Personne : Arsenault, Benoit
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Département de médecine, Faculté de médecine, Université Laval
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- PublicationAccès librePrecision nutrition : a review of personalized nutritional approaches for the prevention and management of metabolic syndrome(MDPI, 2017-08-22) Arsenault, Benoit; Toro Martín, Juan de; Vohl, Marie-Claude; Després, Jean-PierreThe translation of the growing increase of findings emerging from basic nutritional science into meaningful and clinically relevant dietary advices represents nowadays one of the main challenges of clinical nutrition. From nutrigenomics to deep phenotyping, many factors need to be taken into account in designing personalized and unbiased nutritional solutions for individuals or population sub-groups. Likewise, a concerted effort among basic, clinical scientists and health professionals will be needed to establish a comprehensive framework allowing the implementation of these new findings at the population level. In a world characterized by an overwhelming increase in the prevalence of obesity and associated metabolic disturbances, such as type 2 diabetes and cardiovascular diseases, tailored nutrition prescription represents a promising approach for both the prevention and management of metabolic syndrome. This review aims to discuss recent works in the field of precision nutrition analyzing most relevant aspects affecting an individual response to lifestyle/nutritional interventions. Latest advances in the analysis and monitoring of dietary habits, food behaviors, physical activity/exercise and deep phenotyping will be discussed, as well as the relevance of novel applications of nutrigenomics, metabolomics and microbiota profiling. Recent findings in the development of precision nutrition are highlighted. Finally, results from published studies providing examples of new avenues to successfully implement innovative precision nutrition approaches will be reviewed.
- PublicationAccès libreLipoprotein(a), oxidized phospholipids, and aortic valve microcalcification assessed by 18F-sodium fluoride positron emission tomography and computed tomography(ScienceDirect, 2019-04-12) Bilodeau, Anthony; Thériault, Sébastien; Nadeau, Maxime; Arsenault, Benoit; Chen, Hao Yu; Bourgeois, Raphaëlle; Shen, Mylène; Trottier, Mikaël; Tessier, Michel; Després, Audrey-Anne; Guimond, Jean; Bossé, Yohan; Engert, James; Perrot, Nicolas; Couture, Patrick; Mathieu, Patrick; Witztum, Joseph L.; Dweek, MarcBackground Lipoprotein(a) (Lp[a]) is the preferential lipoprotein carrier of oxidized phospholipids (OxPLs) and a well-established genetic risk factor for calcific aortic valve stenosis (CAVS). Whether Lp(a) predicts aortic valve microcalcification in individuals without CAVS is unknown. Our objective was to estimate the prevalence of elevated Lp(a) and OxPL levels in patients with CAVS and to determine if individuals with elevated Lp(a) but without CAVS have higher aortic valve microcalcification. Methods We recruited 214 patients with CAVS from Montreal and 174 patients with CAVS and 108 controls from Québec City, Canada. In a second group of individuals with high (≥75 nmol/L, n = 27) or low (<75 nmol/L, n = 28) Lp(a) levels, 18F-sodium fluoride positron emission tomography/computed tomography was performed to determine the difference in mean tissue-to-background ratio (TBR) of the aortic valve. Results Patients with CAVS had 62.0% higher Lp(a) (median = 28.7, interquartile range [8.2-116.6] vs 10.9 [3.6-28.8] nmol/L, P < 0.0001), 50% higher OxPL-apolipoprotein-B (2.2 [1.3-6.0] vs 1.1 [0.7-2.6] nmol/L, P < 0.0001), and 69.9% higher OxPL-apolipoprotein(a) (7.3 [1.8-28.4] vs 2.2 [0.8-8.4] nmol/L, P < 0.0001) levels compared with individuals without CAVS (all P < 0.0001). Individuals without CAVS but elevated Lp(a) had 40% higher mean TBR compared with individuals with low Lp(a) levels (mean TBR = 1.25 ± 0.23 vs 1.15 ± 0.11, P = 0.02). Conclusions Elevated Lp(a) and OxPL levels are associated with prevalent CAVS in patients studied in an echocardiography laboratory setting. In individuals with elevated Lp(a), evidence of aortic valve microcalcification by 18F-sodium fluoride positron emission tomography/computed tomography is present before the development of clinically manifested CAVS.
