Therapeutic effects of FTY720, a new immunosuppressive agent, in a murine model of acute viral myocarditis

• Published in: Journal of the American College of Cardiology 2001-05, Vol.37 (6), p.1713-1718
• Main Authors: Miyamoto, Tadashi, Matsumori, Akira, Hwang, Myung-Woo, Nishio, Ryosuke, Ito, Haruyasu, Sasayama, Shigetake
• Format: Article
• Language: English
• Subjects: Acute Disease; Animals; Biological and medical sciences; Cardiovascular system; Cardiovirus Infections - complications; Disease Models, Animal; Drug Evaluation, Preclinical; Encephalomyocarditis virus; Fingolimod Hydrochloride; Humans; Immunosuppressive Agents - pharmacology; Immunosuppressive Agents - therapeutic use; Interferon-gamma - analysis; Interleukin-12 - analysis; Interleukin-2 - analysis; Male; Medical sciences; Mice; Mice, Inbred DBA; Miscellaneous; Myocarditis - diagnosis; Myocarditis - drug therapy; Myocarditis - immunology; Myocarditis - mortality; Myocarditis - virology; Nitric Oxide - analysis; Pharmacology. Drug treatments; Proportional Hazards Models; Propylene Glycols - pharmacology; Propylene Glycols - therapeutic use; Severity of Illness Index; Sphingosine - analogs & derivatives; Survival Analysis; Treatment Outcome; Tumor Necrosis Factor-alpha - analysis
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/S0735-1097(01)01204-9

OBJECTIVES This study examines the efficacy of FTY720 (FTY), a new immunosuppressor, in the treatment of acute viral myocarditis in a murine model. BACKGROUND Immunosuppressive agents have no proven therapeutic efficacy in experimental or clinical myocarditis. METHODS Encephalomyocarditis virus was inoculated i.p. in DBA/2 mice on day 0. Postinoculation treatment consisted of FTY 10 mg/kg/day p.o. (FTY group), or cyclosporine A (CsA) 40 mg/kg/day p.o. (CsA group) or distilled water p.o. only (control group). Survival until day 14, as well as cardiac histopathology, virus concentrations, cytokines (interleukin [IL]-2, IL-12, interferon [IFN]-gamma and tumor necrosis factor [TNF]-alpha) and nitric oxide (NO) on day 5 were examined. RESULTS In the control and CsA groups, all mice died within 10 and 7 days, respectively. However, in the FTY group, 27% of the animals survived up to day 14. Compared with the control group, 1) histological scores were significantly lower in the FTY group but unchanged in the CsA group; 2) virus concentration was significantly higher in the CsA group but not in the FTY group; 3) expressions of IL-2, IL-12 and IFN-gamma in the heart were suppressed in both the FTY and CsA groups, though suppression was weaker in the FTY group; 4) TNF-alpha and NO were significantly increased in the CsA group but not in the FTY group. CONCLUSIONS FTY720 had a significant therapeutic effect in acute experimental myocarditis without inducing excessive virus replication. This report is the first to describe a beneficial effect by an immunosuppressive agent in the treatment of acute viral myocarditis.