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Background Data on Device-related Thrombus (DRT) after left atrial appendage closure (LAAC) remain scarce. This study aimed to investigate risk factors for DRT from centers reporting to the EUROC-DRT registry. Methods We included 537 patients (112 with DRT and 425 without DRT) who had undergone LAAC between 12/2008 and 04/2019. Baseline and implantation characteristics, anti-thrombotic treatment and clinical outcomes were compared between both groups in uni- and multivariate analyses. Additional propensity-score matching (PSM) was conducted to focus on the role of implantation characteristics. Results Patients with DRT showed higher rates of previous stroke/transient ischemic attack (TIA) (49.1% vs. 34.7%, p < 0.01), spontaneous echocardiographic contrast (SEC) (44.9% vs. 27.7%, p < 0.01) and lower left atrial appendage (LAA) peak emptying velocity (35.4 +/- 18.5 vs. 42.4 +/- 18.0 cm/s, p= 0.02). Occluders implanted in DRT patients were larger (25.5 +/- 3.8 vs. 24.6 +/- 3.5 mm, p =0.03) and implanted deeper in the LAA (mean depth: 7.6 +/- 4.7 vs. 5.7 +/- 4.7 mm, p

BACKGROUND: The cryoballoon represents the gold standard single-shot device for pulmonary vein isolation (PVI) in patients with atrial fibrillation (AF). Single-shot pulsed field PVI ablation (nonthermal, cardiac tissue selective) has recently entered the arena. We sought to compare procedural data and long-term outcome of both techniques. METHODS: Consecutive AF patients who underwent pulsed field ablation (PFA) and cryoballoon-based PVI were enrolled. Cryoballoon PVI was performed using the second-generation 28-mm cryoballoon; PFA was performed using a 31/35-mm pentaspline catheter. Success was defined as no recurrence of atrial tachyarrhythmia after a 3-month blanking period. RESULTS: Four hundred patients were included (56.5% men; 60.8% paroxysmal AF; age, 70 [interquartile range, 59–77] years), 200 in each group (cryoballoon and PFA), and baseline characteristics did not differ. Acute PVI was achieved in 100% of PFA and in 98% (196/200) of cryoballoon patients ( P =0.123; 4 touch-up ablations). Median procedure time was significantly shorter in PFA (34.5 [29–40] minutes) versus cryoballoon (50 [45–60] minutes; P P =0.1), driven by a higher rate of phrenic nerve palsies using cryoballoon. The 1-year success rates in paroxysmal AF (cryoballoon, 83.1%; PFA, 80.3%; P =0.724) and persistent AF (cryoballoon, 71%; PFA, 66.8%; P =0.629) were similar for both techniques. CONCLUSIONS: PFA compared with cryoballoon PVI shows a similar procedural efficacy but is associated with shorter procedure time and no phrenic nerve palsies. Importantly, 12-month clinical success rates are favorable but not different between both groups.

Aims A novel irrigated radiofrequency (RF) balloon (RFB) for pulmonary vein (PV) isolation (PVI) was released in selected centres. We pooled the procedural data on efficacy and safety of RFB-PVI from two high volume German centres. Methods and results Consecutive patients with RFB procedures were enrolled. A 3D electroanatomical left atrial map guided the RFB navigation. Every RF delivery lasted 60 s, and duration was automatically reduced to 20 s for electrodes facing the posterior wall. Procedural data and post-procedural endoscopy data ( Conclusion The RFB showed a high efficacy allowing for fast PVI procedures, and 60% of PVs could be isolated at the first application. Most safety events were recorded during the learning phase. An oesophageal temperature monitoring is suggested: oesophageal lesions were detected in 8% of patients.

