by apocynin. In addition, a strong increase in the expression of ET within the endothelial cell layer and the adventitia was observed.ConclusionChronic treatment with ISMN causes endothelial dysfunction and oxidative stress, predominantly by an ET-dependent activation of the vascular and phagocytic NADPH oxidase activity and NOS uncoupling. These findings may explain at least in part results from a retrospective analysis indicating increased mortality in post-infarct patients in response to long-term treatment with mononitrates.

• α1AMP-Activated Protein Kinase Mediates Vascular Protective Effects of Exercise.

  Authors: Swenja Kröller-Schön, Thomas Jansen, Felix Hauptmann, Andrea Schüler, Tjebo Heeren, Michael Hausding, Matthias Oelze, Benoit Viollet, John F Keaney, Philip Wenzel, Andreas Daiber, Thomas Münzel, Eberhard Schulz

  Arteriosclerosis, thrombosis, and vascular biology. 04/2012;

  OBJECTIVE: We investigated whether AMP-activated protein kinase (AMPK) may be involved in the signaling processes leading to exercise-mediated vascular protection. METHODS AND RESULTS: The effects ofOBJECTIVE: We investigated whether AMP-activated protein kinase (AMPK) may be involved in the signaling processes leading to exercise-mediated vascular protection. METHODS AND RESULTS: The effects of voluntary exercise on AMPK activity, endothelial NO synthase expression and phosphorylation, vascular reactive oxygen species formation, and cell senescence were tested in α1AMPK knockout and corresponding wild-type mice. Exercise significantly improved endothelial function, and increased plasma nitrite production in wild-type mice, associated with an activation of aortic AMPK assessed by its phosphorylation at threonine 172. In addition, regular physical activity resulted in an upregulation of endothelial NO synthase protein, serine 1177 endothelial NO synthase phosphorylation, and an increase of circulating Tie-2(+)Sca-1(+)Flk-1(+) myeloid progenitor cells. All these changes were absent after α1AMPK deletion. In addition, exercise increased the expression of important regulators of the antioxidative defense including heme oxygenase-1 and peroxisome proliferator-activated receptor γ coactivator 1α, decreased aortic reactive oxygen species levels, and prevented endothelial cell senescence in an α1AMPK-dependent manner. CONCLUSIONS: Intact α1AMPK signaling is required for the signaling events leading to the manifestation of vascular protective effects during exercise. Pharmacological AMPK activation might be a novel approach in the near future to simulate the beneficial vascular effects of physical activity.

• Hyperglycemia and oxidative stress in cultured endothelial cells - a comparison of primary endothelial cells with an immortalized endothelial cell line.

  Authors: Susanne Karbach, Thomas Jansen, Sven Horke, Tjebo Heeren, Alexander Scholz, Meike Coldewey, Angelica Karpi, Michael Hausding, Swenja Kröller-Schön, Matthias Oelze, Thomas Münzel, Andreas Daiber

  Journal of diabetes and its complications. 04/2012;

  Diabetes mellitus is a major risk factor for the development of cardiovascular disease and oxidative stress plays an important role in this process. Therefore, we investigated the effects ofDiabetes mellitus is a major risk factor for the development of cardiovascular disease and oxidative stress plays an important role in this process. Therefore, we investigated the effects of hyperglycemia on the formation of reactive oxygen species (ROS) and nitric oxide/cGMP signaling in two different endothelial cell cultures. Human umbilical vein endothelial cells (HUVEC) and EA.hy 926 cells showed increased oxidative stress and impaired NO-cGMP signaling in response to hyperglycemia. The major difference between the two different cell types was the dramatic decrease in viability in HUVEC whereas EA.hy cells showed rather increased growth under hyperglycemic conditions. Starvation led to an additional substantial decrease in viability and increased superoxide formation in HUVEC. Both endothelial cell types, HUVEC and EA.hy 926, may be used as models for vascular hyperglycemia. However, high growth medium should be used to avoid starvation-induced oxidative stress and cell death.

