Mimicking CHO large-scale effects in the single multicompartment bioreactor: A new approach to access scale-up behavior.

During the scale-up of biopharmaceutical production processes, insufficiently predictable performance losses may occur alongside gradients and heterogeneities. To overcome such performance losses, tools are required to explain, predict, and ultimately prohibit inconsistencies between laboratory and commercial scale. In this work, we performed CHO fed-batch cultivations in the single multicompartment bioreactor (SMCB), a new scale-down reactor system that offers new access to study large-scale heterogeneities in mammalian cell cultures. At volumetric power inputs of 20.4-1.5 W m-3, large-scale characteristics like long mixing times and dissolved oxygen (DO) heterogeneities were mimicked in the SMCB. Compared to a reference bioreactor (REFB) set-up, the conditions in the SMCB provoked an increase in lactate accumulation of up to 87%, an increased glucose uptake, and reduced viable cell concentrations in the stationary phase. All are characteristic for large-scale performance. The unique possibility to distinguish between the effects of changing power inputs and observed heterogeneities provided new insights into the potential reasons for altered product quality attributes. Apparently, the degree of galactosylation in the evaluated glycan patterns changed primarily due to the different power inputs rather than the provoked heterogeneities. The SMCB system could serve as a potent tool to provide new insights into scale-up behavior and to predict cell line-specific drawbacks at an early stage of process development.

Has COVID-19 changed the spectrum of arrhythmias and the incidence of sudden cardiac death?

Arrhythmic manifestations of COVID-19 include atrial arrhythmias such as atrial fibrillation or atrial flutter, sinus node dysfunction, atrioventricular conduction abnormalities, ventricular tachyarrhythmias, sudden cardiac arrest, and cardiovascular dysautonomias including the so-called long COVID syndrome. Various pathophysiological mechanisms have been implicated, such as direct viral invasion, hypoxemia, local and systemic inflammation, changes in ion channel physiology, immune activation, and autonomic dysregulation. The development of atrial or ventricular arrhythmias in hospitalized COVID-19 patients has been shown to portend a higher risk of in-hospital death. Management of these arrhythmias should be based on published evidence-based guidelines, with special consideration of the acuity of COVID-19 infection, concomitant use of antimicrobial and anti-inflammatory drugs, and the transient nature of some rhythm disorders. In view of new SARS-CoV­2 variants that may evolve, the development and use of newer antiviral and immunomodulator drugs, and the increasing adoption of vaccination, clinicians must remain vigilant for other arrhythmic manifestations that may occur in association with this novel but potentially deadly disease.

Stand-alone Focal Impulse and Rotor Modulation (FIRM) ablation versus second-generation cryoballoon pulmonary vein isolation for paroxysmal atrial fibrillation.

INTRODUCTION: Focal Impulse and Rotor Modulation (FIRM) guided catheter ablation aiming at stable rotors has been investigated as a treatment option in patients with atrial fibrillation (AF). The objective of this study was to compare the safety and efficacy of FIRM-guided ablation with second-generation cryoballoon pulmonary vein isolation (CB2-PVI) in paroxysmal AF. METHODS: Consecutive patients (n = 22, mean age 60 ± 11 years, 59.1% of males) who were treated with a stand-alone FIRM-guided ablation were included in this retrospective single-center study. Procedural data and arrhythmia-free survival at 12 months were compared with n = 86 consecutive patients (mean age 62 ± 13 years, 62.4% of males) who received de-novo CB2-PVI. RESULTS: Median procedure duration was significantly longer in the FIRM group than in the CB2-PVI group (152 [IQR 120-176] minutes vs. 122 [110-145] minutes; p = .031). One patient (1.2%) in the CB2-PVI group and five patients (22.7%) in the FIRM group had vascular access complications. Atrial tachyarrhythmias recurred in 15 patients in the FIRM group and 11 in the CB2-PVI group. Kaplan-Meier estimation of single-procedure arrhythmia-free survival at 12 months was 25% (95% confidence interval [CI] 6%-44%) in the FIRM group and 87% (95% CI 78%-96%) in the CB2-PVI group (p < .001). Repeat ablations were performed in 14/20 (70.0%) patients in the FIRM group and in 12/85 (14.1%) in the CB2-PVI group (p < .001). CONCLUSION: De novo ablation of AF using FIRM-guided AF ablation results in shorter arrhythmia-free survival after 12 months compared to CB2-PVI and a need for repeat ablation in the majority of patients to achieve stable sinus rhythm.

