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Mathieu, Patrick

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  • PublicationAccès libre
    Genetic 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-Jacques
    Background: 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 libre
    Impact of C-reactive protein levels on lipoprotein(a)-associated aortic stenosis incidence and progression
    ([Oxford, UK] : Oxford University Press, 2023-03-30) Girard, Arnaud; Gaillard, Emilie; Puri, Rishi; Clavel, Marie-Annick; Mathieu, Patrick; Thériault, Sébastien; Pibarot, Philippe; Arsenault, Benoit
    Aims: Elevated lipoprotein(a) [Lp(a)] levels are associated with the risk of coronary artery disease (CAD) and calcific aortic valve stenosis (CAVS). Observational studies revealed that Lp(a) and C-reactive protein (CRP) levels, a biomarker of systemic inflammation, may jointly predict CAD risk. Whether Lp(a) and CRP levels also jointly predict CAVS incidence and progression is unknown. Methods and results: We investigated the association of Lp(a) with CAVS according to CRP levels in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk study (n = 18 226, 406 incident cases) and the UK Biobank (n = 438 260, 4582 incident cases), as well as in the ASTRONOMER study (n = 220), which assessed the haemodynamic progression rate of pre-existing mild-to-moderate aortic stenosis. In EPIC-Norfolk, in comparison to individuals with low Lp(a) levels (<50 mg/dL) and low CRP levels (<2.0 mg/L), those with elevated Lp(a) (>50 mg/dL) and low CRP levels (<2.0 mg/L) and those with elevated Lp(a) (>50 mg/dL) and elevated CRP levels (>2.0 mg/L) had a higher CAVS risk [hazard ratio (HR) = 1.86 (95% confidence intervals, 1.30–2.67) and 2.08 (1.44–2.99), respectively]. A comparable predictive value of Lp(a) in patients with vs. without elevated CRP levels was also noted in the UK Biobank. In ASTRONOMER, CAVS progression was comparable in patients with elevated Lp(a) levels with or without elevated CRP levels. Conclusion: Lp(a) predicts the incidence and possibly progression of CAVS regardless of plasma CRP levels. Lowering Lp(a) levels may warrant further investigation in the prevention and treatment of CAVS, regardless of systemic inflammation.
  • PublicationAccès libre
    Soluble CD14 is associated with the structural failure of bioprostheses
    (Elsevier, 2018-06-30) Dahou, Abdellaziz; Bouchareb, Rihab; Arsenault, Benoit; Mkannez, Ghada; Boulanger, Marie-Chloé; Bossé, Yohan; Pibarot, Philippe; Clavel, Marie-Annick; Nsaibia, Mohamed Jalloul; Mathieu, Patrick; Salaun, Erwan
    Introduction: Aortic valve bioprostheses, which do not mandate chronic anticoagulation, are prone to structural valve degeneration (SVD). The processes involved in SVD are likely multifactorial. We hypothesized that inflammation and macrophage activation could be involved in SVD. Methods: In 203 patients with an aortic valve bioprosthesis, we evaluated the association between the macrophage activation marker soluble CD14 (sCD14) and SVD. Results: After a mean follow-up of 8 ± 3 years, 42 (21%) patients developed SVD. Patients with SVD had higher peak (44 ± 13 mmHg vs. 25 ± 12 mmHg, p < .0001) and mean (24 ± 7 mmHg vs. 12 ± 5 mmHg, p < .0001) transprosthetic gradients. On univariable analysis, low-density lipoprotein cholesterol (LDL) and sCD14 were associated with SVD. After correction for covariates, sCD14 (OR: 1.12, 95%CI: 1.02–1.23, p = .01) remained independently associated with SVD. In turn, sCD14 was associated with the HOMA index and high-density lipoprotein (HDL) level. Patients with a metabolic syndrome (MetS) had higher level of sCD14. In a model corrected for age, sex, HOMA and HDL, the MetS remained independently associated with sCD14 levels (β = 0.65, SE = 0.30, p = .03). Conclusion: Circulating level of sCD14 is an independent predictor of SVD. In turn, patients with MetS have higher sCD14 levels.
