Pulsed field ablation (PFA) has proven to be a safe and effective non-thermal ablation modality for the treatment of atrial fibrillation (AF), but little outcome data beyond 1 year have been reported. Here we present results from the ADVENT-LTO study, which provides extended follow-up of the ADVENT trial, the first randomized trial comparing PFA with conventional thermal ablation. In ADVENT-LTO, 364 patients with paroxysmal AF (183 PFA, 181 thermal; 237 men, 127 women) participated and were followed for 1,332 ± 147 days. For the primary endpoint of 4-year treatment success, PFA demonstrated preserved effectiveness compared to thermal ablation (72.8% PFA, 64.3% thermal; P = 0.12). Moreover, there was a trend favoring PFA as compared to thermal ablation for the prespecified outcome of freedom from hospital-based arrhythmia intervention (85.6% PFA, 78.6% thermal; hazard ratio (HR) = 0.64, 95% confidence interval (CI): 0.38-1.05), including fewer repeat ablations (10.4% PFA, 17.7% thermal; P = 0.04) as well as a trend favoring PFA as compared to thermal ablation for the prespecified outcome of progression to persistent AF (2.6% PFA, 4.6% thermal; HR = 0.55, 95% CI: 0.16-1.88). Taken together, these data demonstrate that the favorable outcomes of PFA are maintained over the course of 4 years. Coupled with the safety advantages of PFA over thermal ablation, these long-term data support widespread adoption of PFA for the treatment of AF. ClinicalTrials.gov registration: NCT06526546 .

BACKGROUND:Although emerging evidence supports 3-dimensional myocardial activation during atrial fibrillation (AF), human studies remain limited. We thus characterized the endocardial and epicardial left atrial posterior wall (LAPW) in humans to assess the prevalence of asynchronous endocardial-epicardial LAPW conduction during AF.METHODS:Patients with symptomatic nonparoxysmal AF who had unsuccessful antiarrhythmic or catheter ablation therapy referred for hybrid epicardial-endocardial AF ablation and left atrial appendage ligation underwent high-density mapping of LAPW with Grid catheters, including simultaneous endocardial-epicardial mapping.RESULTS:Twenty-seven patients (19 men, median 69 years, 55% long-standing persistent AF) were included. There was significantly greater epicardial compared with endocardial LAPW bipolar voltages during AF. In areas of low endocardial bipolar voltage, normal endocardial unipolar voltage corresponded to normal epicardial bipolar voltage. Asynchronous endocardial-epicardial LAPW AF activation during simultaneous endocardial-epicardial mapping was universal. Furthermore, more rapid epicardial compared with endocardial LAPW AF activity was observed during simultaneous endocardial-epicardial mapping in AF. Conduction block between the endocardial and epicardial LAPW surfaces was also common during organized AF, with instances of isolated or multiple blocked beats, Wenckebach conduction, and sustained endocardial LAPW entrance block with ongoing epicardial AF observed. Epicardial-to-endocardial entrance block was also infrequently observed during sinus rhythm. At 12-month follow-up, freedom from atrial arrhythmias was 68%.CONCLUSIONS:Endocardial-epicardial LAPW asynchrony may be observed during human persistent AF and is characterized by: (1) greater epicardial compared with endocardial bipolar voltages, (2) more frequent epicardial-to-endocardial activation gradients during AF, and (3) conduction block commonly seen between the epicardial and endocardial surfaces during AF. Although the study was predominantly descriptive in nature, the observations suggest a dynamic 3-dimensional arrhythmogenicity of the LAPW and the potential importance of the epicardial layer, with implications for ablation therapies. Future prospective studies are required to determine the significance of these findings to clinical ablation outcomes.

