Christoph Bode

Publications of Christoph Bode

• Diagnosis of viral myocarditis by cardiac magnetic resonance and viral genome detection in peripheral blood.

  Authors: Michael Jeserich, Eva Brunner, Reinhard Kandolf, Manfred Olschewski, Simone Kimmel, Matthias G Friedrich, Daniela Föll, Christoph Bode, Annette Geibel

  The international journal of cardiovascular imaging. 05/2012;

  In patients with acute myocarditis, viral genome can be detected in plasma and peripheral leukocytes. Its relationship with active myocardial inflammation, however, is not well understood. MyocardialIn patients with acute myocarditis, viral genome can be detected in plasma and peripheral leukocytes. Its relationship with active myocardial inflammation, however, is not well understood. Myocardial edema as a feature of inflammation and myocardial necrosis or fibrosis can be frequently observed in patients with acute myocarditis by cardiovascular magnetic resonance (CMR). We assessed the association of viral genome presence in peripheral blood samples with myocardial edema and irreversible injury. We examined consecutive patients with clinically suspected myocarditis after an episode of viral illness. State-of-the-art methods were used for detecting myocardial edema and irreversible injury using CMR and viral genome applying reverse transcribed, nested polymerase chain reaction in peripheral blood samples. The specificity of viral amplification products was confirmed by automatic DNA sequencing. Of a total of 55 patients (53.5 ± 15.6 years), 21 were positive for viral genome in peripheral leukocytes. Interestingly, 18 (86 %) of these patients also showed global myocardial edema, as compared to only 7/34 (21 %) without PCR evidence for viral genome. The overall agreement between CMR criteria for edema and viral PCR was 84 %. In contrast, there was no significant relationship of viral genome presence with myocardial necrosis or scars. In patients with clinically suspected myocarditis, myocardial edema but not irreversible myocardial injury is associated with the presence of viral genome in peripheral blood.

• Evidence of Myocardial Edema in Patients With Nonischemic Dilated Cardiomyopathy.

  Authors: Michael Jeserich, Daniela Föll, Manfred Olschewski, Simone Kimmel, Matthias G Friedrich, Christoph Bode, Annette Geibel

  Clinical cardiology. 03/2012;

  BACKGROUND: Nonischemic dilated cardiomyopathy (DCM) is associated with high mortality and morbidity. Cardiovascular magnetic resonance allows for the noninvasive assessment of function, morphology,BACKGROUND: Nonischemic dilated cardiomyopathy (DCM) is associated with high mortality and morbidity. Cardiovascular magnetic resonance allows for the noninvasive assessment of function, morphology, and myocardial edema. Activation of inflammatory pathways may play an important role in the etiology of chronic DCM and may also be involved in the disease progression. HYPOTHESIS: The purpose of our study was to assess the incidence of myocardial edema as a marker for myocardial inflammation in patients with nonischemic DCM. METHODS: We examined 31 consecutive patients ( mean age, 57 ± 12 years) with idiopathic DCM. Results were compared with 39 controls matched for gender and age (mean age, 53 ± 13 years). Parameters of left ventricular function and volumes, and electrocardiogram-triggered, T2-weighted, fast spin echo triple inversion recovery sequences were applied in all patients and controls. Variables between patients and controls were compared using t tests for quantitative and χ2 tests for categorical variables. RESULTS: Ejection fraction (EF) was 40.3 ± 7.8% in patients and 62.6 ± 5.0% in controls (P < 0.0001). In T2-weighted images, patients with DCM had a significantly higher normalized global signal intensity ratio compared to controls (2.2 ± 0.6 and 1.8 ± 0.3, respectively, P = 0.0006), consistent with global myocardial edema. There was a significant but moderate negative correlation between signal intensity ratio in T2-weighted images and EF (-0.39, P < 0.001). CONCLUSIONS: Evidence shows that myocardial edema is associated with idiopathic nonischemic DCM. Further studies are needed to assess the clinical and prognostic impact of these findings. Clin. Cardiol. 2012 DOI: 10.1002/clc.21979 The authors have no funding, financial relationships, or conflicts of interest to disclose.

• An approach towards molecular imaging of activated platelets allows imaging of symptomatic human carotid plaques in a new model of a tissue flow chamber.