- PublicationAccès libreFacteurs de risque en émergence des maladies cardiovasculaires : de l'épidémiologie au métabolisme(2009) Arsenault, Benoit; Cianflone, Katherine M.; Després, Jean-PierreDepuis les cinquante dernières années, les maladies cardiovasculaires (MeV) représentent la principale cause de décès dans la plupart des pays industrialisés. Malgré le fait que la compréhension des mécanismes sousj acents à ces pathologies, tout comme la qualité du traitement offert aux individus à haut risque de Mev ne cessent de s'améliorer, la morbidité cardiovasculaire diminue très peu et tend même à augmenter dans certaines populations. Plusieurs ont démontré que l'augmentation de la prévalence de l'obésité (particulièrement de l'obésité abdominale) et de la sédentarité pourrait, en partie, expliquer cette observation lourde de conséquences pour les systèmes de santé à travers le globe. Il est maintenant bien reconnu qu'une accumulation de tissu adipeux intra-abdominal ou viscéral est associée à plusieurs complications ± cardiométaboliques¿ qui augmentent le risque de MeV. Parmi ces complications, on retrouve entre autres une perturbation du métabolisme des lipoprotéines et des lipides, un état pro-inflammatoire et une perturbation de l'homéostasie du glucose et de l'insuline. Il est maintenantreconnu que les individus avec obésité viscérale sont caractérisés par de petites particules LDL et HDL. Les travaux de ce présent projet de doctorat ont permis de démonter que les hommes et les femmes caractérisés par ce phénotype ont un risque élevé de Mev. Par ailleurs, nous avons démontré que la sédentarité et l'ob.ésité abdominale augmentent le risque de MeV dans une vaste étude de population européenne. Nous avons également soumis l'hypothèse qu'un profil inflammatoire détérioré pouvait représenter un lien entre ces phénotypes et le risque de Mev. En conclusion, le présent projet de doctorat a démontré qu'au-delà des facteurs de risque traditionnels de MeV, plusieurs facteurs/marqueurs de risque ± en émergence¿ pourraient être utiles afin de raffiner la prédiction du risque de Mev en prévention primaire. Les prochains outils cliniques permettant l'estimation du risque de Mev devront prendre en considération certaines complications associées à l' obésité abdominale.
- 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.
- PublicationRestreintCalcium signaling pathway genes RUNX2 and CACNA1C are associated with calcific aortic valve disease(American Heart Association, 2015-11-09) Gaudreault, Nathalie.; Messika-Zeitoun, David; Arsenault, Benoit; Tremblay-Marchand, Joël; Droit, Arnaud; Lavoie-Charland, Émilie; Guauque-Olarte, Sandra; Bossé, Yohan; Lamontagne, Maxime; Dubé, Marie-Pierre; Pibarot, Philippe; Tardif, Jean-Claude; Mathieu, Patrick; Body, Simon C.; Seidman, Jonathan G.; Boileau, CatherineBACKGROUND—: Calcific aortic valve stenosis (AS) is a life-threatening disease with no medical therapy. The genetic architecture of AS remains elusive. This study combines genome-wide association studies, gene expression, and expression quantitative trait loci mapping in human valve tissues to identify susceptibility genes of AS. METHODS AND RESULTS—: A meta-analysis was performed combining the results of 2 genome-wide association studies in 474 and 486 cases from Quebec City (Canada) and Paris (France), respectively. Corresponding controls consisted of 2988 and 1864 individuals with European ancestry from the database of genotypes and phenotypes. mRNA expression levels were evaluated in 9 calcified and 8 normal aortic valves by RNA sequencing. The results were integrated with valve expression quantitative trait loci data obtained from 22 AS patients. Twenty-five single-nucleotide polymorphisms had P<5×10 in the genome-wide association studies meta-analysis. The calcium signaling pathway was the top gene set enriched for genes mapped to moderately AS-associated single-nucleotide polymorphisms. Genes in this pathway were found differentially expressed in valves with and without AS. Two single-nucleotide polymorphisms located in RUNX2 (runt-related transcription factor 2), encoding an osteogenic transcription factor, demonstrated some association with AS (genome-wide association studies P=5.33×10). The mRNA expression levels of RUNX2 were upregulated in calcified valves and associated with eQTL-SNPs. CACNA1C encoding a subunit of a voltage-dependent calcium channel was upregulated in calcified valves. The eQTL-SNP with the most significant association with AS located in CACNA1C was associated with higher expression of the gene. CONCLUSIONS—: This integrative genomic study confirmed the role of RUNX2 as a potential driver of AS and identified a new AS susceptibility gene, CACNA1C, belonging to the calcium signaling pathway.
