Intraleaflet hematoma has been associated with advanced stages of aortic valve stenosis. Its presence is suspected to be involved in faster disease progression. However, the mechanism whereby the entry and the presence of blood elements into the valves would have an impact on the biology of aortic valvular interstitial cells (VICs) remains to be deciphered. To evaluate the presence of intraleaflet hematoma, in respect to calcium deposition, at all stages of aortic valve calcification (AC) and to assess its putative pathophysiologic implication. The spatial relationship between calcium deposits and intraleaflet hematomas was analyzed by whole-mount staining of calcified and non-calcified human aortic valves, obtained in the context of heart transplantation and from patients who underwent surgical valve replacement. Endothelial micro-fissuring was evaluated by en face immunofluorescence and scanning electron microscope analyses of the fibrosa surface. Red blood cell preparations (RBCs) were used in vitro in order to assess, by immunofluorescence microscopy and Alizarin red staining, the potential impact of intraleaflet hematomas on the phenotype change of human VICs. Intraleaflet hematomas revealed by ferric iron deposits and extensive penetration of RBCs into the fibrosa, secondary to endothelial micro-fissuring, were found both in calcified and non-calcified valves. Primary VICs derived from non-calcified valves and cultured in the presence of senescent RBCs acquired an osteoblastic phenotype, as demonstrated by the production of osteocalcin and the formation of calcium deposits. Intraleaflet hematomas occurring through endothelial micro-fissuring may play a critical role in the initiation of calcium deposition into human aortic valves by driving the acquisition of an osteoblastic phenotype by the VICs that enter in contact with the infiltrated RBCs.

OBJECTIVES This study sought to evaluate the prognostic value of mean pressure gradient (MPG) increase and peak systolic pulmonary artery pressure (SPAP) measured during exercise stress echocardiography in asymptomatic patients with aortic stenosis (AS). BACKGROUND Exercise testing is recommended in asymptomatic AS patients, but the additional value of exercise-stress echocardiography, especially the prognostic value of MPG increase and peak SPAP, is still debated. METHODS We enrolled all consecutive patients with pure, isolated, asymptomatic AS and preserved ejection fraction >= 50% and normal SPAP (<50 mm Hg) who underwent symptom-limited exercise echocardiography at our institution. Occurrence of AS-related events (symptoms or congestive heart failure) or occurrence of aortic valve replacement was recorded. RESULTS We enrolled 148 patients (66 +/- 15 years of age; 74% males; MPG: 47 +/- 13 mm Hg; SPAP: 34 +/- 6 mm Hg). No complications were observed. Thirty-six patients (24%) had an abnormal exercise test result (occurrence of symptoms, fall in blood pressure, and/or ST-segment depression) and were referred for surgery. Among the 112 patients with a normal exercise test result, 38 patients (34%) had abnormal exercise echocardiography scores (MPG increase >20 mm Hg and/or SPAP at peak exercise >60 mm Hg). These 112 patients were managed conservatively. During a mean follow-up of 14 +/- 8 months, an AS-related event occurred in 30 patients, and 25 patients underwent surgery. Neither MPG increase >20 mm Hg nor peak SPAP > 60 mm Hg was predictive of occurrence of AS-related events or aortic valve replacement (all p > 0.20). In contrast, baseline AS severity was an important prognostic factor (all p < 0.01). CONCLUSIONS In this observational study including 148 patients with asymptomatic AS, we confirmed and extended the importance of exercise testing for unveiling functional limitation. More importantly, neither the increase in MPG nor in SPAP at peak exercise was predictive of outcome. Our results do not support the use of these parameters in risk-stratification and clinical management of asymptomatic AS patients. (C) 2018 by the American College of Cardiology Foundation.

Aim: Intra-leaflet hemorrhage has been associated with faster progression of valve calcification in degenerative aortic stenosis (AS). However, past studies were performed during advanced stages of the disease on severely calcified valves, and do not establish a causal relationship between hemorrhage and calcium deposition. In the present study, we assessed the spatio-temporal relationship between intra-leaflet hemorrhage and calcium deposition during early stages of valve calcification.

