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AIMS The aim of this study was to determine the impact of tricuspid regurgitation (TR) on mortality after edge-to-edge percutaneous mitral valve repair (PMVR), and also to analyse whether there is a difference in outcome between patients with improvement of TR after PMVR compared to patients without. METHODS AND RESULTS Out of 197 consecutive patients who underwent PMVR, 139 patients with available follow-up (mean 428±386 days) were included in the study. Concomitant moderate/severe TR was present in 58.3% of patients. Kaplan-Meier analysis showed significantly reduced overall survival for patients with moderate/severe TR, compared to patients with none/mild TR (p=0.003). Cox multivariate regression analysis revealed severe TR at baseline as the strongest independent predictor of mortality (HR 4.367, p=0.003). An improvement of the baseline moderate/severe TR was observed in 45.5% of patients at 30-day follow-up. Patients with no improvement of TR after PMVR had a higher midterm mortality compared to patients in whom TR improved (40.5% versus 11.4%, p=0.005). CONCLUSIONS More than half of patients undergoing PMVR have concomitant moderate/severe TR, which is associated with a worse outcome. Among predictors of mortality after edge-to-edge PMVR, severe TR at baseline is the most important. Patients with no improvement of TR at 30 days after PMVR have a significantly higher mortality at follow-up.

The use of the MitraClip system has gained widespread acceptance for the treatment of patients with mitral regurgitation (MR) who are not suitable for the conventional surgery. This study sought to investigate the early and 1-year outcome after MitraClip therapy of patients with MR and cardiac comorbidities. Outcomes through 12-month follow-up of patients (n = 528) who underwent MitraClip implantation were obtained from the German transcatheter mitral valve interventions (TRAMI) registry. The majority of these patients (n = 409, 77.5 %) also suffered from coronary artery disease (CAD). Patients with a dilated cardiomyopathy (DCM, n = 65, 12.3 %) or concomitant valvular aortic disease (AV, n = 54, 10.2 %) were less frequent. Although the prevalent pathogenesis was functional MR, patients with DCM had significantly more frequent a functional MR (96.9 %) compared to patients with CAD (74.9 %) or AV (62.5 %, p

Aims Transcatheter interventions with balloon-expandable valves have been shown to be efficacious for the treatment of mitral annuloplasty failure but are limited by the fact that there is no opportunity for post-implantation adjustment. The aim of this study was to assess the safety and efficacy of the fully repositionable and retrievable Direct Flow Medical (DFM) valve for the treatment of mitral annuloplasty failure. Methods and results Patients who underwent transcatheter mitral valve-in-ring (VIR) implantation of a DFM valve for failed mitral annuloplasty deemed high risk for redo surgery were included at four institutions. Eight patients underwent transcatheter mitral VIR procedures with implantation of the DFM valve. The DFM prosthesis was successfully positioned in all patients. Two patients required retrieval of the device due to a suboptimal result, and a further patient required repositioning of the valve with an ultimately successful implantation. During the 30-day follow-up period, two patients died for reasons unrelated to the valve implantation. The four patients with successful implantation had normal valve function associated with a significant improvement in their functional status. Conclusions For the first time, we demonstrate the safety, efficacy and advantages of using the DFM prosthesis for the treatment of mitral annuloplasty failure.

Objectives The aim of this study was to assess the 1-year outcome after transcatheter aortic valve replacement (TAVR) of the Direct Flow Medical (DFM) valve in patients with severe symptomatic aortic stenosis who were contraindicated or high risk for surgery. Background The DFM transcatheter heart valve is a new-generation, nonmetallic aortic valve with a pressurized support structure and conformable double-ring annular sealing delivered through an 18-F sheath. The device allows repositioning, retrieval, and assessment of valve performance before permanent implantation. Methods A prospective multicenter European registry was set up to determine the safety and performance of the valve in 100 consecutive patients (10 centers). Echocardiographic and angiographic data were evaluated by an independent core laboratory, and adverse events were adjudicated by a clinical events committee using Valve Academic Research Consortium criteria. Results Patients were 83.1 ± 5.9 years of age and had a logistic EuroSCORE of 22.5 ± 11.3% and a Society of Thoracic Surgeons score of 9.7 ± 8.7%. Correct valve positioning was obtained in 99% of cases with a combined 30-day safety endpoint at 10%, including major stroke in 5.0%, major vascular complications in 2.0%, and death in 1%. At 12 months, 95% of patients were in New York Heart Association functional class I or II. Freedom from any death was 90%, and freedom from any death or major stroke was 85%. Echocardiography demonstrated none/trace to mild aortic regurgitation in 100% of patients and an unchanged mean aortic gradient of 12.2 ± 6.6 mm Hg and effective orifice area of 1.6 ± 0.4 cm 2 . Conclusions At 1 year, the DFM transcatheter heart valve had durable hemodynamics. This study demonstrates that the low rate of early complications and the low risk of significant aortic regurgitation translated into midterm clinical benefit.

Objectives This study sought to evaluate the use of the Direct Flow Medical (DFM) transcatheter heart valve (Direct Flow Medical, Santa Rosa, California) for the treatment of noncalcific pure aortic regurgitation (AR). Background The treatment of noncalcific AR has remained a relative contraindication with transcatheter heart valves due to challenges in anchoring devices in the absence of calcium, concerns of valve embolization, and the high risk of significant residual paravalvular leak. Methods The study population consisted of patients treated for severe noncalcific pure AR with transfemoral implantation of a DFM transcatheter heart valve at 6 European centers. The primary endpoint was the composite endpoint of device success and the secondary endpoint was the composite early safety endpoint (according to the VARC-2 criteria). Results Eleven high-risk (STS score 8.84 ± 8.9, Logistic EuroSCORE 19.9 ± 7.1) patients (mean age 74.7 ± 12.9 years) were included. Device success was achieved in all patients. In 1 patient, the initial valve prosthesis was retrieved after pull-through, and a second valve was successfully deployed. The early safety endpoint was reached in 91% of the patients, with 1 patient requiring surgical aortic valve replacement secondary to downward dislocation of the prosthesis that was successfully managed with surgical aortic valve replacement. DFM implantation resulted in excellent hemodynamics with none or trivial paravalvular regurgitation in 9 patients and a transprosthetic gradient of 7.7 ± 5.1 mm Hg at 30-day follow up. All patients derived symptomatic benefit following the procedure, with 72% in New York Heart Association functional class I or II. Conclusions This study reports the feasibility of treating severe noncalcific AR with the Direct Flow prosthesis via the transfemoral route.

