Personne : Després, Jean-Pierre
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Université Laval. Département de médecine sociale et préventive
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- PublicationRestreintIncreased 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, PatrickAortic 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.
- 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.
- PublicationRestreintAmyloid 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, PatrickAIMS: 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.
- PublicationRestreintElevated proportion of small, dense low-density lipoprotein particles and lower adiponectin blood levels predict early structural valve degeneration of bioprostheses(S. Karger, 2012-02-25) Arsenault, Benoit; Shetty, Rahul; Côté, Nancy; Girerd, Nicolas; Pibarot, Philippe; Després, Jean-Pierre; Mathieu, PatrickOBJECTIVES: Long-term durability of bioprosthetic heart valves (BPs) are limited by structural valve degeneration (SVD) leading to stenosis and/or regurgitation. In this study, we sought to determine the metabolic markers associated with SVD. METHODS: In a cohort of 220 patients with an aortic BP (mean follow-up of 2.5 ± 1.2 years), we compared the metabolic and blood lipid profile including the levels of adiponectin and the proportion of small, dense low-density lipoprotein (LDL) particles (%LDL(<)(255Å)) in individuals developing echocardiographic evidence of early BP hemodynamic dysfunction with subjects having no features of BP dysfunction. RESULTS: Patients developing BP dysfunction (n = 69; 31.3%) had a tendency of higher triglyceride levels. Moreover, patients with BP dysfunction had an increased proportion of %LDL(<)(255Å). In multivariate linear regression analysis, after adjustment for age, gender, BP size and hypertension, the %LDL(<)(255Å) (p = 0.04) was significantly associated with BP dysfunction. In addition, patients with an elevated level of %LDL(<)(255Å) along with a decreased plasma adiponectin level were at a very high risk of developing early BP hemodynamic dysfunction (OR = 2.54, p = 0.04). CONCLUSION: BP dysfunction is significantly associated with an increased proportion of small, dense LDL.
- PublicationRestreintAngiotensin 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, PatrickBACKGROUND: 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.
- PublicationRestreintElevated expression of lipoprotein-associated phospholipase A2 in calcific aortic valve disease : implications for valve mineralization.(Elsevier Biomedical, 2014-02-11) Bouchareb, Rihab; Fournier, Dominique; Boulanger, Marie-Chloé; Bossé, Yohan; El Husseini, Diala; Mahmut, Ablajan; Pibarot, Philippe; Després, Jean-Pierre; Mathieu, PatrickOBJECTIVES: This study sought to document the presence and role of lipoprotein-associated phospholipase A2 (Lp-PLA2) in calcific aortic valve disease (CAVD). BACKGROUND: CAVD is a chronic disorder characterized by pathological mineralization and remodeling. Studies have indicated that human CAVD tissues are infiltrated by lipids and that inflammation may play a role in the pathobiology. We hypothesized that Lp-PLA2 (encoded by the PLA2G7 gene) is expressed in CAVD and may play a role in the mineralization of valve interstitial cells. METHODS: We have documented the expression of the phospholipase A2 family of genes in aortic valves by using a transcriptomic assay. Messenger ribonucleic acid and protein expression were confirmed in aortic valves explanted from 60 patients by quantitative polymerase chain reaction and immunohistochemistry, respectively. The effect of lysophosphatidylcholine, the product of Lp-PLA2 activity, was documented on the mineralization of valve interstitial cell cultures. RESULTS: Transcriptomic analyses of CAVD and control nonmineralized aortic valves revealed that Lp-PLA2 was increased by 4.2-fold in mineralized aortic valves. Higher expression of Lp-PLA2 in stenotic aortic valves was confirmed by quantitative polymerase chain reaction, immunohistochemistry, and enzymatic Lp-PLA2 activity. The number of Lp-PLA2 transcripts correlated with several indexes of tissue remodeling. In vitro, lysophosphatidylcholine increased the expression of alkaline phosphatase, the ectonucleotide pyrophosphatase/phosphodiesterase 1 enzyme, sodium-dependent phosphate cotransporter 1 (encoded by the SLC20A1 gene), and osteopontin. We then showed that lysophosphatidylcholine-induced mineralization involved ectonucleotidase enzyme as well as apoptosis through a protein-kinase-A-dependent pathway. CONCLUSIONS: Together, these results demonstrated that Lp-PLA2 is highly expressed in CAVD, and it plays a role in the mineralization of valve interstitial cells. Further work is necessary to document whether Lp-PLA2 could be considered as a novel target in CAVD.
