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Pépin, Andrée

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Andrée

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Centre de recherche en cardiologie et en pneumologie de Québec (CRIUCPQ), Université Laval

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  • PublicationAccès libre
    Paradoxical low-flow, low-gradient aortic stenosis despite preserved left ventricular ejection fraction : new insights from weights of operatively excised aortic valves
    (European Society of Cardiology, 2014-10-07) Trahan, Sylvain; Audet, Audrey; Côté, Nancy; Pépin, Andrée; Pibarot, Philippe; Dumesnil, Jean G.; Couture, Christian; Clavel, Marie-Annick; Fournier, Dominique; Pagé, Sylvain; Mathieu, Patrick
    Aims : We reported that patients with small aortic valve area (AVA) and low flow despite preserved left ventricular ejection fraction (LVEF), i.e. ‘paradoxical’ low flow (PLF), have worse outcomes compared with patients with normal flow (NF), although they generally have a lower mean gradient (MG). The aortic valve weight (AVW) excised at the time of valve replacement is a flow-independent marker of stenosis severity. The objective of this study was to compare the AVW of patients with PLF and MG,40 mmHg with the AVW of patients with NF and MG=40 mmHg. Methods and results : We recruited 250 consecutive patients undergoing valve replacement (Cohort A) for severe stenosis. Among them, 33 (13%) were in PLF [LVEF > 50% but stroke volume index (SVi) = 35 mL/m2] with MG < 40 mmHg (PLF-LG group) and 105 (42%) were in NF (LVEF > 50% and SVi > 35 mL/m2) with MG = 40 mmHg (NF-HG group). Despite a much lower MG (29 ± 7 vs. 53 ± 10 mmHg; P < 0.0001), patients in the PLF-LG group had a similar AVA (0.73 ± 0.12 vs. 0.69 ± 0.13; P = 0.19) compared with those in the NF-HG group. The AVW [median (interquartile): 1.90 (1.63–2.50) vs. 2.60 (1.66–3.32)] and prevalence of bicuspid phenotype (15 vs. 42%) were lower in the PLF-LG group than in the NF-HG group. However, AVWs analysed separately in the tricuspid and bicuspid valves were similar in both groups [tricuspid valves: 1.80 (1.63–2.50) vs. 2.30 (1.58–3.00) g; P = 0.26 and bicuspid valves: 2.72 (1.73–3.61) vs. 2.60 (2.10–3.55) g; P = 0.93]. When using cut-point values of AVW established in another series of non-consecutive patients (n = 150, Cohort B) with NF and concordant Doppler-echocardiographic findings, we found that the percentage of patients with evidence of severe stenosis in Cohort A was 70% in patients with PLF-LG and 86% in patients with NF-HG. Conclusion : The aortic valve weight data reported in this study provide evidence that a large proportion of patients with PLF and low-gradient have a severe stenosis and that the gradient may substantially underestimate stenosis severity in these patients. A multi-parametric approach including all Doppler-echocardiographic parameters of valve function as well as other complementary diagnostic tests may help correctly identify these patients.
  • PublicationRestreint
    Increased biglycan in aortic valve stenosis leads to the overexpression of phospholipid transfer protein via toll-like receptor 2
    (Elsevier, 2010-06-01) Arsenault, Benoit; Bosse, Yohan; Audet, Audrey; Couture, Christian; Côté, Nancy; Pépin, Andrée; Pibarot, Philippe; Derbali, Habib; Després, Jean-Pierre; Mathieu, Patrick
    Aortic stenosis (AS) is the most common valvular heart disease, and it is suspected that atherosclerotic mechanisms are involved in the development of this disorder. Therefore, the retention of lipids within the aortic valve may play a role in the pathobiology of AS. In this study, a gene expression microarray experiment was conducted on human aortic valves with and without AS. The expression levels of transcripts encoding proteoglycans and enzymes involved in lipid retention were compared between the two groups. The microarray results were subsequently replicated in a cohort of 87 AS valves and 36 control valves. In addition, the interaction between proteoglycan and lipid-modifying enzyme was documented in isolated valve interstitial cells (VICs). The microarray results indicated that only biglycan (BGN) and phospholipid transfer protein (PLTP) were overexpressed in the AS valves. These results were then confirmed by quantitative PCR. The immunohistochemical analysis revealed a colocalization of BGN, PLTP, and Toll-like receptor-2 (TLR 2) in AS valves. In vitro, we showed that BGN induces the production of PLTP in VICs via the stimulation of TLR 2. Thus, increased accumulation of BGN in AS valves contributes to the production of PLTP via TLR 2. These results suggest that intricate links between valve matrix proteins, inflammation, and lipid retention are involved in the pathobiology of AS.
