Nicolas Debry

Transcatheter aortic valve replacement in bicuspid aortic valve disease.

BACKGROUND Limited information exists describing the results of transcatheter aortic valve (TAV) replacement in patients with bicuspid aortic valve (BAV) disease (TAV-in-BAV). OBJECTIVES This study sought to evaluate clinical outcomes of a large cohort of patients undergoing TAV-in-BAV. METHODS We retrospectively collected baseline characteristics, procedural data, and clinical follow-up findings from 12 centers in Europe and Canada that had performed TAV-in-BAV. RESULTS A total of 139 patients underwent TAV-in-BAV with the balloon-expandable transcatheter heart valve (THV) (n = 48) or self-expandable THV (n = 91) systems. Patient mean age and Society of Thoracic Surgeons predicted risk of mortality scores were 78.0 ± 8.9 years and 4.9 ± 3.4%, respectively. BAV stenosis occurred in 65.5%, regurgitation in 0.7%, and mixed disease in 33.8% of patients. Incidence of type 0 BAV was 26.7%; type 1 BAV was 68.3%; and type 2 BAV was 5.0%. Multislice computed tomography (MSCT)-based TAV sizing was used in 63.5% of patients (77.1% balloon-expandable THV vs. 56.0% self-expandable THV, p = 0.02). Procedural mortality was 3.6%, with TAV embolization in 2.2% and conversion to surgery in 2.2%. The mean aortic gradient decreased from 48.7 ± 16.5 mm Hg to 11.4 ± 9.9 mm Hg (p < 0.0001). Post-implantation aortic regurgitation (AR) grade ≥ 2 occurred in 28.4% (19.6% balloon-expandable THV vs. 32.2% self-expandable THV, p = 0.11) but was prevalent in only 17.4% when MSCT-based TAV sizing was performed (16.7% balloon-expandable THV vs. 17.6% self-expandable THV, p = 0.99). MSCT sizing was associated with reduced AR on multivariate analysis (odds ratio [OR]: 0.19, 95% confidence intervals [CI]: 0.08 to 0.45; p < 0.0001). Thirty-day device safety, success, and efficacy were noted in 79.1%, 89.9%, and 84.9% of patients, respectively. One-year mortality was 17.5%. Major vascular complications were associated with increased 1-year mortality (OR: 5.66, 95% CI: 1.21 to 26.43; p = 0.03). CONCLUSIONS TAV-in-BAV is feasible with encouraging short- and intermediate-term clinical outcomes. Importantly, a high incidence of post-implantation AR is observed, which appears to be mitigated by MSCT-based TAV sizing. Given the suboptimal echocardiographic results, further study is required to evaluate long-term efficacy.

Myocardial Contractile Dysfunction Is Associated With Impaired Mitochondrial Function and Dynamics in Type 2 Diabetic but Not in Obese Patients

Background— Obesity and diabetes mellitus are independently associated with the development of heart failure. In this study, we determined the respective effects of obesity, insulin resistance, and diabetes mellitus on the intrinsic contraction and mitochondrial function of the human myocardium before the onset of cardiomyopathy. Methods and Results— Right atrial myocardium was obtained from 141 consecutive patients presenting no sign of cardiomyopathy. We investigated ex vivo isometric contraction, mitochondrial respiration and calcium retention capacity, and respiratory chain complex activities and oxidative stress status. Diabetes mellitus was associated with a pronounced impairment of intrinsic contraction, mitochondrial dysfunction, and increased myocardial oxidative stress, regardless of weight status. In contrast, obesity was associated with less pronounced contractile dysfunction without any significant perturbation of mitochondrial function or oxidative stress status. Tested as continuous variables, glycated hemoglobin A1C, but neither body mass index nor the insulin resistance index (homeostasis model assessment–insulin resistance), was independently associated with cardiac mitochondrial function. Furthermore, diabetes mellitus was associated with cardiac mitochondrial network fragmentation and significantly decreased expression of the mitochondrial fusion related protein MFN1. Myocardial MFN1 content was inversely proportional to hemoglobin A1C. Conclusion— Worsening of intrinsic myocardial contraction in the transition from obesity to diabetes mellitus is likely related to worsening of cardiac mitochondrial function because impaired mitochondrial function and dynamics and contractile dysfunction are observed in diabetic patients but not in “metabolically healthy” obese patients at early stage in insulin resistance.

