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Post-procedural conduction disorders following transcatheter aortic valve replacement remain frequent, especially using the largest self-expandable device (Corevalve Evolut RTM, 34-mm, STHV-34, Medtronic, Minneapolis, Minnesota). Therefore, we assessed previously described, predictive factors of

Real-time fusion imaging has emerged as a sophisticated tool to guide structural heart disease (SHD) interventions. The overlay of 2 different imaging modalities allows the interventionalist to visualize echocardiographic images within a fluoroscopic image that offers intuitive perception of the

Patients in cardiogenic shock (CS) due to decompensated aortic stenosis (AS) evidence poor prognosis. Both emergency transcatheter aortic valve replacement (eTAVR) and emergency balloon aortic valvuloplasty (eBAV) have been reported in CS patients. We aimed to summarize and compare available studies on eBAV and eTAVR in patients suffering from CS due to decompensated AS with regard to safety and efficacy.Study-level data were analyzed. Heterogeneity was assessed using the I2 statistic. Pooled proportions, ie, event rates, were calculated and obtained using a random-effects model (DerSimonian and Laird). Eight studies were found suitable for the final analysis, including 311 patients. Primary endpoint was mortality at 30 days. For eBAV (n = 238), 30-day mortality rate was 46.2% (95% confidence interval [CI], 30.3%-62.5%; I²=74%), major bleeding rate was 10% (95% CI, 5.4%-15.7%; I²=13%), and stroke rate was 0.7% (95% CI, 0.0%-2.7%; I²=0%). Aortic regurgitation (AR) ≥II was present in 8.6% (95% CI, 0.4%-23.5%; I²=86%). For eTAVR (n = 73), 30-day mortality rate was 22.6% (95% CI, 12.0%-35.2%; I²=26%), major bleeding rate was 5.8% (95% CI, 0.5%-14.7%; I²=0%), and stroke rate was 5.8% (95% CI, 0.5%-14.7%; I²=0%). AR ≥II was present in 4% (95% CI, 0.0%-12.1%; I²=0%).Mortality in CS patients due to decompensated severe AS is high, regardless of interventional treatment strategy. Both eBAV and eTAVR seem feasible. As eTAVR is associated with better initial improvements in hemodynamics and simultaneously avoids sequential interventions, it might be favorable to eBAV in select patients. If eTAVR is not available, eBAV might serve as a "bridge" to elective TAVR.

Background Transcatheter aortic valve implantation (TAVI) has become the preferred alternative to surgical valve replacement in high risk patients with severe symptomatic aortic stenosis. Stroke is still a feared complication following TAVI, associated with increased mortality and severe impact on patients' daily living. Despite technological development and knowledge improvement, cerebrovascular events (CVE) are still not predictable so far and simple risk scores are lacking. The expansion of TAVI therapy towards younger and lower risk populations will force us to discover the mechanisms determining stroke after TAVI. Purpose This study aimed to evaluate different patient and procedure related factors for prediction of stroke after TAVI, especially regarding severity of aortic calcification. Methods From May 2011 to January 2018 a total of 1365 patients underwent TAVI with a balloon-expandable (32.4%) or self-expandable (67.6%) valve at our institution. 60 patients (4.4%) suffered from new neurological impairment in terms of CVE after TAVI during hospital stay (mean 11.2±6.7 days). We performed propensity score matching (1:10) to balance baseline characteristics between patients with and without stroke following TAVI, resulting in 56 patients with in-hospital stroke and 521 patients without neurological disorder. Stroke was defined according to the Valve Academic Research Consortium recommendations (VARC-2). Results Body surface area (stroke vs. control: 2.73±0.27 vs. 2.81±0.29 m2; p=0.0451) and prior stroke (stroke vs. control: 17.86% vs. 8.64%; p=0.0256) were patient related predictors of stroke after TAVI during in-hospital stay. While aortic valve Agatston score (stroke vs. control: 2475±1593 vs. 2060±1344 AU; p=0.0383) and ascending thoracic aorta Agatston score (stroke vs. control: 986.5±1989 vs. 505.2±1018 AU; p=0.0045) showed to be good predictors, peripheral vascular diseases were not associated with stroke (stroke vs. control: 35.7% vs. 31.3%; p=0.4986). A procedural predictor of acute CVE was extended procedure time (stroke vs. control: 101.8±39.6 vs. 90.0±31.3 hours; p=0.0105). Finally, stroke after TAVI resulted in clearly prolonged hospital stay (stroke vs. control: 16.1±9.0 vs. 10.7±6.2 days; p Conclusion The severity of aortic valve and ascending thoracic aorta calcification predicts stroke after TAVI as well as extended procedure time, possibly due to increased mechanical intravascular manipulation by prolonged catheterisation. These correlations could guide us in identifying those patients who are most likely to benefit from transcatheter cerebral embolic protection devices.

Background The rising number of new percutaneous interventions for left-sided heart disease leads to increased occurrence of iatrogenic atrial septal defect (iASD). The percutaneous mitral valve repair (PMVR) for severe, symptomatic mitral regurgitation (MR) also requires intraprocedural puncture of the interatrial septum. In some cases iASD is persisting and becomes haemodynamically relevant with enhanced right heart overload due to significant left-to-right-shunting. Purpose This study aimed to evaluate pre- and periprocedural factors that may favour persistence and haemodynamic relevance of iASD in patients after PMVR. Methods In 2015, 75 consecutive patients with severe MR (age 74.8±10.5y) and following PMVR were enrolled. After 12 months, 57 patients completed their follow up (FU) including clinical conditions, transthoracic echocardiography (TTE), and cardiovascular magnetic resonance (CMR) whenever feasible. We evaluated the impact of comorbidities as well as intraprocedural, haemodynamic and functional characteristics that may favour persistence of iASD by multivariate analysis. Haemodynamic relevance of iASD was defined as right heart overload with predominantly significant enlargement of the right atrium (RA), impairment of right heart function as defined by fractional area shortening (FAC), and ratio of pulmonary to systemic blood flow (Qp/Qs>1) when available. Results 18 out of 57 patients (32%) showed a persistent iASD (+iASD), being associated with a specific combination of comorbidities as well as pre-procedural and periprocedural factors that can be summarised by a multifactorial iASD risk calculator (+iASD vs. -iASD: 6.3±2.9 vs. 3.9±2.7; p=0.0058). 11 iASD (61%) became haemodynamically relevant (+hd iASD) with a significant right heart overload (RA area +hd iASD vs. -hd iASD: baseline 23.1±4.1 vs. 23.2±4.3; FU 30.7±6.3 vs. 20.1±4.6; p Conclusion This study shows for the first time, that persistence of iASD can be predicted by pre- and periprocedural factors using a risk calculator that may additionally guide careful follow up imaging and therapeutic action after PMVR to avoid development of progressive heart failure.