  • PublicationRestreint
    Refining molecular pathways leading to calcific aortic valve stenosis by studying gene expression profile of normal and calcified stenotic human aortic valves
    (Lippincott Williams & Wilkins, 2009-10-01) Miqdad, Ahmed; Fournier, Dominique; Bossé, Yohan; Pépin, Andrée; Pibarot, Philippe; Mathieu, Patrick
    Background— Calcific aortic valve stenosis (AS) is a major societal and economic burden that is rising after the current shift toward an older population. Understanding the pathobiology of AS is crucial to implementing better preventive and therapeutic options. Research conducted during the past decade clearly points to active molecular and cellular processes involved in disease pathogenesis. However, no genomic approaches were used to identify genes and pathways that are differentially regulated in aortic valves of patients with and without AS. Methods and Results— A large-scale quantitative measurements of gene expression was performed on 5 normal and 5 AS valves using Affymetrix GeneChips. A total of 409 and 306 genes were significantly up- and downregulated in AS valves, respectively. The 2 most highly upregulated genes were matrix metalloproteinase 12 and chitinase 3-like 1. The upregulation of these 2 biologically relevant genes in AS was validated by real-time polymerase chain reaction in 38 aortic valves (12 normal and 26 AS). To provide a global biological validation of the whole-genome gene expression analysis, the microarray experiment was repeated in a second set of aortic valves with (n=5) or without (n=5) AS. There was an overrepresentation of small P values among genes claimed significant in the first microarray experiment. A total of 223 genes were replicated (P<0.05 and fold change >1.2), including matrix metalloproteinase 12 and chitinase 3-like 1. Conclusions— This study reveals many unrecognized genes potentially implicated in the pathogenesis of AS. These new genes were overlaid on known pathological pathways leading to AS to refine our molecular understanding of this disease.
  • PublicationRestreint
    Inhibition of ectonucleotidase with ARL67156 prevents the development of calcific aortic valve disease in warfarin-treated rats
    (Elsevier, 2012-08-15) Bouvet, Céline; Fournier, Dominique; Audet, Audrey; Côté, Nancy.; Gilbert, Liz-Ann; Moreau, Pierre; El Husseini, Diala; Pépin, Andrée; Pibarot, Philippe; Mathieu, Patrick
    Calcific aortic valve disease is the most common heart valve disorder. So far, there is no medical treatment for calcific aortic valve disease. The expression of ectonucleotidases, which metabolize nucleotides into phosphate products, may influence the calcification of the aortic valve. In this study, we investigated if the administration of an ectonucleotidase inhibitor, ARL67156 (6-N,N-Diethyl-D-ß, [gamma]-dibromomethyleneATP trisodium salt), may prevent the calcification of the aortic valve in the warfarin-induced mineralization rat model. Male Wistar rats were treated with warfarin or warfarin+ARL67156 for 28 days. All rats had comprehensive Doppler-echocardiographic studies at 28 day. A gene profiling of ectonucleotidases expressed in aortas of rats was documented by quantitative real-time PCR. The amount of calcium was determined by quantitative method and von Kossa staining. Ex vivo cultures of rat aortas were also used to further assess the effect of ARL67156 on the calcifying process and Akt signaling. Mineralization of the aorta/aortic valve was documented in warfarin-treated rats and was accompanied by the development of aortic stenosis. These changes were paralleled by an increased of ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1). Administration of the ectonucleotidase inhibitor, ARL67156 prevented the development of aortic stenosis by lowering the level of apoptosis and mineralization of the aortic valve/aorta. In addition, ARL67156 normalized the level of pAkt, an important kinase involved in the survival pathway. Inhibition of ectonucleotidase activity prevented the development of calcific aortic valve disease in a rat model. On that account, ectonucleotidase may represent a novel target in the treatment of calcific aortic valve disease.
