Blood tumor mutational burden and response to pembrolizumab plus chemotherapy in non-small cell lung cancer: KEYNOTE-782.

BACKGROUND: First-line pembrolizumab plus chemotherapy has shown clinical benefit in patients with metastatic non-small cell lung cancer (NSCLC) regardless of tissue tumor mutational burden (tTMB) status. Blood tumor mutational burden (bTMB), assessed using plasma-derived circulating tumor DNA (ctDNA), may be a surrogate for tTMB. The KEYNOTE-782 study evaluated the correlation of bTMB with the efficacy of first-line pembrolizumab plus chemotherapy in NSCLC. METHODS: Previously untreated patients with stage IV nonsquamous NSCLC received pembrolizumab 200 mg plus pemetrexed 500 mg/m2 and investigator's choice of carboplatin area under the curve 5 mg/mL/min or cisplatin 75 mg/m2 for 4 cycles, then pembrolizumab plus pemetrexed for ≤31 additional cycles every 3 weeks. Study objectives were to evaluate the association of baseline bTMB with objective response rate (ORR) (RECIST v1.1 by investigator assessment; primary), progression-free survival (PFS; RECIST v1.1 by investigator assessment), overall survival (OS), and adverse events (AEs; all secondary). A next-generation sequencing assay (GRAIL LLC) with a ctDNA panel that included lung cancer-associated and immune gene targets was used to measure bTMB. RESULTS: 117 patients were enrolled; median time from first dose to data cutoff was 19.3 months (range, 1.0-35.5). ORR was 40.2 % (95 % CI 31.2-49.6 %), median PFS was 7.2 months (95 % CI 5.6-9.8) and median OS was 18.1 months (95 % CI 13.5-25.6). Treatment-related AEs occurred in 113 patients (96.6 %; grade 3-5, n = 56 [47.9 %]). Of patients with evaluable bTMB (n = 101), the area under the receiver operating characteristics curve for continuous bTMB to discriminate response was 0.47 (95 % CI 0.36-0.59). Baseline bTMB was not associated with PFS or OS (posterior probabilities of positive association: 16.8 % and 7.8 %, respectively). CONCLUSIONS: AEs were consistent with the established safety profile of first-line pembrolizumab plus chemotherapy in NSCLC. Baseline bTMB did not show evidence of an association with efficacy.

Key performance indicators and leg positioning for the kick-start in competitive swimmers.

The aim of the study was to (1) assess the test-retest reliability of a novel performance analysis system for swimming (KiSwim) including an instrumented starting block and optical motion capture system, (2) identify key performance indicators (KPI) for the kick-start, (3) determine the most beneficial position of the strong leg and (4) investigate the effect of acute reversal of leg positioning. During three sessions, kick-starts of 15 competitive swimmers were investigated. Eighteen kinematic and kinetic parameters showed high reliability (ICC>0.75) from which principal component analysis identified seven KPI (i.e., time to 15 m, time on-block, depth at 7.5 m, horizontal take-off velocity, horizontal impulse back plate, horizontal peak force back plate and vertical peak force front plate). For the preferred start position, the back plate showed a higher horizontal peak force (0.71 vs. 0.96 x body mass; p < 0.001) and impulse (0.191 vs. 0.28Ns/BW; p < 0.001) compared to front plate. Acute reversal of the leg position reduced performance (i.e., increased time to 15 m and reduced horizontal take-off velocity). However, plate-specific kinetic analysis revealed a larger horizontal peak force (p < 0.001) and impulse (p < 0.001) for the back compared to the front plate in any start position investigated. Therefore, swimmers are encouraged to position the strong leg in the back.

Three-dimensional intracardiac echocardiography for left atrial appendage sizing and percutaneous occlusion guidance.

