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© 2020, The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare. Smac mimetics target inhibitor of apoptosis (IAP) proteins, thereby suppressing their function to facilitate tumor cell death. Here we have evaluated the efficacy of the preclinical Smac-mimetic compound A and the clinical lead birinapant on breast cancer cells. Both exhibited potent in vitro activity in triple-negative breast cancer (TNBC) cells, including those from patient-derived xenograft (PDX) models. Birinapant was further studied using in vivo PDX models of TNBC and estrogen receptor-positive (ER+) breast cancer. Birinapant exhibited single agent activity in all TNBC PDX models and augmented response to docetaxel, the latter through induction of TNF. Transcriptomic analysis of TCGA datasets revealed that genes encoding mediators of Smac-mimetic-induced cell death were expressed at higher levels in TNBC compared with ER+ breast cancer, resulting in a molecular signature associated with responsiveness to Smac mimetics. In addition, the cell death complex was preferentially formed in TNBCs versus ER+ cells in response to Smac mimetics. Taken together, our findings provide a rationale for prospectively selecting patients whose breast tumors contain a competent death receptor signaling pathway for the further evaluation of birinapant in the clinic.

Cardiac disease frequently has a degenerative effect on cardiac pump function and regional myocardial contraction. Therefore, an accurate assessment of regional wall motion is a measure of the extent and severity of the disease. We sought to further validate an intra-operative, sensor-based technology for measuring wall motion and strain by characterizing left ventricular (LV) mechanical and electrical activation patterns in patients with normal (NSF) and impaired systolic function (ISF). NSF (n = 10; ejection fraction = 62.9 ± 6.1%) and ISF (n = 18; ejection fraction = 35.1 ± 13.6%) patients underwent simultaneous electrical and motion mapping of the LV endocardium using electroanatomical mapping and navigational systems (EnSite™ NavX™ and MediGuide™, Abbott). Motion trajectories, strain profiles, and activation times were calculated over the six standard LV walls. NSF patients had significantly greater motion and systolic strains across all LV walls than ISF patients. LV walls with low-voltage areas showed less motion and systolic strain than walls with normal voltage. LV electrical dyssynchrony was significantly smaller in NSF and ISF patients with narrow-QRS complexes than ISF patients with wide-QRS complexes, but mechanical dyssynchrony was larger in all ISF patients than NSF patients. The latest mechanical activation was most often the lateral/posterior walls in NSF and wide-QRS ISF patients but varied in narrow-QRS ISF patients. This intra-operative technique can be used to characterize LV wall motion and strain in patients with impaired systolic function. This technique may be utilized clinically to provide individually tailored LV lead positioning at the region of latest mechanical activation for patients undergoing cardiac resynchronization therapy. URL: http://www.clinicaltrials.gov . Unique identifier: NCT01629160.

INTRODUCTION Template-matching algorithms are routinely used in the catheter ablation of patients with premature ventricular contractions (PVCs). However, systematic analysis of the accuracy and spatial resolution of such systems is lacking. Therefore, the aim of this evaluation was to perform a systematic in vivo validation of performance of a novel automated template-matching algorithm. METHODS AND RESULTS In a porcine model, paced beats simulating PVCs from different origins were investigated. The ability to discriminate between sinus rhythm and PVCs was tested by simulating PVCs using sequential pacing from different cardiac chambers. The accuracy of the algorithm in correctly classifying PVCs was reviewed by an independent investigator. In addition, the spatial resolution of pace matching was evaluated by assessing the QRS morphology discrimination at a distance of 0, 2, 4, and 6 mm of a simulated PVCs focus. The specificity of the algorithm for recognizing simulated PVCs was 99.6% and the sensitivity was 85.3%. There was a significant difference in the discrimination metric discrimination metric (with 0% being a perfect match and 100% being no correlation) between PVC origin (median 0%, interquartile range (IQR) 0-2%) versus at 2 mm (5%, IQR 2-7%), 4 mm (16%, IQR 11-21%), and 6 mm (24%, IQR 19-28%, P < 0.001 for all). The c-statistic for discrimination between PVC origin and a distance ≥ 2 mm was 0.93. CONCLUSIONS Automated template matching had high specificity and sensitivity, with good spatial discrimination and a pace-mapping resolution in range of 2 mm. Clinical application of this algorithm may assist in the interventional treatment of patients with PVCs.

Background Recently, a novel electroanatomic mapping system enabling rapid and automatic acquisition of high-resolution maps has been introduced. Previous reports focused on system use in combination with a mini-basket catheter. However, a novel system-specific, magnet-enabled ablation catheter eliminates the need for the mini-basket catheter and can potentially reduce procedure complexity and cost. Here we present our first experience from two consecutive case series using both procedural settings. Methods In 14 consecutive patients (67±9years, 5 male) with paroxysmal (n=10) or persistent AF (n=4) undergoing de-novo (n=8) or repeat (n=6) AF ablation, left atrial electroanatomical maps were acquired with a mini-basket and in 22 patients (64±9years, 17 male) with paroxysmal (n=4) or persistent AF (n=18) undergoing de-novo (n=12) or repeat (n=10) AF ablation with the new ablation catheter. Results Both complete (7.9 [IQR 4.5–16.2] vs 18.8 [IQR 12.0–25.5] minutes, p=0.005) and partial maps (3.0 [IQR 2.0–4.6] vs 4.5 [IQR 2.0–6.0] minutes, p=0.014) acquired with mini-basket required significantly shorter mapping time and had higher point density: 8832±4809 vs 4460±3914 (p=0.014) and 2483±1774 vs 1111±1926 data points (p=0.002) in partial maps. However, procedural (201±52 vs 159±29min, p=0.004) and fluoroscopy time (33±11 vs 25±6min, p=0.005) was significantly higher in the mini-basket group. Procedural endpoints and complications rates were similar in both groups. Conclusion The high-density mapping system can successfully be used with both mini-basket catheters and ablation catheters employed for electro-anatomic reconstruction of the left atrium. While mapping is faster and point density higher with the mini-basket, procedure and fluoroscopy times are longer. The clinical significance of those findings needs to be investigated in future and larger studies.

