Publications by authors named "Marie Arsenault"

86 Publications

Segmental analysis by speckle-tracking echocardiography of the left ventricle response to isoproterenol in male and female mice.

PeerJ 2021 12;9:e11085. Epub 2021 Mar 12.

Universite Laval, Groupe de recherche sur les valvulopathies, Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Quebec, Quebec, Canada.

We studied by conventional and speckle-tracking echocardiography, the response of the left ventricle (LV) to a three-week continuous infusion of isoproterenol (Iso), a non-specific beta-adrenergic receptor agonist in male and female C57Bl6/J mice. Before and after Iso (30 mg/kg/day), we characterized LV morphology and function as well as global and segmental strain. We observed that Iso reduced LV ejection in both male (-8.7%) and female (-14.7%) mice. Several diastolic function parameters were negatively regulated in males and females such as E/A, E/E', isovolumetric relaxation time. Global longitudinal (GLS) and circumferential (GCS) strains were reduced by Iso in both sexes, GLS by 31% and GCS by about 20%. For the segmental LV analysis, we measured strain, strain rate, reverse strain rate, peak speckle displacement and peak speckle velocity in the parasternal long axis. We observed that radial strain of the LV posterior segments were more severely modulated by Iso than those of the anterior wall in males. In females, on the other hand, both posterior and anterior wall segments were negatively impacted by Iso. Longitudinal strain showed similar results to the radial strain for both sexes. Strain rate, on the other hand, was only moderately changed by Iso. Reverse strain rate measurements (an index of diastolic function) showed that posterior LV segments were negatively regulated by Iso. We then studied the animals 5 and 17 weeks after Iso treatment. Compared to control mice, LV dilation was still present in males. Ejection fraction was decreased in mice of both sex compared to control animals. Diastolic function parameters, on the other hand, were back to normal. Taken together, our study indicates that segmental strain analysis can identify LV regions that are more negatively affected by a cardiotoxic agent such as Iso. In addition, cessation of Iso was not accompanied with a complete restoration of cardiac function after four months.
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http://dx.doi.org/10.7717/peerj.11085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958899PMC
March 2021

Left ventricular asymmetric remodeling and subclinical left ventricular dysfunction in patients with calcific aortic valve stenosis - Results from a subanalysis of the PROGRESSA study.

Int J Cardiol 2021 Jun 13;332:148-156. Epub 2021 Mar 13.

Institut Universitaire de Cardiologie et de Pneumologie de Québec/Quebec Heart and Lung Institute, Laval University, Quebec City, Quebec, Canada. Electronic address:

Background: LV asymmetric remodeling (LVAR) is a feature commonly found in AS patients and it is presumed to be mainly related to the severity of valve stenosis. The aim of this study was to determine the associated factors and impact on left ventricular (LV) systolic function of LVAR in patients with mild and moderate aortic valve stenosis (AS).

Methods: Clinical, Doppler-echocardiographic and computed-tomographic data of 155 AS patients with preserved LV ejection fraction (≥50%) prospectively recruited in the PROGRESSA study (NCT01679431) were analyzed. LVAR was defined as a septal wall thickness ≥ 13 mm and a ratio of septal/posterior wall thickness > 1.5. LV global longitudinal strain (LV-GLS) was available in 129 patients. Plasma levels of N-terminal natriuretic B-type peptides (Nt-proBNP) were also measured.

Results: Mean age was 63 ± 15 years (70% men). LVAR was present in 21% (n = 33) of patients. A series of nested multivariate analysis revealed that age was the only factor associated with LVAR (all p ≤ 0.03). Additionally, these patients had higher baseline Nt-proBNP ratio (median [25-75 percentiles]: 1.04 [0.66-2.41] vs. 0.65 [0.33-1.19], p = 0.02), and significantly reduced LV-GLS (17.9[16.6-19.5] vs. 19.3[17.4-20.7] |%|, p = 0.04). A 1:1 matched analysis showed a significant association of LVAR with reduced LV-GLS (17.9[16.6-19.5] vs. 19.8[18.1-20.7] |%|, p = 0.02) and elevated Nt-proBNP (134[86-348] vs. 83[50-179]pg/ml, p = 0.03). Multivariable analysis also revealed that LVAR remains significantly associated with reduced LV-GLS (p = 0.03) and elevated Nt-proBNP (p = 0.001). LVAR was significantly associated with increased risk of major adverse cardiac events and death (Hazard ratio [95% confidence interval]: 2.32[1.28-4.22], p = 0.006).

Conclusions: LVAR was found in ~20% of patients with mild or moderate AS and was not related to the degree of AS severity or concomitant comorbidities, but rather to older age. LVAR was significantly associated with reduced LV longitudinal systolic function, increased Nt-proBNP levels, and higher risk of major adverse events and death. These findings provide support for closer clinical and echocardiographic surveillance of patients harboring this adverse LV remodeling feature.
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http://dx.doi.org/10.1016/j.ijcard.2021.03.017DOI Listing
June 2021

Ventricular Arrhythmia in Septal and Apical Hypertrophic Cardiomyopathy: The French-Canadian Experience.

Front Cardiovasc Med 2020 22;7:548564. Epub 2020 Oct 22.

Division of Cardiology, Multidisciplinary Cardiovascular Department, Institut Universitaire de Cardiologie et Pneumologie de Québec (IUCPQ-UL), Université Laval, Québec City, QC, Canada.

Apical hypertrophic cardiomyopathy (aHCM) is thought to have a more benign clinical course compared to septal HCM (sHCM), but most data have been derived from Asian cohorts. Comparative data on clinical outcome in Caucasian aHCM cohorts are scarce, and the results are conflicting. The aim of this study was to estimate the prevalence and outcome of aHCM in French-Canadians of Caucasian descent. We conducted a retrospective, single-center cohort study. The primary endpoint was a composite of documented sustained ventricular arrhythmia (VA), appropriate ICD therapy, arrhythmogenic syncope, cardiac arrest, or all-cause mortality. A total of 301 HCM patients (65% males) were enrolled including 80/301 (27%) with aHCM and 221/301 (73%) with sHCM. Maximal wall thickness was similar in both groups. Left ventricular apical aneurysm was significantly more common in aHCM (10 vs. 0.5%; < 0.001). The proportion of patients with myocardial fibrosis ≥ 15% of the left ventricular mass was similar between aHCM and sHCM (21 vs. 24%; = 0.68). Secondary prevention ICDs were more often implanted in aHCM patients (16 vs. 7%; = 0.02). The primary endpoint occurred in 26% of aHCM and 10.4% of sHCM patients ( = 0.001) and was driven by an increased incidence of sustained VA (10 vs. 2.3%; = 0.01). Multivariate analysis identified apical aneurysm and a phenotype of aHCM as independent predictors of the primary endpoint and the occurrence of sustained ventricular tachycardia. Unexplained syncope and a family history of sudden cardiac death were additional predictors for sustained VA. Apical HCM was associated with an increased risk of ventricular arrhythmia even when excluding patients with apical aneurysm. The phenotype of apical HCM is much more common in French-Canadians (27%) of Caucasian descent compared to other Caucasian HCM populations. Apical HCM in French-Canadians is associated with an increased risk for ventricular arrhythmia.
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http://dx.doi.org/10.3389/fcvm.2020.548564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642600PMC
October 2020

Effect of Regional Upper Septal Hypertrophy on Echocardiographic Assessment of Left Ventricular Mass and Remodeling in Aortic Stenosis.

