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Wetzikon, Switzerland

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. Source


Cakic S.,Zurich Regional Health Center | Eriksson U.,Zurich Regional Health Center | Eriksson U.,University of Zurich
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. Source


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. Source


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. Source


Valaperti A.,University of Zurich | 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. Source

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