Atrial fibrillation cryoablation is an effective day case treatment: the UK PolarX vs. Arctic Front Advance experience.

AIMS: Pulmonary vein isolation (PVI) is the cornerstone of catheter ablation for atrial fibrillation (AF). There are limited data on the PolarX Cryoballoon. The study aimed to establish the safety, efficacy, and feasibility of same day discharge for Cryoballoon PVI. METHODS AND RESULTS: Multi-centre study across 12 centres. Procedural metrics, safety profile, and procedural efficacy of the PolarX Cryoballoon with the Arctic Front Advance (AFA) Cryoballoon were compared in a cohort large enough to provide definitive comparative data. A total of 1688 patients underwent PVI with cryoablation (50% PolarX and 50% AFA). Successful PVI was achieved with 1677 (99.3%) patients with 97.2% (n = 1641) performed as day case procedures with a complication rate of <1%. Safety, procedural metrics, and efficacy of the PolarX Cryoballoon were comparable with the AFA cohort. The PolarX Cryoballoon demonstrated a nadir temperature of -54.6 ± 7.6°C, temperature at 30 s of -38.6 ± 7.2°C, time to -40°C of 34.1 ± 13.7 s, and time to isolation of 49.8 ± 33.2 s. Independent predictors for achieving PVI included time to reach -40°C [odds ratio (OR) 1.34; P < 0.001] and nadir temperature (OR 1.24; P < 0.001) with an optimal cut-off of ≤34 s [area under the curve (AUC) 0.73; P < 0.001] and nadir temperature of ≤-54.0°C (AUC 0.71; P < 0.001), respectively. CONCLUSIONS: This large-scale UK multi-centre study has shown that Cryoballoon PVI is a safe, effective day case procedure. PVI using the PolarX Cryoballoon was similarly safe and effective as the AFA Cryoballoon. The cryoablation metrics achieved with the PolarX Cryoballoon were different to that reported with the AFA Cryoballoon. Modified cryoablation targets are required when utilizing the PolarX Cryoballoon.

PolarX Cryoballoon metrics predicting successful pulmonary vein isolation: targets for ablation of atrial fibrillation.

AIM: Evaluate the novel PolarX Cryoballoon in atrial fibrillation (AF) catheter ablation through a propensity-matched comparison with the Arctic Front Advance (AFA). The aim was also to identify cryoablation metrics that are predictive of successful pulmonary vein isolation (PVI) with the PolarX Cryoballoon. METHODS AND RESULTS: This prospective multi-centre study included patients that underwent cryoablation for AF. All patients underwent PVI with reconnection assessed after a 30-min waiting period and adenosine. Safety, efficacy, and cryoablation metrics were compared between PolarX and a propensity-matched AFA cohort. Seventy patients were included with 278 veins treated. In total, 359 cryoablations were performed (1.3 ± 0.6 per vein) to achieve initial PVI with 205 (73.7%) veins isolating with a single cryoablation. Independent predictors for achieving initial PVI included temperature at 30 s [odds ratio (OR) 1.26; P = 0.003] and time to reach -40°C (OR 1.88; P < 0.001) with an optimal cut-off of ≤-38.5°C at 30 s [area under the curve (AUC) 0.79; P < 0.001] and ≤-40°C at ≤32.5 s (AUC 0.77; P < 0.001), respectively. Of the 278 veins, 46 (16.5%) veins showed acute reconnection. Temperature at 30 s (≤-39.5°C, OR 1.24; P = 0.002), nadir temperature (≤-53.5°C, OR 1.35; P = 0.003), and time to isolation (≤38.0 s, OR 1.18; P = 0.009) were independent predictors of sustained PVI. Combining two of these three targets was associated with reconnection in only 2-5% of PVs. Efficacy and safety of the PolarX Cryoballoon were comparable to AFA Cryoballoon, however, cryoablation metrics were significantly different. CONCLUSIONS: The PolarX Cryoballoon has a different cryoablation profile to AFA Cryoballoon. Prospective testing of these proposed targets in large outcomes studies is required.

Adaptive translational reprogramming of metabolism limits the response to targeted therapy in BRAFV600 melanoma.