Individualized or fixed approach to pulmonary vein isolation utilizing the fourth-generation cryoballoon in patients with paroxysmal atrial fibrillation: the randomized INDI-FREEZE trial.

AIMS: Cryoballoon (CB) based pulmonary vein isolation (PVI) is a widely used technique for treatment of atrial fibrillation (AF); however the ideal energy dosing has not yet been standardized. This was a single-centre randomized clinical trial aiming at assessing the safety, acute efficacy, and clinical outcome of an individualized vs. a fixed CB ablation protocol using the fourth-generation CB (CB4) guided by pulmonary vein (PV) potential recordings and CB temperature. METHODS AND RESULTS: Patients were randomized in a 1:1 fashion to two different dosing protocols: INDI-FREEZE group (individualized protocol): freeze-cycle duration of time to effect plus 90 s or interruption of the freeze-cycle and repositioning CB if a CB temperature of -30°C was not within 40 s. Control group (fixed protocol): freeze-cycle duration of 180 s. No-bonus freeze-cycle was applied in either patient group. The primary endpoint was freedom from atrial tachyarrhythmia at 12 months. Secondary end points included procedural parameters and complications. A total of 100 patients with paroxysmal AF were prospectively enrolled. No difference was seen in the primary endpoint [INDI-FREEZE group: 38/47 (81%) vs. control group: 40/47, (85%), P = 0.583]. The total freezing time was significantly shorter in the INDI-FREEZE group (157 ± 56 s vs. 212 ± 83 s, P < 0.001), while procedure duration (57.9 ± 17.9 min vs. 63.2 ± 20.2 min, P = 0.172) was similar. No differences were seen in the minimum CB and oesophageal temperatures as well as in periprocedural complications. CONCLUSION: Compared to the fixed protocol, the individualized approach provides a similar safety profile and clinical outcome, while reducing the total freezing time.

Acute and long-term success of left atrial anterior line and mitral isthmus line ablation in patients after mitral valve surgery.

BACKGROUND: Perimitral flutter and atrial fibrillation may occur in patients with prior surgical mitral valve (MV) repair or replacement and can be challenging for percutaneous catheter ablation. This study sought to determine the feasibility, acute success and durability of catheter ablation of atrial fibrillation or atrial tachycardia by way of a mitral isthmus line (MIL) or an anterior line (AL). METHODS: A total of 81 patients (49 males, mean age 62±11 years) with prior MV replacement (n = 30) or reconstruction (n = 51) underwent creation of a MIL (34) and/or an AL (72). RESULTS: Acute bidirectional block of the MIL was successfully achieved in 24/34 cases and of the AL in 64/72 patients. Patients of the control group without prior MV surgery were matched 1:1 with the valve group. In the AL control subgroup, acute bidirectional block was achieved in 65/72 patients. Acute blockage in the MIL control subgroup could be achieved in 31/34 patients. The MIL valve subgroup showed the worst results in terms of durability, whereas a similar trend emerged in the control group and the AL valve subgroup (probability of failure in MIL valve subgroup 2.224 vs. MIL control subgroup 0.605 [Hazard Ratio (HR) = 0.27, 95% confidence interval (CI), 0.11-0.65), P = .004]; probability of failure in AL valve subgroup 0.844 vs. AL control subgroup 1.03 [HR = 1.22 (95% CI, 0.66-2.26), P = .523]). CONCLUSIONS: Percutaneous creation of MIL and AL is feasible and safe in patients with prior MV replacement/repair and associated with moderate acute and long-term success rates to achieve bidirectional block.

Radon (222Rn) as tracer for submarine groundwater discharge investigation-limitations of the approach at shallow wind-exposed coastal settings.