Background For transcatheter aortic valve replacement (TAVR) morbidity- and outcome relevant factors like paravalvular aortic regurgitation, vascular access complications and the need for permanent pacemaker implantation remain key challenges. New-generation devices for TAVR have been optimized to improve clinical outcome. Purpose We aimed to address safety and effectiveness of new-generation TAVR devices compared with earlier generations in a single centre study. Methods We compared 30 days outcome of the new-generation repositionable MER (n=614) and MEP (n=90) and the balloon-expandable ES3 (n=414) valve with the last-generation self-expandable MCV (n=270) and the balloon-expandable SXT (n=103) in patients treated with TAVR between 2009 and 2018. TAVR endpoints and adverse events were defined according to the Valve Academic Research Consortium-2. Results Logistic EuroSCORE I as predictor for risk stratification and 30-day mortality was comparable between both cohorts (27.3%±2.9 new vs 23.0%±1.4 early; p=n.s.). Compared to early-generation devices (MCV/SXT), new-generation devices (MER/MEP/ES3) had significantly higher primary device success (98.9% new vs 96.8% early; p=0.0089), lower incidence of new renal replacement therapy (2.6% new vs 6.2% early; p=0.0028), new permanent pacemaker therapy for conduction disturbances (12.8% new vs 17.0% early; p=0.0394), and disabling bleeding (1.4% new vs 4.0% early; p=0.0040). No difference could be observed concerning incidence of moderate-to-severe paravalvular leakage (4.2% new vs 5.0% early; p=n.s.), stroke (3.3% new vs 2.1% early; p=n.s.), major vascular complications (2.8% new vs 3.5% early; p=n.s.) and 30-day mortality (2.7% new vs 4.4% early; p=n.s). Conclusion Data from the retrospective analysis indicate higher primary device success and lower incidence of renal replacement, pacemaker therapy and disabling bleeding events in new-generation devices, although praised “hot-item” advantages like paravalvular leackage/aortic regurgitation, vascular complications and mortality remain unacknowledged.

Background and purpose Percutaneous left atrial appendage occlusion (LAAO) depicts an alternative treatment for patients with atrial fibrillation who are deemed for long-term oral anticoagulation therapy. In order to perform a successful LAAO accurate sizing of left atrial appendage (ostium, landing zone and depth) for device selection is essential. Echo-Fluoro fusion imaging in real-time offers with its latest prototype a patient-specific segmented automated 3D heart model and sizing of left atrial appendage (LAA). We therefore aimed to evaluate the automated segmented LAA sizing by comparing to 2D transesophageal (TOE) and MSCT measurements as gold standard. Methods We studied prospectively data of 8 consecutive patients who were admitted to our clinic for left atrial appendage closure. MSCT was performed preprocedural and analyzed with commercially available 3mensio software (Pie medical imaging). 2D TOE measurements and automated segmentation of the LAA and sizing were performed during the procedure by a highly experienced team of periinterventional cardiac imaging specialist and structural heart disease interventionalist who were blinded to the prior MSCT analysis. Dimension of ostium, landing zone (10 mm into the LAA parallel to the ostial plane at the level of the left circumflex for Amplatzer device) and depth (perpendicular to the ostial plane) were obtained in different TOE views according to instructions for use of Amulet Occluder. In order to generate an automated 3 D heart model, a high-quality 3D TOE image of the LAA volume and surrounding structures was acquired. After successful ECG-gated segmentation a 3 D heart model was generated. Automated LAA sizing followed in real-time. All measurements were taken into consideration before device selection. A Kruskal Wallis test was used to compare mean ranks of independent samples. A concordance analysis according to Kendall W was carried out to investigate reliability. Results The mean age of the patients was 82,6±4.15 years and half of the patients were female. All procedures were conducted successfully. The mean values of ostium and landing zone were comparable in TOE, automated sizing and MSCT sizing (ostium: 23,78±2,15 mm vs 25,71±5,25 mm vs 27,35±3,3 mm; (p=0,175); landing zone 22,13±3,18 mm vs 23,57±3,31 mm vs 24,00±3,51 mm; (p=0,377)). Furthermore, a significant concordance between the measurements was shown (ostium W= 0,991; p=0.045, landing zone W=0,835, p=0.014). Conclusion Automated LAA sizing acquired by fusion imaging may be an elegant real-time alternative for precise LAA Occluder device selection and needs to be investigated further.

Background Transcatheter aortic valve replacement (TAVR) is the treatment option of choice in inoperable and high-risk patients and only recently even revealed favorable outcome in an intermediate risk cohort. Morbidity- and outcome relevant factors like paravalvular aortic regurgitation, vascular access complications and the need for permanent pacemaker implantation remain key challenges during balloon- and self-expandable valve-improvement. Purpose We aimed to address safety and effectiveness between balloon- and self-expandable TAVR devices relating to more than one generation. Methods Patients treated with TAVR between 2009 and 2018 were categorized into either balloon-expandable (BAVR, n=516) or self-expandable (SAVR, n=974) groups. TAVR endpoints and adverse events were defined according to the Valve Academic Research Consortium-2. Primary endpoint was 30-day mortality. Results Logistic EuroSCORE I as predictor for risk stratification and 30-day mortality was comparable between both cohorts (BAVR/SAVR: 25.7%±5.2 vs 25.5%±2.5; p=n.s). Compared to SAVR devices, BAVR devices had significantly higher periprocedural gradients (BAVR/SAVR: 11.7mmHg±0.1 vs 8.3mmHg±0.8; p=0.0175), lower incidence of new renal replacement therapy (BAVR/SAVR: 1.8% vs 4.6%; p=0.0025), and new permanent pacemaker therapy for conduction disturbances (BAVR/SAVR: 8.3% vs 17.3%; p Conclusion Data from the retrospective analysis indicate lower incidence of renal replacement and pacemaker therapy, but higher periprocedural gradients, disabling bleeding complications, and enhanced 30-day mortality for the BAVR device as compared to SAVR. Other issues like paravalvular leackage/aortic regurgitation and stroke still remain unacknowledged.