Despite the success of therapies targeting oncogenes in cancer, clinical outcomes are limited by residual disease that ultimately results in relapse. This residual disease is often characterized by non-genetic adaptive resistance, that in melanoma is characterised by altered metabolism. Here, we examine how targeted therapy reprograms metabolism in BRAF-mutant melanoma cells using a genome-wide RNA interference (RNAi) screen and global gene expression profiling. Using this systematic approach we demonstrate post-transcriptional regulation of metabolism following BRAF inhibition, involving selective mRNA transport and translation. As proof of concept we demonstrate the RNA processing kinase U2AF homology motif kinase 1 (UHMK1) associates with mRNAs encoding metabolism proteins and selectively controls their transport and translation during adaptation to BRAF-targeted therapy. UHMK1 inactivation induces cell death by disrupting therapy induced metabolic reprogramming, and importantly, delays resistance to BRAF and MEK combination therapy in multiple in vivo models. We propose selective mRNA processing and translation by UHMK1 constitutes a mechanism of non-genetic resistance to targeted therapy in melanoma by controlling metabolic plasticity induced by therapy.

Ultralow temperature cryoablation: Safety and efficacy of preclinical atrial and ventricular lesions.

BACKGROUND: Ultralow temperature cyroablation (ULTC) is designed to create focal, linear, and circumferential lesions. The aim of this study was to assess the safety, efficacy, and durability of atrial and ventricular ULTC lesions in preclinical large animal models. METHODS AND RESULTS: The ULTC system uses nitrogen near its liquid-vapor critical point to cool 11-cm ablation catheters. The catheter can be shaped to specific anatomies using pre-shaped stylets. ULTC was used in 11 swine and four sheep to create atrial (pulmonary vein isolation and linear ablation) and ventricular lesions. Acute and 90-day success were evaluated by intracardiac mapping and histologic examination. Cryoadherence was observed during all ULTC applications, ensuring catheter stability at target locations. Local electrograms were completely eliminated immediately after the first single-shot ULTC application in 49 of 53 (92.5%) atrial and in 31 of 32 (96.9%) ventricular applications. Lesion depth as measured on histology preparations was 1.96 ± 0.8 mm in atrial and 5.61 ± 2.2 mm in ventricular lesions. In all animals, voltage maps and histology demonstrated transmural and durable lesions without gaps, surrounded by intact collagen fibers without injury to surrounding tissues. Transient coronary spasm could be provoked with endocardial ULTC in the left ventricle in close proximity to a coronary artery. CONCLUSIONS: ULTC created effective and efficient atrial and ventricular lesions in vivo without procedural complications in two large animal models. ULTC lesions were transmural, contiguous, and durable over 3 months.

Atrial fibrillation in Brugada syndrome: Current perspectives.

The incidence of atrial fibrillation (AF) in Brugada syndrome (BrS) has been reported at between 9% and 53% by different series, but the true prevalence is unknown. However, AF may be the presenting feature in some patients. The underlying mechanisms for AF may be a combination of multiple factors, genetic or acquired, that may impact upon autonomic function, atrial structure, and conduction velocities or other unknown factors. The presence of AF has been associated with a more malignant course, with a greater incidence of syncope and ventricular arrhythmias, thus acting as marker of more advanced disease. Regarding the management of patients with AF, antiarrhythmic drugs effective in preventing malignant arrhythmias in BrS such as quinidine or invasive treatment with pulmonary vein isolation (PVI) may be useful in AF treatment. In this review, we aim to present the current perspectives regarding the genetics, pathophysiology, management, and prognosis of AF in patients with BrS.

Mechanism of Recurrence of Atrial Tachycardia: Comparison Between First Versus Redo Procedures in a High-Resolution Mapping System.