AIMS: Left atrial appendage (LAA) imaging is critical during percutaneous occlusion procedures. 3D-intracardiac echocardiography (ICE) features direct visualization of LAA from multiple cross-sectional planes at a time. We aimed at reporting procedural success of 3D-ICE-guided LAA occlusion and the correlation between pre-procedural transoesophageal echocardiography (TEE) and intraprocedural 3D-ICE for LAA sizing. METHODS AND RESULTS: Among 274 patients undergoing left atrial appendage occlusion (LAAO) with a Watchman FLX, periprocedural ICE guidance was achieved via a commercially available 2D-ICE catheter (220 patients) or a novel (NUVISION™) 3D-ICE one (54 patients). Primary endpoint was a composite of procedural success and LAA sealing at follow-up TEE. Secondary endpoint was a composite of periprocedural device recapture/resizing plus presence of leaks ≥ 3 mm at follow-up TEE. 3D-ICE measurements of maximum landing zone correlated highly with pre-procedural TEE reference values [Pearson's: 0.94; P < 0.001; bias: -0.06 (-2.39, 2.27)]. The agreement between 3D-ICE-based device selection and final device size was 96.3% vs. 79.1% with 2D-ICE (P = 0.005). The incidence of the primary endpoint was 98.1% with 3D-ICE and 97.3% with 2D-ICE (P = 0.99). 2D-ICE patients had a trend towards a higher incidence of periprocedural device recapture/redeployment (31.5% vs. 44.5%; P = 0.09). The secondary endpoint occurred in 31.5% of 3D-ICE patients vs. 45.9% of 2D-ICE ones (P = 0.065). CONCLUSION: Intracardiac echocardiography-guided LAAO showed a very high success, with no major adverse events. A very high level of agreement for LAA sizing was found between pre-procedural TEE and periprocedural 3D-ICE. 3D-ICE performed significantly better than 2D-ICE for FLX size selection and may provide better guidance during device deployment.

Safety/Efficacy of DOAC Versus Aspirin for Reduction of Risk of Cerebrovascular Events Following VT Ablation.

OBJECTIVES: The STROKE-VT (Safety and Efficacy of Direct Oral Anticoagulant Versus Aspirin for Reduction of Risk of Cerebrovascular Events in Patients Undergoing Ventricular Tachycardia Ablation) study is a multicenter, randomized controlled trial that examined the differences in cerebrovascular events between direct oral anticoagulant (DOAC) and aspirin (ASA) use postprocedurally in patients who underwent left ventricular arrhythmia (LVA) ablation (ventricular tachycardia [VT] or premature ventricular contraction [PVC]) using radiofrequency ablation (RFA). BACKGROUND: There exists limited data regarding antiplatelet or anticoagulation strategy following LVA ablation. METHODS: A total of 246 patients scheduled for LVA-RFA were randomized 1:1 postprocedurally to receive DOACs or ASA. The study's primary endpoint was the incidence of stroke or transient ischemic attack (TIA) or asymptomatic cerebrovascular events (ACEs) detected by magnetic resonance imaging at 24 hours and 30 days of follow-up. The secondary endpoints included procedure-related complications (composite of any vascular complication, pericardial complication, heart block, and thromboembolic event, excluding stroke or TIA) and in-hospital mortality. RESULTS: There were no differences between groups regarding baseline and ablation characteristics (except the percentage of patients who underwent VT ablation, rate of amiodarone use, and total RFA time). Postprocedure cerebrovascular events (stroke and TIA) were lower in the DOAC arm versus the ASA arm (0% vs 6.5%; P < 0.001 and 4.9% vs. 18%; P < 0.001, respectively). Patients in the ASA group had more MRI-detected ACEs compared with the DOAC group both at 24-hour (23% vs 12%; P = 0.03) and 30-day (18% vs 6.5%; P = 0.006) follow-up. Acute procedure-related complications and in-hospital mortality were similar between the 2 groups. CONCLUSIONS: DOAC use following endocardial and/or epicardial ablation for LVA-RFA was associated with reduced risk of TIA or stroke and asymptomatic MRI-detected cerebrovascular events.

Clinical presentation, diagnosis, and treatment of atrioesophageal fistula resulting from atrial fibrillation ablation.