Background There remains a lack of consensus regarding the ideal ablation strategy for atrial fibrillation (AF), particularly in patients with persistent or longstanding persistent AF. Given increasing evidence from clinical imaging studies that rotors sustain AF, rotor elimination may be a desirable procedural endpoint. However, there is no description to date of the clinical outcomes using rotor elimination during ablation as the procedural endpoint. Moreover, a series of studies question whether procedural AF termination is a desirable endpoint for ablation after many forms of AF ablation. Methods and Results We report a single-center experience of rotor elimination during AF ablation using Focal Impulse and Rotor Mapping (FIRM), describing 20 consecutive patients with case descriptions of 3 patients with recurrent longstanding persistent AF after prior ablation. In all cases, endocardial mapping using a 64-electrode basket catheter was performed to identify rotors, which were eliminated using radiofrequency catheter ablation. After it was verified that all identified rotors were eliminated, standard ablation consisting of PV isolation was performed. Notably, persistent AF terminated in only 1/20 (5%) patients. However, after a follow-up of 6 months, single-procedure freedom from AF was 80% (16/20 patients) with only 1 patient on antiarrhythmic drugs. All three patients in the highlighted series are AF free despite the lack of acute procedural AF termination. Conclusions Patients with persistent AF including those with unsuccessful prior ablation can be treated successfully by rotor targeted ablation, using the elimination of all rotors rather than acute AF termination as the procedural endpoint.

Ultra High-Density Mapping of the Right Atria Introduction Recently, an automatic, high-resolution mapping system has been presented to accurately and quickly identify right atrial geometry and activation patterns in animals, but human data are lacking. This study aims to assess the clinical feasibility and accuracy of high-density electroanatomical mapping of various RA arrhythmias. Methods and Results Electroanatomical maps of the RA (35 partial and 24 complete) were created in 23 patients using a novel mini-basket catheter with 64 electrodes and automatic electrogram annotation. Median acquisition time was 6:43 minutes (0:39–23:05 minutes) with shorter times for partial (4.03 ± 4.13 minutes) than for complete maps (9.41 ± 4.92 minutes). During mapping 3,236 (710–16,306) data points were automatically annotated without manual correction. Maps obtained during sinus rhythm created geometry consistent with CT imaging and demonstrated activation originating at the middle to superior crista terminalis, while maps during CS pacing showed right atrial activation beginning at the infero-septal region. Activation patterns were consistent with cavotricuspid isthmus-dependent atrial flutter (n = 4), complex reentry tachycardia (n = 1), or ectopic atrial tachycardia (n = 2). His bundle and fractionated potentials in the slow pathway region were automatically detected in all patients. Ablation of the cavotricuspid isthmus (n = 9), the atrio-ventricular node (n = 2), atrial ectopy (n = 2), and the slow pathway (n = 3) was successfully and safely performed. Conclusions RA mapping with this automatic high-density mapping system is fast, feasible, and safe. It is possible to reproducibly identify propagation of atrial activation during sinus rhythm, various tachycardias, and also complex reentrant arrhythmias.

Aims Electrical cardioversion is one cornerstone for the rhythm control strategy of atrial fibrillation (AF), which is, however, hampered by immediate AF recurrence (IRAF) or failed electrical cardioversion (FECV). We aimed to investigate the potential role of vernakalant for facilitated electrical cardioversion in cardioversion-resistant AF. Methods and results The subjects of this study were 63 patients referred to the Heart Centre Leipzig between November 2011 and May 2014 for transthoracic electrical cardioversion of AF. All patients experienced after antiarrhythmic-naïve electrical cardioversion either IRAF (n = 44; 70%) or FECV (n = 19; 30%). After drug infusion, electrical cardioversion was successful in 66.7% of vernakalant-treated as opposed to 46.7% of amiodarone-treated patients (P = 0.109). Multivariate analysis revealed treatment with vernakalant (OR 0.057, 95% CI 0.006–0.540, P = 0.013), treatment with ACEI or ARB (OR 0.101, 95% CI 0.015–0.691 P = 0.019), and IRAF after initial CV (OR 0.047, 95% CI 0.004–0.498, P = 0.011) as predictors for successful, drug-facilitated electrical cardioversion. Subgroup analysis of 18 patients with previous AF ablation revealed a significantly higher success rate of electrical cardioversion after infusion of vernakalant than after infusion of amiodarone (66.7 vs. 11.1%, P = 0.016). Conclusion Vernakalant may therefore be considered as a useful agent for facilitated electrical cardioversion in cardioversion-resistant AF.

Template-matching algorithms are routinely used in the catheter ablation of patients with premature ventricular contractions (PVCs). However, systematic analysis of the accuracy and spatial resolution of such systems is lacking. Therefore, the aim of this evaluation was to perform a systematic in vivo validation of performance of a novel automated template-matching algorithm.In a porcine model, paced beats simulating PVCs from different origins were investigated. The ability to discriminate between sinus rhythm and PVCs was tested by simulating PVCs using sequential pacing from different cardiac chambers. The accuracy of the algorithm in correctly classifying PVCs was reviewed by an independent investigator. In addition, the spatial resolution of pace matching was evaluated by assessing the QRS morphology discrimination at a distance of 0, 2, 4, and 6 mm of a simulated PVCs focus. The specificity of the algorithm for recognizing simulated PVCs was 99.6% and the sensitivity was 85.3%. There was a significant difference in the discrimination metric discrimination metric (with 0% being a perfect match and 100% being no correlation) between PVC origin (median 0%, interquartile range (IQR) 0-2%) versus at 2 mm (5%, IQR 2-7%), 4 mm (16%, IQR 11-21%), and 6 mm (24%, IQR 19-28%, P0.001 for all). The c-statistic for discrimination between PVC origin and a distance ≥ 2 mm was 0.93.Automated template matching had high specificity and sensitivity, with good spatial discrimination and a pace-mapping resolution in range of 2 mm. Clinical application of this algorithm may assist in the interventional treatment of patients with PVCs.

Background— Cardiac tamponade is the most dramatic complication observed during atrial fibrillation (AF) ablation and the leading cause of procedure-related mortality. Female sex is a known risk factor for complications during AF ablation; however, it is unknown whether women have a higher risk of tamponade. Methods and Results— A systematic Medline search was used to locate academic electrophysiological centers that reported cases of tamponade occurring during AF ablation. Centers were asked to provide information on cases of acute tamponade according to sex and their mode of management including any case of related mortality. Nineteen electrophysiological centers provided information on 34 943 ablation procedures involving 25 261 (72%) men. Overall, 289 (0.9%) cases of tamponade were reported: 120 (1.24%) in women and 169 (0.67%) in men (odds ratio, 1.83; P Conclusions— Tamponade during AF ablation procedures is relatively rare. Women have an ≈2-fold higher risk for developing this complication. The risk of tamponade among women decreases substantially in high-volume centers. Surgical backup and acute management skills for treating tamponade are important in centers performing AF ablation.