• Establishment and progress of the chest pain unit certification process in Germany and the local experiences of Mainz.

  Authors: Felix Post, Tommaso Gori, Jochen Senges, Evangelos Giannitsis, Hugo Katus, Thomas Münzel

  European heart journal. 03/2012; 33(6):682-6.

  The establishment of chest pain units (CPUs) in the USA and UK has led to improvements in the prognosis of patients with chest pain and myocardial infarction, optimizing access to specializedThe establishment of chest pain units (CPUs) in the USA and UK has led to improvements in the prognosis of patients with chest pain and myocardial infarction, optimizing access to specialized diagnostic and therapeutic facilities and reducing costs. To establish a uniform implementation of this type of service in Germany, the German Cardiac Society (DGK) founded a 'CPU task force' in 2007, which developed a set of standard requirements and a nationwide certification programme. The recommendations for minimum standard requirements were published in 2008. As of November 2011, 132 CPUs were certified and 36 units were in the certification process. The aim of the DGK is to certify as many as 250 centres (units) throughout Germany within the next 2 years, to provide nationwide coverage. Applications from Switzerland are also being filed. Public awareness campaigns in cooperation with national league soccer teams were organized to raise awareness of the importance for early diagnosis and treatment of cardiac diseases and to publicize the existence of these new facilities. The German model of CPU certification allows nationwide and prospectively European-wide standardization of patient care and to improve adherence to international guidelines. Coupled with awareness campaigns and with the launch of a German CPU Registry, this process is aimed at improving the education and treatment of patients with chest pain and to provide scientific information about the quality of patient care.

• Chronic protection against ischemia and reperfusion-induced endothelial dysfunction during therapy with different organic nitrates.

  Authors: Monica Lisi, Matthias Oelze, Saverio Dragoni, Andrew Liuni, Sebastian Steven, Mary-Clare Luca, Dirk Stalleicken, Thomas Münzel, Franco Laghi-Pasini, Andreas Daiber, John D Parker, Tommaso Gori

  Clinical research in cardiology : official journal of the German Cardiac Society. 02/2012;

  INTRODUCTION: Ischemic and pharmacologic preconditioning have great clinical potential, but it remains unclear whether their effects can be maintained over time during repeated exposure.We haveINTRODUCTION: Ischemic and pharmacologic preconditioning have great clinical potential, but it remains unclear whether their effects can be maintained over time during repeated exposure.We have previously demonstrated that the acute protective effect of nitroglycerin (GTN) is attenuated during repeated daily administration. Pentaerythrityl tetranitrate (PETN) is an organic nitrate with different hemodynamic and biochemical properties. The purpose of the current experiment was to study the preconditioning-like effects of PETN and GTN during repeated daily exposure. METHODS AND RESULTS: In a randomized, investigator-blind parallel trial, 30 healthy (age 25-32) volunteers were randomized to receive (1) transdermal GTN (0.6 mg/h) administered for 2 h a day for 6 days; (2) oral PETN (80 mg) once a day for 6 days; or (3) no therapy. One week later, endothelium-dependent flow-mediated dilation was assessed before and after exposure to ischemia and reperfusion (IR). IR caused a significant blunting of the endothelium-dependent relaxation in the control group (FMD before IR: 5.8 ± 2.1%; after IR 1.0 ± 2.1%; P < 0.01). Daily, 2-h exposure to GTN partially prevented IR-induced endothelial dysfunction (FMD before IR: 7.7 ± 2.4%; after IR 4.3 ± 3.0%; P < 0.01 compared to before IR). In contrast, daily PETN administration afforded greater protection from IR-induced endothelial injury (FMD before IR: 7.9 ± 1.7%; after IR 6.4 ± 5.3%, P = ns; P < 0.05 ANOVA across groups). In vitro, incubation of human endothelial cells with GTN (but not PETN) was associated with inhibition (P < 0.01) of aldehyde dehydrogenase, an enzyme that is important for both nitrate biotransformation and ischemic preconditioning. DISCUSSION: We previously showed that upon repeated administration, the preconditioning-like effects of GTN are attenuated. The present data demonstrate a gradient in the extent of protection afforded by the two nitrates, suggesting that PETN-induced preconditioning is maintained after prolonged administration in a human in vivo model of endothelial dysfunction induced by ischemia. Using isolated human endothelial cells, we propose a mechanistic explanation for this observation based on differential effects of GTN versus PETN on the activity of mitochondrial aldehyde dehydrogenase.