BACKGROUND: Atrioesophageal fistula (AEF) is a worrisome complication of atrial fibrillation (AF) ablation. Its clinical manifestations and time course are unpredictable and may contribute to diagnostic and treatment delays. We conducted a systematic review of all available cases of AEF, aiming at characterizing clinical presentation, time course, diagnostic pitfalls, and outcomes. METHODS: The digital search retrieved 150 studies containing 257 cases, 238 (92.6%) of which with a confirmed diagnosis of AEF and 19 (7.4%) of pericardioesophageal fistula. RESULTS: The median time from ablation to symptom onset was 21 days (interquartile range [IQR]: 11-28). Neurological abnormalities were documented in 75% of patients. Compared to patients seen by a specialist, those evaluated at a walk-in clinic or community hospital had a significantly greater delay between symptom onset and hospital admission (median: 2.5 day [IQR: 1-8] vs. 1 day [IQR: 1-5); p = .03). Overall, 198 patients underwent a chest scan (computed tomography [CT]: 192 patients and magnetic resonance imaging [MRI]: 6 patients), 48 (24.2%; 46 CT and 2 MRI) of whom had normal/unremarkable findings. Time from hospital admission to diagnostic confirmation was significantly longer in patients with a first normal/unremarkable chest scan (p < .001). Overall mortality rate was 59.3% and 26.0% survivors had residual neurological deficits at the time of discharge. CONCLUSIONS: Since healthcare professionals of any specialty might be involved in treating AEF patients, awareness of the clinical manifestations, diagnostic pitfalls, and time course, as well as an early contact with the treating electrophysiologist for a coordinated interdisciplinary medical effort, are pivotal to prevent diagnostic delays and reduce mortality.

Catheter ablation of ventricular tachycardia in ischemic cardiomyopathy: Impact of concomitant amiodarone therapy on short- and long-term clinical outcomes.

BACKGROUND: Substrate catheter ablation of scar-related ventricular tachycardia (VT) is a widely accepted therapeutic option for patients with ischemic cardiomyopathy (ICM). OBJECTIVE: The purpose of this study was to investigate whether concomitant amiodarone therapy affects procedural outcomes. METHODS: A total of 134 consecutive patients (89% male; age 66 ± 10 years) with ICM undergoing catheter ablation of VT were included in the study. Patients were sorted by amiodarone therapy before ablation. In all patients, a substrate-based catheter ablation (endocardial ± epicardial) in sinus rhythm abolishing all "abnormal" electrograms within the scar was performed. The endpoint of the procedure was VT noninducibility. After the ablation procedure, all antiarrhythmic medications were discontinued. All patients had an implantable cardioverter-defibrillator, and recurrences were analyzed through the device. RESULTS: In 84 patients (63%), the ablation was performed on amiodarone; the remaining 50 patients (37%) were off amiodarone. Patients had comparable baseline characteristics. Mean scar size area was 143.6 ± 44.9 cm2 on amiodarone vs 139.2 ± 36.8 cm2 off amiodarone (P = .56). More radiofrequency time was necessary to achieve noninducibility in the off-amiodarone group compared to the on-amiodarone group (68.1 ± 20.1 minutes vs 51.5 ± 19.7 minutes; P <.001). In addition, due to persistent VT inducibility, more patients in the off-amiodarone group required epicardial ablation than in the on-amiodarone group (13/50 [26%] vs 5/84 [6%], respectively; P <.001). During mean follow-up of 23.9 ± 11.6 months, recurrence of any ventricular arrhythmias off antiarrhythmic drugs was 44% (37/84) in the on-amiodarone group vs 22% (11/50) in the off-amiodarone group (P = .013). CONCLUSION: Albeit, VT noninducibility after substrate catheter ablation for scar related VT was achieved faster, with less radiofrequency time and less need for epicardial ablation in patients taking amiodarone, these patients had significantly higher VT recurrence at long-term follow-up when this medication was discontinued.

Competition-Based Success Factors During the Talent Pathway of Elite Male Swimmers.

Marginal differences in race results between top swimmers have evoked the interest in competition-based success factors of long-term athlete development. To identify novel factors for the multi-dimensional model of talent development, the aim of the study was to investigate annual variation in competition performance (ACV), number of races per year, and age. Therefore, 45,398 race results of all male participants (n = 353) competing in individual events, i.e., butterfly, backstroke, breaststroke, freestyle, and individual medley, at the 2018 European Long-Course Swimming Championships (2018EC) were analyzed retrospectively for all 10 years prior to the championships with Pearson's correlation coefficient and multiple linear regression analysis. Higher ranked swimmers at the 2018EC showed significant medium correlations with a greater number of races per year and small but significant correlations with higher ACV in 10 and nine consecutive years, respectively, prior to the championships. Additionally, better swimmers were older than their lower ranked peers (r = -0.21, p < 0.001). Regression model explained a significant proportion of 2018EC ranking for 50 m (47%), 100 m (45%), 200 m (31%), and 400 m races (29%) but not for 800 and 1,500 m races with number of races having the largest effect followed by age and ACV. In conclusion, higher performance variation with results off the personal best in some races did not impair success at the season's main event and young competitors at international championships may benefit from success chances that increase with age. The higher number of races swum per year throughout the career of higher ranked swimmers may have provided learning opportunities and specific adaptations. Future studies should quantify these success factors in a multi-dimensional talent development model.

