<div><h4>A Multicenter, Phase 2, Randomized, Controlled Study of the Efficacy and Safety of Etripamil Nasal Spray for the Acute Reduction of Rapid Ventricular Rate in Patients with Symptomatic Atrial Fibrillation (ReVeRA-201).</h4><i>Camm AJ, Piccini JP, Alings M, Dorian P, ... Bharucha DB, Roy D</i><br /><AbstractText><b>Background:</b> Despite chronic therapies, atrial fibrillation (AF) leads to rapid ventricular rates (RVR) often requiring intravenous treatments. Etripamil is a fast-acting, calcium-channel blocker administered intranasally affecting the atrioventricular-node within minutes. <br /><b>Methods:</b><br/>ReVeRA evaluated efficacy and safety of etripamil for the reduction of ventricular rate (VR) in patients presenting urgently with AF-RVR (VR ≥110 bpm), was randomized, double-blind, placebo-controlled, and conducted in Canada and Netherlands. Patients presenting urgently with AF-RVR were randomized (1:1, etripamil nasal spray (NS) 70 mg: placebo-NS). The primary objective was to demonstrate the effectiveness of etripamil in reducing VR in AF-RVR within 60 min of treatment. Secondary objectives assessed achievement of VR <100 bpm, reduction by ≥10 and ≥20%, relief-of-symptoms and treatment-effectiveness; adverse events (AEs); and additional measures to 360 min. <br /><b>Results:</b><br/>69 patients were randomized, 56 dosed with etripamil (n=27) or placebo (n=29). The median age was 65 years; 39% were female; proportions of AF types were similar between groups. The difference of mean maximum reductions in VR over 60 min, etripamil vs placebo, adjusting for baseline VR, was -29.91 bpm (95% confidence interval: -40.31, -19.52; p <0.0001). VR reductions persisted up to 150 min. Significantly greater proportions of patients receiving etripamil achieved VR reductions <100 bpm (with longer median duration <100 bpm), or VR reduction by ≥10% or ≥20%, vs placebo. VR reduction ≥20% occurred in 66.7% of patients in the etripamil arm and no patients in placebo. Using the Treatment Satisfaction Questionnaire for Medication-9, there was significant improvement in satisfaction on symptom-relief and treatment-effectiveness with etripamil vs placebo. Serious AEs were rare; 1 patient in the etripamil arm experienced transient severe bradycardia and syncope, assessed as due to hyper-vagotonia. <b>Conclusions:</b> Intranasal etripamil 70 mg reduced VR and improved symptom-relief and treatment-satisfaction. These data support further development of self-administered etripamil for the treatment of AF-RVR. <b>Clinical Trial Registration:</b> ClinicalTrials.gov; Unique Identifier: NCT04467905.</AbstractText><br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 10 Nov 2023; epub ahead of print</small></div>

<div><h4>Natriuretic Peptide Receptor B Protects Against Atrial Fibrillation by Controlling Atrial cAMP Via Phosphodiesterase 2.</h4><i>Dorey TW, Liu Y, Jansen HJ, Bohne LJ, ... Fedak PWM, Rose RA</i><br /><b>Background</b><br />β-AR (β-adrenergic receptor) stimulation regulates atrial electrophysiology and Ca<sup>2+</sup> homeostasis via cAMP-dependent mechanisms; however, enhanced β-AR signaling can promote atrial fibrillation (AF). CNP (C-type natriuretic peptide) can also regulate atrial electrophysiology through the activation of NPR-B (natriuretic peptide receptor B) and cGMP-dependent signaling. Nevertheless, the role of NPR-B in regulating atrial electrophysiology, Ca<sup>2+</sup> homeostasis, and atrial arrhythmogenesis is incompletely understood.<br /><b>Methods</b><br />Studies were performed using atrial samples from human patients with AF or sinus rhythm and in wild-type and NPR-B-deficient (NPR-B<sup>+/-</sup>) mice. Studies were conducted in anesthetized mice by intracardiac electrophysiology, in isolated mouse atrial preparations using high-resolution optical mapping, in isolated mouse and human atrial myocytes using patch-clamping and Ca<sup>2+</sup> imaging, and in mouse and human atrial tissues using molecular biology.<br /><b>Results</b><br />Atrial NPR-B protein levels were reduced in patients with AF, and NPR-B<sup>+/-</sup> mice were more susceptible to AF. Atrial cGMP levels and PDE2 (phosphodiesterase 2) activity were reduced in NPR-B<sup>+/-</sup> mice leading to larger increases in atrial cAMP in the presence of the β-AR agonist isoproterenol. NPR-B<sup>+/-</sup> mice displayed larger increases in action potential duration and L-type Ca<sup>2+</sup> current in the presence of isoproterenol. This resulted in the occurrence of spontaneous sarcoplasmic reticulum Ca<sup>2+</sup> release events and delayed afterdepolarizations in NPR-B<sup>+/-</sup> atrial myocytes. Phosphorylation of the RyR2 (ryanodine receptor) and phospholamban was increased in NPR-B<sup>+/-</sup> atria in the presence of isoproterenol compared with the wild type. C-type natriuretic peptide inhibited isoproterenol-stimulated L-type Ca<sup>2+</sup> current through PDE2 in mouse and human atrial myocytes.<br /><b>Conclusions</b><br />NPR-B protects against AF by preventing enhanced atrial responses to β-adrenergic receptor agonists.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 07 Nov 2023:e012199; epub ahead of print</small></div>

