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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

View larger version (11K): [in a new window]   Figure 1 Study plan. Animals were ovariectomized (Ovex) 21 days before myocardial infarction (MI), with initiation of placebo or estrogen treatment at day –14 (P/E2), and baseline echocardiographic studies (Echo) performed on day –7 and day 35. Animals were harvested one day after MI for the short-term study (upper panel) and six weeks after MI for the long-term study (lower panel).

View larger version (15K): [in a new window]   Figure 2 Kaplan-Meier survival curve. The mortality in the E2-MI animals was significantly greater than in the Placebo-MI animals p < 0.02. *p 0.05 E2-MI vs. E2-sham, p 0.05 E2-MI vs. placebo-MI. Abbreviations as in Figure 1.

View larger version (13K): [in a new window]   Figure 3 Mean infarct size six weeks after induction of MI (left panel). Transverse section of a heart from a placebo-MI mouse stained with trichrome, which stains myocardium red and scar tissue blue. p 0.05 E2-MI vs. placebo-MI (right panel). Abbreviations as in Figure 1.

View larger version (7K): [in a new window]   Figure 4 Echocardiographic studies at baseline and five weeks after MI demonstrating increased end-diastolic and end-systolic diameters indexed to bodyweight (EDD/BW and ESD/BW), and a decreased fractional shortening (FS) in the infarcted animals. E2 significantly increased both EDD/BW and ESD/BW post-MI. E2 had no effect on fractional shortening. Open circles = placebo; filled circles = E2. Broken lines = sham; solid lines = MI. *p 0.05 placebo-MI vs. placebo-sham and E2-MI vs. E2-sham; p 0.05 E2-MI vs. placebo-MI. BL = baseline; FU = follow-up; other abbreviations as in Figure 1.

View larger version (24K): [in a new window]   Figure 5 (Left panels) Infarct-induced increases in left ventricular (LV) weight indexed to body weight (BW) (upper panels) or femur length (FL) (lower panels) were exacerbated by estrogen treatment. (Right panels) Regression analysis revealed greater left ventricular remodeling with increasing infarct size in E2-treated animals compared with placebo-treated animals. The femur length was only obtained in a subgroup of animals (8 E2-MI and 9 placebo-MI animals). *p 0.05 placebo-MI vs. placebo-sham and E2-MI vs. E2-sham; p 0.05 E2-MI vs. placebo-MI. Abbreviations as in Figure 1.

View larger version (17K): [in a new window]   Figure 6 Bar graphs demonstrating mean myocyte cross sectional areas measured in sham (white bars) and MI hearts (black bars) in the placebo and estrogen treated groups. The increase in myocyte cross-sectional (CS) area in the E2-MI mice was statistically significant whereas the modest increase in the placebo group was not. *p < 0.02 MI group vs. sham. Abbreviations as in Figure 1.

View larger version (20K): [in a new window]   Figure 7 (Left panel) Mean infarct size 24 h after induction of MI. (Right panel) Transverse sections of one heart stained with triphenyltetrazolium chloride demonstrating viable myocardium (red) and infarcted myocardium (white). p 0.01 E2-MI vs. placebo-MI. Abbreviations as in Figure 1.

View larger version (56K): [in a new window]   Figure 8 (A) Examples of transferase uridine nucleotide end-labeling method (TUNEL) staining of the peri-infarct zone in myocardial sections from placebo and 17-beta-estradiol (E2)–treated mice 24 h following coronary ligation. TUNEL-positive nuclei are green. Arrows indicate examples of TUNEL-positive cardiomyocyte nuclei. (B) Quantification of TUNEL-positive nuclei expressed as percent total nuclei on a given section. Infarct zone is shown on the left and peri-infarct zone on the right. (C) Caspase 3 activity measured within the infarct zone 24 h following coronary ligation. *p = 0.065, E2 vs. placebo. p < 0.05, E2 vs. placebo.