Siegfried Lang

Publications of Siegfried Lang

• Tackling myocardial metabolism: One year evaluation of free fatty acids, norephinephrine and NT-proBNP in ventricular fibrillation during STEMI.

  Authors: Michael Behnes, Thorsten Kälsch, Siegfried Lang, Tim Süselbeck, Martin Borggrefe, Elif Elmas

  International journal of cardiology. 01/2012; 155(2):291-3.

• Simvastatin and atorvastatin attenuate VCAM-1 and uPAR expression on human endothelial cells and platelet surface expression of CD40 ligand.

  Authors: Ksenija Stach, Xuan Duc Nguyen, Siegfried Lang, Elif Elmas, Christel Weiss, Martin Borggrefe, Joachim Fischer, Thorsten Kälsch

  Cardiology journal. 01/2012; 19(1):20-8.

  In addition to their cholesterol lowering ability, statins have proven pleiotropic effects in the cardiovascular system. Chronic inflammation with interactions between platelets and endothelial cellsIn addition to their cholesterol lowering ability, statins have proven pleiotropic effects in the cardiovascular system. Chronic inflammation with interactions between platelets and endothelial cells leads to an upregulation of activity markers of atherosclerosis. The purpose of this study was to investigate the effects of simvastatin and atorvastatin on platelets and endothelial cells in an in vitro endothelial cell model. After a 24 h incubation period with either simvastatin or atorvastatin (1 μmol/L), human umbilical vein endothelial cells were stimulated for 1 h with lipopolysaccharide (LPS), and were then incubated in direct contact with activated platelets. Platelet surface expression of CD40L and CD62P and expression of ICAM-1, VCAM-1, uPAR and MT1-MMP on endothelial cells were measured by flow cytometry. Supernatants were analyzed by ELISA for soluble MMP-1. The increased expression of VCAM-1 and uPAR on endothelial cells by stimulation with LPS and by direct contact with activated platelets was significantly reduced to a similar extent through pre-incubation with both atorvastatin and simvastatin (p < 0.05). Platelets without endothelial cell contact, but in direct contact with either statin, showed similar significant reductions in surface expression of CD40L (p < 0.005). These effects may explain the ability of statins to reduce the progression of atherosclerosis in addition to their cholesterol-lowering properties.

• p45NF-E2 represses Gcm1 in trophoblast cells to regulate syncytium formation, placental vascularization and embryonic growth.

  Authors: Muhammed Kashif, Andrea Hellwig, Alexandre Kolleker, Khurrum Shahzad, Hongjie Wang, Siegfried Lang, Juliane Wolter, Madhusudhan Thati, Ilya Vinnikov, Angelika Bierhaus, Peter P Nawroth, Berend Isermann

  Development (Cambridge, England). 06/2011; 138(11):2235-47.

  Absence of the leucine zipper transcription factor p45NF-E2 results in thrombocytopenia, impaired placental vascularization and intrauterine growth restriction (IUGR) in mice. The mechanismAbsence of the leucine zipper transcription factor p45NF-E2 results in thrombocytopenia, impaired placental vascularization and intrauterine growth restriction (IUGR) in mice. The mechanism underlying the p45NF-E2-dependent placental defect and IUGR remains unknown. Here, we show that the placental defect and IUGR of p45NF-E2 (Nfe2) null mouse embryos is unrelated to thrombocytopenia, establishing that embryonic platelets and platelet-released mediators are dispensable for placentation. Rather, p45NF-E2, which was hitherto thought to be specific to hematopoietic cells, is expressed in trophoblast cells, where it is required for normal syncytiotrophoblast formation, placental vascularization and embryonic growth. Expression of p45NF-E2 in labyrinthine trophoblast cells colocalizes with that of Gcm1, a transcription factor crucial for syncytiotrophoblast formation. In the absence of p45NF-E2, the width of syncytiotrophoblast layer 2 and the expression of Gcm1 and Gcm1-dependent genes (Synb and Cebpa) are increased. In vitro, p45NF-E2 deficiency results in spontaneous syncytiotrophoblast formation, which can be reversed by Gcm1 knockdown. Increased Gcm1 expression in the absence of p45NF-E2 is dependent on enhanced protein acetylation, including post-translational modification of Gcm1. Increasing and inhibiting acetylation in the placenta of wild-type control embryos phenocopies and corrects, respectively, the changes observed in p45NF-E2-deficient embryos. These studies identify a novel function of p45NF-E2 during placental development: in trophoblast cells, p45NF-E2 represses Gcm1 and syncytiotrophoblast formation via acetylation.

• Midregional pro-atrial natriuretic peptide: a novel marker of myocardial fibrosis in patients with hypertrophic cardiomyopathy.

  Authors: Elif Elmas, Christina Doesch, Stephan Fluechter, Miriam Freundt, Christel Weiss, Siegfried Lang, Thorsten Kälsch, Dariush Haghi, Jana Papassotiriou, Jan Kunde, Stefan O Schoenberg, Martin Borggrefe, Theano Papavassiliu

  The international journal of cardiovascular imaging. 04/2011; 27(4):547-56.

