Zurich Regional Health Center

Wetzikon, Switzerland

Zurich Regional Health Center

Wetzikon, Switzerland
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Blyszczuk P.,University of Zürich | Blyszczuk P.,Zurich Regional Health Center | Berthonneche C.,University of Lausanne | Behnke S.,Sophistolab AG | And 8 more authors.
Cardiovascular Research | Year: 2013

AimsExperimental autoimmune myocarditis (EAM) model mirrors important mechanisms of inflammatory dilated cardiomyopathy (iDCM). In EAM, inflammatory CD133+ progenitors are a major cellular source of cardiac myofibroblasts in the post-inflammatory myocardium. We hypothesized that exogenous delivery of macrophage-colony-stimulating factor (M-CSF) can stimulate macrophage lineage differentiation of inflammatory progenitors and, therefore, prevent their naturally occurring myofibroblast fate in EAM.Methods and resultsEAM was induced in wild-type (BALB/c) and nitric oxide synthase 2-deficient (Nos2-/-) mice and CD133+ progenitors were isolated from inflamed hearts. In vitro, M-CSF converted inflammatory CD133 + progenitors into nitric oxide-producing F4/80+ macrophages and prevented transforming growth factor-β-mediated myofibroblast differentiation. Importantly, only a subset of heart-infiltrating CD133+ progenitors expresses macrophage-specific antigen F4/80 in EAM. These CD133+/F4/80hi cells show impaired myofibrogenic potential compared with CD133+/F4/80- cells. M-CSF treatment of wild-type mice with EAM at the peak of disease markedly increased CD133+/F4/80hi cells in the myocardium, and CD133+ progenitors isolated from M-CSF-treated mice failed to differentiate into myofibroblasts. In contrast, M-CSF was not effective in converting CD133+ progenitors from inflamed hearts of Nos2 -/- mice into macrophages, and M-CSF treatment did not result in increased CD133+/F4/80hi cell population in hearts of Nos2-/- mice. Accordingly, M-CSF prevented post-inflammatory fibrosis and left ventricular dysfunction in wild-type but not in Nos2-/- mice.ConclusionActive and NOS2-dependent induction of macrophage lineage differentiation abrogates the myofibrogenic potential of heart-infiltrating CD133+ progenitors. Modulating the in vivo differentiation fate of specific progenitors might become a novel approach for the treatment of inflammatory heart diseases. © 2013 The Author.

Blyszczuk P.,University of Zürich | Blyszczuk P.,Zurich Regional Health Center | Behnke S.,Sophistolab AG | Luscher T.F.,University of Zürich | And 4 more authors.
Biochimica et Biophysica Acta - Molecular Cell Research | Year: 2013

Background: Granulocyte macrophage-colony stimulating factor (GM-CSF) is critically required for the induction of experimental autoimmune myocarditis (EAM), a model of post-inflammatory dilated cardiomyopathy. Its specific role in the progression of myocarditis into end stage heart failure is not known. Methods and results: BALB/c mice were immunized with myosin peptide and complete Freund's adjuvant at days 0 and 7. Heart-infiltrating inflammatory CD133+ progenitors were isolated from inflamed hearts at the peak of inflammation (day 21). In the presence of GM-CSF, inflammatory CD133+ progenitors up-regulated integrin, alpha X (CD11c), class II major histocompatibility complex, CD80 and CD86 co-stimulatory molecules reflecting an inflammatory dendritic cell (DC) phenotype. Inflammatory DCs stimulated antigen-specific CD4+ T cell proliferation and induced myocarditis after myosin peptide loading and adoptive transfer in healthy mice. Moreover, GM-CSF treatment of mice after the peak of disease, between days 21 and 29 of EAM, transiently increased accumulation of inflammatory DCs in the myocardium. Importantly, bone marrow-derived CD11b+ monocytes, rather than inflammatory CD133+ progenitors represent the dominant cellular source of heart-infiltrating inflammatory DCs in EAM. In contrast, GM-CSF treatment neither affected numbers of heart-infiltrating CD45+ and CD3+ T cells nor the development of post-inflammatory fibrosis. Conclusions: GM-CSF treatment promotes formation of inflammatory DCs in EAM. In contrast to the active roles of GM-CSF and DCs in EAM induction, GM-CSF-induced inflammatory DCs neither prevent resolution of active inflammation, nor contribute to post-inflammatory cardiac remodelling. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Cardiac Pathways of Differentiation, Metabolism and Contraction. © 2012 Elsevier B.V.

