Sandra Pinkert1,2, Babette Dieringer2, Robert Klopfleisch3, Konstantinos Savvatis4,5, Sophie Van Linthout6, Markian Pryshliak2, Carsten Tschöpe6, Karin Klingel7, Jens Kurreck2, Antje Beling8, Henry Fechner2. 1. Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Institute of Biochemistry, Germany (S.P., A.B.). 2. Department of Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, Germany (S.P., B.D., M.P., J.K., H.F.). 3. Institute of Veterinary Pathology, Freie Universität Berlin, Germany (R.K.). 4. Inherited Cardiovascular Diseases Unit, Barts Heart Centre, Barts Health NHS Trust, London, United Kingdom (K.S.). 5. William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London (K.S.). 6. Berlin-Brandenburg Center for Regenerative Therapies, Campus Virchow Klinikum, Germany (S.V.L., C.T.). 7. Cardiopathology, Institute for Pathology and Neuropathology, University Hospital Tuebingen, Germany (K.K.). 8. DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Germany (A.B.).
Abstract
BACKGROUND: Coxsackie-B-viruses (CVB) are frequent causes of acute myocarditis and dilated cardiomyopathy, but an effective antiviral therapy is still not available. Previously, we and others have demonstrated that treatment with an engineered sCAR-Fc (soluble coxsackievirus-adenovirus receptor fused to the carboxyl-terminus of human IgG) efficiently neutralizes CVB3 and inhibits the development of cardiac dysfunction in mice with acute CVB3-induced myocarditis. In this study, we analyzed the potential of sCAR-Fc for treatment of chronic CVB3-induced myocarditis in an outbred NMRI mouse model. METHODS: NMRI mice were infected with the CVB3 strain 31-1-93 and treated with a sCAR-Fc expressing adeno-associated virus 9 vector 1, 3, and 7 days after CVB3 infection. Chronic myocarditis was analyzed on day 28 after infection. RESULTS: Initial investigations showed that NMRI mice develop pronounced chronic myocarditis between day 18 and day 28 after infection with the CVB3 strain 31-1-93. Chronic cardiac infection was characterized by inflammation and fibrosis as well as persistence of viral genomes in the heart tissue and by cardiac dysfunction. Treatment of NMRI mice resulted in a distinct reduction of cardiac inflammation and fibrosis and almost complete elimination of virus RNA from the heart by day 28 after infection. Moreover, hemodynamic measurement revealed improved cardiac contractility and diastolic relaxation in treated mice compared with mice treated with a control vector (mean±SD; maximal pressure, 81.9±9.2 versus 69.4±8.6 mm Hg, P=0.02; left ventricular ejection fraction, 68.9±8.5 versus 54.2±11.5%, P=0.02; dP/dtmax, 7275.2±1674 versus 4432.6±1107 mm Hg/s, P=0.004; dP/dtmin, -4046.9±776 versus -3146.3±642 mm Hg/s, P=0.046). The therapeutic potential of sCAR-Fc is limited, however, since postponed start of sCAR-Fc treatment either 3 or 7 days after infection could not attenuate myocardial injury. CONCLUSIONS: Early therapeutic employment of sCAR-Fc, initiated at the beginning of the primary viremia, inhibits the development of chronic CVB3-induced myocarditis and improves the cardiac function to a level equivalent to that of uninfected animals.
BACKGROUND: Coxsackie-B-viruses (CVB) are frequent causes of acute myocarditis and dilated cardiomyopathy, but an effective antiviral therapy is still not available. Previously, we and others have demonstrated that treatment with an engineered sCAR-Fc (soluble coxsackievirus-adenovirus receptor fused to the carboxyl-terminus of human IgG) efficiently neutralizes CVB3 and inhibits the development of cardiac dysfunction in mice with acute CVB3-induced myocarditis. In this study, we analyzed the potential of sCAR-Fc for treatment of chronic CVB3-induced myocarditis in an outbred NMRI mouse model. METHODS: NMRI mice were infected with the CVB3 strain 31-1-93 and treated with a sCAR-Fc expressing adeno-associated virus 9 vector 1, 3, and 7 days after CVB3infection. Chronic myocarditis was analyzed on day 28 after infection. RESULTS: Initial investigations showed that NMRI mice develop pronounced chronic myocarditis between day 18 and day 28 after infection with the CVB3 strain 31-1-93. Chronic cardiac infection was characterized by inflammation and fibrosis as well as persistence of viral genomes in the heart tissue and by cardiac dysfunction. Treatment of NMRI mice resulted in a distinct reduction of cardiac inflammation and fibrosis and almost complete elimination of virus RNA from the heart by day 28 after infection. Moreover, hemodynamic measurement revealed improved cardiac contractility and diastolic relaxation in treated mice compared with mice treated with a control vector (mean±SD; maximal pressure, 81.9±9.2 versus 69.4±8.6 mm Hg, P=0.02; left ventricular ejection fraction, 68.9±8.5 versus 54.2±11.5%, P=0.02; dP/dtmax, 7275.2±1674 versus 4432.6±1107 mm Hg/s, P=0.004; dP/dtmin, -4046.9±776 versus -3146.3±642 mm Hg/s, P=0.046). The therapeutic potential of sCAR-Fc is limited, however, since postponed start of sCAR-Fc treatment either 3 or 7 days after infection could not attenuate myocardial injury. CONCLUSIONS: Early therapeutic employment of sCAR-Fc, initiated at the beginning of the primary viremia, inhibits the development of chronic CVB3-induced myocarditis and improves the cardiac function to a level equivalent to that of uninfected animals.
Authors: Fabiola B Sozzi; Elisa Gherbesi; Andrea Faggiano; Eleonora Gnan; Alessio Maruccio; Marco Schiavone; Laura Iacuzio; Stefano Carugo Journal: Front Cardiovasc Med Date: 2022-06-20
Authors: Carsten Tschöpe; Enrico Ammirati; Biykem Bozkurt; Alida L P Caforio; Leslie T Cooper; Stephan B Felix; Joshua M Hare; Bettina Heidecker; Stephane Heymans; Norbert Hübner; Sebastian Kelle; Karin Klingel; Henrike Maatz; Abdul S Parwani; Frank Spillmann; Randall C Starling; Hiroyuki Tsutsui; Petar Seferovic; Sophie Van Linthout Journal: Nat Rev Cardiol Date: 2020-10-12 Impact factor: 49.421