Long-Term Outcomes of Left Atrial Appendage Electrical Isolation in Patients With Nonparoxysmal Atrial Fibrillation: A Propensity Score-Matched Analysis.

BACKGROUND: Left atrial appendage electrical isolation (LAAEI) has been proposed for the treatment of nonparoxysmal atrial fibrillation (AF). The long-term clinical outcomes of this approach remain unclear. The objective of our study was to investigate the incremental benefit and safety of LAAEI in patients undergoing catheter ablation for nonparoxysmal AF. METHODS: Propensity score-matched analysis was performed using a prospective registry database from 2010 to 2014. All patients in the LAAEI group were matched based on baseline characteristics, echocardiographic parameters, and procedural ablation techniques. RESULTS: We identified 1842 patients who underwent catheter ablation for nonparoxysmal AF. Propensity score matching yielded 1092 patients, 546 patients with LAAEI, and 546 patients without LAAEI. At 5-year follow-up, overall freedom from all-atrial arrhythmia recurrence, off-antiarrhythmic drugs, in patients who underwent LAAEI was 68.9% versus 50.2% in those who underwent standard ablation alone (P<0.001). Acute complication rates were similar between groups (LAAEI 1.3% versus non-LAAEI 0.73%, P=0.36). At 5-year follow-up, 382 (70%) patients in the LAAEI group remained on oral anticoagulation versus 217 (39.7%) in the non-LAAEI group. At 5-year follow-up, thromboembolic events occurred in 15/546 (2.75%) in the LAAEI group and 4/546 (0.73%) in the non-LAAEI group (P=0.01). No thromboembolic events occurred in either group on-oral anticoagulation. In patients who were off-oral anticoagulation, at 5-year follow-up, thromboembolic events occurred in 15/164 (9.1%) in the LAAEI group and 4/329 (1.2%) in the non-LAAEI group (P<0.001). CONCLUSIONS: At 5-year follow-up, LAAEI was associated with significantly higher freedom from all-atrial arrhythmia recurrence in patients with persistent and long-standing persistent AF without increasing acute procedural complication rate. In patients off-oral anticoagulation, there appears to be a higher risk of thromboembolic events in the LAAEI group.

Epicardial Ablation Complications.

The percutaneous epicardial approach has become an adjunctive tool for electrophysiologists to treat disparate cardiac arrhythmias, including accessory pathways, atrial tachycardia, and particularly ventricular tachycardia. This novel technique prompted a strong impulse to perform epicardial access as an alternative strategy for pacing and defibrillation, left atrial appendage exclusion, heart failure with preserved ejection fraction, and genetically engineered tissue delivery. However, because of the incremental risk of major complications compared with stand-alone endocardial ablation, it is still practiced in a limited number of highly experienced centers across the world.

Is transesophageal echocardiography necessary in patients undergoing ablation of atrial fibrillation on an uninterrupted direct oral anticoagulant regimen? Results from a prospective multicenter registry.

BACKGROUND: Thromboembolic stroke is a rare but devastating consequence of atrial fibrillation (AF) ablation. Transesophageal echocardiography (TEE) is recommended to rule out left atrial appendage thrombus; however, its use is variable. OBJECTIVE: The purpose of this study was to assess whether TEE is mandatory in patients undergoing AF ablation on uninterrupted direct oral anticoagulants (DOACs). METHODS: Data from our prospective multicenter registry of patients with AF undergoing radiofrequency catheter ablation on uninterrupted DOACs were analyzed. All the included patients were on anticoagulation for at least 4 weeks before ablation. All AF ablation procedures were performed under intracardiac echocardiography guidance. Before transseptal puncture, heparin bolus was administered, followed by continuous infusion, with a target activated clotting time of >300 seconds. RESULTS: A total of 6186 patients (3180 on apixaban [51.4%], 2528 on rivaroxaban [40.9%], 404 on dabigatran [6.5%], and 74 on edoxaban [1.2%]) were analyzed. The mean age of the study population was 69.4 ± 10.3 years; 4194 patients (67.8%) were male, and 5120 patients (82.8%) had persistent and long-standing persistent AF. The mean CHA2DS2-VASc score was 2.86 ± 1.58; the mean CHADS2 score was 1.65 ± 1.14. Intracardiac echocardiography ruled out left atrial appendage and left atrial thrombi in all patients and revealed "smoke" in 1672 patients (27.03%). Transient ischemic attack was noted in 1 patient with long-standing persistent AF in the setting of a missed dose of rivaroxaban before ablation. CONCLUSION: Our study showed that performing AF ablation in patients on uninterrupted DOACs without TEE is safe and feasible in high stroke risk patients. Elimination of routine preablation TEE would have significant economic and clinical implications.

