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.

Oesophageal safety in voltage-guided atrial fibrillation ablation using ablation index or contact force only: a prospective comparison.

AIMS: Left atrial ablation using radiofrequency (RF) is associated with endoscopically detected thermal oesophageal lesions (EDELs). The aim of this study was to compare EDEL occurrence after conventional contact force-guided (CFG) RF ablation vs. an ablation index-guided (AIG) approach in clinical routine of voltage-guided ablation (VGA). Predictors of EDEL were also assessed. METHODS AND RESULTS: This study compared CFG (n = 100) with AIG (n = 100) in consecutive atrial fibrillation ablation procedures, in which both pulmonary vein isolation and VGA were performed. In the AIG group, AI targets were ≥500 anteriorly and ≥350-400 posteriorly. Upper endoscopy was performed after ablation.The CFG and AIG groups had comparable baseline characteristics. The EDEL occurred in 6 and 5% (P = 0.86) in the CFG and AIG groups, respectively. Category 2 lesions occurred in 4 and 2% (P = 0.68), respectively. All EDEL healed under proton pump inhibitor therapy. The AI > 520 was the only predictor of EDEL [odds ratio (OR) 3.84; P = 0.039]. The more extensive Category 2 lesions were predicted by: AI max > 520 during posterior ablation (OR 7.05; P = 0.042), application of posterior or roof lines (OR 5.19; P = 0.039), existence of cardiomyopathy (OR 4.93; P = 0.047), and CHA2DS2-VASc score (OR 1.71; P = 0.044). The only Category 2 lesion with AI max < 520 (467) occurred in a patient with low body mass index. CONCLUSIONS: Both methods were comparable with respect to clinical complications and EDEL. In consideration of previous reconnection data and our study results regarding oesophageal safety, optimal AI target range might be between 400 and 450.

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.

Voltage-guided ablation in persistent atrial fibrillation-favorable 1-year outcome and predictors.

INTRODUCTION: Pulmonary vein isolation (PVI) in persistent atrial fibrillation (AF) has a low success rate. A newer ablation concept targets left atrial (LA) low voltage zones (LVZ) which correlate with fibrosis and predict recurrence after PVI. We aimed to determine the success of combined PVI- and LVZ-guided ablation and to identify the predictors for LVZ and for ablation success. METHODS AND RESULTS: A total of 119 consecutive patients who underwent their first ablation procedure due to persistent AF were included. After acquisition of a high-resolution LA voltage map, PVI- and LVZ-guided ablation were performed. Mean age was 69 ± 8 years, 53% were men, and 8% had longstanding persistent AF. We found LVZ in 55% of patients. Twelve-month freedom from recurrences off drugs was 69%. The only independent predictor for recurrence was the existence of LVZ (OR 4.2, 95% CI 1.54-11.41, p = 0.005). Existence of LVZ was predicted positively by age ≥ 67 years (OR 4.4, 95% CI 1.4-13.7, p = 0.011), LA volume index ≥ 68 ml/m2 (OR 3.9, 95% CI 1.4-10.5, p = 0.008), and GFR ≤ 85 ml/min/1.73 m2 (OR 12.5, 95% CI 2.0-76.6, p = 0.006). BMI ≥ 26 kg/m2 (OR 0.06, 95% CI 0.01-0.30, p = 0.001) was a negative predictor of LVZ. CONCLUSION: LVZ-guided ablation in combination with PVI results in comparably high success rates. However, the existence of LVZ remains the strongest predictor of ablation success.

Catheter ablation of ventricular arrhythmias and in-hospital mortality: insights from the German-wide Helios hospital network of 5052 cases.