Background— Cardiac resynchronization therapy (CRT) device implantation can be challenging, time consuming, and fluoroscopy intense. To facilitate left ventricular lead placement, a novel sensor-based electromagnetic tracking system (MediGuide Technology [MGT], St. Jude Medical) has been developed. We report the results of the First Human Use study evaluating the feasibility, safety, and performance of a novel CRT implantation approach using electromagnetic trackable operation equipment. Methods and Results— Fifteen consecutive patients (66±8 years, 53% male) with an established indication for CRT were implanted using the new tracking technology. Demographics, anatomical information, detailed fluoroscopy need, procedure time, and adverse events were collected. Patients were followed up for 4 weeks after implantation. The CRT system was successfully implanted with a lateral or posterolateral left ventricular lead position in all patients. The total procedure time was 116±43 minutes, the median total fluoroscopy time (skin to skin) was 5.2 (Q1–Q3, 3.0–8.4) minutes, and the median fluoroscopy time for left ventricular lead deployment (coronary sinus [CS] cannulation to withdrawal of CS sheath) measured 2.6 (Q1–Q3, 1.6–5.6) minutes. There were no severe complications that required an acute intervention or reoperation during the perioperative and postoperative periods. Conclusions— Use of the MGT tracking technology allows for safe and successful CRT implantation with the potential for reduced fluoroscopy time. Future randomized studies are needed to validate these data. Clinical Trial Registration— URL http://www.clinicaltrials.gov . Unique identifier: NCT01519739.

Background The MediGuide technology (MGT) represents a novel sensor-based electromagnetic 4-dimensional (4D) navigation system allowing real-time catheter tracking in the environment of prerecorded X-ray loops. Objective To report on our clinical experience in atrial fibrillation (AF) ablation with recently available MGT-enabled ablation catheters. Methods The MGT was used in addition to a conventional 3D mapping system in 80 patients with AF (age 61 ± 10 years; 47 men; 40 with persistent AF), who underwent circumferential pulmonary vein isolation and voltage mapping with and without substrate modification. Short native right anterior oblique/left anterior oblique loops were used as background movies for the nonfluoroscopic placement of sensor-equipped diagnostic catheters into the coronary sinus and the right ventricle. After single transseptal puncture, selective angiograms of the pulmonary veins were used as background movies for near nonfluoroscopic left atrial reconstruction. Computed tomography registration as well as mapping/ablation was performed by using the new open-irrigated MGT-enabled ablation catheter. Results MGT application was not associated with a change in established workflow. Large parts of the procedure (mean entire duration 167 ± 47 minutes) could be done without additional fluoroscopy, whereas median residual fluoroscopy duration of 4.6 (interquartile range: 2.9, 7.1) minutes was mainly used for the acquisition of background loops, transseptal puncture, occasional verification of transseptal sheath position, and manipulation of the circular mapping catheter. Three (4%) minor complications occurred. Conclusions The MGT integrates easily into the workflow of standard AF ablation and allows for high-quality nonfluoroscopic 4D catheter tracking. This results in low radiation exposure for patients and staff without complicating the workflow of the procedure.

Background— Esophageal perforations are a rare but devastating complication of atrial fibrillation catheter ablation. Rapid treatment is crucial to avoid permanent disabilities and death. Surgical treatment is considered the treatment of choice. Alternatively, single case reports describe successful esophageal stenting, but others discourage this approach because of fatal consequences. Methods and Results— We present 3 patients who developed esophagopericardial fistulas after radiofrequency catheter ablation of atrial fibrillation. Diagnosis and management with pericardial drainage and esophageal stenting, as well as long-term follow-up are described. Esophagopericardial fistulas occurred 26, 9, and 18 days after the ablation procedure. Symptoms leading to admission were recurrence of atrial fibrillation (n=1), elective control endoscopy for thermal lesion (n=1), and pain with swallowing (n=1). Computed tomography revealed esophagopericardial fistulas with pericardial effusion in all patients, while contrast leakage and air in the left atrium could be excluded. Broad-spectrum antibiotics were initialized, and minimally invasive pericardial drainage and esophageal stenting were performed. Stent dislocation occurred in 2 patients and was resolved by repositioning and clipping of the proximal stent end. After 45, 22, and 28 days, respectively, fistulas appeared closed and stents were removed. During follow-up, no embolic or septic events occurred. However, 2 patients underwent dilation of symptomatic esophageal stenosis in the formerly stented region. Conclusions— An early minimally invasive approach consisting of pericardial drainage and esophageal stenting proved effective in treating patients with esophagopericardial fistulas. However, constant interdisciplinary communication and attention is needed to recognize and manage potential evolving complications promptly.

Dronedarone is a novel class III antiarrhythmic drug with moderate efficacy in preventing atrial arrhythmias. However, only few data from the real-world use of dronedarone with limited electrocardiographic monitoring are available. The investigators report the incidence, timing, and reasons for discontinuation of dronedarone; maintenance of sinus rhythm; and atrial arrhythmia recurrence patterns in 120 consecutive patients with atrial fibrillation (AF; n = 91) or non-isthmus-dependent atrial flutter (n = 29) treated with dronedarone (400 mg twice daily). Rhythm control was assessed with serial 7-day Holter electrocardiography after 4 weeks and after 6 to 9 months. After drug initiation, dronedarone was discontinued in 19 patients (16%) because of inefficacy (n = 7 [6%]) or adverse events (n = 12 [10%]). At 4 weeks, 44 patients (37%) had stopped taking dronedarone because of inefficacy (n = 27 [23%]) or adverse events (n = 17 [14%]). After 6 to 9 months, 25 patients (21%) had discontinued dronedarone because of clinical inefficacy (n = 16 [13%]) or adverse events (n = 9 [8%]). Overall, dronedarone was still used after 6 to 9 months in 32 patients (27%). Maintenance of sinus rhythm was achieved in 40 patients (33%) after 4 weeks and in 24 patients (20%) after 6 to 9 months. Reversal from persistent to paroxysmal arrhythmias was observed in 23 patients, (29%) whereas progression from paroxysmal to persistent arrhythmias occurred in 6 patients (15%). Conversion from AF to non-isthmus-dependent atrial flutter was noted in 10 patients (13%). In conclusion, dronedarone is associated with frequent adverse events and moderate antiarrhythmic efficacy requiring discontinuation in most patients within the first 9 months of use, and there is a prevalent reversal from persistent to paroxysmal but also from paroxysmal to persistent atrial arrhythmias and from AF to non-isthmus-dependent atrial flutter.

