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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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Voici les éléments 1 - 7 sur 7
  • PublicationAccès libre
    Effects of spironolactone treatment on an experimental model of chronic aortic valve regurgitation
    (ICR, 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.
  • PublicationRestreint
    Angiotensin-converting enzyme inhibitor captopril prevents volume overload cardiomyopathy in experimental chronic aortic valve regurgitation
    (National Research Council of Canada., 2004-03-12) Lachance, Dominic.; Roussel, Élise; Gauthier, Cindy; Couët, Jacques; Lapointe, Évelyne; Drolet, Marie-Claude.; Gaudreau, Martin.; Plante, Éric; Arsenault, Marie
    L'efficacité des inhibiteurs de l'enzyme de conversion de l'angiotensine I (IECA) dans le traitement de l'insuffisance aortique (IA) chronique est encore mal comprise et controversée. Les mécanismes par lesquels les IECA ont un effet protecteur dans la surcharge de volume du ventricule gauche (VG) sont encore peu clairs et les études cliniques ont jusqu'à maintenant donné des résultats contradictoires. Dans cette étude, nous avons cherché à comparer l'efficacité de deux doses différentes d'un IECA (captopril) dans un modèle animal d'IA chronique. Chez des rats Wistar ayant une IA sévère, nous avons étudié les effets d'un traitement de 6 mois avec une faible dose de captopril (FD; 25 mg/kg) ou une haute dose (HD; 75 mg/kg) sur la fonction et l'hypertrophie du VG. Les rats IA témoins ont tous développé une hypertrophie excentrique du VG ainsi qu'une dysfonction systolique. Le traitement FD n'a pu prévenir l'hypertrophie et n'a procuré qu'une protection modeste contre la dysfonction systolique. Le traitement HD a préservé la fonction systolique et a eu tendance à ralentir le développement de l'hypertrophie du VG. L'index cardiaque est demeuré élevé et similaire pour chacun des groupes traités ou non. L'activité du système rénine–angiotensine (SRA) a aussi été étudiée. L'activité de l'ECA a augmenté dans les VGs des animaux IA et le traitement HD a fortement abaissé l'expression des ARNm encodant les différents récepteurs à l'angiotensine II dans ce tissu. L'expression de la fibronectine a augmenté dans les VG des animaux IA mais le traitement HD a presque complètement renversé cet effet de l'IA. L'inhibiteur de l'ECA captopril s'est avéré efficace à haute dose dans notre modèle d'IA. Cette efficacité pourrait être liée à une modulation du SRA tissulaire et de la fibrose dans le VG.
  • PublicationAccès libre
    Usefulness of carvedilol in the treatment of chronic aortic valve regurgitation
    (Lippincott Williams & Wilkins, 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.
  • PublicationAccès libre
    Benefits of long-term beta-blockade in experimental chronic aortic regurgitation
    (American Physiological Society, 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.
  • PublicationAccès libre
    Effectiveness of β-blockade in experimental chronic aortic regurgitation
    (American Heart Association, 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.
  • PublicationAccès libre
    Gene profiling of left ventricle eccentric hypertrophy in aortic regurgitation in rats : rationale for targeting the β-adrenergic and renin-angiotensin systems
    (American Physiological Society, 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.
  • PublicationAccès libre
    A comparative study of vasodilators in an animal model of chronic volume overload caused by severe aortic regurgitation
    (Lippincott Williams & Wilkins, 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.