J Am Soc Echocardiogr 2021 Jan 14;34(1):62-71. Epub 2020 Oct 14.

Institut Universitaire de Cardiologie et de Pneumologie de Québec/Québec Heart and Lung Institute, Laval University, Québec City, Québec, Canada. Electronic address:

Background: Transthoracic echocardiography (TTE) is the reference method for evaluation of aortic stenosis (AS), and it is extensively used to quantitate left ventricular (LV) mass and volumes. Regional upper septal hypertrophy (USH) or septal bulge is a frequent finding in patients with AS and may lead to overestimation of LV mass when using linear measurements. The objective of this study was to compare estimates of LV mass obtained by two-dimensional transthoracic echocardiographic LV dimensions measured at different levels of the LV cavity with those obtained by cardiovascular magnetic resonance (CMR).

Methods: One hundred six patients (mean age, 63 ± 15 years; 68% men) with AS were included in this subanalysis of the PROGRESSA study. Two-dimensional transthoracic echocardiographic measurements of LV dimensions were obtained at the basal level (BL; as recommended in guidelines), immediately below the septal bulge (BSB), and at a midventricular level (ML). Regional USH was defined as a basal interventricular septal thickness ≥ 13 mm and >1.3 times the thickness of the septal wall at the ML. Agreement between transthoracic echocardiographic and CMR measures was evaluated using Bland-Altman analysis.

Results: The distribution of AS severity was mild in 23%, moderate in 57%, and severe in 20% of patients. Regional USH was present in 28 patients (26%). In the whole cohort, two-dimensional TTE overestimated LV mass (bias: BL, +60 ± 31 g; BSB, +59 ± 32 g; ML, +54 ± 32 g; P = .02). The biplane Simpson method slightly but significantly underestimated LV end-diastolic volume (bias -10 ± 20 mL, P < .001) compared with CMR. Overestimation of LV mass was more marked in patients with USH when measuring at the BL and was significantly lower when measuring LV dimensions at the ML (P < .025 vs BL and BSB).

Conclusions: Two-dimensional TTE systematically overestimated LV mass and underestimated LV volumes compared with CMR. However, the bias between TTE and CMR was less important when measuring at the ML. Measurements at the BL as suggested in guidelines should be avoided, and measurements at the ML should be preferred in patients with AS, especially in those with USH.
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http://dx.doi.org/10.1016/j.echo.2020.08.022DOI Listing
January 2021

Estimation of Stroke Volume and Aortic Valve Area in Patients with Aortic Stenosis: A Comparison of Echocardiography versus Cardiovascular Magnetic Resonance.

J Am Soc Echocardiogr 2020 08 21;33(8):953-963.e5. Epub 2020 Jun 21.

Institut Universitaire de Cardiologie et de Pneumologie de Québec/Québec Heart & Lung Institute, Laval University, Québec City, Québec, Canada. Electronic address:

Background: In aortic stenosis, accurate measurement of left ventricular stroke volume (SV) is essential for the calculation of aortic valve area (AVA) and the assessment of flow status. Current American Society of Echocardiography and European Association of Cardiovascular Imaging guidelines suggest that measurements of left ventricular outflow tract diameter (LVOTd) at different levels (at the annulus vs 5 or 10 mm below) yield similar measures of SV and AVA. The aim of this study was to assess the effect of the location of LVOTd measurement on the accuracy of SV and AVA measured on transthoracic echocardiography (TTE) compared with cardiovascular magnetic resonance (CMR).

Methods: One hundred six patients with aortic stenosis underwent both TTE and CMR. SV was estimated on TTE using the continuity equation with LVOTd measurements at four locations: at the annulus and 2, 5, and 10 mm below annulus. SV was also determined on CMR using phase contrast acquired in the aorta (SV), and a hybrid AVA was calculated by dividing SV by the transthoracic echocardiographic Doppler aortic velocity-time integral. Comparison between methods was made using Bland-Altman analysis.

Results: Compared with the referent method of phase-contrast CMR for the estimation of SV and AVA (SV 83 ± 16 mL, AVA 1.27 ± 0.35 cm), the best agreement was obtained by measuring LVOTd at the annulus or 2 mm below (P = NS), whereas measuring 5 and 10 mm below the annulus resulted in significant underestimation of SV and AVA by up to 15.9 ± 17.3 mL and 0.24 ± 0.28 cm, respectively (P < .01 for all). Accuracy for classification of low flow was best at the annulus (86%) and 2 mm below (82%), whereas measuring 5 and 10 mm below the annulus significantly underperformed (69% and 61%, respectively, P < .001).

Conclusions: Measuring LVOTd at the annulus or very close to it provides the most accurate measures of SV and AVA, whereas measuring LVOTd 5 or 10 mm below significantly underestimates these parameters and leads to significant overestimation of the severity of aortic stenosis and prevalence of low-flow status.
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http://dx.doi.org/10.1016/j.echo.2020.03.020DOI Listing
August 2020

Effect of bicuspid aortic valve phenotype on progression of aortic stenosis.

Eur Heart J Cardiovasc Imaging 2020 07;21(7):727-734

Department of Medicine, Institut universitaire de cardiologie et de pneumologie de Québec-Université Laval/Quebec Heart & Lung Institute-Laval University, 2725 Chemin Sainte-Foy, Quebec City, Quebec G1V 4G5, Canada.

Aims: To compare the progression of aortic stenosis (AS) in patients with bicuspid aortic valve (BAV) or tricuspid aortic valve (TAV).

Methods And Results: One hundred and forty-one patients with mild-to-moderate AS, recruited prospectively in the PROGRESSA study, were included in this sub-analysis. Baseline clinical, Doppler echocardiography and multidetector computed tomography characteristics were compared between BAV (n = 32) and TAV (n = 109) patients. The 2-year haemodynamic [i.e. peak aortic jet velocity (Vpeak) and mean transvalvular gradient (MG)] and anatomic [i.e. aortic valve calcification density (AVCd) and aortic valve calcification density ratio (AVCd ratio)] progression of AS were compared between the two valve phenotypes. The 2-year progression rate of Vpeak was: 16 (-0 to 40) vs. 17 (3-35) cm/s, P = 0.95; of MG was: 1.8 (-0.7 to 5.8) vs. 2.6 (0.4-4.8) mmHg, P = 0.56; of AVCd was 32 (2-109) vs. 52 (25-85) AU/cm2, P = 0.15; and of AVCd ratio was: 0.08 (0.01-0.23) vs. 0.12 (0.06-0.18), P = 0.16 in patients with BAV vs. TAV. In univariable analyses, BAV was not associated with AS progression (all, P ≥ 0.26). However, with further adjustment for age, AS baseline severity, and several risk factors (i.e. sex, history of hypertension, creatinine level, diabetes, metabolic syndrome), BAV was independently associated with faster haemodynamic (Vpeak: β = 0.31, P = 0.02) and anatomic (AVCd: β = 0.26, P = 0.03 and AVCd ratio: β = 0.26, P = 0.03) progression of AS.