Background Precise positioning of the prosthesis is a crucial step during transcatheter aortic valve implantation. In some cases, contemporary self-expandable prostheses show micro-movement (MM) during the final phase of release. Purpose We aimed to establish a definition for MM, evaluated the incidence of MM using the CoreValve Evolut RTM, investigated potential risk factors for MM and the associated clinical outcomes. Methods MM was defined as movement of the prosthesis of at least 1.5 mm from its position directly before release compared to its final position. Patients were grouped according to the occurrence (+MM) or absence (-MM) of MM. Baseline characteristics, imaging data and outcome parameters in accordance with the updated valve academic research consortium (VARC-2) criteria were retrospectively analyzed. Results We identified 258 eligible patients. MM occurred in 31.8% (n=82) of cases with a mean magnitude of 2.8±2.2 mm in relation to the left coronary cusp and 3.0±2.1 mm to the non-coronary cusp. Clinical and hemodynamic outcomes were similar in both groups. The mean pressure gradient was effectively reduced after TAVI (-MM vs. +MM: 7±3.4 mmHg vs. 8±3.9 mmHg, p=0.326) with consistency over a follow-up period of at least three months (-MM vs. +MM: 6.7±3.7 mmHg vs. 7.9±8.4 mmHg, p=0.168). At three months follow-up most of the patients presented with no aortic regurgitation (-MM vs. +MM: 64% vs. 67.9%, p=0.569). Mild aortic regurgitation was observed in 34.2% of the -MM group and in 29.5% of the +MD group (p=0.414). Moderate aortic regurgitation occurred in 1.9% of all patients with no differences between groups (-MM vs. +MM: 1.9% vs. 2.6%, p=0.662). Patients with MM presented with a more symmetric calcification pattern (-MM vs. +MM: 27.3% vs. 40.2%; p=0.037) and a larger aortic valve area (-MM vs. +MM: 0.6 cm2 ± 0.3 vs. 0.7 cm2 ± 0.2; p=0.014), which was found to be a potential risk factor for the occurrence of MM in a multivariate regression analysis (OR 3.5; 95% CI: 1.1–10.9; p=0.032) Conclusion MM occurred in nearly one third of patients and did not affect clinical and hemodynamic outcome. A larger aortic valve area was the only independent risk factor for the occurrence of MM.

Background Antithrombotic therapy in transcatheter aortic valve replacement (TAVR) is highly controversial. Dual antiplatelet therapy (DAPT) for 3–6 months with aspirin and clopidogrel is the current recommendation. Whereas in patients with indication for OAC several regimes were described, ranging from OAC monotherapy to dual and even triple therapy. Besides vitamin K antagonists (VKA), non-Vitamin K oral anticoagulants (NOAC) are frequently used in TAVR patients with indication for permanent OAC. Purpose We therefore aimed to evaluated different antithrombotic regimes and their impact on outcome. Methods We performed a single center retrospective analysis in 1160 patients treated by transfemoral approach (TF TAVR). Primary endpoints were 30-day mortality, stroke and bleeding according to VARC-2 criteria. Secondary endpoint was all-cause mortality at 1 year. Results In 1160 patients with TF TAVR, a broad range of regimes occurred in clinical practice. The majority of patients were on DAPT (637 patients, 55.0%), followed by VKA + clopidogrel (186 patients, 16%). Other patients received OAC mono (98 patients; 9%), triple therapy (93 patients; 8%), NOAC mono (31 patients; 3%), single antiplatelet therapy (SAPT, 40 patients; 4%) or NOAC + clopidogrel (31 patients, 3%). All-cause mortality 30 days after TF TAVR differed between the regimens. (SAPT/OAC+SAPT/N-OAC+DAPT 0.0% vs DAPT 3.6% vs OAC 10.2% vs. NOAC 1.3% vs NOAC+SAPT 0.3%; pANOVA Conclusion Data from our retrospective analysis indicate that a variety of different antithrombotic regimes occur even in a single centre analysis. All-cause mortality was enhanced in patients with oral anticoagulation. Therefore, clinical trials need to investigate if this is only explained by additional atrial fibrillation.

OBJECTIVES: To test safety and exploratory effectiveness of a dedicated transcaval closure device. BACKGROUND: Transcaval access enables delivery of large-caliber devices to the aorta in patients ineligible for transfemoral arterial access. Closure of aorto-caval fistulae using off-label nitinol cardiac occluders has been shown to be safe, but persistent aorto-caval fistulae at exit from the catheterization lab and bleeding complications were common in a prospective study. METHODS: Pre-clinical testing of the Transcaval Closure Device (TCD) was performed in 24 Yorkshire swine, including 10 under Good Laboratory Practice (GLP) conditions. Subsequently, subjects undergoing transcatheter aortic valve replacement (TAVR) for symptomatic severe aortic stenosis, ineligible for transfemoral arterial access, were enrolled in a United States Food and Drug Administration (FDA) approved Early Feasibility Study (EFS) of the TCD (Transmural Systems, Andover, MA). Independently-adjudicated endpoints included technical, device and procedural success, incorporating in-hospital and 30-day clinical and imaging follow up. RESULTS: Transcaval access and closure in swine confirmed that at 30 days, TCDs were almost entirely endothelialized. Subsequently, twelve subjects were enrolled in the EFS. Transcaval access, TAVR and aorto-caval fistula closure was successful in all 12 subjects. The primary endpoint of technical success was met in 100% of subjects. Complete closure of the transcaval access tract was achieved in 75% of subjects at exit from the catheterization lab and in 100% of subjects at 30 days. There were zero modified VARC-2 major vascular complications and zero VARC-2 life-threatening or major bleeding complications related to transcaval access or the TCD. CONCLUSIONS: The TCD achieved complete closure of the transcaval access tract in most subjects at exit from the catheterization lab and essentially eliminated transcaval-related bleeding. Dedicated devices for transcaval access and closure could enable more widespread adoption of transcaval without fear of bleeding complications. (https://clinicaltrials.gov/ct2/show/NCT03432494)

Nuhrenberg et al. [(1)][1] reported that hypoattenuated leaflet thickening (HALT) after transcatheter aortic valve replacement (TAVR) is not associated with pharmacodynamic response to clopidogrel. HALT and subclinical leaflet thrombosis are an issue in patients with TAVR. It has already been