BACKGROUND: Atrial fibrillation ablation-related atrial tachycardia (AT) is complex and may demonstrate several forms: anatomic macroreentrant AT (AMAT), non-AMAT, and focal AT. We aimed to elucidate the recurrence rate and mechanisms of atrial fibrillation ablation-related AT recurrence. METHODS: Among 147 patients with ATs treated with the Rhythmia system, 68 (46.3%) had recurrence at mean 4.2 (2.9-11.6) months, and 44 patients received a redo procedure. AT circuits in the first procedure were compared with those in the redo procedure. RESULTS: Although mappable ATs were not observed in 7 patients, 68 ATs were observed in 37 patients during the first procedure: perimitral flutter (PMF) in 26 patients, roof-dependent macroreentrant AT (RMAT) in 18, peritricuspid flutter in 10, non-AMAT in 14, and focal AT in 3. During the redo AT ablation procedure, 54 ATs were observed in 41/44 patients: PMF in 24, RMAT in 14, peritricuspid flutter in 1, non-AMAT in 14, and focal AT in 1. Recurrence of PMF and RMAT was observed in 15 of 26 (57.7%) and 8 of 18 (44.4%) patients, respectively, while peritricuspid flutter did not recur. Neither the same focal AT nor the same non-AMAT were observed except in 1 case with septal scar-related biatrial AT. Epicardial structure-related ATs were involved in 18 of 24 (75.0%) patients in PMF, 4 of 14 (28.6%) in RMAT, and 4 of 14 (28.6%) in non-AMAT. Of 21 patients with a circuit including epicardial structures, 6 patients treated with ethanol infusion in the vein of Marshall did not show any AT recurrence, although 8 of 15 (53.3%) treated with radiofrequency showed AT recurrence (P=0.04). CONCLUSIONS: Although high-resolution mapping may lead to correct diagnosis and appropriate ablation in the first procedure, the recurrence rate is still high. The main mechanism of atrial fibrillation ablation-related AT is the recurrence of PMF and RMAT or non-AMAT different from the first procedure. Epicardial structures (eg, coronary sinus/vein of Marshall system) are often involved, and ethanol infusion in the vein of Marshall may be an additional treatment.

Ultra-High-Density Activation Mapping to Aid Isthmus Identification of Atrial Tachycardias in Congenital Heart Disease.

OBJECTIVES: A new electroanatomic mapping system (Rhythmia, Boston Scientific, Marlborough, Massachusetts) using a 64-electrode mapping basket is now available; we systematically assessed its use in complex congenital heart disease (CHD). BACKGROUND: The incidence of atrial arrhythmias post-surgery for CHD is high. Catheter ablation has emerged as an effective treatment, but is hampered by limitations in the mapping system's ability to accurately define the tachycardia circuit. METHODS: Mapping and ablation data of 61 patients with CHD (35 males, age 45 ± 14 years) from 8 tertiary centers were reviewed. RESULTS: Causes were as follows: Transposition of Great Arteries (atrial switch) (n = 7); univentricular physiology (Fontans) (n = 8); Tetralogy of Fallot (n = 10); atrial septal defect (ASD) repair (n = 15); tricuspid valve (TV) anomalies (n = 10); and other (n = 11). The total number of atrial arrhythmias was 86. Circuits were predominantly around the tricuspid valve (n = 37), atriotomy scar (n = 10), or ASD patch (n = 4). Although the majority of peri-tricuspid circuits were cavo-tricuspid-isthmus dependent (n = 30), they could follow a complex route between the annulus and septal resection, ASD patch, coronary sinus, or atriotomy. Immediate ablation success was achieved in all but 2 cases; with follow-up of 12 ± 8 months, 7 patients had recurrence. CONCLUSIONS: We demonstrate the feasibility of the basket catheter for mapping complex CHD arrhythmias, including with transbaffle and transhepatic access. Although the circuits often involve predictable anatomic landmarks, the precise critical isthmus is often difficult to predict empirically. Ultra-high-density mapping enables elucidation of circuits in this complex anatomy and allows successful treatment at the isthmus with a minimal lesion set.

Three-dimensional image integration guidance for cryoballoon pulmonary vein isolation procedures.