Mapping radon (222Rn) distribution patterns in the coastal sea is a widely applied method for localizing and quantifying submarine groundwater discharge (SGD). While the literature reports a wide range of successful case studies, methodical problems that might occur in shallow wind-exposed coastal settings are generally neglected. This paper evaluates causes and effects that resulted in a failure of the radon approach at a distinct shallow wind-exposed location in the Baltic Sea. Based on a simple radon mass balance model, we discuss the effect of both wind speed and wind direction as causal for this failure. We show that at coastal settings, which are dominated by gentle submarine slopes and shallow waters, both parameters have severe impact on coastal radon distribution patterns, thus impeding their use for SGD investigation. In such cases, the radon approach needs necessarily to allow for the impact of wind speed and wind direction not only during but also prior to the field campaign.

Preventive or Deferred Ablation of Ventricular Tachycardia in Patients With Ischemic Cardiomyopathy and Implantable Defibrillator (BERLIN VT): A Multicenter Randomized Trial.

BACKGROUND: Catheter ablation for ventricular tachycardia (VT) reduces the recurrence of VT in patients with implantable cardioverter-defibrillators (ICDs). The appropriate timing of VT ablation and its effects on mortality and heart failure progression remain a matter of debate. In patients with life-threatening arrhythmias necessitating ICD implantation, we compared outcomes of preventive VT ablation (undertaken before ICD implantation to prevent ICD shocks for VT) and deferred ablation after 3 ICD shocks for VT. METHODS: The BERLIN VT study (Preventive Ablation of Ventricular Tachycardia in Patients With Myocardial Infarction) was a prospective, open, parallel, randomized trial performed at 26 centers. Patients with stable ischemic cardiomyopathy, a left ventricular ejection fraction between 30% and 50%, and documented VT were randomly assigned 1:1 to a preventive or deferred ablation strategy. The primary outcome was a composite of all-cause death and unplanned hospitalization for either symptomatic ventricular arrhythmia or worsening heart failure. Secondary outcomes included sustained ventricular tachyarrhythmia and appropriate ICD therapy. We hypothesized that preventive ablation strategy would be superior to deferred ablation strategy in the intention-to-treat population. RESULTS: During a mean follow-up of 396±284 days, the primary end point occurred in 25 (32.9%) of 76 patients in the preventive ablation group and 23 (27.7%) of 83 patients in the deferred ablation group (hazard ratio, 1.09 [95% CI, 0.62-1.92]; P=0.77). On the basis of prespecified criteria for interim analyses, the study was terminated early for futility. In the preventive versus deferred ablation group, 6 versus 2 patients died (7.9% versus 2.4%; P=0.18), 8 versus 2 patients were admitted for worsening heart failure (10.4% versus 2.3%; P=0.062), and 15 versus 21 patients were hospitalized for symptomatic ventricular arrhythmia (19.5% versus 25.3%; P=0.27). Among secondary outcomes, the proportions of patients with sustained ventricular tachyarrhythmia (39.7% versus 48.2%; P=0.050) and appropriate ICD therapy (34.2% versus 47.0%; P=0.020) were numerically reduced in the preventive ablation group. CONCLUSIONS: Preventive VT ablation before ICD implantation did not reduce mortality or hospitalization for arrhythmia or worsening heart failure during 1 year of follow-up compared with the deferred ablation strategy. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02501005.

Experience and procedural efficacy of pulmonary vein isolation using the fourth and second generation cryoballoon: The shorter, the better?