• Left atrial appendage occlusion in valvular atrial fibrillation following MitraClip implantation.

  Authors: Alexander Jabs, Ulrich Hink, Ascan Warnholtz, Ralph Stephan von Bardeleben, Philipp Nikolai, Thomas Münzel, Tommaso Gori

  Clinical research in cardiology : official journal of the German Cardiac Society. 01/2012;

• Serial changes in highly sensitive troponin I assay and early diagnosis of myocardial infarction.

  Authors: Till Keller, Tanja Zeller, Francisco Ojeda, Stergios Tzikas, Lars Lillpopp, Christoph Sinning, Philipp Wild, Sabine Genth-Zotz, Ascan Warnholtz, Evangelos Giannitsis, Martin Möckel, Christoph Bickel, Dirk Peetz, Karl Lackner, Stephan Baldus, Thomas Münzel, Stefan Blankenberg

  JAMA : the journal of the American Medical Association. 12/2011; 306(24):2684-93.

  Introduction of highly sensitive troponin assays into clinical practice has substantially improved the evaluation of patients with chest pain. To evaluate the diagnostic performance of a highlyIntroduction of highly sensitive troponin assays into clinical practice has substantially improved the evaluation of patients with chest pain. To evaluate the diagnostic performance of a highly sensitive troponin I (hsTnI) assay compared with a contemporary troponin I (cTnI) assay and their serial changes in the diagnosis of acute myocardial infarction (AMI). A total of 1818 patients with suspected acute coronary syndrome were consecutively enrolled at the chest pain units of the University Heart Center Hamburg, the University Medical Center Mainz, and the Federal Armed Forces Hospital Koblenz, all in Germany, from 2007 to 2008. Twelve biomarkers including hsTnI (level of detection, 3.4 pg/mL) and cTnI (level of detection, 10 pg/mL) were measured on admission and after 3 and 6 hours. Diagnostic performance for AMI of baseline and serial changes in hsTnI and cTnI results at 3 hours after admission to the emergency department. Of the 1818 patients, 413 (22.7%) were diagnosed as having AMI. For discrimination of AMI, the area under the receiver operating characteristic (ROC) curve was 0.96 (95% CI, 0.95-0.97) for hsTnI on admission and 0.92 (95% CI, 0.90-0.94) for cTnI on admission. Both were superior to the other evaluated diagnostic biomarkers. The use of hsTnI at admission (with the diagnostic cutoff value at the 99th percentile of 30 pg/mL) had a sensitivity of 82.3% and a negative predictive value (for ruling out AMI) of 94.7%. The use of cTnI (with the diagnostic cutoff value at the 99th percentile of 32 pg/mL) at admission had a sensitivity of 79.4% and a negative predictive value of 94.0%. Using levels obtained at 3 hours after admission, the sensitivity was 98.2% and the negative predictive value was 99.4% for both hsTnI and cTnI assays. Combining the 99th percentile cutoff at admission with the serial change in troponin concentration within 3 hours, the positive predictive value (for ruling in AMI) for hsTnI increased from 75.1% at admission to 95.8% after 3 hours, and for cTnI increased from 80.9% at admission to 96.1% after 3 hours. Among patients with suspected acute coronary syndrome, hsTnI or cTnI determination 3 hours after admission may facilitate early rule-out of AMI. A serial change in hsTnI or cTnI levels from admission (using the 99th percentile diagnostic cutoff value) to 3 hours after admission may facilitate an early diagnosis of AMI.

