Personne : Boulanger, Marie-Chloé
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Boulanger
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Marie-Chloé
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Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval
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- PublicationAccès libreAttenuated mitral leaflet enlargement contributes to functional mitral regurgitation after myocardial infarction(Elsevier Biomedical, 2020-01-27) Clisson, Marine; Hadjadj, Sandra; Couët, Jacques; Boulanger, Marie-Chloé; Beaudoin, Jonathan; Handschumacher, Mark D.; Marsit, Ons; Pibarot, Philippe; Drolet, Marie-Claude.; Clavel, Marie-Annick; Kim, Dae-Hee; Côté-Laroche, Claudia; Guerrero, J. Luis; Bouchard, Marc; Bartko, Philipp Emanuel; Mathieu, Patrick; Arsenault, Marie; Aïkawa, Elena; Bischoff, Joyce; Levine, Robert A.Background: Mitral leaflet enlargement has been identified as an adaptive mechanism to prevent mitral regurgitation in dilated left ventricles (LVs) caused by chronic aortic regurgitation (AR). This enlargement is deficient in patients with functional mitral regurgitation, which remains frequent in the population with ischemic cardiomyopathy. Maladaptive fibrotic changes have been identified in post-myocardial infarction (MI) mitral valves. It is unknown if these changes can interfere with valve growth and whether they are present in other valves. Objectives: This study sought to test the hypothesis that MI impairs leaflet growth, seen in AR, and induces fibrotic changes in mitral and tricuspid valves. Methods: Sheep models of AR, AR + MI, and controls were followed for 90 days. Cardiac magnetic resonance, echocardiography, and computed tomography were performed at baseline and 90 days to assess LV volume, LV function, mitral regurgitation and mitral leaflet size. Histopathology and molecular analyses were performed in excised valves. Results: Both experimental groups developed similar LV dilatation and dysfunction. At 90 days, mitral valve leaflet size was smaller in the AR + MI group (12.8 ± 1.3 cm2 vs. 15.1 ± 1.6 cm2, p = 0.03). Mitral regurgitant fraction was 4% ± 7% in the AR group versus 19% ± 10% in the AR + MI group (p = 0.02). AR + MI leaflets were thicker compared with AR and control valves. Increased expression of extracellular matrix remodeling genes was found in both the mitral and tricuspid leaflets in the AR + MI group. Conclusions: In these animal models of AR, the presence of MI was associated with impaired adaptive valve growth and more functional mitral regurgitation, despite similar LV size and function. More pronounced extracellular remodeling was observed in mitral and tricuspid leaflets, suggesting systemic valvular remodeling after MI.
- PublicationAccès libreThe pathology and pathobiology of bicuspid aortic valve : State of the art and novel research perspectives(Wiley Blackwell, 2015-06-24) Bédard, Élisabeth; Nieto-Dorantes, Arturo; Huggins, Gordon; Boulanger, Marie-Chloé; Della Corte, Alessandro; Bossé, Yohan; Pibarot, Philippe; Michelena, Hector I.; Mathieu, Patrick; Limongelli, Giuseppe; Citro, Rodolfo; Body, Simon C.; Nemer, Mona; Schoen, Frederick J.Bicuspid aortic valve is the most prevalent cardiac valvular malformation. It is associated with a high rate of long-term morbidity including development of calcific aortic valve disease, aortic regurgitation and concomitant thoracic aortic aneurysm and dissection. Recently, basic and translational studies have identified some key processes involved in the development of bicuspid aortic valve and its morbidity. The development of aortic valve disease and thoracic aortic aneurysm and dissection is the result of complex interactions between genotypes, environmental risk factors and specific haemodynamic conditions created by bicuspid aortic valve anatomy. Herein, we review the pathobiology of bicuspid aortic valve with a special emphasis on translational aspects of these basic findings. Important but unresolved problems in the pathology of bicuspid aortic valve and thoracic aortic aneurysm and dissection are discussed, along with the molecular processes involved
