Déterminants métaboliques de la progression de la sténose aortique

La sténose aortique est la maladie cardiovasculaire la plus fréquente dans les pays industrialisés après la maladie coronarienne et l’hypertension artérielle. Malheureusement, il n’existe actuellement aucun traitement médical efficace pour réduire sa progression et ses effets néfastes sur le remodelage et la fonction ventriculaire gauche. Le remplacement valvulaire aortique est le seul traitement efficace de la sténose aortique sévère symptomatique. Afin de développer des approches pharmacologiques efficaces pour réduire la progression de la maladie, il est primordial d’élucider les facteurs et les mécanismes qui sont impliqués dans sa pathogénèse. La sténose aortique, qui se caractérise par un dépôt progressif de calcium au niveau des feuillets et de l’anneau de la valve aortique, a longtemps été considérée comme une maladie dégénérative. Cependant, de récentes études ont suggéré que la sténose aortique était un processus actif vraisemblablement lié à l’athérosclérose. La sténose aortique apparait comme une pathologie complexe faisant intervenir différents processus liés à l’obésité viscérale et au syndrome métabolique, mais aussi à la dérégulation du métabolisme phospho-calcique. De plus, ces processus impliqués au niveau valvulaire peuvent aussi intervenir au niveau de l’aorte et du ventricule gauche. L’évaluation des mécanismes physiopathologiques impliqués à la fois au niveau de la valve, de l’aorte et du ventricule, ainsi que leurs interactions, permettrait de mieux connaitre et comprendre la pathologie valvulaire calcifiante et d’identifier de nouvelles cibles thérapeutiques dans cette population. L’objectif général de mon projet de doctorat est d’identifier et de déterminer l’impact respectif des différents facteurs métaboliques liés à l’obésité viscérale sur la progression de la sténose aortique, et du remodelage et de la dysfonction ventriculaire gauche.Aortic stenosis is the most common cardiovascular disease in developed countries after coronary artery disease and systemic arterial hypertension. Unfortunately, no medical therapies have been proven to decrease either the progression of valve stenosis or the resulting adverse effects on myocardial remodeling or function. Surgical aortic valve replacement is currently the sole option for the treatment of severe symptomatic aortic stenosis. To develop efficient pharmacological approaches to slow the progression of aortic stenosis, it is crucial to elucidate the factors and mechanisms that are involved in the pathogenesis of this disease. Aortic stenosis, which is characterized by a progressive calcium deposition in aortic valve leaflets and annulus, has long been considered as a degenerative disease. However, recent studies have suggested that aortic stenosis was an active process likely related to atherosclerosis. Aortic stenosis appears as a complex disease involving several processes related to visceral obesity and metabolic syndrome, as well as deregulation of the phosphor-calcic metabolism. Furthermore, these processes involved at the valvular level appear to be also implicated at the level of the aorta and the left ventricle. Assessment of the pathophysiological mechanisms involded both at the valve, aorta and ventricle, as well as their interactions, would better know and understand calcific valvular disease and identify new therapeutic targets in this population. The general objective of my PhD project is to identify and determine the respective impact of different metabolic factors related to visceral obesity on the progression of the valve stenosis, as well as left ventricular remodeling and dysfunction

Non-invasive determination of left ventricular workload in patients with aortic stenosis using magnetic resonance imaging and Doppler echocardiographye

Early detection and accurate estimation of aortic stenosis (AS) severity are the most important predictors of successful longterm outcomes in patients. Current clinical parameters used for evaluation of the AS severity have several limitations including flow dependency. Estimation of AS severity is specifically challenging in patients with low-flow and low transvalvular pressure gradient conditions. A proper diagnosis in these patients needs a comprehensive evaluation of the left ventricle (LV) hemodynamic loads. This study has two objectives: (1) developing a lumped-parameter model to describe the ventricular-valvular-arterial interaction and to estimate the LV stroke work (SW); (2) introducing and validating a new index, the normalized stroke work (N-SW), to assess the global hemodynamic load imposed on the LV. N-SW represents the global hemodynamic load that the LV faces for each unit volume of blood ejected. The model uses a limited number of parameters which all can be measured non-invasively using current clinical imaging modalities. The model was first validated by comparing its calculated flow waveforms with the ones measured using Cardiovascular Magnetic Resonance (CMR) in 49 patients and 8 controls. A very good correlation and concordance were found throughout the cycle (median root mean square: 12.21 mL/s) and between the peak values (r = 0.98; SEE = 0.001, p,0.001). The model was then used to determine SW using the parameters measured with transthoracic Doppler-echocardiography (TTE) and CMR. N-SW showed very good correlations with a previously-validated index of global hemodynamic load, the valvular arterial impedance (ZVA), using data from both imaging modalities (TTE: r = 0.82, SEE = 0.01, p,0.001; CMR: r = 0.74, SEE = 0.01, p,0.001). Furthermore, unlike , N-SW was almost independent from variations in the flow rate. This study suggests that considering N-SW may provide incremental diagnostic and prognostic information, beyond what standard indices of stenosis severity and provide, particularly in patients with low LV outflow