BACKGROUND: The second-generation cryoballoon (CB2) provides effective and durable pulmonary vein isolation (PVI) associated with encouraging clinical outcome. The novel fourth-generation cryoballoon (CB4) incorporates a 40% shorter distal tip. This design change may translate into an increased rate of PVI real-time signal recording, facilitating an individualized ablation strategy using the time to effect (TTE). METHODS AND RESULTS: Three hundred consecutive patients with paroxysmal or persistent atrial fibrillation were prospectively enrolled. The first 150 consecutive patients underwent CB2 based PVI (CB2 group) and the last 150 consecutive patients were treated with the CB4 (CB4 group). A total of 594/594 (100%, CB4) and 589/594 (99.2%, CB2) pulmonary veins (PVs) were successfully isolated utilizing the CB4 and CB2, respectively (p = .283). The real-time PVI visualization rate was 47% (CB4) and 39% (CB2; p = .005) and the mean freeze cycle duration 200 ± 90 s (CB4) and 228 ± 110 s (CB2; p < .001), respectively. The total procedure time did not differ between the groups (CB4: 64 ± 32 min) and (CB2: 62 ± 29 min, p = .370). No differences in periprocedural complications were detected. CONCLUSIONS: A higher rate of real-time electrical PV recordings are seen using the CB4 as compared to CB2, which may facilitate an individualized ablation strategy using the TTE.

Comparative investigation of fine bubble and macrobubble aeration on gas utility and biotransformation productivity.

The sufficient provision of oxygen is mandatory for enzymatic oxidations in aqueous solution, however, in process optimization this still is a bottleneck that cannot be overcome with the established methods of macrobubble aeration. Providing higher mass transfer performance through microbubble aerators, inefficient aeration can be overcome or improved. Investigating the mass transport performance in a model protein solution, the microbubble aeration results in higher kL a values related to the applied airstream in comparison with macrobubble aeration. Comparing the aerators at identical kL a of 160 and 60 1/h, the microbubble aeration is resulting in 25 and 44 times enhanced gas utility compared with aeration with macrobubbles. To prove the feasibility of microbubbles in biocatalysis, the productivity of a glucose oxidase catalyzed biotransformation is compared with macrobubble aeration as well as the gas-saving potential. In contrast to the expectation that the same productivities are achieved at identically applied kL a, microbubble aeration increased the gluconic acid productivity by 32% and resulted in 41.6 times higher oxygen utilization. The observed advantages of microbubble aeration are based on the large volume-specific interfacial area combined with a prolonged residence time, which results in a high mass transfer performance, less enzyme deactivation by foam formation, and reduced gas consumption. This makes microbubble aerators favorable for application in biocatalysis.

Catheter ablation or medical therapy to delay progression of atrial fibrillation: the randomized controlled atrial fibrillation progression trial (ATTEST).

AIMS: Delay of progression from paroxysmal to persistent atrial fibrillation (AF) is an important measure of long-term success of AF treatment. However, published data on the impact of catheter ablation on AF progression are limited. This study evaluates whether radiofrequency (RF) catheter ablation delays the progression of AF compared with antiarrhythmic drug (AAD) treatment using current AF management guidelines. METHODS: This prospective, randomized, controlled, two-arm, open-label trial was conducted at 29 hospitals and medical centres across 13 countries. Patients were randomized 1 : 1 to RF ablation or AAD treatment. The primary endpoint was the rate of persistent AF/atrial tachycardia (AT) at 3 years. RESULTS: After early study termination following slow enrolment, 255 (79%) of the planned 322 patients were enrolled (RF ablation, n = 128, AAD, n = 127); 36% of patients in the RF ablation group and 41% in the AAD group completed 3 years of follow-up. For the primary endpoint, the Kaplan-Meier estimate of the rate of persistent AF/AT at 3 years was significantly lower with RF ablation [2.4% (95% confidence interval (CI), 0.6-9.4%)] than with AAD therapy [17.5% (95% CI, 10.7-27.9%); one-sided P = 0.0009]. Patients ≥65 years were ∼4 times more likely to progress to persistent AF/AT than patients <65 years, suggesting RF ablation can delay disease progression [hazard ratio: 3.87 (95% CI, 0.88-17.00); P = 0.0727]. Primary adverse events were reported for eight patients in the RF ablation group. CONCLUSIONS: Radiofrequency ablation is superior to guideline-directed AAD therapy in delaying the progression from paroxysmal to persistent AF.

Novel Cryoballoon Ablation System for Single Shot Pulmonary Vein Isolation　- The Prospective ICE-AGE-X Study.