Aim The retrograde approach in chronic total occlusion (CTO) percutaneous coronary intervention (PCI) is increasingly being used as a first-line intervention despite a higher radiation exposure, contrast volume, and a higher major adverse cardiac event (MACE) rate compared with the antegrade approach. It was aimed to evaluate the overall success rate of CTO-PCI over time when the retrograde approach was restrictively used only after a failed antegrade attempt. Methods and Results In a prospective single operator registry from January 2008 to December 2012 about 436 consecutive patients underwent a CTO-PCI. Mean age was 63.4 ± 10.3 years, and 86% were male. The overall success rate improved significantly over time [68% (first quartile) to 91% (fourth quartile), P

Background Severe tricuspid regurgitation is associated with poor prognosis; however, there are limited Class I indications for intervention, and high–surgical risk patients may go untreated. We report the first-in-human successful transcatheter tricuspid valve repair for severe tricuspid regurgitation. Objectives The objective of this study was to show the feasibility of a transcatheter tricuspid annular repair. Methods Compassionate-use approval for the procedure was obtained from the regulatory organization in Germany. To perform the transcatheter bicuspidization of the tricuspid valve, the Mitralign system was used to place pledgeted sutures by means of a trans-jugular venous approach. Insulated radiofrequency wires were positioned 2 to 5 mm from the base of the posterior leaflet, 2.6 cm apart. The sutures were drawn together and locked, plicating the posterior annulus. Results Reconstruction of the 3-dimensional transesophageal echocardiographic dataset at baseline revealed a tricuspid valve annular area of 14.1 cm 2 , and effective regurgitant orifice area was 1.35 cm 2 . There was a significant reduction in annular area (57%) and effective regurgitant orifice area (53%) measured with 3-dimensional transesophageal echocardiography, at 6.05 cm 2 and 0.63 cm 2 , respectively. Hemodynamic parameters also improved with a reduction in right atrial pressure from 22 mm Hg at baseline, to 9 mm Hg and an increase in left ventricular stroke volume from 42 ml at baseline to 72 ml. Conclusions Transcatheter tricuspid valve repair could become an effective treatment for high–surgical risk patients who are non-responsive to optimal medical therapy.

ObjectivesThe study sought a prospective multicenter nonrandomized evaluation of the Direct Flow Medical (DFM) system for the treatment of severe aortic stenosis.BackgroundThe DFM transcatheter aortic valve system is a nonmetallic design with a pressurized support structure that allows precise positioning, retrieval, and assessment of valve performance prior to permanent implantation.MethodsOne hundred high surgical risk patients with severe aortic stenosis were evaluated for the primary endpoint. There were 75 patients in the group evaluable for the secondary endpoints and 25 in the pre-specified roll-in training phase. Echocardiographic and angiographic data were evaluated by an independent core laboratory and adverse events adjudicated by clinical event committee and classified according to Valve Academic Research Consortium (VARC) criteria.ResultsThere was 99% freedom from all cause mortality at 30 days (primary endpoint). VARC criteria defined 30 day combined freedom from patient safety event rate was 91% and overall device success was 93%. The post-implantation echocardiography results demonstrated mild or no aortic regurgitation in 99% (73 of 74) with a mean gradient of 12.6 ± 7.1 mm Hg (n = 72) and effective orifice area of 1.50 ± 0.56 cm2 and New York Heart Association functional class was I or II in 92% of cases.ConclusionsThe present study demonstrates the safety and efficacy of the DFM system in surgical high risk patients with severe aortic stenosis and complex anatomy aortic regurgitation was less than moderate in 99% of patients.

Background— Meta-analyses of randomized trials have shown an increased risk of periprocedural stroke after carotid artery stenting (CAS) compared with carotid endarterectomy, which may differ in specific patient subgroups. Knowledge of risk factors for cerebral embolic lesions during CAS may impact treatment decisions for the individual patient, but these factors have not been extensively studied. We aimed to identify factors predictive for cerebral ischemic lesions during embolic protected CAS. Methods and Results— Preprocedural and postprocedural diffusion-weighted magnetic resonance imaging was performed for evaluation of new cerebral ischemic lesions in 728 (86.9%) of 837 consecutive patients undergoing CAS with cerebral embolic protection. Multivariable logistic regression analyses were performed to identify factors predictive for embolic lesions. New ischemic lesions were found in 32.8% of patients. Age, hypertension, lesion length, lesion eccentricity, and aortic arch type III were significantly associated with new ischemic lesions; calcified lesions were negatively associated. In 25% of these patients embolic lesions were also found in the contralateral hemisphere. Predictive factors for contralateral lesions were age, >50% stenosis of the contralateral internal carotid artery, and an aortic arch type II, with a trend for aortic arch type III. Conclusions— Age, hypertension, lesion morphology, and aortic arch type were predictive for procedural-related cerebral embolic lesions during embolic protected CAS. Age, significant contralateral carotid stenosis, and complex aortic arch type were predictive for bilateral ischemic lesions. The clinical implications of ischemic lesions are not yet fully understood.