Background— We describe a novel fluoroscopy coregistered, 4-dimensional catheter tracking technology (MediGuide Technology [MGT]) used for treatment of patients with atrial fibrillation. The aim of the study was to investigate (1) the feasibility of nonfluoroscopic catheter manipulation within dynamic left atrial chamber models; (2) the integration of the technology into an established electroanatomical mapping system; and (3) potential clinical impact. Methods and Results— Forty-nine patients received atrial fibrillation ablation using MGT-enabled NavX-EnSite. Matched patients ablated with a conventional NavX-EnSite system served as a control group. MGT was used for the deployment of diagnostic catheters within preacquired cine loops, for nonfluoroscopic chamber mapping within dynamic angiograms, and for 4-dimensional tagging of anatomical landmarks. Integration with the electroanatomical mapping system allowed correction of field distortions and a reference tool to detect and correct map shifts. Catheter ablation was done without MGT because the ablation catheter was not MGT enabled. MGT worked safely and stably in all 49 patients. Catheter deployment within the preacquired cine loops was successfully performed in 45 of 49 (92%) patients. Catheter tracking within dynamic left atrial angiograms allowed nearly nonfluoroscopic creation of NavX-EnSite geometries with subsequent computed tomography model registration in all 49 patients. Overall, MGT significantly reduced total procedural fluoroscopy time (median [quartiles]) from 31 minutes (25, 43 minutes) to 16 minutes (10, 23 minutes) and irradiation dose from 14 453±7403 to 7363±5827 cGy*cm 2 (mean±SD), respectively ( P Conclusions— MGT is a tracking technology that allows 4-dimensional visualization of dedicated catheters within moving chamber models. Integration of the MGT with an established electroanatomical mapping system provided algorithms to facilitate mapping in the electroanatomical mapping system environment. As a first measurable clinical impact, MGT was able to reduce fluoroscopy exposure by nearly 50%.

Recently, an automatic, high-resolution mapping system has been presented to accurately and quickly identify right atrial geometry and activation patterns in animals, but human data are lacking. This study aims to assess the clinical feasibility and accuracy of high-density electroanatomical mapping of various RA arrhythmias.Electroanatomical maps of the RA (35 partial and 24 complete) were created in 23 patients using a novel mini-basket catheter with 64 electrodes and automatic electrogram annotation. Median acquisition time was 6:43 minutes (0:39-23:05 minutes) with shorter times for partial (4.03 ± 4.13 minutes) than for complete maps (9.41 ± 4.92 minutes). During mapping 3,236 (710-16,306) data points were automatically annotated without manual correction. Maps obtained during sinus rhythm created geometry consistent with CT imaging and demonstrated activation originating at the middle to superior crista terminalis, while maps during CS pacing showed right atrial activation beginning at the infero-septal region. Activation patterns were consistent with cavotricuspid isthmus-dependent atrial flutter (n = 4), complex reentry tachycardia (n = 1), or ectopic atrial tachycardia (n = 2). His bundle and fractionated potentials in the slow pathway region were automatically detected in all patients. Ablation of the cavotricuspid isthmus (n = 9), the atrio-ventricular node (n = 2), atrial ectopy (n = 2), and the slow pathway (n = 3) was successfully and safely performed.RA mapping with this automatic high-density mapping system is fast, feasible, and safe. It is possible to reproducibly identify propagation of atrial activation during sinus rhythm, various tachycardias, and also complex reentrant arrhythmias.

Introduction: The porcine model is generally accepted for the development and testing of new forms oftherapy including ablation of atrial fibrillation (AF). However, the challenging left atrial (LA) and pulmonary vein (PV) anatomy enables only limited percutaneous catheter-based PV access. Results: Here we present I) an alternative percutaneous transapical access, which enables easy and safe retrograde transmitral LA and PV mapping and ablation; II) early experience of LA mapping and successful circumferential PV isolation with novel mapping system (RhythmiaTM) and new generation of ablation catheter equipped with micro electrodes (IntellaTip MiFi). Conclusion: Although the experience with the transapical approach is limited, the initial results are promising as this may offer an alternative approach for tasting new technologies and translational research.

Aims Although sinus node modification by catheter ablation is an established therapy for the treatment of inappropriate sinus tachycardia, there is incomplete understanding of sinus node anatomy and function but also limited electroanatomical mapping data. Recently, an automatic, ultra high-resolution mapping system has been presented to accurately and quickly identify right atrial (RA) geometry and activation patterns but detailed assessment of sinus node activation has not been performed which was one aim of this study. Preclinical experiences are compared with previous sinus node mapping studies in animals and humans, and potential clinical implications for catheter ablation are discussed. Methods and results In anaesthetized and ventilated 14 pigs, 30 endocardial and 2 eipcardial RA maps were generated using the Rhythmia™ mapping system without complications and earliest activation sites (EAS) and sinus break-out (SBO) were determined. At baseline, EAS and SBO were located anterior to the middle ( n = 6) or lower third ( n = 8) of the crista terminalis exhibiting a unicentric activation pattern in all cases. Conduction pathways were directed anterior, posterior, superior, or inferior with substantial inter-individual variation in direction, pathway distance, and conduction time. Orciprenaline, propranolol, or amiodarone shifted endocardial activation with considerable variation between animals with inconsistent patterns. Multicentric activation was found in one case after orciprenaline infusion. Sequential endocardial and epicardial high-density mapping of the RA was performed in two animals and showed a high congruence of the sinus node activation in the endo- and the epicardial map. Conclusion Ultra high-density mapping allows fast, simple, and very detailed assessment of sinus node activation. Future studies are clearly needed to evaluate novel mapping and ablation strategies for an improved understanding of sinus node disease and better outcomes.