AIMS: Catheter ablation (CA) of ventricular arrhythmias is one of the most challenging electrophysiological interventions with an increasing use over the last years. Several benefits must be weighed against the risk of potentially life-threatening complications which necessitates a steady reevaluation of safety endpoints. Therefore, the aims of this study were (i) to investigate overall in-hospital mortality in patients undergoing such procedures and (ii) to identify variables associated with in-hospital mortality in a German-wide hospital network. METHODS AND RESULTS: Between January 2010 and September 2018, administrative data provided by 85 Helios hospitals were screened for patients with main or secondary discharge diagnosis of ventricular tachycardia (VT) or premature ventricular contractions (PVCs) in combination with an arrhythmia-related CA using ICD- and OPS codes. In 5052 cases (mean age 60.9 ± 14.3 years, 30.1% female) of 30 different hospitals, in-hospital mortality was 1.27% with a higher mortality in patients ablated for VT (1.99%, n = 2, 955) compared to PVC (0.24%, n = 2, 097, P < 0.01). Mortality rates were 2.06% in patients with ischaemic heart disease (IHD, n = 2, 137), 1.47% in patients with non-ischaemic structural heart disease (NIHD, n = 1, 224), and 0.12% in patients without structural heart disease (NSHD, n = 1, 691). Considering different types of hospital admission, mortality rates were 0.35% after elective (n = 2, 825), 1.60% after emergency admission/hospital transfer <24 h (n = 1, 314) and 3.72% following delayed hospital transfer >24 h after initial admission (n = 861, P < 0.01 vs. elective admission and emergency admission/hospital transfer <24 h). In multivariable analysis, a delayed hospital transfer >24 h [odds ratio (OR) 2.28, 95% confidence interval (CI) 1.59-3.28, P < 0.01], the occurrence of procedure-related major adverse events (OR 6.81, 95% CI 2.90-16.0, P < 0.01), Charlson Comorbidity Index (CCI, OR 2.39, 95% CI 1.56-3.66, P < 0.01) and its components congestive heart failure (OR 8.04, 95% CI 1.71-37.8, P < 0.01), and diabetes mellitus (OR 1.59, 95% CI 1.13-2.22, P < 0.01) were significantly associated with in-hospital death. CONCLUSIONS: We reported in-hospital mortality rates after CA of ventricular arrhythmias in the largest multicentre, administrative dataset in Germany which can be implemented in quality management programs. Aside from comorbidities, a delayed hospital transfer to a CA performing centre is associated with an increased in-hospital mortality. This deserves further studies to determine the optimal management strategy.

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.

In-hospital mortality of patients with atrial arrhythmias: insights from the German-wide Helios hospital network of 161 502 patients and 34 025 arrhythmia-related procedures.

Aims: Atrial fibrillation (AFib) and atrial flutter (AFlut) are common arrhythmias with increased use of invasive procedures. A steady re-evaluation of relevant safety endpoints is recommended and both quality management and pay-for-performance programs are evolving. Therefore, the aims of this study were (i) to investigate and report overall in-hospital mortality and mortality of invasive arrhythmia-related procedures and (ii) to identify mortality predictors in a German-wide hospital network. Methods and results: Administrative data provided by 78 Helios hospitals between 2010 and 2017 were examined using International Statistical Classification of Diseases and Related Health Problems- and Operations and Procedures-codes to identify patients with AFib or AFlut as main discharge diagnosis or secondary diagnosis combined with invasive arrhythmia-related interventions. In 161 502 patients, in-hospital mortality was 0.6% with a significant decrease from 0.75% to 0.5% (P < 0.01) during the observational period. In multivariable analysis, age [odds ratio (OR) 2.69, 95% confidence interval (CI) 2.36-3.05; P < 0.01], high centre volume (OR 0.57, 95% CI 0.50-0.65; P < 0.01), emergency hospital admission (OR 1.57, 95% CI 1.38-1.79; P < 0.01), and Charlson Comorbidity Index (CCI, OR 4.95, 95% CI 4.50-5.44; P < 0.01) were found as independent predictors of in-hospital mortality. Mortality rates were 0.05% for left atrial catheter ablation (CA, n = 21 744), 0.3% for right atrial CA (n = 9972), and 0.56% for implantation of a left atrial appendage occluder (n = 2309), respectively. Conclusion: We analysed for the first time in-hospital mortality rates of patients with atrial arrhythmias in a German-wide, multi-centre administrative dataset. This allows feasible, comparable, and up-to-date performance measurement of clinically important endpoints in a real-world setting which may contribute to quality management programs and towards value-based healthcare.

Cardiac tamponade in catheter ablation of atrial fibrillation: German-wide analysis of 21 141 procedures in the Helios atrial fibrillation ablation registry (SAFER).