The recanalization success rate of chronic total occlusion (CTO) percutaneous coronary interventions (PCI) can be increased by the retrograde approach; however, the long-term outcome of patients undergoing retrograde procedures is unknown. We aimed to evaluate the long-term major adverse cardiac and cerebrovascular event (MACCE) rate (e.g. death, myocardial infarction, coronary artery bypass surgery and stroke) in patients after retrograde versus antegrade CTO-PCI. In a prospective single center study from January 2008 to June 2012, 396 consecutive patients with CTO (≥3 months old) were enrolled. The mean age was 63.4 ± 10.3 years and 86.4% were male. The success rate of the total patient cohort was 88.6%. The retrograde PCI, only attempted after a failed antegrade intervention, was performed in 18% (n = 71) of patients. Long-term MACCE rate (mean follow up 2.3 ± 1.6 years) was significantly higher in the unsuccessful compared to the successful CTO-PCI group (23.1% versus 9.4%, p = 0.01) and this was also the case in the subgroup of antegrade CTO-PCI. In the retrograde subgroup, however, procedural success had no impact on outcome. Patients with unsuccessful retrograde CTO-PCI had a significantly better collateral connection compared to patients with an unsuccessful antegrade approach. Independent predictors for MACCE were peripheral artery disease and an ejection fraction ≤30%. The long-term MACCE rate after unsuccessful recanalization was significantly higher, which was driven by a higher MACCE rate after unsuccessful versus successful antegrade approaches. In contrast, procedural success in the retrograde group had no impact on outcome.

Objectives This study questioned whether transaxillary transcatheter aortic valve implantation (TAVI) is feasible as a true percutaneous approach using percutaneous closure devices. Background Transaxillary TAVI is gaining increasing acceptance as an alternative to the transfemoral route; however, the access has always been done via surgical cutdown so far. Methods Between August 2010 and September 2011, a total of 24 high-risk patients with severe aortic valvular stenosis underwent a percutaneous TAVI procedure by direct puncture of the axillary artery without surgical cutdown. For safety reasons and as a target for the puncture, a wire was advanced via the ipsilateral brachial artery. Moreover, a balloon was placed into the subclavian artery via the femoral artery for temporary vessel blockade before percutaneous vessel closure. Vascular closure was performed using either the ProStar XL system (Abbott VascularDevices, Redwood City, California) or 2 ProGlide systems (Abbott VascularDevices). Results The true percutaneous approach was successfully completed in all patients (14 left and 8 right axillary artery cases). Overall mortality at 30 days was 8.3%. Acute vascular closure device success was achieved in 17 patients (71%). Vascular closure device success rate was 100% for the ProGlide device and 37% for the ProStar device, respectively. Seven patients (29%) with failing closure devices were treated by endovascular stent graft implantation without the need for surgical repair. For the last 12 treated patients, direct closure was achieved in 11 patients. Conclusions Direct puncture of the axillary artery for TAVI is feasible and safe if a wire is placed into the subclavian artery via the ipsilateral brachial artery.

Objectives: The objective of this study was to compare the cerebral embolic load of filter-protected versus proximal balloon–protected carotid artery stenting (CAS).Background: Randomized trials co...

AIMS: The aim of the present study was to evaluate the outcome of carotid artery stenting (CAS) in a single, high-volume centre of a single operator and to analyse the circumstances under which complications occur. Recent trials comparing CAS with carotid endarterectomy demonstrated controversial results. The low experience of interventionists in performing CAS was a major limitation of these studies. The number of procedures needed to achieve optimal skills is unknown. METHODS AND RESULTS: From May 1997 until April 2010, 1,004 patients with symptomatic or asymptomatic carotid artery stenosis underwent CAS by a single operator. A cerebral protection device was in mandatory use since 2000. In-hospital complication rates were defined as the cumulative rate of death, myocardial infarction or stroke. Procedural success was achieved in 97.77% of patients. The perioperative complication rate was 1.69% including 0.2% deaths, 1.1% patients with minor stroke, 0.4% patients with major stroke. In 88% (15 out of 17) of the patients with complications, unfavourable anatomical or procedural factors could be identified. After the first 100 CAS performed,the complication rate was at 3% and significantly decreased to 1% after more than 500 procedures. Patients ≥80 years had a significantly higher complication rate. CONCLUSIONS: In a high-volume experienced centre, the in-hospital complication rate is low. Complications occurred almost exclusively in patients with unfavourable anatomical or procedural characteristics and seem to be avoidable in most patients. A learning curve was observed up to 500 procedures. Elderly patients have a higher complication rate.

This study sought to evaluate the feasibility of the CGuard Carotid Embolic Protective Stent system-a novel thin strut nitinol stent combined with a polyethylene terephthalate mesh covering designed to prevent embolic events from the target lesion in the treatment of carotid artery lesions in consecutive patients suitable for carotid artery stenting.The risk of cerebral embolization persists throughout the carotid artery stenting procedure and remains during the stent healing period.A total of 30 consecutive patients (age 71.6 ± 7.6 years, 63% male) meeting the conventional carotid artery stenting inclusion criteria were enrolled in 4 centers in Germany and Poland.The primary combined endpoint was the procedure success of the CGuard system and the number and volume of new lesions on the ipsilateral side assessed by diffusion-weighted magnetic resonance imaging at 48 h post-procedure and at 30 days. The secondary endpoint was 30-day major adverse cardiac or cerebrovascular events (death, stroke, or myocardial infarction). Protection devices were used in all procedures. Procedure success was 100%, with 0% procedural complications. The 30-day major adverse cardiac or cerebrovascular events rate was 0%. New ipsilateral ischemic lesions at 48 h occurred in 37.0% of patients and the average lesion volume was 0.039 ± 0.08 cm(3). The 30-day diffusion-weighted magnetic resonance imaging showed complete resolution of all but 1 periprocedural lesion and only 1 new minor (0.116 cm(3)) lesion in relation to the 48-h scan.The use of the CGuard system in patients undergoing carotid artery stenting is feasible. In addition, the benefit of using CGuard may extend throughout the stent healing period.