Kania G.,University of Zürich | Kania G.,Zurich Regional Health Center | Siegert S.,University of Lausanne | Behnke S.,Sophistolab AG | And 9 more authors.
Circulation | Year: 2013

Background: Activation of innate pattern-recognition receptors promotes CD4+ T-cell-mediated autoimmune myocarditis and subsequent inflammatory cardiomyopathy. Mechanisms that counterregulate exaggerated heart-specific autoimmunity are poorly understood. Methods and Results: Experimental autoimmune myocarditis was induced in BALB/c mice by immunization with α-myosin heavy chain peptide and complete Freund's adjuvant. Together with interferon-γ, heat-killed Mycobacterium tuberculosis, an essential component of complete Freund's adjuvant, converted CD11bhiCD11c- monocytes into tumor necrosis factor-α- and nitric oxide synthase 2-producing dendritic cells (TipDCs). Heat-killed M. tuberculosis stimulated production of nitric oxide synthase 2 via Toll-like receptor 2-mediated nuclear factor-κB activation. TipDCs limited antigen-specific T-cell expansion through nitric oxide synthase 2-dependent nitric oxide production. Moreover, they promoted nitric oxide synthase 2 production in hematopoietic and stromal cells in a paracrine manner. Consequently, nitric oxide synthase 2 production by both radiosensitive hematopoietic and radioresistant stromal cells prevented exacerbation of autoimmune myocarditis in vivo. Conclusions: Innate Toll-like receptor 2 stimulation promotes formation of regulatory TipDCs, which confine autoreactive T-cell responses in experimental autoimmune myocarditis via nitric oxide. Therefore, activation of innate pattern-recognition receptors is critical not only for disease induction but also for counterregulatory mechanisms, protecting the heart from exaggerated autoimmunity. © 2013 American Heart Association, Inc.

Valaperti A.,University of Ottawa | Nishii M.,University of Ottawa | Liu Y.,University of Ottawa | Naito K.,University of Ottawa | And 8 more authors.
Circulation | Year: 2013

BACKGROUND-: Viral myocarditis follows a fatal course in ≈30% of patients. Interleukin-1 receptor-associated kinase 4 (IRAK4), a major nodal signal transducer in innate immunity, can play a pivotal role in host inflammatory response. We sought to determine how IRAK4 modulates inflammation and outcome in a mouse model of viral myocarditis. METHODS AND RESULTS-: Myocarditis was induced after intraperitoneal inoculation of coxsackievirus B3 into C57Bl/6 IRAK4-deficient mice and their littermate controls. Mortality and viral proliferation were markedly reduced in IRAK4 mice compared with their IRAK4 littermates. Disease resistance of IRAK4 mice paralleled increased amounts of protective heart-infiltrating CCR5 monocytes/macrophages and enhanced interferon-α and interferon-γ production 2 days after infection. Competitive bone marrow chimera demonstrated that intact IRAK4 function inhibited heart-specific migration of bone marrow-derived CCR5 cells. Mechanistically, lack of IRAK4 resulted in interferon regulatory factor 5 homodimerization via reduced melanoma differentiation-associated protein 5 degradation and enhanced Stat1 and Stat5 phosphorylation. Consequently, antiviral interferon-α and interferon-γ production, as well as CCR5 cell recruitment, increased, whereas the overall proinflammatory response was drastically reduced in the absence of IRAK4. CONCLUSIONS-: Innate immunity signal transducer IRAK4 exacerbates viral myocarditis through inhibition of interferon production and reduced mobilization of protective CCR5 monocytes/macrophages to the heart. The combination of IRAK4 inhibitors and antiviral adjuvants may become an attractive therapeutic approach against viral myocarditis in the future. © 2013 American Heart Association, Inc.