Invasive electrophysiology is a rapidly developing field of cardiovascular science with a constant need for inventions and testing of new technologies and concepts. Despite the swine model being an established tool in biomedical research no comprehensive guide for interventional electrophysiologists exists. The aim of the current article is to provide a practical overview of the pig anatomy, fluoroscopic views, and corresponding high density electroanatomic maps using a novel mapping system and a practical guide for interventions and techniques. In 17 pigs, fluoroscopic images of the right atrium, coronary sinus (CS), left atrium, and pulmonary veins as well as the right and left ventricles were obtained and correlated with ultra-high density electroanatomic maps and gross anatomy. Pitfalls of the porcine anatomy are precisely addressed, and alternative access techniques to overcome those issues are suggested. Important differences to human electrophysiological studies are highlighted. Complementary models such as cardiac ischemia induction or renal and pulmonary artery denervation are discussed in detail.

Aims Reduction of radiation exposure using a sensor-based non-fluoroscopic catheter tracking (NFCT) system (MediGuide™, St Jude Medical, Inc.) was recently demonstrated by retrospective comparisons. We aimed to prospectively compare the effects of using NFCT vs. standard fluoroscopy on procedural parameters in patients undergoing radiofrequency ablation of typical atrial flutter. Methods and Results We prospectively randomized 40 patients undergoing cavotricuspid isthmus ablation for typical atrial flutter to either NFCT ( n = 20) or conventional fluoroscopy (CONV, n = 20). Procedural parameters such as fluoroscopy time, radiation dose, and procedure duration, as well as periprocedural complications were compared. There were no statistically significant differences in baseline characteristics between the two groups. Bidirectional isthmus block was achieved in all patients. Fluoroscopy time was significantly reduced in the NFCT group {0.3 \[inter-quartile range (IQR) 0.2; 0.48] min} when compared with CONV [5.7 (IQR 4.2; 11.5) min\] ( P < 0.001). This resulted in a significant reduction in radiation dose in patients randomized to NFCT [17.4 (IQR 11; 206.6) cGy cm2] vs. the CONV group [418.4 (IQR 277; 812.2) cGy cm2] ( P < 0.001). There were no significant differences in procedure duration between the NFCT group \[49.5 (IQR 37; 65) min] when compared with the CONV group [33.5 (IQR 26.3; 55.5) min\] ( P = 0.053). No adverse events were recorded. Freedom from atrial flutter at 6 months of follow-up was 19/20 (95%) in the NFCT and 18/20 (90%) in the CONV group (n.s.). Conclusion In this first prospective randomized study, by comparing NFCT with standard fluoroscopy in patients undergoing radiofrequency ablation of typical atrial flutter, NFCT significantly reduced both radiation dose and fluoroscopy time with no effects on procedural duration. These findings support the incorporation of NFCT in routine clinical use.

Aims Experiences with novel oral anticoagulants (NOACs) early after atrial fibrillation (AF) catheter ablation are limited and show controversial results. We aimed to assess the longer-term safety, efficacy, and acceptance of NOACs in a large real-world cohort of patients presenting for AF catheter ablation. Methods and results From July 2010 until June 2012, 259 patients undergoing AF catheter ablation were prospectively included. Novel oral anticoagulants were given for at least 3 months post-ablation. Clinical outcome (stroke, thromboembolic events, major bleeding), adverse effects, and drug adherence were assessed at discharge and follow-up. On admission patients were presented with a variety of anticoagulants including 54 patients (21%) already on NOACs prior ablation. After ablation 38% of patients received dabigatran 110 mg, 56% 150 mg, and 6% received rivaroxaban 20 mg. There were four periprocedural thromboembolic and major bleeding complications (1.5%), all in patients without NOACs prior ablation (two on warfarin and two on heparin). During long-term follow-up [311 (199; 418) days] no stroke, systemic embolism, or major haemorrhage could be observed. Uneventful electrical cardioversions and reablation procedures were performed in 27 and 12 patients on dabigatran, respectively. Novel oral anticoagulants were prematurely stopped or switched to another anticoagulant due to side effects or at the preference of the treating general practitioner in 9 and 10 patients, respectively. Conclusion In this prospective observational study, anticoagulation with NOACs following AF catheter ablation was safe and effective at long-term follow-up. Fast onset of action makes NOACs especially attractive in patients without effective anticoagulation on admission and in patients following periprocedural complications.

Magnetic resonance imaging (MRI) has evolved as a standard cardiac imaging technique. Interventional procedures guided by real-time MRI may derive potential benefit from a fluoroscopy-free working environment, more detailed insights into the target anatomy, and additional information on organ tissue properties relevant for pathomorphology as well as therapy delivery. Electrophysiological (EP) procedures in a magnetic resonance (MR) scanner require new workflows with different, MR safe, interventional materials and hardware setup, different approaches to intracardiac orientation and catheter tracking, and an adapted patient management. Recently, invasive diagnostic EP procedures have been described in animal studies and in a clinical setting.1,2 Actual catheter ablation has so far only been reported in a limited number of animal series.3 Hereby, we report on a MRI-guided cavotricuspid isthmus ablation. A 74-year-old man without structural heart disease was admitted with documented episodes of paroxysmal symptomatic typical right atrial flutter. At the ablation procedure the patient presented in sinus rhythm. The patient was enrolled into a clinical study approved by the local ethics committee and by the German Federal Institute for Drugs and Medical Devices (BfArM). He provided written and verbal informed consent. In this study, we used MR conditional catheters (Vision, Imricor Medical Systems, Burnsville, MN) and an MR conditional EP recording system (Bridge MR EP Recording System, Imricor Medical Systems, Burnsville, MN). The material is designed for use in 1.5 T closed bore scanners and imposes no limitations on the catheter trajectory, scanner landmark, or patient position. The catheter allows for all clinical scan protocols and is safe for use in normal and first level controlled operating modes. ### MR Conditional Catheters Although the appearance and functionality are similar to conventional ablation catheters, the design of the MR conditional catheter differs substantially. All ferromagnetic materials are removed to eliminate the potential for force and torque …