Ablation of atrial fibrillation in the context of obesity can be challenging. We sought to evaluate the role of cryoballoon pulmonary vein isolation (CB-PVI) in obese patients with symptomatic atrial fibrillation (AF).Patients with a BMI ≥ 25 kg/m600 patients were included (59% male; 66 ± 11 years old); 337, 149, and 114 were assigned to G1, G2, and G3, respectively. Acute procedural success was recorded in 99.7% of patients. Procedural and fluoroscopy time were comparable but the radiation dose was significantly higher in G3. Procedural complications were 3% in G1, 5.4% in G2, and 8.8% in G3 (p = .01). The overall freedom from AF after 1-year was 77%. G3 had a significantly worse 1-year success rate compared to G1 and G2 (G3: 66.5% vs. G1: 78.4%; p = .015 and vs. G2: 82.5%; p = .008) with reduced 1-year success in paroxysmal AF (G1: 84.0%; G2: 86.3%; and G3: 69.6%) but not in persistent AF (G1: 68.7%; G2: 77.4%; and G3: 62.1%). G3 showed similar success rates irrespective of AF form (PAF: 69.6% vs. persAF 62.1%; p = .501).Cryoballoon ablation in obese patients can be effective with an acceptable safety profile, 77% of patients were in stable SR at 1 year. Severe obese patients (BMI ≥ 35) showed reduced procedural safety and 1-year success rate. In association with life style modification, CB ablation may represent a strategy to enhance rhythm control in the context of obesity.

Resistance of tumor cells to cisplatin is a common feature frequently encountered during chemotherapy against melanoma caused by various known and unknown mechanisms. To overcome drug resistance toward cisplatin, a targeted treatment using alternative agents, such as proteasome inhibitors, has been investigated. This combination could offer a new therapeutic approach. Here, we report the biological effects of proteasome inhibitors on the parental cisplatin-sensitive MeWo human melanoma cell line and its cisplatin-resistant MeWocis1 variant. Our experiments show that proteasome inhibitor treatment of both cell lines impairs cell viability at concentrations that are not toxic to primary human fibroblasts in vitro. However, compared with the parental MeWo cell line, significantly higher concentrations of proteasome inhibitor are required to reduce cell viability of MeWocis1 cells. Moreover, whereas proteasome activity was inhibited to the same extent in both cell lines, IκBα degradation and nuclear factor-κB (NF-κB) activation in MeWocis1 cells was proteasome inhibitor independent but essentially calpain inhibitor sensitive. In support, a calpain-specific inhibitor impaired NF-κB activation in MeWocis1 cells. Here, we show that cisplatin resistance in MeWocis1 is accompanied by a change in the NF-κB activation pathway in favor of calpain-mediated IκBα degradation. Furthermore, combined exposure to proteasome and calpain inhibitor resulted in additive effects and a strongly reduced cell viability of MeWocis1 cells. Thus, combined strategies targeting distinct proteolytic pathways may help to overcome mechanisms of drug resistance in tumor cells. (Cancer Res 2006; 66(15): 7598-605)

Supplementary Figure 2 from Combined Effect of Proteasome and Calpain Inhibition on Cisplatin-Resistant Human Melanoma Cells

Supplementary Figure 1 from Combined Effect of Proteasome and Calpain Inhibition on Cisplatin-Resistant Human Melanoma Cells

BACKGROUND: Device-related thrombus (DRT) following left atrial appendage occlusion (LAAO) can lead to adverse clinical outcomes. DRT rates and outcomes from randomized trials are limited.OBJECTIVES: This analysis investigated the incidence, predictors, and clinical outcomes of DRT following LAAO in the Amulet IDE (AMPLATZER Amulet LAA Occluder Trial) trial.METHODS: Successful implants occurred in 903 patients with an Amulet occluder (dual occlusive mechanism device) and 885 patients with a Watchman device (single occlusive mechanism device). These patients were then followed through 18 months and DRT was assessed by transesophageal echocardiography.RESULTS: The overall incidence of DRT was 3.9% (n = 70) with 3.4% (n = 30) in dual occlusive mechanism device patients and 4.8% (n = 40) in single occlusive mechanism device patients. Most DRTs (n = 19 of 31) were identified early (≤45 days) on the dual occlusive mechanism device, whereas most of the DRTs (n = 31 of 42) were identified late (>45 days) on the single occlusive mechanism device. Strong predictors of DRT included atrial fibrillation at time of procedure (HR: 2.44; 95% CI: 1.42-4.22; P < 0.01), female sex (HR: 1.65; 95% CI: 1.01-2.71; P = 0.04), and older age (HR: 1.04; 95% CI: 1.01-1.08; P = 0.02). There were no stroke events following DRT in the dual occlusive mechanism device group and 3 stroke events following DRT in the single occlusive mechanism device group. Patients with DRT were at a greater risk for cardiovascular mortality compared with non-DRT patients (8.7% vs 3.9%; HR: 2.33; 95% CI: 1.01-5.39; P = 0.04).CONCLUSIONS: Incidence of DRT following LAAO was low. Early DRTs are seen with the dual occlusive mechanism device and late DRTs are seen with the single occlusive mechanism device. Increased cardiovascular mortality risk in patients with DRT should be further investigated. (AMPLATZER Amulet LAA Occluder Trial; NCT02879448).