- PublicationRestreintOxidized phospholipids, lipoprotein(a), and progression of calcific aortic valve stenosis(Elsevier Biomedical, 2015-09-15) Arsenault, Benoit; Chan, Kwan L.; Capoulade, Romain; Yeang, Calvin; Bossé, Yohan; Mahmut, Ablajan; Pibarot, Philippe; Dumesnil, Jean G.; Tam, James W.; Després, Jean-Pierre; Teo, Koon Kang; Mathieu, Patrick; Yang, Xiaohong; Witztum, Joseph L.; Tsimikas, SotiriosBACKGROUND: Elevated lipoprotein(a) (Lp[a]) is associated with aortic stenosis (AS). Oxidized phospholipids (OxPL) are key mediators of calcification in valvular cells and are carried by Lp(a). OBJECTIVES: This study sought to determine whether Lp(a) and OxPL are associated with hemodynamic progression of AS and AS-related events. METHODS: OxPL on apolipoprotein B-100 (OxPL-apoB), which reflects the biological activity of Lp(a), and Lp(a) levels were measured in 220 patients with mild-to-moderate AS. The primary endpoint was the progression rate of AS, measured by the annualized increase in peak aortic jet velocity in m/s/year by Doppler echocardiography; the secondary endpoint was need for aortic valve replacement and cardiac death during 3.5 1.2 years of follow-up. RESULTS: AS progression was faster in patients in the top tertiles of Lp(a) (peak aortic jet velocity: þ0.26 0.26 vs. þ0.17 0.21 m/s/year; p ¼ 0.005) and OxPL-apoB (þ0.26 0.26 m/s/year vs. þ0.17 0.21 m/s/year; p ¼ 0.01). After multivariable adjustment, elevated Lp(a) or OxPL-apoB levels remained independent predictors of faster AS progression. After adjustment for age, sex, and baseline AS severity, patients in the top tertile of Lp(a) or OxPL-apoB had increased risk of aortic valve replacement and cardiac death. CONCLUSIONS: Elevated Lp(a) and OxPL-apoB levels are associated with faster AS progression and need for aortic valve replacement. These findings support the hypothesis that Lp(a) mediates AS progression through its associated OxPL and provide a rationale for randomized trials of Lp(a)-lowering and OxPL-apoB-lowering therapies in AS.
