A worldwide survey on incidence, management, and prognosis of oesophageal fistula formation following atrial fibrillation catheter ablation: the POTTER-AF study.

AIMS: Oesophageal fistula represents a rare but dreadful complication of atrial fibrillation catheter ablation. Data on its incidence, management, and outcome are sparse. METHODS AND RESULTS: This international multicentre registry investigates the characteristics of oesophageal fistulae after treatment of atrial fibrillation by catheter ablation. A total of 553 729 catheter ablation procedures (radiofrequency: 62.9%, cryoballoon: 36.2%, other modalities: 0.9%) were performed, at 214 centres in 35 countries. In 78 centres 138 patients [0.025%, radiofrequency: 0.038%, cryoballoon: 0.0015% (P < 0.0001)] were diagnosed with an oesophageal fistula. Peri-procedural data were available for 118 patients (85.5%). Following catheter ablation, the median time to symptoms and the median time to diagnosis were 18 (7.75, 25; range: 0-60) days and 21 (15, 29.5; range: 2-63) days, respectively. The median time from symptom onset to oesophageal fistula diagnosis was 3 (1, 9; range: 0-42) days. The most common initial symptom was fever (59.3%). The diagnosis was established by chest computed tomography in 80.2% of patients. Oesophageal surgery was performed in 47.4% and direct endoscopic treatment in 19.8% and conservative treatment in 32.8% of patients. The overall mortality was 65.8%. Mortality following surgical (51.9%) or endoscopic treatment (56.5%) was significantly lower as compared to conservative management (89.5%) [odds ratio 7.463 (2.414, 23.072) P < 0.001]. CONCLUSION: Oesophageal fistula after catheter ablation of atrial fibrillation is rare and occurs mostly with the use of radiofrequency energy rather than cryoenergy. Mortality without surgical or endoscopic intervention is exceedingly high.

Pulmonary vein isolation using second-generation single-shot devices: not all the same?

INTRODUCTION: Single-shot devices have been developed to simplify pulmonary vein isolation (PVI). Randomized studies of the second-generation cryoballoon (CB 2nd) demonstrated excellent results. There are limited data comparing results of circular pulmonary vein ablation catheter (PVAC) with conventional RF ablation or CB for PVI. OBJECTIVE: Using a sequential registry cohort and a prospective randomized study, we aimed to compare the acute and long-term results of CB 2nd and PVAC Gold. METHODS: In the registry, consecutive patients with paroxysmal atrial fibrillation (AF) undergoing their first PVI were included. The preferred method used was PVAC Gold in 2014 and CB 2nd in 2015. Subsequently, a randomized study (PVAC vs. CB 2nd) was performed. Ablation success was measured as freedom of AF or atrial tachycardias (AT) off antiarrhythmic drugs. RESULTS: In the registry cohort, PVAC Gold was used in 60 patients and CB 2nd in 56 patients (age 66 ± 11 years, 52% male, LAD 43 ± 6). In the randomized study, 20 patients were treated with PVAC Gold and 22 with CB 2nd (age 67 ± 9; 43% men, LAD 40 ± 7 mm). During a mean follow up of 13.2 ± 3.6 months, success was 54% in PVAC Gold patients and 81% in CB 2nd cases (p = 0.001). In the randomized study 12 months success was 50% versus 86%, p < 0.05. Complications occurred rare in both groups. CONCLUSIONS: Our registry data and the randomized study both suggest superiority of PVI using CB 2nd as compared with PVI using PVAC Gold.

Sex differences of resource utilisation and outcomes in patients with atrial arrhythmias and heart failure.