Aims: Catheter ablation is an established therapy in patients with symptomatic atrial fibrillation (AF) with increasing popularity. Pericardial effusion requiring intervention (PE) is one of the most threatening adverse outcomes. The aim of this study was to examine rates of PE after catheter ablation in a large 'real-world' data set in a German-wide hospital network. Methods and results: Using ICD and OPS codes, administrative data of 85 Helios hospitals from 2010 to 2017 was used to identify AF catheter ablation cases [Helios atrial fibrillation ablation registry (SAFER)]. PE occurred in 0.9% of 21 141 catheter ablation procedures. Patients with PE were significantly older, to a higher percentage female, had more frequently hypertension, mild liver disease, diabetes with chronic complications, and renal disease. Low hospital volume (<50 procedures per year) and radiofrequency ablation (vs. cryoablation) were significantly associated with PE. Using two logistic regression models, age, female gender, hypertension, mild liver disease, diabetes with chronic complications, renal disease, low hospital volume, and radiofrequency ablation remained independent predictors for PE. Conclusion: Overall PE rate was 0.9%. Predictors for PE occurrence involved factors ascribed to the patient (age, gender, comorbidities), the type of catheter ablation (radiofrequency), and the institution (low-volume centres).

Clinical Impact of the Microembolic Signal Burden During Catheter Ablation for Atrial Fibrillation: Just a Lot of Noise?

OBJECTIVES: Microembolic signal detection by transcranial Doppler ultrasonography may be considered a surrogate for cerebral events during invasive cardiac procedures. However, the impact of the microembolic signal count during pulmonary vein isolation on the clinical outcome is not well evaluated. We investigated the effect of the microembolic signal count on the occurrence of new silent cerebral embolism measured by diffusion-weighted imaging (DWI)-magnetic resonance imaging (MRI), changes in neuropsychological testing, and the occurrence of clinical events during long-term follow-up after pulmonary vein isolation. METHODS: Pulmonary vein isolation was performed in 41 patients. The total microembolic signal burden (classified into "solid," "gaseous," and "equivocal") and sustained thromboembolic showers of greater than 30 seconds were recorded. Diffusion-weighted imaging-MRI and neuropsychological testing were performed before and after pulmonary vein isolation to assess for silent cerebral embolism and neuropsychological sequelae. Long-term follow-up was performed by telephone to assess for stroke/transient ischemic attack. RESULTS: A total of 68,729 microembolic signals (14,893 solid, 11,909 gaseous, and 41,927 equivocal) with an average of 1676 signals per patient and 42 thromboembolic showers were recorded. No correlation between the microembolic signal/thromboembolic shower count and the occurrence of new DWI lesions or neuropsychological capability was found. After a mean follow-up ± SD of 49 ± 4 months, 1 patient had an overt transient ischemic event, which was not associated with a high microembolic signal count. CONCLUSIONS: In this multicenter study, we found no impact of the intraprocedural microembolic symbol/thromboembolic shower count on the occurrence of new DWI lesions, neuropsychological capability, or overt neurologic deficits after pulmonary vein isolation. Thus, not only the microembolic signal count but also procedural/individual factors may contribute to commensurable clinical damage, which may challenge this method as a valid biomarker during pulmonary vein isolation.

Low rate of access site complications after transradial coronary catheterization: A prospective ultrasound study.

BACKGROUND: Transradial artery (TRA) left heart catheterization is an increasingly used technique for both diagnostic and interventional coronary procedures. This study evaluates the incidence of access site complications in the current interventional era. METHODS AND RESULTS: A total of 507 procedures were performed under standardized conditions. Each procedure was performed using high levels of anticoagulation, hydrophilic sheaths, and short post-procedural compression times. Vascular complications were assessed one day after TRA catheterization using Duplex sonography and classified according to the necessity of additional medical intervention. A simple questionnaire helped identifying upper extremity neurologic or motor complications. Vascular complications were detected in 12 patients (2.36%): radial artery occlusion was detected in 9 patients (1.77%), 1 patient developed an AV-fistula (0.19%), and 2 patients had pseudoaneurysms (0.38%). None of the patients required specialized medical or surgical intervention. Under our procedural conditions, small radial artery diameter was the only significant predictor for the development of post-procedural vascular complications (2.11 ± 0.42 mm vs 2.52 ± 0.39 mm, p = 0.001). None of the previously reported risk factors, namely, advanced renal failure, diabetes, acuteness/complexity of procedure, or sheath and catheter size significantly influenced the rate of vascular complications. No major hematoma or local neurologic or motor complications were identified. CONCLUSIONS: Using current techniques and materials, we report a very low rate of local complications associated with TRA catheterization.

Online Measurement of Microembolic Signal Burden by Transcranial Doppler during Catheter Ablation for Atrial Fibrillation-Results of a Multicenter Trial.