  • PublicationRestreint
    Lipoprotein-associated phospholipase A2 activity, genetics and calcific aortic valve stenosis in humans
    (BMJ Pub. Group, 2020-08-26) Thériault, Sébastien; Arsenault, Benoit; Rigade, Sidwell; Capoulade, Romain; Chen, Hao Yu; Bossé, Yohan; Dina, Christian; Pibarot, Philippe; Martinsson, Andreas; Perrot, Nicolas; Boekholdt, Matthijs; Clavel, Marie-Annick; Mathieu, Patrick; Le Tourneau, Thierry; Messika-Zeitoun, David; Engert, James; Wareham, Nicholas J.; Smith, J. Gustav; Schott, Jean Jacques; Thanassoulis, George
    Background Lipoprotein-associated phospholipase A2 (Lp-PLA2) activity has been shown to predict calcific aortic valve stenosis (CAVS) outcomes. Our objective was to test the association between plasma Lp-PLA2 activity and genetically elevated Lp-PLA2 mass/activity with CAVS in humans. Methods and results Lp-PLA2 activity was measured in 890 patients undergoing cardiac surgery, including 476 patients undergoing aortic valve replacement for CAVS and 414 control patients undergoing coronary artery bypass grafting. After multivariable adjustment, Lp-PLA2 activity was positively associated with the presence of CAVS (OR=1.21 (95% CI 1.04 to 1.41) per SD increment). We selected four single nucleotide polymorphisms (SNPs) at the PLA2G7 locus associated with either Lp-PLA2 mass or activity (rs7756935, rs1421368, rs1805017 and rs4498351). Genetic association studies were performed in eight cohorts: Quebec-CAVS (1009 cases/1017 controls), UK Biobank (1350 cases/349 043 controls), European Prospective Investigation into Cancer and Nutrition-Norfolk (504 cases/20 307 controls), Genetic Epidemiology Research on Aging (3469 cases/51 723 controls), Malmö Diet and Cancer Study (682 cases/5963 controls) and three French cohorts (3123 cases/6532 controls), totalling 10 137 CAVS cases and 434 585 controls. A fixed-effect meta-analysis using the inverse-variance weighted method revealed that none of the four SNPs was associated with CAVS (OR=0.99 (95% CI 0.96 to 1.02, p=0.55) for rs7756935, 0.97 (95% CI 0.93 to 1.01, p=0.11) for rs1421368, 1.00 (95% CI 1.00 to 1.01, p=0.29) for rs1805017, and 1.00 (95% CI 0.97 to 1.04, p=0.87) for rs4498351). Conclusions Higher Lp-PLA2 activity is significantly associated with the presence of CAVS and might represent a biomarker of CAVS in patients with heart disease. Results of our genetic association study suggest that Lp-PLA2 is however unlikely to represent a causal risk factor or therapeutic target for CAVS.
  • PublicationRestreint
    B-Type natriuretic peptide and high-sensitivity cardiac troponin for risk stratification in low-flow, low-gradient aortic stenosis a substudy of the TOPAS study
    (American College of Cardiology Foundation, 2017-10-05) Dahou, Abdellaziz; O'Connor, Kim; Rodés-Cabau, Josep; Le Ven, Florent; Côté, Nancy; Capoulade, Romain; Pibarot, Philippe; Dumesnil, Jean G.; Clavel, Marie-Annick; Ribeiro, Henrique B.; Mathieu, Patrick
    OBJECTIVES: The objective of this study was to determine the prognostic value of combined measures of B-type natriuretic peptide (BNP) and high-sensitivity cardiac troponin T (hsTnT) in patients with low-flow, low-gradient aortic stenosis (LF-LG AS) who had either a preserved or reduced left ventricular ejection fraction (LVEF). BACKGROUND: An elevated BNP level is associated with increased risk of mortality in patients with LF-LG AS. The incremental prognostic value of hsTnT in these patients is unknown. METHODS: Ninety-eight patients (74 10 years; 75% men) with LF-LG AS (LVEF <50% and/or stroke volume index <35 ml/m2 , mean gradient <40 mm Hg, indexed aortic valve area <0.6 cm2 /m2 ) who were prospectively enrolled in the TOPAS (Truly or Pseudo-Severe Aortic