OBJECTIVE: Atrial fibrillation or atrial flutter (AF) and heart failure (HF) often go hand in hand and, in combination, lead to an increased risk of death compared with patients with just one of both entities. Sex-specific differences in patients with AF and HF are under-reported. Therefore, the aim of this study was to investigate sex-specific catheter ablation (CA) use and acute in-hospital outcomes in patients with AF and concomitant HF in a retrospective cohort study. METHODS: Using International Statistical Classification of Diseases and Related Health Problems and Operations and Procedures codes, administrative data of 75 hospitals from 2010 to 2018 were analysed to identify cases with AF and HF. Sex differences were compared for baseline characteristics, right and left atrial CA use, procedure-related adverse outcomes and in-hospital mortality. RESULTS: Of 54 645 analysed cases with AF and HF, 46.2% were women. Women were significantly older (75.4±9.5 vs 68.7±11.1 years, p<0.001), had different comorbidities (more frequently: cerebrovascular disease (2.4% vs 1.8%, p<0.001), dementia (5.3% vs 2.2%, p<0.001), rheumatic disease (2.1% vs 0.8%, p<0.001), diabetes with chronic complications (9.7% vs 9.1%, p=0.033), hemiplegia or paraplegia (1.7% vs 1.2%, p<0.001) and chronic kidney disease (43.7% vs 33.5%, p<0.001); less frequently: myocardial infarction (5.4% vs 10.5%, p<0.001), peripheral vascular disease (6.9% vs 11.3%, p<0.001), mild liver disease (2.0% vs 2.3%, p=0.003) or any malignancy (1.0% vs 1.3%, p<0.001), underwent less often CA (12.0% vs 20.7%, p<0.001), had longer hospitalisations (6.6±5.8 vs 5.2±5.2 days, p<0.001) and higher in-hospital mortality (1.6% vs 0.9%, p<0.001). However, in the multivariable generalised linear mixed model for in-hospital mortality, sex did not remain an independent predictor (OR 0.96, 95% CI 0.82 to 1.12, p=0.579) when adjusted for age and comorbidities. Vascular access complications requiring interventions (4.8% vs 4.2%, p=0.001) and cardiac tamponade (0.3% vs 0.1%, p<0.001) occurred more frequently in women, whereas stroke (0.6% vs 0.5%, p=0.179) and death (0.3% vs 0.1%, p=0.101) showed no sex difference in patients undergoing CA. CONCLUSIONS: There are sex differences in patients with AF and HF with respect to demographics, resource utilisation and in-hospital outcomes. This needs to be considered when treating women with AF and HF, especially for a sufficient patient informed decision making in clinical practice.

Functional characterization of phospholipase C-γ2 mutant protein causing both somatic ibrutinib resistance and a germline monogenic autoinflammatory disorder.

Depending on its occurrence in the germline or somatic context, a single point mutation, S707Y, of phospholipase C-γ2 (PLCγ2) gives rise to two distinct human disease states: acquired resistance of chronic lymphocytic leukemia cells (CLL) to inhibitors of Brutons´s tyrosine kinase (Btk) and dominantly inherited autoinflammation and PLCγ2-associated antibody deficiency and immune dysregulation, APLAID, respectively. The functional relationships of the PLCγ2S707Y mutation to other PLCG2 mutations causing (i) Btk inhibitor resistance of CLL cells and (ii) the APLAID-related human disease PLCγ2-associated antibody deficiency and immune dysregulation, PLAID, revealing different clinical characteristics including cold-induced urticaria, respectively, are currently incompletely understood. Here, we show that PLCγ2S707 point mutants displayed much higher activities at 37° C than the CLL Btk inhibitor resistance mutants R665W and L845F and the two PLAID mutants, PLCγ2Δ19 and PLCγ2Δ20-22. Combinations of CLL Btk inhibitor resistance mutations synergized to enhance PLCγ2 activity, with distinct functional consequences for different temporal orders of the individual mutations. Enhanced activity of PLCγ2S707Y was not observed in a cell-free system, suggesting that PLCγ2 activation in intact cells is dependent on regulatory rather than mutant-enzyme-inherent influences. Unlike the two PLAID mutants, PLCγ2S707Y was insensitive to activation by cooling and retained marked hyperresponsiveness to activated Rac upon cooling. In contrast to the PLAID mutants, which are insensitive to activation by endogenously expressed EGF receptors, the S707Y mutation markedly enhanced the stimulatory effect of EGF, explaining some of the pathophysiological discrepancies between immune cells of PLAID and APLAID patients in response to receptor-tyrosine-kinase activation.

