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This Article Full Text Full Text (PDF) All Versions of this Article: 93/8/982    most recent expphysiol.2008.042788v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Zhan, E. Articles by Yang, X.-P. PubMed PubMed Citation Articles by Zhan, E. Articles by Yang, X.-P. Related Collections Heart/Cardiac Muscle

¹ Hypertension and Vascular Research Division, Department of Internal Medicine² Department of Biostatistics and Research Epidemiology, Henry Ford Hospital, Detroit, MI, USA

Hormonal replacement therapy (HRT) has recently been shown to increase the risk of cardiovascular events in women. However, it is not clear whether the adverse effect of HRT is related to dosage and/or the presence of progestin. Using a mouse model of myocardial infarction (MI), we studied the dose-effect of oestrogen replacement on mortality and cardiac remodelling and dysfunction post-MI in the absence of progestin. Six-week-old females were subjected to ovariectomy (OVX). A pellet containing a low, moderate or high dose of 17β-oestradiol (E₂; 0.42, 4.2 or 18.8 µg day^–1) or placebo was implanted subcutaneously on the day of OVX. Myocardial infarction was induced 8 weeks later, and cardiac morphology and function were evaluated 8 weeks after MI. We found that E₂ at moderate and high doses adversely affected mortality. A low dose of E₂ that restored plasma oestrogen close to physiological levels had no significant effect on mortality but tended to improve cardiac function and remodelling, associated with reduced fibrosis and increased capillary density. At the moderate dose, E₂ exacerbated cardiac fibrosis, hypertrophy, dysfunction and dilatation, associated with liver and kidney enlargement and ascites. Protein kinase C and extracellular signal-regulated kinase were increased by MI but were not affected by E₂. In summary, E₂ at a low dose tended to be cardioprotective. At increased doses that raised plasma oestrogen far beyond the physiological level, E₂ was detrimental to the heart. Our data suggest that dosage should be an important consideration when studying the effect of oestrogen replacement on the heart.

(Received 24 March 2008; accepted after revision 14 May 2008; first published online 16 May 2008)
Corresponding author X.-P. Yang: Hypertension and Vascular Research Division, Department of Medicine, Henry Ford Hospital & Wayne State University, 2799 West Grand Boulevard, Detroit, MI 48202, USA. Email: xpyang1{at}hfhs.org