Sex-related survival differences in murine cardiomyopathy are associated with differences in TNF-receptor expression

Epidemiological evidence suggests that the prognosis of heart failure in wo men is better than in men. In our murine model of dilated cardiomyopathy ar ising from cardiac-specific overexpression of TNF-alpha, the 6-month surviv al rate mas significantly better in females than in males. Young female tra nsgenic mice exhibited left ventricular mall thickening without dilatation, whereas age-matched male transgenic hearts were markedly dilated. Basal an d isoproterenol-stimulated fractional shortening was preserved in female tr ansgenic mice, but not in male transgenic mice. Myocardial expression of pr oinflammatory cytokines and the extent of myocardial infiltrates were simil ar in male and female transgenic mice. Myocardial expression of TNF-recepto r mRNAs (type I and type II) was significantly higher in male mice in both transgenic and wild-type littermates, whereas sex-specific differences were not observed in either peripheral white blood cells or liver tissue. After TNF-alpha challenge, myocardial but not liver production of ceramide was s ignificantly higher in male than in female mice. Thus, differential express ion of myocardial TNF receptors may contribute to sex differences in the se verity of congestive heart failure and mortality consequent to cardiac-spec ific overexpression of TNF-alpha.