  We aimed to determine the diagnostic performance of biomarkers in predicting myocardial fibrosis assessed by late gadolinium enhancement (LGE) cardiovascular magnetic resonance imaging (CMR) inWe aimed to determine the diagnostic performance of biomarkers in predicting myocardial fibrosis assessed by late gadolinium enhancement (LGE) cardiovascular magnetic resonance imaging (CMR) in patients with hypertrophic cardiomyopathy (HCM). LGE CMR was performed in 40 consecutive patients with HCM. Left and right ventricular parameters, as well as the extent of LGE were determined and correlated to the plasma levels of midregional pro-atrial natriuretic peptide (MR-proANP), midregional pro-adrenomedullin (MR-proADM), carboxy-terminal pro-endothelin-1 (CT-proET-1), carboxy-terminal pro-vasopressin (CT-proAVP), matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1) and interleukin-8 (IL-8). Myocardial fibrosis was assumed positive, if CMR indicated LGE. LGE was present in 26 of 40 patients with HCM (65%) with variable extent (mean: 14%, range: 1.3-42%). The extent of LGE was positively associated with MR-proANP (r = 0.4; P = 0.01). No correlations were found between LGE and MR-proADM (r = 0.1; P = 0.5), CT-proET-1 (r = 0.07; P = 0.66), CT-proAVP (r = 0.16; P = 0.3), MMP-9 (r = 0.01; P = 0.9), TIMP-1 (r = 0.02; P = 0.85), and IL-8 (r = 0.02; P = 0.89). After adjustment for confounding factors, MR-proANP was the only independent predictor associated with the presence of LGE (P = 0.007) in multivariate analysis. The area under the ROC curve (AUC) indicated good predictive performance (AUC = 0.882) of MR-proANP with respect to LGE. The odds ratio was 1.268 (95% confidence interval 1.066-1.508). The sensitivity of MR-proANP at a cut-off value of 207 pmol/L was 69%, the specificity 94%, the positive predictive value 90% and the negative predictive value 80%. The results imply that MR-proANP serves as a novel marker of myocardial fibrosis assessed by LGE CMR in patients with HCM.

• Platelet and monocyte activity markers and mediators of inflammation in Takotsubo cardiomyopathy.

  Authors: Rainer Pirzer, Elif Elmas, Dariusch Haghi, Christiane Lippert, Stefan Kralev, Siegfried Lang, Martin Borggrefe, Thorsten Kälsch

  Heart and vessels. 03/2011;

  Patients with Takotsubo cardiomyopathy (TC) often present with symptoms similar to those of myocardial infarction (MI). We analyzed blood concentrations of mediators of inflammation and platelet- andPatients with Takotsubo cardiomyopathy (TC) often present with symptoms similar to those of myocardial infarction (MI). We analyzed blood concentrations of mediators of inflammation and platelet- and monocyte-activity markers in patients with TC and MI for significant differences. Clinical data of patients with TC (n = 16) and acute MI (n = 16) were obtained. Serial blood samples were taken at the time of hospital admission (t (0)), after 2-4 days (t (1)) and after 4-7 weeks (t (2)), respectively. Plasma concentrations of interleukin (IL)-6, IL-7, soluble CD40 ligand (sCD40L), and monocyte chemotactic protein 1 (MCP-1) were determined with an ELISA. Tissue factor binding on monocytes, platelet-activation marker CD62P, platelet CD40-ligand (CD40L), and platelet-monocyte aggregates were measured using flow cytometry. Expression of CD62P on platelets and IL-6 plasma levels were significantly lower in patients with TC compared to MI at the time of hospital admission. IL-7 plasma levels were significantly elevated in patients with TC compared to patients with MI at 2-4 days after hospital admission. No significant differences were observed concerning sCD40L and MCP-1 plasma levels, tissue factor binding on monocytes, CD40L expression on platelets, and platelet-monocyte aggregates at any point in time. Our results indicate that inflammatory mediators and platelet-activity markers contribute to the differences in the pathogenesis of MI and TC.

• Incidence and severity of coronary artery disease in patients with atrial fibrillation undergoing first-time coronary angiography.

  Authors: Stefan Kralev, Kathrin Schneider, Siegfried Lang, Tim Süselbeck, Martin Borggrefe

  PloS one. 01/2011; 6(9):e24964.

  In standard reference sources, the incidence of coronary artery disease (CAD) in patients with atrial fibrillation (AF) ranged between 24 and 46.5%. Since then, the incidence of cardiovascular riskIn standard reference sources, the incidence of coronary artery disease (CAD) in patients with atrial fibrillation (AF) ranged between 24 and 46.5%. Since then, the incidence of cardiovascular risk factors (CRF) has increased and modern treatment strategies ("pill in the pocket") are only applicable to patients without structural heart disease. The aim of this study was to investigate the incidence and severity of CAD in patients with AF. From January 2005 until December 2009, we included 261 consecutive patients admitted to hospital with paroxysmal, persistent or permanent AF in this prospective study. All patients underwent coronary angiography and the Framingham risk score (FRS) was calculated. Patients with previously diagnosed or previously excluded CAD were excluded. The overall incidence of CAD in patients presenting with AF was 34%; in patients >70 years, the incidence of CAD was 41%. The incidence of patients undergoing a percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) was 21%. Patients with CAD were older (73±8 years vs 68±10 years, p = 0.001), had significantly more frequent hypercholesterolemia (60% vs 30%, p<0.001), were more frequent smokers (26% vs 13%, p = 0.017) and suffered from angina more often (37% vs 2%, p<0.001). There was a significant linear trend among the FRS categories in percentage and the prevalence of CAD and PCI/CABG (p<0.0001). The overall incidence of CAD in patients presenting with AF was relatively high at 34%; the incidence of PCI/CABG was 21%. Based upon increasing CRF in the western world, we recommend a careful investigation respecting the FRS to either definitely exclude or establish an early diagnosis of CAD--which could contribute to an early and safe therapeutic strategy considering type Ic antiarrhythmics and oral anticoagulation.

