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Couture, Christian

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Université Laval.Département de biologie moléculaire, de biochimie médicale et de pathologie
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Voici les éléments 1 - 10 sur 17
  • Publication
    Sex-specific associations of genetically predicted circulating Lp(a) (Lipoprotein(a)) and hepatic LPA gene expression levels with cardiovascular outcomes : mendelian randomization and observational analyses
    (Lippincott Williams & Wilkins, 2021-07-19) Thériault, Sébastien; Kaiser, Yannick; Guertin, Jakie; Perrot, Nicolas; Bourgeois, Raphaëlle; Couture, Christian; Manikpurage, Hasanga D.; Wareham, Nicholas J.; Arsenault, Benoit; Pibarot, Philippe; Stroes, Erik S.; Clavel, Marie-Annick; Mathieu, Patrick; Boekholdt, Matthijs; Bossé, Yohan
    Background: Elevated Lp(a) (Lipoprotein(a)) levels are associated with coronary artery disease (CAD), ischemic stroke (IS), and calcific aortic valve stenosis (CAVS). Studies investigating the association between Lp(a) levels and these diseases in women have yielded inconsistent results. Methods: To investigate the association of Lp(a) with sex-specific cardiovascular outcomes, we determined the association between genetically predicted Lp(a) levels (using 27 single nucleotide polymorphisms at the LPA locus) and hepatic LPA expression (using 80 single nucleotide polymorphisms at the LPA locus associated with LPA mRNA expression in liver samples from the Genotype-Tissue Expression dataset) on CAD, IS, and CAVS using individual participant data from the UK Biobank: 408 403 participants of European ancestry (37 102, 4283, and 2574 with prevalent CAD, IS, and CAVS, respectively). The long-term association between Lp(a) levels and incident CAD, IS, and CAVS was also investigated in European Prospective Investigation into Cancer and Nutrition-Norfolk: 18 721 participants (3964, 846, and 424 with incident CAD, IS, and CAVS, respectively). Results: Genetically predicted plasma Lp(a) levels were positively and similarly associated with prevalent and incident CAD and CAVS in men and women. Genetically predicted plasma Lp(a) levels were associated with prevalent and incident IS when we studied men and women pooled together, and in men only. Genetically predicted LPA expression levels were associated with prevalent CAD and CAVS in men and women but not with IS. Conclusions: Genetically predicted blood Lp(a) and hepatic LPA gene expression as well as serum Lp(a) levels predict the risk of CAD and CAVS in men and in women. Whether RNA interference therapies aiming at lowering Lp(a) levels could be useful in reducing cardiovascular disease risk in both men and women with high Lp(a) levels needs to be determined in large-scale cardiovascular outcomes trials.
  • Publication
    Accès libre
    Contrast-enhanced computed tomography assessment of aortic stenosis.
    (2021-01-29) Timothy Robert, Graham Cartlidge; Guzzetti, Ezequiel; Bing, Rong; Couture, Christian; Kwiecinski, Jacek; Pibarot, Philippe; Clavel, Marie-Annick; Pawade, Tania; Doris, Mhairi K; Adamson, Philip D; Massera, Daniele; Lembo, Maria; Peeters, Frederique E. C. M.; Berman, Daniel S; Dey, Damini; Slomka, Piotr; Newby, David E; Dweck, Marc R
    Abstract Objectives Non-contrast CT aortic valve calcium scoring ignores the contribution of valvular fibrosis in aortic stenosis. We assessed aortic valve calcific and non-calcific disease using contrast-enhanced CT. Methods This was a post hoc analysis of 164 patients (median age 71 (IQR 66–77) years, 78% male) with aortic stenosis (41 mild, 89 moderate, 34 severe; 7% bicuspid) who underwent echocardiography and contrast-enhanced CT as part of imaging studies. Calcific and non-calcific (fibrosis) valve tissue volumes were quantified and indexed to annulus area, using Hounsfield unit thresholds calibrated against blood pool radiodensity. The fibrocalcific ratio assessed the relative contributions of valve fibrosis and calcification. The fibrocalcific volume (sum of indexed non-calcific and calcific volumes) was compared with aortic valve peak velocity and, in a subgroup, histology and valve weight. Results Contrast-enhanced CT calcium volumes correlated with CT calcium score (r=0.80, p<0.001) and peak aortic jet velocity (r=0.55, p<0.001). The fibrocalcific ratio decreased with increasing aortic stenosis severity (mild: 1.29 (0.98–2.38), moderate: 0.87 (1.48–1.72), severe: 0.47 (0.33–0.78), p<0.001) while the fibrocalcific volume increased (mild: 109 (75–150), moderate: 191 (117–253), severe: 274 (213–344) mm3/cm2). Fibrocalcific volume correlated with ex vivo valve weight (r=0.72, p<0.001). Compared with the Agatston score, fibrocalcific volume demonstrated a better correlation with peak aortic jet velocity (r=0.59 and r=0.67, respectively), particularly in females (r=0.38 and r=0.72, respectively). Conclusions Contrast-enhanced CT assessment of aortic valve calcific and non-calcific volumes correlates with aortic stenosis severity and may be preferable to non-contrast CT when fibrosis is a significant contributor to valve obstruction.