• Association between chromosome 9p21 variants and the ankle-brachial index identified by a meta-analysis of 21 genome-wide association studies.

  Authors: Joanne M Murabito, Charles C White, Maryam Kavousi, Yan V Sun, Mary F Feitosa, Vijay Nambi, Claudia Lamina, Arne Schillert, Stefan Coassin, Joshua C Bis [......] H-Erich Wichmann, James F Wilson, Jacqueline C M Witteman, Yongmei Liu, Caroline Hayward, Ingrid B Borecki, Andreas Ziegler, Kari E North, L Adrienne Cupples, Florian Kronenberg

  Circulation. Cardiovascular genetics. 12/2011; 5(1):100-12.

  Background- Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure ofBackground- Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts. Methods and Results- Continuous ABI and PAD (ABI ≤0.9) phenotypes adjusted for age and sex were examined. Each study conducted genotyping and imputed data to the ≈2.5 million single nucleotide polymorphisms (SNPs) in HapMap. Linear and logistic regression models were used to test each SNP for association with ABI and PAD using additive genetic models. Study-specific data were combined using fixed effects inverse variance weighted meta-analyses. There were a total of 41 692 participants of European ancestry (≈60% women, mean ABI 1.02 to 1.19), including 3409 participants with PAD and with genome-wide association study data available. In the discovery meta-analysis, rs10757269 on chromosome 9 near CDKN2B had the strongest association with ABI (β=-0.006, P=2.46×10(-8)). We sought replication of the 6 strongest SNP associations in 5 population-based studies and 3 clinical samples (n=16 717). The association for rs10757269 strengthened in the combined discovery and replication analysis (P=2.65×10(-9)). No other SNP associations for ABI or PAD achieved genome-wide significance. However, 2 previously reported candidate genes for PAD and 1 SNP associated with coronary artery disease were associated with ABI: DAB21P (rs13290547, P=3.6×10(-5)), CYBA (rs3794624, P=6.3×10(-5)), and rs1122608 (LDLR, P=0.0026). Conclusions- Genome-wide association studies in more than 40 000 individuals identified 1 genome wide significant association on chromosome 9p21 with ABI. Two candidate genes for PAD and 1 SNP for coronary artery disease are associated with ABI.

• Integrating genome-wide genetic variations and monocyte expression data reveals trans-regulated gene modules in humans.

  Authors: Maxime Rotival, Tanja Zeller, Philipp S Wild, Seraya Maouche, Silke Szymczak, Arne Schillert, Raphaele Castagné, Arne Deiseroth, Carole Proust, Jessy Brocheton [......] Gilles Montalescot, Willem H Ouwehand, Nilesh J Samani, Heribert Schunkert, David-Alexandre Tregouet, Andreas Ziegler, Alison H Goodall, François Cambien, Laurence Tiret, Stefan Blankenberg

  PLoS genetics. 12/2011; 7(12):e1002367.

  One major expectation from the transcriptome in humans is to characterize the biological basis of associations identified by genome-wide association studies. So far, few cis expression quantitativeOne major expectation from the transcriptome in humans is to characterize the biological basis of associations identified by genome-wide association studies. So far, few cis expression quantitative trait loci (eQTLs) have been reliably related to disease susceptibility. Trans-regulating mechanisms may play a more prominent role in disease susceptibility. We analyzed 12,808 genes detected in at least 5% of circulating monocyte samples from a population-based sample of 1,490 European unrelated subjects. We applied a method of extraction of expression patterns-independent component analysis-to identify sets of co-regulated genes. These patterns were then related to 675,350 SNPs to identify major trans-acting regulators. We detected three genomic regions significantly associated with co-regulated gene modules. Association of these loci with multiple expression traits was replicated in Cardiogenics, an independent study in which expression profiles of monocytes were available in 758 subjects. The locus 12q13 (lead SNP rs11171739), previously identified as a type 1 diabetes locus, was associated with a pattern including two cis eQTLs, RPS26 and SUOX, and 5 trans eQTLs, one of which (MADCAM1) is a potential candidate for mediating T1D susceptibility. The locus 12q24 (lead SNP rs653178), which has demonstrated extensive disease pleiotropy, including type 1 diabetes, hypertension, and celiac disease, was associated to a pattern strongly correlating to blood pressure level. The strongest trans eQTL in this pattern was CRIP1, a known marker of cellular proliferation in cancer. The locus 12q15 (lead SNP rs11177644) was associated with a pattern driven by two cis eQTLs, LYZ and YEATS4, and including 34 trans eQTLs, several of them tumor-related genes. This study shows that a method exploiting the structure of co-expressions among genes can help identify genomic regions involved in trans regulation of sets of genes and can provide clues for understanding the mechanisms linking genome-wide association loci to disease.

