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Dumesnil, Jean G.

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Jean G.

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Université Laval. Faculté de médecine

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  • 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.
  • PublicationRestreint
    Significant interaction between the nonprescription antihistamine diphenhydramine and the CYP2D6 substrate metoprolol in healthy men with high or low CYP2D6 activity
    (C.V. Mosby, 2000-05-23) Hamelin, Bettina; Bouayad, Asmàa; Méthot, Julie; Turgeon, Jacques; Pierre Desgagnés; Poirier, Paul; Dumesnil, Jean G.; Allaire, Joakim; Jobin, Jean
    The prototype “classic” over-the-counter antihistamine diphenhydramine was shown to interact with the polymorphic P450 enzyme CYP2D6. This project was undertaken to investigate (1) whether diphenhydramine inhibits the biotransformation of the clinically relevant CYP2D6 substrate metoprolol in vitro and (2) whether this in vitro interaction results in a clinically significant pharmacokinetic and pharmacodynamic drug interaction in vivo. In vitro incubations were carried out with microsomes obtained from lymphoblastic cells transfected with CYP2D6 complementary deoxyribonucleic acid to determine the type and extent of inhibition. We then randomized 16 subjects with genetically determined high (extensive metabolizers) or low (poor metabolizers) CYP2D6 activity to receive metoprolol (100 mg) in the presence of steady-state concentrations of diphenhydramine or placebo. In vitro, diphenhydramine was a potent competitive inhibitor of metoprolol α-hydroxylation, exhibiting an inhibitory constant of 2 µmol/L and increasing the Michaelis-Menten constant of metoprolol sixfold. In vivo, diphenhydramine decreased metoprolol oral and nonrenal clearances twofold and metoprolol→α-hydroxymetoprolol partial metabolic clearance 2.5-fold in extensive metabolizers (all P < .05) but not in poor metabolizers (P > .2). Although the hemodynamic response to metoprolol was unaltered by diphenhydramine in poor metabolizers (P > .05), metoprolol-related effects on heart rate, systolic blood pressure, and Doppler-derived aortic blood flow peak velocity were more pronounced and lasted significantly longer in extensive metabolizers receiving diphenhydramine compared with poor metabolizers and extensive metabolizers receiving placebo. We conclude that diphenhydramine inhibits the metabolism of metoprolol in extensive metabolizers, thereby prolonging the negative chronotropic and inotropic effects of the drug. Clinically relevant drug interactions may occur between diphenhydramine and many CYP2D6 substrates, particularly those with a narrow therapeutic index.
  • PublicationAccès libre
    Forward left ventricular ejection fraction: a simple risk marker in patients with primary mitral regurgitation
    (Wiley-Blackwell, 2017-10-27) Dahou, Abdellaziz; O'Connor, Kim; Thébault, Christophe; Mahjoub, Haïfa; Toubal, Oumhani; Ruest Bélanger, Catherine Éva; Côté, Nancy; Beaudoin, Jonathan; Dupuis, Marlène; Bernier, Mathieu; Pibarot, Philippe; Dumesnil, Jean G.; Clavel, Marie-Annick; Tastet, Lionel; Arsenault, Marie
    Background: The timing of mitral valve surgery in asymptomatic patients with primary mitral regurgitation (MR) is controversial. We hypothesized that the forward left ventricular (LV) ejection fraction (LVEF; ie, LV outflow tract stroke volume divided by LV end‐diastolic volume) is superior to the total LVEF to predict outcomes in MR. The objective of this study was to examine the association between echocardiographic parameters of MR severity and LV function and outcomes in patients with MR. Methods and Results: The clinical and Doppler‐echocardiographic data of 278 patients with ≥mild MR and no class I indication of mitral valve surgery at baseline were retrospectively analyzed. The primary study end point was the composite of mitral valve surgery or death. During a mean follow‐up of 5.4±3.2 years, there were 147 (53%) events: 96 (35%) MV surgeries and 66 (24%) deaths. Total LVEF and global longitudinal strain were not associated with the occurrence of events, whereas forward LVEF (P<0.0001) and LV end‐systolic diameter (P=0.0003) were. After adjustment for age, sex, MR severity, Charlson probability, coronary artery disease, and atrial fibrillation, forward LVEF remained independently associated with the occurrence of events (adjusted hazard ratio: 1.09, [95% confidence interval]: 1.02–1.17 per 5% decrease; P=0.01), whereas LV end‐systolic diameter was not (P=0.48). Conclusions: The results of this study suggest that the forward LVEF may be superior to the total LVEF and LV end‐systolic diameter to predict outcomes in patients with primary MR. This simple and easily measurable parameter may be useful to improve risk stratification and select the best timing for intervention in patients with primary MR.
