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Personne :
Lachance, Dominic.

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Lachance

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Dominic.

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Département de Médecine expérimentale, Faculté de Médecine, Université Laval

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Effects of spironolactone treatment on an experimental model of chronic aortic valve regurgitation

2012-07-01, Lachance, Dominic., Roussel, Élise, Couët, Jacques, Zendaoui, Adnane, Arsenault, Marie

BACKGROUND AND AIM OF THE STUDY : Aortic regurgitation (AR) is a disease for which there is currently no effective medical treatment. It has been shown previously in an experimental model of AR that the renin-angiotensin-aldosterone system (RAAS) plays a major role, and that medications blocking the RAAS are effective to protect against left ventricular (LV) hypertrophy and also help to maintain a normal systolic function. The role of aldosterone receptor blockers in this disease has never been evaluated. Thus, the effects were studied of the aldosterone receptor blocking agent spironolactone in a model of chronic AR in rats. METHODS : The effects of a six-month treatment with spironolactone were evaluated in adult Wistar rats with severe AR, compared to sham-operated and untreated AR animals. RESULTS : Spironolactone treatment decreased the total heart weight. In addition, the LV expression of atrial natriuretic peptide mRNA was decreased by spironolactone treatment, as was the expression of collagen 1 and LOX1 mRNAs. Left ventricular fibrosis was decreased by spironolactone treatment. CONCLUSION : Spironolactone protected against volume-overload cardiomyopathy in this model of aortic valve regurgitation. The predominant protective effect was a decrease in myocardial fibrosis.

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A high fructose diet worsens eccentric left ventricular hypertrophy in experimental volume overload

2010-10-22, Lachance, Dominic., Couët, Jacques, Bouchard Thomassin, Andrée-Anne, Drolet, Marie-Claude., Arsenault, Marie

The development of left ventricular (LV) hypertrophy (LVH) can be affected by diet manipulation. Concentric LVH resulting from pressure overload can be worsened by feeding rats with a high-fructose diet. Eccentric LVH is a different type of hypertrophy and is associated with volume overload (VO) diseases. The impact of an abnormal diet on the development of eccentric LVH and on ventricular function in chronic VO is unknown. This study therefore examined the effects of a fructose-rich diet on LV eccentric hypertrophy, ventricular function, and myocardial metabolic enzymes in rats with chronic VO caused by severe aortic valve regurgitation (AR). Wistar rats were divided in four groups: sham-operated on control diet (SC; n = 13) or fructose-rich diet (SF; n = 13) and severe aortic regurgitation fed with the same diets [aortic regurgitation on control diet (ARC), n = 16, and aortic regurgitation on fructose-rich diet (ARF), n = 13]. Fructose-rich diet was started 1 wk before surgery, and the animals were euthanized 9 wk later. SF and ARF had high circulating triglycerides. ARC and ARF developed significant LV eccentric hypertrophy after 8 wk as expected. However, ARF developed more LVH than ARC. LV ejection fraction was slightly lower in the ARF compared with ARC. The increased LVH and decreased ejection fraction could not be explained by differences in hemodynamic load. SF, ARC, and ARF had lower phosphorylation levels of the AMP kinase compared with SC. A fructose-rich diet worsened LV eccentric hypertrophy and decreased LV function in a model of chronic VO caused by AR in rats. Normal animals fed the same diet did not develop these abnormalities. Hypertriglyceridemia may play a central role in this phenomenon as well as AMP kinase activity.

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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.

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Effets d'un programme d'entraînement en endurance sur le remodelage et la fonction ventriculaire gauche chez un modèle animal d'insuffisance aortique

2010, Lachance, Dominic., Couët, Jacques, Arsenault, Marie

L'insuffisance aortique (IA) chronique est une pathologie valvulaire occasionnant une surcharge de volume (SV) pathologique dans le ventricule gauche (VG) au cours de la diastole. Cette surcharge est conséquente de la perte d'étanchéité de la valve aortique qui laisse régurgiter anormalement du sang de l'aorte vers le VG. En réponse à la SV auquel il est contraint, le VG enclenche différents mécanismes compensatoires en vue de conserver une fonction cardiaque normale et adaptée. Ces mécanismes s'avèrent toutefois néfastes à long terme puisqu'ils favorisent la progression vers l'insuffisance cardiaque (IC). La prise en charge clinique des patients ayant une IA chronique modérée à sévère est actuellement controversée. En effet, aucune recommandation de classe A (bienfaits reconnus) n'est disponible chez ces patients. En marge de la médication, les effets chroniques de l'exercice physique en endurance (EPE) sur le remodelage et la fonction ventriculaire gauche de patients IA n'ont jamais été étudiés. Les cardiologues doivent donc user de leur jugement clinique pour permettre ou proscrire l'EPE à leur patient IA. Les craintes associées à l'EPE sont d'une part d'imposer une charge de travail trop importante sur le coeur à l'effort. D'autre part, puisque l'EPE occasionne une SV physiologique en augmentant le volume plasmatique, la question qui se pose est la suivante : est-ce que le VG de patients IA est en mesure de gérer une double SV et tirer profits des bienfaits cardiovasculaires engendrés par l'exercice ou, au contraire, est-ce lui imposer une charge de travail trop importante qui accélérerait la progression de la pathologie vers 1TC ? L'objectif général de cette thèse était d'évaluer les effets cardiovasculaires de l'EPE ainsi que de sa sécurité en condition d'IA. Mes travaux ont démontré, chez des rats IA chroniques et sévères, que l'EPE augmente leur survie à neuf mois par rapport à des rats IA sédentaires. Ce gain de survie est principalement associé à la préservation d'une meilleure fonction diastolique du VG. Elle s'accompagne également d'un métabolisme oxydatif cardiaque plus efficace et d'une meilleure balance entre les systèmes sympathique et parasympathique. Bref, ces résultats laissent croire que des patients IA soumis à un programme adapté d'EPE augmenteraient leur qualité ainsi que leur durée de vie.

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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.

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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.

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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.

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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.