Sex differences in the response to angiotensin II receptor blockade in a rat model of eccentric cardiac hypertrophy

Aim of study was to evaluate the development of cardiac hypertrophy (CH) in response to left ventricle (LV) volume overload (VO) caused by chronic aortic valve regurgitation (AR) in male and female rats treated or not with angiotensin II receptor blocker (ARB), valsartan. We studied 8 groups of Wistar rats: male or female, AR or sham-operated (sham) and treated or not with valsartan (30 mg/kg/day) for 9 weeks starting one week before AR surgical induction. As expected, VO from AR resulted for both male and female rats in significant LV dilation (39% vs. 40% increase of end-diastolic LV diameter, respectively; p<0.0001) and CH (53% vs. 64% increase of heart weight, respectively; p<0.0001) compared to sham. Sex differences were observed in the LV wall thickening in response to VO. In untreated AR males, relative LV wall thickness (a ratio of wall thickness to end-diastolic diameter) was reduced compared to sham, whereas this ratio in females remained unchanged. ARB treatment did not prevent LV dilation for both male and female animals but reversed LV wall thickening in females. Systolic and diastolic functions in AR animals were altered similarly for both sexes compared to sham. ARB treatment did not improve systolic function but help normalizing diastolic parameters in female AR rats. Increased LV expression of Anp and Bnp genes was normalized by ARB treatment in AR females but not in males. Other hypertrophy gene markers (Fos, Trpc6, Klf15, Myh6 and Myh7) were not modulated by ARB treatment. The same was true for genes related to LV extracellular matrix remodeling (Col1a1, Col3a1, Fn1, Mmp2, Timp1 and Lox). In summary, ARB treatment of rats with severe AR blocked the female-specific hypertrophic response characterized by LV chamber wall thickening. LV dilation, on the other hand, was not significantly decreased by ARB treatment.