AIMS:Prior case series showed promising results for cardioneuroablation in patients with vagally induced atrioventricular blocks (VAVBs). We aimed to examine the acute procedural characteristics and intermediate-term outcomes of electroanatomical-guided cardioneuroablation (EACNA) in patients with VAVB. METHODS AND RESULTS:This international multicentre retrospective registry included data collected from 20 centres. Patients presenting with symptomatic paroxysmal or persistent VAVB were included in the study. All patients underwent EACNA. Procedural success was defined by the acute reversal of atrioventricular blocks (AVBs) and complete abolition of atropine response. The primary outcome was occurrence of syncope and daytime second- or advanced-degree AVB on serial prolonged electrocardiogram monitoring during follow-up. A total of 130 patients underwent EACNA. Acute procedural success was achieved in 96.2% of the cases. During a median follow-up of 300 days (150, 496), the primary outcome occurred in 17/125 (14%) cases with acute procedural success (recurrence of AVB in 9 and new syncope in 8 cases). Operator experience and use of extracardiac vagal stimulation were similar for patients with and without primary outcomes. A history of atrial fibrillation, hypertension, and coronary artery disease was associated with a higher primary outcome occurrence. Only four patients with primary outcome required pacemaker placement during follow-up. CONCLUSION:This is the largest multicentre study demonstrating the feasibility of EACNA with encouraging intermediate-term outcomes in selected patients with VAVB. Studies investigating the effect on burden of daytime symptoms caused by the AVB are required to confirm these findings.

BACKGROUND Current annotation of local fractionated signals during ventricular electroanatomic mapping (EAM) requires manual input subject to variability and error. OBJECTIVES The purpose of this study was to evaluate a novel peak frequency (PF) annotation software for its ability automatically detect late potentials (LPs) and local abnormal ventricular activity (LAVA), determine an optimal range for display, and assess its impact on isochronal late activation mapping (ILAM). METHODS EAM data from 25 patients who underwent ventricular tachycardia (VT) ablation were retrospectively analyzed. Sam-plings of electrogram PFs from areas of normal bipolar voltage, areas of low voltage, and areas of low voltage with fractioned signals were performed. An optimal range of frequency display was identified from these patients and applied to a validation cohort of 10 prospective patients to assess high PF within scar as a predictor of VT ablation target sites, in particular deceleration zones (DZs) identified by ILAM, LP, and LAVA. RESULTS Voltage and PF ranges of normal endocardial tissue varied widely. Using 220 Hz as a frequency cutoff value in areas low bipolar voltage, areas of high fractionation were identified with sensitivity of 91% and specificity of 85% There was no nificant reduction in targeted DZ surface areas, and colocalization with DZs was observed in all cases. Applied to the prospective cohort, PF predicted fractionated areas and DZ in 9 of 10 patients. CONCLUSION A PF annotation algorithm with a cutoff of 220 Hz accurately identifies areas of fractioned signals and accurately predicts DZs during ILAM.

Catheter-based neuromodulation of intrinsic cardiac autonomic nervous system is increasingly being used to improve outcomes in patients with vasovagal syncope and bradyarrhythmias caused by vagal overactivity. However, there is still no consensus for patient selection, technical steps, and procedural end points. This review takes the reader on a practical exploration of neuromodulation for bradyarrhythmias, concentrating on the critical aspects of proper patient selection, evidence-based insights, and anatomic intricacies within the intrinsic cardiac autonomic nervous system. Also discussed are different mapping techniques and outcome measures. Future directions to optimize the utilization of this technique in clinical practice are highlighted.