Epicardial Interventions: Impact of Liposomal Bupivacaine on Postprocedural Management (The EPI-LIBRE Study).

BACKGROUND: Electrophysiological procedures such as epicardial ventricular tachycardia ablation and Lariat left atrial appendage ligation that involve the epicardial space are typically associated with significant postoperative pain due to mechanical irritation and associated inflammation. There is an unmet need for an effective pain management strategy in this group of patients. We studied how this impacts patient comfort and duration of hospitalization and other associated comorbidities related to pericardial access. METHODS: This is a multicenter retrospective study including 104 patients who underwent epicardial ventricular tachycardia ablation and Lariat left atrial appendage exclusion. We compared 53 patients who received postprocedural intrapericardial liposomal bupivacaine (LB)+oral colchicine (LB group) and 51 patients who received colchicine alone (non-LB group) between January 2015 and March 2018. RESULTS: LB was associated with significant lowering of median pain scale at 6 hours (1.0 [0-2.0] versus 8.0 [6.0-8.0], P<0.001), 12 hours (1.0 [1.0-2.0] versus 6.0 [5.0-6.0], P<0.001), and up to 48 hours postprocedure. Incidence of acute severe pericarditis delayed pericardial effusion and gastrointestinal adverse effects were similar in both groups. Median length of stay was significantly lower in LB group (2.0 versus 3.0; adjusted linear coefficient -1 [CI -1.3 to -0.6], P<0.001). Subgroup analysis demonstrated similar favorable outcomes in both Lariat and epicardial ventricular tachycardia ablation groups. CONCLUSIONS: Addition of intrapericardial postprocedural LB to oral colchicine in patients undergoing epicardial access during ventricular tachycardia ablation or Lariat procedure is associated with significantly decreased numeric pain score up to 48 hours compared with colchicine alone. It is also associated with significantly shorter length of hospital stay without an increase in the risk of adverse events.

Analysis of Freestyle Swimming Sprint Start Performance After Maximal Strength or Vertical Jump Training in Competitive Female and Male Junior Swimmers.

Born, DP, Stöggl, T, Petrov, A, Burkhardt, D, Lüthy, F, and Romann, M. Analysis of freestyle swimming sprint start performance after maximal strength or vertical jump training in competitive female and male junior swimmers. J Strength Cond Res 34(2): 323-331, 2020-To investigate the freestyle swimming sprint start performance before and after 6 weeks of maximal strength compared with vertical jump training. With a between-group repeated-measure design, 21 junior swimmers (12 female and 9 male) competing in national and international championships performed 2 weekly sessions of either maximal strength (heavy-loaded back squat and deadlift exercise) or vertical jump training (unloaded box jumps) for 6 weeks during the precompetition phase of the seasonal main event. Session ratings of perceived exertion were used to compare the load of both training programs. Before and after the training period, sprint start performance was investigated on a starting block equipped with force plates synchronized to a 2-dimensional motion capture system. Total training load did not differ between the 2 groups. Sprint start performance and most kinematic and kinetic parameters remained unaffected. In pooled data of the U17 swimmers, however, 5-m, 15-m, and 25-m split times were improved with maximal strength (p = 0.02, 0.03, and 0.01), but not with vertical jump training (p = 0.12, 0.16, and 0.28). Although there was no global effect, focus on the subgroup of U17 swimmers showed an improved sprint start performance with 2 sessions of maximal strength training integrated into a 16-hour training week. Although outcomes of the conditioning program seemed to be affected by the training history and performance level of the athletes involved, strength and conditioning coaches are encouraged to introduce maximal strength training at a young age.

Outcomes of Catheter Ablation in Arrhythmogenic Right Ventricular Cardiomyopathy Without Background Implantable Cardioverter Defibrillator Therapy: A Multicenter International Ventricular Tachycardia Registry.