  • PublicationRestreint
    Impact of left ventricular remodelling patterns on outcomes in patients with aortic stenosis
    (Oxford University Press, 2017-01-07) Dahou, Abdellaziz; O'Connor, Kim; Thébault, Christophe; Shen, Mylène; Le Ven, Florent; Bédard, Élisabeth; Capoulade, Romain; Beaudoin, Jonathan; Bernier, Mathieu; Pibarot, Philippe; Dumesnil, Jean G.; Clavel, Marie-Annick; Tastet, Lionel; Arsenault, Marie
    Aims: The objective of this study was to examine the association between the different patterns of left ventricular (LV) remodelling/hypertrophy on all-cause and cardiovascular mortality in patients with aortic stenosis (AS). Methods and results: In total, 747 consecutive patients (69 ± 14 years, 57% men) with AS and preserved LV ejection fraction were included in this study. According to LV mass index and relative wall thickness, patients were classified into four LV patterns: normal, concentric remodelling (CR), concentric hypertrophy (CH), and eccentric hypertrophy (EH). One hundred and sixteen patients (15%) had normal pattern, 66 (9%) had EH, 169 (23%) had CR, and 396 (53%) had CH. During a median follow-up of 6.4 years, 339 patients died (242 from cardiovascular causes). CH was associated with higher risk of all-cause mortality compared with the three other LV patterns (all P < 0.05). After multivariable adjustment, CH remained associated with higher risk of mortality (HR = 1.27, 95% CI 1.01–1.61, P = 0.046). There was a significant interaction (P < 0.05) between sex and CH with regards to the impact on mortality: CH was associated with worse outcome in women (P = 0.0001) but not in men (P = 0.22). In multivariable analysis, CH remained associated with higher risk of worse outcome in women (HR = 1.56, 95% CI 1.08–2.24, P = 0.018). Conclusions: This study shows that CH was independently associated with increased risk of mortality in AS patients with preserved ejection fraction. This association was observed in women but not in men. The pattern of LV remodelling/hypertrophy should be integrated in the risk stratification process in patients with AS.
  • PublicationRestreint
    Systolic hypertension and progression of aortic valve calcification in patients with aortic stenosis : results from the PROGRESSA study
    (Oxford University Press, 2016-02-18) Larose, Éric; Shen, Mylène; Capoulade, Romain; Bossé, Yohan; Pibarot, Philippe; Dumesnil, Jean G.; Tremblay, Alexe; Clavel, Marie-Annick; Després, Jean-Pierre; Tastet, Lionel
    Background : Systolic hypertension is one of the most frequent comorbidities encountered in patients with aortic stenosis (AS). In a recent study, we reported that systolic hypertension is associated with faster hemodynamic progression of AS and reduced survival. However, the impact of hypertension on the progression of aortic valve calcification (AVC), which is the culprit lesion of AS, is unknown. The main objective of this prospective study was to assess the impact of systolic hypertension on the progression of AVC in AS patients. Methods : One hundred and one patients with AS were prospectively recruited in the PROGRESSA study (NCT01679431). AVC and coronary artery calcification (CAC) were measured by multidetector computed tomography at baseline and at 2-year follow-up using the Agatston method. Results : The mean age was 65 ±13 years and 74% were male. During the 2-year follow-up, patients with systolic hypertension (i.e. systolic blood pressure =140 mmHg; n=37) at baseline had faster progression of AVC compared to those with no systolic hypertension (AVC: +370 [126-824] vs. +157 [58-303] AU; p=0.007; Figure). In multivariable analysis adjusted for age, sex, antihypertensive treatment, dyslipidemia, diabetes, metabolic syndrome, creatinine level, baseline hemodynamic AS severity, and baseline AVC, systolic hypertension remained an independent predictor of faster progression of AVC (p=0.001). In contrast, there was no significant difference in the progression of CAC between patients with versus without systolic hypertension (CAC: +39 [3-199] vs. +116 [28-189] AU; p=0.17; Figure). Conclusion : This prospective study shows that systolic hypertension is a powerful and independent predictor of faster progression of AVC but not of CAC in patients with AS. These findings emphasize the difference in the pathological processes leading to valvular versus vascular mineralization, and provide further to support the elaboration of randomized clinical trials targeting the treatment of hypertension in patients with AS
  • PublicationAccès libre
    Impact of plasma Lp-PLA2 activity on the progression of aortic stenosis : the PROGRESSA study.