BACKGROUND: The arctic front cryoballoon (AF-CB) provides effective and durable pulmonary vein isolation (PVI) associated with encouraging clinical outcome. The POLARx cryoballoon incorporates unique features and design changes that may translate into improved efficacy, safety and further simplified balloon-based procedures. Efficacy and safety of the novel POLARx cryoballoon was compared to the fourth generation AF-CB (AF-CB4).Methods and Results:Twenty-five consecutive patients with paroxysmal or persistent atrial fibrillation were prospectively enrolled, underwent POLARx-based PVI (POLARx group) and were compared to 25 consecutive patients treated with the AF-CB4 (AF-CB4 group). All PVs were successfully isolated utilizing the POLARx and AF-CB4. A significant difference regarding the mean minimal cryoballoon temperatures reached using the AF-CB4 and POLARx (-50±6℃ vs. -57±7℃, P=0.004) was observed. Real-time PVI was visualized in 81% of POLARx patients and 42% of AF-CB4 patients (P<0.001). Utilizing the POLARx, a trend towards shorter median procedure time (POLARx: 45 [39, 53] min vs. AF-CB4: 55 [50, 60] min; P=0.062) was found. No differences were observed between AF-CB4 and POLARx concerning catheter maneuverability, catheter stability and periprocedural complications. CONCLUSIONS: The novel POLARx showed similar safety and efficacy compared to the AF-CB4. A higher rate of real-time PV recordings and significantly lower minimal balloon temperatures were observed using the POLARx.

Ultra-high-density mapping of conduction gaps and atrial tachycardias: Distinctive patterns following pulmonary vein isolation with cryoballoon or contact-force-guided radiofrequency current.

INTRODUCTION: The aim of this study was to investigate electrophysiological findings in patients with arrhythmia recurrence undergoing a repeat ablation procedure using ultra-high-density (UHDx) mapping following an index procedure using either contact-force (CF)-guided radiofrequency current (RFC) pulmonary vein isolation (PVI) or second-generation cryoballoon (CB) PVI for treatment of atrial fibrillation (AF). METHODS AND RESULTS: Fifty consecutive patients with recurrence of AF and/or atrial tachycardia (AT) following index CF-RFC PVI (n = 21) or CB PVI (n = 29) were included. A 64-pole mini-basket mapping catheter in combination with an UHDx-mapping system-guided ablation was used. RFC was applied using a catheter tip with three incorporated mini-electrodes. PV reconnection rates were higher after CF-RFC PVI (CF-RFC: 2.5 ± 1.3 PVs vs CB: 1.4 ± 0.9 PVs; P = .0025) and left PVs were more frequently reconnected (CF-RFC: 64% PVs vs CB: 35% PVs; P = .0077). Fractionated signals along the antral index ablation line (FS) were found in 30% of CB-PVI patients (CF-RFC: 9.5% vs CB:30%; P = .098) targeted for ablation. In five cases, FS were a critical part of maintaining consecutive AT. The main AT mechanism found during reablation (n = 45 ATs) was macroreentry (80% [36/45], CF-RFC: 78.9% vs CB: 80.8%; P = 1.0) with a variety of circuits throughout both atria. CONCLUSION: UHDx mapping is sensitive in detecting conduction gaps along the index ablation line. Left PVs are more frequently reconnected after initial CF-RFC PVI. FS are a common finding after CB PVI and can maintain certain forms of ATs. ATs after index PVI are mostly macroreentries with a broad spectrum of entities.

Outcome of cardiac tamponades in interventional electrophysiology.

