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Sex Hormones and Cardiomyopathic Phenotype Induced by Cardiac ß₂-Adrenergic Receptor Overexpression

Baker Heart Research Institute and Alfred Heart Centre, Alfred Hospital, Melbourne, Victoria 8008, Australia

Address all correspondence and requests for reprints to: Xiao-Jun Du, Baker Medical Research Institute, PO Box 6492, St Kilda Road Central, Melbourne, Victoria 8008, Australia. E-mail: xiaojun.du{at}baker.edu.au.

Sex differences in cardiomyopathic phenotype and the role of gonadal status were studied in mice with cardiac overexpression of ß₂-adrenergic receptors (ARs) over 6–15 months (mo) of age. Survival to 15 mo was 96% in wild-type mice but was poorer in transgenic (TG) mice and lower for males than females (13% vs. 56%, P < 0.001). Echocardiography demonstrated progressive left ventricular (LV) dilatation and reduction in LV fractional shortening in male but much less marked changes in female TG mice. Incidences of atrial thrombosis, pleural effusion and lung congestion were higher and myocyte size and fibrosis in the LV were greater in TG males than females. Deprivation of testicular hormones by castration during 3–15 mo of age improved survival and significantly ameliorated LV dysfunction, remodeling, and hypertrophy compared with intact TG males. No significant effect, except for a trend of a better survival, was detected by ovariectomy in TG females. In conclusion, cardiac ß₂-AR overexpression at a high level leads to cardiomyopathy and heart failure with aging. Female mice had less cardiac remodeling, dysfunction, and pathology and a marked survival advantage over male mice, and this was independent of prevailing levels of ovarian hormones. TG males showed benefit from orchiectomy, suggesting a contribution by testicular hormones to the progression of the cardiomyopathic phenotype.

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