Current guidelines for the management of atrial fibrillation (AF) recommend dronedarone for the prevention of recurring AF [1]. Especially in patients with structural heart disease, e.g. hypertension with left ventricular hypertrophy, dronedarone is a welcome alternative to amiodarone due to its favorable safety profile. However, the antiarrhythmic efficacy of dronedarone is lower than that of amiodarone as exemplified in the DIONYSOS trial [2]. This observation is supported by experimental studies showing much weaker atrial electrophysiologic effects and anti-AF efficacy of dronedarone compared with amiodarone in a canine AF model [3]. However, there is a lack of studies investigating specific antiarrhythmic effects of amiodarone and dronedarone in human AF that are, moreover, restricted to in-vitro experiments of human atrial myocytes [4]. Consequently, we applied time–frequency analysis to the surface ECG for determination of atrial fibrillatory rate (AFR) as a measure of atrial refractoriness for in-vivo monitoring of amiodarone and dronedarone effects in patients with persistent AF. In patients with persistent AFN7 days but b1 year, 2-minute 12 lead ECG recordings were made at baseline and after 3 days of antiarrhythmic drug treatment with all subjects relaxed in a supine position after a 5-minute equilibration period. Dronedarone (2×400 mg/day) or amiodarone (1,200 mg/day loading dose) was initiated prior to external electrical cardioversion on an inpatient basis under continuous electrocardiographic monitoring. All patients were adequately anticoagulated using either oral anticoagulation therapy with an international normalized ratio between 2 and 3 or weight-adapted low molecular weight heparin following exclusion of left atrial thrombus formation by transesophageal echocardiography. Twenty-one consecutive patients treated with dronedarone were prospectively included in our AF registry and matched for age and genderwith 20patientswhowere treatedwith amiodarone. The clinical characteristics of the study population are summarized in Table 1 and showed no difference between the two groups. All patients provided informed consent for study participation, i.e. acquisition and analysis of baseline and on-treatment ECG for evaluation of drug effects. Time–frequency analysis was performed a posteriori on ECG lead V1 as described previously (Fig. 1) [5]. Briefly, after analog-to-digital conversion (1,000 Hz, 12 bit, 0.05–300 Hz) and high-pass filtering to remove baseline wander, QRST complexes were subtracted using spatiotemporal QRST cancelation (Fig. 1, top). One frequency estimate of the atrial signal was obtained every second from overlapping 2.5-second windows by short-term Fourier transform (segment-wise Fast Fourier transform). Thus, this instantaneous signal was represented in a spectral profile. Subsequently, the frequency of the atrial signal was trended as a function of time and mean atrial frequency determined. Frequencies were converted to AFR with its unit fibrillations per minute (fpm; AFR=frequency∗60). All continuous variables are presented as mean±one standard deviation. ECG parameters before and after drug administration were compared using Student's t-test for paired data. Differences in ECG parameter changes between dronedarone and amiodarone were evaluated using t-test for unpaired data. A p valueb .05 was considered statistically significant. The authors of this manuscript certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology. At baseline, mean AFR measured 396±44 fpm in the dronedarone group, comparable to 410±32 fpm in the amiodarone group. AFR was reduced by 25±23 fpm with dronedarone (pb .001 for on-treatment vs. baseline) and by 70±29 fpm with amiodarone (pb .001 for on-treatment vs. baseline). The amiodarone-induced AFR reduction was significantly higher than the AFR reduction with dronedarone (pb .001 for amiodarone vs. dronedarone; Fig. 2, left). Ventricular rate at baseline showed no difference between the dronedarone and the amiodarone group. Both drugs slowed ventricular rate significantly; dronedarone by 18±19 beats per minute (bpm, pb .001 for on-treatment vs. baseline) and amiodarone by 9±12 bpm, (p=.002 for on-treatment vs. baseline). There was a trend for greater magnitude of ventricular rate slowingwith dronedarone comparedwith amiodarone (p=.086; Fig. 2, right). Class I and III antiarrhythmic drugs have been shown to increase atrial cycle length (decrease AFR) which coincides with increased refractoriness and decreased conduction velocity [6]. Previous studies [5,7–9] have subsequently demonstrated a substantial AFR

AB Purpose: The study's purpose was to assess the effectiveness of a short-duration three-times-weekly high-load resistive exercise program on preventing deterioration in neuromuscular function after prolonged bed rest. Methods: Twenty-four male subjects performed high-load resistive exercise (n = 8), high-load resistive exercise with whole-body vibration (n = 9), or no exercise (control, n = 9) during 60-d head-down tilt bed rest as part of the 2nd Berlin Bed Rest Study. Peak countermovement jump power and height, sit-to-stand performance, sprint time over 15 and 30 m, and leg press one-repetition maximum were measured before and after bed rest. Results: The exercise interventions were capable of ameliorating losses of peak countermovement jump power (P < 0.001) and height (P < 0.001), deterioration of sit-to-stand time from 45-cm (P = 0.034) and 30-cm (P < 0.001) sitting positions, increases of 15-m (P = 0.037) and 30-m (P = 0.005) sprint time, and losses of leg press one-repetition maximum (P < 0.001). Conclusions: The short-duration (6-min time under tension per training session) exercise countermeasure program performed three times a week was capable of reducing the effect of prolonged bed rest on many neuromuscular function measures. (C)2012The American College of Sports Medicine

Background Galectin-3 (Gal-3) is an emerging biomarker in heart failure that is involved in fibrosis and inflammation. However, its potential value as a prognostic marker in atrial fibrillation (AF) is unknown. The aim of this study was to assess the impact of AF catheter ablation on Gal-3 and evaluate its prognostic impact for predicting rhythm outcome after catheter ablation. Methods Gal-3 was measured at baseline and after 6 months using specific ELISA. AF recurrences were defined as any atrial arrhythmia lasting longer than 30 sec within 6 months after ablation. Results In 105 AF patients (65% males, age 62±9 years, 52% paroxysmal AF) undergoing catheter ablation, Gal-3 was measured at baseline and after 6 months and compared with an AF-free control cohort (n=14, 50 % males, age 58±11 years). Gal-3 was higher in AF patients compared with AF-free controls (7.8±2.9 vs. 5.8±1.8, ng/mL, p=0.013). However, on multivariable analysis, BMI (p=0.007) but not AF (p=0.068) was associated with Gal-3. In the AF cohort, on univariable analysis higher Gal-3 levels were associated with female gender (p=0.028), higher BMI (p=0.005) and both CHADS2 (p=0.008) and CHA2DS2-VASC (p=0.016) scores, however, on multivariable analysis only BMI remained significantly associated with baseline Gal-3 (p=0.016). Gal-3 was similar 6 months after AF catheter ablation and was not associated with sinus rhythm maintenance. Conclusions Although galectin-3 levels are higher in AF patients, this is driven by cardiometabolic co-morbidities and not heart rhythm. Gal-3 is not useful for predicting rhythm outcome of catheter ablation.