BACKGROUND:Aortic stenosis (AS) is an active disease, but the determinants of AS progression remain largely unknown. Low levels of Fetuin-A, a powerful inhibitor of ectopic calcification, have been linked to ectopic calcium tissue deposition but its role in AS progression has not been clearly evaluated.METHODS:In our ongoing prospective cohort (COFRASA/GENERAC), serum Fetuin-A level was measured at baseline and AS severity was evaluated at baseline and yearly thereafter using echocardiography (mean pressure gradient (MPG)) and computed tomography (degree of aortic valve calcification (AVC)). Annual progression was calculated as [(final measurement-baseline measurement)/follow-up duration] for both MPG and AVC measurements.RESULTS:We enrolled 296 patients (74 ± 10 years,73% men); mean follow-up duration was 3.0 ± 1.7 years. No correlation was found between baseline serum Fetuin-A (0.55 ± 0.15 g/L) and baseline AS severity (r = 0.25, p = 0.87 for MPG; r = 0.06, p = 0.36 for AVC). More importantly, there was no correlation between baseline serum Fetuin-A level and AS progression either assessed using MPG or AVC (both r = 0.01, p = 0.82). In bivariate analysis, after adjustment for age, gender, baseline AS severity, or valve anatomy, Fetuin-A was not associated with AS progression (all p > 0.20). The absence of link with AS progression was further confirmed by the absence of link betwen serum Fetuin-A and the occurrence of AS-related events (p = 0.17).CONCLUSIONS:In a large prospective cohort of AS patients, serum Fetuin-A was not associated to hemodynamic or anatomic AS progression. Despite its capacity to inhibit ectopic calcium deposition, Fetuin-A serum level seemed to have minor influence on AS progression.

BACKGROUND:Mitral annulus (MA) enlargement can be observed in various cardiac conditions but respective influence of left atrial (LA) and left ventricle (LV) size remained unclear. METHODS:In 120 patients who underwent a clinically indicated 3D-transesophageal-echocardiography, 30 atrial fibrillation (AF), 30 secondary mitral regurgitation (SMR), 30 primary myxomatous mitral regurgitation (PMR) and 30 mitral stenosis (MS), we evaluated the association between MA area (MA-area) and LA volume (LAvol) measured using the biplane area-length method, end-diastolic (LVEDV) and end-systolic (LVESV) volumes measured using the biplane Simpson method. MA-area was measured based on 3D datasets using QLab10. RESULTS:MA-area was correlated to LVEDV (r = 0.42, p < 0.0001), LVESV (r = 0.29, p = 0.001) but more markedly to LAvol (r = 0.62, p < 0.0001). Correlation between MA-area and LAvol was sustained in all subsets whereas MA-area was not correlated to LVEDV and LVESV in patients with SMR and with PMR (all p > 0.10). In multivariate analysis main predictors of MA-area were LAvol (p < 0.0001) and myxomatous etiology of MR (p = 0.0003) followed by LVEDV (p = 0.006) and LVESV (p = 0.02). CONCLUSION:In a population of patients with a wide range of LA/LV size related to various conditions, LA volume and myxomatous MR etiology appeared as main predictors of MA size whereas LV size had a more modest influence.

BackgroundDeterminants of the progression of aortic stenosis (AS) remained unclear. Metabolic syndrome (MetS) and diabetes are suspected to play an active role but literature is scarce and results conflicting. We sought to assess their impact in an ongoing prospective cohort of asymptomatic patients with at least mild AS.MethodsWe enrolled 203 patients (73±9years, 75% men) with at least 2years of follow-up. Risk-factors assessment was performed at baseline. Annual progression was calculated as [(final-baseline measurements)/follow-up duration] for both mean pressure gradient (MPG) and degree of aortic valve calcification (AVC) measurements.ResultsNinety-nine patients (49%) had MetS and 50 (25%) had diabetes (including 39 with MetS). After a mean follow-up of 3.2±1.2years, AS progression was not different between patients with and without MetS either using MPG (+3±3 vs. +4±4mmHg/year, p=0.25) or AVC (+211±231 vs. +225±222AU/year, p=0.75). Same results were obtained for patients with diabetes (3±3 vs. 4±4mmHg/year p=0.53, 187±140 vs. 229±248AU/year p=0.99). MetS had no impact on AS progression in all tested subgroups based on age, statin prescription, valve anatomy and AS severity (all p≥0.10).ConclusionIn our prospective cohort of AS patients, we found no impact of MetS or diabetes on AS progression. Although MetS and diabetes should be actively treated, no impact on AS progression should be expected. Our results support the theory that if cardiovascular risk-factors may play a role at the early phase of AS disease they have no or limited influence on AS progression.