BackgroundPulmonary vein isolation (PVI) ablation is a standard therapy for paroxysmal atrial fibrillation (PAF). Lesion Index (LSI) is a metric to guide radiofrequency (RF) ablation using the TactiCath Ablation Catheter, Sensor Enabled with the EnSite Cardiac Mapping System (Abbott).ObjectiveThis study (NCT-03906461) was designed to capture best practices using LSI-guided catheter ablation to treat PAF subjects in a real-world setting.MethodsThis prospective single-arm observational study enrolled 143 PAF subjects in the United States, Europe, and Japan undergoing de novo PVI with RF ablation. PVI lesions were assigned to 10 anatomically defined segments. Mean LSIs achieved for all lesions were analyzed. Follow-up was conducted between 3–6 months and 12 months after the procedure.ResultsPulmonary veins were isolated in all subjects. The mean achieved LSI was 4.9, with lower values in Europe (4.4) and Japan (4.5) than the United States (5.5). First-pass success, defined as no gaps requiring touch-up ablation after 20 minutes post isolation, was achieved in 76.2% of subjects. Use of high LSI (≥5) resulted in shorter procedure, RF, and fluoroscopy times and fewer touch-up ablations compared to low LSI (<5). At 12 months, 99.3% of subjects were free from procedure- or device-related serious adverse events and 95.7% (112/117) (35.0% on antiarrhythmic drugs) were free from recurrence and/or a repeat ablation procedure for atrial fibrillation / atrial flutter / atrial tachycardia.ConclusionLSI-guided ablation strategies proved safe and effective despite differences in LSI workflows. Use of high LSI values resulted in shorter procedure, RF, and fluoroscopy times and fewer touch-up ablations compared to low LSI.

Background:Atypical left atrial flutter (AFL) may be macroreentrant or spatially localized. The relationship between the critical isthmus (CI) for localized reentry with sinus rhythm (SR) conduction slowing has not been systematically examined. Objective:To examine the correlation between CI sites for localized AFL (L-AFL) and deceleration zones (DZ) identified by isochronal late activation mapping (ILAM) during baseline rhythm. Methods:Patients with localized AFL who underwent high-density activation mapping of both SR and AFL were retrospectively analyzed. L-AFL was defined as reentry restricted to 2 wall segments of the left atrium. CI was defined by activation mapping and sites of successful termination during ablation. DZ, defined as >3 isochrones within 1 cm radius during baseline rhythm, were correlated to the locations of the CI. Results:Thirty-one consecutive patients that underwent detailed sinus rhythm and AFL high-density activation maps were analyzed at 3 centers. A mean 4060 ± 3275 and 6209 ± 8656 points were collected in ILAM and AFL activation maps, respectively. At least 1 DZ (1.7 ± 0.77) was identified in all patients. ILAM showed 3.27 ± 0.52 isochrones per DZ (168 ± 32 ms), and co-localized to CI sites at a distance of 6.7 ± 3 mm. A total of 34% ± 14% of the AFL cycle length was contained within 0.5 cm of the DZ. Conclusions:In patients with L-AFL, CI co-localized with DZ during baseline rhythm, suggesting that DZ mapping during SR may yield candidate targets for ablation as an adjunct to pulmonary vein isolation to prevent a subtype of AFL.

INTRODUCTION:Single-center observational studies have shown promising results with fragmented electrogram (FE)-guided ganglionated plexus (GP) ablation in patients with vagally mediated bradyarrhythmia (VMB). We aimed to compare the acute procedural characteristics during FE-guided GP ablation in patients with VMB performed by first-time operators and those of a single high-volume operator.METHODS AND RESULTS:This international multicenter cohort study included data collected over 2 years from 16 cardiac hospitals. The primary operators were classified according to their prior GP ablation experience: a single high-volume operator who had performed > 50 GP ablation procedures (Group 1), and operators performing their first GP ablation cases (Group 2). Acute procedural characteristics and syncope recurrence were compared between groups. Forty-seven consecutive patients with VMB who underwent FE-guided GP ablation were enrolled, n = 31 in Group 1 and n = 16 in Group 2. The mean number of ablation points in each GP was comparable between groups. The ratio of positive vagal response during ablation on the left superior GP was higher in Group 1 (90.3% vs. 62.5%, p = .022). Ablation of the right superior GP increased heart rate acutely without any vagal response in 45 (95.7%) cases. The procedure time was longer in group 2 (83.4 ± 21 vs. 118.0 ± 21 min, respectively, p < .001). Over a mean follow-up duration of 8.0 ± 3 months (range 2-24 months), none of the patients suffered from syncope.CONCLUSION:This multi-center pilot study shows for the first time the feasibility of FE-guided GP ablation across a large group of procedure-naïve operators.