  Authors: Dominik von Elverfeldt, Mirko Meißner, Karlheinz Peter, Dominik Paul, Fabian Meixner, Irene Neudorfer, Annette Merkle, Andreas Harloff, Andreas Zirlik, Joachim Schöllhorn, Michael Markl, Jürgen Hennig, Christoph Bode, Constantin von Zur Muhlen

  Contrast media & molecular imaging. 03/2012; 7(2):204-213.

  The development of magnetic resonance imaging (MRI) contrast agents targeting epitopes in atherosclerosis is of general interest. In particular, early detection of activated platelets as key playersThe development of magnetic resonance imaging (MRI) contrast agents targeting epitopes in atherosclerosis is of general interest. In particular, early detection of activated platelets as key players in plaque rupture could provide improved triage of patients. However, so far the efficiency of contrast agents targeting human pathologies can only be examined in animal experiments, which do not necessarily reflect human in vivo conditions. We therefore describe application of a contrast agent targeting activated human platelets in an MRI tissue flow chamber, allowing detection and characterization of contrast agent binding. Microparticles of iron oxide (MPIO) were conjugated to an antibody targeting ligand-induced binding sites (LIBS) on the activated platelet glycoprotein IIb/IIIa-receptor or to control antibody, resulting in LIBS-MPIO or control-MPIO contrast agent. Human endarterectomy specimens from patients with acute stroke or transient ischemic attack were imaged ex vivo before and after contrast agent perfusion using a 9.4 T MRI system. Specimens were measured under static (n = 18) or flow conditions (n = 18) in a specially designed flow chamber setup, simulating physiological conditions in a stenosed vessel. A significant MPIO-induced negative contrast was achieved in MRI by LIBS-MPIO in specimens under static and flow conditions (LIBS-MPIO vs control-MPIO: p < 0.01), and the location of LIBS-MPIO binding corresponded well between histology and MRI (p < 0.05). The number of MPIOs per platelet area on endarterectomy specimens in histology was significantly higher with LIBS-MPIO (p < 0.001). Furthermore, the intensity of contrast agent binding and signal change showed the potential to reflect the severity of clinical symptoms. LIBS-MPIO allows the detection of activated platelets on the surface of symptomatic atherosclerotic human plaques using molecular MRI. Furthermore, the MRI tissue flow chamber setup described could help to evaluate binding properties of contrast agents, and might therefore be an interesting tool for contrast agent development from animal experiments towards clinical application. Copyright © 2012 John Wiley & Sons, Ltd.

• Urine proteome analysis reflects atherosclerotic disease in an ApoE-/- mouse model and allows the discovery of new biomarkers in mouse and human atherosclerosis.

  Authors: Constantin von Zur Muhlen, Eric Schiffer, Christine Sackmann, Petra Zürbig, Irene Neudorfer, Andreas Zirlik, Nay Htun, Alexander Iphöfer, Lothar Jänsch, Harald Mischak, Christoph Bode, Yung C Chen, Karlheinz Peter

  Molecular & cellular proteomics : MCP. 02/2012;

  Non-invasive diagnosis of atherosclerosis via single biomarkers has been attempted but remains elusive. However, a previous polymarker or pattern approach of urine polypeptides in humans reflectedNon-invasive diagnosis of atherosclerosis via single biomarkers has been attempted but remains elusive. However, a previous polymarker or pattern approach of urine polypeptides in humans reflected coronary artery disease with high accuracy. The aim of the current study is to use urine proteomics in ApoE-/- mice to discover proteins with pathophysiological roles in atherogenesis and to identify urinary polypeptide patterns reflecting early stages of atherosclerosis. Urine of ApoE-/- mice either on high fat diet (HFD) or chow diet (CD) was collected over 12 weeks; urine of wild type mice on HFD was used to exclude diet-related proteome changes. Capillary electrophoresis coupled to mass spectrometry (CE-MS) of samples identified 16 polypeptides specific for ApoE-/- mice on HFD. In a blinded test set, these polypeptides allowed identification of atherosclerosis at a sensitivity of 90% and specificity of 100%, as well as monitoring of disease progression. Sequencing of the discovered polypeptides identified fragments of α1-antitrypsin, EGF, kidney androgen regulated protein (KAP) and collagen. Using immunohistochemistry, α1-antitrypsin, EGF and collagen type I were shown to be highly expressed in atherosclerotic plaques of ApoE-/- mice on HFD. Urinary excretion levels of collagen and α1-antitrypsin fragments also significantly correlated with intraplaque collagen and α1-antitrypsin content, mirroring plaque protein expression in the urine proteome. To provide further confirmation that the newly identified proteins are relevant in humans, presence of collagen type I, α1-antitrypsin, and EGF was also confirmed in human atherosclerotic disease. Urine proteome analysis in mice exemplifies the potential of a novel multimarker approach for the non-invasive detection of atherosclerosis and monitoring of disease progression. Furthermore, this approach represents a novel discovery tool for the identification of proteins relevant in murine and human atherosclerosis and thus also defines potential novel therapeutic targets.