Background Ascending aorta (AA) dilatation is common in aortic valve stenosis (AS) but data regarding AA progression, its determinants and impact of valve anatomy [bicuspid (BAV), or tricuspid (TAV)] are scarce. Methods and Results Asymptomatic AS patients enrolled in a prospective cohort (COFRASA/GENERAC) with at least 2 years of follow-up were considered in the present analysis. A transthoracic echocardiography (TTE) and a computed tomography (CT) scan were performed at inclusion and yearly thereafter. We enrolled 195 patients [mean gradient 22 ± 11 mmHg, 42 BAV patients (22%)]. Mean aorta diameters assessed using TTE were 35 ± 4 and 36 ± 5 mm at the sinuses of Valsalva and tubular level, respectively. Ascending aorta diameter was >40 mm in 29% of patients (24% in TAV vs. 52% in BAV, P < 0.01). Determinants of AA diameters were age, sex, BSA, and BAV, but not AS severity. After a mean follow-up of 3.8 ± 1.5years, AA enlargement rate assessed using TTE was +0.18 ± 0.34 mm/year and +0.36 ± 0.54 mm/year at the Valsalva and tubular level, respectively. Determinants of the progression of AA size were smaller AA diameter (P < 0.01) but not baseline AS severity or valve anatomy (all P > 0.05). Only four patients presented an AA progression ≥2 mm/year. Correlations between TTE and CT scan were excellent (all r >0.74) and similar results were obtained using CT. During follow-up, two BAV patients underwent a combined AA surgery; no surgery was primarily performed for AA aneurysm and no dissection was observed. Conclusion In this prospective cohort of AS patients determinants of AA diameters were age, sex, BSA, and valve anatomy but not AS severity. AA progression rates were low and not influenced by AS severity or valve anatomy.

The study of interlanguage (IL) is crucial for the understanding of the acquisition and development of human languages. But there are very few empirical investigations into IL from a perspective of general linguistics or/and linguistic typology. Based on a dependency treebank of Chinese EFL learners' English writings from eight consecutive grades, we quantitatively analyzed the typological features of IL. It was found that: (1) Chinese EFL learners' IL linguistic system is a language with SV and VO preference. (2) From the perspective of linguistic typology, IL progressively approaches from native language to target language with the increase of second language proficiency. (3) Dependency direction can well measure learners' IL at different learning stages. (4) The dependency directions of adverbials and attributives can well reflect the typological changes of Chinese EFL learners' IL and learners’ language proficiency.

Background: To describe our updated minimalist approach (MA) for transfemoral transcatheter aortic valve replacement (TF-TAVR) using the SAPIEN 3 device and its evolution, as well as associated safety and efficacy parameters from a large cohort of patients. Methods: A stepwise description of the MA technique for TAVR for 300 consecutive patients was detailed. Safety and efficacy parameters were assessed using the VARC-2 criteria at the in-hospital and 30-days follow-up. Results: A total of 300 consecutive patients (80 +/- 7 years; median Logistic EuroSCORE of 11.4% [7.5-17.8]) between January 2014 and May 2016 were evaluated. TF-TAVR was performed under conscious sedation in 247 (82%) patients. Device success was achieved in 286 (95.6%) patients, and intended prosthesis performance in 289 (96.3%) patients. Significant paravalvular leak (PVL) graded more than mild was noted in 7 (2%) patients. No patient had severe PVL. All-cause mortality was noted in one (0.3%) patient in-hospital and in 2 (0.7%) patients at the 30-days follow-up. Major stroke occurred in 4 (1.3%) patients. 9 (3%) patients had major vascular complications at 30-days follow up. MACCE (VARC-2 criteria) were observed in 21 (7%) in-hospital and 25 (8.3%) at 30 days. A new permanent pacemaker implantation was required in 29 (10.7%) patients, and was reduced from 18% to 5.6% (p = 0.001) in a subgroup analysis considering higher implantation position of the valve after the first year of experience. Conclusion: MA of TF-TAVR, when simplified and standardized, is reproducible, safe and efficient, and should be encouraged to be accepted as the standard method of care.