Background: Currently fluoroscopy-based catheter visualization is the standard modality in invasive electrophysiological procedures. Since May 2012 a new technology for non-fluoroscopic visualization of diagnostic and ablation catheters is available. The MediGuide®-system projects the catheter tips on prerecorded cine loops in a high time resolution; it has been introduced as real time 4D tracking. Methods: We report on MediGuide®-based SVT cases (AVRT; AVRT; WPW, EAT and typical atrial flutter) from 2 European centers. In all patients diagnostic and/or ablation catheters with a special sensor were used to perform the ablation procedures. All procedural data such as acute success, duration of the procedure, fluoroscopy time and –dose and patients' characteristics were analyzed. Procedure-related complications during the hospital stay were revealed. Results: A total of 23 patients were analyzed. Those patients were predominantly male (65%), aged 58±14 years and were ablated with the MediGuide® system for 6 AVNRT (26%), 4 AVRT/WPW (17%), 1 EAT (4%) and 13 typical atrial flutter (57%). The acute success rate was 100%. The median fluoroscopy time was 0,5±1,4min, the median fluoroscopy dose was 200±561cGy cm2. Mean procedure time was 74,6±25min. No complications during the hospital stay were recorded. ![Figure][1] Figure 1. MediGuide Conclusion: In different forms of supraventricular tachycardias the MediGuide® contributed to a dramatic reduction in irradiation exposure. At a median fluoroscopy time of 30s all SVT cases were effectively performed with no complications; the fluoroscopy burden can significantly be reduced not only for the patient but also for the nurses and the physicians. The overall procedure times are not prolonged due to the application of the MediGuide® system. [1]: pending:yes

Background: Cardiac resynchronization therapy (CRT) device implantation can be challenging, time consuming and fluoroscopy intense. To facilitate left ventricular (LV) lead placement, a novel sensor-based electromagnetic tracking system (MediGuide [MG], St. Jude Medical) has been developed. Purpose: To report the results of the First Human Use (FHU) study evaluating the feasibility, safety, and performance of a novel CRT implantation approach using MG-enabled operation equipment. Methods: Fifteen consecutive patients (66±8 years, 53% male) with an established indication for CRT were implanted using the MG tracking technology. Demographics, anatomical information, detailed fluoroscopy need, procedure time, and adverse events were collected. Patients were followed for 4 weeks after implantation. Results: The CRT system was successfully implanted with a lateral or posterolateral LV lead position in all patients. The total procedure time was 116±43 minutes, the median total fluoroscopy time (skin to skin) 5.2 (IQR 3.0 - 8.4) minutes, and the median fluoroscopy time for LV lead deployment (CS cannulation to withdrawl of CS sheath) measured 2.6 (IQR 1.6 - 5.6) minutes. There were no severe complications that required an acute intervention or re-operation during the peri- and postoperative period. ![Figure][1] Conclusions: Use of the MG tracking technology allows for safe and successful CRT implantation with an indication for substantially reduced fluoroscopy time. Future randomized studies are needed to validate these data. [1]: pending:yes

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

XIAP prevents apoptosis by binding to and inhibiting caspases, and this inhibition can be relieved by IAP antagonists, such as Smac/DIABLO. IAP antagonist compounds (IACs) have therefore been designed to inhibit XIAP to kill tumor cells. Because XIAP inhibits postmitochondrial caspases, caspase 8 inhibitors should not block killing by IACs. Instead, we show that apoptosis caused by an IAC is blocked by the caspase 8 inhibitor crmA and that IAP antagonists activate NF-kappaB signaling via inhibtion of cIAP1. In sensitive tumor lines, IAP antagonist induced NF-kappaB-stimulated production of TNFalpha that killed cells in an autocrine fashion. Inhibition of NF-kappaB reduced TNFalpha production, and blocking NF-kappaB activation or TNFalpha allowed tumor cells to survive IAC-induced apoptosis. Cells treated with an IAC, or those in which cIAP1 was deleted, became sensitive to apoptosis induced by exogenous TNFalpha, suggesting novel uses of these compounds in treating cancer.

Cellular inhibitor of apoptosis (cIAP) proteins, cIAP1 and cIAP2, are important regulators of tumor necrosis factor (TNF) superfamily (SF) signaling and are amplified in a number of tumor types. They are targeted by IAP antagonist compounds that are undergoing clinical trials. IAP antagonist compounds trigger cIAP autoubiquitylation and degradation. The TNFSF member TWEAK induces lysosomal degradation of TRAF2 and cIAPs, leading to elevated NIK levels and activation of non-canonical NF-kappaB. To investigate the role of the ubiquitin ligase RING domain of cIAP1 in these pathways, we used cIAP-deleted cells reconstituted with cIAP1 point mutants designed to interfere with the ability of the RING to dimerize or to interact with E2 enzymes. We show that RING dimerization and E2 binding are required for IAP antagonists to induce cIAP1 degradation and protect cells from TNF-induced cell death. The RING functions of cIAP1 are required for full TNF-induced activation of NF-kappaB, however, delayed activation of NF-kappaB still occurs in cIAP1 and -2 double knock-out cells. The RING functions of cIAP1 are also required to prevent constitutive activation of non-canonical NF-kappaB by targeting NIK for proteasomal degradation. However, in cIAP double knock-out cells TWEAK was still able to increase NIK levels demonstrating that NIK can be regulated by cIAP-independent pathways. Finally we show that, unlike IAP antagonists, TWEAK was able to induce degradation of cIAP1 RING mutants. These results emphasize the critical importance of the RING of cIAP1 in many signaling scenarios, but also demonstrate that in some pathways RING functions are not required.