BACKGROUND: Adhesion of intratubular leukocytes to proximal tubules in biopsies of patients with rapidly progressive glomerulonephritis and the appearance of leukocytes in the urine in interstitial nephritis suggest interactions between leukocytes and tubular epithelia in renal diseases. The aim of this study was to investigate the effect of cytokines and endotoxin on leukocyte migration through proximal tubular epithelial cells and also to determine the role of the transmembrane adhesion molecules ICAM-1 and CD47 in this process.METHODS: Experiments determined transepithelial migration (TEM) of PMN (polymorphonuclear) leukocytes through monolayers of HK-2. Expression of ICAM-1 and CD47 was assessed via confocal immunofluorescence, FACS analysis and western blotting. The effect of antibodies against ICAM-1 and CD47 on TEM was examined. Furthermore measurements of cytokine release (IL- 6 and IL-8) were performed.RESULTS: Preincubation of HK-2 cells with either TNFalpha or LPS resulted in stimulation of PMN migration through monolayers of HK-2 cells. There was no preferred direction of transmigration. ICAM-1 was expressed by HK-2 cells and expression was increased after 4 h stimulation with TNFalpha or LPS. Application of ICAM-1 antibodies inhibited TEM. CD47 was expressed in both HK-2 cells and PMN. CD47 antibodies inhibited predominantly basolateral-to-apical TEM. HK-2 cells released IL-8 and IL-6 preferably into the apical compartment. Additionally, we showed that fMLP induced transmigration through monolayers of HK-2 cells was associated with significant increased CD47 expression on PMN cell surfaces.CONCLUSIONS: Inflammatory mediators stimulate TEM of PMN through monolayers of HK-2 cells without a clearly discernible preference of direction. Mechanisms involved in TEM stimulated by cytokines or endotoxin appear to be mainly changes in surface receptor densities of HK-2 cells with ICAM-1 and CD47 playing an essential role.

Background Increased vascularity of bronchial mucosa is closely related to the expression of angiogenic factors, which contribute to the pathogenesis of diseases such as asthma bronchiale. Objective Here we examine the effects of the angiogenic growth factors angiopoietin 1 and angiopoietin 2 on eosinophil function in vitro and possible involvement of the angiopoietin receptor Tie-2. Methods Eosinophil migration was studied by micropore filter assays. Signaling mechanisms required for angiopoietin-dependent migration were tested by using signaling enzyme blockers. Tie-2 mRNA and receptor expression on the cell surface of eosinophils was demonstrated in RT-PCR and by fluorescence-activated cell sorting analysis. Results Angiopoietin 1 significantly stimulated eosinophil chemotaxis via activation of phosphodiesterase, phosphatidylinositol 3′-kinase, and tyrosine kinases. The effect on eosinophil migration of angiopoietin 1 was reversed by an antibody against the Tie-2 receptor and by angiopoietin 2. Incubation of eosinophils with angiopoietin 1 abolished the chemotactic effects of vascular endothelial growth factor on human eosinophils via the Tie-2 receptor. Finally, Tie-2 expression by human eosinophils was demonstrated on the transcriptional and protein level. Conclusions Data suggest that angiopoietin 1 stimulates directed migration and possibly inhibits vascular endothelial growth factor–induced eosinophil chemotaxis via its Tie-2 receptor, which is expressed by eosinophils. Thus, angiopoietin 1 may play an important role in the modulation of eosinophilic inflammation.

We thank Dr. Palmer and colleagues for their interest in our work [(1)][1] and appreciate their comments. As mentioned in the discussion section of our paper, one major limitation of the study is the retrospective design with a small number of patients. The Edwards SAPIEN 3 (Edwards Lifesciences

INTRODUCTION Fissures sliced through Kīlauea Volcano’s lower east rift zone on 3 May 2018, eventually engulfing hundreds of structures in lava flows and triggering a collapse at the summit. During the eruption, we employed a rapid routine for geochemical analysis of lava, developed over 6 years of monitoring the prior continuous eruption at Kīlauea. The application of this routine elevated lava chemistry to a near real-time data stream in eruption monitoring, similar to seismic and geodetic data. It provided an unparalleled opportunity to understand changes in magma characteristics during a rapidly evolving eruptive crisis. RATIONALE Lava chemistry provides vital information on the underground sources of magma, eruptive conditions, temperature, and physical properties of lava flows. However, analytical techniques are typically slow, leaving chemical analysis of lava as a retrospective tool in the volcano sciences. We developed an analytical procedure to characterize the geochemistry of lava within a few hours of sample collection, allowing us to identify a specific suite of major and trace elements that track lava compositions and estimate lava temperatures through chemical geothermometers. This information was used to inform response teams of shifts in eruptive conditions. RESULTS The initial fissures erupted low volumes of chemically evolved basaltic lavas from 3 to 9 May, which were viscous and cool (~1110°C). On 13 May we detected less-evolved compositions and an increase in inferred lava temperatures (~1130°C). We informed science and response teams that the arrival of more fluid and voluminous lava was likely. Beginning 17 to 18 May, the lava from the primary fissures became increasingly less chemically evolved, hotter, and more fluid. By 28 May, activity focused on a single vent (fissure 8). This vent fed a massive outpouring of hotter (~1145°C) lava that continued for more than 2 months. During this stage, lavas became slightly hotter and lost the cargo of lower-temperature minerals that were initially abundant. The lava carried olivine crystals with unusually high MgO, indicative of the presence of much hotter magma (>1270°C) somewhere in the plumbing system. A second dominant olivine population formed in cooler magma similar to what was being erupted previously at the summit lava lake. We also identified simultaneous, but more explosive, repetitive outbursts of andesite lava. This highly viscous and evolved composition, not previously known from Kīlauea, erupted at low temperatures (1060° to 1090°C) on a fissure offset from the other eruption fissures. The chemical and mineralogical fingerprint of this lava was also detected at other fissures several kilometers from the andesite vent. CONCLUSION Analysis of the data during the eruption revealed that at least three different sources of magma were feeding the eruption. The first two were the chemically evolved basalt of the initial fissures and the highly viscous andesite. Both are volumetrically minor sources that represent distinct pockets of old residual magma from Kīlauea’s east rift zone that evolved for more than 55 years, cooling and crystallizing at depth. The third and volumetrically more substantial source was less-evolved and hotter basalt of fissure 8. This source was similar in composition to the magma erupted at Kīlauea in the years before 2018 and was ultimately derived from the summit region. Draining and collapse of the summit by this voluminous eruption may have stirred up deeper, hotter parts of the summit magma system and sent mixed magma down the rift. By the final 20 days of the eruption, most magma stored within the active rift system had flushed out. Posteruption analyses done by traditional geochemical methods confirmed that the rapid-response routine produced comparable data and validated the models proposed during the active eruption. Our work has demonstrated that geochemical analyses of lava samples in near-real-time can yield critical information that enhances hazard assessments and risk mitigation during an eruption.

