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Background: We have shown previously that 17beta-estradiol (E2) increases left ventricular (LV) and cardiomyocyte hypertrophy after myocardial infarction (MI). However, E2 decreases hypertrophy in pressure overload models. We hypothesized that the effect of estrogen on cardiac hypertrophy was dependent on the type of hypertrophic stimulus., Methods and Results: Ovariectomized wild-type female mice (n = 192) were given vehicle or E2 treatment followed by coronary ligation (MI), transverse aortic constriction (TAC), or sham operation. Signaling pathway activation was studied at 3, 24, and 48 hours, whereas echocardiography and hemodynamic studies were performed at 14 days. MI induced early but transient activation of p38 and p42/44 MAPK pathways, whereas TAC induced sustained activation of both pathways. E2 had no effect on these pathways, but increased Stat3 activation after MI while decreasing Stat3 activation after TAC. MI caused LV dilation and decreased fractional shortening (FS) that were unaltered by E2. TAC caused LV dilation, reduced FS, and increased LV mass, but in this model, E2 improved these parameters. After MI, E2 led to increases in myocyte cross-sectional area, atrial natriuretic peptide (ANP) and beta-myosin heavy chain (MHC) gene expression, but E2 diminished TAC-induced increases ANP and beta-MHC gene expression., Conclusions: These data demonstrate that the effects of E2 on LV and myocyte remodeling depend on the nature of the hypertrophic stimulus. The opposing influence of E2 on hypertrophy in these models may, in part, result from differential effects of E2 on Stat3 activation. Further work will be necessary to explore this and other potential mechanisms by which estrogen affects hypertrophy in these models.

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.

Left ventricular (LV) remodelling following myocardial infarction (MI) is associated with increased morbidity and mortality. Previous data suggest that angiotensin II (Ang II) plays a central role in the molecular events contributing to LV remodelling. We explored the effects of angiotensin-converting-enzyme (ACE) inhibition versus Ang II (AT(1)) receptor blockade on LV remodelling in mice post-MI. Mice underwent sham procedure or left coronary artery ligation, and received placebo, the AT(1) receptor antagonist, losartan or the ACE inhibitor, enalapril. At 6 weeks, echocardiography and haemodynamic studies were performed. Infarct size and interstitial collagen content were determined. Expression of genes encoding atrial natriuretic peptide (ANP), collagen type I, AT(1a) and AT(1b) receptors were measured. The placebo MI group showed increased LV end-diastolic diameter, LV end-systolic diameter with depressed fractional shortening ( P <0.01 versus shams), increased LV mass and volume (both P <0.01 versus shams). The placebo MI group also exhibited increased non-infarct zone collagen content ( P <0.01), ANP ( P <0.01) and collagen type 1 ( P <0.01) gene expression, with a non-significant rise in AT(1a) receptor gene expression. Neither losartan or enalapril prevented LV dilation or improved fractional shortening. Both similarly lowered systolic blood pressure ( P <0.01 for each versus placebo). Losartan and enalapril inhibited LV hypertrophy ( P <0.01), and decreased ANP ( P <0.01) and collagen type 1 gene expression ( P <0.05). Levels of AT(1a) receptor gene expression were higher than shams ( P <0.05 for both), but similar to placebo. AT(1b) receptor gene expression was much lower than that for AT(1a) receptor and similar in all groups. Thus, in this model, AT(1) receptor antagonism and ACE inhibition have equivalent inhibitory effects on myocardial hypertrophy and fibrosis. These results serve as an important basis for planned investigations to evaluate the anti-remodelling effects of these agents on mice in which genetic manipulations are used to disrupt components of the Ang II signalling system.

Presents information on a study on ventricular remodeling following myocardial infarction in a mouse. Importance of transgenic strains of mice as experimental species; Methods used in the study; Results of the study.