- PublicationRestreintAutotaxin Derived From Lipoprotein(a) and Valve Interstitial Cells Promotes Inflammation and Mineralization of the Aortic Valve(American Heart Association, etc., 2015-08-25) Dahou, Abdellaziz; Bouchareb, Rihab; Arsenault, Benoit; Trahan, Sylvain; Marette, André.; Couture, Christian; Lépine, Jamie-Lee; Boulanger, Marie-Chloé; Bossé, Yohan; Mahmut, Ablajan; Pibarot, Philippe; Hadji, Fayez; Pagé, Sylvain; Scipione, Corey A.; Nsaibia, Mohamed Jalloul; Romagnuolo, Rocco; Laflamme, Marie-Hélène; Koschinsky, Marlys L.; Mathieu, PatrickBackground—Mendelian randomization studies have highlighted that lipoprotein(a) [Lp(a)] was associated with calcific aortic valve disease (CAVD). Lp(a) transports oxidized phospholipids (OxPLs) with a high content in lysophosphatidylcholine (LPC). Autotaxin (ATX) transforms LPC into lysophosphatidic acid. We hypothesized that ATX-lysophosphatidic acid could promote inflammation/mineralization of the aortic valve. Methods and Results—We have documented the expression of ATX in control and mineralized aortic valves. By using different approaches we have also investigated the role of ATX- lysophosphatidic acid on the mineralization of isolated valves interstitial cells (VICs) and in a mouse model of CAVD. Enzyme specific ATX activity was elevated by 60% in mineralized aortic valves compared to control valves. Immunohistochemistry studies showed a high level of ATX in mineralized aortic valves, which co-localized with OxPL and apolipoprotein(a). We detected a high level of ATX activity in the Lp(a) fraction in circulation. Interaction between ATX and Lp(a) was confirmed by in situ proximity ligation assay. Moreover, we documented that VICs also expressed ATX in CAVD. We showed that ATX-lysophosphatidic acid promote the mineralization of the aortic valve through a NF-¿B/IL-6/BMP2 pathway. In LDLR-/-/ApoB100/100/IGFII mice, ATX is overexpressed and lysophosphatidic acid promotes a strong deposition of hydroxyapatite of calcium in aortic valve leaflets and accelerates the development of CAVD. Conclusions—ATX is transported in the aortic valve by Lp(a) and is also secreted by VICs. ATX-lysophosphatidic acid promotes inflammation and mineralization of the aortic valve and thus could represent novel therapeutic targets in CAVD.
- PublicationRestreintEvaluation of links between high-density lipoprotein genetics, functionality, and aortic valve stenosis risk in humans(American Heart Association, 2013-12-12) Arsenault, Benoit; Dubé, Marie-Pierre; Rhainds, David; Brodeur, Mathieu; Guauque-Olarte, Sandra; Oliveira Moraes, Adriana Benjamim de; Bossé, Yohan; Lavoie, Véronique; Pibarot, Philippe; Kernaleguen, Anne-Elen; Mathieu, Patrick; Messika-Zeitoun, David; Rhéaume, Éric; Tardif, Jean-ClaudeObjective—Studies have shown that high-density lipoprotein (HDL)–raising compounds induce regression of aortic valve stenosis (AVS) in animal models. However, whether patients with AVS have an impaired HDL metabolism is unknown. Approach and Results—A total of 1435 single nucleotide polymorphisms in genes associated with HDL cholesterol levels (in or around GALNT2, LPL, ABCA1, APOA5, SCARB1, LIPC, CETP, LCAT, LIPG, APOC4, and PLTP) were genotyped in 382 patients with echocardiography-confirmed AVS (aortic jet velocity =2.5 m/s) and 401 controls. After control for multiple testing, none of the genetic variants showed a positive association with case/control status (adjusted P=0.05 for all single nucleotide polymorphisms tested). In a subsample of this cohort, HDL cholesterol levels, apolipoprotein AI levels, lecithin-cholesterol acyltransferase activity, pre–ß-HDL, HDL size, and 4 parameters of cholesterol efflux capacity were measured in apolipoprotein B–depleted serum samples from 86 patients with and 86 patients without AVS. Cholesterol efflux capacity was measured using J774 macrophages with and without stimulation of ATP-binding cassette A-1 expression by cAMP, and HepG2 hepatocytes for scavenger receptor class B type 1–mediated efflux. None of these parameters were different between cases and controls. However, compared with patients without coronary artery disease, sera from patients with coronary artery disease had lower HDL cholesterol levels, scavenger receptor class B type 1–mediated efflux, and HDL size (P=0.003), independently of the presence or absence of AVS. Conclusions—Results of the present study suggest that, based on HDL genetics and HDL functionality, HDL metabolism does not seem to predict the risk of AVS. Because of our limited sample size, additional studies are needed to confirm these findings.