• Expansion of the Multi-Link Frontier™ coronary bifurcation stent: micro-computed tomographic assessment in human autopsy and porcine heart samples.

  Authors: Stefan Kralev, Benjamin Haag, Jens Spannenberger, Siegfried Lang, Marc A Brockmann, Soenke Bartling, Alexander Marx, Karl-Konstantin Haase, Martin Borggrefe, Tim Süselbeck

  PloS one. 01/2011; 6(7):e21778.

  Treatment of coronary bifurcation lesions remains challenging, beyond the introduction of drug eluting stents. Dedicated stent systems are available to improve the technical approach to the treatmentTreatment of coronary bifurcation lesions remains challenging, beyond the introduction of drug eluting stents. Dedicated stent systems are available to improve the technical approach to the treatment of these lesions. However dedicated stent systems have so far not reduced the incidence of stent restenosis. The aim of this study was to assess the expansion of the Multi-Link (ML) Frontier™ stent in human and porcine coronary arteries to provide the cardiologist with useful in-vitro information for stent implantation and selection. Nine ML Frontier™ stents were implanted in seven human autopsy heart samples with known coronary artery disease and five ML Frontier™ stents were implanted in five porcine hearts. Proximal, distal and side branch diameters (PD, DD, SBD, respectively), corresponding opening areas (PA, DA, SBA) and the mean stent length (L) were assessed by micro-computed tomography (micro-CT). PD and PA were significantly smaller in human autopsy heart samples than in porcine heart samples (3.54±0.47 mm vs. 4.04±0.22 mm, p = 0.048; 10.00±2.42 mm(2) vs. 12.84±1.38 mm(2), p = 0.034, respectively) and than those given by the manufacturer (3.54±0.47 mm vs. 4.03 mm, p = 0.014). L was smaller in human autopsy heart samples than in porcine heart samples, although data did not reach significance (16.66±1.30 mm vs. 17.30±0.51 mm, p = 0.32), and significantly smaller than that given by the manufacturer (16.66±1.30 mm vs. 18 mm, p = 0.015). Micro-CT is a feasible tool for exact surveying of dedicated stent systems and could make a contribution to the development of these devices. The proximal diameter and proximal area of the stent system were considerably smaller in human autopsy heart samples than in porcine heart samples and than those given by the manufacturer. Special consideration should be given to the stent deployment procedure (and to the follow-up) of dedicated stent systems, considering final intravascular ultrasound or optical coherence tomography to visualize (and if necessary optimize) stent expansion.

• 1α,25-dihydroxyvitamin D3 attenuates platelet activation and the expression of VCAM-1 and MT1-MMP in human endothelial cells.

  Authors: Ksenija Stach, Anna-Isabelle Kälsch, Xuan Duc Nguyen, Elif Elmas, Stefan Kralev, Siegfried Lang, Christel Weiss, Martin Borggrefe, Thorsten Kälsch

  Cardiology. 01/2011; 118(2):107-15.

  Inflammatory conditions contribute to increased expression of various activity markers in platelets and endothelial cells, leading to atherosclerotic changes in the vascular wall. The objective ofInflammatory conditions contribute to increased expression of various activity markers in platelets and endothelial cells, leading to atherosclerotic changes in the vascular wall. The objective of this study was to investigate possible protective effects of 1α,25-dihydroxyvitamin D3 in an endothelial cell model. After a 24-hour incubation with 1α,25-dihydroxyvitamin D3, human umbilical vein endothelial cells were stimulated with lipopolysaccharide (LPS) and incubated in direct contact with platelets. The expression of CD40L and CD62P in platelets, the expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1 (VCAM-1), the urokinase receptor uPAR and membrane type 1 matrix metalloproteinase (MT1-MMP) in endothelial cells and endothelial cell reactive oxygen species generation were measured by flow cytometry. Endothelial nitric oxide synthase was analyzed by Western blot. The increased expression of VCAM-1 and MT1-MMP in endothelial cells by proinflammatory stimulation with LPS and by direct contact with activated platelets was significantly reduced through preincubation with 1α,25-dihydroxyvitamin D3. Platelets in direct contact with preincubated endothelial cells showed significantly reduced CD62P expression when compared to platelets incubated with untreated endothelial cells. 1α,25-Dihydroxyvitamin D3 attenuates platelet activation and the expression of VCAM-1 and MT1-MMP in human endothelial cells and could have early therapeutic relevance in atherosclerotic diseases.