Objectives This study sought to evaluate SAPIEN 3 (S3) (Edwards Lifesciences, Irvine, California) positioning using different strategies. Background Aortic valve-in-valve (ViV) is associated with high risk of elevated gradients. Methods S3 aortic ViV procedures in stented bioprostheses were studied. Transcatheter heart valve (THV) positioning was analyzed in a centralized core lab blinded to clinical outcomes. A combined endpoint of severely elevated mean gradient (≥30 mm Hg) or pacemaker need was established. Two positioning strategies were compared: central marker method and top of S3 method. Optimal final depth was defined as S3 depth ≤20%. Results A total of 113 patients met inclusion criteria and were analyzed (76.5 ± 9.7 years of age, 65.8% male, STS score 8 ± 7.6%). THVs had incomplete shortening in comparison to fully expanded valves (92 ± 3.4%), and expansion was more complete in optimal positioning cases compared with others (93.2 ± 2.7% vs. 91.5 ± 3.5%; p = 0.027). The central marker method demonstrated greater correlation with final implantation depth than the top of S3 method (R2 of 0.48 and 0.14; p Conclusions Optimal S3 positioning in aortic ViV is associated with better outcomes. Central marker positioning is more reliable than top of S3 positioning. Central marker bottom position should be 3 mm to 6 mm above the ring.

Objectives To evaluate the incidence, risk factors and the clinical outcome of micro-dislodgement (MD) with a contemporary self-expandable prosthesis during transcatheter aortic valve implantation. Methods MD was defined as movement of the prosthesis of at least 1.5 mm upwards or downwards from its position directly before release compared to its final position. Patients were grouped according to the occurrence (+MD) or absence (-MD) of MD. Baseline characteristics, imaging data and outcome parameters were retrospectively analyzed. Results We identified 258 eligible patients. MD occurred in 31.8% (n = 82) of cases with a mean magnitude of 2.8 mm ± 2.2 in relation to the left coronary cusp and 3.0 mm ± 2.1 to the non-coronary cusp. Clinical and hemodynamic outcomes were similar in both groups with consistency over a follow-up period of three months. A larger aortic valve area (AVA) (-MD vs. +MD: 0.6 cm2 ± 0.3 vs. 0.7cm2 ± 0.2; p = 0.014), was the only independent risk factor for the occurrence of MD in a multivariate regression analysis (OR 5.3; 95% CI: 1.1–24.9; p = 0.036). Conclusions MD occurred in nearly one third of patients and did not affect clinical and hemodynamic outcome. A larger AVA seems to be a potential risk factor for MD.

Aims: Enhanced left ventricular end-diastolic pressure (LVEDP) has been shown to be associated with worse outcome after acute myocardial infarction, cardiac surgery and in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR). Nowadays, pulmonary artery wedge pressure (PCWP) has largely replaced direct measurement of LVEDP but several patient series have demonstrated a poor agreement between both methods. Different AS-entities by the meaning of normal-flow high-gradient (NFHG), paradoxical and true low-flow lowgradient ((p)LFLG) AS may be also linked to high left ventricular filling pressures that can be measured by LVEDP and PCWP. Therefore, we analyzed 1) role and agreement of LVEDP and PCWP in patients with highgrade AS and 2) influence of AS-entities on LVEDP/PCWP pressure gradients.Methods and Results: From 2009 to 2018, a total of 788 patients with highgrade AS prior to TAVR, completed hemodynamic status and echocardiographic data were retrospectively enrolled. LVEDP was significantly higher as the PCWP (23.3 ± 8.4 vs. 19.0 ± 8.9; p

Objectives Aim of this study is to elucidate the impact of pulmonary hypertension on patients treated with a transapical aortic valve replacement. Background In patients with aortic stenosis (AS) the coexistence of pulmonary hypertension (PH) is associated with increased peri-operative risk for surgical aortic valve replacement. For transcatheter aortic valve replacement (TAVR), it is unknown whether transapical TAVR (TA-TAVR) is associated with increased peri-interventional risk in PH patients. Methods We performed a single center analysis in 189 patients with severe AS with (AS + PH) or without PH (AS - PH) undergoing TA-TAVR. PH was defined by mean pulmonary artery pressure ≥25 mmHg assessed by right heart catheterization (exclusion of 64 patients due to missing results). As the primary endpoint a combination of 30-day mortality or cardiopulmonary resuscitation (CPR) was analyzed. Results Seventy three patients (58.4%) had PH. Increased peri-interventional risk in AS + PH patients was reflected by an increased rate of the primary endpoint in comparison to AS - PH patients (24.7 vs. 3.8%; p = .002). A higher proportion of acute kidney injury (34.2 vs. 15.7%; p = .025) was found in AS + PH patients while AS - PH patients showed a higher rate of bleeding in comparison AS + PH patients (18.5 vs. 6.8% p = .050). Conclusion Patients with AS + PH treated by TA-TAVR are at increased peri-interventional risk for severe complications in comparison to AS - PH patients. Therefore, the identification of preventive therapeutic strategies is needed. Classifications TAVR, transapical, pulmonary hypertension, aortic stenosis.

Balloon aortic valvuloplasty (BAV) as a bridge to transcatheter aortic valve implantation (TAVI) is a well-established treatment option in patients who are in a critical state or who suffer from underlying comorbidities that disguise the severity of aortic stenosis (AS). If convalescence is achieved, TAVI can be performed with good results in high-gradient aortic stenosis (HG-AS) patients. Whether this approach is safe and effective in low-flow low-gradient aortic stenosis (LFLG-AS) has not been analyzed; therefore, we investigated whether BAV followed by TAVI as a staged procedure is an effective treatment option in patients with LFLG-AS.Patients with severe AS who received BAV followed by staged TAVI were identified. Baseline data, periprocedural and postprocedural information, echocardiographic data, and follow-up data were collected. The patient population was divided into LFLG-AS and HG-AS groups.From July 2009 until September 2017, we identified 38 eligible patients (16 LFLG-AS and 22 HG-AS). Log EuroScore I (51.8 ± 20.9% LFLG-AS vs 33.7 ± 19.1% HG-AS; P.01) differed significantly between groups, as did baseline echocardiographic data that were used to categorize groups. BAV and staged TAVI were carried out 100% successfully with comparable results. Instant symptom relief and pressure gradient reduction were accomplished after both procedures. Thirty-day mortality rates (0% LFLG-AS vs 9% HG-AS; P=.21) and 1-year mortality rates (18.8% LFLG-AS vs 27.2% HG-AS; P=.54) did not differ between groups.BAV followed by staged TAVI is a safe and effective treatment option in sick or questionable candidates, irrespective whether LFLG-AS or HG-AS is present.