Conclusion: In patients with mild-to-moderate AS, patients with BAV have faster haemodynamic and anatomic progression of AS when compared to TAV patients with similar age and risk profile. This study highlights the importance and necessity to closely monitor patients with BAV and to adequately control and treat their risk factors.

Clinical Trial Registration: https://clinicaltrials.gov Unique identifier: NCT01679431.
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http://dx.doi.org/10.1093/ehjci/jeaa068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306858PMC
July 2020

Sex differences in the evolution of left ventricle remodeling in rats with severe volume overload.

BMC Cardiovasc Disord 2020 02 3;20(1):51. Epub 2020 Feb 3.

Groupe de recherche en valvulopathies, Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, 2725, Chemin Sainte-Foy, Québec City, G1V 4G5, Canada.

Background: Aortic valve regurgitation (AR) results in left ventricle (LV) volume overload (VO) leading to its dilation and hypertrophy (H). We study a rat model of severe AR induced by puncturing one or two leaflets using a catheter. Most of our studies were conducted in male animals. Recently, we started investigating if sex dimorphism existed in the AR rat model. We observed that AR females developed as much LVH as males but morphological remodeling differences were present. A head-to-head comparison of LV morphological and functional changes had never been performed in AR males (M) and females (F) using the latest modalities in cardiac imaging by echocardiography.

Methods: We performed a longitudinal study to evaluate the development of LV hypertrophy caused by chronic AR in male and female rats over 6 months. Sham-operated (sham) animals were used as controls.

Results: LV diastolic volumes (EDV) increased more over 6 months in sham males than in females (38% vs. 23% for EDV, both p < 0.01). AR resulted in significant LV dilation for both sexes (54% vs. 51% increase in EDV) vs. baseline values. Since normal cardiac growth was less in females, dilation from AR was relatively more important for them (88% (M) vs. 157% (F) increase in EDV over sham). AR caused LV wall thickening in both males and females. It happened sooner for AR females and was more important than in males (25% (M) vs. 56% (F) increase in septum thickness at 2 months and 10% (M) vs. 30% (F) at 6 months). We then evaluated if AR was associated with changes in LV strain using speckle-tracking 2D echocardiography. Global longitudinal strain remained similar between AR and sham animals. Circumferential strain was negatively modulated by AR but only in females and early after VO induction (13% (M) vs. 26% (F)).

Conclusion: AR resulted in more LV dilation and quicker wall thickening in female AR rats compared to males. Global circumferential strain was negatively modulated in AR females but not in males. AR also seemed to lead to a more spherical LV shape in females whereas; it kept mostly an ellipsoid shape in males. This can influence validity of mass estimation of the dilated LV in females by echocardiography.
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http://dx.doi.org/10.1186/s12872-020-01360-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6998357PMC
February 2020

Attenuated Mitral Leaflet Enlargement Contributes to Functional Mitral Regurgitation After Myocardial Infarction.

J Am Coll Cardiol 2020 02;75(4):395-405

Institut Universitaire de Cardiologie et de Pneumologie de Québec-Université Laval, Québec City, Quebec, Canada. Electronic address:

Background: Mitral leaflet enlargement has been identified as an adaptive mechanism to prevent mitral regurgitation in dilated left ventricles (LVs) caused by chronic aortic regurgitation (AR). This enlargement is deficient in patients with functional mitral regurgitation, which remains frequent in the population with ischemic cardiomyopathy. Maladaptive fibrotic changes have been identified in post-myocardial infarction (MI) mitral valves. It is unknown if these changes can interfere with valve growth and whether they are present in other valves.

Objectives: This study sought to test the hypothesis that MI impairs leaflet growth, seen in AR, and induces fibrotic changes in mitral and tricuspid valves.

Methods: Sheep models of AR, AR + MI, and controls were followed for 90 days. Cardiac magnetic resonance, echocardiography, and computed tomography were performed at baseline and 90 days to assess LV volume, LV function, mitral regurgitation and mitral leaflet size. Histopathology and molecular analyses were performed in excised valves.

Results: Both experimental groups developed similar LV dilatation and dysfunction. At 90 days, mitral valve leaflet size was smaller in the AR + MI group (12.8 ± 1.3 cm vs. 15.1 ± 1.6 cm, p = 0.03). Mitral regurgitant fraction was 4% ± 7% in the AR group versus 19% ± 10% in the AR + MI group (p = 0.02). AR + MI leaflets were thicker compared with AR and control valves. Increased expression of extracellular matrix remodeling genes was found in both the mitral and tricuspid leaflets in the AR + MI group.

Conclusions: In these animal models of AR, the presence of MI was associated with impaired adaptive valve growth and more functional mitral regurgitation, despite similar LV size and function. More pronounced extracellular remodeling was observed in mitral and tricuspid leaflets, suggesting systemic valvular remodeling after MI.
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http://dx.doi.org/10.1016/j.jacc.2019.11.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946170PMC
February 2020

Effects of the loss of estrogen on the heart's hypertrophic response to chronic left ventricle volume overload in rats.

PeerJ 2019 21;7:e7924. Epub 2019 Oct 21.

Groupe de Recherche sur les Valvulopathies, Centre de Recherche, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Québec, Canada.