Background The second- and third-generation endoscopic ablation systems (EAS2 and EAS3) have been launched in recent years. We aimed to assess the lesion durability as well as gap localization using the multigenerational novel technologies in patients with recurrent atrial fibrillation (AF). Methods Consecutive patients who underwent second ablation for recurrent AF following the initial pulmonary vein isolation (PVI) with EAS2 or EAS3 were retrospectively investigated. The persistent durability of PVI, gap localization at the second procedure, and procedural/anatomical features of durable PVI were analyzed. Results Among 225 patients treated with EAS3 (N = 125) and EAS2 (N = 100), 34 patients (EAS3: 13 patients, 50 PVs, EAS2: 21 patients, 82 PVs) underwent a second procedure because of recurrent AF mean 11.9 ± 9.3 months after the initial procedure. Persistent isolation of all four PVs was recorded in 6 (46.2%) patients in EAS3 group and 4 (19.1%) patients in EAS2 group (p = 0.130). Ninety-one out of 132 (68.9%) PVs were persistently isolated with a higher rate in EAS3 group (82.0% vs. EAS2 group: 61.0%, p = 0.0113). A total of 45 gaps were recorded in 41 PVs. Right superior PV (RSPV) was the predominantly common reconnected vein (15 gaps, 14 PVs) irrespective of generations (EAS3: 4 gaps in 3 PVs and EAS2: 12 gaps in 11 PVs). Logistic multivariate regression analysis revealed ablation without reduced energy dose (5.5–7 W) as an independent predictor of durable PVI [adjusted OR: 3.70, 95% CI (1.408–10.003)], p = 0.008]. Conclusion The technical innovation resulted in a higher lesion durability in EAS3-guided PVI in patients with recurrent AF. The most common gap location was found at RSPV in successor EASs. Ablation without reduced energy was a predictor of durable PVI in successor EASs.

Visually guided laser balloon (LB) catheter has been an established modality dedicated for pulmonary vein (PV) isolation in patients with atrial fibrillation. The newly updated version of this novel device has technically evolved recent years.This review will summarize the contemporary technical evolution of LB catheter. Available efficacy outcomes and the historical change of ablation style will be evaluated. Furthermore, the future perspectives for clinical practice are discussed.The initial LB ablation system provided comparable clinical results in PV isolation with other technologies, but with a unique strategical concept enabling the direct visualization of the tissue to cauterize. With multigenerational development, the LB catheter has been equipped with more compliant balloon for favorable PV occlusion and a robotically motor driven continuous ablation mode (RAPID mode). These technical innovations changed the concept of the ablation strategy using LB catheter as 'point-by-point' into 'single-shot' fashion. The remaining tasks are further improvements such as equipping with real-time recording system of intracardiac electrogram, durable structured balloon and the instrument for visualizing the cauterization area in a 360-degree panoramic view, which includes potential possibilities to develop this novel device to the more optimal device for PV isolation.