Stenosis) study were included. The cohort was divided into 3 groups according to BNP and hsTnT levels: group A: BNP <550 pg/ml and hsTnT <15 ng/l; group B: BNP $550 pg/ml or hsTnT $15 ng/l; and group C: BNP $550 pg/ml and hsTnT $15 ng/l. The primary endpoint was all-cause mortality. RESULTS: Twenty-seven patients (27%) were in group A, 39 (40%) were in group B, and 32 (33%) were in group C. During a median follow-up of 2.8 years, 43 patients died. Two-year mortality was higher in group C (41 9%) than in group B (23 7%) and group A (5 4%) (p ¼ 0.002). In group B, there was no significant difference in 2-year mortality rates between the subgroup with hsTnT $15 ng/l (n ¼ 29) and the subgroup with BNP $550 pg/ml (n ¼ 10) (26 9% vs. 11 10%, respectively; p ¼ 0.21). In multivariable analysis adjusted for age, type of treatment (aortic valve replacement vs. conservative therapy), coronary artery disease, and LVEF, being in group C remained independently associated with an increased risk of mortality (hazard ratio [HR]: 4.25; p ¼ 0.023), and group B tended to have higher mortality (HR: 3.63; p ¼ 0.058) compared with group A. CONCLUSIONS: This study demonstrated the usefulness of combined measures of BNP and hsTnT to enhance risk stratification in patients with LF-LG AS. Patients with elevation of both BNP and hsTnT had a markedly increased risk of mortality. (Multicenter Prospective Study of Low-Flow Low-Gradient Aortic Stenosis [TOPAS]; NCT01835028)
  • PublicationAccès libre
    Relationship between QT interval and outcome in low-flow low-gradient aortic stenosis with low left ventricular ejection fraction
    (John Wiley & Sons, 2016-10-20) Dahou, Abdellaziz; Toubal, Oumhani; Larose, Éric; Magne, Julien; Rodés-Cabau, Josep; Beaudoin, Jonathan; Philippon, François; Pibarot, Philippe; Dumesnil, Jean G.; Clavel, Marie-Annick; Puri, Rishi; Mathieu, Patrick; Ribeiro, Henrique B.
    Background QT interval has been shown to be associated with cardiovascular events. There is no data regarding the association between QT interval and left ventricular (LV) function and prognosis in patients with low LV ejection fraction (LVEF), low‐flow, low‐gradient aortic stenosis (LF‐LG AS). We aimed to examine the relationship between corrected QT interval (QTc) and LV function and outcome in these patients. Methods and Results Ninety‐three patients (73±10 years; 74% men) with LF‐LG AS (mean gradient <40 mm Hg and indexed aortic valve area ≤0.6 cm2/m2) and reduced LVEF (≤40%) were prospectively included in this analysis and 63 of them underwent aortic valve replacement within 3 months following inclusion. Prolonged QTc was defined as QTc >450 ms in men and >470 ms in women. LV global longitudinal strain was measured by speckle tracking and expressed in absolute value |%|. QTc correlated with the following: global longitudinal strain (r=−0.40, P=0.005), LVEF (r=−0.27, P=0.02), stroke volume (r=−0.35, P=0.007), and B‐type natriuretic peptide (r=0.45, P=0.0006). During a median follow‐up of 2.0 years, 49 patients died. Prolonged QTc was associated with a 2‐fold increase in all‐cause mortality (hazard ratio=2.05; P=0.01) and cardiovascular mortality (hazard ratio=1.89; P=0.04). In multivariable analysis adjusted for EuroSCORE, aortic valve replacement, previous myocardial infarction, LVEF, and ß‐blocker medication, prolonged QTc was independently associated with all‐cause mortality (hazard ratio=2.56; P=0.008) and cardiovascular mortality (hazard ratio=2.50; P=0.02). Conclusions In patients with LF‐LG AS and reduced LVEF, longer QTc interval was associated with worse LV function and increased risk of death. Assessment of QTc may provide a simple and inexpensive tool to enhance risk stratification in LF‐LG AS patients.