- PublicationRestreintAssociation between plasma lipoprotein levels and bioprosthetic valve structural degeneration(BMJ, 2016-07-04) Dahou, Abdellaziz; Bouchareb, Rihab; Arsenault, Benoit; Larose, Éric; Mahjoub, Haïfa; Boulanger, Marie-Chloé; Bossé, Yohan; Mahmut, Ablajan; Pibarot, Philippe; Després, Jean-Pierre; Nsaibia, Mohamed Jalloul; Mathieu, PatrickIntroduction: Structural valve degeneration (SVD) leads to the failure of aortic valve bioprostheses. It is suspected that lipid-derived factors could play a role in SVD. We hypothesised that oxidised low-density lipoprotein (OxLDL), OxLDL/LDL, OxLDL/high-density lipoprotein (OxLDL/HDL) and proprotein convertase subtilisin/kexin 9 (PCSK9) may be associated with SVD. Methods: We included 199 patients who underwent an aortic valve replacement with a bioprosthesis and had an echocardiography follow-up to evaluate the function of the prosthesis. SVD was defined as an increase in mean transprosthetic gradient (=10 mm Hg) or a worsening of transprosthetic regurgitation (=1/3) during the follow-up. Results: After a mean follow-up of 8±3.5 years, 41(21%) patients developed SVD. The univariate predictors of SVD were LDL (p=0.03), apolipoprotein B (p=0.01), OxLDL (p=0.02), OxLDL/HDL (p=0.009) and LDL associated with small, dense particles (LDL-C<255Å) (p=0.02). In a model adjusted for covariates, only OxLDL/HDL (OR 1.49, 95%CI 1.08 to 2.07 per 10 units, p=0.01) remained associated with SVD. There was a significant interaction between OxLDL/HDL and PCSK9 on SVD (p=0.05). After adjustment, compared with patients with low OxLDL/HDL (median, <25.4) and low PCSK9 (median, <298 ng/mL) (referent), patients with both an elevated OxLDL/HDL ratio and PCSK9 had a higher risk of SVD (OR 2.93, 95% CI 1.02 to 9.29, p=0.04). Conclusions: OxLDL/HDL ratio is independently associated with SVD.
- PublicationRestreintCirculating Lp-PLA2 is associated with high valvuloarterial impedance and low arterial compliance in patients with aortic valve bioprostheses(Elsevier, 2016-04-01) Dahou, Abdellaziz; Bouchareb, Rihab; Arsenault, Benoit; Larose, Éric; Mahjoub, Haïfa; Boulanger, Marie-Chloé; Capoulade, Romain; Bossé, Yohan; Mahmut, Ablajan; Pibarot, Philippe; Mathieu, PatrickBackground: We previously reported that plasma Lp-PLA2 was associated with aortic valve disease progression and degeneration of bioprostheses. Low systemic arterial compliance and high valvuloarterial impedance (Zva) are predictors of poor survival in patients with aortic valve disease. However, the prevalence of high Zva after AVR is largely unknown and whether Lp-PLA2 could predict Zva has not been documented. We investigated the relationships between plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) mass and activity and valvuloarterial impedance (Zva), an index of global LV hemodynamic load, in patients that underwent aortic valve replacement (AVR). Methods: A total of 195 patients with aortic bioprostheses underwent echocardiographic assessment of the prosthetic aortic valve function 8 ± 3.4 years after AVR. Lp-PLA2 mass and activity were measured. Results: In this group of patients, the mean Zvawas elevated (5.73±1.21mmHg·ml-1·m2). In univariate analyses, Lp-PLA2 mass (p=0.003) and Lp-PLA2 activity (p=0.046) were associated with Zva. After adjustment for covariates including age, gender, clinical risk factors, anti-hypertensive medications, body mass index and prosthesis size, Lp-PLA2 mass was associatedwith high Zva (=4.5mmHg·ml-1·m2) (OR: 1.29, 95%CI: 1.10–1.53; p= 0.005) and was inversely related with the systemic arterial compliance (ß =-0.01, SEM=0.003; p=0.003). Conclusions: An increased Zva, an index of excessive hemodynamic load, was highly prevalent 8-year post-AVR and was independently related to circulating Lp-PLA2.
