Received March 24, 2008
Revised April 23, 2008
Accepted after revision May 14, 2008

¹ Henry Ford Hospital
² Henry Ford Health System & Wayne State University

^* To whom correspondence should be addressed. E-mail: xpyang1{at}hfhs.org.

	Abstract

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 estrogen replacement on mortality and cardiac remodeling 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 17-estradiol (E2, 0.42, 4.2, or 18.8 µg/day) or placebo was implanted subcutaneously on the day of ovx. MI 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 estrogen close to physiological levels had no significant effect on mortality but tended to improve cardiac function and remodeling, associated with reduced fibrosis and increased capillary density. At an increased dose, E2 exacerbated cardiac fibrosis, hypertrophy, dysfunction and dilatation, associated with liver and kidney enlargement and ascites. PKC and ERK1/2 were enhanced 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 estrogen 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 estrogen replacement on the heart.

Key Words: Cardiovascular, Heart, Ischaemia