BACKGROUND Stereotactic ablative radiotherapy (SAbR) is an emerging therapy for refractory ventricular tachycardia (VT). However, the current workflow is complicated, and the precision and safety in patients with significant cardiorespiratory motion and VT targets near the stomach may be suboptimal. OBJECTIVE We hypothesized that automated 12-lead electrocardiogram (ECG) mapping and respiratory-gated therapy may improve the ease and precision of SAbR planning and facilitate safe radiation delivery in patients with refractory VT. METHODS Consecutive patients with refractory VT were studied at 2 hospitals. VT exit sites were localized using a 3-D computational ECG algorithm noninvasively and compared to available prior invasive mapping. Radiotherapy (25 Gy) was delivered at end-expiration when cardiac respiratory motion was >= 0.6 cm or targets were <= 2 cm from the stomach. RESULTS In 6 patients (ejection fraction 29% +/- 13%), 4.2 +/- 2.3 VT morphologies per patient were mapped. Overall, 7 out of 7 computational ECG mappings (100%) colocalized to the identical cardiac segment when prior invasive electrophysiology study was available. Respiratory gating was associated with smaller planning target volumes compared to nongated volumes (71 +/- 7 vs 153 +/- 35 cc, P < .01). In 2 patients with inferior wall VT targets close to the stomach (6 mm proximity) or significant respiratory motion (22 mm excursion), no GI complications were observed at 9- and 12-month follow-up. Implantable cardioverter-defibrillator shocks decreased from 23 +/- 12 shocks/patient to 0.67 +/- 1.0 (P < .001) post-SAbR at 6.0 +/- 4.9 months follow-up. CONCLUSIONS A workflow including computational ECG mapping and protocol-guided respiratory gating is feasible, is safe, and may improve the ease of SAbR planning. Studies to validate this workflow in larger populations are required.

This commentary roundtable offers insights from experts on how Advisor™ HD Grid Mapping Catheter, Sensor Enabled™ has impacted their practice, including challenges it has helped to overcome and contexts in which its use has proved particularly valuable.

Accessory pathway (AP) mapping is currently based on point-by-point mapping and identifying if a local electrogram’s origin is atrial, pathway, or ventricular, which is time-consuming and prone to insufficient mapping. We sought to determine the feasibility of automated and high-density mapping to define AP location using open-window mapping (OWM), which does not rely on defining the electrogram’s origin but simply detects the sharpest local signal at each point. We enrolled 23 consecutive patients undergoing catheter ablation for atrioventricular reentrant tachycardia. High-density mapping was performed using OWM and ablation was performed. The successful site of ablation was determined by the loss of pathway function. OWM was 100% effective at identifying the successful site of ablation (average mapping time 7.3 ± 4.3 min.) Permanent AP elimination was achieved using a mean radiofrequency energy time of 18.5 ± 24.5 s/patient. Transiently successful ablations were 4.0 ± 1.8 mm from permanently successful sites and had lower contact force (5.1 ± 2.5 g vs. 11.7 ± 9.0 g; P = 0.041). Unsuccessful sites had similar contact force to permanently successful sites (12.2 ± 9.2 g vs. 11.7 ± 9.0 g; P = 0.856) but were 6.4 ± 2.0 mm away from successful sites. A novel technique of high-density, automated, and open-window mapping (OWM) effectively localizes APs without the need to differentiate the signal’s site of origin. These findings suggest that OWM can be used to rapidly and successfully map and ablate APs. Both distances from the pathway and contact force were shown to be important for pathway ablation.

