Personne : Lachance, Dominic.
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Effectiveness of β-blockade in experimental chronic aortic regurgitation
2004-09-13, Lachance, Dominic., Roussel, Élise, Couët, Jacques, Drolet, Marie-Claude., Gaudreau, Martin., Plante, Éric, Arsenault, Marie
Background— Past studies have suggested that the adrenergic system becomes abnormally activated in chronic volume overload, such as in severe aortic valve regurgitation (AR). However, the effectiveness of agents directed against this adrenergic activation has never been adequately tested in chronic AR. We therefore tested the effects of metoprolol treatment on the left ventricular (LV) function and remodeling in severe chronic AR in rats. Methods and Results— Severe AR was created in adult male Wistar rats by retrograde puncture of the aortic leaflets under echocardiographic guidance. Two weeks later, some animals received metoprolol treatment (25 mg/kg) orally for 24 weeks, and some were left untreated. LV dimensions, ejection fraction, and filling parameters were evaluated by echocardiography. Hearts were harvested at 1, 2, 14, and 180 days for the evaluation of hypertrophy, β-adrenergic receptor status, and extracellular matrix remodeling. We found that metoprolol treatment prevented LV dilatation and preserved the ejection fraction and filling parameters compared with untreated animals. Metoprolol increased the expression of β1-adrenoreceptor mRNA and reduced G protein receptor kinase 2 levels. Collagen I and III mRNA levels were reduced. Cardiac myocyte hypertrophy was also prevented. Conclusions— In our experimental model of severe AR, metoprolol treatment had a significant beneficial global effect on LV remodeling and function. These results suggest that the adrenergic system is important in the development of volume-overload cardiomyopathy in AR and that adrenergic-blocking agents may play a role in the treatment of this disease.
Gene profiling of left ventricle eccentric hypertrophy in aortic regurgitation in rats : rationale for targeting the β-adrenergic and renin-angiotensin systems
2009-03-01, Lachance, Dominic., Roussel, Élise, Couët, Jacques, Bojmehrani, Azadeh, Beaudoin, Jonathan, Champetier, Serge., Plante, Éric, Arsenault, Marie
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-β2, 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.
Early development of calcific aortic valve disease and left ventricular hypertrophy in a mouse model of combined dyslipidemia and type 2 diabetes mellitus.
2014-08-14, Lachance, Dominic., Bouchareb, Rihab, Kohen Avramoglu, Rita, Fournier, Dominique, Marette, André, Boulanger, Marie-Chloé, Le Quang, Khai, El Husseini, Diala, Fang, Xiang Ping, Pibarot, Philippe, Deshaies, Yves, Sweeney, Gary, Mathieu, Patrick, Laplante, Marc André
Objective—This study aimed to determine the potential impact of type 2 diabetes mellitus on left ventricular dysfunction and the development of calcified aortic valve disease using a dyslipidemic mouse model prone to developing type 2 diabetes mellitus. Approach and Results—When compared with nondiabetic LDLr-/-/ApoB100/100, diabetic LDLr-/-/ApoB100/100/IGF-II mice exhibited similar dyslipidemia and obesity but developed type 2 diabetes mellitus when fed a high-fat/sucrose/cholesterol diet for 6 months. LDLr-/-/ApoB100/100/IGF-II mice showed left ventricular hypertrophy versus C57BL6 but not LDLr-/-/ ApoB100/100 mice. Transthoracic echocardiography revealed significant reductions in both left ventricular systolic fractional shortening and diastolic function in high-fat/sucrose/cholesterol fed LDLr-/-/ApoB100/100/IGF-II mice when compared with LDLr-/-/ApoB100/100. Importantly, we found that peak aortic jet velocity was significantly increased in LDLr-/-/ApoB100/100/ IGF-II mice versus LDLr-/-/ApoB100/100 animals on the high-fat/sucrose/cholesterol diet. Microtomography scans and Alizarin red staining indicated calcification in the aortic valves, whereas electron microscopy and energy dispersive x-ray spectroscopy further revealed mineralization of the aortic leaflets and the presence of inflammatory infiltrates in diabetic mice. Studies showed upregulation of hypertrophic genes (anp, bnp, b-mhc) in myocardial tissues and of osteogenic genes (spp1, bglap, runx2) in aortic tissues of diabetic mice. Conclusions—We have established the diabetes mellitus –prone LDLr-/-/ApoB100/100/IGF-II mouse as a new model of calcified aortic valve disease. Our results are consistent with the growing body of clinical evidence that the dysmetabolic state of type 2 diabetes mellitus contributes to early mineralization of the aortic valve and calcified aortic valve disease pathogenesis.