Low-Gradient, Low-Flow Severe Aortic Stenosis With Preserved Left Ventricular Ejection Fraction: Characteristics, Outcome, and Implications for Surgery

BACKGROUND Severe low-gradient, low-flow (LG/LF) aortic stenosis with preserved left ventricular ejection fraction (EF) has been described as a more advanced form of aortic stenosis. However, the natural history and need for surgery in patients with LG/LF aortic stenosis remain subjects of intense debate. OBJECTIVES We sought to investigate the outcome of LG/LF aortic stenosis in comparison with moderate aortic stenosis and with high-gradient (HG) aortic stenosis in a real-world study, in the context of routine practice. METHODS This analysis included 809 patients (ages 75 ± 12 years) diagnosed with aortic stenosis and preserved EF (≥50%). Patients were divided into 4 groups: mild-to-moderate aortic stenosis; HG aortic stenosis; LG/LF aortic stenosis; and low-gradient, normal-flow (LG/NF) aortic stenosis. RESULTS Compared with mild-to-moderate aortic stenosis patients, LG/LF aortic stenosis patients had smaller valve areas and stroke volumes, higher mean gradients, and comparable degrees of ventricular hypertrophy. Under medical management (22.8 months; range 7 to 53 months), compared with mild-to-moderate aortic stenosis patients, HG aortic stenosis patients were at higher risk of death (adjusted hazard ratio [HR]: 1.47; 95% confidence interval [CI]: 1.03 to 2.07), whereas LG/LF aortic stenosis patients did not have an excess mortality risk (adjusted HR: 0.88; 95% CI: 0.53 to 1.48). During the entire (39.0 months; range 11 to 69 months) follow-up (with medical and surgical management), the mortality risk associated with LG/LF aortic stenosis was close to that of mild-to-moderate aortic stenosis (adjusted HR: 0.96; 95% CI: 0.58 to 1.53), whereas the excess risk of death associated with HG aortic stenosis was confirmed (adjusted HR: 1.74; 95% CI: 1.27 to 2.39). The benefit associated with aortic valve replacement was confined to the HG aortic stenosis group (adjusted HR: 0.29; 95% CI: 0.18 to 0.46) and was not observed for LG/LF aortic stenosis (adjusted HR: 0.75; 95% CI: 0.14 to 4.05). CONCLUSIONS In this study, the outcome of severe LG/LF aortic stenosis with preserved EF was similar to that of mild-to-moderate aortic stenosis and was not favorably influenced by aortic surgery. Further research is needed to better understand the natural history and the progression of LG/LF aortic stenosis.