Transcatheter aortic valve replacement (TAVR) is associated with the risk of symptomatic or silent cerebral infarcts (CIs). The role of aortic valve calcification on CIs is not well known. The purpose of this study was to investigate the impact of aortic valve complex calcification on CIs in

The retrograde approach in chronic total occlusion (CTO) percutaneous coronary intervention (PCI) is increasingly being used as a first-line intervention despite a higher radiation exposure, contrast volume, and a higher major adverse cardiac event (MACE) rate compared with the antegrade approach. It was aimed to evaluate the overall success rate of CTO-PCI over time when the retrograde approach was restrictively used only after a failed antegrade attempt.In a prospective single operator registry from January 2008 to December 2012 about 436 consecutive patients underwent a CTO-PCI. Mean age was 63.4 ± 10.3 years, and 86% were male. The overall success rate improved significantly over time [68% (first quartile) to 91% (fourth quartile), P0.001] due to a significant increase of the antegrade success rate. This could be achieved by a retrograde approach of less than 20% with no change over time. The overall in-hospital MACE rate was 0.69% with no difference between antegrade and retrograde procedures.A high CTO-PCI success rate of above 90% could be achieved with a restrictive use of the retrograde technique.

The 18F Direct Flow Medical transcatheter aortic valve system is a second generation technology that has the potential to improve the outcome of TAVR. This design has conformable sealing rings which minimizes aortic regurgitation and permits full assessment of valve performance prior to permanent

Background Pro-inflammatory, cytotoxic CD4(+)CD28(-) T-cells with known defects in apoptosis have been investigated as markers of premature immuno-senescence in various immune-mediated diseases. In this study we evaluated the influence of polyclonal antilymphocyte globulins (ATG-Fresenius, ATG-F) on CD4(+)CD28(-) T-cells in vivo and in vitro. Principal findings Surface and intracellular three colour fluorescence activated cell sorting analyses of peripheral blood mononuclear cells from 16 consecutive transplant recipients and short-term cell lines were performed. In vivo, peripheral levels of CD3(+)CD4(+)CD28(-) T-cells decreased from 3.7 ± 7.1% before to 0 ± 0% six hours after ATG-F application (P = 0.043) in 5 ATG-F treated but not in 11 control patients (2.9 ± 2.9% vs. 3.9 ± 3.0%). In vitro, ATG-F induced apoptosis even in CD4(+)CD28(-) T-cells, which was 4.3-times higher than in CD4(+)CD28(+) T-cells. ATG-F evoked apoptosis was partially reversed by the broad-spectrum caspase inhibitor benzyloxycarbonyl (Cbz)-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD-fmk) and prednisolon-21-hydrogensuccinate. ATG-F triggered CD25 expression and production of pro-inflammatory cytokines, and induced down-regulation of the type 1 chemokine receptors CXCR-3, CCR-5, CX3CR-1 and the central memory adhesion molecule CD62L predominately in CD4(+)CD28(-) T-cells. Conclusion In summary, in vivo depletion of peripheral CD3(+)CD4(+)CD28(-) T-cells by ATG-F in transplant recipients was paralleled in vitro by ATG-F induced apoptosis. CD25 expression and chemokine receptor down-regulation in CD4(+)CD28(-) T-cells only partly explain the underlying mechanism.

Background— Misplacement during percutaneous aortic valve implantation can be associated with severe complications. The direct flow medical (DFM) valve is repositionable and retrievable; however, the nonmetallic inflatable and conformable design of the valve results in less radial force, which may have an impact on stability and valve function over time. We, therefore, analyzed the midterm stability of the position, shape, and hemodynamic performance of the DFM percutaneous aortic valve. Methods and Results— Sixteen symptomatic high-risk for surgery patients with aortic stenosis and a logistic EuroSCORE >20 underwent implantation and were the subject of this analysis. Clinical, echocardiographic, and dual-source multislice computed tomography data were obtained during 2-year follow-up. The 1- and 2-year survival rates were 81% and 69%, respectively. The dual-source multislice computed tomography follow-up indicated no changes in position, diameter, and orifice area of the DFM valve over time. Echocardiography revealed a significant decrease of the mean gradient from baseline (50.1±11.3 mm Hg) to 30 days (19.6±5.7 mm Hg, P 2 at baseline to 1.47±0.35 cm 2 at 30 days ( P Conclusions— In this preliminary series, the 2-year follow-up data of patients, in whom the nonmetallic, repositionable, and retrievable DFM valve was successfully implanted, show stability of the position, shape, and hemodynamic performance, with no AR in most patients.