Aortic valve regurgitation (AR) can result in heart failure from chronic overloading of the left ventricle (LV). Little is known of the role of estrogens in the LV responses to this condition. The aim of the study was to compare LV remodeling in female rats with severe AR in absence of estrogens by ovariectomy (Ovx). In a first study, we investigated over 6 months the development of hypertrophy in four groups of female Wistar rats: AR or sham-operated (sham) and Ovx or not. Ovx reduced normal heart growth. As expected, volume overload (VO) from AR resulted in significant LV dilation (42% and 32% increase LV end-diastolic diameter in intact and Ovx groups vs. their respective sham group;  < 0.0001). LV weight was also significantly and similarly increased in both AR groups (non-Ovx and Ovx). Increase in stroke volume or cardiac output and loss of systolic function were similar between AR intact and AR Ovx groups compared to sham. We then investigated what were the effects of 17beta-estradiol (E2; 0.03 mg/kg/day) treatment on the parameters studied in Ovx rats. Ovx reduced uterus weight by 85% and E2 treatment restored up to 65% of the normal weight. E2 also helped normalize heart size to normal values. On the other hand, it did not influence the extent of the hypertrophic response to AR. In fact, E2 treatment further reduced LV hypertrophy in AR Ovx rats (41% over Sham Ovx + E2). Systolic and diastolic functions parameters in AR Ovx + E2 were similar to intact AR animals. Ovx in sham rats had a significant effect on the LV gene expression of several hypertrophy markers. Atrial natriuretic peptide () gene expression was reduced by Ovx in sham-operated females whereas brain natriuretic peptide () expression was increased. Alpha () and beta () myosin heavy chain genes were also significantly modulated by Ovx in sham females. In AR rats, LV expression of both and genes were increased as expected. Ovx further increased it of AR rats for and did the opposite for . Interestingly, AR in Ovx rats had only minimal effects on and genes whereas they were modulated as expected for intact AR animals. In summary, loss of estrogens by Ovx in AR rats was not accompanied by a worsening of hypertrophy or cardiac function. Normal cardiac growth was reduced by Ovx in sham females but not the hypertrophic response to AR. On the other hand, Ovx had important effects on LV gene expression both in sham and AR female rats.
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http://dx.doi.org/10.7717/peerj.7924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812667PMC
October 2019

Sex-Related Differences in the Extent of Myocardial Fibrosis in Patients With Aortic Valve Stenosis.

JACC Cardiovasc Imaging 2020 03 14;13(3):699-711. Epub 2019 Aug 14.

Institut Universitaire de Cardiologie et de Pneumologie de Québec/Québec Heart & Lung Institute, Laval University, Québec City, Québec, Canada. Electronic address:

Objectives: The aim of this study was to assess the effect of sex on myocardial fibrosis as assessed by using cardiac magnetic resonance (CMR) imaging in aortic stenosis (AS).

Background: Previous studies reported sex-related differences in the left ventricular (LV) remodeling response to pressure overload in AS. However, there are very few data regarding the effect of sex on myocardial fibrosis, a key marker of LV decompensation and adverse cardiac events in AS.

Methods: A total of 249 patients (mean age 66 ± 13 years; 30% women) with at least mild AS were recruited from 2 prospective observational cohort studies and underwent comprehensive Doppler echocardiography and CMR examinations. On CMR, T1 mapping was used to quantify extracellular volume (ECV) fraction as a marker of diffuse fibrosis, and late gadolinium enhancement (LGE) was used to assess focal fibrosis.

Results: There was no difference in age between women and men (age 66 ± 15 years vs 66 ± 12 years; p = 0.78). However, women presented with a better cardiovascular risk profile than men with less hypertension, dyslipidemia, diabetes, and coronary artery disease (all, p ≤ 0.10). As expected, LV mass index measured by CMR imaging was smaller in women than in men (p < 0.0001). Despite fewer comorbidities, women presented with larger ECV fraction (median: 29.0% [25th to 75th percentiles: 27.4% to 30.6%] vs. 26.8% [25th to 75th percentiles: 25.1% to 28.7%]; p < 0.0001) and similar LGE (median: 4.5% [25th-75th percentiles: 2.3% to 7.0%] vs. 2.8% [25th-75th percentiles: 0.6% to 6.8%]; p = 0.20) than men. In multivariable analysis, female sex remained an independent determinant of higher ECV fraction and LGE (all, p ≤ 0.05).

Conclusions: Women have greater diffuse and focal myocardial fibrosis independent of the degree of AS severity. These findings further emphasize the sex-related differences in LV remodeling response to pressure overload.
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http://dx.doi.org/10.1016/j.jcmg.2019.06.014DOI Listing
March 2020

Sex differences in the response to angiotensin II receptor blockade in a rat model of eccentric cardiac hypertrophy.

PeerJ 2019 5;7:e7461. Epub 2019 Aug 5.

Université Laval, Groupe de recherche sur les valvulopathies, Centre de recherche, Institut universitaire de cardiologie et de pneumologie de Quebec, Québec, Québec, Canada.

Men and women differ in their susceptibility to cardiovascular disease, though the underlying mechanism has remained elusive. Heart disease symptoms, evolution and response to treatment are often sex-specific. This has been studied in animal models of hypertension or myocardial infarction in the past but has received less attention in the context of heart valve regurgitation. The aim of the study was to evaluate the development of cardiac hypertrophy (CH) in response to left ventricle (LV) volume overload (VO) caused by chronic aortic valve regurgitation (AR) in male and female rats treated or not with angiotensin II receptor blocker (ARB), valsartan. We studied eight groups of Wistar rats: male or female, AR or sham-operated (sham) and treated or not with valsartan (30 mg/kg/day) for 9 weeks starting one week before AR surgical induction. As expected, VO from AR resulted for both male and female rats in significant LV dilation (39% vs. 40% end-diastolic LV diameter increase, respectively;  < 0.0001) and CH (53% vs. 64% heart weight increase, respectively;  < 0.0001) compared to sham. Sex differences were observed in LV wall thickening in response to VO. In untreated AR males, relative LV wall thickness (a ratio of wall thickness to end-diastolic diameter) was reduced compared to sham, whereas this ratio in females remained unchanged. ARB treatment did not prevent LV dilation in both male and female animals but reversed LV wall thickening in females. Systolic and diastolic functions in AR animals were altered similarly for both sexes. ARB treatment did not improve systolic function but helped normalizing diastolic parameters such as left atrial mass and E wave slope in female AR rats. Increased LV gene expression of  and was normalized by ARB treatment in AR females but not in males. Other hypertrophy gene markers ( and ) were not modulated by ARB treatment. The same was true for genes related to LV extracellular matrix remodeling ( and ). In summary, ARB treatment of rats with severe AR blocked the female-specific hypertrophic response characterized by LV chamber wall thickening. LV dilation, on the other hand, was not significantly decreased by ARB treatment. This also indicates that activation of the angiotensin II receptor is probably more involved in the early steps of LV remodeling caused by AR in females than in males.
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http://dx.doi.org/10.7717/peerj.7461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686841PMC
August 2019

Staging Cardiac Damage in Patients With Asymptomatic Aortic Valve Stenosis.

J Am Coll Cardiol 2019 07;74(4):550-563

Québec Heart and Lung Institute, Laval University, Québec City, Québec, Canada. Electronic address:

Background: The optimal timing of intervention in patients with asymptomatic severe aortic stenosis (AS) remains controversial.

Objectives: This multicenter study sought to test and validate the prognostic value of the staging of cardiac damage in patients with asymptomatic moderate to severe AS.