OBJECTIVES: This study sought to determine the long-term outcomes of catheter ablation (CA) of ventricular tachycardia (VT) in a series of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) without background implantable cardioverter-defibrillator (ICD) therapy. BACKGROUND: Endo-epicardial CA of VT has been demonstrated to be highly effective in reducing recurrent VT in patients with ARVC. METHODS: Thirty-two patients (age 45 ± 13 years, 72% male) with ARVC and VT underwent CA in the absence of ICD therapy. ICD was recommended in all cases, but implantation was not performed due to patient refusal (63%) or financial hardship (37%). CA was guided by activation/entrainment mapping for mappable VT and pace mapping/targeting of abnormal substrate in cases of unmappable VT. RESULTS: Symptoms associated with clinical VT included palpitations (78%), chest pain and shortness of breath (22%), pre-syncope (16%), and syncope (13%). Prior to ablation, 22 patients (69%) failed a mean of 1.3 ± 0.5 antiarrhythmic drugs. Epicardial mapping and ablation was performed as first-line strategy (20 [63%]) or in case of recurrent VT or persistent inducibility after endocardial-only ablation (3 [9%]-surgical epicardial cryoablation in 1 patient). After a mean of 1.6 (range 1 to 3) procedures, all patients demonstrated noninducibility of sustained VT from at least 2 RV sites; 75% also had stimulation on isoproterenol with no inducible VT. At a median follow-up of 46 months (range 26 to 65 months) following the last ablation, no deaths were observed and freedom from recurrent VT was 81%. CONCLUSIONS: In this multicenter international registry of patients with ARVC and VT, CA performed in the absence of background ICD was associated with a low rate of symptomatic VT recurrence (19%) without mortality during 46-month median follow-up. These data suggest that further prospective studies may refine selection of patients with structural heart disease at low risk for SCD, possibly obviating the benefit of ICD therapy.

Thromboembolic events and need for anticoagulation therapy following left atrial appendage occlusion in patients with electrical isolation of the appendage.

INTRODUCTION: Electrical isolation of the left atrial appendage (LAA) is an important adjunctive ablation strategy in patients with nonparoxysmal atrial fibrillation (AF). Patients who have impaired LAA contractility following isolation may require long-term oral anticoagulant (OAC) therapy irrespective of their CHADS2 -VASc score. Percutaneous LAA occlusion (LAAO) is a potential alternative to life-long OAC therapy. We aimed to assess the rate of OAC discontinuation and thromboembolic (TE) events following percutaneous LAAO in patients who underwent LAA electrical isolation (LAAI). METHODS: This is a retrospective two-center study of patients who underwent percutaneous LAAO following LAAI. Patients with at least 3-month follow-up were included in the study. The antithrombotic therapy and TE events at the time of the last follow-up were noted. RESULTS: The LAA was successfully occluded in 162 (with Watchman device in 140 [86.4%] and Lariat in 22 [13.6%]). A total of 32 patients had leaks detected on the 45-day transesophageal echocardiogram (TEE); 21 (15%) Watchman and 11 (50%) Lariat cases (P = 0.0001). Two (one Watchman and one Lariat) of the 32 leaks were more than 5 mm. After the 45-day TEE, 150 (92.6%) patients were off-OAC. No TE events were reported in the 150 patients who stopped the anticoagulants. Four (2.47%) patients experienced stroke following the LAAO (three Watchman and one Lariat) procedure while on-OAC, two of which were fatal. At the median follow-up of 18.5 months, 159 (98.15%) patients were off-anticoagulant. CONCLUSION: Up to 98% of patients with LAAI could safely discontinue OAC after undergoing the appendage closure procedure.

Arrhythmogenecity and thrombogenicity of the residual left atrial appendage stump following surgical exclusion of the appendage in patients with atrial fibrillation.

