TRANSGENIC EXPRESSION OF REPLICATION-RESTRICTED ENTEROVIRAL GENOMES IN HEART-MUSCLE INDUCES DEFECTIVE EXCITATION-CONTRACTION COUPLING AND DILATED CARDIOMYOPATHY

Numerous studies have implicated Coxsackievirus in acute and chronic h eart failure. Although enteroviral nucleic acids have been detected in selected patients with dilated cardiomyopathy, the significance of su ch persistent nucleic acids is unknown. To investigate the mechanisms by which restricted viral replication with low level expression of Cox sackieviral proteins may be able to induce cardiomyopathy, we generate d transgenic mice which express a replication-restricted full-length C oxsackievirus B3 (CVB3) cDNA mutant (CVB3 Delta VP0) in the heart driv en by the cardiac myocyte-specific myosin light chain-2v (MLC-2v) prom oter. CVB3 Delta VP0 was generated by mutating infectious CVB3 cDNA at the VP4/VP2 autocatalytic cleavage site from Asn-Ser to Lys-Ala. Card iac-specific expression of this cDNA leads to synthesis of positive- a nd negative-strand viral RNA in the heart without formation of infecti ous viral progeny. Histopathologic analysis of transgenic hearts revea led typical morphologic features of myocardial interstitial fibrosis a nd in some cases degeneration of myocytes, thus resembling dilated car diomyopathy in humans. There was also an increase in ventricular atria l natriuretic factor mRNA levels, demonstrating activation of the embr yonic program of gene expression typical of ventricular hypertrophy an d failure. Echocardiographic analysis demonstrated the presence of lef t ventricular dilation and decreased systolic function in the transgen ic mice compared with wild-type littermates, evidenced by increased ve ntricular end-diastolic and end-systolic dimensions and decreased frac tional shortening. Analysis of isolated myocytes from transgenic mice demonstrate that there is defective excitation-contraction coupling an d a decrease in the magnitude of isolated cell shortening. These data demonstrate that restricted replication of enteroviral genomes in the heart can induce dilated cardiomyopathy with excitation-contraction co upling abnormalities similar to pressure overload models of dilated ca rdiomyopathy.