  • Publication
    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.
  • Publication
    Accès libre
    Sex-related discordance between aortic valve calcification and hemodynamic severity of aortic stenosis : is valvular fibrosis the explanation?
    (Grune & Stratton, 2016-11-22) Trahan, Sylvain; Couture, Christian; Mohammadi, Siamak; Côté, Nancy; Joubert, Philippe; Bossé, Yohan; Clavel, Marie-Annick; Pagé, Sylvain; Dagenais, François.; Mathieu, Patrick; Simard, Louis
    Rationale: Calcific aortic stenosis (AS) is characterized by calcium deposition in valve leaflets. However, women present lower aortic valve calcification (AVC) loads than men for the same AS hemodynamic severity. Objective: We thus aimed to assess sex-differences in aortic valve fibro-calcific remodelling. Methods and Results: One hundred and twenty-five patients underwent Doppler-echocardiography and multidetector-computed-tomography within 3 months prior to aortic valve replacement. Explanted stenotic tricuspid aortic valves were weighed and fibrosis degree was determined. Sixty-four men and 39 women were frequency-matched for age, body mass index (BMI), hypertension, renal disease, diabetes, and AS severity. Mean age was 75±9years, mean gradient (41±18mmHg) and indexed aortic valve area (0.41±0.12cm2/m2) were similar between men and women (all p=0.18). Median AVC (1973[1124-3490]AU) and mean valve weight (2.36±0.99g) were lower in women compared to men (both p<0.0001). AVC density correlated better with valve weight in men (r2=0.57; p<0.0001) than in women (r2=0.26; p=0.0008). After adjustment for age, BMI, AVC density and aortic annulus diameter, female sex was an independent risk factor for higher fibrosis score in AS valves (p=0.003). Picrosirius red staining of explanted valves showed greater amount of collagen fibers (p=0.01) and Masson's trichrome staining revealed a greater proportion of dense connective tissue (p=0.02) in women compared to men. Conclusions: In this series with tricuspid aortic valve and similar AS severity, women have less valvular calcification but more fibrosis compared to men. These findings suggest that the pathophysiology of the disease and thus potential targets for drug development may be different according to sex.
  • Publication
    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.
  • Publication
    Inflammation is associated with the remodeling of calcific aortic valve disease
    (Kluwer Academic Publishers, 2012-12-09) Trahan, Sylvain; Fournier, Dominique; Couture, Christian; Côté, Nancy; Boulanger, Marie-Chloé; Bossé, Yohan; Mahmut, Ablajan; Pibarot, Philippe; Pagé, Sylvain; Mathieu, Patrick
    Calcific aortic valve disease (CAVD) is the most frequent heart valve disorder. Studies indicate that mineralization of the aortic valve may be related to the inflammatory process. However, no clear evidence has been given regarding clinical evolution of aortic stenosis and the inflammatory process within the aortic valve. Aortic valves excised from 285 patients with CAVD undergoing aortic valve replacement were analyzed for the presence of chronic inflammatory infiltrates, and those findings were related to the hemodynamic severity of aortic stenosis. In a subset of 57 patients, in whom additional valvular tissue and the clinical progression rate of aortic stenosis were available, the density of leukocytes was determined as well as the number of TNF-a transcripts. Histological analyses revealed that in 81 (28.4 %) patients, the presence of chronic inflammatory infiltrates was documented within CAVD tissue, which was characterized by the existence of a cluster of cells as well as the presence of neovascularisation and osseous metaplasia. The presence of an inflammatory process within the CAVD tissue was independently related to the remodeling process and the peak transaortic gradient. In addition, the density of leukocytes within CAVD tended to correlate (r¿=¿0.25, p¿=¿0.05) with the progression rate of aortic stenosis. Dense inflammatory infiltrate within CAVD is associated with an active remodeling process, the severity of aortic stenosis, and the hemodynamic progression rate.