- PublicationRestreintAutotaxin Derived From Lipoprotein(a) and Valve Interstitial Cells Promotes Inflammation and Mineralization of the Aortic Valve(American Heart Association, etc., 2015-08-25) Dahou, Abdellaziz; Bouchareb, Rihab; Arsenault, Benoit; Trahan, Sylvain; Marette, André; Couture, Christian; Lépine, Jamie-Lee; Boulanger, Marie-Chloé; Bossé, Yohan; Mahmut, Ablajan; Pibarot, Philippe; Hadji, Fayez; Pagé, Sylvain; Scipione, Corey A.; Nsaibia, Mohamed Jalloul; Romagnuolo, Rocco; Laflamme, Marie-Hélène; Koschinsky, Marlys L.; Mathieu, PatrickBackground—Mendelian randomization studies have highlighted that lipoprotein(a) [Lp(a)] was associated with calcific aortic valve disease (CAVD). Lp(a) transports oxidized phospholipids (OxPLs) with a high content in lysophosphatidylcholine (LPC). Autotaxin (ATX) transforms LPC into lysophosphatidic acid. We hypothesized that ATX-lysophosphatidic acid could promote inflammation/mineralization of the aortic valve. Methods and Results—We have documented the expression of ATX in control and mineralized aortic valves. By using different approaches we have also investigated the role of ATX- lysophosphatidic acid on the mineralization of isolated valves interstitial cells (VICs) and in a mouse model of CAVD. Enzyme specific ATX activity was elevated by 60% in mineralized aortic valves compared to control valves. Immunohistochemistry studies showed a high level of ATX in mineralized aortic valves, which co-localized with OxPL and apolipoprotein(a). We detected a high level of ATX activity in the Lp(a) fraction in circulation. Interaction between ATX and Lp(a) was confirmed by in situ proximity ligation assay. Moreover, we documented that VICs also expressed ATX in CAVD. We showed that ATX-lysophosphatidic acid promote the mineralization of the aortic valve through a NF-¿B/IL-6/BMP2 pathway. In LDLR-/-/ApoB100/100/IGFII mice, ATX is overexpressed and lysophosphatidic acid promotes a strong deposition of hydroxyapatite of calcium in aortic valve leaflets and accelerates the development of CAVD. Conclusions—ATX is transported in the aortic valve by Lp(a) and is also secreted by VICs. ATX-lysophosphatidic acid promotes inflammation and mineralization of the aortic valve and thus could represent novel therapeutic targets in CAVD.
- PublicationRestreintCarbonic anhydrase XII in valve interstitial cells promotes the regression of calcific aortic valve stenosis.(Academic Press Inc, Ltd., 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, PatrickAims: 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.
- PublicationRestreintEarly development of calcific aortic valve disease and left ventricular hypertrophy in a mouse model of combined dyslipidemia and type 2 diabetes mellitus.(American Heart Association, 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 AndréObjective—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.
- PublicationRestreintParathyroid hormone is associated with the LV mass after aortic valve replacement(BMJ Publishing Group, 2014-12-01) Larose, Éric; Mahjoub, Haïfa; Boulanger, Marie-Chloé; Mahmut, Ablajan; Pibarot, Philippe; Laflamme, Marie-Hélène; Mathieu, PatrickAims : LV hypertrophy (LVH) is frequent after aortic valve replacement (AVR) and is often associated with comorbidities, including hypertension, obesity, renal failure and prosthesis-patient mismatch (PPM). However, whether other biological mechanism(s) may participate to LVH after AVR is still unknown. Parathyroid hormone (PTH) may play a role in LVH. However, it is presently unknown whether PTH is associated with LVH in patients that have undergone an AVR. Methods : In this cross-sectional study, 195 patients have been investigated at a mean of 8±3.5 years following AVR. LV function and mass were evaluated by Doppler echocardiography. The plasma levels of PTH, 25-hydroxyvitamin D (25-OHD), calcium and phosphate were measured. Results : There were 102 (52%) patients with LVH after AVR. In univariate analyses, PTH blood level was associated with LV mass (LVMi) and LVH. After adjustment for other risk factors, elevated PTH remained associated with LVMi (p=0.003) and LVH (p=0.02). In turn, the blood levels of 25-OHD and the renal function (GFR) were independently and inversely related to the blood level of PTH. Conclusions : After AVR, the level of PTH is independently associated with LVH. In turn, the level of PTH is related with the renal function and the level of 25-OHD.