• Perturbation of the endothelial glycocalyx in post cardiac arrest syndrome.

  Authors: Sebastian Grundmann, Katrin Fink, Lyubomira Rabadzhieva, Natascha Bourgeois, Tilmann Schwab, Martin Moser, Christoph Bode, Hans-Joerg Busch

  Resuscitation. 02/2012;

  BACKGROUND: The prognosis of immediate survivors of cardiac arrest remains poor, as the majority of these patients develops an inflammatory disorder known as the post-cardiac arrest syndrome (PCAS).BACKGROUND: The prognosis of immediate survivors of cardiac arrest remains poor, as the majority of these patients develops an inflammatory disorder known as the post-cardiac arrest syndrome (PCAS). Recently, the endothelial glycocalyx has been shown to be a key modulator of vascular permeability and inflammation, but its role in PCAS remains unknown. METHODS: Plasma levels of the glycocalyx components syndecan-1, heparan sulfate and hyaluronic acid were measured in 25 patients after immediate survival of cardiac arrest during different phases of PCAS. Twelve hemodynamically stable patients with acute coronary syndrome served as controls. RESULTS: Cardiac arrest resulted in a significant increase in syndecan-1, heparan sulfate and hyaluronic acid levels compared to controls, indicating a shedding of the endothelial glycocalyx as a pathophysiological component of the post cardiac arrest syndrome. The time course differed between the individual glycocalyx components, with a higher increase of syndecan-1 in the early phase of PCAS (2.8-fold increase vs. controls) and a later peak of heparan sulfate (1.7-fold increase) and hyaluronic acid (2-fold increase) in the intermediate phase. Only the plasma levels of syndecan-1 correlated positively with the duration of CPR and negatively with the glycocalyx-protective protease inhibitor antithrombin III. Plasma levels of both syndecan-1 and heparan sulfate were higher in eventual non-survivors than in survivors of cardiac arrest. CONCLUSION: Our data for the first time demonstrates a perturbation of the endothelial glycocalyx in immediate survivors of cardiac arrest and indicate a potential important role of this endothelial surface layer in the development of post-cardiac arrest syndrome.

• Serotonin antagonism improves platelet inhibition in clopidogrel low-responders after coronary stent placement: an in vitro pilot study.

  Authors: Daniel Duerschmied, Ingo Ahrens, Maximilian Mauler, Christoph Brandt, Stefanie Weidner, Christoph Bode, Martin Moser

  PloS one. 01/2012; 7(2):e32656.

  Increased residual platelet reactivity remains a burden for coronary artery disease (CAD) patients who received a coronary stent and do not respond sufficiently to treatment with acetylsalicylic acidIncreased residual platelet reactivity remains a burden for coronary artery disease (CAD) patients who received a coronary stent and do not respond sufficiently to treatment with acetylsalicylic acid and clopidogrel. We hypothesized that serotonin antagonism reduces high on-treatment platelet reactivity. Whole blood impedance aggregometry was performed with arachidonic acid (AA, 0.5 mM) and adenosine diphosphate (ADP, 6.5 µM) in addition to different concentrations of serotonin (1-100 µM) in whole blood from 42 CAD patients after coronary stent placement and 10 healthy subjects. Serotonin increased aggregation dose-dependently in CAD patients who responded to clopidogrel treatment: After activation with ADP, aggregation increased from 33.7±1.3% to 40.9±2.0% in the presence of 50 µM serotonin (p<0.05) and to 48.2±2.0% with 100 µM serotonin (p<0.001). The platelet serotonin receptor antagonist ketanserin decreased ADP-induced aggregation significantly in clopidogrel low-responders (from 59.9±3.1% to 37.4±3.5, p<0.01), but not in clopidogrel responders. These results were confirmed with light transmission aggregometry in platelet-rich plasma in a subset of patients. Serotonin hence increased residual platelet reactivity in patients who respond to clopidogrel after coronary stent placement. In clopidogrel low-responders, serotonin receptor antagonism improved platelet inhibition, almost reaching responder levels. This may justify further investigation of triple antiplatelet therapy with anti-serotonergic agents.