INTRODUCTION: It is common to find residual stump after the amputation or clip exclusion of the left atrial appendage (LAA). We evaluated the arrhythmogenic and thrombogenic potential of LAA stumps in atrial fibrillation (AF) patients. METHODS: Consecutive patients undergoing catheter ablation for AF recurrence with LAA stump detected at baseline transesophageal echocardiogram (TEE) were included in the analysis. Nonpulmonary vein (non-PV) triggers were ablated based on operator's discretion. RESULTS: A total of 213 patients with LAA stump were included in the analysis. Firing from the LAA stump was detected in 186 cases, of which 145 received stump isolation (group I) and the stump was not targeted for isolation in 41 (group II) patients. In 27 patients with no firing from the stump (group III) only non-PV triggers from sites other than the LAA stump were targeted for ablation. At 16.7 ± 8.5 months of follow-up, 126 (86.9%) patients from group I, eight (19.5%) from group II, and eight (33.3%) from group III remained arrhythmia-free off antiarrhythmic drugs (AAD) (P < 0.001). Sixty out of 70 patients underwent redo procedure; electrical isolation of the stump and ablation of other non-PV triggers was done in all 60 cases. At 1 year after the repeat procedure, 55 (91.7%) patients remained arrhythmia-free off-AAD. A total of four (1.88%) thromboembolic (TE) events reported, three of which were transient ischemic attacks and all three patients had "smoke" detected in the left atrium. CONCLUSION: LAA stump is arrhythmogenic and electrical isolation improves clinical outcome. TE events are rare and mostly associated with left atrial smoke in this subset of AF population.

A Stress Response that Monitors and Regulates mRNA Structure Is Central to Cold Shock Adaptation.

Temperature influences the structural and functional properties of cellular components, necessitating stress responses to restore homeostasis following temperature shift. Whereas the circuitry controlling the heat shock response is well understood, that controlling the E. coli cold shock adaptation program is not. We found that during the growth arrest phase (acclimation) that follows shift to low temperature, protein synthesis increases, and open reading frame (ORF)-wide mRNA secondary structure decreases. To identify the regulatory system controlling this process, we screened for players required for increased translation. We identified a two-member mRNA surveillance system that enables recovery of translation during acclimation: RNase R assures appropriate mRNA degradation and the Csps dynamically adjust mRNA secondary structure to globally modulate protein expression level. An autoregulatory switch in which Csps tune their own expression to cellular demand enables dynamic control of global translation. The universality of Csps in bacteria suggests broad utilization of this control mechanism.

Translation efficiency is maintained at elevated temperature in Escherichia coli.

Cellular protein levels are dictated by the balance between gene transcription, mRNA translation, and protein degradation, among other factors. Translation requires the interplay of several RNA hybridization processes, which are expected to be temperature-sensitive. We used ribosome profiling to monitor translation in Escherichia coli at 30 °C and to investigate how this changes after 10-20 min of heat shock at 42 °C. Translation efficiencies are robustly maintained after thermal heat shock and after mimicking the heat-shock response transcriptional program at 30 °C by overexpressing the heat shock σ factor encoded by the rpoH gene. We compared translation efficiency, the ratio of ribosome footprint reads to mRNA reads for each gene, to parameters derived from gene sequences. Genes with stable mRNA structures, non-optimal codon use, and those whose gene product is cotranslationally translocated into the inner membrane are generally less highly translated than other genes. Comparison with other published datasets suggests a role for translational elongation in coupling mRNA structures to translation initiation. Genome-wide calculations of the temperature dependence of mRNA structure predict that relatively few mRNAs show a melting transition between 30 and 42 °C, consistent with the observed lack of changes in translation efficiency. We developed a linear model with six parameters that can predict 38% of the variation in translation efficiency between genes, which may be useful in interpreting transcriptome data.

Operon mRNAs are organized into ORF-centric structures that predict translation efficiency.

Bacterial mRNAs are organized into operons consisting of discrete open reading frames (ORFs) in a single polycistronic mRNA. Individual ORFs on the mRNA are differentially translated, with rates varying as much as 100-fold. The signals controlling differential translation are poorly understood. Our genome-wide mRNA secondary structure analysis indicated that operonic mRNAs are comprised of ORF-wide units of secondary structure that vary across ORF boundaries such that adjacent ORFs on the same mRNA molecule are structurally distinct. ORF translation rate is strongly correlated with its mRNA structure in vivo, and correlation persists, albeit in a reduced form, with its structure when translation is inhibited and with that of in vitro refolded mRNA. These data suggest that intrinsic ORF mRNA structure encodes a rough blueprint for translation efficiency. This structure is then amplified by translation, in a self-reinforcing loop, to provide the structure that ultimately specifies the translation of each ORF.