    (American College of Cardiology Foundation, 2015-01-01) Arsenault, Benoit; Mahmut, Ablajan; Larose, Éric; Bédard, Élisabeth; Capoulade, Romain; Bossé, Yohan; Pibarot, Philippe; Dumesnil, Jean G.; Després, Jean-Pierre; Tastet, Lionel; Mathieu, Patrick; Arsenault, Marie
    Objectives : The purpose of this prospective study was to examine the relationship between plasma lipoprotein–associated phospholipase A2 (Lp-PLA2) activity and the progression rate of aortic stenosis (AS). Background : We recently reported that Lp-PLA2 is highly expressed in stenotic aortic valves where it may contribute to the mineralization of valvular interstitial cells. Methods : Patients with AS were prospectively recruited in the PROGRESSA (Metabolic Determinants of the Progression of Aortic Stenosis) study. AS progression rate was assessed by annualized increase in peak aortic jet velocity (Vpeak), mean gradient (MG), and aortic valve area index (AVAi). Circulating Lp-PLA2 activity was measured and dichotomized based on the median value. Results : Of 183 patients included in this subanalysis of the PROGRESSA study, 70% were men and the mean age was 66 ± 13 years. Over the 2.5 ± 1.4 years of follow up, the AS progression rate tended to be higher in patients with high versus low Lp-PLA2 activity (annualized Vpeak = 0.17 ± 0.23 m/s vs. 0.12 ± 0.18 m/s; p = 0.14). There was a significant interaction (p < 0.05) between baseline AS severity and Lp-PLA2 activity with respect to impact on AS progression rate. In patients with mild AS (i.e., Vpeak <3 m/s; n = 123), increased Lp-PLA2 activity was associated with a significantly faster AS progression rate (Vpeak 0.16 ± 0.18 m/s vs. 0.09 ± 0.14 m/s; p = 0.01) but not in patients with moderate or severe AS (p = 0.99). After adjustment for other risk factors, increased Lp-PLA2 activity remained independently associated with faster AS progression rate (p = 0.005) in the former subset. Conclusions : There was no significant association between plasma Lp-PLA2 activity or mass and stenosis progression in the whole cohort. However, increased Lp-PLA2 activity was associated with a faster stenosis progression rate in the subset of patients with mild AS. These findings provide an impetus for the elaboration of a randomized trial targeting Lp-PLA2 activity in patients with early stages of calcific aortic valve disease.
  • PublicationRestreint
    Usefulness of global left ventricular longitudinal strain for risk stratification in low ejection fraction, low-gradient aortic stenosis : results from the multicenter true or pseudo-severe aortic stenosis study
    (American Heart Association, 2015-02-13) Dahou, Abdellaziz; Bartko, Philipp Emanuel; O'Connor, Kim; Sénéchal, Mario; Capoulade, Romain; Mundigler, Gerald; Pibarot, Philippe; Larue-Grondin, Samuel; Dumesnil, Jean G.; Bergler-Klein, Jutta; Clavel, Marie-Annick; Burwash, Ian; Baumgartner, Helmut
    Background — The objective of this study was to examine the impact of left ventricular (LV) global longitudinal strain (GLS) measured at rest and at dobutamine stress echocardiography on the outcome of patients with low LV ejection fraction and low-gradient aortic stenosis. Methods and Results — Among the 202 patients with low LV ejection fraction (=40%), low-gradient aortic stenosis (mean transvalvular gradient <40 mm¿Hg and indexed aortic valve area =0.6 cm2/m2) prospectively enrolled in the multicenter True or Pseudo-Severe Aortic Stenosis study, 126 patients with resting GLS and 73 patients with stress GLS available were included in this substudy. Three-year survival rate was 49% in patients with rest GLS <|9|% compared with 68% in patients with GLS >|9|% (P=0.02). In a multivariable Cox model adjusted for age, coronary artery disease, projected aortic valve area at a normal flow rate and type of treatment (aortic valve replacement versus conservative), rest GLS <|9|% (hazard ratio, 2.18; P=0.015) remained independently associated with all-cause mortality. GLS <|10|% measured during dobutamine stress echocardiography was also independently associated with mortality (hazard ratio, 2.67; P=0.01). In the subset of patients with stress GLS (n=73), the ¿2 of the multivariable model to predict all-causes mortality was 21.96 for stress GLS versus 17.78 for rest GLS. Conclusions — GLS is independently associated with mortality in patients with low LV ejection fraction, low-gradient aortic stenosis. Stress GLS measured during dobutamine stress echocardiography may provide incremental prognostic value beyond GLS measured at rest. Hence, measurement of GLS at rest and during dobutamine stress echocardiography may be helpful to enhance risk stratification in low LV ejection fraction, low-gradient aortic stenosis.