The G protein-coupled receptor APJ is a promising therapeutic target for heart failure. Constitutive deletion of APJ in the mouse is protective against the hypertrophy-heart failure transition via elimination of ligand-independent, β-arrestin-dependent stretch transduction. However, the cellular origin of this stretch transduction and the details of its interaction with apelin signaling remain unknown. We generated mice with conditional elimination of APJ in the endothelium (APJendo-/-) and myocardium (APJmyo-/-). No baseline difference was observed in left ventricular function in APJendo-/-, APJmyo-/-, or control (APJendo+/+, APJmyo+/+) mice. After exposure to transaortic constriction, APJendo-/- mice displayed decreased left ventricular systolic function and increased wall thickness, whereas APJmyo-/- mice were protected. At the cellular level, carbon fiber stretch of freshly isolated single cardiomyocytes demonstrated decreased contractile responses to stretch in APJ-/- cardiomyocytes compared with APJ+/+ cardiomyocytes. Ca2+ transients did not change with stretch in either APJ-/- or APJ+/+ cardiomyocytes. Application of apelin to APJ+/+ cardiomyocytes resulted in decreased Ca2+ transients. Furthermore, hearts of mice treated with apelin exhibited decreased phosphorylation in cardiac troponin I NH2-terminal residues (Ser22 and Ser23) consistent with increased Ca2+ sensitivity. These data establish that APJ stretch transduction is mediated specifically by myocardial APJ, that APJ is necessary for stretch-induced increases in contractility, and that apelin opposes APJ's stretch-mediated hypertrophy signaling by lowering Ca2+ transients while maintaining contractility through myofilament Ca2+ sensitization. These findings underscore apelin's unique potential as a therapeutic agent that can simultaneously support cardiac function and protect against the hypertrophy-heart failure transition. NEW & NOTEWORTHY These data address fundamental gaps in our understanding of apelin-APJ signaling in heart failure by localizing APJ's ligand-independent stretch sensing to the myocardium, identifying a novel mechanism of apelin-APJ inotropy via myofilament Ca2+ sensitization, and identifying potential mitigating effects of apelin in APJ stretch-induced hypertrophic signaling.

The apelin peptide is described as one of the most potent inotropic agents, produced endogenously in a wide range of cells, including cardiomyocytes. Despite positive effects on cardiac contractility in multicellular preparations, as well as indications of cardio-protective actions in several diseases, its effects and mechanisms of action at the cellular level are incompletely understood. Here, we report apelin effects on dynamic mechanical characteristics of single ventricular cardiomyocytes, isolated from mouse models (control, apelin-deficient [Apelin-KO], apelin-receptor KO mouse [APJ-KO]), and rat. Dynamic changes in maximal velocity of cell shortening and relaxation were monitored. In addition, more traditional indicators of inotropic effects, such as maximum shortening (in mechanically unloaded cells) or peak force development (in auxotonic contracting cells, preloaded using the carbon fibre technique) were studied. The key finding is that, using Apelin-KO cardiomyocytes exposed to different preloads with the 2-dcarbon fibre technique, we observe a lowering of the slope of the end-diastolic stress-length relation in response to 10 nM apelin, an effect that is preload-dependent. This suggests a positive lusitropic effect of apelin, which could explain earlier counter-intuitive findings on an apelin-induced increase in contractility occurring without matching rise in oxygen consumption. (C) 2017 The Authors. Published by Elsevier Ltd.

BACKGROUND: Survival after sudden cardiac arrest is limited by postarrest myocardial dysfunction, but understanding of this phenomenon is constrained by a lack of data from a physiological model of disease. In this study, we established an in vivo model of cardiac arrest and resuscitation, characterized the biology of the associated myocardial dysfunction, and tested novel therapeutic strategies.METHODS: We developed rodent models of in vivo postarrest myocardial dysfunction using extracorporeal membrane oxygenation resuscitation followed by invasive hemodynamics measurement. In postarrest isolated cardiomyocytes, we assessed mechanical load and Ca2+-induced Ca2+ release (CICR) simultaneously using the microcarbon fiber technique and observed reduced function and myofilament calcium sensitivity. We used a novel fiberoptic catheter imaging system and a genetically encoded calcium sensor, GCaMP6f, to image CICR in vivo.RESULTS: We found potentiation of CICR in isolated cells from this extracorporeal membrane oxygenation model and in cells isolated from an ischemia/reperfusion Langendorff model perfused with oxygenated blood from an arrested animal but not when reperfused in saline. We established that CICR potentiation begins in vivo. The augmented CICR observed after arrest was mediated by the activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII). Increased phosphorylation of CaMKII, phospholamban, and ryanodine receptor 2 was detected in the postarrest period. Exogenous adrenergic activation in vivo recapitulated Ca2+ potentiation but was associated with lesser CaMKII activation. Because oxidative stress and aldehydic adduct formation were high after arrest, we tested a small-molecule activator of aldehyde dehydrogenase type 2, Alda-1, which reduced oxidative stress, restored calcium and CaMKII homeostasis, and improved cardiac function and postarrest outcome in vivo.CONCLUSIONS: Cardiac arrest and reperfusion lead to CaMKII activation and calcium long-term potentiation, which support cardiomyocyte contractility in the face of impaired postarrest myofilament calcium sensitivity. Alda-1 mitigates these effects, normalizes calcium cycling, and improves outcome.

