Abdellaziz Dahou

Incidence, Timing, and Predictors of Valve Hemodynamic Deterioration After Transcatheter Aortic Valve Replacement: Multicenter Registry.

BACKGROUND Scarce data exist on the incidence of and factors associated with valve hemodynamic deterioration (VHD) after transcatheter aortic valve replacement (TAVR). OBJECTIVES This study sought to determine the incidence, timing, and predictors of VHD in a large cohort of patients undergoing TAVR. METHODS This multicenter registry included 1,521 patients (48% male; 80 ± 7 years of age) who underwent TAVR. Mean echocardiographic follow-up was 20 ± 13 months (minimum: 6 months). Echocardiographic examinations were performed at discharge, at 6 to 12 months, and yearly thereafter. Annualized changes in mean gradient (mm Hg/year) were calculated by dividing the difference between the mean gradient at last follow-up and the gradient at discharge by the time between examinations. VHD was defined as a ≥10 mm Hg increase in transprosthetic mean gradient during follow-up compared with discharge assessment. RESULTS The overall mean annualized rate of transprosthetic gradient progression during follow-up was 0.30 ± 4.99 mm Hg/year. A total of 68 patients met criteria of VHD (incidence: 4.5% during follow-up). The absence of anticoagulation therapy at hospital discharge (p = 0.002), a valve-in-valve (TAVR in a surgical valve) procedure (p = 0.032), the use of a 23-mm valve (p = 0.016), and a greater body mass index (p = 0.001) were independent predictors of VHD. CONCLUSIONS There was a mild but significant increase in transvalvular gradients over time after TAVR. The lack of anticoagulation therapy, a valve-in-valve procedure, a greater body mass index, and the use of a 23-mm transcatheter valve were associated with higher rates of VHD post-TAVR. Further prospective studies are required to determine whether a specific antithrombotic therapy post-TAVR may reduce the risk of VHD.

Downregulation of MicroRNA-126 Contributes to the Failing Right Ventricle in Pulmonary Arterial Hypertension.

Background— Right ventricular (RV) failure is the most important factor of both morbidity and mortality in pulmonary arterial hypertension (PAH). However, the underlying mechanisms resulting in the failed RV in PAH remain unknown. There is growing evidence that angiogenesis and microRNAs are involved in PAH-associated RV failure. We hypothesized that microRNA-126 (miR-126) downregulation decreases microvessel density and promotes the transition from a compensated to a decompensated RV in PAH. Methods and Results— We studied RV free wall tissues from humans with normal RV (n=17), those with compensated RV hypertrophy (n=8), and patients with PAH with decompensated RV failure (n=14). Compared with RV tissues from patients with compensated RV hypertrophy, patients with decompensated RV failure had decreased miR-126 expression (quantitative reverse transcription–polymerase chain reaction; P<0.01) and capillary density (CD31+ immunofluorescence; P<0.001), whereas left ventricular tissues were not affected. miR-126 downregulation was associated with increased Sprouty-related EVH1 domain-containing protein 1 (SPRED-1), leading to decreased activation of RAF (phosphorylated RAF/RAF) and mitogen-activated protein kinase (MAPK); (phosphorylated MAPK/MAPK), thus inhibiting the vascular endothelial growth factor pathway. In vitro, Matrigel assay showed that miR-126 upregulation increased angiogenesis of primary cultured endothelial cells from patients with decompensated RV failure. Furthermore, in vivo miR-126 upregulation (mimic intravenous injection) improved cardiac vascular density and function of monocrotaline-induced PAH animals. Conclusions— RV failure in PAH is associated with a specific molecular signature within the RV, contributing to a decrease in RV vascular density and promoting the progression to RV failure. More importantly, miR-126 upregulation in the RV improves microvessel density and RV function in experimental PAH.

Comparison of hemodynamic performance of the balloon-expandable SAPIEN 3 versus SAPIEN XT transcatheter valve.