A comparative study of vasodilators in an animal model of chronic volume overload caused by severe aortic regurgitation
2009-01-20, Lachance, Dominic., Roussel, Élise, Couët, Jacques, Beaudoin, Jonathan, Champetier, Serge., Plante, Éric, Arsenault, Marie
Background— Aortic regurgitation (AR) is a disease of chronic left ventricular (LV) volume overload. Over time, AR will lead to LV dilatation, hypertrophy, and loss of function. There is currently no medical treatment proven effective to slow the evolution of this cardiomyopathy. Vasodilators were once thought to have protective effects, but recent publications have cast some doubts about their effectiveness. We hypothesized that drugs targeting the renin-angiotensin system should be more effective than those having no direct effect on the renin-angiotensin system. Methods and Results— We designed a protocol comparing the effects of 3 vasodilators in a rat AR model (n=9 to 11 animals per group). The effects of a 6-month treatment of (1) nifedipine, (2) captopril, or (3) losartan were compared in male AR rats. Sham-operated and untreated AR animals were used as controls. Nifedipine-treated animals displayed hemodynamics, LV dilatation, hypertrophy, and loss of function similar to those of the untreated group. Both captopril and losartan were effective in improving hemodynamics, slow LV dilatation, hypertrophy, and dysfunction. Gene expression analysis confirmed the lack of effects of the nifedipine treatment at the molecular level. Conclusions— Using an animal model of severe AR, we found that vasodilators targeting the renin-angiotensin system were effective to slow the development of LV remodeling and to preserve LV function. As recently shown in the most recent human clinical trial, nifedipine was totally ineffective. Targeting the renin-angiotensin system seems a promising avenue in the treatment of this disease, and clinical trials should be carefully designed to re-evaluate the effectiveness of angiotensin I–converting enzyme inhibitors or angiotensin II receptor blockers in AR.
Endurance training or beta-blockade can partially block the energy metabolism remodeling taking place in experimental chronic left ventricle volume overload.
2014-12-17, Lachance, Dominic., Roussel, Élise, Dhahri, Wahiba, Drolet, Marie-Claude., Gascon, Suzanne, Arsenault, Marie, Sarrhini, Otman, Rousseau, Jacques A., Lecomte, Roger
BACKGROUND: Patients 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. METHODS: LV 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. RESULTS: MicroPET 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. CONCLUSION: This 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.
Transcriptional changes associated with long-term left ventricle volume overload in rats : impact on enzymes related to myocardial energy metabolism.
2015-10-25, Lachance, Dominic., Roussel, Élise, Couët, Jacques, Walsh-Wilkinson, Élisabeth, Dhahri, Wahiba, Gascon, Suzanne, Drolet, Marie-Claude., Sarrhini, Otman, Arsenault, Marie, Rousseau, Jacques A., Lecomte, Roger
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.
Usefulness of carvedilol in the treatment of chronic aortic valve regurgitation
2011-03-15, Lachance, Dominic., Roussel, Élise, Couët, Jacques, Zendaoui, Adnane, Arsenault, Marie
Background — Aortic regurgitation (AR) is a chronic disease for which there is currently no approved medical treatment. We previously reported in an animal model that β-blockade with metoprolol exerted beneficial effects on left ventricular remodeling and survival. Despite the recent publication of promising human data, β-blockade in chronic AR remains controversial. More data are needed to support this potentially new treatment strategy. We hypothesized that carvedilol might be another safe treatment option in chronic AR, considering its combined β-blocking and α-blocking effects and proven efficacy in patients with established heart failure. Methods and Results — The effects of a 6-month treatment with carvedilol 30 mg/kg/d orally were evaluated in adult Wistar rats with severe AR. Sham-operated and untreated AR animals were used as controls. Carvedilol treatment resulted in less left ventricular hypertrophy and dilatation. Ejection fraction was improved and filling pressures were reduced by carvedilol. β1-Receptor expression was also improved as well as myocardial capillary density. Those beneficial effects were noted despite the presence of drug-induced bradycardia. Conclusions — Carvedilol exerted protective effects against volume-overload cardiomyopathy in this model of aortic valve regurgitation with preserved ejection fraction. These results suggest a protective class effect of β-blockers. Combined with the recent publication of promising human data, our findings support the need to carefully design a prospective study in humans to evaluate the effects of β-blockers in chronic aortic valve regurgitation.