  • PublicationRestreint
    Oxidized low-density lipoprotein, angiotensin II and increased waist cirumference are associated with valve inflammation in prehypertensive patients with aortic stenosis
    (Elsevier, 2009-06-13) Arsenault, Benoit; Fournier, Dominique; Audet, Audrey; Couture, Christian; Côté, Nancy; Poirier, Paul; Pépin, Andrée; Pibarot, Philippe; Després, Jean-Pierre; Mathieu, Patrick
    Introduction: The progression of aortic stenosis (AS) has been shown to be faster in patients with the metabolic syndrome. We sought to determine the relationships between blood pressure, inflammation, oxidative stress and valvular inflammation in a population of normotensive and prehypertensive patients with AS. Methods: In this study, 36 male patients (age: 61.5 ± 2 years) with AS undergoing an aortic valve replacement were investigated. Plasma levels of adiponectin, oxidized-LDL (ox-LDL), angiotensinogen (AGN) and angiotensin I-II (Ang I-II) were measured. On explanted aortic valves, immunohistochemistry studies and quantitative PCR (q-PCR) analyses were performed to document the expression of inflammatory cytokines. Results: Systolic blood pressure (SBP) was positively correlated with plasma level of ox-LDL ( r = 0.4; p = 0.02), AGN ( r = 0.41; p = 0.01), and white blood cells count ( r = 0.33; p = 0.04), whereas it was inversely related to plasma level of adiponectin ( r = - .35; p = 0.04). After adjustment for covariates, plasma level of ox-LDL ( p = 0.01) remained significantly associated with SBP ( p = 0.01). Within the aortic valve, expression of TNF-a was significantly associated with plasma levels of ox-LDL ( r = 0.58; p = 0.03), Ang II ( r = 0.69; p = 0.013), and waist circumference ( r = 0.60; p = 0.02), whereas valvular expression of IL-6 was associated with plasma level of Ang II ( r = 0.51; p = 0.03). In explanted AS valves, ox-LDL was documented near calcified areas and colocalized with Ang II, IL-6, and TNF-a. Conclusion: Conditions associated with a higher oxidative stress and activation of the renin angiotensin system, such as encountered in viscerally obese and prehypertensive patients, contribute to higher valvular inflammation in AS.
  • PublicationAccès libre
    Expression of bone-regulatory proteins in human valve allografts
    (BMJ Publishing Group, 2006-09-01) Shetty, Rahul; Voisine, Pierre; Perron, Jean; Doyle, Daniel; Charest, A.; Pépin, Andrée; Pibarot, Philippe; Dagenais, François; Mathieu, Patrick
    Objective : To test the hypothesis that valve allograft (VA) calcification results from an ossification process in which bone-regulatory proteins are expressed. Methods : 15 VA that were explanted at the time of surgery for dysfunction were studied. VA were analysed and compared with normal aortic valves (n = 20). Results : All the VA (5 aortic, 10 pulmonary) exhibited heavy calcification and important fibrosis. Immunohistochemistry studies showed that the bone-specific transcription factor Cbfa-1 was expressed by stromal cells. Bone alkaline phosphatase was expressed in calcified regions. Immunostaining for a smooth muscle (a-SM) actin was increased in VA compared with normal valves and in 6 of the 15 valves formed cellular clusters close to the calcified nodules. In VA osteopontin and osteonectin were expressed by stromal cells, whereas osteocalcin was closely associated with the calcified regions. Furthermore, analysis of the bone-regulatory proteins that control bone resorption showed that receptor activator of nuclear factor kB ligand (RANKL), receptor activator of nuclear factor kB (RANK) and osteoprotegerin (OPG) were differentially expressed in calcified VA and normal valves. Normal valve leaflets expressed OPG, whereas OPG expression was absent or faint in calcified VA. RANKL and RANK were not detected in normal valves, whereas calcified VA expressed RANKL and RANK. Conclusion : These data suggest that calcification of VA results from an ossification process, which relies on tight control of bone-regulatory protein expression. The expression pattern of the RANKL/RANK/OPG system suggests that it may have a regulatory role not only in osteoclastogenesis but also in the calcification of human VA.