Background: Whether risk-stratification in aortic valve stenosis (AS) should rely on a single hemodynamic parameter or a combination of hemodynamic parameters is still debated. We aimed to evaluate the prognostic value of mean pressure gradient (MPG), aortic valve area (AVA), and the dimensionless index (DI) in patients with AS and to test whether their combination provides additional prognostic information. Methods: We enrolled 319 asymptomatic patients with AS (90 mild, 173 moderate, and 56 severe AS). All patients were prospectively followed on a yearly basis and AS-related events (sudden death, heart failure, or new onset of AS-related symptoms) were collected. Results: After a mean follow-up of 3.1 +/- 1.7 years, an AS-related event occurred in 84 patients (26%). When considered in isolation, after adjustment for age, sex, history of coronary artery disease, valve anatomy, and left ventricular ejection fraction, each parameter (MPG, AVA, and DI) independently predicted the occurrence of AS-related events (all p<0.0001). When considered in combination, MPG and AVA (p=0.0009 and p<0.0001 respectively) or MPG and DI (p=0.0001 and p<0.0001 respectively) remained independent predictors of outcome. Results were sustained after exclusion of 31 patients (10%) with discordant grading. Conclusion: In a large prospective cohort of asymptomatic patients with a wide range of AS severity, AVA, MPG, and DI were all important prognostic factors. More importantly, irrespective of the presence of patients with discordant grading, MPG and either the AVA or the DI provided complementary prognostic information. Our results show that these hemodynamic parameters should be considered in combination in the clinical management of AS patients.

BackgroundLongitudinal strain has been proposed as a sensitive marker of left ventricular systolic dysfunction. However its prognostic value in patients with aortic stenosis (AS) remains debated.MethodsIn a prospective cohort of asymptomatic patients with at least mild, isolated AS and preserved left ventricular ejection fraction (LVEF), clinical, biological measurements, global longitudinal strain (GLS) and basal longitudinal strain (BLS) were performed at study entry. The occurrence of AS-related events (sudden death, congestive heart failure, new onset of symptoms) or aortic valve replacement within two years was recorded prospectively.ResultsA total of 140 patients were enrolled and 21 events occurred. In contrast to GLS, BLS was significantly correlated to AS severity (p = 0.0006 with PV, p = 0.0002 with MPG, p = 0.01 with AVA, and p = 0.0009 with AVAi) and predicted the occurrence of AS-related events in the subset of severe AS in univariate analysis (p = 0.03) and after adjustment for AVA (p = 0.01), AVAi (p = 0.01), PV (p = 0.045), and MPG (p = 0.05). However, there was an important overlap of baseline BLS values between patients who developed symptoms and those who did not and repeated BLS measurements showed no difference between baseline values and those obtained at the time of overt symptoms in nine patients (p = 0.38).ConclusionBLS was statistically predictive of AS-related events in the subset of severe AS. However, overlap of BLS values between groups of symptomatic status and similar values at baseline and at the time of overt symptoms raise the question of its use at an individual level at least as a single isolated parameter.

It has been suggested that myocardial systolic deformation parameters may be a more sensitive marker of left ventricular (LV) systolic dysfunction than LV ejection fraction (LVEF). However, its prognostic value in patients with aortic stenosis (AS) remains debated. In an ongoing prospective cohort of asymptomatic patients with at least mild, pure, isolated AS, global longitudinal strain (GLS) was measured at baseline using 2D speckle tracking imaging, and AS related events (occur-rence of symptoms, congestive heart failure and sudden death) were prospectively collected. We prospectively enrolled 176 patients (mean age 72 years, 70% male). Mean aortic valve area was 1.25cm2 and mean gradient 28.8mmHg. Overall, 88 patients had mild AS, 50 patients moderate AS and 38 patients severe AS. During a mean follow up period of 2.2 years, 38 events occurred. GLS was not correlated to pic velocity, mean gradient or aortic valve area (AVA) (all p>0.05). In univariate analysis, neither in the whole cohort (p=0.75), nor in the subgroup of moderate/severe AS, GLS was predictive of future AS related events. Results were unchanged after adjustment for AS hemodynamic severity (p=0.66 and p=0.82, respectively). Our data suggest that longitudinal strain assessed by 2D speckle tracking echocardiography, is not predictive of future symptomatic status in asymptomatic patients with AS and preserved LVEF. Thus, this index should not be recommended in daily practice, in order to select patients who should undergo an early aortic valve replacement.