SHARPIN regulates immune signaling and contributes to full transcriptional activity and prevention of cell death in response to TNF in vitro. The inactivating mouse Sharpin cpdm mutation causes TNF-dependent multi-organ inflammation, characterized by dermatitis, liver inflammation, splenomegaly, and loss of Peyer's patches. TNF-dependent cell death has been proposed to cause the inflammatory phenotype and consistent with this we show Tnfr1, but not Tnfr2, deficiency suppresses the phenotype (and it does so more efficiently than Il1r1 loss). TNFR1-induced apoptosis can proceed through caspase-8 and BID, but reduction in or loss of these players generally did not suppress inflammation, although Casp8 heterozygosity significantly delayed dermatitis. Ripk3 or Mlkl deficiency partially ameliorated the multi-organ phenotype, and combined Ripk3 deletion and Casp8 heterozygosity almost completely suppressed it, even restoring Peyer's patches. Unexpectedly, Sharpin, Ripk3 and Casp8 triple deficiency caused perinatal lethality. These results provide unexpected insights into the developmental importance of SHARPIN. DOI: http://dx.doi.org/10.7554/eLife.03464.001, eLife digest In response to an injury or infection, areas of the body can become inflamed as the immune system attempts to repair the damage and/or destroy any microbes or toxins that have entered the body. At the level of individual cells inflammation can involve cells being programmed to die in one of two ways: apoptosis and necroptosis. Apoptosis is a highly controlled process during which the contents of the cell are safely destroyed in order to prevent damage to surrounding cells. Necroptosis, on the other hand, is not controlled: the cell bursts and releases its contents into the surroundings. Inflammation is activated by a protein called TNFR1, which is controlled by a complex that includes a protein called SHARPIN. Mice that lack the SHARPIN protein develop inflammation on the skin and internal organs, even in the absence of injury or infection. However, it is not clear how SHARPIN controls TNFR1 to prevent inflammation. Rickard et al. and, independently Kumari et al. have now studied this process in detail. Rickard et al. cross bred mice that lack SHARPIN with mice lacking other proteins involved in inflammation and cell death. The experiments show that apoptosis is the main form of cell death in skin inflammation, but necroptosis has a bigger role in the inflammation of internal organs. Mice that lack both the apoptotic and necroptotic cell-death pathways can develop relatively normally, but they die shortly after birth if they also lack SHARPIN. Experiments on these mice could help us to understand how SHARPIN works. DOI: http://dx.doi.org/10.7554/eLife.03464.002

The regulation of metal ion transport within neurons is critical for normal brain function. Of particular importance is the regulation of redox metals such as iron (Fe), where excess levels can contribute to oxidative stress and protein aggregation, leading to neuronal death. The divalent metal transporter 1 (DMT1) plays a central role in the regulation of Fe as well as other metals; hence, failure of DMT1 regulation is linked to human brain pathology. However, it remains unclear how DMT1 is regulated in the brain. Here, we show that DMT1 is regulated by Ndfip1 (Nedd4 family-interacting protein 1), an adaptor protein that recruits E3 ligases to ubiquitinate target proteins. Using human neurons we show the Ndfip1 is upregulated and binds to DMT1 in response to Fe and cobalt (Co) exposure. This interaction results in the ubiquitination and degradation of DMT1, resulting in reduced metal entry. Induction of Ndfip1 expression protects neurons from metal toxicity, and removal of Ndfip1 by shRNAi results in hypersensitivity to metals. We identify Nedd4–2 as an E3 ligase recruited by Ndfip1 for the ubiquitination of DMT1 within human neurons. Comparison of brains from Ndfip1 −/− with Ndfip1 +/+ mice exposed to Fe reveals that Ndfip1 −/− brains accumulate Fe within neurons. Together, this evidence suggests a critical role for Ndfip1 in regulating metal transport in human neurons.

The ability to remove unwanted proteins is an important cellular feature. Classically, this involves the enzymatic addition of ubiquitin moieties followed by degradation in the proteasome. Nedd4 proteins are ubiquitin ligases important not only for protein degradation, but also for protein trafficking. Nedd4 proteins can bind to target proteins either by themselves or through adaptor protein Ndfip1 (Nedd4 family-interacting protein 1). An alternative mechanism for protein removal and trafficking is provided by exosomes, which are small vesicles (50-90-nm diameter) originating from late endosomes and multivesicular bodies (MVBs). Exosomes provide a rapid means of shedding obsolete proteins and also for cell to cell communication. In the present work, we show that Ndfip1 is detectable in exosomes secreted from transfected cells and also from primary neurons. Compared with control, Ndfip1 increases exosome secretion from transfected cells. Furthermore, while Nedd4, Nedd4-2, and Itch are normally absent from exosomes, expression of Ndfip1 results in recruitment of all three Nedd4 proteins into exosomes. Together, these results suggest that Ndfip1 is important for protein trafficking via exosomes, and provides a mechanism for cargoing passenger proteins such as Nedd4 family proteins. Given the positive roles of Ndfip1/Nedd4 in improving neuronal survival during brain injury, it is possible that exosome secretion provides a novel route for rapid sequestration and removal of proteins during stress.

Synthetic inhibitor of apoptosis (IAP) antagonists induce degradation of IAP proteins such as cellular IAP1 (cIAP1), activate nuclear factor kappaB (NF-kappaB) signaling, and sensitize cells to tumor necrosis factor alpha (TNFalpha). The physiological relevance of these discoveries to cIAP1 function remains undetermined. We show that upon ligand binding, the TNF superfamily receptor FN14 recruits a cIAP1-Tnf receptor-associated factor 2 (TRAF2) complex. Unlike IAP antagonists that cause rapid proteasomal degradation of cIAP1, signaling by FN14 promotes the lysosomal degradation of cIAP1-TRAF2 in a cIAP1-dependent manner. TNF-like weak inducer of apoptosis (TWEAK)/FN14 signaling nevertheless promotes the same noncanonical NF-kappaB signaling elicited by IAP antagonists and, in sensitive cells, the same autocrine TNFalpha-induced death occurs. TWEAK-induced loss of the cIAP1-TRAF2 complex sensitizes immortalized and minimally passaged tumor cells to TNFalpha-induced death, whereas primary cells remain resistant. Conversely, cIAP1-TRAF2 complex overexpression limits FN14 signaling and protects tumor cells from TWEAK-induced TNFalpha sensitization. Lysosomal degradation of cIAP1-TRAF2 by TWEAK/FN14 therefore critically alters the balance of life/death signals emanating from TNF-R1 in immortalized cells.