Aortic Valve Regurgitation Rats Research Articles

Effects of the loss of estrogen on the heart's hypertrophic response to chronic left ventricle volume overload in rats.

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.

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

Background. Men and women differ in their susceptibility to cardiovascular disease, though the underlying mechanism has remained elusive. Heart disease symptoms, evolution and response to treatment are often sex-specific. This has been studied in animal models of hypertension or myocardial infarction in the past but has received less attention in the context of heart valve regurgitation. The aim of the 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 eight 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.Results. As expected, VO from AR resulted for both male and female rats in significant LV dilation (39% vs. 40% end-diastolic LV diameter increase, respectively; p < 0.0001) and CH (53% vs. 64% heart weight increase, respectively; p < 0.0001) compared to sham. Sex differences were observed in 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 in 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. ARB treatment did not improve systolic function but helped normalizing diastolic parameters such as left atrial mass and E wave slope in female AR rats. Increased LV gene expression of Anp and Bnp 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. This also indicates that activation of the angiotensin II receptor is probably more involved in the early steps of LV remodeling caused by AR in females than in males.

Multiple short-chain dehydrogenases/reductases are regulated in pathological cardiac hypertrophy.

Cardiac hypertrophy (CH) is an important and independent predictor of morbidity and mortality. Through expression profiling, we recently identified a subset of genes (Dhrs7c, Decr, Dhrs11, Dhrs4, Hsd11b1, Hsd17b10, Hsd17b8, Blvrb, Pecr), all of which are members of the short‐chain dehydrogenase/reductase (SDR) superfamily and are highly expressed in the heart, that were significantly dysregulated in a rat model of CH caused by severe aortic valve regurgitation (AR). Here, we studied their expression in various models of CH, as well as factors influencing their regulation. Among the nine SDR genes studied, all but Hsd11b1 were down‐regulated in CH models (AR rats or mice infused with either isoproterenol or angiotensin II). This regulation showed a clear sex dimorphism, being more evident in males than in females irrespective of CH levels. In neonatal rat cardiomyocytes, we observed that treatment with the α1‐adrenergic receptor agonist phenylephrine mostly reproduced the observations made in CH animals models. Retinoic acid, on the other hand, stimulated the expression of most of the SDR genes studied, suggesting that their expression may be related to cardiomyocyte differentiation. Indeed, levels of expression were found to be higher in the hearts of adult animals than in neonatal cardiomyocytes. In conclusion, we identified a group of genes modulated in animal models of CH and mostly in males. This could be related to the activation of the fetal gene expression program in pathological CH situations, in which these highly expressed genes are down‐regulated in the adult heart.

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

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 (Errα, Errγ or Pgc1α). 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.

Transcriptional Changes Associated with Long-Term Left Ventricle Volume Overload in Rats: Impact on Enzymes Related to Myocardial Energy Metabolism.

Patients with left ventricle (LV) volume overload (VO) remain in a compensated state for many years although severe dilation is present. The myocardial capacity to fulfill its energetic demand may delay decompensation. We performed a gene expression profile, a model of chronic VO in rat LV with severe aortic valve regurgitation (AR) for 9 months, and focused on the study of genes associated with myocardial energetics. Methods. LV gene expression profile was performed in rats after 9 months of AR and compared to sham-operated controls. LV glucose and fatty acid (FA) uptake was also evaluated in vivo by positron emission tomography in 8-week AR rats treated or not with fenofibrate, an activator of FA oxidation (FAO). Results. Many LV genes associated with mitochondrial function and metabolism were downregulated in AR rats. FA β-oxidation capacity was significantly impaired as early as two weeks after AR. Treatment with fenofibrate, a PPARα agonist, normalized both FA and glucose uptake while reducing LV dilation caused by AR. Conclusion. Myocardial energy substrate preference is affected early in the evolution of LV-VO cardiomyopathy. Maintaining a relatively normal FA utilization in the myocardium could translate into less glucose uptake and possibly lesser LV remodeling.

Endurance training or beta-blockade can partially block the energy metabolism remodeling taking place in experimental chronic left ventricle volume overload.

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.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2261-14-190) contains supplementary material, which is available to authorized users.

Chronic high-fat diet-induced obesity decreased survival and increased hypertrophy of rats with experimental eccentric hypertrophy from chronic aortic regurgitation.

BackgroundThe composition of a diet can influence myocardial metabolism and development of left ventricular hypertrophy (LVH). The impact of a high-fat diet in chronic left ventricular volume overload (VO) causing eccentric LVH is unknown. This study examined the effects of chronic ingestion of a high-fat diet in rats with chronic VO caused by severe aortic valve regurgitation (AR) on LVH, function and on myocardial energetics and survival.MethodsMale Wistar rats were divided in four groups: Shams on control or high-fat (HF) diet (15 rats/group) and AR rats fed with the same diets (ARC (n = 56) and ARHF (n = 32)). HF diet was started one week before AR induction and the protocol was stopped 30 weeks later.ResultsAs expected, AR caused significant LV dilation and hypertrophy and this was exacerbated in the ARHF group. Moreover, survival in the ARHF group was significantly decreased compared the ARC group. Although the sham animals on HF also developed significant obesity compared to those on control diet, this was not associated with heart hypertrophy. The HF diet in AR rats partially countered the expected shift in myocardial energy substrate preference usually observed in heart hypertrophy (from fatty acids towards glucose). Systolic function was decreased in AR rats but HF diet had no impact on this parameter. The response to HF diet of different fatty acid oxidation markers as well as the increase in glucose transporter-4 translocation to the plasma membrane compared to ARC was blunted in AR animals compared to those on control diet.ConclusionsHF diet for 30 weeks decreased survival of AR rats and worsened eccentric hypertrophy without affecting systolic function. The expected adaptation of myocardial energetics to volume-overload left ventricle hypertrophy in AR animals seemed to be impaired by the high-fat diet suggesting less metabolic flexibility.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2261-14-123) contains supplementary material, which is available to authorized users.