INTRODUCTION: Left atrial pulmonary vein isolation (PVI) is an accepted treatment option for patients with symptomatic atrial fibrillation (AF). This procedure can be complicated by stroke or silent cerebral embolism. Online measurement of microembolic signals (MESs) by transcranial Doppler (TCD) may be useful for characterizing thromboembolic burden during PVI. In this prospective multicenter trial, we investigated the burden, characteristics, and composition of MES during left atrial catheter ablation using a variety of catheter technologies. MATERIALS AND METHODS: PVI was performed in a total of 42 patients using the circular-shaped multielectrode pulmonary vein ablation catheter (PVAC) technology in 23, an irrigated radiofrequency (IRF) in 14, and the cryoballoon (CB) technology in 5 patients. TCD was used to detect the total MES burden and sustained thromboembolic showers (TESs) of >30 s. During TES, the site of ablation within the left atrium was registered. MES composition was classified manually into "solid," "gaseous," or "equivocal" by off-line expert assessment. RESULTS: The total MES burden was higher when using IRF compared to CB (2,336 ± 1,654 vs. 593 ± 231; p = 0.007) and showed a tendency toward a higher burden when using IRF compared to PVAC (2,336 ± 1,654 vs. 1,685 ± 2,255; p = 0.08). TES occurred more often when using PVAC compared to IRF (1.5 ± 2 vs. 0.4 ± 1.3; p = 0.04) and most frequently when ablation was performed close to the left superior pulmonary vein (LSPV). Of the MES, 17.004 (23%) were characterized as definitely solid, 13.204 (18%) as clearly gaseous, and 44.366 (59%) as equivocal. DISCUSSION: We investigated the burden and characteristics of MES during left atrial catheter ablation for AF. All ablation techniques applied in this study generated a relevant number of MES. There was a significant difference in total MES burden using IRF compared to CB and a tendency toward a higher burden using IRF compared to PVAC. The highest TES burden was found in the PVAC group, particularly during ablation close to the LSPV. The composition of thromboembolic particles was balanced. The impact of MES, TES, and composition of thromboembolic particles on neurological outcome needs to be evaluated further. (Clinical Trial Registration: Deutsches Register Klinischer Studien, https://drks-neu.uniklinik-freiburg.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00003465. DRKS00003465.).

Decreasing incidence of coronary heart disease in extreme obesity (BMI≥40)-A single centre experience.

AIM: The aim of our comprehensive single centre analysis was to evaluate the incidence of coronary heart disease (CHD) in extremely obese patients. METHODS AND RESULTS: Between 2005 and 2015 we investigated retrospectively 23,359 patients undergoing cardiac catheterisation in our institution. Patients were divided in six weight classes according to World Health Organization (WHO) criteria [1] (WHO, 2000). Cardiovascular risk factors, comorbidities, CCS stadium [2] (Cox and Naylor, 1992) and NYHA functional class [3] (The Criteria Committee of the New York Heart Association, 1994) were retrieved from electronic patient records. Using multivariable analysis the odds ratio for the target variable CHD with presence of >50% angiographic stenosis was ≥1 with regard to age (OR 1.049, 95% CI 1.045-1.052), male sex (OR 2.507, 95% CI 2.329-2.699), cardiovascular risk factors, atherosclerosis (OR 1.651, 95% CI 1.498-1.820), and presence of angina (OR 4.408, 95% CI 3.892-4.993). NYHA functional class I-IV, absence of angina (OR 0.818, 95% CI 0.729-0.918), and BMI≥40 (OR 0.592, 95% CI 0.494-0.709) resulted in an odds ratio of ≤1. Underweight patients had a higher (5.3%) and overweight (1.2%) and obese patients (class I 0.9% and II 1.1%) a slightly lower all-cause in-hospital mortality compared to extremely obese patients (1.6%). CONCLUSION: Severely obese patients treated in our hospital surprisingly showed a decreased incidence of CHD (46.1% in normal weight and 38.6% in extremely obese patients) while comorbidities increased CHD as expected. Although CHD burden was lower, obesity and associated comorbidities resulted in higher all-cause-in-hospital mortality.

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.

Spatial Relationship of Focal Impulses, Rotors and Low Voltage Zones in Patients With Persistent Atrial Fibrillation.