Methods: This study retrospectively analyzed the clinical, Doppler echocardiographic, and outcome data that were prospectively collected in 735 asymptomatic patients (71 ± 14 years of age; 60% men) with at least moderate AS (aortic valve area <1.5 cm) and preserved left ventricular ejection fraction (≥50%) followed in the heart valve clinics of 4 high-volume centers. Patients were classified according to the following staging classification: no cardiac damage associated with the valve stenosis (Stage 0), left ventricular damage (Stage 1), left atrial or mitral valve damage (Stage 2), pulmonary vasculature or tricuspid valve damage (Stage 3), or right ventricular damage or subclinical heart failure (Stage 4). The primary endpoint was all-cause mortality.

Results: At baseline, 89 (12%) patients were classified in Stage 0, 200 (27%) in Stage 1, 341 (46%) in Stage 2, and 105 (14%) in Stage 3 or 4. Median follow-up was 2.6 years (interquartile range: 1.1 to 5.2 years). There was a stepwise increase in mortality rates according to staging: 13% in Stage 0, 25% in Stage 1, 44% in Stage 2, and 58% in Stages 3 to 4 (p < 0.0001). The staging was significantly associated with excess mortality in multivariable analysis adjusted for aortic valve replacement as a time-dependent variable (hazard ratio: 1.31 per each increase in stage; 95% CI: 1.06 to 1.61; p = 0.01), and showed incremental value to several clinical variables (net reclassification index = 0.34; p = 0.003).

Conclusions: The new staging system characterizing the extra-aortic valve cardiac damage provides incremental prognostic value in patients with asymptomatic moderate to severe AS. This staging classification may be helpful to identify asymptomatic AS patients who may benefit from elective aortic valve replacement.
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http://dx.doi.org/10.1016/j.jacc.2019.04.065DOI Listing
July 2019

Testosterone deficiency reduces cardiac hypertrophy in a rat model of severe volume overload.

Physiol Rep 2019 05;7(9):e14088

Groupe de recherche sur les valvulopathies, Centre de Recherche, Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Quebec City, Canada.

The aim of the study was to characterize if the development of cardiac hypertrophy (CH) caused by severe left ventricle (LV) volume overload (VO) from chronic aortic valve regurgitation (AR) in male rats was influenced by androgens. We studied Wistar rats with/without orchiectomy (Ocx) either sham-operated (S) or with severe AR for 26 weeks. Loss of testosterone induced by Ocx decreased general body growth. Cardiac hypertrophy resulting from AR was relatively more important in intact (non-Ocx) animals than in Ocx ones compared to their respective S group (60% vs. 40%; P = 0.019). The intact AR group had more LV dilation, end-diastolic LV diameter being increased by 37% over S group and by 17% in AROcx rats (P < 0.0001). Fractional shortening (an index of systolic function) decreased only by 15% in AROcx compared to 26% for intact AR animals (P = 0.029). Changes in LV gene expression resulting from CH were more marked in intact rats than in AROcx animals, especially for genes linked to extracellular matrix remodeling and energy metabolism. The ratio of hydroxyacyl-Coenzyme A dehydrogenase activity over hexokinase activity, an index of the shift of myocardial substrate use toward glucose from the preferred fatty acids, was significantly decreased in the AR group but not in AROcx. Finally, pJnk2 LV protein content was more abundant in AR than in AROcx rats, indicating decreased activation of this stress pathway in the absence of androgens. In summary, testosterone deficiency in rats with severe LV VO resulted in less CH and a normalization of the LV gene expression profile.
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http://dx.doi.org/10.14814/phy2.14088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499867PMC
May 2019

Prevalence of left ventricle non-compaction criteria in adult patients with bicuspid aortic valve versus healthy control subjects.

Open Heart 2018;5(2):e000869. Epub 2018 Oct 7.

Institut Universitaire de Cardiologie et de Pneumologie de Québec / Quebec Heart & Lung Institute, Laval University, Quebec City, Quebec, Canada.

Objective: The aim of this study was to compare the prevalence of left ventricle non-compaction (LVNC) criteria (or hypertrabeculation) in a cohort of patients with bicuspid aortic valve (BAV) and healthy control subjects (CTL) without cardiovascular disease using cardiovascular MR (CMR).

Methods: 79 patients with BAV and 85 CTL with tricuspid aortic valve and free of known cardiovascular disease underwent CMR to evaluate the presence of LVNC criteria. The left ventricle was assessed at end-systole and end-diastole, in the short-axis, two-chamber and four-chamber views and divided into the 16 standardised myocardial segments. LVNC was assessed using the non-compacted/compacted (NC/C) myocardium ratio and was considered to be present if at least one of the myocardial segments had a NC/C ratio superior to the cut-off values defined in previous studies: Jenni (>2.0 end-systole); Petersen (>2.3 end-diastole); or Fazio (>2.5 end-diastole).

Results: 15 CTL (17.6%) vs 8 BAV (10.1%) fulfilled Jenni 's criterion; 69 CTL (81.2%) vs 49 BAV (62.0%) fulfilled Petersen 's criterion; and 66 CTL (77.6%) vs 43 BAV (54.4%) fulfilled Fazio 's criterion. Petersen and Fazio 's LVNC criteria were met more often by CTL (p=0.006 and p=0.002, respectively) than patients with BAV, whereas this difference was not statistically significant according to Jenni 's criterion (p=0.17). In multivariable analyses, after adjusting for age, sex, the presence of significant valve dysfunction (>mild stenosis or >mild regurgitation), indexed LV mass, indexed LV end-diastolic volume and LV ejection fraction, BAV was not associated with any of the three LVNC criteria.

Conclusion: Patients with BAV do not harbour more LVNC than the general population and there is no evidence that they are at higher risk for the development of LVNC cardiomyopathy.
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http://dx.doi.org/10.1136/openhrt-2018-000869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196966PMC
February 2021

Multiple short-chain dehydrogenases/reductases are regulated in pathological cardiac hypertrophy.

FEBS Open Bio 2018 Oct 17;8(10):1624-1635. Epub 2018 Sep 17.

Groupe de recherche sur les valvulopathies Centre de Recherche Institut universitaire de cardiologie et de pneumologie de Québec Université Laval Quebec City Canada.

Cardiac hypertrophy (CH) is an important and independent predictor of morbidity and mortality. Through expression profiling, we recently identified a subset of genes (, , , , , , , , ), all of which are members of the short-chain dehydrogenase/reductase (SDR) superfamily and are highly expressed in the heart, that were significantly dysregulated in a rat model of CH caused by severe aortic valve regurgitation (AR). Here, we studied their expression in various models of CH, as well as factors influencing their regulation. Among the nine SDR genes studied, all but were down-regulated in CH models (AR rats or mice infused with either isoproterenol or angiotensin II). This regulation showed a clear sex dimorphism, being more evident in males than in females irrespective of CH levels. In neonatal rat cardiomyocytes, we observed that treatment with the α-adrenergic receptor agonist phenylephrine mostly reproduced the observations made in CH animals models. Retinoic acid, on the other hand, stimulated the expression of most of the SDR genes studied, suggesting that their expression may be related to cardiomyocyte differentiation. Indeed, levels of expression were found to be higher in the hearts of adult animals than in neonatal cardiomyocytes. In conclusion, we identified a group of genes modulated in animal models of CH and mostly in males. This could be related to the activation of the fetal gene expression program in pathological CH situations, in which these highly expressed genes are down-regulated in the adult heart.
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http://dx.doi.org/10.1002/2211-5463.12506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168690PMC
October 2018

ApoB/ApoA-I Ratio is Associated With Faster Hemodynamic Progression of Aortic Stenosis: Results From the PROGRESSA (Metabolic Determinants of the Progression of Aortic Stenosis) Study.