<div><h4>No Effect of Continued Antiarrhythmic Drug Treatment on Top of Optimized Pulmonary Vein Isolation in Patients With Persistent Atrial Fibrillation: Results From the POWDER-AF2 Trial.</h4><i>Demolder A, O\'Neill L, El Haddad M, Scherr D, ... Tavernier R, Duytschaever M</i><br /><b>Background</b><br />In patients with persistent atrial fibrillation (PersAF), catheter ablation aiming for pulmonary vein isolation (PVI) is associated with moderate clinical effectiveness. We investigated the benefit of continuing previously ineffective class 1C or 3 antiarrhythmic drug therapy (ADT) in the setting of a standardized PVI-only ablation strategy.<br /><b>Methods</b><br />In this multicenter, randomized controlled study, patients with PersAF (≥7 days and <12 months) despite ADT were prospectively randomized 1:1 to PVI with ADT continued versus discontinued beyond the blanking period (ADT ON versus ADT OFF). Standardized catheter ablation was performed aiming for durable isolation with stable, contiguous, and optimized radio frequency applications encircling the pulmonary veins (CLOSE protocol). Clinical visits and 1-to-7-day Holter were performed at 3, 6, and 12 months. The primary end point was any documented atrial tachyarrhythmia lasting >30 seconds beyond 3 months. Prospectively defined secondary end points included repeat ablations, unscheduled arrhythmia-related visits, and quality of life among groups.<br /><b>Results</b><br />Of 200 PersAF patients, 98 were assigned to ADT OFF and 102 to ADT ON. The longest atrial fibrillation episode qualifying for PersAF was 28 (10-90) versus 30 (11-90) days. Clinical characteristics and procedural characteristics were similar. Recurrence of atrial tachyarrhythmia was comparable in both groups (20% OFF versus 21.2% ON). No differences were observed in repeat ablations and unscheduled arrhythmia-related visits. Marked improvement in quality of life was observed in both groups.<br /><b>Conclusions</b><br />In patients with PersAF, there is no benefit in continuing previously ineffective ADT beyond the blanking period after catheter ablation. The high success rate of PVI-only might be explained by the high rate of durable isolation after optimized PVI and the early stage of PersAF (POWDER-AF2).<br /><b>Registration</b><br />URL: https://www.<br /><b>Clinicaltrials</b><br />gov; Unique identifier: NCT03437356.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 03 Nov 2023:e012043; epub ahead of print</small></div>

<div><h4>Hypertrophic Cardiomyopathy and Ventricular Preexcitation in the Young: Etiology and Accessory Pathway Characteristics.</h4><i>Przybylski R, Saravu Vijayashankar S, O\'Leary E, Hylind RJ, ... Bezzerides VJ, Abrams DJ</i><br /><b>Background</b><br />The etiology of hypertrophic cardiomyopathy (HCM) in the young is highly varied. Ventricular preexcitation (preexcitation) is well recognized, yet little is known about the specificity of any etiology and the characteristics of the responsible accessory pathways (APs).<br /><b>Methods</b><br />Retrospective cohort study of patients <21 years of age with HCM/preexcitation from 2000 to 2022. The etiology of HCM was defined as isolated HCM, storage disorder, metabolic disease, or genetic syndrome. Atrioventricular APs (true APs) were distinguished from fasciculoventricular fibers (FVFs) using standard invasive electrophysiology study criteria. APs were defined as high risk if any of the following were <250 ms: shortest preexcited RR interval in atrial fibrillation, shortest paced preexcited cycle length, or anterograde AP effective refractory period.<br /><b>Results</b><br />We identified 345 patients with HCM and 28 (8%) had preexcitation (isolated HCM, 10/220; storage disorder, 8/17; metabolic disease, 5/19; and genetic syndrome, 5/89). Six (21%) patients had clinical atrial fibrillation (1 with shortest preexcited RR interval <250 ms). Twenty-two patients underwent electrophysiology study that identified 23 true APs and 16 FVFs. Preexcitation was exclusively FVF mediated in 8 (36%) patients. Five (23%) patients had APs with high-risk conduction properties (including ≥1 patient in each etiologic group). Multiple APs were seen in 8 (36%) and AP plus FVF in 10 (45%) patients. Ablation was acutely successful in 13 of 14 patients with recurrence in 3. One procedure was complicated by CHB after ablation of a high-risk midseptal AP. There were significant differences in QRS amplitude and delta wave amplitude between groups. There were no surface ECG features that differentiated APs from FVFs.<br /><b>Conclusions</b><br />Young patients with HCM and preexcitation have a high likelihood of underlying storage disease or metabolic disease. Nonisolated HCM should be suspected in young patients with large QRS and delta wave amplitudes. Surface ECG is not adequate to discriminate preexcitation from a benign FVF from that secondary to potentially life-threatening APs.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 25 Oct 2023:e012191; epub ahead of print</small></div>