  • PublicationRestreint
    Right ventricular longitudinal strain for risk stratification in low-flow, low-gradient aortic stenosis with low ejection fraction
    (BMJ, 2016-01-13) Dahou, Abdellaziz; Sénéchal, Mario; Larose, Éric; Bartko, Philipp Emanuel; Magne, Julien; Rodés-Cabau, Josep; Mundigler, Gerald; Capoulade, Romain; Bergler-Klein, Jutta; Pibarot, Philippe; Burwash, Ian; Dumesnil, Jean G.; Mascherbauer, Julia; Clavel, Marie-Annick; Ribeiro, Henrique B.; O’Connor, Kim; Mathieu, Patrick; Baumgartner, Helmut; Rosenhek, Raphael
    Background : Left ventricular global longitudinal strain (LVLS) is a powerful predictor of outcome in patients with low-flow, low-gradient aortic stenosis (LF-LG AS) and low LV ejection fraction (LVEF). However, the impact of right ventricular (RV) function on the outcome of these patients remains unknown. Objectives : The aim of this study was to examine the impact of RV function as evaluated by RV free wall longitudinal strain (RVLS) on mortality in patients with LF-LG AS and low LVEF. Methods : 211 patients with LF-LG AS (mean gradient <40 mm Hg and indexed aortic valve area (AVA) =0.6 cm2/m2) and low LVEF (=40%)) were prospectively recruited in the True or Pseudo-severe Aortic Stenosis study. AS severity was assessed using the projected AVA (AVAproj) at normal flow rate. Among the 211 patients, 128 had RVLS measurement available at rest and were included in this analysis. RVLS measurement at dobutamine stress echocardiography (DSE) was available in 58 of the 128 patients. Results : Two-year survival was lower in patients with RVLS<|13|% (53%±9%) compared with those with RVLS>|13|% (69%±5%) (p=0.04). In multivariable Cox analysis stratified for the type of treatment (aortic valve replacement vs conservative) and adjusted for age, AS severity, previous myocardial infarction and LVLS, rest RVLS<|13|% (HR=2.70; 95% CI 1.19 to 6.11; p=0.018) was independently associated with all-cause mortality. RVLS had incremental prognostic value over baseline risk factors and LVLS (¿2=20.13 vs 13.56; p=0.01). Reduced stress RVLS was also associated with increased risk of mortality (stress RVLS<|14|%: HR=2.98; 95% CI 1.30 to 6.52; p=0.01). In multivariable Cox analysis, stress RVLS<|14|% remained independently associated with mortality (HR=2.94; 95% CI 1.23 to 7.02; p=0.015). After further adjustment for rest RVLS, stress RVLS<|14|% remained independently associated with mortality (HR=3.29; 95% CI 1.17 to 9.25; p=0.024), whereas rest RVLS was not (p>0.05). Conclusions : In this series of patients with LF-LG AS and low LVEF, reduced RVLS was independently associated with increased risk of mortality. Furthermore, stress RVLS provided incremental prognostic value beyond that obtained from rest RVLS. Thus, RVLS measurement at rest and at DSE may be helpful to enhance risk stratification in this high-risk population.