DILATED CARDIOMYOPATHY IN TRANSGENIC MICE WITH CARDIAC-SPECIFIC OVEREXPRESSION OF TUMOR-NECROSIS-FACTOR-ALPHA

The failing human heart expresses tumor necrosis factor-alpha (TNF-alp ha). However, its pathophysiological significance is not clear. We pre viously reported that robust overexpression of TNF-alpha in the murine heart causes lethal myocarditis. In this study, we modified the trans gene to reduce the production of TNF-alpha by preserving the destabili zing sequence in TNF-alpha cDNA. Expression was driven by the murine a lpha-myosin heavy chain promoter. Use of this modified construct allow ed us to establish a murine transgenic line (TG). TG offspring were ex amined at 6, 12, and 24 weeks. All showed a significantly higher heart weight-to-body weight ratio. Northern blot analysis confirmed the exp ression of transgene in the heart, and enzyme-linked immunosorbent ass ay demonstrated the presence of TNF-alpha protein. The TG heart demons trated a mild, diffuse, lymphohistiocytic interstitial inflammatory in filtrate. Cardiomyocyte necrosis and apoptosis were present but not ab undant. Magnetic resonance imaging showed that the TG heart was signif icantly dilated with reduced ejection fraction. Although the left vent ricular dP/dt(max) was not different at baseline, its responsiveness t o isoproterenol was significantly blunted in TG. Atrial natriuretic fa ctor was expressed in the TG ventricle. A group of TG died spontaneous ly, and subsequent autopsies revealed exceptional dilatation of the he art, increased lung weight, and pleural effusion, suggesting that they died of congestive heart failure. The cumulative mortality rate at 6 months was 23%. In conclusion, the mouse overexpressing TNF-alpha reca pitulated the phenotype of congestive heart failure. This provides a n ovel model to elucidate the role of this cytokine in the development o f congestive heart failure.