• Transforming growth factor beta 1 (TGF-beta 1) in atrial fibrillation and acute congestive heart failure.

  Authors: Michael Behnes, Ursula Hoffmann, Siegfried Lang, Christel Weiss, Parviz Ahmad-Nejad, Michael Neumaier, Martin Borggrefe, Martina Brueckmann

  Clinical research in cardiology : official journal of the German Cardiac Society. 11/2010; 100(4):335-42.

  Atrial fibrillation (AF) and acute congestive heart failure (aCHF) are characterized by an adverse cardiac remodeling. Arrhythmogenic or structural remodeling can be caused by interstitial fibrosis.Atrial fibrillation (AF) and acute congestive heart failure (aCHF) are characterized by an adverse cardiac remodeling. Arrhythmogenic or structural remodeling can be caused by interstitial fibrosis. Transforming growth factor beta 1 (TGF-beta 1) represents a central regulator of cardiac fibrosis. This study investigates serum levels of TGF-beta 1 in patients with AF and aCHF. 401 patients presenting with symptoms of dyspnea or peripheral edema were prospectively enrolled. Blood samples for measurement of TGF-beta 1 (R&D Systems, Inc.) and amino-terminal pro-brain natriuretic peptide (NT-proBNP) (DadeBehring ltd.) were collected after the initial clinical evaluation. Median TGF-beta 1 levels were lower in patients with AF (21.0 ng/ml, interquartile range (IR) 15.4-27.6 ng/ml, n = 107) compared to those without (25.0 ng/ml, IR 18.5-31.6 ng/ml, n = 294) (p = 0.009). Patients with aCHF had lower TGF-beta 1 levels (median 22.0 ng/ml, IR 15.6-27.1 ng/ml, n = 122) than those without (median 24.9 ng/ml, IR 18.1-31.9 ng/ml, n = 279) (p = 0.0005). In logistic regression models TGF-beta 1 was still associated with AF (odds ratio (OR) 3.00, 95% CI 1.37-6.61, p = 0.0001) and aCHF (OR 3.98, 95% CI 1.55-10.19, p = 0.004). TGF-beta 1 inversely correlated with left atrial diameter (r = -0.30, p = 0.007) and NT-proBNP (r = -0.14, p = 0.007). Low serum levels of TGF-beta 1 are associated with AF and aCHF. This decrease may result from a higher consumption of TGF-beta 1 within the impaired myocardium or antifibrotic functions of natriuretic peptides.

• The P-selectin gene polymorphism Val168Met: a novel risk marker for the occurrence of primary ventricular fibrillation during acute myocardial infarction.

  Authors: Elif Elmas, Peter Bugert, Tatjana Popp, Siegfried Lang, Christel Weiss, Michael Behnes, Martin Borggrefe, Thorsten Kälsch

  Journal of cardiovascular electrophysiology. 11/2010; 21(11):1260-5.

  The P-Selectin Gene Polymorphism Val168Met. Ventricular fibrillation (VF) in the setting of acute myocardial infarction (AMI) is the leading cause of sudden cardiac death (SCD). Family history of SCDThe P-Selectin Gene Polymorphism Val168Met. Ventricular fibrillation (VF) in the setting of acute myocardial infarction (AMI) is the leading cause of sudden cardiac death (SCD). Family history of SCD is described as risk factor for primary VF during acute AMI. Genetic factors may be associated with primary VF. We examined polymorphisms in genes related to the activation and adhesion of blood platelets in patients with and without VF in the setting of AMI and among healthy controls. Two hundred and forty patients with a history of AMI and 475 healthy controls were studied. Seventy-three patients (30%) had primary VF during AMI. By using PCR techniques with sequence-specific primers (PCR-SSP), we genotyped 5 single nucleotide polymorphisms (SNPs) in P-selectin (SELP) (V168M, S290N, N592D, V599L, T715P), 2 SNPs (M62I, S273F) in P-selectin glycoprotein ligand-1 (SELPLG), 5 SNPs in CD40LG (-3459A>G, -122A>C, -123A>C, 148T>C, intr4-13T>C), the H558R SNP in SCN5A, and rs2106261 in ZFHX3. In addition, length polymorphisms in SELPLG (36bp-tandem repeat) and CD40LG (CA-repeat) were genotyped by PCR methods. Results were evaluated by 2-sided t-tests, chi-square tests, and logistic regression analysis. None of the gene polymorphisms showed significant differences between AMI patients and healthy controls. Among patients with a history of VF, however, the SELP 168M variant showed a significantly higher prevalence (14/73 patients; 19.2%) as compared with patients without VF (13/167 patients; 7.8%; P < 0.01). This association remained significant in a logistic regression analysis after adjustment for age and gender (P = 0.013; odds ratio 2.8; 95% confidence interval 1.2-6.3). This is the first description of an association of the SELP gene variant 168M with primary VF during acute MI. This variant may be a candidate polymorphism for evaluating the susceptibility for VF in the setting of acute MI.

• Sex-based differences in clinical and angiographic outcomes in patients with ST-elevation myocardial infarction treated with concomitant use of glycoprotein IIb/IIIa inhibitors.

