Ganciclovir and cidofovir treatment of cytomegalovirus-induced myocarditis in mice

Abstract

The cardiovascular disease myocarditis is characterized by inflammation and necrosis of cardiac muscle. This disease has been associated with various viral etiologies, including cytomegalovirus (CMV). Murine CMV (MCMV) infection of adult BALB/c mice produces a disease with acute and chronic phases similar to that found in humans. In our murine model, we have investigated the therapeutic efficacy of antiviral drug administration on myocarditis. Two drugs commonly used for CMV treatment, ganciclovir and cidofovir, were subjected to trials, with both drugs showing potent antiviral activity against MCMV both in vitro and in vivo. The acute phase of myocarditis was significantly reduced when antiviral therapy commenced 24 h postinfection. Such treatment also reduced the severity of the chronic phase of myocarditis. In contrast, antiviral treatment commencing after the acute phase had no effect on chronic myocarditis. Reinfection of mice with MCMV caused exacerbation of myocardial inflammation. Such an increase in severity of myocarditis could be prevented with either ganciclovir or cidofovir treatment, but the preexisting inflammation and necrosis of the myocardium persisted. These data highlight possible therapeutic uses of antiviral drugs in viral myocarditis as well as further elucidating the pathogenic nature of the disease.

FIG. 1

Antiviral therapy reduces MCMV titers in major target organs. BALB/c mice were inoculated with 10⁴ PFU of MCMV i.p. at day 0 and treated with GCV (A) or CDV (B) daily from day 1 to 7 p.i. or treated with saline as a placebo. The average numbers (+SD) of PFU per gram of liver, spleen, and salivary gland at day 7 p.i. from groups of five mice per dose are shown.

FIG. 2

Early antiviral treatment reduces the severity of acute MCMV-induced myocarditis. BALB/c mice were inoculated with 10⁴ PFU of MCMV i.p. at day 0 and treated with either GCV (A) or CDV (B) daily from day 1 to 7 p.i. or treated with saline as a placebo. The average numbers (+SD) of inflammatory foci per heart section at day 7 p.i. from groups of five mice per dose are shown.

FIG. 3

Early antiviral therapy reduces the severity of chronic MCMV-induced myocarditis. BALB/c mice were inoculated with 10⁴ PFU of MCMV i.p. on day 0 and treated with either GCV at 40 mg/kg/day (A) or CDV at 5 mg/kg/day (B) from day 1 to 7 p.i. or treated with saline as a placebo. The average numbers (+SD) of inflammatory foci per heart section on day 35 p.i. from groups of five mice are shown.

FIG. 4

Late antiviral therapy has no therapeutic effect on chronic MCMV-induced myocarditis. BALB/c mice were inoculated with 10⁴ PFU of MCMV i.p. on day 0 and treated with either GCV at 40 mg/kg/day (A) or CDV at 5 mg/kg/day (B) from day 14 to 35 p.i. or treated with saline as a placebo. The average numbers (+SD) of inflammatory foci per heart section on day 35 p.i. from groups of five mice are shown.

FIG. 5

Exacerbation of myocarditis by virus reinfection is prevented with antiviral therapy. BALB/c mice were inoculated with 10⁴ PFU of MCMV (K181 strain) i.p. on day 0. The mice were then reinfected with 10⁴ PFU of either K181 (K181/K181) or G4 (K181/G4) MCMV i.p. on day 56 p.i. and then treated with either GCV at 40 mg/kg/day or CDV at 5 mg/kg/day from day 57 to day 63 p.i. or treated with saline as a placebo. The average numbers (+ SD) of inflammatory foci per heart section at day 63 p.i. from groups of five mice are shown.