J Am Heart Assoc 2018 02 10;7(4). Epub 2018 Feb 10.

Institut Universitaire de Cardiologie et de Pneumologie de Québec/Québec Heart & Lung Institute, Laval University, Québec City, QC, Canada

Background: Previous studies reported that middle-aged patients with atherogenic lipoprotein-lipid profile exhibit faster progression of aortic valve stenosis (AS). The ratio of apolipoprotein B/apolipoprotein A-I (apoB/apoA-I) reflects the balance between atherogenic and anti-atherogenic lipoproteins. The aim of this study was to examine the association between apoB/apoA-I ratio and AS hemodynamic progression and to determine whether this association varies according to age.

Methods And Results: A total of 159 patients (66±13 years, 73% men) with AS were prospectively recruited in the PROGRESSA (Metabolic Determinants of the Progression of Aortic Stenosis) study. Hemodynamic progression of AS was determined by the change in peak aortic jet velocity (V) measured by Doppler-echocardiography between baseline and 2-year follow-up. Patients in the top tertile of apoB/apoA-I ratio (≥0.62) had a faster progression rate of AS compared with those in the bottom/mid tertiles (V progression: 0.30 [0.09-0.49] versus 0.16 [0.01-0.36] m/s, =0.02). There was a significant interaction (=0.007) between apoB/apoA-I ratio and age. Among younger patients (ie, aged <70 years; median value of the cohort), those in the top tertile of apoB/apoA-I ratio had a 3.4-fold faster AS progression compared with those in the bottom/mid tertiles (V progression: 0.34 [0.13-0.69] versus 0.10 [-0.03-0.31] m/s, =0.002), whereas there was no significant difference between tertiles in the subgroup of older patients (=0.83). After comprehensive adjustment, higher apoB/apoA-I ratio was significantly associated with faster AS progression in the subset of younger patients (all, standardized β≥0.36; ≤0.01).

Conclusions: Higher apoB/apoA-I ratio is significantly associated with faster hemodynamic progression of AS in the younger patients. These findings suggest that atherogenic lipid factors may play a crucial role in the pathogenesis of AS in younger patients, but may be are less important in older patients.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01679431.
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http://dx.doi.org/10.1161/JAHA.117.007980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850203PMC
February 2018

Early Activation of Growth Pathways in Mitral Leaflets Exposed to Aortic Regurgitation: New Insights from an Animal Model.

J Heart Valve Dis 2017 05;26(3):281-289

Groupe de Recherche en Valvulopathies, Centre de Recherche, Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Québec, Canada. Electronic correspondence:

Background And Aim Of The Study: Mitral leaflet enlargement in patients with chronic aortic regurgitation (AR) has been identified as an adaptive mechanism potentially able to prevent functional mitral regurgitation (FMR) in response to left ventricular (LV) dilatation. The timing of valve enlargement is not known, and the related mechanisms are largely unexplored.

Methods: AR was induced in 58 rats, and another 54 were used as sham controls. Animals were euthanized at different time points after AR creation (48 h, one week, and three months), and AR severity, FMR and LV dilatation were assessed using echocardiography. Mitral valves were harvested to document the reactivation of embryonic growth pathways.

Results: AR animals had increased LV dimensions and mitral annulus size. No animal developed FMR. No change in leaflet length or thickness was seen at 48 h; however, anterior mitral leaflets were longer and thicker in AR animals at one week and three months. Molecular changes were present early (at 48 h and at one week), with positive staining for transforming growth factor-b1 (TGF-b1), Alpha-smooth muscle actin (α-SMA) and matrix metalloproteinase-2 (MMP-2), which suggested active matrix remodeling. Increased gene expression for collagen 1, TGF-β1, α-SMA and MMP-2 was found in the mitral valve at 48 h and at one week, but after three months their expression had returned to normal.

Conclusions: This model of AR induces active expansion and thickening of the mitral leaflets. Growth signals are expressed acutely, but not at three months, which suggests that most of this enlargement occurs at an early stage. The stimulation of valvular growth could represent a new strategy for the prevention of FMR.
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May 2017

Forward Left Ventricular Ejection Fraction: A Simple Risk Marker in Patients With Primary Mitral Regurgitation.

J Am Heart Assoc 2017 Oct 27;6(11). Epub 2017 Oct 27.

Institut Universitaire de Cardiologie et de Pneumologie de Québec/Québec Heart & Lung Institute Laval University, Québec City, Québec, Canada

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 (<0.0001) and LV end-systolic diameter (=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; =0.01), whereas LV end-systolic diameter was not (=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.
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http://dx.doi.org/10.1161/JAHA.117.006309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5721745PMC
October 2017

Association of Paravalvular Regurgitation With 1-Year Outcomes After Transcatheter Aortic Valve Replacement With the SAPIEN 3 Valve.

JAMA Cardiol 2017 11;2(11):1208-1216

Columbia University Medical Center/New York Presbyterian Hospital, New York, New York.

Importance: Moderate/severe and even mild paravalvular regurgitation (PVR) are associated with increased mortality following transcatheter aortic valve replacement (TAVR) with first and second generations of transcatheter valves.

Objective: To examine the incidence, evolution, and effect on 1-year outcomes of PVR following TAVR with a third-generation balloon-expandable transcatheter heart valve.

Design, Setting, And Participants: Prespecified analysis of PVR in the Placement of Aortic Transcatheter Valves (PARTNER) II SAPIEN 3 trial, conducted between October 1, 2013, and September 3, 2014. Multicenter, nonrandomized registry of 1661 patients at intermediate or high surgical risk undergoing TAVR with the SAPIEN 3. Patients with severe, symptomatic aortic stenosis and high/intermediate surgical risk were enrolled in the registry at 51 sites in the United States and Canada.

Interventions: Transcatheter aortic valve replacement with the SAPIEN 3 valve.

Main Outcomes And Measures: Paravalvular regurgitation was assessed in a core laboratory at 30 days and 1 year according to a 5-class scheme: 0, none or trace; 1, mild; 2, mild to moderate; 3, moderate; 4, moderate to severe; and 5, severe. We assessed the effect of PVR on 1-year mortality and heart failure rehospitalization.