• Midregional proadrenomedullin for prediction of cardiovascular events in coronary artery disease: results from the AtheroGene study.

  Authors: Philipp S Wild, Renate B Schnabel, Edith Lubos, Tanja Zeller, Christoph R Sinning, Till Keller, Stergios Tzikas, Karl J Lackner, Dirk Peetz, Hans J Rupprecht, Christoph Bickel, Nils G Morgenthaler, Jana Papassotiriou, Laurence Tiret, Thomas Münzel, Stefan Blankenberg

  Clinical chemistry. 11/2011; 58(1):226-36.

  Midregional proadrenomedullin (MR-proADM) is a newly identified prognostic marker in heart failure. We evaluated the prognostic impact of MR-proADM in a cohort of patients with symptomatic coronaryMidregional proadrenomedullin (MR-proADM) is a newly identified prognostic marker in heart failure. We evaluated the prognostic impact of MR-proADM in a cohort of patients with symptomatic coronary artery disease according to their clinical presentation. We measured baseline MR-proADM concentrations in 2240 individuals from the prospective AtheroGene study and evaluated the prognostic impact on future fatal and nonfatal cardiovascular events during a follow-up period of 3.6 (1.6) years. The sample comprised 1355 individuals with stable angina pectoris (SAP) and 885 with acute coronary syndrome (ACS). A cardiovascular event occurred in 192 people. Individuals presenting with SAP had only slightly lower plasma MR-proADM concentrations than those with ACS (0.53 vs 0.55 nmol/L, P=0.006). MR-proADM showed a moderate association with age, serum N-terminal pro-B-type natriuretic peptide (NT-proBNP), glomerular filtration rate, serum C-reactive protein, hypertension, diabetes, and prevalent multivessel disease (all P<0.0005). Individuals suffering from a cardiovascular event had higher MR-proADM concentrations at baseline in both groups (SAP 0.63 vs 0.53 nmol/L and ACS 0.65 nmol/L vs 0.55 nmol/L, both P<0.0005). Cox regression analysis incorporating various variables of cardiovascular risk and NT-proBNP revealed a hazard ratio of 1.4 (95% CI 1.2-1.6; P<0.0005) per increment of MR-proADM by 1SD. In risk models for secondary prevention, MR-proADM provided information comparable to that of NT-proBNP. MR-proADM is an independent predictor for future cardiovascular events in patients with symptomatic coronary artery disease, providing information comparable to NT-proBNP for secondary risk stratification.

• Chronic inflammatory cardiomyopathy of interferon γ-overexpressing transgenic mice is mediated by tumor necrosis factor-α.

  Authors: Michael Torzewski, Philip Wenzel, Hartmut Kleinert, Christoph Becker, Jasmin El-Masri, Elena Wiese, Moritz Brandt, Andrea Pautz, Laura Twardowski, Edgar Schmitt, Thomas Münzel, Kurt Reifenberg

  The American journal of pathology. 10/2011; 180(1):73-81.