This study questioned whether transaxillary transcatheter aortic valve implantation (TAVI) is feasible as a true percutaneous approach using percutaneous closure devices.Transaxillary TAVI is gaining increasing acceptance as an alternative to the transfemoral route; however, the access has always been done via surgical cutdown so far.Between August 2010 and September 2011, a total of 24 high-risk patients with severe aortic valvular stenosis underwent a percutaneous TAVI procedure by direct puncture of the axillary artery without surgical cutdown. For safety reasons and as a target for the puncture, a wire was advanced via the ipsilateral brachial artery. Moreover, a balloon was placed into the subclavian artery via the femoral artery for temporary vessel blockade before percutaneous vessel closure. Vascular closure was performed using either the ProStar XL system (Abbott Vascular Devices, Redwood City, California) or 2 ProGlide systems (Abbott Vascular Devices).The true percutaneous approach was successfully completed in all patients (14 left and 8 right axillary artery cases). Overall mortality at 30 days was 8.3%. Acute vascular closure device success was achieved in 17 patients (71%). Vascular closure device success rate was 100% for the ProGlide device and 37% for the ProStar device, respectively. Seven patients (29%) with failing closure devices were treated by endovascular stent graft implantation without the need for surgical repair. For the last 12 treated patients, direct closure was achieved in 11 patients.Direct puncture of the axillary artery for TAVI is feasible and safe if a wire is placed into the subclavian artery via the ipsilateral brachial artery.

Interstitial inflammation has emerged as a key event in the development of acute renal failure. To gain better insight into the nature of these inflammatory processes, the interplay between tubular epithelial cells, endothelial cells, and neutrophils (PMN) was investigated. A coculture transmigration model was developed, composed of human dermal microvascular endothelial (HDMEC) and human renal proximal tubular cells (HK-2) cultured on opposite sides of Transwell growth supports. Correct formation of an endoepithelial bilayer was verified by light and electron microscopy. The model was used to study the effects of endotoxin (LPS), tumor necrosis factor (TNF)-alpha, and alpha-melanocyte-stimulating hormone (alpha-MSH) by measuring PMN migration and cytokine release. To distinguish between individual roles of microvascular endothelial and epithelial cells in transmigration processes, migration of PMN was investigated separately in HK-2 and HDMEC monolayers. Sequential migration of PMN through endothelium and epithelium could be observed and was significantly increased after proinflammatory stimulation with either TNF-alpha or LPS (3.5 +/- 0.58 and 2.76 +/- 0.64-fold vs. control, respectively). Coincubation with alpha-MSH inhibited the transmigration of PMN through the bilayer after proinflammatory stimulation with LPS but not after TNF-alpha. The bilayers produced significant amounts of IL-8 and IL-6 mostly released from the epithelial cells. Furthermore, alpha-MSH decreased LPS-induced IL-6 secretion by 30% but had no significant effect on IL-8 secretion. We established a transmigration model showing sequential migration of PMN across microvascular endothelial and renal tubular epithelial cells stimulated by TNF-alpha and LPS. Anti-inflammatory effects of alpha-MSH in this bilayer model are demonstrated by inhibition on PMN transmigration and IL-6 secretion.

Subclinical cerebral ischemic lesions are detected by diffusion- weighted magnetic resonance imaging (DW-MRI) in the majority of patients after TAVR which may be associated with impaired short term neurological outcome. The impact of the TAVR device on cerebral ischemic lesions is not well defined.

Growing evidence indicates that inducible cyclooxygenase-2 (COX-2) is involved in the pathogenesis of inflammatory disorders and various types of cancer. Endothelial progenitor cells recruited from the bone marrow have been shown to be involved in the formation of new vessels in malignancies and discussed for being a key point in tumour progression and metastasis. However, until now, nothing is known about an interaction between COX and endothelial progenitor cells (EPC). Expression of COX-1 and COX-2 was detected by semiquantitative RT-PCR and Western blot. Proliferation kinetics, cell cycle distribution and rate of apoptosis were analysed by MTT test and FACS analysis. Further analyses revealed an implication of Akt phosphorylation and caspase-3 activation. Both COX-1 and COX-2 expression can be found in bone-marrow-derived endothelial progenitor cells in vitro. COX-2 inhibition leads to a significant reduction in proliferation of endothelial progenitor cells by an increase in apoptosis and cell cycle arrest. COX-2 inhibition leads further to an increased cleavage of caspase-3 protein and inversely to inhibition of Akt activation. Highly proliferating endothelial progenitor cells can be targeted by selective COX-2 inhibition in vitro. These results indicate that upcoming therapy strategies in cancer patients targeting COX-2 may be effective in inhibiting tumour vasculogenesis as well as angiogenic processes.

After an ischemic event vascular growth factors are involved in regulating leukocyte infiltration in inflammatory processes. This study focused on effects of 2 other angiogenic growth factors, angiopoietin-1 and angiopoietin-2, on human neutrophils and on the involvement of the angiopoietin receptor Tie-2.Neutrophils were from venous blood of healthy donors and cell migration was studied by micropore filter assays. Receptor expression was investigated by reverse transcriptase-polymerase chain reaction (PCR) for mRNA and fluorescence-activated cell-sorter scanner (FACS) analysis. Signaling mechanisms required for angiopoietin-dependent effects were tested functionally by using signaling enzyme blockers.The angiopoietins were chemotactic for neutrophils. They showed antagonistic effects on each other and both inhibited VEGF-directed migration of neutrophils. The effects of both angiopoietins were Tie-2 dependent. Tie-2 receptor immunoreactivity was confirmed on neutrophils by FACS. De novo synthesis is suggested by Tie-2 receptor mRNA expression as demonstrated by reverse transcriptase PCR.Data suggest that a Tie-2 receptor is expressed by human neutrophils whose active site ligation with either angiopoietin-1 or angiopoietin-2 exerts migratory effects on the one hand and arrests VEGF-mediated chemotaxis on the other. These effects suggest a role of angiopoietins in modulating neutrophilic inflammation.

