Abstract 3263: Enhanced Cardiac Inflammation and Myocardial Fibrosis in Ovariectomized, Pressure-overloaded Rats: A Possible Mechanism of Aggravation of Diastolic Dysfunction in the Post-menopause
Background: The prevalence of diastolic dysfunction is high in hypertensives, particularly in postmenopausal women. However, the pathogenesis remains unknown. We have shown that pressure overload (PO) activates cardiac inflammation, which induces myocardial fibrosis and diastolic dysfunction, in rats with a suprarenal aortic constriction (AC). We assessed the hypothesis that estrogen deficiency after bilateral ovariectomy (OVX) would aggravate the PO-induced cardiac inflammation and remodeling, resulting in the aggravation of diastolic dysfunction in female rats.
Methods and Results: Rats were randomized to OVX+AC, OVX, and AC groups and Controls receiving both sham operations. Rats underwent OVX at 6-week-old and AC at 10-week-old (Day 0). OVX did not affect the AC-induced blood pressure elevation,Å@cardiac hypertrophy and LV fractional shortening, but exaggerated the AC-induced myocardial fibrosis and diastolic dysfunction (LV end-diastolic pressure elevation and transmitral Doppler spectra E/A ratio reduction) at Day 28. AC induced transient myocardial MCP-1 induction and macrophage infiltration, peaking at Day 3. OVX augmented and prolonged the AC-induced MCP-1 induction and macrophage infiltration. Dihydroxyethidium staining revealed that superoxide generation was detected in the intramyocardial arterioles in AC rats at Day 3, which disappeared at Day 28, whereas OVX+AC group showed superoxide generation at both Days 3 and 28. NOX1, a functional subunit of NAD(P)H oxidase, was upregulated only in OVX+AC rats at Day 28. Chronic 17<<26>-estradiol treatment prevented the aggravations of macrophage infiltration, myocardial fibrosis, and diastolic dysfunction in OVX+AC rats.
Conclusions: Estrogen deficiency aggravated the PO-induced cardiac inflammation and myocardial fibrosis and thereby exacerbated diastolic dysfunction in hypertensive female rats. Sustained superoxide generation might enhance the PO-induced inflammation in AC+OVX rats. These findings provided an insight into the mechanism underling diastolic dysfunction in the postmenopausal hypertensive women.