  We recently described a model of inflammatory cardiomyopathy in interferon (IFN)-γ overexpressing transgenic mice stably circulating IFN-γ in the serum referred to as SAP--IFN-γ mice. SAP-IFN-γWe recently described a model of inflammatory cardiomyopathy in interferon (IFN)-γ overexpressing transgenic mice stably circulating IFN-γ in the serum referred to as SAP--IFN-γ mice. SAP-IFN-γ transgenic mice show cardiac infiltration by mononuclear leukocytes, culminating in dilated cardiomyopathy characterized by an increase of left ventricular end diastolic diameter and reduction of fractional shortening. We hypothesized that the pathological mechanism underlying SAP-IFN-γ cardiomyopathy might be mediated by (auto)immune processes or tumor necrosis factor (TNF)-α synthesis from IFN-γ-activated macrophages. To verify these hypotheses, we crossed SAP-IFN-γ transgenic mice with immunodeficient Rag1(-/-) or TNF-α(-/-) knockout mice and analyzed the cardiac phenotype of the resulting double-mutant offspring. Immunodeficient Rag1(-/-) SAP-IFN-γ mice had a decreased impaired life span and intensive cardiac inflammatory reactions, showing that the cardiotoxic IFN-γ effect operative in SAP-IFN-γ mice was not mediated by an adaptive immune mechanism. SAP-IFN-γ TNF-α(-/-) hearts showed virtually no histopathological alterations, a significant reduction of cardiac infiltration by CD11c(+) dendritic cells and F4/80(+) macrophages, almost complete normalization of cardiac troponin T levels in serum and of left ventricular end diastolic diameter and fractional shortening, and a dramatic increase of life span, compared with SAP-IFN-γ transgenic controls. Thus, myocarditis and cardiomyopathy developing in IFN-γ-overexpressing transgenic mice is, to a significant degree, mediated by TNF-α. TNF-α-mediated cardiotoxicity in SAP-IFN-γ transgenic mice is independent of changes of apoptosis.

• Intracellular pH: a fundamental modulator of vascular function.

  Authors: Eberhard Schulz, Thomas Münzel

  Circulation. 10/2011; 124(17):1806-7.

• CRP and CD14 polymorphisms correlate with coronary plaque volume in patients with coronary artery disease--IVUS substudy of the ENCORE trials.

  Authors: Matthias Hermann, Dieter Fischer, Michael M Hoffmann, Theo Gasser, Kurt Quitzau, Thomas Meinertz, Thomas Münzel, Thomas F Lüscher

  Atherosclerosis. 10/2011; 220(1):172-6.

  Several proinflammatory single-nucleotide polymorphisms (SNPs) have been linked to the progression of atherosclerosis and coronary artery disease (CAD). Plaque size and its destabilization bySeveral proinflammatory single-nucleotide polymorphisms (SNPs) have been linked to the progression of atherosclerosis and coronary artery disease (CAD). Plaque size and its destabilization by inflammatory processes are major determinants of ischemia and acute coronary syndromes. Intravascular ultrasound (IVUS) allows for quantification of plaque size in vivo. We therefore investigated the relation of plaque size with mutations of proinflammatory genes in patients with CAD. In 196 patients with stable CAD enrolled in the ENCORE trials coronary plaque and vessel volume was assessed by IVUS. 173 patients were successfully genotyped for polymorphisms of proinflammatory genes CD14 C(-260)T and CRP C(+1444)T using the single-nucleotide polymorphism polymerase chain reaction (SNP PCR) approach. Baseline characteristics were comparable for all genotype groups. Higher ratios of plaque volume/vessel volume were observed in patients with the CRP 1444TT (n=11) and CD14 260TT (n=33) genotypes (p=0.016 and p=0.026, respectively). In patients with stable coronary artery disease the CRP 1444TT and CD14 260TT variants are associated with larger coronary plaque volume independently of concomitant cardiovascular risk factors.

• Differential effects of heart rate reduction with ivabradine in two models of endothelial dysfunction and oxidative stress.

