CARDIAC-FAILURE IN TRANSGENIC MICE WITH MYOCARDIAL EXPRESSION OF TUMOR-NECROSIS-FACTOR-ALPHA

Background-Tumor necrosis factor-alpha (TNF-alpha) is a multifunctiona l cytokine that has been detected in several human cardiac-related con ditions, including congestive heart failure and septic cardiomyopathy. In these conditions, the origin of TNF-alpha secretion is, at least i n part, cardiac myocytes, Methods and Results-To determine the consequ ences of TNF-alpha production by cardiac myocytes in vivo, we develope d transgenic mice in which expression of a murine TNF-alpha coding seq uence was driven by the murine alpha-myosin heavy chain promoter. Four transgenic founders developed an identical illness consisting of tach ypnea, decreased activity, and hunched posture. In vivo, EGG-gated MRI of symptomatic transgenic mice documented a severe impairment of card iac function evidenced by biventricular dilatation and depressed eject ion fractions. All transgenic mice died prematurely. Pathological exam ination of affected animals revealed a globular dilated heart, bilater al pleural effusions, myocyte apoptosis, and transmural myocarditis in both the right and left ventricular free walls, septum, and atrial ch ambers. In all terminally ill animals, there was significant biventric ular fibrosis and atrial thrombosis. Conclusions-This is the first rep ort detailing the effects of tissue-specific production of TNF-alpha b y cardiac myocytes in vivo. These findings indicate that production of TNF-alpha by cardiac myocytes is sufficient to cause severe cardiac d isease and support a causal role for this cytokine in the pathogenesis of human cardiac disease.