Metformin Reduces Left Ventricular Eccentric Re-modeling In Experimental volume Overload in the Rat

Left ventricular hypertrophy (LVH) is often associated with a change in myocardial energy substrate preference from fatty acids to glucose. A possible anti hypertrophic treatment strategy could aim at stimulating or restoring normal myocardial energy metabolism. Metformin, an adenosine monophosphate-activated protein kinase (AMPK) activator used in the management of glucose metabolism in diabetes, is also a fatty acid oxidation stimulator. The effect of metformin on the development of eccentric LVH and ventricular function in chronic left ventricular (LV) volume overload (VO) is unknown. This study was designed to study this question in a VO rat model caused by severe aortic valve regurgitation (AR). Male Wistar rats were divided in four groups (13-15 animals / group): Shams (S) treated or not (C) with metformin (M; 100 mg/kg/d PO) and severe ARreceiving or not metformin. Treatment was started one week before surgery and the animals were sacrificed 9 weeks later. As expected AR rats developed severe eccentric LVH during the course of the protocol. Metformin treatment did not influence the total heart weight. However, LV remodeling associated with the severe VO was severe in ARM than in ARC. Fractional shortening, a marker of systolic function, was significantly higher in ARM compared to ARC group. Metformin also increased the activity of enzymes associated with fatty acid oxidation while inhibiting phosphofructokinase, a glycolytic enzyme. A 2 month treatment with metformin reduced LV eccentric remodeling associated with severe VO and helped maintain a better systolic function.

Gene profiling of left ventricle eccentric hypertrophy in aortic regurgitation in rats: rationale for targeting the β-adrenergic and renin-angiotensin systems

Aortic valve regurgitation (AR) imposes a severe volume overload to the left ventricle (LV), which results in dilation, eccentric hypertrophy, and eventually loss of function. Little is known about the impact of AR on LV gene expression. We, therefore, conducted a gene expression profiling study in the LV of rats with acute and severe AR. We identified 64 genes that were specifically upregulated and 29 that were downregulated out of 21,910 genes after 2 wk. Of the upregulated genes, a good proportion was related to the extracellular matrix. We subsequently studied a subset of 19 genes by quantitative RT-PCR (qRT-PCR) to see if the modulation seen in the LV after 2 wk persisted in the chronic phase (after 6 and 12 mo) and found that it did persist. Knowing that the adrenergic and renin-angiotensin systems are overactivated in our animal model, we were interested to see if blocking those systems using metoprolol (25 mg.kg(-1).day(-1)) and captopril (100 mg.kg(-1).day(-1)) would alter the expression of some upregulated LV genes in AR rats after 6 mo. By qRT-PCR, we observed that upregulations of LV mRNA levels encoding for procollagens type I and III, fibronectin, atrial natriuretic peptide, transforming growth factor-beta(2), and connective tissue growth factor were totally or partially reversed by this treatment. These observations provide a molecular rationale for a medical strategy aiming these systems in the medical treatment of AR and expand the paradigm in the study of this form of LV volume overload.

Treatment of Combined Aortic Regurgitation and Systemic Hypertension: Insights From an Animal Model Study

Hypertension (HT) and aortic valve regurgitation (AR) often coexist but the specific impacts of AR + HT on the left ventricle (LV) are still unknown. The best treatment strategy for this combination of diseases is also unclear. The objectives of this study were 1) to evaluate LV function, remodeling and 2) to assess the effects of the angiotensin-converting enzyme (ACE) inhibitor captopril (C) in rats with AR +/- HT in spontaneously hypertensive rats (SHR). Animals were grouped as follows: normotensive (NT) Wistar-Kyoto, NT + AR, hypertensive SHR (HT), and HT + AR receiving or not captopril (150 mg/kg/d). Hearts were evaluated in vivo by echocardiography and harvested for tissue analysis after 6 months of evolution. The HT + AR rats had the worst LV hypertrophy (LVH), subendocardial fibrosis, and lowest ejection fraction. Captopril normalized BP in HT and HT + AR, but could not prevent LVH in HT + AR as well as it did in isolated HT. The LV ejection fraction remained below normal in HT + AR + captopril compared to HT alone + captopril. Cardiomyocyte hypertrophy remained in HT + AR + captopril but was normalized in HT + captopril. Subendocardial fibrosis was reduced by captopril in HT + AR. The AR + HT rats had the most severe myocardial abnormalities. High dose captopril was effective to slow LVH and preserve normal LV ejection fraction in isolated HT or AR, but was less effective when both pathologies were combined. Prohypertrophic stimuli clearly remain active in HT + AR despite ACE inhibition. These results suggest that a very aggressive medical treatment strategy may be required to optimize LV protection when AR and HT co-exist.