Von Willebrand Factor Multimers during Transcatheter Aortic-Valve Replacement

BACKGROUND Postprocedural aortic regurgitation occurs in 10 to 20% of patients undergoing transcatheter aortic-valve replacement (TAVR) for aortic stenosis. We hypothesized that assessment of defects in high-molecular-weight (HMW) multimers of von Willebrand factor or point-of-care assessment of hemostasis could be used to monitor aortic regurgitation during TAVR. METHODS We enrolled 183 patients undergoing TAVR. Patients with aortic regurgitation after the initial implantation, as identified by means of transesophageal echocardiography, underwent additional balloon dilation to correct aortic regurgitation. HMW multimers and the closure time with adenosine diphosphate (CT-ADP), a point-of-care measure of hemostasis, were assessed at baseline and 5 minutes after each step of the procedure. Mortality was evaluated at 1 year. A second cohort (201 patients) was studied to validate the use of CT-ADP in order to identify patients with aortic regurgitation. RESULTS After the initial implantation, HMW multimers normalized in patients without aortic regurgitation (137 patients). Among the 46 patients with aortic regurgitation, normalization occurred in 20 patients in whom additional balloon dilation was successful but did not occur in the 26 patients with persistent aortic regurgitation. A similar sequence of changes was observed with CT-ADP. A CT-ADP value of more than 180 seconds had sensitivity, specificity, and negative predictive value of 92.3%, 92.4%, and 98.6%, respectively, for aortic regurgitation, with similar results in the validation cohort. Multivariable analyses showed that the values for HMW multimers and CT-ADP at the end of TAVR were each associated with mortality at 1 year. CONCLUSIONS The presence of HMW-multimer defects and a high value for a point-of-care hemostatic test, the CT-ADP, were each predictive of the presence of aortic regurgitation after TAVR and were associated with higher mortality 1 year after the procedure. (Funded by Lille 2 University and others; ClinicalTrials.gov number, NCT02628509.).

Transcarotid Transcatheter Aortic Valve Replacement: Feasibility and Safety.

OBJECTIVES The purpose of this study was to assess the feasibility and safety of transcarotid transcatheter aortic valve replacement (TAVR). BACKGROUND Many candidates for TAVR have challenging vascular anatomy that precludes transfemoral access. Transcarotid arterial access may be an option for such patients. METHODS The French Transcarotid TAVR Registry is a voluntary database that prospectively collected patient demographics, procedural characteristics, and clinical outcomes among patients undergoing transcarotid TAVR. Outcomes are reported according to the updated Valve Academic Research Consortium criteria. RESULTS Among 96 patients undergoing transcarotid TAVR at 3 French sites (2009 to 2013), the mean age and Society of Thoracic Surgeons predicted risk of mortality were 79.4 ± 9.2 years and 7.1 ± 4.1%, respectively. Successful carotid artery access was achieved in all patients. The Medtronic CoreValve (Medtronic, Inc., Minneapolis, Minnesota) (n = 89; 92.7%) and Edwards SAPIEN valves (Edwards Lifesciences, Irvine, California) (n = 7; 7.3%) were used. Procedural complications included: valve embolization (3.1%), requirement for a second valve (3.1%), and tamponade (4.2%). There were no major bleeds or major vascular complications related to the access site. There were 3 (3.1%) procedural deaths and 6 (6.3%) deaths at 30 days. The 1-year mortality rate was 16.7%. There were 3 (3.1%) cases of Valve Academic Research Consortium-defined in-hospital stroke (n = 0) or transient ischemic attack (TIA) (n = 3). None of these patients achieved the criteria for stroke and none manifested new ischemic lesions on cerebral computed tomography or magnetic resonance imaging. At 30 days, a further 3 TIAs were observed, giving an overall stroke/TIA rate of 6.3%. CONCLUSIONS Transcarotid vascular access for TAVR is feasible and is associated with encouraging short- and medium-term clinical outcomes. Prospective studies are required to ascertain if transcarotid TAVR yields equivalent results to other nonfemoral vascular access routes.

Outcome Implication of Aortic Valve Area Normalized to Body Size in Asymptomatic Aortic StenosisCLINICAL PERSPECTIVE