Results: Among the 1661 included in the registry, 1592 received a SAPIEN 3 valve and had assessment of PVR. Of these patients, 55.7% had none-trace PVR, 32.6% had mild, 8.2% had mild to moderate, and 3.5% had at least moderate PVR at 30 days. At 1 year, 9.3% of patients had died and 14.2% had been rehospitalized. Only patients with at least moderate PVR had higher 1-year mortality (hazard ratio [HR], 2.40; 95% CI, 1.30-4.43; P = .005) and composite of mortality/rehospitalization (HR, 2.35; 95% CI, 1.52-3.62; P < .001). In a paired comparison including 1213 patients, 73% of the patients with at least moderate PVR at 30 days showed a reduction in PVR severity of at least 1 PVR class at 1 year.

Conclusions And Relevance: In this series of patients undergoing TAVR with the SAPIEN 3 valve, at least moderate PVR was rare but associated with increased risk of death and heart failure rehospitalization at 1 year. Even the upper range of the mild class in the 3-class grading scheme (ie, mild to moderate in the 5-class scheme) had no significant effect on short-term mortality or rehospitalization. Most patients with at least moderate PVR at 30 days showed a decrease of PVR severity grade at 1 year.

Trial Registration: clinicaltrials.gov Identifier: NCT01314313.
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http://dx.doi.org/10.1001/jamacardio.2017.3425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710359PMC
November 2017

Female rats with severe left ventricle volume overload exhibit more cardiac hypertrophy but fewer myocardial transcriptional changes than males.

Sci Rep 2017 04 7;7(1):729. Epub 2017 Apr 7.

Groupe de recherche sur les valvulopathies, Centre de Recherche, Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Quebec City, Canada.

Aortic valve regurgitation (AR) imposes a volume overload (VO) to the left ventricle (LV). Male rats with a pathological heart overload usually progress more quickly towards heart failure than females. We examined whether a sexual dimorphism exists in the myocardial transcriptional adaptations to AR. Adult Wistar male and female rats either underwent a sham operation or were induced with AR and then followed for 26 weeks. Female AR rats gained relatively more LV mass than males (75 vs. 42%). They had a similar increase in LV chamber dimensions compared to males but more wall thickening. On the other hand, fatty acid oxidation (FAO)-related LV enzyme activity was only decreased in AR males. The expression of genes encoding FAO-related enzymes was only reduced in AR males and not in females. A similar situation was observed for the expression of genes involved in mitochondrial biogenesis or function as well as for genes encoding for transcription factors implicated in the control of bioenergetics and mitochondrial function (Errα, Errγ or Pgc1α). Although females develop more LV hypertrophy from severe VO, their myocardial gene expression remains closer to normal. This could provide survival benefits for females with severe VO.
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http://dx.doi.org/10.1038/s41598-017-00855-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5429715PMC
April 2017

Impact of left ventricular remodelling patterns on outcomes in patients with aortic stenosis.

Eur Heart J Cardiovasc Imaging 2017 Dec;18(12):1378-1387

Institut Universitaire de Cardiologie et de Pneumologie de Québec/Québec Heart & Lung Institute, Laval University, 2725 Chemin Sainte-Foy, Québec City, QC, Canada G1V-4G5.

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.
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http://dx.doi.org/10.1093/ehjci/jew288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837780PMC
December 2017

Determinants of Improvement In Left Ventricular Diastolic Function Following a 1-Year Lifestyle Modification Program in Abdominally Obese Men with Features of the Metabolic Syndrome.

Metab Syndr Relat Disord 2016 12 18;14(10):483-491. Epub 2016 Oct 18.

1 Centre de recherche , Institut universitaire de cardiologie et de pneumologie de Québec, Québec, Canada .

Background: Abdominal obesity and presence of the metabolic syndrome (MetS) are associated with cardiac abnormalities. Among those, left ventricular diastolic dysfunction (LVDD) is the most frequently encountered in clinical practice. Few studies evaluated the reversibility of LVDD by an approach promoting lifestyle modifications in abdominally obese subjects with MetS.

Methods: We assessed the impact of a 1-year lifestyle modification program combining nutritional and physical activity counseling on LVDD and metabolic profile of abdominally obese men with MetS. Echocardiograms, oral glucose tolerance test, lipids profile, dual energy X-ray absorptiometry, computed tomography scans (visceral obesity assessment), heart rate variability (HRV), as well as maximal and submaximal exercise tests were performed in participants before and after a 1-year program combining healthy eating and a physical activity/exercise program.

Results: Fifty-one abdominally obese men participated in this study. At baseline, 86% of the participants had LVDD (n = 44). After the 1-year program, LVDD improved in 57% of participants (n = 29, P < 0.0001). All metabolic, adiposity, and exercise tolerance measures improved from baseline (P < 0.0001), but were not associated with improvement in LVDD. Participants who improved LVDD had better exercise performance at baseline. Exercise tolerance during the submaximal exercise test, parasympathetic cardiac autonomic activity, and fasting insulin predicted 50% of LVDD improvements.

Conclusions: There was a significant improvement in LVDD after a 1-year lifestyle intervention program in abdominally obese men with MetS, such an improvement being associated with increased exercise tolerance, enhanced HRV, and reduced insulin levels.
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http://dx.doi.org/10.1089/met.2016.0021DOI Listing
December 2016

Effect of age and aortic valve anatomy on calcification and haemodynamic severity of aortic stenosis.

Heart 2017 01 8;103(1):32-39. Epub 2016 Aug 8.

Institut Universitaire de Cardiologie et de Pneumologie de Québec/Quebec Heart & Lung Institute, Laval University, Quebec City, Quebec, Canada.

Objective: To evaluate the effect of age and aortic valve anatomy (tricuspid (TAV) vs bicuspid (BAV) aortic valve) on the relationship between the aortic valve calcification (AVC) and the haemodynamic 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 CT (MDCT). Mean transvalvular gradient (MG) measured by Doppler echocardiography was used to assess AS haemodynamic 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 dichotomisation 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.

Conclusions: In patients with TAV as well as in older patients with BAV, AVCd appears to be the main factor significantly associated with the haemodynamic 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 haemodynamically significant stenosis with minimal AVCd. The results of MDCT AVCd should thus be interpreted cautiously in this subset of patients.

Trial Registration Number: NCT01679431; Pre-results.
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http://dx.doi.org/10.1136/heartjnl-2016-309665DOI Listing
January 2017

Echocardiographic predictors of outcomes in adults with aortic stenosis.

Heart 2016 06 5;102(12):934-42. Epub 2016 Apr 5.

Institut Universitaire de Cardiologie et de Pneumologie de Québec/Québec Heart & Lung Institute, Laval University, Québec City, Québec, Canada.

Objective: The study purpose was to assess the usefulness of echocardiographic parameters of aortic stenosis (AS) severity and left ventricular (LV) systolic function to predict mortality in AS. The main hypothesis is that parameters of LV systolic function are the most important independent predictors of mortality, whereas parameters of stenosis severity are not.

