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Female rats with severe left ventricle volume overload exhibit more cardiac hypertrophy but fewer myocardial transcriptional changes than males.

ABSTRACT: Aortic valve regurgitation (AR) imposes a volume overload (VO) to the left ventricle (LV). Male rats with a pathological heart overload usually progress more quickly towards heart failure than females. We examined whether a sexual dimorphism exists in the myocardial transcriptional adaptations to AR. Adult Wistar male and female rats either underwent a sham operation or were induced with AR and then followed for 26 weeks. Female AR rats gained relatively more LV mass than males (75 vs. 42%). They had a similar increase in LV chamber dimensions compared to males but more wall thickening. On the other hand, fatty acid oxidation (FAO)-related LV enzyme activity was only decreased in AR males. The expression of genes encoding FAO-related enzymes was only reduced in AR males and not in females. A similar situation was observed for the expression of genes involved in mitochondrial biogenesis or function as well as for genes encoding for transcription factors implicated in the control of bioenergetics and mitochondrial function (Err?, Err? or Pgc1?). Although females develop more LV hypertrophy from severe VO, their myocardial gene expression remains closer to normal. This could provide survival benefits for females with severe VO.

SUBMITTER: Beaumont C

PROVIDER: S-EPMC5429715 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Female rats with severe left ventricle volume overload exhibit more cardiac hypertrophy but fewer myocardial transcriptional changes than males.

Beaumont Catherine C Walsh-Wilkinson Élisabeth É Drolet Marie-Claude MC Roussel Élise É Arsenault Marie M Couet Jacques J

Scientific reports 20170407 1

Aortic valve regurgitation (AR) imposes a volume overload (VO) to the left ventricle (LV). Male rats with a pathological heart overload usually progress more quickly towards heart failure than females. We examined whether a sexual dimorphism exists in the myocardial transcriptional adaptations to AR. Adult Wistar male and female rats either underwent a sham operation or were induced with AR and then followed for 26 weeks. Female AR rats gained relatively more LV mass than males (75 vs. 42%). The ...[more]

PMID: 28389667

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Project description:BACKGROUND:Aortic valve regurgitation (AR) results in left ventricle (LV) volume overload (VO) leading to its dilation and hypertrophy (H). We study a rat model of severe AR induced by puncturing one or two leaflets using a catheter. Most of our studies were conducted in male animals. Recently, we started investigating if sex dimorphism existed in the AR rat model. We observed that AR females developed as much LVH as males but morphological remodeling differences were present. A head-to-head comparison of LV morphological and functional changes had never been performed in AR males (M) and females (F) using the latest modalities in cardiac imaging by echocardiography. METHODS:We performed a longitudinal study to evaluate the development of LV hypertrophy caused by chronic AR in male and female rats over 6?months. Sham-operated (sham) animals were used as controls. RESULTS:LV diastolic volumes (EDV) increased more over 6?months in sham males than in females (38% vs. 23% for EDV, both p?<?0.01). AR resulted in significant LV dilation for both sexes (54% vs. 51% increase in EDV) vs. baseline values. Since normal cardiac growth was less in females, dilation from AR was relatively more important for them (88% (M) vs. 157% (F) increase in EDV over sham). AR caused LV wall thickening in both males and females. It happened sooner for AR females and was more important than in males (25% (M) vs. 56% (F) increase in septum thickness at 2?months and 10% (M) vs. 30% (F) at 6?months). We then evaluated if AR was associated with changes in LV strain using speckle-tracking 2D echocardiography. Global longitudinal strain remained similar between AR and sham animals. Circumferential strain was negatively modulated by AR but only in females and early after VO induction (13% (M) vs. 26% (F)). CONCLUSION:AR resulted in more LV dilation and quicker wall thickening in female AR rats compared to males. Global circumferential strain was negatively modulated in AR females but not in males. AR also seemed to lead to a more spherical LV shape in females whereas; it kept mostly an ellipsoid shape in males. This can influence validity of mass estimation of the dilated LV in females by echocardiography.

Project description: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.

Project description:BackgroundPatients with chronic aortic valve regurgitation (AR) causing left ventricular (LV) volume overload can remain asymptomatic for many years despite having a severely dilated heart. The sudden development of heart failure is not well understood but alterations of myocardial energy metabolism may be contributive. We studied the evolution of LV energy metabolism in experimental AR.MethodsLV glucose utilization was evaluated in vivo by positron emission tomography (microPET) scanning of 6-month AR rats. Sham-operated or AR rats (n = 10-30 animals/group) were evaluated 3, 6 or 9 months post-surgery. We also tested treatment intervention in order to evaluate their impact on metabolism. AR rats (20 animals) were trained on a treadmill 5 times a week for 9 months and another group of rats received a beta-blockade treatment (carvedilol) for 6 months.ResultsMicroPET revealed an abnormal increase in glucose consumption in the LV free wall of AR rats at 6 months. On the other hand, fatty acid beta-oxidation was significantly reduced compared to sham control rats 6 months post AR induction. A significant decrease in citrate synthase and complex 1 activity suggested that mitochondrial oxidative phosphorylation was also affected maybe as soon as 3 months post-AR.Moderate intensity endurance training starting 2 weeks post-AR was able to partially normalize the activity of various myocardial enzymes implicated in energy metabolism. The same was true for the AR rats treated with carvedilol (30 mg/kg/d). Responses to these interventions were different at the level of gene expression. We measured mRNA levels of a number of genes implicated in the transport of energy substrates and we observed that training did not reverse the general down-regulation of these genes in AR rats whereas carvedilol normalized the expression of most of them.ConclusionThis study shows that myocardial energy metabolism remodeling taking place in the dilated left ventricle submitted to severe volume overload from AR can be partially avoided by exercise or beta-blockade in rats.

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Female rats with severe left ventricle volume overload exhibit more cardiac hypertrophy but fewer myocardial transcriptional changes than males.

Publications

Female rats with severe left ventricle volume overload exhibit more cardiac hypertrophy but fewer myocardial transcriptional changes than males.

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