We thank Drs. Paraskevas and Giannoukas for their appraisal of our work [(1)][1]. The purpose of our study was to analyze the impact of post-procedural asymptomatic cerebral ischemic lesions on diffusion-weighted magnetic resonance imaging (DW-MRI) after carotid artery stenting (CAS) on the hard

Background: The Direct Flow Medical (DFM) valve is repositionable and retrievable. The non metallic inflatable and conformable design of the valve results in better sealing but in less radial force which may have an impact on stability and valve function over time. Aim of the study: To evaluate the 4-year clinical and echocardiographic outcome of the first generation 22F-DFM percutaneous aortic valve. Methods and results: From 2007 to 2008 31 symptomatic high-risk for surgery patients (mean age 82±4y) with severe aortic stenosis and a mean logistic EuroSCORE of 29±7% were the subject of this analysis. Clinical, echocardiographic and hemodynamic follow-up were obtained during 4 years. Survival rates were 81%, 69%, 60%, and 54% at 1,2,3,4 years, respectively. At 4 years, 83% of the patients, who survived, were in NYHA-class I, 17% in class II. Echocardiography revealed a significant decrease of the mean gradient from baseline (49.1±13.8 mmHg) to 30 days (19.1±6.8 mmHg, p < 0.001), which remained stable over 4 years. At 4-year follow-up, 80% of the patients had no aortic regurgitation, 20% had trace aortic regurgitation. Conclusions: In this preliminary series, the first generation of the nonmetallic, repositionable and retrievable 22F-DFM valve was associated with acceptable clinical outcome and stable hemodynamic performance with no aortic regurgitation in the majority of patients.

Background: The 18F Direct Flow Medical transcatheter aortic valve system is a next generation technology that has the potential to improve the outcome of TAVR. This design has conformable sealing rings which minimizes paravalvular aortic regurgitation (AR) and permits full assessment of valve performance prior to permanent implantation. Objectives: The DISCOVER Trial is a prospective, multicenter, non-randomized CE evaluation of the safety and performance of the Direct Flow Medical Percutaneous Aortic Valve 18F System for the treatment of severe aortic stenosis in patients considered ineligible for surgery or at high risk for surgical complications. Methods: Patients were required to have a logistic EuroScore ≥ 20 or other high surgical risk features not reflected by the logistic EuroSCORE. Patients were reviewed by an independent Patient Review Committee consisting of cardiac surgeons and interventional cardiologists. Acute procedural, 6 and 12 month clinical and echocardiographic VARC defined outcomes are assessed. All echocardiographic and angiographic data are evaluated by an independent core laboratory (Medstar) and adverse events adjudicated by an independent clinical event committee. Results: At the time of abstract submission, 50 patients have been enrolled in the CE cohort. The average age was 84±5 (range of 71 to 94) years. The baseline logistic EuroSCORE was 27±12% (range: 2 – 55%) and STS score was 11.3±10.3%. Other baseline characteristics included: LVEF = 55.4±10%, 50% with CAD, 15% prior CABG, and 29% with CKD. A 25mm valve was used in 48% and 27 mm in 52%. There was 98% freedom from all cause mortality at 30 days. VARC defined 30 day patient safety freedom from events was 91% and device success was 97%. Core lab assessment of post procedure echocardiograms demonstrated 97% mild or less paravalvular AR and a mean gradient of 11.4±5.2 mmHg. 82% of the patients were reported in NYHA Class I/II at 30 days. The complete 6 month and available 12 month clinical and echocardiographic data will be presented. Conclusions: The Direct Flow Medical Transcatheter Aortic Valve System provides excellent acute and midterm results including virtual elimination of aortic regurgitation. This technology has the potential to provide next generation clinical outcomes. The complete 6 month and available 12 month hemodynamic and clinical data will be available at the time of presentation.

Objective: We aimed to identify factors predictive for new ipsi- and contralateral cerebral ischemic lesions during embolic protected carotid artery stenting (CAS). Background: Carotid endarterectomy and CAS appear to have similar overall perioperative stroke rates, which, however, may differ in specific patient subgroups. Knowledge of the risk factors for cerebral embolic events during CAS may impact treatment decisions for the individual patient, but have not been extensively studied. Aim of the study: To evaluate the risk factors for cerebral embolization after carotid artery stenting with embolic protection. Methods: Out of 837 consecutive patients undergoing CAS with cerebral embolic protection pre- and post-procedural diffusion weighted magnetic resonance imaging (DW-MRI) was performed for evaluation of new cerebral ischemic lesions in 728 patients (86.9%). Multivariate logistic regression analyses were performed to identify factors predictive for embolic events. Results: New ischemic lesions were found in 32.8% of the patients. Age, hypertension, lesion length, lesion excentricity, and aortic arch type III were significantly associated with new ischemic lesions, calcified lesions were negatively associated. In 25% of patients with embolic events lesions were also found in the contralateral hemisphere. Predictive factors for contralateral lesions were age, > 50% stenosis of the contralateral internal carotid artery, and an aortic arch type II, with a trend for aortic arch type III. Conclusions: Age, hypertension, lesion morphology, and aortic arch type were predictive for procedural related cerebral embolic events during embolic protected CAS. Age, significant contralateral carotid stenosis and complex aortic arch type were predictive for contralateral ischemic events. These findings may help to find the optimal treatment decision for the individual patient with carotid artery stenosis.