AIMS: The aim of this study was to analyse tamponades following electrophysiological procedures regarding frequency and mortality in a high-volume centre and to identify independent predictors for severe tamponades. METHODS AND RESULTS: We performed a retrospective study on 34 982 consecutive patients undergoing diagnostic electrophysiological studies or catheter ablation of cardiac arrhythmias. The combined endpoint was defined as severe tamponade. Criteria for severe tamponade included surgical repair, repeat pericardiocentesis, cardiopulmonary resuscitation, intrahospital death or death during follow-up, and thrombo-embolic events or complications due to therapeutic management. Multivariate analysis was performed to identify independent predictors for severe tamponade. A total of 226 tamponades were identified. Overall frequency of tamponades was 0.6%. Procedures requiring epicardial approach had the highest rate of tamponades (9.4%). Twenty-nine patients with tamponade underwent surgery (12.8% of all tamponades and 21.4% of tamponades during epicardial procedures). Overall tamponade-related mortality was 0.03% (9 deaths). Fifty-six patients (24.8%) experienced severe tamponade. Independent risk factors for severe tamponades were endocardial ablation of ventricular tachycardia, epicardial approach, balloon device ablation, high aspiration volume during pericardiocentesis and structural heart disease. CONCLUSION: The frequency of tamponades is strongly dependent on the type of procedure performed. Overall tamponade-related mortality was low but significantly higher in patients undergoing epicardial procedures. Surgical backup should be considered for patients undergoing complex ventricular tachycardia ablation and left atrial ablation procedures.

Correlation between Doppler echocardiography and right heart catheterization assessment of systolic pulmonary artery pressure in patients with severe aortic stenosis.

OBJECTIVES: The aim of this study was to investigate reliability and accuracy of noninvasive measurement method by echocardiography compared to invasive measurement of systolic pulmonary artery pressure (SPAP) in a large cohort of aortic stenosis (AS) patients. BACKGROUND: Pulmonary hypertension (PH) is common in patients with cardiac disease, especially in left heart disease like severe AS. Invasive measurement by right heart catheterization (RHC) is the gold standard to assess pulmonary pressures. Nevertheless, echocardiography is widely used in everyday practice for estimation of pulmonary pressures and diagnosing PH. METHODS: A total of 1400 patients with AS and full invasive hemodynamic assessment by RHC and noninvasive measurements by Doppler echocardiography were included. RESULTS: Mean patient age was 81.5 ± 6.8 years, and 46.3% were males. SPAP was 44.7 ± 15.1 mm Hg by echocardiography and 45.3 ± 15.2 mm Hg by RHC. Pearson's correlation coefficient was r = .820 (P < .0001). Bland-Altman analysis showed a bias of -0.56 mm Hg (95% limits of agreement -18.38 to + 17.26 mm Hg) and 80.6% measurement accuracy. Pulmonary hypertension defined by RHC as a mean PAP ≥25 mm Hg was reliably diagnosed via an echocardiographically measured SPAP of >40 mm Hg (82.2% sensitivity, 80.2% specificity, 83.1% positive predictive value, 79.2% negative predictive value). CONCLUSIONS: In a large cohort of patients with severe aortic stenosis, we could demonstrate a very good correlation of SPAP between Doppler echocardiography and invasive RHC measurement. Pulmonary hypertension could be diagnosed by echocardiography with high sensitivity and specificity.

Predictors of freedom from atrial arrhythmia recurrence after cryoballoon ablation for persistent atrial fibrillation: A multicenter study.

AIMS: We sought to assess (1) clinical outcomes of second-generation cryoballoon (CB) ablation for persistent atrial fibrillation (AF), and (2) the association of baseline and procedural covariates with atrial arrhythmia recurrence (AAR) after ablation. METHODS: A total of 135 patients (63 ± 11 years, 96 men [71%]) with persistent AF underwent CB ablation at three experienced electrophysiology centers. Freedom from AAR was estimated with the Kaplan-Meier method. A Cox proportional-hazards model was used to estimate the effects of baseline and procedural covariates on the likelihood of AAR. RESULTS: Freedom from AAR at 6, 12, and 18 months was estimated at 91% (95% confidence interval [CI] 86%-96%), 75% (95% CI, 67%-83%), and 53% (95% CI, 43%-65%), respectively. The presence of an implantable cardiac device (Hazard ratio [HR] 3.09; 95% CI, 1.37-7.00; P = .007), a left atrial (LA) diameter > 50 mm (HR 1.69; 95% CI, 1.02-2.79; P = .043), and absence of antiarrhythmic drug (AAD) therapy before the ablation procedure (HR 3.12; 95% CI, 1.72-5.64; P < .001) were associated with AAR. A trend toward an increased risk of AAR was revealed for women (HR 1.73; 95% CI, 0.96-3.11; P = .069). CONCLUSIONS: CB ablation for persistent AF resulted in freedom from AAR about that reported for RF ablation. The presence of an implantable cardiac device, LA size, and absence of AAD therapy at baseline were associated with the risk of AAR.