BACKGROUND:The prognostic value of N-terminal fragment of pro B-type natriuretic peptide (Nt-proBNP) in aortic stenosis (AS) is still being debated. We sought to evaluate the determinants of Nt-proBNP in AS and its prognostic value in asymptomatic patients. METHODS:Patients with pure isolated at least mild degenerative AS enrolled in our prospective cohort (2006-2013) constituted our population. Clinical and biological measurements as well as echocardiographic evaluations were performed at study entry for all patients. Severe AS was defined by a valve area <1cm2. Asymptomatic patients were contacted every six months and seen every year. The occurrence of AS-related events (sudden death, congestive heart failure or new onset of symptoms) within two years was recorded prospectively. RESULTS:We enrolled 809 patients. Nt-proBNP increased with AS severity (p<0.0001) and symptomatic status (p<0.0001) but there was a wide overlap between groups of AS severity or symptomatic status. Nt-proBNP was the result of complex interactions between multiple determinants, including AS severity and symptomatic status but also age (p=0.0008), history of coronary artery disease (p=0.03), rhythm (p=0.007) and diastolic function (p<0.0001). Consequently, in asymptomatic patients with moderate/severe AS, normal ejection fraction and in sinus rhythm, Nt-proBNP was associated with AS-related events in univariate analysis (p=0.009) but not after adjustment for AS severity (p=0.12). Repeated Nt-proBNP measurements at one year did not improve their predictive value (p=0.43). CONCLUSION:This study highlights the limitations of Nt-proBNP in AS and raises caution regarding its use, at least as a single factor, in the decision-making process regarding asymptomatic patients with AS.

Objective Myocardial fibrosis has been proposed as an outcome predictor in asymptomatic patients with severe aortic stenosis (AS) that may lead to consider prophylactic surgery. It can be detected using MRI but its widespread use is limited and development of substitute biomarkers is highly desirable. We analysed the determinants and prognostic value of galectin-3, one promising biomarker linked to myocardial fibrosis.Methods Patients with at least mild degenerative AS enrolled between 2006 and 2013 in two ongoing studies, COFRASA/GENERAC (COhorte Francaise de Retrecissement Aortique du Sujet Age/GENEtique du Retrecissement Aortique), aiming at assessing the determinants of AS occurrence and progression, constituted our population.Results We prospectively enrolled 583 patients. The mean galectin-3 value was 14.3+/-5.6 ng/mL. There was no association between galectin-3 and functional status (p=0.55) or AS severity (p=0.58). Independent determinants of galectin-3 were age (p=0.0008), female gender (p=0.04), hypertension (p=0.002), diabetes (p=0.02), reduced left ventricular ejection fraction (p=0.01), diastolic dysfunction (E/e', p=0.02) and creatinine clearance (p<0.0001). Among 330 asymptomatic patients at baseline, galectin-3 was neither predictive of outcome in univariate analysis (p=0.73), nor after adjustment for age, gender, rhythm, creatinine clearance and AS severity (p=0.66).Conclusions In a prospective cohort of patients with a wide range of AS severity, galectin-3 was not associated with AS severity or functional status. Main determinants of galectin-3 were age, hypertension and renal function. Galectin-3 did not provide prognostic information on the occurrence of AS-related events. Our results do not support the use of galectin-3 in the decision-making process of asymptomatic patients with AS.

In patients with aortic stenosis (AS), degree of aortic valve calcification (AVC) measured using multislice computed tomography is closely related to hemodynamic severity as assessed using transthoracic echocardiography [(1)][1]; but for similar hemodynamic severity, AVC load is lower in females