  Authors: Stefan Kralev, Oliver Hennig, Siegfried Lang, Thorsten Kälsch, Martin Borggrefe, Carl-Erik Dempfle, Tim Süselbeck

  Cardiology journal. 01/2010; 17(6):580-6.

  The widespread use of primary coronary intervention (PCI) has significantly improved the prognosis of men presenting with acute coronary syndromes, but the cardiovascular event rate among women hasThe widespread use of primary coronary intervention (PCI) has significantly improved the prognosis of men presenting with acute coronary syndromes, but the cardiovascular event rate among women has either levelled off or increased. The purpose of the present prospective study was to compare the clinical outcome of women and men presenting with ST-elevation myocardial infarction (STEMI) undergoing primary PCI with concomitant usage of GP IIb/IIIa inhibitors. Between January 2006 and December 2007, 297 consecutive patients presenting with STEMI were prospectively included in this single center investigation. Overall, 82 (27.6%) women and 215 (72.4%) men were treated by PCI with additional bare metal stent implantation and a GP IIb/IIIa inhibitor. Women were significantly older (65 ± 10 vs 60 ± 12 years, p = 0.04), presented with a smaller reference luminal diameter (2.83 ± 0.51 vs 2.94 ± 0.43, p = 0.03) and had a higher prevalence of hypertension (68% vs 53%, p = 0.025) and obesity (30% vs 18%, p = 0.03). The incidence of major adverse cardiac events (MACE, defined as death, re-myocardial infarction, target lesion revascularization and coronary artery bypass graft) during long-term follow-up was similar in women and men (20% vs 26%, p = 0.29). Age, C-reactive protein, platelet count and cardiogenic shock were identified as independent predictors for MACE, whereas gender was not predictive. In this study, female gender did not emerge as an independent predictor for MACE, but women presenting with STEMI had a higher cardiovascular risk profile; this emphasizes the need for a more extensive therapeutic strategy. Combination therapy with primary PCI and GP IIb/IIIa inhibitors might mitigate gender-related differences in clinical outcomes.

• Effect of atorvastatin on haemostasis, fibrinolysis and inflammation in normocholesterolaemic patients with coronary artery disease: a post hoc analysis of data from a prospective, randomized, double-blind study.

  Authors: Thomas Walter, Sebastian Szabo, Tim Suselbeck, Martin Borggrefe, Siegfried Lang, Stefanie Swoboda, Hans Martin Hoffmeister, Carl-Erik Dempfle

  Clinical drug investigation. 01/2010; 30(7):453-60.

  Treatment with HMG-CoA reductase inhibitors (statins) reduces the morbidity and mortality of coronary artery disease (CAD). In addition to their lipid-lowering actions, pleiotropic effects of statinsTreatment with HMG-CoA reductase inhibitors (statins) reduces the morbidity and mortality of coronary artery disease (CAD). In addition to their lipid-lowering actions, pleiotropic effects of statins have been demonstrated. The aim of the present study was to assess if atorvastatin therapy has an impact on haemostasis, fibrinolysis and inflammation in normocholesterolaemic patients with CAD. Fifty-four patients with CAD who had received atorvastatin treatment for at least 8 weeks (mean dosage 30 mg/day) and 54 patients with CAD who had not received atorvastatin therapy were selected from a larger prospective, randomized, double-blind study for inclusion in this post hoc analysis. Patients were matched by their total cholesterol levels. All patients were normocholesterolaemic. In the atorvastatin-treated patients significantly lower plasma levels of thrombin-antithrombin complexes (p < 0.05), plasminogen activator inhibitor-1 activity (PAI-1) [p < 0.05], soluble vascular cell adhesion molecule-1 (p < 0.05), soluble platelet selectin (p < 0.05) and high-sensitivity C-reactive protein (p < 0.05) were measured compared with patients not on atorvastatin therapy. Additionally, a strong trend towards lower soluble intercellular adhesion molecule-1 plasma levels was detected in patients treated with atorvastatin. No differences were found in tissue-type plasminogen activator antigen, plasmin-plasmin inhibitor complexes, fibrinogen, D-dimer and activated factor XII values. Atorvastatin appears to have an effect on coagulation activation, fibrinolysis and inflammation in patients with CAD. Reduction in PAI-1 and reduced thrombin formation may have an impact on cardiovascular morbidity and mortality in patients with CAD.

• Comparison of long-term prognostic value of N-terminal-proBNP and midregional-pro-adrenomedullin in patients with acute myocardial infarction.

  Authors: Thomas Walter, Martina Brueckmann, Siegfried Lang, Tamara Sauer, Esther Fiedler, Jana Papassotiriou, Michael Behnes, Elif Elmas, Martin Borggrefe, Thomas Bertsch

  Clinical laboratory. 01/2010; 56(7-8):303-9.