  • Publication
    Amyloid substance within stenotic aortic valves promotes mineralization
    (Blackwell Scientific, 2012-10-01) Audet, Audrey; Couture, Christian; Côté, Nancy; Bossé, Yohan; Pibarot, Philippe; Després, Jean-Pierre; Mathieu, Patrick
    AIMS: Accumulation of apolipoproteins may play an important role in the pathobiology of calcific aortic valve disease (CAVD). We aimed to explore the hypothesis that apolipoprotein-derived amyloid could play a role in the development of CAVD. METHODS AND RESULTS: In 70 explanted CAVD valves and 15 control non-calcified aortic valves, we assessed the presence of amyloid by using Congo red staining. Immunohistochemistry was performed to document the presence of apolipoprotein AI (Apo-AI). Apoptosis was documented by terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) studies performed in control and CAVD valves. Control valves were free of amyloid. Deposition of amyloid was detected in all CAVD valves, and the amount was positively correlated with plasma high-density lipoprotein and Apo-AI levels. Apo-AI within CAVD valves co-localized with intense staining of fibrillar amyloid. In turn, deposition of amyloid co-localized with apoptosis near mineralized areas. Isolation of amyloid fibrils confirmed that Apo-AI is a major component of amyloid deposits in CAVD. In vitro, CAVD-derived amyloid extracts increased apoptosis and mineralization of isolated aortic valvular interstitial cells. CONCLUSION: Apo-AI is a major component of amyloid substance present within CAVD valves. Furthermore, amyloid deposits participate in mineralization in CAVD by promoting apoptosis of valvular interstitial cells.
  • Publication
    Angiotensin receptor blockers are associated with a lower remodelling score of stenotic aortic valves
    (Blackwell Scientific Publications, 2011-04-01) Couture, Christian; Côté, Nancy; Pibarot, Philippe; Després, Jean-Pierre; Mathieu, Patrick
    BACKGROUND: Experimental and clinical studies have suggested that inhibitors of the renin angiotensin system (RAS) might be useful to slow the progression of valvular calcification in patients with aortic stenosis (AS). OBJECTIVES: The aim of this study was to evaluate the relationships between the weight and tissue remodelling score of stenotic aortic valves explanted at the time of valve replacement surgery and to determine the effect of medications including angiotensin II receptor type I blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors on these variables. METHODS: Aortic valve and blood plasma were collected in 208 patients with AS (mean age: 69 ± 9) who underwent aortic valve replacement. Valves were weighed and the degree of valve tissue remodelling was assessed using a modified scoring system from Warren (Score: 1-4). Also, the 0-cresolphtalein complexone method was used to measure the amount of calcium within the valve cusps. RESULTS: The mean weight of aortic valves was higher in men than in women (2·83 ± 0·09 vs. 1·91 ± 0·09 g, P < 0·0001), in patients with bicuspid vs. tricuspid valves (3·21 ± 0·15 vs. 2·23 ± 0·07 g, P < 0·0001), and in patients with higher remodelling score (score 2: 1·86 ± 0·19 g; score 3: 2·08 ± 0·12 g; score 4: 3·08 ± 0·1 g, P < 0·0001). The remodelling score was higher in men (3·35 ± 0·05 vs. 2·94 ± 0·07, P < 0·0001) and in bicuspid valves (3·38 ± 0·07 vs. 3·14 ± 0·05, P = 0·006). Both valve weight (r = 0·44, P < 0·0001) and remodelling score (r = 0·23, P = 0·002) correlated with calcium content within the aortic valve. Patients under ARBs medication (n = 47, 22·6%) had lower aortic valve weights (2·14 ± 0·13 g vs. 2·63 ± 0·09 g, P = 0·001) and remodelling scores (3·01 ± 0·09 vs. 3·26 ± 0·04, P = 0·009). On multivariate analyses, ARBs were significantly associated with a lower aortic valve remodelling score (P = 0·04) and weight (P = 0·02). CONCLUSIONS: ARBs were associated with lower aortic valve weight and less pronounced tissue remodelling. Further studies are needed to determine if ARBs could be used as a therapeutic avenue in AS.