Valaperti A.,University of Zürich | Valaperti A.,Toronto General Research Institute | Nishii M.,Toronto General Research Institute | Nishii M.,Kitasato University | And 5 more authors.
Vaccine | Year: 2013

Experimental autoimmune myocarditis (EAM) represents a CD4+ T helper (Th) cell-mediated mouse model of inflammatory heart disease. Interferon (IFN)-γ, typically produced by Th1 cells, reduces EAM severity in myosin heavy-chain-(MyHC)-α peptide/Complete Freund adjuvant-immunized mice. Thus, developing a vaccination strategy that promotes differentiation of Th1 cells may be beneficial in EAM. FMS-like tyrosine kinase 3 ligand (Flt3L)-induced splenic CD8α+ dendritic cells (DC), which produce interleukin (IL)-12p35, were identified to selectively induce biased differentiation towards Th1. Mice vaccinated with MyHC-α-loaded Flt3L-induced splenic CD8α+ DC were protected from EAM. In contrast, when Flt3L-induced splenic CD8α+ DC were pre-stimulated and over-activated with LPS and αCD40 antibodies or loaded with unspecific OVA323-339 peptide instead of MyHC-α peptide, mice developed similar disease scores as non-vaccinated controls. Vaccination efficacy depended on IFN-γ, since CD8α+-vaccinated IFN-γR-/- mice were not protected. Importantly, splenic CD8α+ vaccination was independent of regulatory T cells. Taken together, Flt3L-induced dendritic cell-based antigen-specific vaccination limits expansion of auto-reactive Th cells and protects mice from autoimmune heart inflammation. © 2013 Elsevier Ltd.

Cakic S.,Zurich Regional Health Center | Eriksson U.,Zurich Regional Health Center | Eriksson U.,University of Zürich
Schweizerische Zeitschrift fur Sportmedizin und Sporttraumatologie | Year: 2011

Regular and moderate training reduces the individual cardiovascular risk in the long term. Nevertheless, physical activity may impose a considerable risk of sudden cardiac death on patients with heart diseases. This is particularly the case with myocarditis and pericarditis, which often affect younger people. So far, there is no evidence that sports by itself increase individual susceptibility to inflammatory heart diseases. In patients with symptomatic or asymptomatic cardiac inflammation, however, physical activity is clearly pro-arrhythmic and might even promote myocarditis progression. From these points of view, all patients with cardiac inflammation, in particular if they are involved in competitive sports, need clear recommendations regarding their physical training.

Fox J.,Hirslanden Accident and Emergency Center Zurich | Fiechter R.,Zurich Regional Health Center | Gerstl P.,Zurich Regional Health Center | Gerstl P.,Zurich Regional Emergency Service Center | And 6 more authors.
Acute Cardiac Care | Year: 2013

Background: Novel mechanical chest compression devices offer the possibility to transport cardiac arrest patients with ongoing CPR and might shorten significantly the time delay to post-resuscitation care. Methods: We simulated an eight-minute cardiac resuscitation situation during ambulance transport using CPR training manikins. We compared teams consisting of two experienced resuscitators with the performance of a mechanical chest compression device (LUCAS). Results: CPR-performance by two experienced resuscitators demonstrated ambivalent results. Whereas mean compression rate was within the recommended range (103/min, 95% CI: 93-113/min), mean compression depth was closely below the actually recommended compression depth of >5 cm (49.7 mm, 95% CI: 46.1-53.3mm). Nevertheless, only a mean of two thirds (67%) of all compressions were classified as manually correct (defined as sternal compression depth >5 cm). In contrast, the LUCAS device showed a constant and reliable CPR performance (99.96% correctly applied chest compressions correctly applied within the device programmed parameters, P = 0.0162) with almost no variance between the different sequences. Conclusion: The LUCAS CPR device represents a reliable alternative to manual CPR in a moving ambulance vehicle during emergency evacuation. Furthermore, it needs less human resources and is safer for the EMS personnel. © 2013 Informa UK, Ltd.