  N-terminal-proBNP (NT-proBNP) and Midregional-pro-Adrenomedullin (MR-proADM) predict mortality of patients with acute myocardial infarction (AMI). Comparison of the prognostic values of NT-proBNP andN-terminal-proBNP (NT-proBNP) and Midregional-pro-Adrenomedullin (MR-proADM) predict mortality of patients with acute myocardial infarction (AMI). Comparison of the prognostic values of NT-proBNP and MR-proADM to predict long-term adverse clinical events (AE) after AMI has not been evaluated yet. 30 patients with AMI were enrolled into this prospective study. Measurements of NT-proBNP and MR-proADM were performed at initial presentation, two or three days and four months after AMI. Long-term AE defined as recurrent AMI, need for repeated percutaneous transluminal angioplasty or coronary bypass graft surgery, congestive heart failure, cardiopulmonary resuscitation, cardiogenic shock, syncope, and death were documented during a follow-up period of ten months. At initial presentation, NT-proBNP values were significantly higher in patients with AE compared to patients without AE (p < 0.05). The area under the ROC curve (AUC) indicated good predictive performance of NT-proBNP (AUC 0.78, 95% CI 0.59-0.91, p = 0.003) and MR-proADM (AUC 0.71, 95% CI 0.51-0.86, p = 0.046) regarding AE. Comparing both AUC revealed no differences between NT-proBNP and MR-proADM as predictors of AE (p = 0.59). Patients with NT-proBNP levels > or = 370 pg/mL were more likely to suffer from AE than patients with lower levels (relative risk 6.7, 95% CI 1.0-46, p = 0.018). With this cutoff, NT-proBNP could exclude AE with a negative predictive value of 92% being similar to MR-proADM (negative predictive value 76%, relative risk 2.8, 95% CI 1.2-6.9, p = 0.042). Early measurements of NT-proBNP or MR-proADM during the acute phase of AMI may allow the risk of a long-term AE to be excluded, based on the comparable test characteristics,.

• Sudden death: Do cytokines and prothrombotic peptides contribute to the occurrence of ventricular fibrillation during acute myocardial infarction?

  Authors: Elif Elmas, Tatjana Popp, Siegfried Lang, Carl-Erik Dempfle, Thorsten Kälsch, Martin Borggrefe

  International journal of cardiology. 07/2009;

  AIMS: Sudden cardiac death (SCD) is frequently caused by ventricular fibrillation (VF) occurring in the course of acute myocardial infarction (AMI). It has not been investigated yet, to what extentAIMS: Sudden cardiac death (SCD) is frequently caused by ventricular fibrillation (VF) occurring in the course of acute myocardial infarction (AMI). It has not been investigated yet, to what extent markers of coagulation activation and inflammation differ between patients with and without VF in the acute phase of AMI.

• Clinical outcome of patients with diabetes presenting with ST-elevation myocardial infarction and treated with concomitant use of glycoprotein IIb/IIIa inhibitors.

  Authors: Stefan Kralev, Barbara Krause, Theano Papavassiliu, Siegfried Lang, Dariusch Haghi, Thorsten Kälsch, Carl-Erik Dempfle, Martin Borggrefe, Tim Süselbeck

  Cardiology journal. 02/2009; 16(3):234-40.

  BACKGROUND: Percutaneous coronary intervention (PCI) with stent implantation is considered to be the standard treatment in patients presenting with ST-elevation myocardial infarction (STEMI).BACKGROUND: Percutaneous coronary intervention (PCI) with stent implantation is considered to be the standard treatment in patients presenting with ST-elevation myocardial infarction (STEMI). According to the American Heart Association (AHA)/American College of Cardiology (ACC) guidelines for STEMI, there is a class IIa recommendation (treatment reasonable) for platelet glycoprotein (GP) IIb/IIIa inhibitors. This study aims to compare the clinical outcome of patients with and without diabetes, presenting with STEMI undergoing primary PCI with concomitant usage of GP IIb/IIIa inhibitors in real clinical practice. METHODS: Over the course of three years (2004-2006) 394 consecutive patients presenting with STEMI were included in this single centre experience. There were 95 patients (24%) with, and 299 patients (76%) without, diabetes. A GP IIb/IIIa inhibitor was administered to all patients without contraindications (316 patients, 80%). RESULTS: Patients with diabetes were significantly older, more often suffered from hypertension and had a higher incidence of obesity. The rate of administration of GP IIb/IIIa inhibitors was similar in both groups (74% vs. 82%, p = 0.14). The in-hospital incidence of major adverse cardiac events (MACE, defined as death, re-myocardial infarction, target lesion revascularisation and coronary artery bypass graft) was similar in both patient groups (18 [19%] diabetics vs. 51 [17%] non-diabetics, p = 0.65). Hypertension, age and obesity were identified as predictors for MACE, whereas diabetes was not predictive. CONCLUSIONS: In this single centre experience, in diabetic and non-diabetic patients presenting with STEMI, combination therapy with primary PCI and GP IIb/IIIa inhibitors might have contributed to a similar clinical outcome.

• Levels of oxidized low-density lipoproteins are increased in patients with severe sepsis.

  Authors: Michael Behnes, Martina Brueckmann, Volker Liebe, Claudia Liebetrau, Siegfried Lang, Christian Putensen, Martin Borggrefe, Ursula Hoffmann

  Journal of critical care. 01/2009; 23(4):537-41.