  • PublicationAccès libre
    Effect of age and aortic valve anatomy on calcification and haemodynamic severity of aortic stenosis
    (British Cardiac Society, 2016-12-09) Larose, Éric; Shen, Mylène; Chetaille, Philippe; Bédard, Élisabeth; Capoulade, Romain; Pibarot, Philippe; Dumesnil, Jean G.; Clavel, Marie-Annick; Tastet, Lionel; Mathieu, Patrick; Arsenault, Marie
    Objective: To evaluate the effect of age and aortic valve anatomy (tricuspid [TAV] versus bicuspid [BAV] aortic valve) on the relationship between the aortic valve calcification (AVC) and the hemodynamic parameters of aortic stenosis (AS) severity. Methods: Two hundred patients with AS and preserved left ventricular ejection fraction were prospectively recruited in the PROGRESSA (Metabolic Determinants of the Progression of Aortic Stenosis) study and underwent a comprehensive Doppler echocardiography and multidetector computed tomography (MDCT). Mean transvalvular gradient (MG) measured by Doppler echocardiography was used to assess AS hemodynamic severity and AVC was evaluated by MDCT using the Agatston method and indexed to the left ventricular outflow tract area to obtain AVC density (AVCd). All analyses were adjusted for sex. Results: Thirty-nine patients had a BAV and 161 a TAV. Median age was 51 and 72 years for BAV and TAV patients respectively. There was a modest correlation between MG and AVCd (ρ=0.51, p<0.0001) in the whole cohort. After dichotomization for valve anatomy, there was a good correlation between AVCd and MG in the TAV group (ρ=0.61, p<0.0001) but weak correlation in the BAV group (ρ=0.32, p=0.046). In the TAV group, the strength of the AVCd-MG correlation was similar in younger (<72 years old; ρ=0.59, p<0.0001) versus older (≥72 years old; ρ=0.61, p<0.0001) patients. In the BAV group, there was no correlation between AVCd and MG in younger patients (<51 years old; ρ=0.12, p=0.65), whereas there was a good correlation in older patients (≥51 years old; ρ=0.55, p=0.009). AVCd (p=0.005) and age (p=0.02) were both independent determinants of MG in BAV patients while AVCd (p<0.0001) was the only independent determinant of MG in TAV patients. Conclusion: In patients with TAV as well as in older patients with BAV, AVCd appears to be the main factor significantly associated with the hemodynamic severity of AS and so it may be used to corroborate AS severity in case of uncertain or discordant findings at echocardiography. However, among younger patients with BAV, some may have a hemodynamically significant stenosis with minimal AVCd. The results of MDCT AVCd should thus be interpreted cautiously in this subset of patients.
  • PublicationAccès libre
    Hemodynamic deterioration of surgically implanted bioprosthetic aortic valves
    (Elsevier Biomedical, 2018-07-09) Dahou, Abdellaziz; Arsenault, Benoit; Larose, Éric; Mahjoub, Haïfa; Rodés-Cabau, Josep; Pibarot, Philippe; Clavel, Marie-Annick; Puri, Rishi; Després, Jean-Pierre; Mathieu, Patrick; Salaun, Erwan
    BACKGROUND: Dysmetabolic profile has been associated with native aortic valve stenosis. However, there are imited data on the effects of an atherogenic milieu and its potential implications on the structural and hemodynamic deterio- ration of aortic bioprosthetic valves. OBJECTIVES: This prospective longitudinal study sought to determine the predictors and impact on outcomes of he- modynamic valve deterioration (HVD) of surgically implanted aortic bioprostheses. METHODS: A total of 137 patients with an aortic bioprosthesis implanted for a median time of 6.7 (interquartile range: 5.1 to 9.1) years prospectively underwent a first (baseline) assessment with complete Doppler echocardiography, quantitation of bioprosthesis leaflet calcification by multidetector computed tomography (CT), and a fasting blood sample to assess cardiometabolic risk profile. All patients underwent a second (follow-up) Doppler echocardiography examination at 3 (interquartile