After embolic protected CAS, new cerebral ischemic lesions have been reported in up to 70 % of patients. There impact on long-term prognosis after CAS is unknown. Aim of the study was to evaluate the impact of new asymptomatic cerebral ischemic lesions, found in diffusion weighted magnetic resonance

Introduction Levosimendan is an extensively investigated inodilator showing also cardioprotective and antiinflammatory effects. The aim of our study was to explore the influence of levosimendan on polymorphonuclear leucocytes (PMN), a main source of reactive oxygen species, in vitro and in patients with acute heart failure or septic myocardial depression. Methods PMN isolated from healthy volunteers were incubated with levosimendan in vitro. After stimulation with N-formyl-Met-Leu-Phe (fMLP) or phorbol 12-myristate 13-acetate (PMA) respiratory burst was quantified using a fluorescent dye. Apoptosis and expression of cell adhesion molecules of PMN were measured by flow cytometry. For determination of in vivo effects patients with acute heart failure (n = 16) or septic cardiac failure (n = 9) receiving levosimendan treatment were enrolled consecutively. PMN were isolated to measure respiratory burst activity before treatment as well as one and two hours after initiation of levosimendan administration. Furthermore inflammatory, hemodynamic and renal function parameters were obtained. Results In vitro, levosimendan suppressed respiratory burst activity in fMLP or PMA stimulated PMN in a dose dependent manner by 30 ± 11% (P < 0.001) at 100 ng/mL and by 27 ± 17% (P < 0.001) at 1000 ng/mL respectively. Markers of apoptosis and PMN cell adhesion molecule expression remained unaffected by levosimendan treatment. In vivo, levosimendan treatment for two hours resulted in a significant reduction of PMA stimulated oxidative burst by 45% (P < 0.01) and fMLP stimulated oxidative burst by 49% (P < 0.05) in patients with acute heart failure. In patients suffering from septic shock levosimendan treatment decreased oxidative burst activity in unstimulated, fMLP and PMA stimulated PMN by 48% (P < 0.05), 46% (P < 0.01) and 43% (P < 0.01) respectively. Conclusions Levosimendan appears to exert distinct immunomodulatory effects by decreasing oxidative burst activity of PMN. This property might contribute to the previously described cardioprotective effects of the drug.

In acute disseminated intravascular coagulation, the effect of antithrombin (AT) administration on elevated levels of D-dimer is not well established. In the present study, we report on changes in circulating levels of D-dimer in response to administration of AT in a series of patients with acquired AT deficiency due to severe sepsis. Eight consecutive critically ill medical patients presenting with acute disseminated intravascular coagulation associated with severe sepsis/septic shock received a single bolus infusion of AT over 30 minutes, aiming to achieve physiological AT levels. Haemostatic parameters including D-dimer were assessed prior to, 6 and 24 h after AT administration. An average of 42 ± 9 U/kg body weight was infused. Following AT substitution, elevated levels of D-dimer fell whereas AT levels rose. These observations support the notion that AT can favourably affect fibrin degradation accompanying disseminated intravascular coagulation of severe sepsis.

Objectives The purpose of this study was to analyze the effect of transcatheter aortic valve replacement (TAVR) without versus with prior balloon aortic valvuloplasty (BAV) on the risk of cerebral embolization in patients who receive a balloon-expandable valve. Background Avoiding BAV prior to TAVR may simplify the procedure, but the risk of cerebral embolization is currently unknown. Methods A total of 87 consecutive high surgical-risk patients with no contraindications for diffusion-weighted magnetic resonance imaging (DW-MRI) were enrolled. Thirty-two patients received a balloon-expandable aortic valve with and 55 patients without BAV. The incidence, number, and volume of new ischemic lesions in DW-MRI performed 2 to 7 days after TAVI were evaluated. Results Mean age (83.8 ± 5.2 years vs. 82.9 ± 6.8 years) and sex (43.8% vs. 52.7% male) of the patients with versus without BAV, respectively, as well as other demographic and hemodynamic data were not significantly different between both groups. The procedural success rate was 93.5% with and 98.2% without BAV, and procedure duration and contrast volume were significantly lower without BAV. The incidence of new cerebral ischemic lesions in the total cohort was 66.7%. Compared with patients with BAV, those without BAV had a significantly higher total volume of cerebral ischemic lesions (235.4 ± 331.4 mm3 vs. 89.5 ± 128.2 mm3; p = 0.01). Conclusions The implantation of a balloon-expandable aortic valve without versus with prior BAV, although performed with a shorter procedure time and lower contrast volume, is associated with a significantly higher volume of cerebral ischemic lesions.

ObjectivesThis study sought to analyze the impact of new asymptomatic cerebral ischemic lesions, found in diffusion-weighted magnetic resonance imaging (DW-MRI) after carotid artery stenting (CAS) in relation to other risk factors for major adverse cerebral and cardiovascular events (MACCE) defined as death, stroke, and myocardial infarction.BackgroundAfter CAS, new cerebral lesions have been reported in up to 70% of patients. The impact of asymptomatic lesions on prognosis after CAS has not been studied.MethodsEight hundred thirty-seven consecutive patients underwent CAS with cerebral embolic protection. In 728 patients (86.9%), a pre- and post-procedural DW-MRI was available; these patients were included in the analyses. Multivariate Cox regression analysis and Kaplan-Meier estimates were performed to identify independent risk factors for MACCE at follow-up. Clinical, procedural, and lesion characteristics and DW-MRI findings were included in the analyses.ResultsPost-procedure new cerebral ischemic lesions were detected in 32.8% (n = 241) of patients. Fifteen patients (1.79%) had a periprocedural MACCE and were therefore excluded from the analysis. At a mean follow-up of 766.8 ± 513.4 days (range 30 to 2,577 days), MACCE occurred in 45 patients (6.2%). Cox regression analysis and Kaplan-Meier estimates both identified diabetes as the only significant independent risk factor of MACCE. Asymptomatic cerebral lesions after CAS were not associated with MACCE.ConclusionsBeyond 30 days, diabetes is the only risk factor of MACCE at follow-up. Asymptomatic cerebral embolic events after CAS had no prognostic impact.