Benefits of long-term beta-blockade in experimental chronic aortic regurgitation
2008-04-01, Lachance, Dominic., Roussel, Élise, Couët, Jacques, Champetier, Serge., Drolet, Marie-Claude., Plante, Éric, Arsenault, Marie
The objective of this study was to assess the long-term effects of beta-blockade on survival and left ventricular (LV) remodeling in rats with aortic valve regurgitation (AR). The pharmacological management of chronic AR remains controversial. No drug has been definitively proven to delay the need for valve replacement or to affect morbidity and/or mortality. Our group has reported that the adrenergic system is activated in an animal model of AR and that adrenergic blockade may help maintain normal LV function. The effects of prolonged treatment with a beta-blocker are unknown. Forty Wistar rats with severe AR were divided into 2 groups of 20 animals each and treated with metoprolol (Met, 25 mg.kg(-1).day(-1)) or left untreated for 1 yr. LV remodeling was evaluated by echocardiography. Survival was assessed by Kaplan-Meir curves. Hearts were harvested for tissue analysis. All Met-treated animals were alive after 6 mo vs. 70% of untreated animals. After 1 yr, 60% of Met-treated animals were alive vs. 35% of untreated animals (P = 0.028). All deaths, except one, were sudden. There were no differences in LV ejection fraction (all >50%) or LV dimensions. LV mass tended to be lower in the Met-treated group. There was less subendocardial fibrosis in this group, as well as lower LV filling pressures (LV end-diastolic pressure). beta-Adrenergic receptor ratio (beta(1)/beta(2)) was improved. One year of treatment with Met was well tolerated. Met improved 1-yr survival, minimized LV hypertrophy, improved LV filling pressures, decreased LV subendocardial fibrosis, and helped restore the beta-adrenergic receptor ratio.
Carbonic anhydrase XII in valve interstitial cells promotes the regression of calcific aortic valve stenosis.
2016-03-11, Lachance, Dominic., Bouchareb, Rihab, Asselin, Jérémie, Boudreau, Denis, Marette, André, Boulanger, Marie-Chloé, Le Quang, Khai, Côté, Nancy., Bossé, Yohan, Shayhidin, Elnur Elyar, Messaddeq, Younès, El Husseini, Diala, Mahmut, Ablajan, Pibarot, Philippe, Hadji, Fayez, Mathieu, Patrick
Aims: Calcific aortic valve stenosis (CAVS) is the most common heart valve disease. In the present work we sought to determine the reversibility of mineralization in the aortic valve. Methods and results: By using in vitro analyses we found that valve interstitial cells (VICs) have the ability to resorb minerals. We documented that agonist of P2Y2 receptor (P2Y2R) promoted the expression of carbonic anhydrase XII (CAXII) at the cell membrane of VICs, whereby minerals are resorbed. P2Y2R-mediated mineral resorption was corroborated by using mouse VICs isolated from wild type and P2Y2R-/- mice. Measurements of extracellular pH (pHe) by using core–shell nanosensors revealed that P2Y2R-mediated CAXII export to the cell membrane led to an acidification of extracellular space, whereby minerals are resorbed. In vivo, we next treated LDLR-/-/ApoB100/100/IGF2 mice, which had developed CAVS under a high-fat/high-sucrose diet for 8 months, with 2-thioUTP (a P2Y2R agonist) or saline for the next 2 months. The administration of 2-thioUTP (2 mg/kg/day i.p.) reduced the mineral volume in the aortic valve measured with serial microCT analyses, which improved hemodynamics and reduced left ventricular hypertrophy (LVH). Examination of leaflets at necropsy confirmed a lower level of mineralization and fibrosis along with higher levels of CAXII in mice under 2-thioUTP. In another series of experiment, the administration of acetazolamide (a CA inhibitor) prevented the acidification of leaflets and the regression of CAVS induced by 2-thioUTP in LDLR-/-/ApoB100/100/IGF2 mice. Conclusion: P2Y2R-mediated expression of CAXII by VICs acidifies the extracellular space and promotes the regression of CAVS.
Treatment of combined aortic regurgitation and systemic hypertension : insights from an animal model study.
2006-08-01, Lachance, Dominic., Roussel, Élise, Couët, Jacques, Drolet, Marie-Claude., Gaudreau, Martin., Plante, Éric, Arsenault, Marie
Background : 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). Methods : 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. Results : 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. Conclusions : 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.