Management of arrhythmia recurrence in patients with pulmonary vein stenosis following atrial fibrillation ablation.

AIMS: Arrhythmia recurrence is a common clinical problem in patients with pulmonary vein stenosis (PVS) following catheter ablation of atrial fibrillation. The study sought to analyse the management of arrhythmia recurrence in patients with PVS. METHODS AND RESULTS: Retrospective analysis was performed on 29 patients with high-degree PVS. Follow-up contained clinical visits, Holter-electrocardiogram recordings and invasive pulmonary vein (PV) angiography and electrophysiological studies. Arrhythmia recurrence was observed in 18 patients (62%) after PVS formation. Fifteen of 18 patients (83.3%) with and 1 of 11 patients (9.1%) without arrhythmia recurrence had electrical PV reconnection (P = 0.0003). In 14 of 16 patients repeat pulmonary vein isolation (PVI) was conducted (radiofrequency ablation in 12 and cryoballoon ablation in 2 cases). Repeat PVI was successful in all PVs in nine patients and incomplete in five patients (failed attempt in two patients with stent implantation, no attempt in three patients with stenotic PVs). Freedom from arrhythmia recurrence was estimated at 56.3% [95% confidence interval (CI) 36.4-72.0%] after 24 months. At the end of the follow-up, complete PVI was documented in 19 of 23 patients (82.6%) with stable sinus rhythm and in 2 of 6 patients with arrhythmia recurrence (33.3%) (P = 0.0335). The Kaplan-Meier estimate of recurrence-free survival of restenosis after interventional PVS treatment was similar in patients without and with repeat ablation [75.6% (95% CI 57.0-94.3%) and 67.0% (95% CI 43.2-90.7%) after 500 days, P = 0.77]. CONCLUSIONS: Pulmonary vein reconnection is the major driver of arrhythmia recurrence in PVS patients. Repeat PVI is feasible and does not lead to progression of PVS or restenosis if the procedure is carefully performed.

Pulmonary vein stenosis or occlusion after catheter ablation of atrial fibrillation: long-term comparison of drug-eluting versus large bare metal stents.

Aims: Pulmonary vein stenosis or occlusion (PVS/O) following catheter ablation of atrial fibrillation is a rare but potentially severe complication. Treatment options include angioplasty with or without stent implantation, but data on outcome and optimal treatment strategy are limited. We report long-term results after catheter-based treatment of patients with symptomatic PVS/O. Methods and results: Retrospective analysis was performed in patients undergoing pulmonary vein (PV) angiography for suspected PVS/O. All patients with PVS/O were treated with balloon angioplasty and implantation of a coronary drug-eluting stent (DES) or a peripheral large-diameter bare metal stent (LD-BMS). A total of 25 high-degree PVS/Os in 19 patients were treated. Nine PVs were treated with angioplasty and DES implantation and 16 with angioplasty and LD-BMS implantation. The ostial PV diameter was not different in the DES and LD-BMS groups (10.2 ± 2.5 mm vs. 11.1 ± 1.9 mm, P = 0.34), but the PV/stent diameter ratio was significantly lower in the former (0.43 ± 0.13 vs. 0.82 ± 0.13, P < 0.0001). Angiographic stent restenosis was observed at a median of 539 (interquartile range 99-774) days in 9 of 23 (39%) treated PVs. The restenosis rate in the LD-BMS group was only one-third of that in the DES group [3/14 (21%) vs. 6/9 (67%), respectively; P = 0.08]. Conclusion: The use of LD-BMS for the treatment of PVS/O was associated with an acceptable long-term outcome. Coronary DES implantation resulted in a high rate of restenosis and should therefore not be performed. Larger trials are needed to confirm our findings.