Background—Current guidelines define severe aortic stenosis in patients with aortic valve area normalized to body surface area (AVA/BSA) <0.6 cm2/m2; yet, this cutoff has never been validated. Moreover, it is not known whether AVA normalization to other body size indexes allows improved outcome prediction. We aim to test the value of AVA normalized to body size for outcome prediction in asymptomatic aortic stenosis. Methods and Results—We included 289 patients with asymptomatic aortic stenosis, preserved ejection fraction, and AVA<1.3 cm2 at diagnosis. The outcome measure was the occurrence of aortic valve replacement or all-cause death or during follow-up. AVA was normalized to BSA, height, weight, and body mass index. For each normalized index, patients in the lowest tertile were at high risk of events whereas outcome was similar for the other tertiles. High risk of events was observed with AVA/BSA <0.4 cm2/m2 (adjusted hazard ratio [HR], 3.42 [2.09–5.60]), AVA/height <0.45 cm2/m (adjusted HR, 3.99 [2.42–6.60]), AVA/weight <0.01 cm2/kg (adjusted HR, 3.37 [2.07–5.49]), and AVA/body mass index <0.029 cm2/kg per meter square (adjusted HR, 3.23 [1.99–5.24]). Mortality risk was high with AVA/height <0.45 cm2/m (adjusted HR, 2.18 [1.28–3.71]), followed by AVA/BSA <0.40 cm2/m2 (adjusted HR, 1.84 [1.09–3.11]), AVA/weight <0.01 cm2/kg (adjusted HR, 1.78 [1.07–2.98]), and AVA/body mass index <0.029 cm2/kg per meter square (adjusted HR, 1.75 [1.04–2.93]). AVA/height showed better predictive performance than AVA/BSA with improved reclassification and better discrimination (net reclassification improvement: 0.33 versus 0.28; integrated discrimination improvement: 0.10 versus 0.08; C statistic: 0.67 versus 0.65), whereas AVA/weight and AVA/body mass index showed lower predictive capacity. Conclusions—Among AVA normalization methods, AVA/height <0.45 cm2/m followed by AVA/BSA <0.40 cm2/m2 seem as robust parameters for defining high risk in asymptomatic aortic stenosis. The prognostic value of AVA/height deserves future research.

Transcatheter aortic valve implantation versus redo surgery for failing surgical aortic bioprostheses: a multicentre propensity score analysis

AIMS Transcatheter aortic valve implantation for a failing surgical bioprosthesis (TAV-in-SAV) has become an alternative for patients at high risk for redo surgical aortic valve replacement (redo-SAVR). Comparisons between these approaches are non-existent. This study aimed to compare clinical and echocardiographic outcomes of patients undergoing TAV-in-SAV versus redo-SAVR after accounting for baseline differences by propensity score matching. METHODS AND RESULTS Patients from seven centres in Europe and Canada who had undergone either TAV-in-SAV (n=79) or redo-SAVR (n=126) were identified. Significant independent predictors used for propensity scoring were age, NYHA functional class, number of prior cardiac surgeries, urgent procedure, pulmonary hypertension, and COPD grade. Using a calliper range of ±0.05, a total of 78 well-matched patient pairs were found. All-cause mortality was similar between groups at 30 days (6.4% redo-SAVR vs. 3.9% TAV-in-SAV; p=0.49) and one year (13.1% redo-SAVR vs. 12.3% TAV-in-SAV; p=0.80). Both groups also showed similar incidences of stroke (0% redo-SAVR vs. 1.3% TAV-in-SAV; p=1.0) and new pacemaker implantation (10.3% redo-SAVR vs. 10.3% TAV-in-SAV; p=1.0). The incidence of acute kidney injury requiring dialysis was numerically lower in the TAV-in-SAV group (11.5% redo-SAVR vs. 3.8% TAV-in-SAV; p=0.13). The TAV-in-SAV group had a significantly shorter median total hospital stay (12 days redo-SAVR vs. 9 days TAV-in-SAV; p=0.001). CONCLUSIONS Patients with aortic bioprosthesis failure treated with either redo-SAVR or TAV-in-SAV have similar 30-day and one-year clinical outcomes.