Catheter ablation of asymptomatic longstanding persistent atrial fibrillation: impact on quality of life, exercise performance, arrhythmia perception, and arrhythmia-free survival.

BACKGROUND: Impact of catheter ablation on exercise performance, quality of life (QoL) and symptom perception in asymptomatic longstanding persistent AF (LSP-AF) patients has not been reported yet. METHODS AND RESULTS: Sixty-one consecutive patients (mean age 62 ±13 years, 71% males) with asymptomatic LSP-AF undergoing first catheter ablation were enrolled. Extended pulmonary vein antrum isolation plus ablation of complex fractionated atrial electrograms and nonpulmonary vein triggers was performed in all. QoL survey was taken at baseline and 12-months postablation, using Short Form-36 (SF-36). Information on arrhythmia perception was obtained using a standard questionnaire and corroborating symptoms with documented evidence of arrhythmia. Exercise tests were performed on 38 patients at baseline and 5 months after procedure. Recurrence was assessed using event recorder, cardiology evaluation, electrocardiogram, and 7-day holter monitoring. After 20 ± 5 months follow-up, 36 (57%) patients remained recurrence-free off-AAD. Of the 25 patients experiencing recurrence, 21 (84%) were symptomatic. Compared to baseline, follow-up SF-36 scores improved significantly in many measures. For patients with successful ablation, physical component summary (PCS) and mental component summary (MCS) demonstrated substantial improvement ( MCS: 64.2 ± 22.3 to 70.1 ± 18.6 [P = 0.041]; PCS: 62.6 ± 18.4 to 70.0 ± 14.4 [P = 0.032]). Postablation exercise study in recurrence-free patients showed significant reduction in resting and peak heart rate (75 ± 11 vs. 90 ± 17 and 132 ± 20 vs. 154.5 ± 36, respectively, P < 0.001), increase in peak oxygen pulse (13.4 ± 3 vs. 18.9 ± 16 mL/beat, Δ5.5 ± 15, P = 0.001), peak VO2 /kg (19.7 ± 5 to 23.4 ± 13 mL/kg/min [Δ 3.7 ± 10, P = 0.043]), and corresponding MET (5.6 ± 1 to 6.7 ± 4 [Δ1.1 ± 3, P = 0.03]). No improvement was observed in patients with failed procedures. CONCLUSION: Successful ablation improves exercise performance and QoL in asymptomatic LSP-AF patients.

Long-term outcome of catheter ablation in atrial fibrillation patients with coexistent metabolic syndrome and obstructive sleep apnea: impact of repeat procedures versus lifestyle changes.

INTRODUCTION: Metabolic syndrome (MS) and obstructive sleep apnea (OSA) are well-known independent risk factors for atrial fibrillation (AF) recurrence. This study evaluated ablation outcome in AF patients with coexistent MS and OSA and influence of lifestyle modifications (LSM) on arrhythmia recurrence. METHODS AND RESULTS: We included 1,257 AF patients undergoing first catheter ablation (30% paroxysmal AF). Patients having MS + OSA were classified into Group 1 (n = 126; 64 ± 8 years; 76% male). Group 2 (n = 1,131; 62 ± 11 years; 72% male) included those with either MS (n = 431) or OSA (n = 112; no CPAP users) or neither of these comorbidities (n = 588). Patients experiencing recurrence after first procedure were divided into 2 subgroups; those having sporadic events (frequency < 2 months) remained on previously ineffective antiarrhythmic drugs (AAD) and aggressive LSM, while those with persistent arrhythmia (incessant or ≥2 months) underwent repeat ablation. After 34 ± 8 months of first procedure, 66 (52%) in Group 1 and 386 (34%) in Group 2 had recurrence (P < 0.001). Recurrence rate in only-MS, only-OSA, and without MS/OSA groups were 40%, 38%, and 29%, respectively. Patients with MS + OSA experienced substantially higher recurrence compared to those with lone MS or OSA (52% vs. 40% vs. 38%; P = 0.036). Of the 452 patients having recurrence, 250 underwent redo-ablation and 194 remained on AAD and LSM. At 20 ± 6 months, 76% of the redo group remained arrhythmia-free off AAD whereas 74% of the LSM group were free from recurrence (P = 0.71), 33% of which were off AAD. CONCLUSIONS: MS and OSA have additive negative effect on arrhythmia recurrence following single procedure. Repeat ablation or compliant LSM increase freedom from recurrent AF.