Personne : Mathieu, Patrick
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Université Laval. Département de chirurgie
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- PublicationAccès libreNOTCH1 genetic variants in patients with tricuspid calcific aortic valve stenosis(Middlesex, 2013-03-01) Gaudreault, Nathalie; Guauque-Olarte, Sandra; Bossé, Yohan; Ducharme, Valérie; Pibarot, Philippe; Mathieu, PatrickBACKGROUND AND AIM OF THE STUDY: Calcific aortic valve stenosis (AS) affects 2-5% of the population aged > 65 years. Functional DNA variants at the NOTCH1 locus result in bicuspid aortic valve (BAV) and severe valve calcification. The contribution of these variants to AS in the population with tricuspid aortic valve (TAV) remains to be determined. METHODS: Fourteen genetic variants surrounding the NOTCH1 gene were genotyped, including rare mutations previously reported, and common polymorphisms. The study involved 457 French Canadian patients with severe tricuspid AS. Genotyping was carried out using the Illumina BeadXpress platform. Allele frequencies of common single nucleotide polymorphisms (SNPs) for patients with AS were compared to a shared control group of European ancestry (n = 3,294). In total, 88 ancestry-informative markers were used to correct for population stratification. RESULTS: The mutation R1107X, previously associated with AS and BAV, was identified in a relatively young patient (aged 58 years). The mutations R1279H and V2285I were detected in 18 and 14 heterozygotes, respectively. A common polymorphism (rs13290979) located in intron 2 was significantly associated with AS (p = 0.003), which remained significant after correction for multiple testing. However, this association was no longer significant after accounting for population stratification (p = 0.088). CONCLUSION: In this study, rare functional variants were found in the NOTCH1 gene in a French Canadian population of patients with severe tricuspid AS. This also suggests, for the first time, the presence of a common polymorphism in this gene conferring susceptibility to 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.
- PublicationRestreintATP 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, PatrickCalcific 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.
- PublicationAccès librePredictors of atrial fibrillation following coronary artery bypass surgery : increased waist circumference rather than increased body mass index?(International Scientific Information, 2011-02-25) Girerd, Nicolas; Pibarot, Philippe; Mathieu, Patrick
- PublicationRestreintReplication of genetic association studies in aortic stenosis in adults(Elsevier, 2011-11-01) Gaudreault, Nathalie; Guauque-Olarte, Sandra; Bossé, Yohan; Ducharme, Valérie; Lamontagne, Maxime; Pibarot, Philippe; Mathieu, PatrickOnly a handful of studies have attempted to unravel the genetic architecture of calcific aortic valve stenosis (AS). The goal of this study was to validate genes previously associated with AS. Seven genes were assessed: APOB, APOE, CTGF, IL10, PTH, TGFB1, and VDR. Each gene was tested for a comprehensive set of single-nucleotide polymorphisms (SNPs). SNPs were genotyped in 457 patients who underwent surgical aortic valve replacement, and allele frequencies were compared to 3,294 controls. A missense mutation in the APOB gene was significantly associated with AS (rs1042031, E4181K, p = 0.00001). A second SNP located 5.6 kilobases downstream of the APOB stop codon was also associated with the disease (rs6725189, p = 0.000013). Six SNPs surrounding the IL10 locus were strongly associated with AS (0.02 > p > 6.2 × 10¯¹¹). The most compelling association for IL10 was found with a promoter polymorphism (rs1800872) well known to regulate the production of the encoded anti-inflammatory cytokine. The frequency of the low-producing allele was greater in cases compared to controls (30% vs 20%, p = 6.2 × 10¯¹¹). SNPs in PTH, TGFB1, and VDR had nominal p values <0.05 but did not resist Bonferroni correction. In conclusion, this study suggests that subjects carrying specific polymorphisms in the IL10 and APOB genes are at higher risk for developing AS.
- 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.
- PublicationRestreintAge-related differences in the pathogenesis of calcific aortic stenosis : the potential role of resistin(Elsevier, 2009-01-21) Arsenault, Benoit; Picard, Frédéric; Mohty, Dania; Cartier, Amélie.; Pibarot, Philippe; Després, Jean-Pierre; Mathieu, PatrickBackground: Aortic stenosis (AS) is considered as an atherosclerotic related process. However, there are uncertainties whether AS in the elderly is associated with the same pathophysiological processes as in younger patients. We hypothesized that the metabolic determinants of the valvular inflammatory and calcifying processes occurring in elderly patients are different from those observed earlier in life. Methods: Among 114 patients operated for a severe AS, a complete plasma lipid blood profile and plasma levels of adipokines (resistin, leptin) were determined. The calcium content of the aortic valve was measured and valvular inflammation was quantified. Results Elderly patients (= 70 years) had significantly lower LDL-C ( p = 0.02), lower LDL-C associated with small size particles (LDL-C < 255 Å) ( p = 0.003), and higher HDL peak particle size than younger patients ( p = 0.03). In addition, elderly patients had increased plasma leptin ( p = 0.04) and resistin ( p = 0.0004) levels compared to the middle-aged group (< 70 years). In the elderly patients, higher plasma resistin blood levels were associated with increased valve calcium content and inflammation. Conclusion: The lipid profile of elderly patients was found less atherogenic than that of middle-aged patients. On the other hand, older patients with AS had higher plasma level of resistin which was associated with the degree of valvular calcification and inflammation. These results suggest that, beyond lipid model of atherosclerosis, age-related processes affecting resistin blood levels may also be involved in the late development of AS.