• CD40L Deficiency Attenuates Diet-Induced Adipose Tissue Inflammation by Impairing Immune Cell Accumulation and Production of Pathogenic IgG-Antibodies.

  Authors: Dennis Wolf, Felix Jehle, Alexandra Ortiz Rodriguez, Bianca Dufner, Natalie Hoppe, Christian Colberg, Andrey Lozhkin, Nicole Bassler, Benjamin Rupprecht, Ansgar Wiedemann, Ingo Hilgendorf, Peter Stachon, Florian Willecke, Mark Febbraio, Christoph J Binder, Christoph Bode, Andreas Zirlik, Karlheinz Peter

  PloS one. 01/2012; 7(3):e33026.

  Adipose tissue inflammation fuels the metabolic syndrome. We recently reported that CD40L - an established marker and mediator of cardiovascular disease - induces inflammatory cytokine production inAdipose tissue inflammation fuels the metabolic syndrome. We recently reported that CD40L - an established marker and mediator of cardiovascular disease - induces inflammatory cytokine production in adipose cells in vitro. Here, we tested the hypothesis that CD40L deficiency modulates adipose tissue inflammation in vivo. WT or CD40L(-/-) mice consumed a high fat diet (HFD) for 20 weeks. Inflammatory cell recruitment was impaired in mice lacking CD40L as shown by a decrease of adipose tissue macrophages, B-cells, and an increase in protective T-regulatory cells. Mechanistically, CD40L-deficient mice expressed significantly lower levels of the pro-inflammatory chemokine MCP-1 both, locally in adipose tissue and systemically in plasma. Moreover, levels of pro-inflammatory IgG-antibodies against oxidized lipids were reduced in CD40L(-/-) mice. Also, circulating low-density lipoproteins and insulin levels were lower in CD40L(-/-) mice. However, CD40L(-/-) mice consuming HFD were not protected from the onset of diet-induced obesity (DIO), insulin resistance, and hepatic steatosis, suggesting that CD40L selectively limits the inflammatory features of diet-induced obesity rather than its metabolic phenotype. Interestingly, CD40L(-/-) mice consuming a low fat diet (LFD) showed both, a favorable inflammatory and metabolic phenotype characterized by diminished weight gain, improved insulin tolerance, and attenuated plasma adipokine levels. We present the novel finding that CD40L deficiency limits adipose tissue inflammation in vivo. These findings identify CD40L as a potential mediator at the interface of cardiovascular and metabolic disease.

• Binding of CD40L to Mac-1's I-domain involves the EQLKKSKTL motif and mediates leukocyte recruitment and atherosclerosis--but does not affect immunity and thrombosis in mice.

  Authors: Dennis Wolf, Jan-David Hohmann, Ansgar Wiedemann, Kamila Bledzka, Hermann Blankenbach, Timoteo Marchini, Katharina Gutte, Katharina Zeschky, Nicole Bassler, Natalie Hoppe [......] Florian Willecke, Daniel Duerschmied, Constantin von zur Muhlen, Dmitry A Soloviev, Li Zhang, Christoph Bode, Edward F Plow, Peter Libby, Karlheinz Peter, Andreas Zirlik

  Circulation research. 11/2011; 109(11):1269-79.