- PublicationRestreintLipoprotein 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, PatrickBackground: 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.
- PublicationRestreintHypoadiponectinemia is associated with valvular inflammation and faster disease progression in patients with aortic stenosis(S. Karger, 2011-05-19) Mohty, Dania; Cartier, Amélie.; Côté, Nancy; Pibarot, Philippe; Després, Jean-Pierre; Mathieu, PatrickObjectives: Adiponectin is a protein secreted by adipocytes which has anti-inflammatory properties. The objective of this study was to examine the relationship between adiponectinemia and the hemodynamic progression of aortic stenosis (AS) as well as the degree of inflammation in the valve explanted at the time of aortic valve replacement (AVR). Methods: The plasma level of adiponectin was measured in 122 patients undergoing AVR. The explanted aortic valves were analyzed and the density of leukocytes (CD45+), T cells (CD3+) and blood vessels (von Willebrand factor positive; vWF+) was documented. Also, a subset of patients (n = 67) had ¿2 echocardiographic studies separated by at least 6 months, thereby allowing assessment of the rate of progression of stenosis during the preoperative period. Results: Patients with lower plasma levels of adiponectin (<5.4 µg/ml) had a faster progression rate of the mean transvalvular gradient before surgery than those with higher levels (9 ± 1 vs. 4 ±1 mm Hg/year; p = 0.008). Moreover, these patients with hypoadiponectinemia had significantly more leukocytes (CD45+), T cells and blood vessels (vWF+) in their explanted valves compared to those with higher adiponectin levels. Conclusion: These findings support the concept that adiponectin may play a protective role against the inflammatory process and progression of calcific AS.
- PublicationRestreintOxidized 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, PatrickIntroduction: 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.
- PublicationRestreintVisceral obesity : the link among inflammation, hypertension, and cardiovascular disease(American Heart Association, 2009-02-23) Poirier, Paul; Pibarot, Philippe; Després, Jean-Pierre; Mathieu, Patrick; Lemieux, Isabelle.The worldwide epidemic of obesity, fostered by the modern lifestyle characterized by the lack of physical activity and an energy-dense diet, has contributed to create an unprecedented condition in human history where a majority of overfed individuals will soon surpass the number of malnourished. Obesity-associated disorders, such as diabetes mellitus, an atherogenic dyslipidemia, and hypertension, have undoubtedly contributed to create an atherosclerosis-prone environment and thereby the development of cardiovascular disease (CVD), a leading cause of mortality in Westernized societies. A growing body of evidence indicates that obesity is a heterogeneous condition in which body fat distribution is closely associated with metabolic perturbations and, thus, with CVD risk. In this regard, accumulation of visceral (intra-abdominal) fat is strongly associated with insulin resistance and with a typical atherogenic dyslipidemic state. The adipose tissue, once considered a simple energy warehouse, is now regarded as a complex organ not only contributing to the management of energy flux within the body but also interacting with the inflammatory system and the vascular wall. Furthermore, recent studies have underlined that there are intricate interplays among adipocytes, the sympathetic nervous system (SNS), and the renin-angiotensin system (RAS), which participate in the obesity-associated dysmetabolic state. Thus, the adipose tissue is believed to play an important role in the development of both hypertension and other complications related to insulin resistance. However, it should be pointed out that different fat depots have distinct metabolic characteristics, leading to individual differences in the impact of obesity on cardiometabolic risk. Herein, we reviewed the complex links among visceral adiposity, inflammation, and hypertension, along with an attempt to address the clinical implications of these interactions.