Personne : Dagenais, François.
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Département chirurgie, Faculté de médecine, Université Laval
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- PublicationRestreintRNA expression profile of calcified bicuspid, tricuspid, and normal human aortic valves by RNA sequencing(American Physiological Society, 2016-10-01) Gaudreault, Nathalie; Tremblay-Marchand, Joël; Kalavrouziotis, Dimitri; Droit, Arnaud; Guauque-Olarte, Sandra; Bossé, Yohan; Seidman, Jonathan G.; Pibarot, Philippe; Body, Simon C.; Dagenais, François.; Mathieu, PatrickThe molecular mechanisms leading to premature development of aortic valve stenosis (AS) in individuals with a bicuspid aortic valve are unknown. The objective of this study was to identify genes differentially expressed between calcified bicuspid aortic valves (BAVc) and tricuspid valves with (TAVc) and without (TAVn) AS using RNA sequencing (RNA-Seq). We collected 10 human BAVc and nine TAVc from men who underwent primary aortic valve replacement. Eight TAVn were obtained from men who underwent heart transplantation. mRNA levels were measured by RNA-Seq and compared between valve groups. Two genes were upregulated, and none were downregulated in BAVc compared with TAVc, suggesting a similar gene expression response to AS in individuals with bicuspid and tricuspid valves. There were 462 genes upregulated and 282 downregulated in BAVc compared with TAVn. In TAVc compared with TAVn, 329 genes were up- and 170 were downregulated. A total of 273 upregulated and 147 downregulated genes were concordantly altered between BAVc vs. TAVn and TAVc vs. TAVn, which represent 56 and 84% of significant genes in the first and second comparisons, respectively. This indicates that extra genes and pathways were altered in BAVc. Shared pathways between calcified (BAVc and TAVc) and normal (TAVn) aortic valves were also more extensively altered in BAVc. The top pathway enriched for genes differentially expressed in calcified compared with normal valves was fibrosis, which support the remodeling process as a therapeutic target. These findings are relevant to understand the molecular basis of AS in patients with bicuspid and tricuspid valves.
- PublicationAccès libreSex-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, LouisRationale: 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.
- PublicationAccès libreImpact of aortic stenosis severity and its interaction with prosthesis-patient mismatch on operative mortality following aortic valve replacement.(ICR, 2012-03-02) Girerd, Nicolas; Charbonneau, Éric; Dumont, Éric; Magne, Julien; Baillot, Richard; Voisine, Pierre; Pibarot, Philippe; Dumesnil, Jean G.; Dagenais, François.; Mathieu, PatrickThe optimal timing of aortic valve replacement (AVR) in patients with severe aortic stenosis (AS) is a source of debate. Moreover, it has been shown previously that prosthesis-patient mismatch (PPM) is an independent predictor of operative mortality after AVR. The study aim was to assess the effect of the preoperative severity of AS and its interaction with PPM with respect to operative mortality after AVR.
- PublicationAccès libreGenetic association analyses highlight IL6, ALPL, and NAV1 as three new susceptibility genes underlying calcific aortic valve stenosis(American Heart Association, 2019-10-15) Gaudreault, Nathalie; Dina, Christian; Thériault, Sébastien; Messika-Zeitoun, David; Arsenault, Benoit; Le Scouarnec, Solena; Capoulade, Romain; Boureau, Anne-Sophie; Bossé, Yohan; Rigade, Sidwell; Lamontagne, Maxime; Li, Zhonglin; Pibarot, Philippe; Simonet, Floriane; Clavel, Marie-Annick; Dagenais, François.; Mathieu, Patrick; Lecointe, Simon; Baron, Estelle; Bonnaud, Stéphanie; Karakachoff, Matilde; Charpentier, Eric; Fellah, Imen; Roussel, Jean-Christian; Verhoye, Jean Philippe; Baufreton, Christophe; Probst, Vincent; Roussel, Ronan; Redon, Richard; Le Tourneau, Thierry; Schott, Jean-JacquesBackground: Calcific aortic valve stenosis (CAVS) is a frequent and life-threatening cardiovascular disease for which there is currently no medical treatment available. To date, only 2 genes, LPA and PALMD, have been identified as causal for CAVS. We aimed to identify additional susceptibility genes for CAVS. Methods: A GWAS (genome-wide association study) meta-analysis of 4 cohorts, totaling 5115 cases and 354 072 controls of European descent, was performed. A TWAS (transcriptome-wide association study) was completed to integrate transcriptomic data from 233 human aortic valves. A series of post-GWAS analyses were performed, including fine-mapping, colocalization, phenome-wide association studies, pathway, and tissue enrichment as well as genetic correlation with cardiovascular traits. Results: In the GWAS meta-analysis, 4 loci achieved genome-wide significance, including 2 new loci: IL6 (interleukin 6) on 7p15.3 and ALPL (alkaline phosphatase) on 1p36.12. A TWAS integrating gene expression from 233 human aortic valves identified NAV1 (neuron navigator 1) on 1q32.1 as a new candidate causal gene. The CAVS risk alleles were associated with higher mRNA expression of NAV1 in valve tissues. Fine-mapping identified rs1800795 as the most likely causal variant in the IL6 locus. The signal identified colocalizes with the expression of the IL6 RNA antisense in various tissues. Phenome-wide association analyses in the UK Biobank showed colocalized associations between the risk allele at the IL6 lead variant and higher eosinophil count, pulse pressure, systolic blood pressure, and carotid artery procedures, implicating modulation of the IL6 pathways. The risk allele at the NAV1 lead variant colocalized with higher pulse pressure and higher prevalence of carotid artery stenosis. Association results at the genome-wide scale indicated genetic correlation between CAVS, coronary artery disease, and cardiovascular risk factors. Conclusions: Our study implicates 3 new genetic loci in CAVS pathogenesis, which constitute novel targets for the development of therapeutic agents.