  CD40L figures prominently in chronic inflammatory diseases such as atherosclerosis. However, since CD40L potently regulates immune function and hemostasis by interaction with CD40 receptor and theCD40L figures prominently in chronic inflammatory diseases such as atherosclerosis. However, since CD40L potently regulates immune function and hemostasis by interaction with CD40 receptor and the platelet integrin GPIIb/IIIa, its global inhibition compromises host defense and generated thromboembolic complications in clinical trials. We recently reported that CD40L mediates atherogenesis independently of CD40 and proposed Mac-1 as an alternate receptor. Here, we molecularly characterized the CD40L-Mac-1 interaction and tested whether its selective inhibition by a small peptide modulates inflammation and atherogenesis in vivo. CD40L concentration-dependently bound to Mac-1 I-domain in solid phase binding assays, and a high-affinity interaction was revealed by surface-plasmon-resonance analysis. We identified the motif EQLKKSKTL, an exposed loop between the α1 helix and the β-sheet B, on Mac-1 as binding site for CD40L. A linear peptide mimicking this sequence, M7, specifically inhibited the interaction of CD40L and Mac-1. A cyclisized version optimized for in vivo use, cM7, decreased peritoneal inflammation and inflammatory cell recruitment in vivo. Finally, LDLr(-/-) mice treated with intraperitoneal injections of cM7 developed smaller, less inflamed atherosclerotic lesions featuring characteristics of stability. However, cM7 did not interfere with CD40L-CD40 binding in vitro and CD40L-GPIIb/IIIa-mediated thrombus formation in vivo. We present the novel finding that CD40L binds to the EQLKKSKTL motif on Mac-1 mediating leukocyte recruitment and atherogenesis. Specific inhibition of CD40L-Mac-1 binding may represent an attractive anti-inflammatory treatment strategy for atherosclerosis and other inflammatory conditions, potentially avoiding the unwanted immunologic and thrombotic effects of global inhibition of CD40L.

• Anomalous hypoplastic left anterior descending artery.

  Authors: Michael Jeserich, Christian Schlundt, Christoph Bode, Annette Geibel

  Heart, lung & circulation. 11/2011; 20(11):736-7.

• Circulating annexin V positive microparticles in patients after successful cardiopulmonary resuscitation.

  Authors: Katrin Fink, Linda Feldbrügge, Meike Schwarz, Natascha Bourgeois, Thomas Helbing, Christoph Bode, Tilmann Schwab, Hans-Jörg Busch

  Critical care (London, England). 10/2011; 15(5):R251.

  ABSTRACT: INTRODUCTION: Ischemia/reperfusion after cardiopulmonary resuscitation (CPR) induces systemic inflammatory response and activation of endothelium and coagulation, resulting in aABSTRACT: INTRODUCTION: Ischemia/reperfusion after cardiopulmonary resuscitation (CPR) induces systemic inflammatory response and activation of endothelium and coagulation, resulting in a post-cardiac arrest syndrome. We analysed circulating (annexin V+) microparticles and their conjugates in resuscitated patients. METHODS: 36 patients after successful resuscitation, 20 control patients with stable cardiac disease and 15 healthy subjects were included prospectively. Two blood samples were drawn, one immediately and one 24 hours after return of spontaneous circulation (ROSC) to detect (annexin V+) monocyte-derived microparticles (MMPs) or procoagulant (annexin V+) platelet-derived microparticles (PMPs) and conjugates of endothelial-derived (annexin V+) microparticles (EMPs) with monocytes (EMP-MC) or platelets (EMP-PC). Measurements were performed by flow cytometric analysis. Additionally, the effect of isolated microparticles on cultured endothelial cells was assessed by ELISA. RESULTS: MMPs were significantly elevated immediately after ROSC compared to the cardiological control group (control; p < 0.01) and healthy subjects (healthy; p < 0.05) and persisted to be elevated in the following 24 hours after CPR (p < 0.05 vs. control and healthy, respectively). Procoagulant PMPs increased within the first 24 hours after ROSC (p < 0.01 vs. control and p < 0.005 vs. healthy). Conjugates of EMP with monocytes and platelets were both significantly elevated immediately after CPR (EMP-MC: p < 0.05 vs. control and p < 0.05 vs. healthy; EMP-PC: p < 0.05 vs. control and p < 0.05 vs. healthy), while only EMP-MC showed persisting high levels within 24 hours after CPR (p < 0.05 vs. control and p < 0.01 vs. healthy). MMP levels of ≥1.0/μL 24 hours after CPR predicted adverse outcome at 20 days (p < 0.05). Furthermore, isolated microparticles circulating in CPR patients early after ROSC led to enhanced endothelial apoptosis ex vivo compared to those of the healthy controls (p < 0.005). CONCLUSIONS: Resuscitated patients show substantially increased levels of different (annexin V+) microparticles and their conjugates immediately and 24 hours after cardiopulmonary resuscitation, suggesting an early onset of inflammation, an ongoing endothelial activation and a procoagulatory state. Additionally, microparticles of CPR patients may contribute to endothelial apoptosis. These results point to an involvement of microparticles in the development of the post-cardiac arrest syndrome.

• BMP activity controlled by BMPER regulates the proinflammatory phenotype of endothelium.