Hemodynamic Improvement at Three Months after MitraClip® Treatment in End-Stage Heart Failure Patients with Functional Mitral Regurgitation.

BACKGROUND: Functional mitral regurgitation (FMR) is common in patients with advanced heart failure and impaired left ventricular function. The study aim was to examine functional and hemodynamic effects at three months after MitraClip® implantation in high-risk surgical patients with FMR. METHODS: A group of 93 patients was rejected for surgical treatment by heart-team decisions due to an inacceptable risk for conventional mitral valve surgery. Between October 2011 and May 2015, 89 of these patients (96%) were treated successfully with MitraClip implantation. A subsequent complete follow up was performed over three months in 32 patients with FMR, including pro-brain natriuretic peptide (pro-BNP) measurements, six-minute walk test, echocardiography, and right heart catheterization. RESULTS: The patients (mean age 73 ± 7 years) presented with a mean left ventricular ejection fraction (LVEF) of 32 ± 13%, and mitral regurgitation (MR) grade ≥3 in 30 of 32 cases (93%). All patients suffered from severe FMR and were highly symptomatic (NYHA functional class III or IV). The mean logistic EuroSCORE was 33%. MitraClip implantation resulted in a significant clinical improvement and reverse cardiac remodelling with a decrease in LV end-diastolic and LV endsystolic diameters, while LVEF was unchanged. In addition, a statistically relevant reduction of systolic, diastolic and mean pulmonary artery pressures (PAPsystolic -7.2 mmHg, p = 0.011; PAPdiastolic -4.5 mmHg, p = 0.003; and PAPmean -5.3 mmHg, p = 0.007) were measured, while the cardiac index (+0.3 l/min/m2, p <0.001) and cardiac output (+0.5 l/min, p <0.001) were increased significantly. The 30-day mortality was 8.6% (n = 8). CONCLUSIONS: Among the study population, MitraClip implantation led to clinical improvement, reverse cardiac remodeling, and a sustained hemodynamic benefit during the three-month follow up period.

The Phospholipase Cγ2 Mutants R665W and L845F Identified in Ibrutinib-resistant Chronic Lymphocytic Leukemia Patients Are Hypersensitive to the Rho GTPase Rac2 Protein.

Mutations in the gene encoding phospholipase C-γ2 (PLCγ2) have been shown to be associated with resistance to targeted therapy of chronic lymphocytic leukemia (CLL) with the Bruton's tyrosine kinase inhibitor ibrutinib. The fact that two of these mutations, R665W and L845F, imparted upon PLCγ2 an ∼2-3-fold ibrutinib-insensitive increase in the concentration of cytosolic Ca2+ following ligation of the B cell antigen receptor (BCR) led to the assumption that the two mutants exhibit constitutively enhanced intrinsic activity. Here, we show that the two PLCγ2 mutants are strikingly hypersensitive to activation by Rac2 such that even wild-type Rac2 suffices to activate the mutant enzymes upon its introduction into intact cells. Enhanced "basal" activity of PLCγ2 in intact cells is shown using the pharmacologic Rac inhibitor EHT 1864 and the PLCγ2F897Q mutation mediating Rac resistance to be caused by Rac-stimulated rather than by constitutively enhanced PLCγ2 activity. We suggest that R665W and L845F be referred to as allomorphic rather than hypermorphic mutations of PLCG2 Rerouting of the transmembrane signals emanating from BCR and converging on PLCγ2 through Rac in ibrutinib-resistant CLL cells may provide novel drug treatment strategies to overcome ibrutinib resistance mediated by PLCG2 mutations or to prevent its development in ibrutinib-treated CLL patients.

Cool-temperature-mediated activation of phospholipase C-γ2 in the human hereditary disease PLAID.