  BACKGROUND: It was hypothesized that the inflammatory response of patients with severe sepsis may result in changes of plasma levels of oxidized low-density lipoproteins (ox-LDLs) and thatBACKGROUND: It was hypothesized that the inflammatory response of patients with severe sepsis may result in changes of plasma levels of oxidized low-density lipoproteins (ox-LDLs) and that drotrecogin alpha (activated) (DAA) (Xigris, Eli Lilly and Company [Indiana 46285, USA]) may influence ox-LDL levels. MATERIALS AND METHODS: The ox-LDL levels were measured in severe septic patients on day 1, 4, and 7 of severe sepsis. Patients were treated either with or without DAA. RESULTS: The ox-LDL levels increased significantly (P < .05) from day 1 to day 7 (day 1, mean +/- SEM, 25.4 +/- 1.8 U/L; day 4, mean +/- SEM, 34.3 +/- 2.1 U/L; day 7, mean +/- SEM, 38.3 +/- 2.1 U/L) in all patients (n = 68). The ox-LDL levels increased significantly from day 1 to day 7 both in patients treated with (n = 31) and without DAA (n = 37) (P < .001) (DAA-group: day 1, mean +/- SEM, 24.4 +/- 2.8 U/L; day 4, mean +/- SEM, 35.5 +/- 2.9 U/L; day 7, mean +/- SEM, 40.7 +/- 3.2 U/L) (control group: day 1, mean +/- SEM, 26.3 +/- 2.8 U/L; day 4, mean +/- SEM, 33.2 +/- 2.9 U/L; day 7, mean +/- SEM, 36.4 +/- 2.9 U/L). No significant differences of ox-LDL levels were observed between both groups at any point of time (P > .05). CONCLUSIONS: The ox-LDL concentrations increase significantly during the first week of severe sepsis and are not affected by administration of drotrecogin alpha (activated) (Xigris).

• Elevation of the glycoxidation product N(epsilon)-(carboxymethyl)lysine in patients presenting with acute myocardial infarction.

  Authors: Stefan Kralev, Elke Zimmerer, Martina Brueckmann, Siegfried Lang, Thorsten Kälsch, Anja Rippert, Jihong Lin, Martin Borggrefe, Hans-Peter Hammes, Tim Süselbeck

  Clinical chemistry and laboratory medicine : CCLM / FESCC. 01/2009; 47(4):446-51.

  Abstract Background: An important role in the acceleration of vascular disease has been previously suggested for advanced glycation end products. N(epsilon)-(carboxymethyl)lysine (CML) is an advancedAbstract Background: An important role in the acceleration of vascular disease has been previously suggested for advanced glycation end products. N(epsilon)-(carboxymethyl)lysine (CML) is an advanced glycation end product formed on protein by combined non-enzymatic glycation and glycoxidation reactions. CML reacts with the receptor of advanced glycation end products inducing impairment of endothelium dependent relaxation and is a marker of oxidative stress. Methods: A total of 40 patients with acute myocardial infarction (17 patients with ST-elevation myocardial infarction, 23 patients with non-ST-elevation myocardial infarction) and 40 patients with stable coronary artery disease were included consecutively in this study. During coronary angiography, peripheral venous blood sample was taken for measuring CML. Results: Serum levels of CML were significantly increased in patients with acute myocardial infarction [17.9+/-10.7 vs. 6.6+/-3.1 arbitrary units (AU)/mg protein, p<0.001]. A cut-off value of CML>9.5 AU/mg protein was associated with an odds ratio of acute myocardial infarction of 39.7 [95% confidence interval (CI): 11.1-142, p<0.001], a sensitivity of 0.85 (95% CI: 0.70-0.94) and a specificity of 0.88 (95% CI: 0.73-0.96). Conclusions: CML levels are significantly elevated in patients presenting with acute myocardial infarction. These results suggest the involvement of endothelial dysfunction (through receptor interaction) and oxidative stress in acute myocardial infarction. Clin Chem Lab Med 2009;47:446-51.

• Association of NT-proBNP with severity of heart valve disease in a medical patient population presenting with acute dyspnea or peripheral edema.

  Authors: Michael Behnes, Siegfried Lang, Ole A Breithardt, Jens J Kaden, Dariusch Haghi, Parviz Ahmad-Nejad, Elif Elmas, Christian Wolpert, Martin Borggrefe, Michael Neumaier, Martina Brueckmann

  The Journal of heart valve disease. 09/2008; 17(5):557-65.