Impact of classic and paradoxical low flow on survival after aortic valve replacement for severe aortic stenosis

BackgroundLow flow (LF) can occur with reduced (classic) or preserved (paradoxical) left ventricular ejection fraction (LVEF). ObjectivesThe objective of this study was to compare outcomes of patients with low ejection fraction (LEF), paradoxical low flow (PLF), and normal flow (NF) after aortic valve replacement (AVR). MethodsWe examined 1,154 patients with severe aortic stenosis (AS) who underwent AVR with or without coronary artery bypass grafting. ResultsAmong these patients, 206 (18%) had LEF as defined by LVEF of 35 ml · m2. Aortic valve area was lower in low flow/LVEF groups (LEF: 0.71 ± 0.20 cm2 and PLF: 0.65 ± 0.23 cm2 vs. NF: 0.77 ± 0.18 cm2; p < 0.001). The 30-day mortality was higher (p < 0.001) in LEF and PLF groups than in the NF group (6.3% and 6.3% vs. 1.8%, respectively). SVi and PLF group were independent predictors of operative mortality (odds ratio [OR]: 1.18, p < 0.05; and OR: 2.97, p = 0.004; respectively). At 5 years after AVR, overall survival was 72 ± 4% in LEF group, 81 ± 2% in PLF group, and 85 ± 2% in NF group (p < 0.0001). ConclusionsPatients with LEF or PLF AS have a higher operative risk, but pre-operative risk score accounted only for LEF and lower LVEF. Patients with LEF had the worst survival outcome, whereas patients with PLF and normal flow had similar survival rates after AVR. As a major predictor of perioperative mortality, SVi should be integrated in AS patients’ pre-operative evaluation

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

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 (p=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 (p=0.61, p<0.0001) but weak correlation in the BAV group (p=0.32, p=0.046). In the TAV group, the strength of the AVCd-MG correlation was similar in younger (<72 years old; p=0.59, p<0.0001) versus older (=72 years old; p=0.61, p<0.0001) patients. In the BAV group, there was no correlation between AVCd and MG in younger patients (<51 years old; p=0.12, p=0.65), whereas there was a good correlation in older patients (=51 years old; p=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

Impact of plasma Lp-PLA2 activity on the progression of aortic stenosis : the PROGRESSA study.

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

Deleterious variants in DCHS1 are prevalent in sporadic cases of mitral valve prolapse

Background: A recent study identified DCHS1 as a causal gene for mitral valve prolapse. The goal of this study is to investigate the presence and frequency of known and novel variants in this gene in 100 asymptomatic patients with moderate to severe organic mitral regurgitation. Methods: DNA sequencing assays were developed for two previously identified functional missense variants, namely p.R2330C and p.R2513H, and all 21 exons of DCHS1. Pathogenicity of variants was evaluated in silico. Results: p.R2330C and p.R2513H were not identified in this cohort. Sequencing all coding regions revealed eight missense variants including six considered deleterious. This includes one novel variant (p.A2464P) and two rare variants (p.R2770Q and p.R2462Q). These variants are predicted to be deleterious with combined annotation-dependent depletion (CADD) scores greater than 25, which are in the same range as p.R2330C (CADD = 28.0) and p.R2513H (CADD = 24.3). More globally, 24 of 100 cases were carriers of at least one in silico-predicted deleterious missense variant in DCHS1, suggesting that this single gene may account for a substantial portion of cases. Conclusion: This study reveals an important contribution of germline variants in DCHS1 in unrelated patients with mitral valve prolapse and supports genetic testing of this gene to screen individuals at risk

Visceral adiposity and left ventricular mass and function in patients with aortic stenosis : the PROGRESSA study