  Authors: Swenja Kröller-Schön, Eberhard Schulz, Philip Wenzel, Andrei L Kleschyov, Marcus Hortmann, Michael Torzewski, Matthias Oelze, Thomas Renné, Andreas Daiber, Thomas Münzel

  Basic research in cardiology. 10/2011; 106(6):1147-58.

  Heart rate reduction with the I(f)-channel-inhibitor ivabradine is a novel and appealing option in the therapy of patients with ischemic heart disease. The aim of the current study was to determineHeart rate reduction with the I(f)-channel-inhibitor ivabradine is a novel and appealing option in the therapy of patients with ischemic heart disease. The aim of the current study was to determine the effects of ivabradine in two different animal models of vascular disease characterized by increased oxidative stress and endothelial dysfunction. Wistar rats with angiotensin II induced hypertension and ApoE knockout mice were used as animal models of endothelial dysfunction and oxidative stress, with half of the animals receiving ivabradine 10 mg/kg/day in parallel. Ivabradine lead to a sustained 15-20% heart rate reduction, but had no effect on blood pressure. While ivabradine had no effect on endothelial function and vascular reactive oxygen species production in angiotensin II-treated rats, it improved both parameters in ApoE knockout mice. These antioxidative effects were associated with a decreased NADPH oxidase activity and the prevention of eNOS uncoupling. In addition, ivabradine treatment led to an attenuation of angiotensin II signaling and increased the expression of telomere-stabilizing proteins in ApoE knockout mice, which may explain its beneficial effects on the vasculature. The absence of these protective ivabradine effects in angiotensin II-infused rats may relate to the treatment duration or the presence of arterial hypertension.

• Endothelial function assessment: flow-mediated dilation and constriction provide different and complementary information on the presence of coronary artery disease.

  Authors: Tommaso Gori, Selina Muxel, Ana Damaske, Marie-Christine Radmacher, Federica Fasola, Sarina Schaefer, Andreas Schulz, Alexander Jabs, John D Parker, Thomas Münzel

  European heart journal. 09/2011; 33(3):363-71.

  A number of risk factors for atherosclerosis have been identified, but it remains difficult, on an individual patient basis, to predict how these factors interact in determining the development ofA number of risk factors for atherosclerosis have been identified, but it remains difficult, on an individual patient basis, to predict how these factors interact in determining the development of coronary artery disease (CAD). It also remains unclear whether the study of endothelial function provides information that is additive to that of traditional risk factors. Flow-mediated dilation (FMD) and low-flow-mediated constriction (L-FMC) were measured in 451 consecutive patients before coronary angiography. Low-flow-mediated constriction (P< 0.0001) and FMD (P=0.0005) progressively decreased with the number of diseased vessels, and L-FMC showed a significant linear correlation with the SYNTAX score (R=0.38; P< 0.0001). Logistic regression analysis confirmed the association between endothelial function parameters and CAD (P=0.001 for L-FMC, P=0.02 for FMD). Receiver operating characteristic analysis demonstrated that the addition of L-FMC alone and of the combination of FMD and L-FMC improved the predictive power of a model based on traditional risk factors for CAD (area under the curve of the risk factor model=0.716; risk factor model + FMD=0.734, P=0.1 compared with risk factor model; risk factor model + L-FMC=0.771, P=0.004; risk factor model + L-FMC + FMD=0.779, P=0.002). Reclassification statistics showed that the introduction of FMD to the model based on the traditional risk factors correctly reclassified an additional 5% of patients, and that the introduction of L-FMC net correctly reclassified 19% of the patients. There was no correlation between different parameters of endothelial function. Endothelial function assessment provides modest but statistically significant additional information in predicting the presence of CAD.

• Changes in endothelial function in healthy volunteers during soccer World Cup 2010 games.

  Authors: Selina Muxel, Marie Christine Radmacher, Sarina Schäfer, Ana Damaske, Thomas Münzel, Tommaso Gori

  International journal of cardiology. 09/2011; 152(3):395-6.

• Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque.