Deletions in the gene encoding signal-transducing inositol phospholipid-specific phospholipase C-γ2 (PLCγ2) are associated with the novel human hereditary disease PLAID (PLCγ2-associated antibody deficiency and immune dysregulation). PLAID is characterized by a rather puzzling concurrence of augmented and diminished functions of the immune system, such as cold urticaria triggered by only minimal decreases in temperature, autoimmunity, and immunodeficiency. Understanding of the functional effects of the genomic alterations at the level of the affected enzyme, PLCγ2, is currently lacking. PLCγ2 is critically involved in coupling various cell surface receptors to regulation of important functions of immune cells such as mast cells, B cells, monocytes/macrophages, and neutrophils. PLCγ2 is unique by carrying three Src (SH) and one split pleckstrin homology domain (spPH) between the two catalytic subdomains (spPHn-SH2n-SH2c-SH3-spPHc). Prevailing evidence suggests that activation of PLCγ2 is primarily due to loss of SH-region-mediated autoinhibition and/or enhanced plasma membrane translocation. Here, we show that the two PLAID PLCγ2 mutants lacking portions of the SH region are strongly (>100-fold), rapidly, and reversibly activated by cooling by only a few degrees. We found that the mechanism(s) underlying PLCγ2 PLAID mutant activation by cool temperatures is distinct from a mere loss of SH-region-mediated autoinhibition and dependent on both the integrity and the pliability of the spPH domain. The results suggest a new mechanism of PLCγ activation with unique thermodynamic features and assign a novel regulatory role to its spPH domain. Involvement of this mechanism in other human disease states associated with cooling such as exertional asthma and certain acute coronary events appears an intriguing possibility.

Association between left atrial low-voltage area, serum apoptosis, and fibrosis biomarkers and incidence of silent cerebral events after catheter ablation of atrial fibrillation.

BACKGROUND: Silent cerebral events (SCE) have been identified on cerebral diffusion-weighted cerebral magnetic resonance imaging (DE-MRI) after catheter ablation (CA) of atrial fibrillation (AF). The purpose of this study was to investigate the impact of atrial remodeling on the incidence of SCE after AF CA. METHODS: Forty patients (67.8 ± 10 years, 47.5 % women) with symptomatic paroxysmal (n = 11, 27.5 %) or persistent AF undergoing AF CA were prospectively enrolled. LA fibrosis was estimated by intraprocedural bipolar voltage mapping in sinus rhythm. Apoptosis-stimulating fragment (Fas-Ligand) and amino terminal peptide from collagen III (PIIINP) concentrations were analyzed of LA and femoral vein blood. Cerebral DE-MRI was performed 1 to 2 days after CA of AF for detection of SCE. In nine patients (22.5 %), new SCE were detected on DE-MRI after AF CA. RESULTS: Patients with SCE had higher CHA2DS2-VASc score, larger left atrial diameter (LADmax), and higher surface area of left atrial low-voltage (24 ± 11.2 vs 3.5 ± 4.2 %, p < 0.0001). Concentrations of peripheral PIIINP (103.7 ± 25.9 vs 81.8 ± 16.7 pg/ml, p < 0.01) and Fas-Ligand (124.1 ± 22.4 vs 87.6 ± 19.4 pg/ml, p < 0.01) were significantly higher in patients with SCE and correlated to low-voltage surface area (p < 0.01). Multivariable logistic regression analysis revealed peripheral Fas-Ligand, LADmax, CHA2DS2-Vasc score, and LA low-voltage area proportion to be independent predictors for the development of SCE. CONCLUSIONS: LA remodeling, estimated by LADmax and LA low-voltage area, has significant relationship with the risk of SCE after AF ablation. Moreover, Fas-Ligand may act as an independent predictor for SCE in the context of AF CA.

Higher incidence of esophageal lesions after ablation of atrial fibrillation related to the use of esophageal temperature probes.