AIM To investigate the accuracy of a rotational C-arm CT-based 3D heart model to predict an optimal C-arm configuration during transcatheter aortic valve replacement (TAVR). METHODS Rotational C-arm CT (RCT) under rapid ventricular pacing was performed in 57 consecutive patients with severe aortic stenosis as part of the pre-procedural cardiac catheterization. With prototype software each RCT data set was segmented using a 3D heart model. From that the line of perpendicularity curve was obtained that generates a perpendicular view of the aortic annulus according to the right-cusp rule. To evaluate the accuracy of a model-based overlay we compared model- and expert-derived aortic root diameters. RESULTS For all 57 patients in the RCT cohort diameter measurements were obtained from two independent operators and were compared to the model-based measurements. The inter-observer variability was measured to be in the range of 0°-12.96° of angular C-arm displacement for two independent operators. The model-to-operator agreement was 0°-13.82°. The model-based and expert measurements of aortic root diameters evaluated at the aortic annulus (r = 0.79, P < 0.01), the aortic sinus (r = 0.93, P < 0.01) and the sino-tubular junction (r = 0.92, P < 0.01) correlated on a high level and the Bland-Altman analysis showed good agreement. The interobserver measurements did not show a significant bias. CONCLUSION Automatic segmentation of the aortic root using an anatomical model can accurately predict an optimal C-arm configuration, potentially simplifying current clinical workflows before and during TAVR.

While transcatheter aortic valve implantation (TAVI) is established for treating high-operative risk surgical aortic valve replacement candidates, until recently the smallest transcatheter heart valve (THV) measured 23 mm, posing greater risk for annular rupture and THV failure in patients with aortic stenosis (AS) with small aortic annuli (≤20 mm).In the setting of a multicentre registry, we report on the safety, efficacy and early clinical outcomes of the SAPIEN XT 20 mm balloon-expanding THV.Among TAVI 55 recipients (n=30 for native AS, n=25 for a valve-in-valve procedure (V-in-V)), median age and Society of Thoracic Surgeons score were 85 (81 to 87) years and 7.8 (4.7 to 12.4)%, respectively. Mean and minimum annular diameters were 19±1 and 17±2 mm, respectively, in native patients with AS, and 17±1 mm (internal diameter) in V-in-V recipients. Successful device implantation rate was 96%, with no procedural-related death. Overall in-hospital-30-day death, stroke and major bleeding rates were 5%, 2% and 9%, respectively. In native AS TAVI recipients, mean transaortic gradient decreased from 54±20 to 12±5 mm Hg (p0.001), and from 45±17 to 24±8 mm Hg (p0.001) in V-in-V recipients. Severe prosthesis-patient mismatch (PPM) rates were 10% and 48% in native AS and V-in-V TAVI recipients, respectively (p=0.03). Post-TAVI, the rate of moderate aortic regurgitation was 7% and 0% in native AS and V-in-V TAVI recipients, respectively.TAVI with the 20 mm SAPIEN XT THV appears safe and technically feasible, with acceptable short-term clinical outcomes and low rates of severe PPM in those with native AS.

Die akute Herzinsuffizienz (AHF) stellt eine akut lebensbedrohliche klinische Situation dar, die rasches Handeln erfordert, um die Entwicklung des Vollbildes eines kardiogenen Schocks mit Multiorganversagen zu verhindern. Neben kausalen Therapieansatzen, wie der koronaren Revaskularisation im akuten Myokardinfarkt, stehen etablierte intensivmedizinische Masnahmen zur Aufrechterhaltung von suffizientem Kreislauf und Oxygenierung, in Verbindung mit kreislaufwirksamen Medikamenten sowie moderne Therapieansatze der extrakorporalen Kreislaufunterstutzung zur Verfugung. Die hier aufgefuhrten Therapieanweisungen spiegeln die aktuellen Leitlinien zur Therapie der AHF wider und basieren zum grosen Teil noch auf Expertenmeinungen, da hier im Gegensatz zur chronischen Herzinsuffizienz noch eine harte evidenzbasierte Datenlage geschaffen werden muss.

Background A novel software (“Dynamic Coronary Roadmap”) was developed, which offers a real-time, dynamic overlay of the coronary tree on fluoroscopy. Once the roadmap has been automatically generated during angiography it can be used for navigation during percutaneous coronary interventions (PCI). As a feasibility study, we aimed to investigate the feasibility of real-time dynamic coronary roadmapping and consecutive coronary overlay during elective PCI. Methods and results We studied 936 overlay runs, created following the same amount of angiographies, which were generated during 36 PCIs. Feasibility of dynamic coronary roadmapping was analyzed using a dedicated software tool. Roadmap quality (correct dynamic imaging of the vessels without relevant artefacts or missing parts) was distinguished from overlay quality (congruence of dynamic coronary roadmapping and coronary anatomy). Additionally, we assessed procedural success and the occurrence of major cardiac and cerebrovascular events (MACCE). Roadmap quality was defined as “fit for use” in 99.5%. In 97.4% of runs overlay quality was deemed “fit for use”. Overall, we observed low inter and intra observer variability (ICC R = 0.84 for roadmap quality and R = 0.75 for overlay quality). Procedural success rate was 100%. MACCE occurred in two (5.6%) patients during post-interventional in-hospital stay and were not software-related. Conclusions Dynamic coronary roadmapping provides in > 98% of cases sufficient roadmap quality with an anatomically correct overlay of the coronary vessels with good inter and intra observer variability. Future randomized studies are warranted to test possible advantages like procedure time reduction and less consumption of contrast medium. Electronic supplementary material The online version of this article (10.1186/s40001-018-0333-x) contains supplementary material, which is available to authorized users.