BACKGROUND: We present a new, easily applicable approach for the guidance of cryoballoon (CB) pulmonary vein isolation (PVI) procedures that use the combination of a 3D-mapping system image integration module and computed tomographic (CT)-derived anatomy. The aim of this retrospective, nonrandomized study was to investigate: (a) an alternative use for an established radiofrequency image integration module for cryo procedures; (b) a guidance technology for cryo PVI based on integrated CT anatomy; and (c) its clinical impact. METHODS AND RESULTS: CT left atrium-angiography was performed in 50 consecutive patients before a CB PVI procedure, and a 3D reconstruction of the cardiac anatomy was segmented. A total of 25 patients were treated using conventional fluoroscopy; 25 patients were treated using the 3D image integration technique. In the image integration group, the CARTO3 UNIVU (Biosense Webster) module was used for image integration of 3D anatomy and fluoroscopic imaging. Transseptal puncture and cryo PVI were guided by 3D-overlay imaging. Procedures were feasible without complications in all patients and cryo PVI procedures were successfully guided using the image integration technique. The intraprocedural time needed to perform image integration was 37 ± 10 seconds. Fluoroscopy time was 31.7 ± 11.7 minutes in the conventional group and 20.1 ± 7.9 minutes in the image integration group (P < .001), procedure time was 116.3 ± 29.0 minutes in the conventional group vs 101.2 ± 20.9 minutes in the 3D group (P = .04). CONCLUSION: 3D-overlay guidance of CB PVI is feasible, safe, and applicable in real time with minimal effort. It may significantly reduce radiation exposure by introducing 3D information, known from electroanatomic mapping systems, into cryo PVI procedures.

A novel immunogenic mouse model of melanoma for the preclinical assessment of combination targeted and immune-based therapy.

Both targeted therapy and immunotherapy have been used successfully to treat melanoma, but the development of resistance and poor response rates to the individual therapies has limited their success. Designing rational combinations of targeted therapy and immunotherapy may overcome these obstacles, but requires assessment in preclinical models with the capacity to respond to both therapeutic classes. Herein, we describe the development and characterization of a novel, immunogenic variant of the BrafV600ECdkn2a-/-Pten-/- YUMM1.1 tumor model that expresses the immunogen, ovalbumin (YOVAL1.1). We demonstrate that, unlike parental tumors, YOVAL1.1 tumors are immunogenic in vivo and can be controlled by immunotherapy. Importantly, YOVAL1.1 tumors are sensitive to targeted inhibitors of BRAFV600E and MEK, responding in a manner consistent with human BRAFV600E melanoma. The YOVAL1.1 melanoma model is transplantable, immunogenic and sensitive to clinical therapies, making it a valuable platform to guide strategic development of combined targeted therapy and immunotherapy approaches in BRAFV600E melanoma.

Characteristics of Single-Loop Macroreentrant Biatrial Tachycardia Diagnosed by Ultrahigh-Resolution Mapping System.

BACKGROUND: Biatrial tachycardia (BiAT) is a rare form of atrial macroreentrant tachycardia, in which both atria form a critical part of the circuit. We aimed to identify the characteristics and precise circuits of single-loop macroreentrant BiATs. METHODS AND RESULTS: We identified 8 patients (median age, 59.5 years old) with 9 BiATs in a cohort of 336 consecutive patients from 2 institutions who had undergone AT catheter ablation using an automatic ultrahigh-resolution mapping system. Seven of the 8 patients had a history of persistent AF ablation, including septal or anterior left atrium ablation before developing BiAT. One of the 8 patients had a history of an atrial septal patch closure with a massively enlarged right atrium. Nine ATs (median cycle length, 334 ms; median 12 561 points in the left atrium; 8814 points in the right atrium) were diagnosed as single-loop macroreentrant BiATs. We observed 3 types of BiAT (1) BiAT with a perimitral and peritricuspid reentrant circuit (n=3), (2) BiAT using the right atrium septum and a perimitral circuit (n=3), and (3) BiAT using only the left atrium and right atrium septum (n=3). Catheter ablation successfully terminated 8 of the 9 BiATs. CONCLUSIONS: All patients who developed BiAT had an electric obstacle on the anteroseptal left atrium, primarily from prior ablation lesions. In this situation, mapping of both atria should be considered during AT. Because 3 types of single-loop BiAT were observed, ablation strategies should be adjusted to the type of BiAT circuit.

Improved outcome and cost effectiveness in ablation of persistent atrial fibrillation under general anaesthetic.