Methods: 1065 consecutive patients with AS referred to the echocardiography laboratory and meeting the inclusion/exclusion criteria were included and followed during 5.7 years. The end points were aortic valve replacement (AVR) (n=584), composite of AVR or death (n=932), all-cause mortality (n=550) and cardiovascular mortality (n=398).

Results: The most powerful echocardiographic predictors of valve-related events were parameters of AS severity, such as peak aortic jet velocity (VPeak), mean gradient (MG) and aortic valve area (AVA) (all p<0.001). Regarding mortality, the main predictors were LV ejection fraction (LVEF) and stroke volume index (SVi) (p<0.05). After multivariable adjustment, LVEF (p<0.001) and SVi (p=0.02) remained the only echocardiographic predictors of mortality, even after adjustment for symptomatic status. AVA was also associated with mortality, whereas VPeak and MG were not.

Conclusions: The most powerful echocardiographic predictors of mortality are low LVEF and low flow, whereas AS severity parameters predict valve-related events but not overall mortality. Hence, low flow should be integrated in the risk stratification and therapeutic decision-making in patients with AS.
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http://dx.doi.org/10.1136/heartjnl-2015-308742DOI Listing
June 2016

Systolic hypertension and progression of aortic valve calcification in patients with aortic stenosis: results from the PROGRESSA study.

Eur Heart J Cardiovasc Imaging 2017 Jan 18;18(1):70-78. Epub 2016 Feb 18.

Institut Universitaire de Cardiologie et de Pneumologie de Québec/Québec Heart and Lung Institute, Laval University, 2725 Chemin Sainte-Foy, Québec city, Québec, Canada G1V-4G5

Aims: Hypertension is highly prevalent in patients with aortic stenosis (AS) and is associated with worse outcomes. The current prospective study assessed the impact of systolic hypertension (SHPT) on the progression of aortic valve calcification (AVC) measured by multidetector computed tomography (MDCT) in patients with AS.

Methods And Results: The present analysis includes the first series of 101 patients with AS prospectively recruited in the PROGRESSA study. Patients underwent comprehensive Doppler echocardiography and MDCT exams at baseline and after 2-year follow-up. AVC and coronary artery calcification (CAC) were measured using the Agatston method. Patients with SHPT at baseline (i.e. systolic blood pressure ≥140 mmHg; n = 37, 37%) had faster 2-year AVC progression compared with those without SHPT (i.e. systolic blood pressure <140 mmHg) (AVC median [25th percentile-75th percentile]: +370 [126-824] vs. +157 [58-303] AU; P = 0.007, respectively). Similar results were obtained with the analysis of AVC progression divided by the cross-sectional area of the aortic annulus (AVC: +96 [34-218] vs. +45 [14-82] AU/cm, P = 0.01, respectively). In multivariable analysis, SHPT remained significantly associated with faster progression of AVC or AVC (all P = 0.001). There was no significant difference between groups with respect to progression of CAC (+39 [3-199] vs. +41 [0-156] AU, P = 0.88).

Conclusion: This prospective study shows for the first time that SHPT is associated with faster AVC progression but not with CAC progression in AS patients. These findings provide further support for the elaboration of randomized clinical trials to assess the efficacy of antihypertensive medication to slow the stenosis progression in patients with AS.
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http://dx.doi.org/10.1093/ehjci/jew013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5217738PMC
January 2017

Transcriptional Changes Associated with Long-Term Left Ventricle Volume Overload in Rats: Impact on Enzymes Related to Myocardial Energy Metabolism.

Biomed Res Int 2015 25;2015:949624. Epub 2015 Oct 25.

Groupe de Recherche sur les Valvulopathies, Centre de Recherche, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Quebec City, QC, Canada G1V 4G5.

Patients with left ventricle (LV) volume overload (VO) remain in a compensated state for many years although severe dilation is present. The myocardial capacity to fulfill its energetic demand may delay decompensation. We performed a gene expression profile, a model of chronic VO in rat LV with severe aortic valve regurgitation (AR) for 9 months, and focused on the study of genes associated with myocardial energetics. Methods. LV gene expression profile was performed in rats after 9 months of AR and compared to sham-operated controls. LV glucose and fatty acid (FA) uptake was also evaluated in vivo by positron emission tomography in 8-week AR rats treated or not with fenofibrate, an activator of FA oxidation (FAO). Results. Many LV genes associated with mitochondrial function and metabolism were downregulated in AR rats. FA β-oxidation capacity was significantly impaired as early as two weeks after AR. Treatment with fenofibrate, a PPARα agonist, normalized both FA and glucose uptake while reducing LV dilation caused by AR. Conclusion. Myocardial energy substrate preference is affected early in the evolution of LV-VO cardiomyopathy. Maintaining a relatively normal FA utilization in the myocardium could translate into less glucose uptake and possibly lesser LV remodeling.
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http://dx.doi.org/10.1155/2015/949624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4637065PMC
August 2016

Blockade of the acute activation of mTOR complex 1 decreases hypertrophy development in rats with severe aortic valve regurgitation.

Springerplus 2015 20;4:435. Epub 2015 Aug 20.

Groupe de Recherche sur les Valvulopathies, Centre de Recherche de l'Institut universitaire de Cardiologie et pneumologie de Québec, Université Laval, 2725, Chemin Sainte-Foy, Quebec, QC G1V 4G5 Canada.

Background: Hypertrophy (H) is an adaptive response of the heart to a hemodynamic overload. Severe left ventricular (LV) volume overload (VO) from valve regurgitations (aortic (AR) or mitral regurgitation) leads to eccentric LVH. Increased protein turnover is a major event during development of LVH and the mechanistic target of rapamycin (mTOR) is a key molecule for its control. The role of mTOR inhibition in the development of LVH using rapamycin for relatively short periods of time (days to a few weeks) has been studied in the past in pressure overload models but not in VO models. We investigated if mTOR pathway was activated during LVH development in a model of severe VO (AR) in rats and if a rapamycin treatment can slow heart remodeling in this situation.

Methods And Results: Male rats with severe AR were studied acutely at 2 days, at 8 weeks (compensated phase) and 6 months (late phase) after VO induction. mTOR complex (mTORC) 1 (ribosomal S6 protein phosphorylation) was activated early after AR induction but not later in the disease whereas mTORC2 activity levels (Akt phosphorylation at Ser473) remained stable. We observed that a moderate dose of rapamycin (2 mg/kg/day; orally) for 8 weeks prevented severe LVH caused by AR (-46 %: p < 0.001). Rapamycin treatment specifically inhibited LV mTORC1 without altering mTORC2 activity at 8 weeks. Rapamycin also prevented cardiac myocyte hypertrophy caused by AR.

Conclusion: Rapamycin slows hypertrophy in LV VO by inhibiting early activation of mTORC1 without modulating mTORC2.
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http://dx.doi.org/10.1186/s40064-015-1230-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4542859PMC
August 2015