Abstract. Background: Vascular access site-related complications are frequent in the context of transfemoral transcatheter aortic valve replacement (TAVR). The implantation of a covered stent graft is an effective treatment option for bleeding control. However, the external iliac and common femoral arteries are exposed to flexion of the hip joint. Therefore, stent compression and stent/strut fractures may occur, facilitating stent occlusion. Patients and methods: In all 389 patients who received transfemoral TAVR from 2013–2015 at the Düsseldorf Heart Centre, we monitored the management of vascular access site-related complications. Our analyses focused on immediate technical success and bleeding control, primary patency, and the occurrence of stent/strut fractures after six to 12 months of follow-up. Results: Vascular access site-related complications occurred in 13 % (n = 51), whereof in 10 patients, the bleeding was successfully managed by prolonged compression. In 40 out of 51 patients, a covered stent graft was implanted in the common femoral artery, leading to 100 % immediate bleeding control. After a mean follow-up of 334 ± 188 days, 28 stents out of 29 patients with completed follow-up (excluding e. g. death) were without flow-limiting stenosis (primary patency 97 %) or relevant stent compression (diameter pre/post 8.6/8.1 mm, p = 0.048, late lumen loss 1.1 ± 0.2 mm, mean flow velocity 92 ± 34 cm/s). In four asymptomatic patients, stent/strut fractures were detected (14 %) without flow-limiting stenosis. Conclusions: The implantation of a covered stent graft is highly effective and safe to control vascular access site-related complications after TAVR. Stent/strut fractures in the flexible segment of the common femoral artery may occur, as consequently verified by X-ray visualization, but show no impairment on flow or clinical parameters after six to 12 months.

Although next-generation cardiac prostheses have shown favorable results in transcatheter aortic valve implantation (TAVI), these have mostly been documented in intermediate-risk patients. Whether this could be translated to high-risk patients is not known. Hence, the safety and clinical performance of the new, repositionable CoreValve Evolut R-System (ERS) was evaluated by comparison with a non-repositionable CoreValve-System (CVS), in 96 high-risk/inoperable (HRI) patients.The primary safety end points were mortality and stroke, defined by VARC-2 criteria, at 30 days. Clinical performance end points were described by VARC-2 criteria, focusing on: (i) higher-grade atrioventricular conduction blocks with concomitant permanent pacemaker (PM) implantation; (ii) vascular complications (VCs); and (iii) aortic regurgitation (AR). The ERS and CVS patients underwent TAVI in equal proportions.In this study, 63% of patients in the CVS group and 82% in the ERS group were defined as HRI. One in-hospital death was documented after 30 days. With regards to the HRI cohort, no difference in rates of PM use were noted (ERS 20% versus CVS 20%; p0.9999). ERS patients were characterized by a higher prevalence of peripheral vascular disease (PVD) (46% versus 21%; p0.05), but fewer VCs (13% versus 41%; p0.01). Both cohorts showed low rates of moderate-to-severe paravalvular AR (ERS 6% versus CVS 5%; p = 0.8639). However, ERS seemed to offer a favorable hemodynamic performance, with a significantly improved AR index (26.3 versus 22.3; p0.05). TAVI with the ERS was associated with a higher stroke rate (3% versus 0%; p = 0.1232) after necessary postdilatation processes.In comparison to last-generation CVS, the repositionable ERS is safe and effective in HRI patients. Similar rates of PM use were noted for each group. together with a favorable hemodynamic performance and fewer vascular complications.

In the REAC-TAVI (Assessment of platelet REACtivity after Transcatheter Aortic Valve Implantation) trial, Jimenez Diaz et al. [(1)][1] were able to demonstrate that pharmacodynamic response to ticagrelor is superior as compared with clopidogrel in transcatheter aortic valve replacement (TAVR). The

AIMS: Degenerative aortic valve stenosis (AVS) is independently associated with endothelial dysfunction and increased levels of circulating endothelium-derived microparticles (EMPs) as a marker of compromised endothelial integrity. The aim of this study was to investigate whether therapy for severe AVS by transcatheter aortic valve implantation (TAVI) improves endothelial function and decreases EMPs. METHODS AND RESULTS: Fifty-six patients with indication for TAVI due to symptomatic severe AVS were prospectively enrolled. Brachial wall shear stress (WSS), endothelial function and circulating microparticles (MPs) were measured before and three months following TAVI. Endothelial function was assessed as flow-mediated dilation (FMD) using ultrasound. MP subpopulations were discriminated by flow cytometry according to the expression of established surface antigens: CD31+/CD41-, CD144+ and CD62E+ as EMPs and CD41+ as platelet-derived MPs (PMPs). In patients with severe AVS, decreased brachial WSS was an independent predictor of low FMD. At three-month follow-up after TAVI, WSS and FMD increased along with decreased levels of EMPs as compared to pre TAVI. Decrease of CD31+/CD41-, CD144+ and CD62E+ EMP levels correlated with the increase of FMD. CONCLUSIONS: Therapy for AVS by TAVI was associated with improved endothelial function and integrity indicating beneficial effects of TAVI on systemic arterial function.

Aims Visual guidance through echocardiography and fluoroscopy is crucial for a successful transseptal puncture (TSP) in a prespecified region of the fossa ovalis. The novel EchoNavigator system Release II (EchoNav II, Philips Healthcare, Andover, Massachusetts, USA) enables the real-time fusion of fluoroscopic and echocardiographic images. We evaluated this new imaging method in respect to safety and efficacy of TSP during MitraClip implantation and left atrial appendage closure. Methods Forty-four patients before (−EchoNav) and 44 patients after (+EchoNav) the introduction of real-time fusion were included in our retrospective, single-centre study. The primary endpoint was the occurrence of adverse events due to TSP. Secondary endpoints were successful puncture at the prespecified region and time until TSP (min). Results In both groups TSP was performed successfully in the prespecified region and no adverse events occurred during or due to the accomplishment of TSP. Time until TSP was significantly reduced in the +EchoNav group in comparison with the EchoNav group (18.48 ± 5.62 min vs. 23.20 ± 9.61 min, p = 0.006). Conclusions Real-time fusion of echocardiography and fluoroscopy proved to be as safe and successful as standard best practice for TSP. Moreover, efficacy was improved through significant reduction of time until TSP.

Transcatheter aortic valve implantation (TAVI) is an emerging treatment for high-risk patients with aortic stenosis. Aortic regurgitation is considered to be a relative contraindication for transcatheter procedures, as a non-calcified aortic annulus poses the risk of an insufficient anchoring of the transcatheter aortic valve prosthesis. Herein is described the case of a patient who suffered from recurrent aortic valve regurgitation after valve-sparing repair, and which was successfully treated by the transcatheter implantation of an Edwards SAPIEN 3™ prosthesis. This case report demonstrated the suitability of this prosthesis to treat pure aortic valve regurgitation, without excessive oversizing of the valve.