Is less more? Impact of different ablation protocols on periprocedural complications in second-generation cryoballoon based pulmonary vein isolation.

Aims: Second-generation cryoballoon (CB2) based pulmonary vein isolation (PVI) has emerged as an effective treatment option for symptomatic atrial fibrillation (AF). The current study sought to assess the impact of different ablation protocols on the incidence and characteristics of procedural complications in a large patient cohort. Methods and results: A total of 563 consecutive patients with symptomatic AF who underwent CB2-based ablation between July 2012 and January 2016, were assessed. Three different ablation protocols were applied and characterized by (#1) a bonus-freeze following PVI, (#2) no bonus-freeze after PVI, and (#3) a 'time-to-effect'-guided strategy. Major complications occurred in 30/563 patients (5.3%) with phrenic nerve palsy (PNP) as the most frequent complication occurring in 2.7% of the cases. The overall incidence of complications was significantly lower in patients treated with a 'time-to-effect' guided ablation strategy compared with the other ablation protocols (8.1% [17/211] (protocol #1+#2) vs. 3.7% [13/352] (protocol #3), respectively; P = 0.026). The 'time-to-effect' guided ablation protocol was associated with less applied freeze-cycles and shorter freeze-cycle durations. Additionally, shorter procedure times, radiation exposures and lower volumes of contrast medium needed were assessed for the 'time-to-effect' guided protocol as compared with the other ablation protocols. Conclusion: The overall incidence of complications was 5.3% in our analysis. The most frequent complication was PNP. The use of a time-to-effect guided ablation protocol was associated with a lower incidence of major complications compared with a bonus-freeze and no bonus-freeze protocol.

Does Size Matter? Cryoballoon-Based Pulmonary Vein Isolation Using a Novel 25-mm Circular Mapping Catheter.

BACKGROUND: Real-time recording of pulmonary vein isolation (PVI) using a circular mapping catheter has become a key aspect of cryoballoon (CB) ablation. The aim of this study was to investigate the procedural safety, efficacy and rate of real-time pulmonary vein (PV) recording using a novel circular mapping catheter with a 25-mm loop size for CB-based PVI.Methods and Results:A total of 40 patients with symptomatic atrial fibrillation (AF) underwent PVI using a second-generation CB and a novel 25-mm circular mapping catheter. A total of 159 PV were identified and successfully isolated. Real-time PV recording was achieved in 80% of the PV. In 3 right inferior PV the circular mapping catheter had to be exchanged for a stiff guidewire due to insufficient mechanical support. Therefore, acute PVI using exclusively the circular mapping catheter was achieved in 156/159 PV (98%). Mean procedure and fluoroscopy times were 66±21 min and 15±6 min, respectively. Transient phrenic nerve palsy occurred in 1 patient as the only procedural complication. CONCLUSIONS: The exclusive use of a novel 25-mm circular mapping catheter for CB ablation of AF results in a real-time PV recording rate of 80% and isolation of 98% of targeted PV.

Oil Droplet Size Distributions in Deep-Sea Blowouts: Influence of Pressure and Dissolved Gases.

To date, experimental investigations to determine the droplet size distribution (DSD) of subsea oil spills were mostly conducted at surface conditions, i.e. at atmospheric pressure, and with dead, i.e. purely liquid, oils. To investigate the influence of high hydrostatic pressure and of gases dissolved in the oil on the DSD, experiments with a downscaled blowout are conducted in a high-pressure autoclave at 150 bar hydrostatic pressure. Jets of "live", i.e. methane-saturated, crude oil and n-decane are compared to jets of "dead" hydrocarbon liquids in artificial seawater. Experiments show that methane dissolved in the liquid oil increases the volume median droplet diameter significantly by up to 97%. These results are not in good accordance with state-of-the-art drop formation models, which are based on oil-only experiments at atmospheric pressure, and therefore show the need for a modification of such models which incorporates effects of hydrostatic pressure and dissolved gases for the modeling of deep-sea oil spills and blowouts.