We have previously demonstrated that TNF-α is produced locally within the heart during endotoxemia and following thermal injury. To determine the specific effects of TNF-α production by myocytes in vivo, we developed transgenic mice in which expression of the murine TNF-cDNA was driven by the complete murine alpha-myosin heavy chain promoter. An SV-40 3' sequence was included for transcription termination and polyadenylation.

Six transgenic founders (3 male) were produced. Three of the founders developed an identical illness consisting of tachypnea, decreased activity, and hunched posture. One founder died on day of life 41, and two additional founders were euthanized prior to death on days of life 50 and 85. All three founders were clinically normal until the day of their death. Anatomic and histologic findings were similar in all three animals. Gross examination revealed normal anatomic relationships, a globular dilated heart, and bilateral pleural effusions. Histologic examination revealed significant dilatation of right and left ventricular chambers, and atrial thrombosis. The myocardium was altered by prominent myocarditis affecting both the free walls and the septum. Inflammatory cells consisted primarily of macrophages, but with pronounced focal areas of neutrophilic or lymphocytic infiltrate. Fibrosis was noted in the midzonal areas of the free wall, and to a lesser degree in the subendocardium. There was no inflammation or pathological alteration in any cardiac valve.

This is the first report detailing the effects of isolated, tissue-specific production of TNF-α by cardiac myocytes in vivo. This transgenic model may be useful for elucidating the molecular and physiologic pathogenesis of cardiac dysfunction, as well as novel strategies for its treatment.