  BACKGROUND AND AIM OF THE STUDY: The study aim was to perform a comprehensive evaluation of the association between N-terminal pro B-type natriuretic peptide (NT-proBNP) and the severity of heartBACKGROUND AND AIM OF THE STUDY: The study aim was to perform a comprehensive evaluation of the association between N-terminal pro B-type natriuretic peptide (NT-proBNP) and the severity of heart valve diseases in a typical clinical population presenting with acute dyspnea or peripheral edema. METHODS: Among 401 eligible patients, 210 demonstrated evaluable complete echocardiographic examinations. Plasma levels of NT-proBNP were measured after the initial clinical evaluation. RESULTS: Patients with a prior valve replacement had higher plasma levels of NT-proBNP (median 3,366 pg/ml; n = 10) compared to all other patients (median 931 pg/ml; n = 200) (p < 0.05). In univariable analyses, NT-proBNP levels correlated with multiple valve diseases (r = 0.5; p < 0.001) and the severities of specific heart valve diseases, including aortic valve stenosis (AS) and regurgitation (AR), tricuspid (TR) and mitral valve regurgitation (MR) (p < 0.001). Within multivariable linear regression models, multiple heart valve diseases (Beta = 0.21; T = 3.56; p = 0.0001) and specifically valve regurgitations (AR (Beta = 0.16; T = 2.54; p = 0.012), MR (Beta = 0.36; T = 5.55; p = 0.0001), TR (Beta = 0.17; T = 2.55; p = 0.012)) were associated with increasing plasma levels of NT-proBNP. Patients with NT-proBNP plasma levels > 1,100 pg/ml showed the highest risk for future clinical events (odds ratio (OR) 4.86; p = 0.02), followed by patients with TR (OR 3.17; p = 0.03) and AS (OR 3.49; p = 0.06). CONCLUSION: In addition to clinical assessment and echocardiographic evaluation, the measurement of plasma NT-proBNP levels may serve as a valuable additional indicator of the severity of heart valve disease in individual patients.

• Diagnostic performance of mid-regional pro-adrenomedullin as an analyte for the exclusion of left ventricular dysfunction.

  Authors: Elif Elmas, Siegfried Lang, Carl-Erik Dempfle, Thorsten Kälsch, Jana Papassotiriou, Nils G Morgenthaler, Martin Borggrefe, Martina Brueckmann

  International journal of cardiology. 08/2008; 128(1):107-11.

  AIMS: In ambulatory patients with coronary artery disease (CAD) we aimed to evaluate the diagnostic performance of mid-regional pro-adrenomedullin (MR-proADM) for the detection or exclusion ofAIMS: In ambulatory patients with coronary artery disease (CAD) we aimed to evaluate the diagnostic performance of mid-regional pro-adrenomedullin (MR-proADM) for the detection or exclusion of impaired left ventricular ejection fraction (LVEF). METHODS AND RESULTS: MR-proADM levels were measured in blood samples taken from 102 outpatients with CAD classified according to the New York Heart Association (NYHA) and Canadian Cardiovascular society (CCS) I-II. Increased levels of MR-proADM correlated with impaired LVEF (r=-0.21, p=0.046). The optimal threshold of MR-proADM for identification of impaired LVEF <50% was 0.54 nmol/L with an area under the ROC curve (AUC) of 0.64 (p=0.06). In univariate and multivariate calculation, MR-proADM >0.54 nmol/L remained associated with left ventricular dysfunction even after adjusting for age and gender. The negative predictive value (NPV) for MR-proADM <or=0.54 nmol/L was 88%, the specificity was 66%. CONCLUSIONS: We showed that MR-proADM is related to impaired LVEF. With an NPV of 88% MR-proADM might be a supportive tool to exclude negatively tested outpatients with CAD from further LVEF-diagnosis with moderate reliability.

• Diagnostic performance and cost effectiveness of measurements of plasma N-terminal pro brain natriuretic peptide in patients presenting with acute dyspnea or peripheral edema.

  Authors: Michael Behnes, Martina Brueckmann, Parviz Ahmad-Nejad, Siegfried Lang, Christian Wolpert, Elif Elmas, Thorsten Kaelsch, Joachim Gruettner, Christel Weiβ, Martin Borggrefe, Michael Neumaier

  International journal of cardiology. 07/2008;

  BACKGROUND: The purpose of this study was to determine the diagnostic power of a newly available assay for amino-terminal pro-brain natriuretic peptide (NT-proBNP) to identify patients with acuteBACKGROUND: The purpose of this study was to determine the diagnostic power of a newly available assay for amino-terminal pro-brain natriuretic peptide (NT-proBNP) to identify patients with acute heart failure. In addition, the influence of initial NT-proBNP measurements on economic consequences, diagnostic procedures and staff involvement was evaluated. METHODS AND RESULTS: 401 patients presenting with acute dyspnea or peripheral edema in the emergency department were enrolled. NT-proBNP was measured after initial clinical evaluation. Clinical routine care and diagnostic assessment were blinded to NT-proBNP results. Two cardiologists independently validated the period of hospitalization, clinical examinations and medical therapies of each patient considering NT-proBNP results. The median NT-proBNP level among patients with acute congestive heart failure (CHF) (n=122) was 3497 pg/ml as compared to 320 pg/ml in patients without (n=279) (p<0.0001). An NT-proBNP cutoff level <300 pg/ml was optimal to rule out acute CHF (negative predictive value 96%; sensitivity 96%). NT-proBNP >/=300 pg/ml could strongly predict acute CHF when compared to patients' history or physical examination (odds ratio 9.5; p<0.0001) and diagnostic technical findings (odds ratio 14.7; p<0.05). In patients with NT-proBNP<300 pg/ml, 14% of the period of hospitalization could be saved, corresponding to savings of US $481 per patient. In addition, 9% of the number and time of staff involvement of clinical examinations and therapies could be saved, 10% of the costs of clinical examinations. Chest X-rays were saved in 34%, echocardiography in 9%. CONCLUSIONS: Measurement of NT-proBNP leads to multiple saving amounts and optimizes diagnostic pathways and resource allocation.