The SAPIEN 3 valve (S3V) is a new-generation transcatheter valve with enhanced anti-paravalvular leak properties, but no data comparing with earlier transcatheter valve systems are available. We aimed to compare the hemodynamic performance of the S3V and the SAPIEN XT valve (SXTV) in a case-matched study with echo core laboratory analysis. A total of 27 patients who underwent transcatheter aortic valve replacement (TAVR) with the S3V were matched for prosthesis size (26 mm), aortic annulus area, and mean diameter measured by computed tomography, left ventricular ejection fraction, body surface area, and body mass index with 50 patients treated with the SXTV. The prosthesis size was determined by oversizing of 1% to 15% of annulus area. Doppler echocardiographic images collected at baseline and 1-month follow-up were analyzed in a central echocardiography core laboratory. The need for postdilation was higher in the SXTV group (20% vs 4%, p=0.047), and mean residual gradient and effective orifice area were similar in both groups (p>0.05). The incidence of paravalvular aortic regurgitation was greater with the SXTV (≥mild: 42%, moderate: 8%) than with the S3V (≥mild: 7%, moderate: 0%; p=0.002 for ≥mild vs SXTV). The implantation of an S3V was the only factor associated with trace or no paravalvular leak after TAVR (p=0.007). In conclusion, TAVR with the S3V was associated with a very low rate of paravalvular leaks and need for balloon postdilation, much lower than that observed with the earlier generation of balloon-expandable valve (SXTV). The confirmation of these results in a larger cohort of patients will represent a major step forward in using transcatheter valves for the treatment of aortic stenosis.

Cardiac magnetic resonance versus transthoracic echocardiography for the assessment and quantification of aortic regurgitation in patients undergoing transcatheter aortic valve implantation

Background The transthoracic echocardiographic (TTE) evaluation of the severity of residual aortic regurgitation (AR) following transcatheter aortic valve implantation (TAVI) has been controversial and lacks validation. Objectives This study sought to compare TTE and cardiac magnetic resonance (CMR) for assessment of AR in patients undergoing TAVI with a balloon-expandable valve. Methods TTE and CMR exams were performed pre-TAVI in 50 patients and were repeated postprocedure in 42 patients. All imaging data were analysed in centralised core laboratories. Results The severity of native AR as determined by multiparametric TTE approach correlated well with the regurgitant volume and regurgitant fraction determined by CMR prior to TAVI (Rs=0.79 and 0.80, respectively; p<0.001 for both). However, after TAVI, the correlation between the prosthetic AR severity assessed by TTE and regurgitant volume and fraction measured by CMR was only modest (Rs=0.59 and 0.59, respectively; p<0.001 for both), with an underestimation of AR severity by TTE in 61.9% of patients (1 grade in 59.5%). The TTE jet diameter in parasternal view and the multiparametric approach (Rs=0.62 and 0.59, respectively; both with p<0.001) showed the best correlation with CMR regurgitant fraction post-TAVI. The circumferential extent of prosthetic paravalvular regurgitation showed a poor correlation with CMR regurgitant volume and fraction (Rs=0.32, p=0.084; Rs=0.36, p=0.054, respectively). Conclusions The severity of AR following TAVI with a balloon-expandable valve was underestimated by echocardiography as compared with CMR. The jet diameter, but not the circumferential extent of the leaks, and the multiparametric echocardiography integrative approach best correlated with CMR findings. These results provide important insight into the evaluation of AR severity post-TAVI.

Usefulness of Global Left Ventricular Longitudinal Strain for Risk Stratification in Low Ejection Fraction, Low-Gradient Aortic Stenosis Results From the Multicenter True or Pseudo-Severe Aortic Stenosis Study

Background—The objective of this study was to examine the impact of left ventricular (LV) global longitudinal strain (GLS) measured at rest and at dobutamine stress echocardiography on the outcome of patients with low LV ejection fraction and low-gradient aortic stenosis. Methods and Results—Among the 202 patients with low LV ejection fraction (⩽40%), low-gradient aortic stenosis (mean transvalvular gradient <40 mm Hg and indexed aortic valve area ⩽0.6 cm2/m2) prospectively enrolled in the multicenter True or Pseudo-Severe Aortic Stenosis study, 126 patients with resting GLS and 73 patients with stress GLS available were included in this substudy. Three-year survival rate was 49% in patients with rest GLS <|9|% compared with 68% in patients with GLS >|9|% (P=0.02). In a multivariable Cox model adjusted for age, coronary artery disease, projected aortic valve area at a normal flow rate and type of treatment (aortic valve replacement versus conservative), rest GLS <|9|% (hazard ratio, 2.18; P=0.015) remained independently associated with all-cause mortality. GLS <|10|% measured during dobutamine stress echocardiography was also independently associated with mortality (hazard ratio, 2.67; P=0.01). In the subset of patients with stress GLS (n=73), the &khgr;2 of the multivariable model to predict all-causes mortality was 21.96 for stress GLS versus 17.78 for rest GLS. Conclusions—GLS is independently associated with mortality in patients with low LV ejection fraction, low-gradient aortic stenosis. Stress GLS measured during dobutamine stress echocardiography may provide incremental prognostic value beyond GLS measured at rest. Hence, measurement of GLS at rest and during dobutamine stress echocardiography may be helpful to enhance risk stratification in low LV ejection fraction, low-gradient aortic stenosis. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01835028.