Background : Recent studies have reported that obesity, metabolic syndrome, and diabetes are associated with left ventricular (LV) hypertrophy (LVH) and dysfunction in patients with aortic stenosis (AS). The purpose of this study was to examine the association between amount and distribution of body fat and LVH and systolic dysfunction in AS patients. Methods : One hundred twenty-four patients with AS were prospectively recruited in the PROGRESSA (Metabolic Determinants of the Progression of Aortic Stenosis) study and underwent Doppler echocardiography and computed tomography scan. Presence and severity of LVH was assessed according to LV mass indexed for height2.7 and LV dysfunction according to global longitudinal strain (GLS). Computed tomography was used to quantify abdominal visceral (VAT) and subcutaneous (SAT) adipose tissue, and total adipose tissue (TAT). Results : Body mass index (BMI) correlated strongly with TAT (r = 0.85), moderately with VAT (r = 0.70), and SAT (r = 0.69), and weakly with the proportion of VAT (VAT/TAT ratio: r = 0.19). In univariate analysis, greater BMI, TAT, VAT, SAT, and VAT/TAT were associated with increased LV mass index and greater VAT and VAT/TAT ratio were associated with reduced GLS. Multivariate analysis revealed that larger BMI (P < 0.0001) and greater VAT/TAT ratio (P = 0.01) were independently associated with higher prevalence of LVH, and only the VAT/TAT ratio (P = 0.03) was independently associated with reduced GLS. Conclusions : The results of this study suggest that total and visceral adiposity are independently associated with LVH in patients with AS. Furthermore, impairment of LV systolic function does not appear to be influenced by total obesity but is rather related to excess visceral adiposity. These findings provide impetus for elaboration of interventional studies aiming at visceral adiposity in the AS population.De récentes études ont rapporté que l’obésité, le syndrome métabolique et le diabète étaient associés à l’hypertrophie (HVG) et à la dysfonction ventriculaire gauche des patients souffrant d’une sténose aortique (SA). Le but de cette étude était d’examiner le lien entre la quantité et la répartition de la graisse corporelle, l’HVG et la dysfonction systolique chez les patients souffrant d’une SA. Méthodes : Cent vingt-quatre patients souffrant d’une SA ont été recrutés de manière prospective dans l’étude PROGRESSA (Metabolic Determinants of the Progression of Aortic Stenosis), et ont subi une échocardiographie Doppler et une tomodensitométrie. La présence et la sévérité de l’HVG ont été évaluées au moyen de la masse VG indexée par la taille2.7 et la dysfonction systolique du VG par la déformation longitudinale globale du VG (DLG). La tomodensitométrie a été utilisée pour quantifier le tissu adipeux abdominal viscéral (TAV) et sous-cutané (TAS), et le tissu adipeux total (TAT). Résultats : L’indice de masse corporelle (IMC) corrélait fortement avec le TAT (r = 0,85), modérément avec le TAV (r = 0,70) et le TAS (r = 0,69), et faiblement avec la proportion de TAV (rapport TAV/TAT : r = 0,19). En analyse multivariée, des IMC, TAT, TAV, TAS et VAT/TAT plus élevés étaient associés à une augmentation de la masse VG indexée et un TAV et un rapport TAV/TAT plus élevés étaient associés à la réduction de la DLG. L’analyse multivariée a révélé qu’un IMC plus élevé (P < 0,0001) et un rapport TAV/TAT plus élevé (P = 0,01) étaient indépendamment associés à une HVG plus importante, et seul un rapport TAV/TAT était indépendamment associé à une réduction de la DLG. Conclusions : Les résultats de cette étude montrent que l’adiposité totale et l'adiposité viscérale sont indépendamment associées à une HVG chez les patients souffrant d’une SA. De plus, la détérioration de la fonction systolique VG ne semble pas être influencée par l’obésité totale, mais est plutôt liée à une adiposité viscérale excessive. Ces résultats incitent à l’élaboration d’études interventionnelles visant l’adiposité viscérale dans la population souffrant de SA

Effect of regional upper septal hypertrophy on echocardiographic assessment of left ventricular mass and remodeling in aortic stenosis

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 6 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 6 31 g; BSB, +59 6 32 g; ML, +54 6 32 g; P = .02). The biplane Simpson method slightly but significantly underestimated LV end-diastolic volume (bias 10 6 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

Tricuspid regurgitation is associated with increased risk of mortality in patients with low-flow low-gradient aortic stenosis and reduced ejection fraction : results of the multicenter TOPAS study (true or pseudo-severe aortic stenosis)