- PublicationRestreintP2Y2 receptor represses IL-6 expression by valve interstitial cells through Akt : implication for calcific aortic valve disease(Academic Press Inc, Ltd., 2014-03-11) Bouchareb, Rihab; Fournier, Dominique; Boulanger, Marie-Chloé; Bossé, Yohan; El Husseini, Diala; Mahmut, Ablajan; Pibarot, Philippe; Laflamme, Marie-Hélène; Mathieu, PatrickCalcific aortic valve disease (CAVD) is a disorder characterized by an abnormal mineralization, which may have intricate links with inflammation. Interleukin-6 (IL-6) and its cognate cytokines are widely expressed and exert pleiotropic effects on different tissues. In this study, we examined the expression of the IL-6 family of cytokines in human CAVD by using a transcriptomic approach and we performed in-depth functional assays with valve interstitial cells (VICs) to unravel the process regulating IL-6 expression and its role during the mineralization of the aortic valve. We documented by both microarray and q-PCR analyses an elevated expression of IL-6 in human CAVD, which was correlated with the remodeling process. IL-6 was highly expressed by VICs. We found that following treatment with a phosphate-containing medium the level of IL-6 expressed by VICs increased by several-fold. Phosphate-induced expression of IL-6 relied on reduced PI3K/Akt signaling downstream of the P2Y2 receptor (P2Y2R). In this regard, we found by using transfection experiments that Akt-1 is a negative regulator of the NF-¿B pathway. In addition, by using a siRNA targeting IL-6 we found that phosphate-induced mineralization was largely dependent on IL-6 expression. A transfection of Akt-1 rescued the hypermineralizing phenotype of P2Y2R-/- mouse VICS (MVICs). Hence, we documented a novel mechanism whereby P2Y2R and Akt modulate the NF-¿B pathway and its downstream target IL-6, which is a strong promoter of the mineralization of VICs
- PublicationRestreintMechanical strain induces the production of spheroid mineralized microparticles in the aortic valve through a RhoA/ROCK-dependent mechanism.(Academic Press Inc, Ltd., 2013-12-22) Bouchareb, Rihab; Fournier, Dominique; Boulanger, Marie-Chloé; Messaddeq, Younès; Pibarot, Philippe; Mathieu, PatrickCalcific aortic valve disease (CAVD) is a chronic disorder characterized by an abnormal mineralization of the leaflets, which is accelerated in bicuspid aortic valve (BAV). It is suspected that mechanical strain may promote/enhance mineralization of the aortic valve. However, the effect of mechanical strain and the involved pathways during mineralization of the aortic valve remains largely unknown. Valve interstitial cells (VICs) were isolated and studied under strain conditions. Human bicuspid aortic valves were examined as a model relevant to increase mechanical strain. Cyclic strain increased mineralization of VICs by several-fold. Scanning electron microscope (SEM) and energy dispersive X-ray (EDX) analyses revealed that mechanical strain promoted the formation of mineralized spheroid microparticles, which coalesced into larger structure at the surface of apoptotic VICs. Apoptosis and mineralization were closely associated with expression of ENPP1. Inhibition of ENPP1 greatly reduced mineralization of VIC cultures. Through several lines of evidence we showed that mechanical strain promoted the export of ENPP1-containing vesicles to the plasma membrane through a RhoA/ROCK pathway. Studies conducted in human BAV revealed the presence of spheroid mineralized structures along with the expression of ENPP1 in areas of high mechanical strain. Mechanical strain promotes the production and accumulation of spheroid mineralized microparticles by VICs, which may represent one important underlying mechanism involved in aortic valve mineralization. RhoA/ROCK-mediated export of ENPP1 to the plasma membrane promotes strain-induced mineralization of VICs.