BACKGROUND: Major bleeding (MB) events are independent predictors of mortality after cardiac interventional procedures. The clinical relevance of MB following left atrial appendage occlusion (LAAO) remains unclear.AIMS: This study aimed to investigate the incidence and clinical impact of MB after LAAO in a real-world population at high risk for bleeding and contraindicated to anticoagulation.METHODS: The two-year results of the Amplatzer Amulet Observational Post-Market Study were analysed. An independent committee adjudicated MBs according to the Bleeding Academic Research Consortium scale. Cox proportional hazards regression identified variables associated with MB events and mortality.RESULTS: The MB rate was 7.2%/year, with a rate of 10.1%/year during year one, decreasing to 4.0%/year over year two. The most common bleeding location was gastrointestinal, accounting for 48% of MBs. Pre-LAAO MB was associated with an increased risk for post-LAAO MB (HR 2.34, 95% CI: 1.37-3.99). The occurrence of post-LAAO MB was associated with increased mortality (37.3% vs 12.7%; pCONCLUSIONS: In real-world patients at high bleeding risk, MB following LAAO was not uncommon and associated with a significant increase in mortality, without increasing the risk of stroke. ClinicalTrials.gov Identifier: NCT02447081. https://clinicaltrials.gov/ct2/show/NCT02447081.

Background Atrial fibrillation (AF) and chronic kidney disease (CKD) often coexist and share an increased risk of thromboembolic events. CKD concomitantly contributes to several pathophysiological changes predisposing towards a pro-haemorrhagic state. Objective To evaluate the impact of kidney function on peri-procedural complications and clinical outcomes in AF patients undergoing left atrial appendage occlusion (LAAO) with a Watchman device. Methods 2124 consecutive AF patients undergoing Watchman implantation at 8 different centers were categorized into CKD stage 1+2 (n=1089), CKD stage 3 (n=796), CKD stage 4 (n=170), CKD stage 5 (n=69) based on the estimated glomerular filtration rate at baseline. The primary efficacy endpoint included a composite of cardiovascular (CV) mortality, stroke, transient ischemic attack, peripheral thromboembolism (TE), and major bleeding. Results A non-significant higher incidence of major peri-procedural adverse events (1.7% vs. 2.3% vs. 4.1% vs. 4.3%) was observed with worsening baseline kidney function (p=0.14). The mean follow-up period was 13 ± 7 months [2226 patient-years (PY)]. In comparison to CKD stage 1+2 as a reference, the incidence of the primary endpoint was significantly higher in CKD stage 3 (log-rank p-value= 0.04), CKD stage 4 (log-rank p-value= 0.01), and CKD stage 5 (log-rank p-value= 0.001). A non-significant increase in event rates for stroke/TIA and clinically relevant bleeding was observed among the four groups. LAAO led to a TE risk reduction of 72%, 66%, 62%, and 41% in each group. The relative risk reduction in the incidence of major bleeding was 58%, 44%, 51%, and 52%, respectively. Conclusion Patients with moderate-to-severe CKD had a higher incidence of the primary composite endpoint. The relative risk reduction in the incidence of TE and major bleeding was consistent across CKD groups, irrespective of the very different risk profiles at baseline.

ZUSAMMENFASSUNGBedauerlicherweise existieren bisher keine randomisierten Studiendaten hinsichtlich des Stellenwerts eines Vorhofohrverschlusssystems (LAAC: „left atrial appendage closure“) im Vergleich zu oralen Antikoagulanzien (OAK) bei CKD-Patienten (CKD: „chronic kidney disease“). Eine derartige Studie (WATCH AFIB in CKD) wurde wegen geringer Rekrutierungszahlen eingestellt. Aus den im Beitrag angesprochenen Beobachtungsstudien kann allerdings eine gute Sicherheit und Effektivität der Therapie abgeleitet werden. In Anbetracht der unzureichenden Evidenz sollte bei VHF Patienten (VHF: Vorhofflimmern) mit CKD bis zu einer glomerulären Filtrationsrate (GFR) von 30 ml/min/1,73 m2 primär eine NOAK-Therapie (NOAK: neue OAK) verordnet werden. Im Falle von Blutungen kann dann gemäß Leitlinienempfehlung eine LAAC alternativ angeboten werden. Im Falle von Patienten mit dialysepflichtiger CKD muss eine individuelle Entscheidung getroffen werden, ob und wie eine Thromboembolieprophylaxe durchgeführt werden soll.