Aims: Outcome of persistent atrial fibrillation (AF) ablation remains suboptimal. Techniques employed to reduce arrhythmia recurrence rate are more likely to be embraced if cost-effectiveness can be demonstrated. A single-centre observational study assessed whether use of general anaesthesia (GA) in persistent AF ablation improved outcome and was cost-effective. Methods and results: Two hundred and ninety two patients undergoing first ablation procedures for persistent AF under conscious sedation or GA were followed. End points were freedom from listing for repeat ablation at 18 months and freedom from recurrence of atrial arrhythmia at 1 year. Freedom from atrial arrhythmia was higher in patients who underwent ablation under GA rather than sedation (63.9% vs. 42.3%, hazard ratio (HR) 1.87, 95% confidence interval (CI): 1.23-2.86, P = 0.002). Significantly fewer GA patients were listed for repeat procedures (29.2% vs. 42.7%, HR 1.62, 95% CI: 1.01-2.60, P = 0.044). Despite GA procedures costing slightly more, a saving of £177 can be made per patient in our centre for a maximum of two procedures if all persistent AF ablations are performed under GA. Conclusions: In patients with persistent AF, it is both clinical and economically more effective to perform ablation under GA rather than sedation.

Palbociclib synergizes with BRAF and MEK inhibitors in treatment naïve melanoma but not after the development of BRAF inhibitor resistance.

Increased CDK4 activity occurs in the majority of melanomas and CDK4/6 inhibitors in combination with BRAF and MEK inhibitors are currently in clinical trials for the treatment of melanoma. We hypothesize that the timing of the addition of CDK4/6 inhibitors to the current BRAF and MEK inhibitor regime will impact on the efficacy of this triplet drug combination. The efficacy of BRAF, MEK and CDK4/6 inhibitors as single agents and in combination was assessed in human BRAF mutant cell lines that were treatment naïve, BRAF inhibitor tolerant or had acquired resistance to BRAF inhibitors. Xenograft studies were then performed to test the in vivo efficacy of the BRAF and CDK4/6 inhibitor combination. Melanoma cells that had developed early reversible tolerance or acquired resistance to BRAF inhibition remained sensitive to palbociclib. In drug-tolerant cells, the efficacy of the combination of palbociclib with BRAF and/or MEK inhibitors was equivalent to single agent palbociclib. Similarly, acquired BRAF inhibitor resistance cells lost efficacy to the palbociclib and BRAF combination. In contrast, upfront treatment of melanoma cells with palbociclib in combination with BRAF and/or MEK inhibitors induced either cell death or senescence and was superior to a BRAF plus MEK inhibitor combination. In vivo palbociclib plus BRAF inhibitor induced rapid and sustained tumor regression without the development of therapy resistance. In summary, upfront dual targeting of CDK4/6 and mutant BRAF signaling enables tumor cells to evade resistance to monotherapy and is required for robust and sustained tumor regression. Melanoma patients whose tumors have acquired resistance to BRAF inhibition are less likely to have favorable responses to subsequent treatment with the triplet combination of BRAF, MEK and CDK4/6 inhibitors.

Palpitations in a 72-year-old woman.

CLINICAL INTRODUCTION: A 72-year-old woman presented with an 8-year history of palpitations occurring every few weeks. They were sudden in onset, were associated with dizziness and could last for up to 2 hours. She was prescribed bisoprolol which reduced the frequency of events but did not abolish them. Baseline ECG and echocardiography were normal. She was referred for electrophysiological study. Despite initial difficulties, diagnostic catheters were placed in the right ventricular (RV) apex and in the coronary sinus (CS) via the right internal jugular vein and superior vena cava (SVC) (figure 1A). A narrow complex tachycardia was easily induced, and ablation was then delivered during tachycardia with the ablation catheter positioned as shown in (figure 1A). This terminated tachycardia 4 s after onset of energy delivery and on follow-up she has remained asymptomatic. She later underwent a CT scan (figure 1B,C; online supplementary video).DC1SP110.1136/heartjnl-2017-311734.supp1Supplementary file 1 heartjnl;103/19/1554/F1F1F1Figure 1(A) Fluoroscopy of catheter placement. (B) Sagittal contrast-enhanced CT image. (C) Axial contrast-enhanced CT. QUESTION: What anatomical abnormality caused difficulty in catheter placement during the procedure?Azygous continuation of the inferior vena cava (IVC)Giant Eustachian valveDextrocardiaRenal tumour compressing IVC.