BACKGROUND: Endoscopically detected esophageal lesions (EDELs) have been identified in apparently asymptomatic patients after catheter ablation of atrial fibrillation (AF). The use of esophageal probes to monitor luminal esophageal temperature (LET) during catheter ablation to protect esophageal damage is currently controversial. OBJECTIVE: The purpose of this study was to investigate the impact of the use of esophageal temperature probes during AF catheter ablation on the incidence of EDELs. METHODS: Eighty consecutive patients (mean age 63.8 ± 11.36 years; 68.8% men) with symptomatic, drug-refractory paroxysmal (n = 52, 65%) or persistent AF who underwent left atrial radiofrequency catheter ablation were prospectively enrolled. Posterior wall ablation was power limited (≤25 W). In the first 40 patients, LET was monitored continuously (group A), whereas no esophageal temperature probe was used in group B (n = 40 patients). Assessment of EDEL was performed by endoscopy within 2 days after radiofrequency catheter ablation. RESULTS: Overall, 13 patients (16%) developed EDELs after AF ablation. The incidence of EDELs was significantly higher in group A than group B (30% vs 2.5%, P < .01). Within group A, patients who developed EDEL had higher maximal LET during AF ablation than patients without EDEL (40.97 ± 0.92°C vs 40.14 ± 1.1°C, P = .02). Multivariable logistic regression analysis revealed the use of an esophageal temperature probe as the only independent predictor for the development of EDEL (odds ratio 16.7, P < .01). CONCLUSION: The use of esophageal temperature probes in the setting of AF catheter ablation per se appears to be a risk factor for the development of EDEL.

Stand-alone mapping using different transluminal mapping catheters--an accurate and safe way to isolate all pulmonary veins with the cryoballoon?

PURPOSE: Cryoballoon isolation of the pulmonary veins (PVI) is an effective and safe method in the treatment of patients with paroxysmal atrial fibrillation (PAF). The circular mapping catheter Achieve® (Medtronic Inc., Minneapolis, USA) can be introduced into the pulmonary vein (PV) through the inner lumen of the balloon catheter, allowing online mapping of the PV electrograms during ablation. We prospectively compared the accuracy of this catheter in both available sizes to a standard circular mapping catheter (SCMC) in order to determine bidirectional PV block. METHODS: Patients with symptomatic PAF underwent cryoballoon ablation using either the Achieve® 15-mm catheter (group 1, 15 patients) or the Achieve® 20 mm (group 2, 15 patients). PV potentials were recorded using Achieve® before, during, and after ablation, and exit block was obtained by pacing from inside the PV. Accuracy of PV potential detection was controlled by a SCMC before and after ablation. RESULTS: Rate of PV which could be isolated exclusively using the Achieve® as guidewire was 98 % (59/60) in group 1 and 93 % (57/60) in group 2. Online signal recording during ablation was possible in 40 and 60 % of PV (p = 0.037), respectively. Final Achieve® diagnosis was accurate in 55/60 (92 %) of the PVs and 12/15 (80 %) of patients in group 1 and 60/60 (100 %) of PV and 15/15 (100 %) of patients in group 2. CONCLUSION: Stand-alone mapping using Achieve® 15 mm resulted in a significant lack of diagnostic accuracy. Achieve® 20 mm provided excellent diagnostic accuracy comparable to a SCMC and should be preferentially used.

Two in a single procedure: combined approach for MitraClip implantation and left atrial appendage occlusion using the Watchman device.

Percutaneous mitral valve repair (MVR) using MitraClip is an effective alternative treatment for patients with severe mitral valve insufficiency and high perioperative risk for surgery. Atrial fibrillation is frequent in patients needing MVR and some of these patients have contraindications for oral anticoagulation. Combining MitraClip implantation and occlusion of the left atrial appendage (LAA) may be of value in these patients with high thromboembolic risk. We report the first case of combined MitraClip procedure and percutaneous LAA closure in a single procedure.

Recurrence of paroxysmal atrial fibrillation after cryoisolation of the pulmonary veins. Is a "redo" procedure using the cryoballoon useful?