Atrial fibrillation (AF) is a complex disease with multiple inter-relating causes culminating in rapid, seemingly disorganized atrial activation. Therapy targeting AF is rapidly changing and improving. The purpose of this review is to summarize current state-of-the-art diagnostic and therapeutic modalities for treatment of AF. The review focuses on reviewing treatment as it relates to the pathophysiological basis of disease and reviews preclinical and clinical evidence for potential new diagnostic and therapeutic modalities, including imaging, biomarkers, pharmacological therapy, and ablative strategies for AF. Current ablation and drug therapy approaches to treating AF are largely based on treating the arrhythmia once the substrate occurs and is more effective in paroxysmal AF rather than persistent or permanent AF. However, there is much research aimed at prevention strategies, targeting AF substrate, so-called upstream therapy. Improved diagnostics, using imaging, genetics, and biomarkers, are needed to better identify subtypes of AF based on underlying substrate/mechanism to allow more directed therapeutic approaches. In addition, novel antiarrhythmics with more atrial specific effects may reduce limiting proarrhythmic side effects. Advances in ablation therapy are aimed at improving technology to reduce procedure time and in mechanism-targeted approaches.

Atrial fibrillation (AF) is a complex disease with multiple inter-relating causes culminating in rapid, seemingly disorganized atrial activation. Therapy targeting AF is rapidly changing and improving. The purpose of this review is to summarize current state-of-the-art diagnostic and therapeutic modalities for treatment of AF. The review focuses on reviewing treatment as it relates to the pathophysiological basis of disease and reviews preclinical and clinical evidence for potential new diagnostic and therapeutic modalities, including imaging, biomarkers, pharmacological therapy, and ablative strategies for AF. Current ablation and drug therapy approaches to treating AF are largely based on treating the arrhythmia once the substrate occurs and is more effective in paroxysmal AF rather than persistent or permanent AF. However, there is much research aimed at prevention strategies, targeting AF substrate, so-called upstream therapy. Improved diagnostics, using imaging, genetics, and biomarkers, are needed to better identify subtypes of AF based on underlying substrate/mechanism to allow more directed therapeutic approaches. In addition, novel antiarrhythmics with more atrial specific effects may reduce limiting proarrhythmic side effects. Advances in ablation therapy are aimed at improving technology to reduce procedure time and in mechanism-targeted approaches.

Atrial fibrillation (AF) is characterized by rapid, seemingly chaotic atrial activation, characterized by the lack of an organized P wave and irregularly irregular ventricular activation (QRSs) on surface ECG. AF manifests as a result of multiple heterogeneous groups of disorders. For example, AF can occur idiopathically (so-called lone AF), be related to familial inheritance with specific genetic mutations, or, most commonly, associated with hypertension or underlying structural heart diseases, such as valvular heart disease or cardiomyopathy. Current therapy for AF is targeted at treating symptoms and reducing risk of tachycardia-induced cardiomyopathy and stroke. Stroke has been addressed elsewhere recently. In many patients, symptoms of AF can be treated with rate control, typically achieved by atrioventricular nodal blocking drugs, such as β-blockers or L-type calcium channel blockers. In patients in whom rate control is insufficient, antiarrhythmic drugs (AADs) and ablation are used to attempt to maintain sinus rhythm (rhythm control). This review will focus on strategies aimed at rhythm control. Compendium