Abstract
Aortic valve regurgitation (AR) can result in heart failure from chronic overloading of the left ventricle (LV). Little is known of the role of estrogens in the LV responses to this condition. The aim of the study was to compare LV remodeling in female rats with severe AR in absence of estrogens by ovariectomy (Ovx). In a first study, we investigated over 6 months the development of hypertrophy in four groups of female Wistar rats: AR or sham-operated (sham) and Ovx or not. Ovx reduced normal heart growth. As expected, volume overload (VO) from AR resulted in significant LV dilation (42% and 32% increase LV end-diastolic diameter in intact and Ovx groups vs. their respective sham group; p < 0.0001). LV weight was also significantly and similarly increased in both AR groups (non-Ovx and Ovx). Increase in stroke volume or cardiac output and loss of systolic function were similar between AR intact and AR Ovx groups compared to sham. We then investigated what were the effects of 17beta-estradiol (E2; 0.03 mg/kg/day) treatment on the parameters studied in Ovx rats. Ovx reduced uterus weight by 85% and E2 treatment restored up to 65% of the normal weight. E2 also helped normalize heart size to normal values. On the other hand, it did not influence the extent of the hypertrophic response to AR. In fact, E2 treatment further reduced LV hypertrophy in AR Ovx rats (41% over Sham Ovx + E2). Systolic and diastolic functions parameters in AR Ovx + E2 were similar to intact AR animals. Ovx in sham rats had a significant effect on the LV gene expression of several hypertrophy markers. Atrial natriuretic peptide (Nppa) gene expression was reduced by Ovx in sham-operated females whereas brain natriuretic peptide (Nppb) expression was increased. Alpha (Myh6) and beta (Myh7) myosin heavy chain genes were also significantly modulated by Ovx in sham females. In AR rats, LV expression of both Nppa and Nppb genes were increased as expected. Ovx further increased it of AR rats for Nppa and did the opposite for Nppb. Interestingly, AR in Ovx rats had only minimal effects on Myh6 and Myh7 genes whereas they were modulated as expected for intact AR animals. In summary, loss of estrogens by Ovx in AR rats was not accompanied by a worsening of hypertrophy or cardiac function. Normal cardiac growth was reduced by Ovx in sham females but not the hypertrophic response to AR. On the other hand, Ovx had important effects on LV gene expression both in sham and AR female rats.
Highlights
Severe aortic valve regurgitation (AR) is a chronic disease that results in progressive left ventricular (LV) dilatation and eccentric hypertrophy
In prior studies using a rat model of chronic and severe AR, we showed that females had a hypertrophic response similar or stronger to LV volume overload (VO) than males (Drolet et al, 2006; Beaumont et al, 2017)
We studied the effects of 17beta-estradiol (E2) supplementation in AR Ovx female rats to investigate if it was associated with a reversal of the effects associated with the loss of estrogens
Summary
Severe aortic valve regurgitation (AR) is a chronic disease that results in progressive left ventricular (LV) dilatation and eccentric hypertrophy. It is not the most frequent valvular disease in the Western world, it is estimated, based on the Framingham study, that 13% of the population suffers from some degree of AR (Singh et al, 1999). Mitral and/or aortic valve regurgitation is a frequent complication of acute rheumatic fever. Gender differences in cardiac remodeling, hypertrophy and clinical outcome have been identified in various cardiac diseases such as heart failure, hypertension, aortic valve stenosis and experimental models of pressure and volume overload (VO) (Blenck et al, 2016; Maric-Bilkan et al, 2016). Most clinical trials on chronic AR have focused mainly on male cohorts and gender specific adaptations of the LV in subjects suffering from chronic severe AR have not been investigated (Evangelista et al, 2005; Lin et al, 1994; Greenberg et al, 1988)
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