  Authors: Joshua C Bis, Maryam Kavousi, Nora Franceschini, Aaron Isaacs, Gonçalo R Abecasis, Ulf Schminke, Wendy S Post, Albert V Smith, L Adrienne Cupples, Hugh S Markus [......] Stefan Blankenberg, Anne B Newman, Jacqueline Witteman, Gerardo Heiss, Cornelia van Duijn, Angelo Scuteri, Georg Homuth, Braxton D Mitchell, Vilmundur Gudnason, Christopher J O'Donnell

  Nature genetics. 09/2011; 43(10):940-7.

  Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. WeCarotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10(-8)). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events.

• Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

  Authors: Georg B Ehret, Patricia B Munroe, Kenneth M Rice, Murielle Bochud, Andrew D Johnson, Daniel I Chasman, Albert V Smith, Martin D Tobin, Germaine C Verwoert, Shih-Jen Hwang [......] P H Maxwell, M I McCarthy, M R Jarvelin, V Mooser, G R Abecasis, L Lightstone, J Scott, G Navis, P Elliott, J S Kooner

  Nature. 09/2011; 478(7367):103-9.

  Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic bloodBlood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

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• Lysozyme M-positive monocytes mediate angiotensin II-induced arterial hypertension and vascular dysfunction.

  Authors: Philip Wenzel, Maike Knorr, Sabine Kossmann, Jan Stratmann, Michael Hausding, Swenja Schuhmacher, Susanne H Karbach, Melanie Schwenk, Nir Yogev, Eberhard Schulz, Matthias Oelze, Stephan Grabbe, Helmut Jonuleit, Christian Becker, Andreas Daiber, Ari Waisman, Thomas Münzel

  Circulation. 08/2011; 124(12):1370-81.

  BACKGROUND: Angiotensin II (ATII), a potent vasoconstrictor, causes hypertension, promotes infiltration of myelomonocytic cells into the vessel wall, and stimulates both vascular and inflammatoryBACKGROUND: Angiotensin II (ATII), a potent vasoconstrictor, causes hypertension, promotes infiltration of myelomonocytic cells into the vessel wall, and stimulates both vascular and inflammatory cell NADPH oxidases. The predominant source of reactive oxygen species, eg, vascular (endothelial, smooth muscle, adventitial) versus phagocytic NADPH oxidase, and the role of myelomonocytic cells in mediating arterial hypertension have not been defined yet. METHODS AND RESULTS: Angiotensin II (1 mg · kg(-1) · d(-1) for 7 days) increased the number of both CD11b(+)Gr-1(low)F4/80(+) macrophages and CD11b(+)Gr-1(high)F4/80(-) neutrophils in mouse aorta (verified by flow cytometry). Selective ablation of lysozyme M-positive (LysM(+)) myelomonocytic cells by low-dose diphtheria toxin in mice with inducible expression of the diphtheria toxin receptor (LysM(iDTR) mice) reduced the number of monocytes in the circulation and limited ATII-induced infiltration of these cells into the vascular wall, whereas the number of neutrophils was not reduced. Depletion of LysM(+) cells attenuated ATII-induced blood pressure increase (measured by radiotelemetry) and vascular endothelial and smooth muscle dysfunction (assessed by aortic ring relaxation studies) and reduced vascular superoxide formation (measured by chemiluminescence, cytochrome c assay, and oxidative fluorescence microtopography) and the expression of NADPH oxidase subunits gp91(phox) and p67(phox) (assessed by Western blot and mRNA reverse-transcription polymerase chain reaction). Adoptive transfer of wild-type CD11b(+)Gr-1(+) monocytes into depleted LysM(iDTR) mice reestablished ATII-induced vascular dysfunction, oxidative stress, and arterial hypertension, whereas transfer of CD11b(+)Gr-1(+) neutrophils or monocytes from gp91(phox) or ATII receptor type 1 knockout mice did not. CONCLUSIONS- Infiltrating monocytes with a proinflammatory phenotype and macrophages rather than neutrophils appear to be essential for ATII-induced vascular dysfunction and arterial hypertension.

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