Mitral regurgitation causes left atrial (LA) and left ventricular (LV) dysfunction, dilatation, and remodeling. Following percutaneous mitral valve repair (PMVR) using the MitraClip® approach, reverse cardiac remodeling is desirable. To date, the influence of PMVR on LA and segmental LV function and remodeling has not been investigated in detail.Twenty-six patients who received the MitraClip device were enrolled in an open-label, single-center observational study. Patients underwent clinical assessment, conventional echocardiography and global and segmental longitudinal strain analysis of the left atrium and left ventricle by speckle tracking echocardiography at baseline and at a three-month follow up.PMVR improved both LV systolic function (from 40.5 ± 2.5% to 45.0 ± 2.5%, p = 0.04) and LV global longitudinal strain (from -8.9 ± 0.7% to -10.7 ± 0.9%, p = 0.004). Segmental analysis revealed improved myocardial deformation mainly in the basal (basalseptal -8.9 ± 0.8% to -12.9 ± 0.8%, p = 0.0002; basallateral -7.9 ± 1.1% to -13.9 ± 1.4%, p = 0.0005) and midventricular segments (mid-septal -12.7 ± 0.9% to -14.5 ± 1.1%, p = 0.02; mid-lateral -7.5 ± 0.8% to -10.8 ± 1.2%, p = 0.006). In patients with pre-procedural preserved LA function with sinus rhythm the impact of PMVR revealed an improvement in LA global conduit function (from 10.6 ± 1.2% to 13.9 ± 1.6%, p = 0.003) and global contractile function (from -2.1 ± 0.47% to -3.5 ± 0.5%, p = 0.03). The reversed remodeling was not associated with altered levels of the cardiac biomarkers matrix metalloproteinase 2 (MMP-2) and MMP-9, tissue-inhibitors of MMPs (TIMP-2 and ST-2).PMVR improves global segmental LV and LA function and leads to a reverse remodeling.

Background: In-depth knowledge about potential predictors of mortality in transcatheter aortic valve replacement (TAVR) is still warranted. Currently used risk stratification models for TAVR often fail to reach a holistic approach. We, therefore, aimed to create a new staged risk model for 1-year mortality including several new categories including (a) AS-entities (b) cardiopulmonary hemodynamics (c) comorbidities, and (d) different access routes. Methods: 737 transfemoral (TF) TAVR (84.3%) and 137 transapical (TA) TAVR (15.7%) patients were included. Predictors of 1-year mortality were assessed according to the aforementioned categories. Results: Over-all 1-year mortality (n = 100, 11.4%) was significantly higher in the TA TAVR group (TF vs. TA TAVR: 10.0% vs. 18.9 %, p = 0.0050*). By multivariate cox-regression analysis, a three-staged model was created in patients with fulfilled categories (TF TAVR: n = 655, 88,9%, TA TAVR: n = 117, 85.4%). Patients in &ldquo, stage 2&rdquo, showed 1.7-fold (HR 1.67, CI 1.07&ndash, 2.60, p = 0.024*) and patients in &ldquo, stage 3&rdquo, 3.5-fold (HR 3.45, CI 1.97&ndash, 6.05, p &lt, 0.0001*) enhanced risk to die within 1 year. Mortality increased with every stage and reached the highest rates of 42.5% in &ldquo, (plogrank &lt, 0.0001*), even when old- and new-generation devices (plogrank = n.s) were sub-specified. Conclusions: This new staged mortality risk model had incremental value for prediction of 1-year mortality after TAVR independently from the TAVR-era.

With the 1-year results of the CENTERA-EU (Safety and Performance of the Edwards CENTERA-EU Self-Expanding Transcatheter Heart Valve) trial, Tchetche et al. [(1)][1] added further data on the transcatheter heart valve (THV), which is designed to combine the advantages of balloon- and self

Multislice computed tomography (MSCT) has emerged as an integral part of patient evaluation in transcatheter aortic valve implantation (TAVI). Beyond sizing, it offers valuable information especially in challenging anatomies and helps to provide accurate dimensions and highlight potential pitfalls. We present the case of a 94-year-old woman with a coronary anomaly who was initially scheduled for TAVI. Based on MSCT scan and clinical evaluation we decided to perform a less invasive approach. In this setting MSCT evaluation allowed an appropriate benefit-risk assessment and substantially influenced the interventional strategy.

We present the case of a 71-year-old woman who showed recurrent signs of congestive heart failure with the need of rehospitalization after double valve (mitral and aortic) replacement. Extensive diagnostic workup revealed a moderate aortic stenosis and additionally a significant left ventricular outflow tract obstruction. The tissue overgrowth might be attributed to an inflammatory reaction with extensive pannus deposit after aortic valve surgery. With no-option for re-do surgery we performed the first-in-man off-label valve-in-left ventricular outflow tract procedure with an Edwards Sapien III 23 mm in deep orientation.

Objective— Vascular calcification is an independent risk factor for cardiovascular disease. Once thought to be a passive process, vascular calcification is now known to be actively prevented by proteins acting systemically (fetuin-A) or locally (matrix Gla protein). Warfarin is a vitamin K antagonist, widely prescribed to reduce coagulation by inhibiting vitamin K–dependent coagulation factors. Recently, it became clear that vitamin K antagonists also affect vascular calcification by inactivation of matrix Gla protein. Here, we investigated functional cardiovascular characteristics in a mouse model with warfarin-induced media calcification. Approach and Results— DBA/2 mice received diets with variable concentrations of warfarin (0.03, 0.3, and 3 mg/g) with vitamin K1 at variable time intervals (1, 4, and 7 weeks). Von Kossa staining revealed that warfarin treatment induced calcified areas in both medial layer of aorta and heart in a dose- and time-dependent fashion, which could be inhibited by simultaneous vitamin K2 treatment. With ongoing calcification, matrix Gla protein mRNA expression decreased, and inactive matrix Gla protein expression increased. TdT-mediated dUTP-biotin nick end labeling–positive apoptosis increased, and vascular smooth muscle cell number was concomitantly reduced by warfarin treatment. On a functional level, warfarin treatment augmented aortic peak velocity, aortic valve–peak gradient, and carotid pulse-wave velocity. Conclusion— Warfarin induced significant calcification with resulting functional cardiovascular damage in DBA/2 wild-type mice. The model would enable future researchers to decipher mechanisms of vascular calcification and may guide them in the development of new therapeutic strategies.

