Early signs of cardiac diastolic dysfunction in ovariectomized WKY and SHR female rats

Abstract

Half of patients with heart failure (HF) have diastolic dysfunction but preserved EF (> 50%; HFpEF). There is no specific treatment. Aging populations, and particularly women, are more widely concerned. Why are women more likely than men to develop HFpEF? Despite possible limitations, small animal models could provide comprehensive approaches to identify/test novel therapeutic targets. Determine whether loss of estrogens could promote diastolic dysfunction in a rat model of menopause induced by bilateral ovariectomy. The spontaneously hypertensive rat (SHR) model was investigated in parallel as a potential positive control. 7-weeks-old female WKY rats were ovariectomized (OVX-WKY, n = 7) and compared to sham (WKY, n = 7) and sex and age-matched SHR rats ( n = 7). They were followed by Doppler echocardiography and Tissue Doppler Imaging (Vevo2100, VisualSonics). After final examination (12 weeks post-surgery), cardiomyocytes were enzymatically isolated. Cell shortening and intracellular Ca 2+ (dye indo-1AM) were measured (IonOptix ® system). Echocardiographic parameters were similar in all 7-week old rats. At week 19, EF was also comparable in all groups and considered as preserved (WKY: 60 ± 7%, OVX-WKY: 58 ± 5%, SHR: 52 ± 6%). Hearts morphology was also comparable. However, increased myocardial performance index (Tei), prolonged isovolumic relaxation time and increased left ventricular filling pressure (E/e’ ratio) suggested diastolic dysfunction both in OVX-WKY and SHR, yet with more marked effects in SHR. Single cell contraction and Ca 2+ cycling were modified both in OVX-WKY and SHR, yet differently between the two groups. Estrogen depletion promoted signs of diastolic dysfunction early. In young SHR females, diastolic dysfunction also developed rapidly, presumably in parallel with onset of hypertension. Ca 2+ cycling alterations are involved, yet differently suggesting distinct and complex mechanisms.