INTRODUCTION: Focal impulses (FI) and rotors are sources associated with the initiation and maintenance of atrial fibrillation (AF). Their ablation results in a lower recurrence rate. The aim of this study was to characterize for the first time the spatial relationship between such sources and atrial low voltage zones (LVZ) representing fibrosis. METHODS: Twenty-five consecutive patients undergoing their first ablation for persistent AF were included. Voltage mapping of both atria was done during AF. Endocardial mapping of FI and rotors (sources) was performed using a basket catheter and displayed using RhythmView(TM) (Topera Inc.) before ablation. Spatial relationship of LVZ and sources was analyzed. RESULTS: LVZs covered 13 ± 12% of right atrial (RA) endocardial surface and 33 ± 25% of left atrial (LA) endocardial surface. The median number of sources was 1 [1-3] in RA and 3 [1-4] in LA. Of LA sources, 18 (30%) were definitely not associated with LVZs or pulmonary vein (PV) antra. Of RA sources, 32 (84%) were remote from LVZ. During ablation of such sources substantial cycle length (CL) prolongation or AF conversion occurred in 11/23 patients (48%). Altogether, 8/11 (73%) of these pertinent sources were located remotely from LVZ and PV antra. CONCLUSIONS: There is a wide discrepancy in distribution of LVZ areas and sites of identified rotors. Site and incidence of FIRM sources appear to be unpredictable with atrial substrate mapping. Further prospective, randomized studies are necessary to elucidate the impact of additional ablation of such sources in patients with persistent or longstanding persistent AF.

Acute and early outcomes of focal impulse and rotor modulation (FIRM)-guided rotors-only ablation in patients with nonparoxysmal atrial fibrillation.

BACKGROUND: Focal impulse and rotor modulation (FIRM)-guided ablation targets sites that are thought to sustain atrial fibrillation (AF). OBJECTIVE: The purpose of this study was to evaluate the acute and mid-term outcomes of FIRM-guided only ablation in patients with nonparoxysmal AF. METHODS: We prospectively enrolled patients with persistent and long-standing persistent (LSP) AF at three centers to undergo FIRM-guided only ablation. We evaluated acute procedural success (defined as AF termination, organization, or ≥10% slowing), safety (incidence of periprocedural complications), and long-term success (single-procedure freedom from atrial tachycardia [AT]/AF off antiarrhythmic drugs [AAD] after a 2-month blanking period). RESULTS: Twenty-nine patients with persistent (N = 20) and LSP (N = 9) AF underwent FIRM mapping. Rotors were presents in all patients, with a mean of 4 ± 1.2 per patient (62% were left atrial); 1 focal impulse was identified. All sources were successfully ablated, and overall acute success rate was 41% (0 AF termination, 2 AF slowing, 10 AF organization). There were no major procedure-related adverse events. After a mean 5.7 months of follow-up, single-procedure freedom from AT/AF without AADs was 17%. CONCLUSION: In nonparoxysmal AF patients, targeted ablation of FIRM-identified rotors is not effective in obtaining AF termination, organization, or slowing during the procedure. After mid-term follow-up, the strategy of ablating FIRM-identified rotors alone did not prevent recurrence from AT/AF.

Effect of Different Ablation Settings on Acute Complications Using the Novel Irrigated Multipolar Radiofrequency Ablation Catheter (nMARQ).

BACKGROUND: Single-shot ablation devices for pulmonary vein isolation (PVI) in patients with symptomatic atrial fibrillation (AF) have been increasingly used in clinical practice. OBJECTIVE: A novel mapping-system integrated irrigated multipolar circular ablation catheter (nMARQ) has been introduced for PVI but data on larger patient cohorts on acute safety and efficacy are lacking. METHODS: A total of 145 consecutive patients undergoing AF ablation treated with the nMARQ underwent endoscopic evaluation of esophageal thermal damage (EDEL) and brain MRI for detection of silent cerebral events (SCE). During the course of our experience different modifications of the ablation strategy, including energy delivery at the left atrial posterior wall, were evaluated. RESULTS: Effective PVI was achieved in 99% of all PVs during a mean procedure-duration of 115 (±36) minutes and ablation-duration of 18 (±8) minutes. Acute major complications occurred in 3 patients (2.1%) and asymptomatic complications like SCE in 26% and EDEL in 21%. There was a significant reduction in EDEL when not using a thermal esophageal probe (0% vs. 28%, P < 0.0001). Ablation under oral anticoagulation led to lower SCE incidences compared to interrupted anticoagulation regimen (15% vs. 31%, P = 0.7). Out of 65 patients with completed 12-month follow-up, 43 (66%) were in stable sinus rhythm. CONCLUSIONS: PVI using the nMARQ is safe and effective in patients with symptomatic AF. Not using an esophageal temperature probe during ablation has relevantly reduced the incidence of EDEL. Ablations under continued oral anticoagulation have reduced incidence of SCE. Further studies on long-term efficacy are needed.