  • PublicationAccès libre
    Distribution of SPARC during neovascularisation of degenerative aortic stenosis
    (British Cardiac Society, 2006-05-18) Côté, Claude H.; Charest, Amélie.; Shetty, Rahul; Voisine, Pierre; Pépin, Andrée; Pibarot, Philippe; Dagenais, François; Mathieu, Patrick
    Objective: To examine the hypothesis that degenerative aortic stenosis (AS) is associated with the development of blood vessels and the expression of the secreted protein, acidic and rich in cysteine/osteonectin (SPARC), a matricellular protein that is involved in ossification, the modulation of angiogenesis and the production of metalloproteinases. Methods: 30 surgically excised AS valves and 20 normal aortic valves were studied. Results: Blood vessels were detected in the aortic valves from patients with degenerative AS, whereas normal valves were avascular structures. Blood vessels in AS valves expressed endothelial nitric oxide synthase, CD34 and von Willebrand factor (vWF). Blood vessels were located in three distinct regions: near calcified nodules, under the leaflet border and in rich cellular areas forming cell islands. Blood vessels were predominantly present in early and intermediate grades of calcification. Cell islands were densely populated by CD45-positive cells where endothelial cells (CD34+, vWF+) forming cord-like structures were present. Immunoblotting detected SPARC only in AS valves and immunohistological analysis located SPARC in mature blood vessels. The proportion of blood vessels positive for SPARC was higher in valves with a lower grade of calcification. In cell islands, SPARC was distributed to mature blood vessels and to macrophages, where it co-located with matrix metalloproteinase-9, whereas no expression was detected in endothelial cells forming cord-like structures. Conclusion: The localisation of SPARC to mature blood vessels and its predominant expression in AS valves with a lower calcification grade suggest that the spatial and temporal distribution of this matricellular protein is tightly controlled to participate in the neovascularisation of AS valves.
  • PublicationRestreint
    ATP acts as a survival signal and prevents the mineralization of aortic valve
    (Academic Press Inc, Ltd., 2012-05-01) Gaudreault, Nathalie; Fournier, Dominique; Audet, Audrey; Côté, Nancy; Bouchard-Cannon, Pascale; Guauque-Olarte, Sandra; Bossé, Yohan; El Husseini, Diala; Ducharme, Valérie; Pépin, Andrée; McKee, Marc D.; Simard, Chantale; Pibarot, Philippe; Derbali, Habib; Després, Jean-Pierre; Mathieu, Patrick
    Calcific aortic valve disease (CAVD) is a disorder related to progressive mineralization of valvular tissue that is a leading cause of heart disease. Thus far, there is no medical treatment to prevent the mineralization of aortic valves. It is generally thought that pathologic mineralization is linked to apoptosis of vascular cells. However, the role of apoptosis during mineralization as well as the survival signals for valvular interstitial cells (VICs), the main cellular component of aortic valves, remains to be identified. Here, through several lines of evidence, we show that bioavailability of extracellular ATP is a signal which determines survival or apoptosis of VICs and, in doing so, plays a major role in the development of CAVD. Specifically, in CAVD and in VIC cultures undergoing mineralization, we found a high level of the ectonucleotidase ENPP1. In addition, a genetic polymorphism in the intron 9 of the ENPP1 gene was associated with CAVD in a case-control cohort as well as with mRNA expression levels of ENPP1 in aortic valves. A high level of ENPP1 in CAVD promoted apoptosis-mediated mineralization of VICs by depleting the extracellular pool of ATP. We then documented that release of ATP by VICs promoted cell survival via the P2Y(2) receptor and the PI3K/Akt signaling pathway. Hence, our results show that level of ENPP1 modulates extracellular concentration of ATP, which is an important survival signal for VICs. These findings may help to develop novel pharmacological treatment for CAVD.