Long-term prognostic value and serial changes of plasma N-terminal prohormone B-type natriuretic peptide in patients undergoing transcatheter aortic valve implantation.

Little is known about the usefulness of evaluating cardiac neurohormones in patients undergoing transcatheter aortic valve implantation (TAVI). The objectives of this study were to evaluate the baseline values and serial changes of N-terminal prohormone B-type natriuretic peptide (NT-proBNP) after TAVI, its related factors, and prognostic value. A total of 333 consecutive patients were included, and baseline, procedural, and follow-up (median 20 months, interquartile range 9 to 36) data were prospectively collected. Systematic NT-proBNP measurements were performed at baseline, hospital discharge, 1, 6, and 12 months, and yearly thereafter. Baseline NT-proBNP values were elevated in 86% of the patients (median 1,692 pg/ml); lower left ventricular ejection fraction and stroke volume index, greater left ventricular mass, and renal dysfunction were associated with greater baseline values (p <0.01 for all). Higher NT-proBNP levels were independently associated with increased long-term overall and cardiovascular mortalities (p <0.001 for both), with a baseline cut-off level of ∼2,000 pg/ml best predicting worse outcomes (p <0.001). At 6- to 12-month follow-up, NT-proBNP levels had decreased (p <0.001) by 23% and remained stable up to 4-year follow-up. In 39% of the patients, however, there was a lack of NT-proBNP improvement, mainly related to preprocedural chronic atrial fibrillation, lower mean transaortic gradient, and moderate-to-severe mitral regurgitation (p <0.01 for all). In conclusion, most patients undergoing TAVI presented high NT-proBNP levels, and a lack of improvement was observed in >1/3 of the patients after TAVI. Also, higher NT-proBNP levels predicted greater overall and cardiac mortalities at a median follow-up of 2 years. These findings support the implementation of NT-proBNP measurements for the clinical decision-making process and follow-up of patients undergoing TAVI.

Echocardiographic predictors of outcomes in adults with aortic stenosis

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.

OxLDL-derived lysophosphatidic acid promotes the progression of aortic valve stenosis through a LPAR1-RhoA–NF-κB pathway

Aims Oxidatively modified lipoproteins may promote the development/progression of calcific aortic valve stenosis (CAVS). Oxidative transformation of low-density lipoprotein (OxLDL) generates lysophosphatidic acid (LPA), a lipid mediator that accumulates in mineralized aortic valves. LPA activates at least six different G protein-coupled receptors, which may play a role in the pathophysiology of CAVS. We hypothesized that LPA derived from OxLDL may promote a NF-κB signature that drives osteogenesis in the aortic valve. Methods and results The role of OxLDL-LPA was examined in isolated valve interstitial cells (VICs) and the molecular pathway was validated in human explanted aortic valves and in a mouse model of CAVS. We found that OxLDL-LPA promoted the mineralization and osteogenic transition of VICs through LPAR1 and the activation of a RhoA-NF-κB pathway. Specifically, we identified that RhoA/ROCK activated IκB kinase alpha, which promoted the phosphorylation of p65 on serine 536 (p65 pS536). p65 pS536 was recruited to the BMP2 promoter and directed an osteogenic program not responsive to the control exerted by the inhibitor of kappa B. In LDLR-/-/ApoB100/100/IGFII transgenic mice (IGFII), which develop CAVS under a high-fat and high-sucrose diet the administration of Ki16425, a Lpar1 blocker, reduced by three-fold the progression rate of CAVS and also decreased the osteogenic activity as measured with a near-infrared fluorescent probe that recognizes hydroxyapatite of calcium. Conclusions OxLDL-LPA promotes an osteogenic program in the aortic valve through a LPAR1-RhoA/ROCK-p65 pS536 pathway. LPAR1 may represent a suitable target to prevent the progression of CAVS.

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.

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

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 (AVCdensity: +96 [34–218] vs. +45 [14–82] AU/cm2, P = 0.01, respectively). In multivariable analysis, SHPT remained significantly associated with faster progression of AVC or AVCdensity (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.