  Authors: Thomas Helbing, René Rothweiler, Elena Ketterer, Lena Goetz, Jennifer Heinke, Sebastian Grundmann, Daniel Duerschmied, Cam Patterson, Christoph Bode, Martin Moser

  Blood. 09/2011; 118(18):5040-9.

  The endothelium plays a pivotal role in vascular inflammation. Here we study bone morphogenetic protein (BMP) signaling in endothelial inflammation and in particular the role of BMPER, anThe endothelium plays a pivotal role in vascular inflammation. Here we study bone morphogenetic protein (BMP) signaling in endothelial inflammation and in particular the role of BMPER, an extracellular BMP modulator that is important in vascular development and angiogenesis. Using the BMP antagonist dorsomorphin or BMP2 as an agonist we show that BMP signaling is essential for the inflammatory response of vascular endothelial cells as demonstrated by intravital microscopy. We found that BMPER is decreased in inflammation similar to vascular protective genes like KLF2 and eNOS. Using in vitro and in vivo models we show that BMPER is down-regulated through the TNFα-NFκB-KLF2 signaling pathway. Functionally, lack of BMPER induced by siRNA or in BMPER(+/-) mice confers a proinflammatory endothelial phenotype with reduced eNOS levels and enhanced expression of adhesion molecules leading to increased leukocyte adhesion and extravasation in ex vivo and in vivo experiments. Vice versa, addition of BMPER exerts endothelium protective functions and antagonizes TNFα induced inflammation. Mechanistically, we demonstrate that these effects of BMPER are dependent on BMP signaling because of enhanced NFκB activity. In conclusion, the BMP modulator BMPER is a new protective regulator of vascular inflammation that modulates leukocyte adhesion and migration in vitro and in vivo.

• New Parenteral Anticoagulants: Focus on Factor Xa and Thrombin Inhibitors.

  Authors: Ingo Ahrens, Christoph Bode

  Current drug discovery technologies. 08/2011;

  For decades, unfractionated heparin (UFH) was the most widely used parenteral anticoagulant in a variety of clinical scenarios requiring rapid and reversible anticoagulation. The shortcomings of UFHFor decades, unfractionated heparin (UFH) was the most widely used parenteral anticoagulant in a variety of clinical scenarios requiring rapid and reversible anticoagulation. The shortcomings of UFH include a high inter-individual variability and the occurrence of heparin induced thrombocytopenia with the potential for serious thromboembolic complications. These shortcomings prompted the successful clinical development of low molecular weight heparins (LMWH) and indirect factor Xa inhibitors such as fondaparinux. LMWH and fondaparinux demonstrated superiority in many clinical scenarios including acute coronary syndromes (ACS). However the long half-life and the lack of a specific antidote still require the usage of UFH in clinical situation where a rapid reversibility of the anticoagulation is required. Especially in ACS patients undergoing PCI, a direct parenteral inhibition of thrombin with the direct thrombin inhibitor (DTI) bivalirudin proved to be an alternative anticoagulant strategy. This has set the stage for the clinical development of other parenteral DTIs. The reduction in clinical ischemic events that were achieved with indirect factor Xa inhibitors in patients with ACS facilitated the clinical development of the first parenteral direct factor Xa inhibitor, otamixaban which is currently investigated in a phase III clinical trial in patients with ACS undergoing PCI. This article discusses novel parenteral factor Xa and thrombin inhibitors currently under clinical investigation including aptamers, a new class of drugs that allows the parallel development of the combination of active drug and reversal agent, which is facilitated by the DNA or RNA structure of which aptamers are composed of.

• Measuring oxidative burden and predicting pharmacological response in coronary artery disease patients with a novel direct activator of haem-free/oxidised sGC.

  Authors: Ingo Ahrens, Jonathon Habersberger, Nadège Baumlin, Hongwei Qian, Belinda K Smith, Johannes-Peter Stasch, Christoph Bode, Harald H H W Schmidt, Karlheinz Peter

  Atherosclerosis. 06/2011; 218(2):431-4.