  • Publication
    Lipoprotein lipase in aortic valve stenosis is associated with lipid retention and remodelling
    (Blackwell Scientific Publications, 2013-06-01) Arsenault, Benoit; Trahan, Sylvain; Fournier, Dominique; Couture, Christian; Boulanger, Marie-Chloé; Mahmut, Ablajan; Pibarot, Philippe; Pagé, Sylvain; Després, Jean-Pierre; Mathieu, Patrick
    Background: Calcific aortic valve disease (CAVD) is a chronic disorder characterized by a fibrocalcific remodelling. It is suspected that lipid retention within the aortic valve may be one important mechanism participating to aortic valve remodelling. Lipoprotein lipase (LPL) is implicated in lipid metabolism and may play a role in lipid retention within the aortic valve. Methods: In 57 patients, CAVD were analysed for the expression of LPL by q-PCR and immunohistochemistry. Expression of oxidized-LDL (ox-LDL) and decorin was also documented. In addition, a complete blood profile, including the size of LDL and high-density lipoprotein (HDL) particles, were performed to find associations between the blood lipid profile and expression of ox-LDL and LPL within CAVD. Results: Immunohistochemistry studies revealed that LPL was expressed in stenotic aortic valves as a diffuse staining and also in dense cellular areas where macrophages were abundant. Expression of LPL co-localized with decorin and ox-LDL. In turn, valves with higher amount of ox-LDL had elevated number of LPL transcripts. In addition, we documented that the small, dense HDL phenotype was associated with an elevated amount of ox-LDL and LPL transcripts within CAVD. Furthermore, expression of LPL was associated with several indices of fibrocalcific remodelling of the aortic valve. Conclusion: Expression of LPL within CAVD is related to the amount of ox-LDL, which is, in turn, associated with the small, dense HDL phenotype. Lipid retention associated with smaller HDL particles may participate in the expression of LPL, whereby a fibrocalcific remodelling of the aortic valve is promoted.
  • Publication
    Lipid-mediated inflammation and degeneration of bioprosthetic heart valves
    (Springer, 2009-06-01) Lavoie, Michel; Shetty, Rahul; Audet, Audrey; Couture, Christian; Voisine, Pierre; Perron, Jean; Pibarot, Philippe; Dagenais, François.; Després, Jean-Pierre; Mathieu, Patrick
    BACKGROUND: The durability of bioprosthetic valves is limited by structural valve degeneration (SVD) leading to bioprostheses (BPs) stenosis or regurgitation. We hypothesized that a lipid-mediated inflammatory mechanism is involved in the SVD of BPs. MATERIAL AND METHODS: Eighteen Freestyle stentless BP valves were explanted for SVD at a mean time of 5.9 +/- 3 years after implantation and were analysed by immunohistochemistry and transmission electron microscopy (TEM). RESULTS: The mean age of the patients was 65 +/- 8 years and there were 11 male and seven female patients. Two of the 18 BPs had macroscopic calcification, whereas the other valves had minimal or no macroscopic calcification. Tears at the commissures leading to regurgitation was present in 16 BPs. Immunohistochemistry showed the presence of oxidized low-density lipoprotein (ox-LDL) and glycosaminoglycans in the fibrosa layer of 13 BPs. Areas with ox-LDL were infiltrated by macrophages (CD68(+)) co-expressing the scavenger receptor CD36 and metalloproteinase-9 (MMP-9). Zymogram showed the active form of MMP-9 within explanted BPs. EM studies revealed the presence of lipid-laden cells featuring foam cells and fragmented collagen. Nonimplanted control BPs obtained from the manufacturer (n = 4) had no evidence of lipid accumulation, inflammatory cell infiltration or expression of MMP9 within the leaflets. CONCLUSIONS: These results support the concept that lipid-mediated inflammatory mechanisms may contribute to the SVD of BPs. These findings suggest that modification of atherosclerotic risk factors with the use of behavioural or pharmacological interventions could help to reduce the incidence of SVD.