Aims Catheter ablation (CA) is recommended for patients with atrial fibrillation (AF) after failure of antiarrhythmic drugs (AADs). The role of CA as ‘initial therapy’ for AF is to be determined. Methods and results Following PRISMA guideline an up-to-date pooled analysis of randomized data comparing ablation vs. AADs as first-line therapy for symptomatic AF was performed. The primary outcome was recurrence of atrial tachyarrhythmia. The secondary outcomes were improvement in quality-of-life (QoL) and major adverse events. A total of 997 patients from five randomized trials were enrolled (mean age 57.4 years, 68.6% male patients, 98% paroxysmal AF, mean follow-up 1.4 years). The baseline characteristics were similar between the ablation and AADs group. Overall pooled analysis showed that, as compared with AADs, CA as first-line therapy was associated with significantly higher freedom from arrhythmia recurrence (69% vs. 48%, odds ratio: 0.36, 95% confidence interval: 0.27–0.48, P Conclusions Catheter ablation as ‘initial therapy’ was superior to AADs in maintenance of sinus rhythm and improving QoL for patients with symptomatic paroxysmal AF, without increasing risk of serious adverse events.

Background Pulsed field ablation (PFA) is a new feasible and safe method for the ablative treatment of cardiac arrhythmias, such as atrial fibrillation (AF). Through the use of electric fields, it causes pore-like openings in the cell’s wall, leading to cell death. The most appealing characteristic of this new technique is its selectivity for cardiomyocytes and consequently its low risk of collateral damage to extracardiac tissues. We present three cases of a PFA-induced transient phrenic nerve (PN) injury documented during pulmonary vein isolation (PVI). Case summaries Three patients aged 55–81 years underwent PFA for symptomatic AF. Cases 1 and 3 were affected by paroxysmal AF without evidence of structural heart disease. Case 2 had persistent AF and ischaemic cardiomyopathy with preserved ejection fraction. We observed a transient right hemidiaphragm palsy during the delivery of impulses in the right superior pulmonary vein (Cases 1 and 2) and in the right inferior pulmonary vein (Case 3). The palsy lasted Discussion Transient PN dysfunction can be observed following PFA in AF ablation. According to our initial experience, a full recovery of the PN function can be expected within seconds. We hypothesize a hyperpolarization of neuronal cells or a depletion of acetylcholine in the motoric endplate to explain this event. Further studies are required to understand the exact pathophysiological mechanism.

AimsPulsed-field ablation (PFA) can offer a novel perspective for atrial fibrillation (AF) ablation. We aimed to characterize the incidence of pulmonary vein (PV) reconnection, types of recurrent atrial tachyarrhythmia (ATa) and lesion quality after PFA-guided PV isolation (PVI).Methods and resultsPatients undergoing second ablation for recurrent ATa following the initial PVI using the pentaspline PFA catheter were investigated. The rate of PV reconnection, the features of recurrent ATa, and the amount of isolated posterior wall (PW) surface area (ISAPW%) (ratio of the isolated- to total surface area on PW) were analyzed.ResultsAmong 360 patients treated with PFA, 25 patients (paroxysmal AF, n = 19) with 99 PVs underwent a second procedure 6.1 ± 4.0 months after the initial procedure. The rate of PV reconnection was 9.1% (9 PVs). Patients presented with atrial tachycardia (AT) (n = 16), AF (n = 8) and typical atrial flutter (n = 1). The mechanism of all but one AT was macro-reentry. The critical isthmus was found to be linked to the initial lesion set at the left atrial (LA) PW in eight patients and linked to pre-existing substrate at the LA anterior wall in four patients. One AT had a focal origin at the septum. In three patients, AT were unmappable. Mean ISAPW% was 72.7 ± 19.0%.ConclusionWe revealed a remarkable low reconnection rate with a large antral lesion at the PW after pentaspline PFA catheter-guided PVI. However, macro-reentrant AT with a critical isthmus at the LAPW linked to the PVI lesion set was commonly observed.

