Sex-related Differences in Heart Failure May be Related to Differences in TNF-Receptor Expression
Data from epidemiological studies suggests that the prognosis for heart failure in women is better than in men. Dilated cardiomyopathy can be induced in mice by overexpressing tumor necrosis factor-a(TNF-a). Similar to human disease, these TNF1.6 mice develop ventricular hypertrophy, cardiac dilatation, interstitital infiltrates and fibrosis, and attenuation of adrenergic responsiveness. In the current study (Kadokami, et al Journal of Clinical Investigation 106:589, 2000), sex-related difference in survival of TNF1.6 mice was examined, as well as cellular pathways that might mediate these differences.
Results: 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 was similar in males and females. However, myocardial expression of TNF receptor mRNAs (both type I and type II) was significantly higher in male mice in both transgenic and wild-type littermates, whereas no sex-specific differences were observed in peripheral white blood cells or liver tissue. After TNF-achallenge, myocardial but not liver production of ceramide was significantly higher in male than in female mice.
Conclusion: 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-a.
Editorial Note: These data are interesting since heart disease is one of the major causes of death in patients with rheumatoid arthritis (RA). Overexpression of TNF-aoccurs in the joints of RA patients and the new anti-TNF agents such as etanercept (Enbrel™) and infliximab (Remicade™) are very effective treatments for RA. Whether overexpression of TNF-aoccurs in the hearts of RA patients and contributes to the cardiac moritality of RA is not clear but is an interesting question for future investigation. If true, treatment with anti-TNF agents could reduce mortality in RA.