Van Heeswijk R.B.,University of Lausanne | Van Heeswijk R.B.,Biomedical Imaging Center | De Blois J.,University of Lausanne | De Blois J.,Laval University | And 9 more authors.
Circulation: Cardiovascular Imaging | Year: 2013

Background-The goal of this study was to characterize the performance of fluorine-19 (19F) cardiac magnetic resonance (CMR) for the specific detection of inflammatory cells in a mouse model of myocarditis. Intravenously administered perfluorocarbons are taken up by infiltrating inflammatory cells and can be detected by 19F-CMR. 19F-labeled cells should, therefore, generate an exclusive signal at the inflamed regions within the myocardium. Methods and Results-Experimental autoimmune myocarditis was induced in BALB/c mice. After intravenous injection of 2×200 μL of a perfluorocarbon on day 19 and 20 (n=9) after immunization, in vivo 19F-CMR was performed at the peak of myocardial inflammation (day 21). In 5 additional animals, perfluorocarbon combined with FITC (fluorescein isothiocyanate) was administered for postmortem immunofluorescence and flow-cytometry analyses. Control experiments were performed in 9 animals. In vivo 19F-CMR detected myocardial inflammation in all experimental autoimmune myocarditis-positive animals. Its resolution was sufficient to identify even small inflammatory foci, that is, at the surface of the right ventricle. Postmortem immunohistochemistry and flow cytometry confirmed the presence of perfluorocarbon in macrophages, dendritic cells, and granulocytes, but not in lymphocytes. The myocardial volume of elevated 19F signal (rs=0.96; P<0.001), the 19F signal-to-noise ratio (rs=0.92; P<0.001), and the 19F signal integral (r s=0.96; P<0.001) at day 21 correlated with the histological myocarditis severity score.Conclusions-In vivo 19F-CMR was successfully used to visualize the inflammation specifically and robustly in experimental autoimmune myocarditis, and thus allowed for an unprecedented insight into the involvement of inflammatory cells in the disease process. © 2013 American Heart Association, Inc.

Kania G.,University of Zürich | Kania G.,Zurich Regional Health Center | Blyszczuk P.,University of Zürich | Blyszczuk P.,Zurich Regional Health Center | And 4 more authors.
Swiss Medical Weekly | Year: 2013

Inflammatory dilated cardiomyopathy (iDCM) denotes cardiac dysfunction due to myocardial inflammation (myocarditis). Progressively impaired cardiac contractility, fibrosis and dilation of heart chambers characterise iDCM phenotypically, and are associated with poor clinical prognosis. Cardiotropic infections followed by autoimmune responses against heart tissue are the most common cause of iDCM. The pathophysiology of iDCM is still poorly understood. Nevertheless, our understanding of the molecular mechanisms of inflammatory heart failure advanced during recent years. In fact, recent mechanistic insights might open the view for novel diagnostic and therapeutic approaches for iDCM patients in the future. In this review we update our knowledge on disease mechanisms, summarise current clinical approaches for iDCM patients, and discuss future therapeutic options.

PubMed | University of Zürich and Zurich Regional Health Center
Type: Journal Article | Journal: PloS one | Year: 2016

Perioperative myocardial ischemia is common in high-risk patients. The use of interventional revascularisation or even thrombolysis is limited in this patient subset due to exceedingly high bleeding risks. Blockade of voltage-gated sodium channels (VGSC) with lidocaine had been suggested to reduce infarct size and cardiomyocyte cell death in ischemia/reperfusion models. However, the impact of lidocaine on cardiac function during sustained ischemia still remains unclear.Sustained myocardial ischemia was induced by ligation of the left anterior descending artery in 12-16 weeks old male BALB/c mice. Subcutaneous lidocaine (30 mg/kg) was used to block VGSC. Cardiac function was quantified at baseline and at 72h by conventional and speckle-tracking based echocardiography to allow high-sensitivity in vivo phenotyping. Infarct size and cardiomyocyte cell death were assessed post mortem histologically and indirectly using troponin measurements.Ischemia strongly impaired both, global systolic and diastolic function, which were partially rescued in lidocaine treated in mice. No differences regarding infarct size and cardiomyocyte cell death were observed. Mechanistically, and as shown with speckle-tracking analysis, lidocaine specifically improves residual contractility in the ischemic but not in the remote, non-ischemic myocardium.VGSC blockade with lidocaine rescues function of ischemic myocardium as a potential bridging to revascularisation in the setting of perioperative myocardial ischemia.

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