BACKGROUND: Pulmonary vein (PV) isolation with the cryoballoon technique is an effective and safe method to treat patients with paroxysmal atrial fibrillation (AF). However, the optimal treatment strategy for patients with recurrences after this ablation is unclear. AIMS: The aim of this single centre study was to evaluate the efficacy and safety of a "redo" procedure using the cryoballoon in this patient cohort. The secondary study objectives were to determine the rate of reconduction for individual PVs of the patients undergoing "redo" ablation and potential predictors of persistent PV isolation (PVI). METHODS: Between April 2006 and September 2009, all patients with paroxysmal AF recurrences after cryoballoon ablation a "redo" ablation with the cryoballoon was offered. PV conduction was determined and cryoapplications were performed in all reconnected PVs. Every 3 months, 7-day Holter ECG, symptom-driven transtelephonic ECG recordings, and questionnaires were collected for 12 months. RESULTS: Forty-seven patients underwent "redo" cryoballoon ablation. In all these patients, at least one PV with reconduction was found. Recurrent conduction was documented in 63 % of the left superior PV, 56 % of the left inferior PV, 43 % of the right superior PV, and 56 % of the right inferior PV. In 28 of the 47 patients (60 %), no AF recurrence was detectable during the 12-month follow-up (after 3 months blanking period). Rate of severe complications was low and not significantly different from that of the initial ablations. CONCLUSION: "Redo" ablation using cryoballoon technology may be an effective and safe method to treat patients with recurrence of paroxysmal AF after cryoballoon PVI.

Pulmonary vein isolation with a novel endoscopic ablation system using laser energy.

Pulmonary vein isolation (PVI) is the basis of all ablation techniques for paroxysmal atrial fibrillation. Performing conventional radiofrequency ablation for PVI is time consuming and sometimes challenging when using point-by-point applications to create continuous lesions. Small electrically conducting gaps evolving in the ablation lines may cause recurrences of atrial fibrillation or regular atrial re-entry tachycardias. Development of novel anatomically designed ablation catheters for PVI aim to facilitate the ablation procedure, to produce continuous and durable lesions with a limited number of ablation impulses and to reduce the complication rate. The endoscopic laser balloon ablation system (HeartLight® EAS, Cardiofocus Inc.) is the first system that allows direct visual guidance of energy delivery at the antral level of each pulmonary vein and uses a completely new energy source for ablation.

Incidence of silent cerebral thromboembolic lesions after atrial fibrillation ablation may change according to technology used: comparison of irrigated radiofrequency, multipolar nonirrigated catheter and cryoballoon.

INTRODUCTION: Silent cerebral ischemic lesions have recently emerged as the most frequent complications after pulmonary vein isolation (PVI). To reduce thromboembolic complications, new types of catheters and energy source have been introduced in clinical practice. The study purpose is to compare the incidence of new silent cerebral ischemic events in patients with paroxysmal atrial fibrillation (PAF) undergoing PVI with different ablation technologies. METHODS AND RESULTS: One hundred and eight patients (67% men; age 56 ± 9 years) with PAF were enrolled in a consecutive manner to undergo PVI performed with irrigated radiofrequency (RF) catheter (Group 1, 36 patients), multielectrode catheter (PVAC) associated with duty-cycled RF generator (Group 2, 36 patients) and cryoballoon (Group 3, 36 patients). The protocol included a cerebral magnetic resonance imaging before and after the procedure. After PVI, the following patients showed new silent cerebral ischemic lesions at postprocedural cerebral MRI: 3 patients in Group 1 (8.3%), 14 patients in Group 2 (38.9%), 2 patients in Group 3 (5.6%). PVAC related to higher incidence of silent cerebral ischemic events compared to irrigated RF (P = 0.002) and cryoballoon (P = 0.001), whereas no statistical differences were found between irrigated RF catheter and cryoballoon groups (8.3% vs 5.6%, P = 0.5). At the multivariate analysis, the only independent predictor of new ischemic asymptomatic cerebral lesions after PVI was ablation performed with PVAC (OR 1.48 95% CI 1.19-1.62, P < 0.001). CONCLUSION: The incidence of silent cerebral lesions after PVI is different depending on technologies used: PVAC increases the risk of 1.48 times compared to irrigated RF and cryoballoon ablation.