Objectives : This study sought to examine the impact of tricuspid regurgitation (TR) on mortality in patients with low-flow, low-gradient (LF-LG) aortic stenosis (AS) and reduced left ventricular ejection fraction (LVEF). Background : TR is often observed in patients with LF-LG AS and low LVEF, but its impact on prognosis remains unknown. Methods : A total of 211 patients (73 ± 10 years of age; 77% men) with LF-LG AS (mean gradient <40 mm Hg and indexed aortic valve area [AVA] =0.6 cm2/m2) and reduced LVEF (=40%) were prospectively enrolled in the TOPAS (True or Pseudo-Severe Aortic Stenosis) study and 125 (59%) of them underwent aortic valve replacement (AVR) within 3 months following inclusion. The severity of AS was assessed by the projected AVA (AVAproj) at normal flow rate (250 ml/s), as previously described and validated. The severity of TR was graded according to current guidelines. Results : Among the 211 patients included in the study, 22 (10%) had no TR, 113 (54%) had mild (grade 1), 50 (24%) mild-to-moderate (grade 2), and 26 (12%) moderate-to-severe (grade 3) or severe (grade 4) TR. During a mean follow-up of 2.4 ± 2.2 years, 104 patients (49%) died. Univariable analysis showed that TR =2 was associated with increased risk of all-cause mortality (hazard ratio [HR]: 1.82, 95% confidence interval [CI]: 1.22 to 2.71; p = 0.004) and cardiovascular mortality (HR: 1.85, 95% CI: 1.20 to 2.83; p = 0.005). After adjustment for age, sex, coronary artery disease, AVAproj, LVEF, stroke volume index, right ventricular dysfunction, mitral regurgitation, and type of treatment (AVR vs. conservative), the presence of TR =2 was an independent predictor of all-cause mortality (HR: 1.88, 95% CI: 1.08 to 3.23; p = 0.02) and cardiovascular mortality (HR: 1.92, 95% CI: 1.05 to 3.51; p = 0.03). Furthermore, in patients undergoing AVR, TR =3 was an independent predictor of 30-day mortality compared with TR = 0/1 (odds ratio [OR]: 7.24, 95% CI: 1.56 to 38.2; p = 0.01) and TR = 2 (OR: 4.70, 95% CI: 1.00 to 25.90; p = 0.05). Conclusions : In patients with LF-LG AS and reduced LVEF, TR is independently associated with increased risk of cumulative all-cause mortality and cardiovascular mortality regardless of the type of treatment. In patients undergoing AVR, moderate/severe TR is associated with increased 30-day mortality. Further studies are needed to determine whether TR is a risk marker or a risk factor of mortality and whether concomitant surgical correction of TR at the time of AVR might improve outcomes for this high-risk population

Progression of Hypertrophy and Myocardial Fibrosis in Aortic Stenosis: A Multicenter Cardiac Magnetic Resonance Study

Background: Aortic stenosis is accompanied by progressive left ventricular hypertrophy and fibrosis. We investigated the natural history of these processes in asymptomatic patients and their potential reversal post-aortic valve replacement (AVR).  Methods: Asymptomatic and symptomatic patients with aortic stenosis underwent repeat echocardiography and magnetic resonance imaging. Changes in peak aortic-jet velocity, left ventricular mass index, diffuse fibrosis (indexed extracellular volume), and replacement fibrosis (late gadolinium enhancement [LGE]) were quantified.  RESULTS: In 61 asymptomatic patients (43% mild, 34% moderate, and 23% severe aortic stenosis), significant increases in peak aortic-jet velocity, left ventricular mass index, indexed extracellular volume, and LGE mass were observed after 2.1±0.7 years, with the most rapid progression observed in patients with most severe stenosis. Patients with baseline midwall LGE (n=16 [26%]; LGE mass, 2.5 g [0.8–4.8 g]) demonstrated particularly rapid increases in scar burden (78% [50%–158%] increase in LGE mass per year). In 38 symptomatic patients (age, 66±8 years; 76% men) who underwent AVR, there was a 19% (11%–25%) reduction in left ventricular mass index (P<0.0001) and an 11% (4%–16%) reduction in indexed extracellular volume (P=0.003) 0.9±0.3 years after surgery. By contrast midwall LGE (n=10 [26%]; mass, 3.3 g [2.6–8.0 g]) did not change post-AVR (n=10; 3.5 g [2.1–8.0 g]; P=0.23), with no evidence of regression even out to 2 years.  Conclusions: In patients with aortic stenosis, cellular hypertrophy and diffuse fibrosis progress in a rapid and balanced manner but are reversible after AVR. Once established, midwall LGE also accumulates rapidly but is irreversible post valve replacement. Given its adverse long-term prognosis, prompt AVR when midwall LGE is first identified may improve clinical outcomes