Estrogen attenuates chronic volume overload induced structural and functional remodeling in male rat hearts

Abstract

We have previously reported gender differences in ventricular remodeling and development of heart failure using the aortocaval fistula model of chronic volume overload in rats. In contrast to males, female rats exhibited no adverse ventricular remodeling and less mortality in response to volume overload. This gender-specific cardioprotection was lost following ovariectomy and was partially restored using estrogen replacement. However, it is not known if estrogen treatment would be as effective in males. The purpose of this study was to evaluate the structural and functional effects of estrogen in male rats subjected to chronic volume overload. Four groups of male rats were studied at 3 days and 8 wk postsurgery as follows: fistula and sham-operated controls, with and without estrogen treatment. Biochemical and histological studies were performed at 3 days postsurgery, with chronic structural and functional effects studied at 8 wk. Measurement of systolic and diastolic pressure-volume relationships was obtained using a blood-perfused isolated heart preparation. Both fistula groups developed significant ventricular hypertrophy after 8 wk of volume overload. Untreated rats with fistula exhibited extensive ventricular dilatation, which was coupled with a loss of systolic function. Estrogen attenuated left ventricular dilatation and maintained function in treated rats. Estrogen treatment was also associated with a reduction in oxidative stress and circulating endothelin-1 levels, as well as prevention of matrix metalloproteinase-2 and -9 activation and breakdown of ventricular collagen in the early stage of remodeling. These data demonstrate that estrogen attenuates ventricular remodeling and disease progression in male rats subjected to chronic volume overload.

Estrogen improves TIMP-MMP balance and collagen distribution in volume-overloaded hearts of ovariectomized females

“…In previous studies using male rats, a significant number developed symptomatic CHF by 8 wk postfistula (12). Further, we demonstrated a significant cardioprotective effect of estrogen treatment in male and ovariectomized female rats with volume overload at this time point (13,14).…”

Estrogenic modulation of inflammation-related genes in male rats following volume overload

“…This cardioprotection is lost in ovariectomized rats but can be largely restored by supplementary estrogen (8,16,18). Likewise, the adverse remodeling in male rats can be significantly attenuated by estrogen supplementation (19). However, the specific mechanisms underlying estrogen's protective effects on the heart have thus far not been elucidated.…”

“…Congruent with this, the cardioprotection produced by estrogen supplementation was also equally effective in males, as reflected by significant attenuation of myocardial remodeling following volume overload, thereby maintaining LV pump function (19). This compelling observation in male rats demonstrates the powerful effects that estrogen can exert.…”

Effects of a myofilament calcium sensitizer on left ventricular systolic and diastolic function in rats with volume overload heart failure

“…In this model, chronically increased LV preload leads to progressive LV pump failure, which is classified into three clinically relevant stages: 1) pre-HF [4-wk ACF; marked LV dilation, increased LV wall stress, mild LV dysfunction (ϳ10% decrease in % fractional shortening, %FS); no pulmonary congestion/edema], 2) established HF [8-wk ACF; severe LV dilation, significant LV systolic (25% decrease in %FS, ϳ50% decrease in end-systolic elastance, Ees, and preload-recruitable stroke work, PRSW) and diastolic dysfunction (10 -27% increase in and dP/dt min , respectively); no pulmonary congestion or edema], and 3) end-stage HF (15-21-wk ACF; LV pump failure with pulmonary congestion/edema) (17,19,34). This model is commonly used to identify molecular and cellular mechanisms driving disease progression and to test novel therapeutic approaches for improving LV structure and function (13,21,40).We have previously characterized a technique to reverse (REV, close) the ACF (19). In that report, REV during pre-HF (i.e., 4 wk post-ACF) results in rapid structural recovery but delayed functional recovery (19).…”