To investigate in a series of 232 patients whether the MitraClipTranscatheter mitral valve repair using the MitraClipBetween 2011 and 2015, we performed 232 MitraClipAge, logistic EuroScore, severity of MR, left and right ventricular function, and renal function did not differ between the groups. The primary combined safety endpoint, which was defined as the occurrence of major adverse cardiac and cerebrovascular events, conversion to surgery, major vascular complications or pneumonia, did not differ between MitraClipThe MitraClip

Percutaneous catheter-based techniques for the treatment of structural heart disease are becoming more complex, and current imaging techniques have limitations: while fluoroscopy gives poor visualisation of cardiac anatomical structures, echocardiography is limited in its ability to detect the position of catheters and devices. The EchoNavigator® (Philips) live image guidance tool is a novel system that integrates real-time echocardiography with fluoroscopic X-ray imaging, optimising the guidance and positioning of devices. Use of the EchoNavigator system facilitates improved understanding of anatomical structures while showing enhanced visualisation of catheter and device movements. Early clinical experience suggests that the technology is feasible and safe, and provides enhanced understanding of the relationship between soft tissue anatomy and catheter devices in structural heart disease. The use of the EchoNavigator system can improve the confidence of interventional cardiologists in the targeting and positioning of devices in percutaneous interventions in structural heart disease, and has the potential to reduce procedural time, reduce the dosage of contrast and radiation and increase safety in the performance of procedural steps.

Background Preprocedural manual multi-slice-CT-segmentation tools (MSCT-ST) define the gold standard for planning transcatheter aortic valve replacement (TAVR). They are able to predict the perpendicular line of the aortic annulus (PPL) and to indicate the corresponding C-arm angulation (CAA). Fully automated planning-tools and their clinical relevance have not been systematically evaluated in a real world setting so far. Methods and Results The study population consists of an all-comers cohort of 160 consecutive TAVR patients with a drop out of 35 patients for technical and anatomical reasons. 125 TAVR patients underwent preprocedural analysis by manual (M-MSCT) and fully automated MSCT-ST (A-MSCT). Method-comparison was performed for 105 patients (Cohort A). In Cohort A, CAA was defined for each patient, and accordance within 10° between M-MSCT and A-MSCT was considered adequate for concept-proof (95% in LAO/RAO; 94% in CRAN/CAUD). Intraprocedural CAA was defined by repetitive angiograms without utilizing the preprocedural measurements. In Cohort B, intraprocedural CAA was established with the use of A-MSCT (20 patients). Using preprocedural A-MSCT to indicate the corresponding CAA, the levels of contrast medium (ml) and radiation exposure (cine runs) were reduced in Cohort B compared to Cohort A significantly (23.3±10.3 vs. 35.3 ±21.1 ml, p = 0.02; 1.6±0.7 vs. 2.4±1.4 cine runs; p = 0.02) and trends towards more safety in valve-positioning could be demonstrated. Conclusions A-MSCT-analysis provides precise preprocedural information on CAA for optimal visualization of the aortic annulus compared to the M-MSCT gold standard. Intraprocedural application of this information during TAVR significantly reduces the levels of contrast and radiation exposure. Trial Registration ClinicalTrials.gov NCT01805739

Left ventricular (LV) perforation accompanied by acute cardiac tamponade is a rare but one of the most feared complication during transcatheter aortic valve implantation. Few cases with the need of emergent surgical repair are described in literature. Handling of this uncommon but possible life-threatening event requires well-considered action by the implanting team and is associated with substantially increased intrahospital mortality. We present a unique case of LV perforation management with percutaneous pericardiocentesis only. As a possible underlying physiological mechanism, we identified the movement of the ventricular muscle band which possibly sealed the perforation side due to transverse and circumferential muscle contractions.

To present our initial clinical experience using this innovative software solution for guidance of percutaneous structural heart disease interventions.Left atrial appendage, atrial septal defect and paravalvular leak closure, transaortic valve repair and MitraClip(®) procedures were performed in the catheter laboratory under fluoroscopic and echocardiographic guidance. The two-dimensional and three-dimensional images generated by the transesophageal echocardiography probe were interfaced with the fluoroscopic images in real-time using the EchoNavigator(®)-system.The application of the novel image fusion technology was safe and led to a better appreciation of multimodality imaging guidance due to improved visualization of the complex relationship between catheter devices and anatomical structures.The EchoNavigator(®)-system is a feasible and safe tool for guidance of interventional procedures in structural heart disease. This innovative technology may improve confidence of interventional cardiologists in targeting and positioning interventional devices in order to increase safety, accuracy, and efficacy of percutaneous interventions in the catheter laboratory.

Cardiovascular calcification is prevalent in the aging population and in patients with chronic kidney disease (CKD) and diabetes mellitus, giving rise to substantial morbidity and mortality. Vitamin K-dependent matrix Gla-protein (MGP) is an important inhibitor of calcification. The aim of this study was to evaluate the impact of high-dose menaquinone-7 (MK-7) supplementation (100 µg/g diet) on the development of extraosseous calcification in a murine model. Calcification was induced by 5/6 nephrectomy combined with high phosphate diet in rats. Sham operated animals served as controls. Animals received high or low MK-7 diets for 12 weeks. We assessed vital parameters, serum chemistry, creatinine clearance, and cardiac function. CKD provoked increased aortic (1.3 fold, p &lt, 0.05) and myocardial (2.4 fold, 0.05) calcification in line with increased alkaline phosphatase levels (2.2 fold, 0.01). MK-7 supplementation inhibited cardiovascular calcification and decreased aortic alkaline phosphatase tissue concentrations. Furthermore, MK-7 supplementation increased aortic MGP messenger ribonucleic acid (mRNA) expression (10-fold, 0.05). CKD-induced arterial hypertension with secondary myocardial hypertrophy and increased elastic fiber breaking points in the arterial tunica media did not change with MK-7 supplementation. Our results show that high-dose MK-7 supplementation inhibits the development of cardiovascular calcification. The protective effect of MK-7 may be related to the inhibition of secondary mineralization of damaged vascular structures.

PLoS one 7(8), e43229 (2012). doi:10.1371/journal.pone.0043229, Published by PLoS [u.a.], Lawrence, Kan.