  The soluble guanylate cyclase (sGC) activator Cinaciguat (BAY 58-2667) represents a novel class of drugs that selectively activate oxidised sGC. The extent of oxidised sGC depends on the patient'sThe soluble guanylate cyclase (sGC) activator Cinaciguat (BAY 58-2667) represents a novel class of drugs that selectively activate oxidised sGC. The extent of oxidised sGC depends on the patient's oxidative burden. We here describe two platelet-based assays that allow determining the extent of oxidised sGC and thus provide a basis for an individualised pharmacotherapy. Platelets obtained from patients with (n=12) and without (n=12) coronary artery disease (CAD) were examined by flow cytometry (P-selectin expression), and Western blots (vasodilator associated phosphoprotein, VASP-phosphorylation). Results were compared to maximal oxidation of sGC achieved by the oxidising agent ODQ (1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one). Treatment of platelets with Cinaciguat resulted in differential activation of oxidised sGC. Platelet P-selectin expression and VASP-phosphorylation revealed significant differences (p=0.012, p=0.039, respectively) between CAD and non-CAD patients. We describe platelet-based assays that allow the determination of patients' oxidative status and thus allow the prediction of pharmacological response to direct sGC activators.

• The oral spleen tyrosine kinase inhibitor fostamatinib attenuates inflammation and atherogenesis in low-density lipoprotein receptor-deficient mice.

  Authors: Ingo Hilgendorf, Sara Eisele, Imke Remer, Jochen Schmitz, Katharina Zeschky, Christian Colberg, Peter Stachon, Dennis Wolf, Florian Willecke, Maike Buchner, Katja Zirlik, Alexandra Ortiz-Rodriguez, Andrey Lozhkin, Natalie Hoppe, Constantin von zur Muhlen, Axel zur Hausen, Christoph Bode, Andreas Zirlik

  Arteriosclerosis, thrombosis, and vascular biology. 06/2011; 31(9):1991-9.

  Spleen tyrosine kinase (SYK) has come into focus as a potential therapeutic target in chronic inflammatory diseases, such as rheumatoid arthritis and asthma, as well as in B-cell lymphomas. SYK hasSpleen tyrosine kinase (SYK) has come into focus as a potential therapeutic target in chronic inflammatory diseases, such as rheumatoid arthritis and asthma, as well as in B-cell lymphomas. SYK has also been involved in the signaling of immunoreceptors, cytokine receptors, and integrins. We therefore hypothesized that inhibition of SYK attenuates the inflammatory process underlying atherosclerosis and reduces plaque development. Low-density lipoprotein receptor-deficient mice consuming a high-cholesterol diet supplemented with 2 doses of the orally available SYK inhibitor fostamatinib for 16 weeks showed a dose-dependent reduction in atherosclerotic lesion size by up to 59±6% compared with the respective controls. Lesions of fostamatinib-treated animals contained fewer macrophages but more smooth muscle cells and collagen-characteristics associated with more stable plaques in humans. Mechanistically, fostamatinib attenuated adhesion and migration of inflammatory cells and limited macrophage survival. Furthermore, fostamatinib normalized high-cholesterol diet -induced monocytosis and inflammatory gene expression. We present the novel finding that the SYK inhibitor fostamatinib attenuates atherogenesis in mice. Our data identify SYK inhibition as a potentially fruitful antiinflammatory therapeutic strategy in atherosclerosis.

• Shock lead impedance alert: replace or reconsider?

  Authors: Ingo Hilgendorf, Juergen Biermann, Thomas Faber, Christoph Bode, Stefan Asbach

  Circulation. Arrhythmia and electrophysiology. 06/2011; 4(3):e15-7.

• Molecular magnetic resonance imaging allows the detection of activated platelets in a new mouse model of coronary artery thrombosis.

  Authors: Daniel Duerschmied, Mirko Meisner, Karlheinz Peter, Irene Neudorfer, Freya Roming, Andreas Zirlik, Christoph Bode, Dominik von Elverfeldt, Constantin von Zur Muhlen

  Investigative radiology. 05/2011; 46(10):618-23.