- PublicationRestreintAssociation between plasma LDL particle size, valvular accumulation of oxidized LDL, and inflammation in patients with aortic stenosis(American Heart Association, 2007-11-01) Côté, Claude H.; Arsenault, Benoit; Mohty, Dania; Couture, Christian; Cartier, Amélie.; Pibarot, Philippe; Cosnay, Pierre; Després, Jean-Pierre; Mathieu, PatrickObjective— In patients with severe aortic stenosis (AS), we examine the association between: (1) the content of oxidized LDL (oxLDL) in the aortic valve and the degree of inflammation and remodeling; (2) The proportion of small dense LDL particles in the plasma and the presence of oxLDL in the valve along with hemodynamic progression of valve stenosis. Methods and Results— We have examined 102 explanted AS valves. Tissue remodeling, inflammation, and accumulation of oxLDL were determined. A complete plasma lipid profile including the measurement of the relative proportion of small low-density lipoprotein (%LDL<255Å) was obtained. Valves with higher oxLDL content had a significantly higher density of inflammatory cells, expression of tumor necrosis factor (TNF)-a, and increased tissue remodeling score. The %LDL<255Å was significantly associated with oxLDL score within the aortic valve. In a subset of 59 patients in whom stenosis progression was measured, the %LDL<255Å correlated with the annualized peak gradient (r=0.29; P=0.04). Conclusion— Increased proportion of circulating small dense LDL particles is associated with faster progression rate of stenosis and greater accumulation of oxLDL in the aortic valve. These findings suggest that therapeutic interventions aimed at lowering the production of small dense LDL particles in patients with AS might represent a potentially interesting therapeutic avenue.
- PublicationRestreintAssociation between circulating oxidised low-density lipoprotein and fibrocalcific remodelling of the aortic valve in aortic stenosis(BMJ Publishing Group, 2008-09-01) Arsenault, Benoit; Mohty, Dania; Couture, Christian; Cartier, Amélie.; Côté, Claude; Pibarot, Philippe; Després, Jean-Pierre; Mathieu, PatrickIntroduction : Aortic stenosis (AS) is the most common valvular heart disease in westernised societies. AS is a disease process akin to atherosclerosis in which calcification and tissue remodelling play a crucial role. In patients with moderate/severe AS, we sought to determine whether the remodelling process would be in relationship with transvalvular gradients and circulating oxidised low-density lipoprotein (ox-LDL) levels. Methods : In 105 patients with AS, the aortic valve and blood plasma were collected at the time of valve replacement surgery. The degree of valve tissue remodelling was assessed using a scoring system (Score: 1-4) and the amount of calcium within the valve cusps was determined. The standard plasma lipid profile, the size of LDL particles and the plasma level of circulating ox-LDL (4E6 antibody) were determined. Results : After adjustment for covariables, aortic remodelling score was significantly related to transvalvular gradients measured by Doppler echocardiography before surgery. Patients with higher valve remodelling score had higher circulating ox-LDL levels (score 2: 27.3 (SEM 2.6) U/l; score 3: 32.2 (SEM 2.3) U/l; score 4: 38.3 (SEM 2.3) U/l; p = 0.02). After correction for age, gender, hypertension and HDL-C, the plasma level of ox-LDL remained significantly associated with the aortic valve remodelling score (p<0.001). The plasma level of ox-LDL was significantly associated with LDL-C (r = 0.41; p<0.001), apoB (r = 0.59; p<0.001), triglyceride (r = 0.39; p<0.001), Apo A-I (r = 0.23; p = 0.01) and cholesterol in small (<255 Å) LDL particles (r = 0.22; p = 0.02). After correction for covariables, circulating ox-LDL levels remained significantly associated with apoB (p<0.001) and triglyceride (p = 0.01) levels. Conclusion : Increased level of circulating ox-LDL is associated with worse fibrocalcific remodelling of valvular tissue in AS. It remains to be determined whether circulating ox-LDL is a risk marker for a highly atherogenic profile and/or a circulating molecule which is actively involved in the pathogenesis of calcific aortic valve disease.