BASIC SCIENCE
17-Beta-Estradiol increases cardiac remodeling and mortality in mice with myocardial infarction
Martin van Eickels, MD*,
Richard D. Patten, MD ,
Mark J. Aronovitz, MS,
Alawi Alsheikh-Ali, MD,
Kim Gostyla, BS,
Flore Celestin, BS,
Christian Grohe, MD*,
Michael E. Mendelsohn, MD, FACC and
Richard H. Karas, MD, PhD, FACC,*
* Medizinsche Poliklinik II, University of Bonn, Bonn, Germany
Molecular Cardiology Research Institute, Division of Cardiology and Department of Medicine, Tufts-New England Medical Center Hospitals Inc., Tufts University School of Medicine, Boston, Massachusetts, USA
Manuscript received September 9, 2002;
revised manuscript received February 11, 2003,
accepted February 20, 2003.
* Reprint requests and correspondence: Dr. Richard H. Karas, Molecular Cardiology Research Institute, New England Medical Center, 750 Washington Street, Box #80, Boston, Massachusetts 02111, USA.
rkaras{at}tufts-nemc.org
OBJECTIVES: This study was designed to examine the effects of estrogen replacement on infarct size, ventricular remodeling, and mortality after myocardial infarction (MI) in mice.
BACKGROUND: Observational and clinical studies suggest that the cardiovascular effects of hormone replacement therapy can differ depending on the patient population studied. No prospective studies have examined the effect of estrogen on outcomes following MI. We now examine the effects of estrogen replacement on infarct size, ventricular remodeling, and mortality after MI in mice.
METHODS: Myocardial infarction was induced by left coronary artery ligation in ovariectomized female mice treated with 17-beta-estradiol (E2) or placebo. At either one day or six weeks after MI, hemodynamic function was assessed, animals were euthanized, and infarct size was determined.
RESULTS: 17-Beta-estradiol–treated mice had smaller infarcts than placebo-treated animals both one day (18% decrease; p < 0.01), and six weeks (14% decrease; p < 0.05) following MI. E2 reduced cardiomyocyte apoptosis as assessed by the terminal deoxynucleotidyl transferase uridine nucleotide end-labeling method (50% reduction, p < 0.05) and caspase 3 activation (33% reduction, p < 0.05). Despite having smaller infarcts, however, left ventricular mass increased more in the E2-treated animals (16% greater; p < 0.01). Left ventricular weight was positively correlated with infarct size in the estrogen-treated animals (R2 = 0.79, p = 0.0001). 17-Beta-estradiol treatment also significantly increased mortality in the infarcted animals (relative risk of death = 2.4; 95% confidence interval 1.2 to 5.3).
CONCLUSIONS: Estrogen replacement therapy reduces infarct size and cardiomyocyte apoptosis in mice. However, estrogen increased post-MI ventricular remodeling and mortality. Further studies will be necessary to elucidate the mechanisms underlying the complex effects of estrogen observed in the present study.
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Abbreviations and Acronyms
| | BW | | body weight | | E2 | | 17-beta-estradiol | | ER | | estrogen receptor | | FL | | femur length | | HRT | | hormone replacement therapy | | LV | | left ventricular | | LVW | | left ventricular weight | | MI | | myocardial infarction | | TUNEL | | transferase uridine nucleotide end-labeling method |
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