Metabolic syndrome is defined by the simultaneous occurrence of the cardiovascular risk factors obesity, hypertension, diabetes and dyslipidemia. Overweight, in particular, is continuously increasing in many countries. In this respect, metabolic syndrome is a strong risk factor for atrial fibrillation. Only few data are available on the influence of obesity on antiarrhythmic drugs. Sodium channel blockers, in particular, appear to show a reduced effectiveness. Direct oral anticoagulants can be used for anticoagulation in obese patients. With a body weight 140 kg, a plasma level measurement is recommended. Severe overweight reduces the chances of successful ablation treatment and leads to more complications. Consistent treatment of the metabolic syndrome, and in particular weight reduction, can significantly improve the risk and the frequency of atrial fibrillation, the associated symptoms and the success of treatment for maintaining cardiac rhythm.Das metabolische Syndrom ist durch das gemeinsame Auftreten der kardiovaskulären Risikofaktoren Adipositas, Hypertonie, Diabetes und Fettstoffwechselstörung definiert. Insbesondere Übergewicht nimmt hierbei in vielen Ländern ständig zu. Das metabolische Syndrom ist dabei ein starker Risikofaktor für Vorhofflimmern. Für Antiarrhythmika liegen nur wenige Daten zum Einfluss von Übergewicht vor, hier scheinen insbesondere Natriumkanalblocker eine verminderte Wirksamkeit zu zeigen. Für die Antikoagulation bei Patienten mit Adipositas können direkte orale Antikoagulanzien (DOAK) eingesetzt werden. Bei einem Gewicht 140 kg wird eine Spiegelbestimmung empfohlen. Starkes Übergewicht vermindert die Erfolgsaussichten einer Ablationsbehandlung und führt zu mehr Komplikationen. Durch eine konsequente Behandlung des metabolischen Syndroms, und insbesondere eine Gewichtsreduktion, können das Risiko und die Häufigkeit von Vorhofflimmern, die assoziierte Symptomatik und die Erfolge einer rhythmuserhaltenden Therapie erheblich verbessert werden.

Aims Anticoagulation for atrial fibrillation patients with liver disease represents a clinical dilemma. We sought to evaluate the efficacy/safety of different anticoagulation, i.e. vitamin K antagonist (VKA) and non-VKA oral anticoagulants (NOACs) in such patient group. Methods and results This was a pooled-analysis enrolling up-to-date clinical data. Two subsets: subset A (VKA vs. Non-Anticoagulation) and subset B (NOACs vs. VKA) were pre-specified. The study outcomes were ischaemic stroke (IS)/thromboembolism (TE), major bleeding (MB), intracranial bleeding (ICB), gastrointestinal bleeding (GIB), and all-cause mortality. A total of 20 042 patients’ data were analysed (subset A: N = 10 275, subset B: N = 9767). Overall mean age: 71 ± 11 years, mean CHA2DS2-VASc score: 4.0 ± 1.8, mean HAS-BLED score: 3.6 ± 1.2. The majority of the patients had Child-Pugh category (A-B). As compared with Non-Anticoagulation, VKA seemed to reduce the risk of IS/TE [odds ratio (OR): 0.60, P = 0.05], but heighten the risk of all-bleeding events including MB (OR: 2.81, P = 0.01), ICB (OR: 1.60, P = 0.01), and GIB (OR: 3.32, P = 0.01). When compared with VKA, NOACs had similar efficacy in reducing the risk of IS/TE (OR: 0.82, P = 0.64), significantly lower risk of MB (OR: 0.54, P = 0.0003) and ICB (OR: 0.35, P Conclusions VKA appears to reduce the risk of IS/TE but increase all-bleeding events. NOACs have similar effect in reducing the risk of IS/TE and have significantly lower risk of MB and ICB as compared with VKA. NOACs seem to be associated with better clinical outcome than VKA in patients with mild–moderate liver disease.