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Sex-related survival differences in murine cardiomyopathy are associated with differences in TNF-receptor expression
Toshiaki Kadokami, … , Carole S. Frye, Arthur M. Feldman
Toshiaki Kadokami, … , Carole S. Frye, Arthur M. Feldman
Published August 15, 2000
Citation Information: J Clin Invest. 2000;106(4):589-597. https://doi.org/10.1172/JCI9307.
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Article

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

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Abstract

Epidemiological evidence suggests that the prognosis of heart failure in women is better than in men. In our murine model of dilated cardiomyopathy arising from cardiac-specific overexpression of TNF-α, the 6-month survival rate was significantly better in females than in males. Young female transgenic mice exhibited left ventricular wall thickening without dilatation, whereas age-matched male transgenic hearts were markedly dilated. Basal and isoproterenol-stimulated fractional shortening was preserved in female transgenic mice, but not in male transgenic mice. Myocardial expression of proinflammatory cytokines and the extent of myocardial infiltrates were similar in male and female transgenic mice. Myocardial expression of TNF-receptor 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-α challenge, myocardial but not liver production of ceramide was significantly higher in male than in female mice. Thus, differential expression of myocardial TNF receptors may contribute to sex differences in the severity of congestive heart failure and mortality consequent to cardiac-specific overexpression of TNF-α.

Authors

Toshiaki Kadokami, Charles F. McTiernan, Toru Kubota, Carole S. Frye, Arthur M. Feldman

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Figure 2

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Echocardiographic studies in TNF1.6 mice. (a–h) Representative images of...
Echocardiographic studies in TNF1.6 mice. (a–h) Representative images of M-mode echocardiogram of TNF1.6 mice (a–d) and wild-type littermates (e–h). Male TNF1.6 mice exhibited a markedly dilated left ventricle with reduced fractional shortening (a) and poor responsiveness to isoproterenol (b). Female TNF1.6 mice showed hypertrophied but not dilated left ventricle (c) with relatively preserved isoproterenol responsiveness (d). Both male and female wild-type mice had good left ventricular systolic function and showed a significant increase in fractional shortening after isoproterenol challenge (e–h). (i) Left ventricular fractional shortening before (filled bars) and after (open bars) isoproterenol injection in TNF1.6 and wild-type mice. Wild-type mice of both sexes showed preserved systolic function at baseline measurement, and fractional shortening was significantly increased up to 40% after isoproterenol challenge. By contrast, male TNF1.6 mice exhibited decreased fractional shortening at baseline and completely lost the responsiveness to β-adrenergic stimulation. Basal left ventricular contraction was preserved in female TNF1.6 mice, whereas the increase in fractional shortening after isoproterenol injection was significant but impaired. Values are mean ± SD. TG, TNF1.6 mice; WT, wild-type mice; M, male; F, female; FS, fractional shortening; NS, not significant. AP < 0.05 vs. WT; BP < 0.01; CP = 0.001. (j) Correlation of left ventricular mass estimated from echocardiographic measurements and gravimetric mass determination. A total of 16 TNF1.6 or wild-type mice were sacrificed immediately after echocardiographic examination, hearts were excised, and left ventricles were trimmed and weighed. Left ventricular mass was calculated using the formula in the text. Left ventricular mass determined by the two different methods showed an excellent correlation (P < 0.001).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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