Enhanced cardiac inflammation and fibrosis in ovariectomized hypertensive rats: a possible mechanism of diastolic dysfunction in postmenopausal women

Abstract

Diastolic dysfunction is more prevalent in individuals with hypertension, particularly postmenopausal women; however, the pathogenesis of diastolic dysfunction remains unknown. Pressure overload activates cardiac inflammation, which induces myocardial fibrosis and diastolic dysfunction in rats with a suprarenal aortic constriction (AC). Therefore, we examined the effects of bilateral ovariectomy (OVX) on left ventricle (LV) remodeling, diastolic dysfunction and cardiac inflammation in hypertensive female rats. Rats were randomized to OVX+AC, OVX and AC groups as well as a Control group receiving sham operations for both the procedures. Rats underwent OVX at 6 weeks and AC at 10 weeks (Day 0). At Day 28, OVX did not appear to affect arterial pressure, cardiac hypertrophy or LV fractional shortening in AC rats. However, OVX increased myocardial fibrosis, elevated LV end-diastolic pressure and reduced the transmitral Doppler spectra early to late filling velocity ratio in AC rats. AC-induced transient myocardial monocyte chemoattractant protein-1 expression and macrophage infiltration, both of which peaked at Day 3 and were augmented and prolonged by OVX. At Day 28, dihydroethidium staining revealed superoxide generation in the intramyocardial arterioles in the OVX+AC group but not in the AC group. NOX1, a functional subunit of nicotinamide adenine dinucleotide phosphate oxidase, was upregulated only in the OVX+AC group at Day 28. Chronic 17b-estradiol replacement prevented the increases in macrophage infiltration, NOX1 upregulation, myocardial fibrosis and diastolic dysfunction in OVX+AC rats. In conclusion, we suggest that estrogen deficiency augments cardiac inflammation and oxidative stress and thereby aggravates myocardial fibrosis and diastolic dysfunction in hypertensive female rats. The findings provide insight into the mechanism underlying diastolic dysfunction in hypertensive postmenopausal women. Hypertension Research (2011) 34, 496-502; doi:10.1038/hr.2010; published online 20 January 2011Keywords: estradiol; gender medicine; macrophage; myocardial fibrosis; oxidative stress INTRODUCTIONThe ejection fraction of the left ventricle (LV) is normal in approximately half of all patients with congestive heart failure, which indicates that impaired diastolic function in these patients is the major cause of heart failure. [1][2][3] Hypertension is the most common coexisting disease in patients with diastolic heart failure. Diastolic heart failure is more prevalent in women than in men, especially in postmenopausal hypertensive women, which may be due to decreased estrogen levels. 2,3 Determinants of diastolic function include active myocardial relaxation and passive properties of the LV wall. 2 Sequestration of calcium and cross-bridge uncoupling after systole are involved in the active process of relaxation. Previous studies have shown that estrogen

Estrogen variation during the menstrual cycle does not influence left ventricular diastolic function and untwisting rate in premenopausal women

“…LV diastolic dysfunction involves increased passive stiffness of LV, which is primarily linked to the effect of tissue fibrosis and LV remodeling [11]. Cardioprotective effect of estrogen for LV remodeling is assumed to be mediated by regulation of renin-angiotensin-aldosterone system (RAAS), which contributes to tissue fibrosis [7][8][9]. Presumably, this effect is more exerted in patients with highly activated RAAS conditions, such as hypertension, diabetes, and obesity, than in healthy women.…”

“…There are many experimental reports that show that estrogen improves LV diastolic indices, such as E/A, E/e 0 , and IRT [7][8][9]. However, those reports showed a cardioprotective effect of estrogen by comparing ovariectomized animals without hormone treatment to those with estradiol treatment, as a model of hormone replacement therapy (HRT) in postmenopausal females.…”

“…Cardioprotective effects of estrogen in diastolic function were reported to be mediated by various steps, via estrogen receptors on vascular endothelial cells as the first step, to collagen synthesis and LV remodeling as the final step [7][8][9].…”

“…Some previous investigations [5,6] showed a sharp decrease in left ventricular (LV) diastolic function in healthy women after 50-60 years of age compared with men, suggesting that the loss of a cardioprotective effect of estrogen after menopause may accelerate the progression of LV diastolic dysfunction with advancing age in women. Indeed, some animal studies [7][8][9][10][11] have shown that estrogen has a cardioprotective effect, and its deficiency may result in a deterioration of LV diastolic function. However, there is a paucity of clinical data regarding the effect of estrogen on LV diastolic function, and the effect of estrogen on LV diastolic function in the clinical setting is still controversial.…”

Blood Pressure Variability Activates Cardiac Mineralocorticoid Receptor and Induces Cardiac Remodeling in Hypertensive Rats

“…17-20 ED-1-labeled macrophages were counted at ×200 magnification in 3 independent entire cross-sections of each rat. 21,22 Immunofluorescence Study Immediately after hemodynamic monitoring, rats were killed with an overdose of ketamine and xylazine by intraperitoneal injection and then perfused with ice-cold saline for 5 min. The unfixed LV was isolated, snap-frozen in liquid nitrogen, and stored at -80°C until use.…”