Prognostic Value of Aortic Valve Area by Doppler Echocardiography in Patients With Severe Asymptomatic Aortic Stenosis

Background The aim of this study was to evaluate the relationship between aortic valve area (AVA) obtained by Doppler echocardiography and outcome in patients with severe asymptomatic aortic stenosis and to define a specific threshold of AVA for identifying asymptomatic patients at very high risk based on their clinical outcome. Methods and Results We included 199 patients with asymptomatic severe aortic stenosis (AVA ≤1.0 cm2). The risk of events (death or need for aortic valve replacement) increased linearly on the scale of log hazard with decreased AVA (adjusted hazard ratio 1.17; 95% CI 1.06–1.29 per 0.1 cm2 AVA decrement; P=0.002). Event‐free survival at 12, 24, and 48 months was 63±6%, 51±6%, and 34±6%, respectively, for AVA 0.8 to 1 cm2; 49±6%, 36±6%, and 26±6%, respectively, for AVA 0.6 to 0.8 cm2; and 33±8%, 20±7%, and 11±5%, respectively, for AVA ≤0.6 cm2 (P trend=0.002). Patients with AVA ≤0.6 cm2 had a significantly increased risk of events compared with patients with AVA 0.8 to 1 cm2 (adjusted hazard ratio 2.22; 95% CI 1.41–3.52; P=0.001), whereas patients with AVA 0.6 to 0.8 cm2 had an increased risk of events compared with those with AVA 0.8 to 1 cm2, but the difference was not statistically significant (adjusted hazard ratio 1.38; 95% CI 0.93–2.05; P=0.11). After adjustment for covariates and aortic valve replacement as a time‐dependent variable, patients with AVA ≤0.6 cm2 had a significantly greater risk of all‐cause mortality than patients with AVA >0.6 cm2 (hazard ratio 3.39; 95% CI 1.80–6.40; P<0.0001). Conclusions Patients with severe asymptomatic aortic stenosis and AVA ≤0.6 cm2 displayed an important increase in the risk of adverse events during short‐term follow‐up. Further studies are needed to determine whether elective aortic valve replacement improves outcome in this high‐risk subgroup of patients.

Transcatheter aortic valve implantation for paradoxical low-flow low-gradient aortic stenosis patients

We compared the outcomes of transcatheter aortic valve implantation (TAVI) in three different aortic stenosis syndromes: paradoxical low‐flow low‐gradient aortic stenosis (PLFLG), high‐gradient aortic stenosis (HGAS), and low ejection fraction low‐gradient severe aortic stenosis (LEF‐LG).

Arterial Pulsatility and Circulating von Willebrand Factor in Patients on Mechanical Circulatory Support

BACKGROUND The main risk factor for bleeding in patients with continuous-flow mechanical circulatory support (CF-MCS) is the acquired von Willebrand factor (VWF) defect related to the high shear-stress forces developed by these devices. Although a higher bleeding rate has been reported in CF-MCS recipients who had reduced pulsatility, the relation between pulsatility and the VWF defect has never been studied. OBJECTIVES The purpose of this study was to investigate the relation between pulsatility and VWF under CF-MCS. METHODS We assessed the effect of 2 CF-MCS on VWF multimer degradation in a mock circulatory loop (model 1). Using these devices, we investigated in a dose-effect model (model 2) 3 levels of pulsatility in 3 groups of swine. In a cross-over model (model 3), we studied the effects of sequential changes of pulsatility on VWF. We reported the evolution of VWF multimerization in a patient undergoing serial CF-MCS and/or pulsatile-MCS. RESULTS We demonstrated the proteolytic degradation of VWF multimers by high shear CF-MCS in a circulatory loop without pulsatility. We observed both in swine models and in a patient that the magnitude of the VWF degradation is modulated by the pulsatility level in the high shear-stress level condition, and that the restoration of pulsatility is a trigger for the endothelial release of VWF. CONCLUSIONS We demonstrated that the VWF defect reflects the balance between degradation induced by the shear stress and the endothelial release of new VWF triggered by the pulsatility. This modulation of VWF levels could explain the relationship between pulsatility and bleeding observed in CF-MCS recipients. Preservation of pulsatility may be a new target to improve clinical outcomes of patients.