- PublicationAccès libreTransvalvular flow, sex, and survival after valve replacement surgery in patients with severe aortic stenosis(Elsevier, 2020-04-28) Bilodeau, Anthony; Guzzetti, Ezequiel; Kalavrouziotis, Dimitri; Zhang, Bin; Couture, Christian; Annabi, Mohamed Salah; Pibarot, Philippe; Clavel, Marie-Annick; Dagenais, François.Background : The respective impacts of transvalvular flow, gradient, sex, and their interactions on mortality in patients with severe aortic stenosis undergoing surgical aortic valve replacement (AVR) are unknown. Objectives : This study sought to compare the impact of pre-operative flow-gradient patterns on mortality after AVR and to examine whether there are sex differences. Methods : This study analyzed clinical, echocardiographic, and outcome data prospectively collected in 1,490 patients (544 women [37%]), with severe aortic stenosis and preserved left ventricular ejection fraction who underwent AVR. Results : In this cohort, 601 patients (40%) had normal flow (NF) with high gradient (HG), 405 (27%) NF with low gradient (LG), 246 (17%) paradoxical low flow (LF)/HG, and 238 (16%) LF/LG. During a median follow-up of 2.42 years (interquartile range: 1.04 to 4.29 years), 167 patients died. Patients with LF/HG exhibited the highest mortality after AVR (hazard ratio [HR]: 2.01; 95% confidence interval [CI]: 1.33 to 3.03; p < 0.01), which remained significant after multivariate adjustment (HR: 1.96; 95% CI: 1.29 to 2.98; p < 0.01). Both LF/LG and NF/LG patients had comparable outcome to NF/HG (p ≥ 0.47). Optimal thresholds of stroke volume index were obtained for men (40 ml/m2) and women (32 ml/m2). Using these sex-specific cutpoints, paradoxical LF was independently associated with increased mortality in both women (adjusted HR: 2.05; 95% CI: 1.21 to 3.47; p < 0.01) and men (adjusted HR: 1.54; 95% CI: 1.02 to 2.32; p = 0.042), whereas guidelines’ threshold (35 ml/m2) does not. Conclusions : Paradoxical LF/HG was associated with higher mortality following AVR, suggesting that a reduced flow is a marker of disease severity even in patients with HG aortic stenosis. Early surgical AVR (i.e., before gradient attains 40 mm Hg) might be preferable in these patients. Furthermore, the use of sex-specific thresholds (<40 ml/m2 for men and <32 ml/m2 for women) to define low-flow outperforms the guidelines’ threshold of 35 ml/m2 in risk stratification after AVR.
- PublicationAccès libreImpact of metabolic syndrome and/or diabetes mellitus on left ventricular mass and remodeling in patients with aortic stenosis before and after aortic valve replacement(ScienceDirect, 2019-01-01) Guzzetti, Ezequiel; Shen, Mylène; Voisine, Pierre; Annabi, Mohamed Salah; Poirier, Paul; Piché, Marie-Eve; Zenses, Anne-Sophie; Pibarot, Philippe; Clavel, Marie-Annick; Ong, Géraldine; Dagenais, François.; Tastet, Lionel; Salaun, ErwanBackground: In aortic stenosis (AS), metabolic syndrome (MetS) and diabetes mellitus (DM) are associated with more pronounced left ventricular hypertrophy (LVH) and more concentric remodeling. We aimed to assess the impact of MetS and DM on left ventricular (LV) mass, remodeling and LV mass regression after aortic valve replacement (AVR) in patients with severe AS. Method: We included 177 patients with severe AS and preserved LVEF (>50%). All patients had comprehensive echocardiography before and one year after AVR. Results: Twenty-seven percent (27%) of patients had MetS, 21% DM and 52% neither MetS nor DM (No MetS-DM). Prior to AVR, indexed LV mass (LVMi) was higher in MetS and DM groups compared to NoMetS-DM group (56.1±14.2, 56.2±18.2 vs. 49.2±14.1 g/m2.7 respectively; p<0.01). Prevalence of LV hypertrophy was higher in MetS and DM than in NoMetS-DM patients (66%, 65% vs 44%, p<0.01) as well as LV mass to-end-diastolic volume ratio (2.10±0.44 and 2.21±0.63 vs 1.96±0.41 g/ml respectively, p=0.03). One year after AVR, decrease in LVMi was significant (p<0.001) in all 3 groups. DM and MetS were independently associated with higher baseline LVMi (p<0.05). MetS was independently associated with less LVM regression and higher LVMi 1 year after AVR. MetS and DM groups showed more residual LV hypertrophy than NoMetS-DM patients (57%, 38% and 17%, p<0.01). Conclusions: MetS and DM were independently associated with a higher preoperative LVMi and more concentric remodeling. One year after AVR, MetS was associated with less LVMi regression and higher LVMi. MetS and DM patients remained with more residual LV hypertrophy
- PublicationRestreintPre- and post-operative stroke volume impact after surgical aortic valve replacement for severe aortic stenosis(Elsevier Biomedical, 2020-10-19) Guzzetti, Ezequiel; Poulin, Anthony; Kalavrouziotis, Dimitri; Annabi, Mohamed Salah; Pibarot, Philippe; Clavel, Marie-Annick; Dagenais, François.
- PublicationAccès libreDistribution 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, PatrickObjective: 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.