  : The final event leading to myocardial infarction is adhesion and activation of platelets after rupture of an atherosclerotic plaque, ending in thrombotic occlusion of the coronary artery. Imaging: The final event leading to myocardial infarction is adhesion and activation of platelets after rupture of an atherosclerotic plaque, ending in thrombotic occlusion of the coronary artery. Imaging of imminent vessel occlusion may improve patient care. The feasibility of molecular magnetic resonance imaging (MRI) for the detection of coronary artery thrombosis in mice was examined. : The left anterior descending coronary artery was exposed by lateral thoracotomy and incubated with ferric chloride to induce nonocclusive thrombosis in C57Bl/6 mice. A single chain antibody targeting ligand-induced binding sites (LIBS) of the activated glycoprotein IIb/IIIa or control antibody was conjugated to 1 μm-sized microparticles of iron oxide (MPIOs), resulting in LIBS-MPIO or control-MPIO MRI contrast agent, and injected intravenously. Hearts were subjected to histology and ex vivo MRI at 9.4 Tesla. : Thrombus size was comparable in mice injected with control-MPIO and LIBS-MPIO in histology. Significant binding of MPIOs to thrombi was observed in LIBS-MPIO-injected animals while no binding was observed in control animals (P < 0.05). In MRI, LIBS-MPIO binding to thrombi of the left anterior descending coronary artery resulted in significant MPIO-induced signal void compared with controls (P < 0.05). MRI signal void and the amount of bound contrast agent particles in histology showed a significant positive linear correlation (r = 0.939, P < 0.001). : We established a new mouse model of nonocclusive coronary artery thrombosis. LIBS-MPIO contrast agent binds to activated platelets in this model, allowing molecular MRI of coronary thrombosis. This could have important implications on the timely noninvasive detection of arterial thrombosis, helping to initiate early therapeutic interventions.

• Redemption by RE-DEEM?

  Authors: Martin Moser, Christoph Bode

  European heart journal. 05/2011; 32(22):2734-5.

• Discontinuation of long term clopidogrel therapy induces platelet rebound hyperaggregability between 2 and 6 weeks post cessation.

  Authors: Philipp Diehl, Christoph Halscheid, Christoph Olivier, Thomas Helbing, Christoph Bode, Martin Moser

  Clinical research in cardiology : official journal of the German Cardiac Society. 04/2011; 100(9):765-71.

  Stent thrombosis occurs frequently within the first weeks after cessation of longterm clopidogrel therapy. We investigated if rebound platelet hyperreactivity occurs to provide a mechanism for thisStent thrombosis occurs frequently within the first weeks after cessation of longterm clopidogrel therapy. We investigated if rebound platelet hyperreactivity occurs to provide a mechanism for this clinical observation. ADP- and TRAP-induced platelet aggregation was measured by impedance aggregometry in 28 patients with coronary stent implantation (observational group, OG) before and 1, 2, 6 and 17 weeks after clopidogrel cessation. Data were compared intraindividually as well as to 67 controls (control group, CG). On-clopidogrel platelet activity was significantly reduced (ADP-stimulation, OG vs. CG, 30 ± 3 U vs. 67 ± 3 U, p < 0.001) and reached control levels 1 week after clopidogrel cessation (ADP-stimulation, OG vs. CG, 70 ± 4 U vs. 67 ± 3 U, p = n.s.). Most patients (57%) showed a significant platelet hyperaggregation after 2 weeks (ADP, OG vs. CG, 83 ± 6 U vs. 67 ± 3 U, p = 0.02) to 6 weeks (ADP, OG vs. CG, 85 ± 5 U vs. 67 ± 3 U, p = 0.01) post-cessation. This temporary hyperaggregability was also observed in intra-individual time courses (ADP, 2 vs. 17 weeks, 83 ± 6 U vs. 73 ± 4 U, p = 0.007; 6 vs. 17 weeks, 85 ± 5 U vs. 73 ± 4 U, p = 0.0002). After 17 weeks post-cessation, ADP-induced platelet aggregation returned towards physiological levels. The total capacity of platelet aggregability as reflected by stimulation with thrombin receptor activating peptide (TRAP) was not different between time points confirming a clopidogrel-specific rebound effect. Abrupt clopidogrel cessation after 1 year of clopidogrel treatment results in ADP specific platelet hyperreactivity between 2 and 6 weeks post withdrawal. This mechanism may contribute to explain increased rates of stent thrombosis at this time as it was observed in clinical studies.

• Images in cardiovascular medicine. Recurrence of a familial giant multilocular cardiac myxoma in a patient with Carney's complex.

  Authors: Felix Guenther, Matthias Siepe, Christian Schlensak, Konrad Aumann, Alexandra Anton, Wolf-Dirk Niesen, Filiz Markfeld-Erol, Christoph Bode, Annette Geibel

  Circulation. 03/2011; 123(8):929-32.

• Inflammasome activation in reperfusion injury: friendly fire on myocardial infarction?

  Authors: Sebastian Grundmann, Christoph Bode, Martin Moser

  Circulation. 02/2011; 123(6):574-6.