range: 2.9 to 3.3) years post-baseline visit. HVD was defined by an annualized change in mean transprosthetic gradient $3 mm Hg/year and/or worsening or transprosthetic regurgitation by $1/3 class. The primary endpoint was a nonhierarchical composite of death from any cause or aortic reintervention procedure (redo surgical valve replacement or transcatheter valve-in-valve implantation) for bioprosthesis failure. RESULTS Thirty-four patients (25.6%) had leaflet calcification on baseline CT, and 18 patients (13.1%) developed an HVD between baseline and follow-up echocardiography. Fifty-two patients (38.0%) met the primary endpoint during subsequent follow-up after the second echocardiographic examination. Leaflet calcification (hazard ratio [HR]: 2.58; 95% confidence interval [CI]: 1.35 to 4.82; p ¼ 0.005) and HVD (HR: 5.12; 95% CI: 2.57 to 9.71; p < 0.001) were independent predictors of the primary endpoint. Leaflet calcification, insulin resistance (homeostatic model assessment index $2.7), lipoprotein-associated phospholipase A2 activity (Lp-PLA2 per 0.1 nmol/min/ml increase), and high level of proprotein convertase subtilisin/kexin 9 (PCSK9) ($305 ng/ml) were associated with the development of HVD after adjusting for age, sex, and time interval since aortic valve replacement. CONCLUSIONS: HVD identified by Doppler echocardiography is independently associated with a marked increase in the risk of valve reintervention or mortality in patients with a surgical aortic bioprosthesis. A dysmetabolic profile charac- terized by elevated plasma Lp-PLA2, PCSK9, and homeostatic model assessment index was associated with increased risk of HVD. The presence of leaflet calcification as detected by CT was a strong predictor of HVD, providing incremental risk- predictive capacity. (J Am Coll Cardiol 2018;72:241–51) © 2018 by the American College of Cardiology Foundation.
  • PublicationRestreint
    Association between remant cholesterol and progression of bioprosthetic valve degeneration
    (Oxford University Press, 2023-07-06) Li, Ziang; Zhang, Bin; Salaun, Erwan; Côté, Nancy; Mahjoub, Haïfa; Mathieu, Patrick; Dahou, Abdellaziz; Zenses, Anne-Sophie; Xu, Yujun; Pibarot, Philippe; Wu, Yongjian; Clavel, Marie-Annick
    Aims Remnant cholesterol (RC) seems associated with native aortic stenosis. Bioprosthetic valve degeneration may share similar lipid-mediated pathways with aortic stenosis. We aimed to investigate the association of RC with the progression of bioprosthetic aortic valve degeneration and ensuing clinical outcomes. Methods and results We enrolled 203 patients with a median of 7.0 years (interquartile range: 5.1–9.2) after surgical aortic valve replacement. RC concentration was dichotomized by the top RC tertile (23.7 mg/dL). At 3-year follow-up, 121 patients underwent follow-up visit for the assessment of annualized change in aortic valve calcium density (AVCd). RC levels showed a curvilinear relationship with an annualized progression rate of AVCd, with increased progression rates when RC >23.7 mg/dL (P = 0.008). There were 99 deaths and 46 aortic valve re-interventions in 133 patients during a median clinical follow-up of 8.8 (8.7–9.6) years. RC >23.7 mg/dL was independently associated with mortality or re-intervention (hazard ratio: 1.98; 95% confidence interval: 1.31–2.99; P = 0.001). Conclusion Elevated RC is independently associated with faster progression of bioprosthetic valve degeneration and increased risk of all-cause mortality or aortic valve re-intervention.
  • PublicationRestreint
    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) Guertin, Jakie; Kaiser, Yannick; Manikpurage, Hasanga D.; Perrot, Nicolas; Bourgeois, Raphaëlle; Couture, Christian; Wareham, Nicholas J.; Bossé, Yohan; Pibarot, Philippe; Stroes, Erik S.; Mathieu, Patrick; Clavel, Marie-Annick; Thériault, Sébastien; Boekholdt, Matthijs; Arsenault, Benoit
    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.