<div><h4>Retrieval of Chronically Implanted Dual-Chamber Leadless Pacemakers in an Ovine Model.</h4><i>Banker RS, Rippy MK, Cooper N, Neužil P, ... Rashtian M, Reddy VY</i><br /><b>Background</b><br />The clinical utilization of leadless pacemakers (LPs) as an alternative to traditional transvenous pacemakers is likely to increase with the advent of dual-chamber LP systems. Since device retrieval to allow LP upgrade or replacement will become an important capability, the first such dual-chamber, helix-fixation LP system (Aveir DR; Abbott, Abbott Park, IL) was specifically designed to allow catheter-based retrieval. In this study, the preclinical performance and safety of retrieving chronically implanted dual-chamber LPs was evaluated.<br /><b>Methods</b><br />Atrial and ventricular LPs were implanted in the right atrial appendage and right ventricular apex of 9 healthy ovine subjects. After ≈2 years, the LPs were retrieved using a dedicated transvenous retrieval catheter (Aveir Retrieval Catheter; Abbott) by snaring, docking, and unscrewing from the myocardium. Comprehensive necropsy/histopathology studies were conducted to evaluate device- and procedure-related outcomes.<br /><b>Results</b><br />At a median of 1.9 years postimplant (range, 1.8-2.6), all 18 of 18 (100%) LPs were retrieved from 9 ovine subjects without complications. The median retrieval procedure duration for both LPs, from first-catheter-in to last-catheter-out, was 13.3 minutes (range, 2.5-36.4). Postretrieval, all right atrial, and right ventricular implant sites demonstrated minimal tissue disruption, with intact fibrous tissue limited to the distal device body. No significant device-related trauma, perforation, pericardial effusion, right heart or tricuspid valve injury, or chronic pulmonary thromboembolism were observed at necropsy.<br /><b>Conclusions</b><br />This preclinical study demonstrated the safe and effective retrieval of chronically implanted, helix-fixation, dual-chamber LP systems, paving the way for clinical studies of LP retrieval.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 28 Sep 2023:e012232; epub ahead of print</small></div>

<div><h4>Abnormal Atrial Potentials Recorded During Sinus Rhythm or Pacing Represent Substrates for Reentrant Atrial Tachycardia.</h4><i>Nakatani Y, Daniel Ramirez F, Takigawa M, Nakashima T, ... Haïssaguerre M, Jaïs P</i><br /><b>Background</b><br />Abnormal atrial potentials (AAPs) recorded during sinus rhythm/atrial pacing may indicate areas of slow conduction capable of supporting reentrant atrial tachycardia (AT). Therefore, we sought to examine the relationship between AAPs and AT circuits.<br /><b>Methods</b><br />One hundred twenty-three reentrant ATs in 104 patients were analyzed. AAPs, consisting of fragmented potentials and split potentials, were assessed using the Rhythmia LUMIPOINT algorithm.<br /><b>Results</b><br />There was 93±13% overlap between areas with AAPs during sinus rhythm/atrial pacing and areas of slow conduction along the reentry circuit during AT. The cumulative area of AAPs was smaller in patients with localized-reentrant ATs compared with anatomic macro-reentrant ATs (20.0 [14.6-30.5] versus 28.9 [21.8-35.6] cm<sup>2</sup>; <i>P</i>=0.021). Patients with perimitral ATs had larger areas of AAPs on the lateral wall whereas patients with roof-dependent ATs had larger areas of AAPs on the roof and posterior wall (<i>P</i>≤0.018 for all comparisons). The patchy scar that was associated with localized-reentrant AT exhibited a larger area of AAPs at its periphery than the scar that did not participate in localized-reentrant AT (3.1 [2.4-4.5] versus 1.0 [0.7-1.6] cm<sup>2</sup>; <i>P</i><0.001).<br /><b>Conclusions</b><br />AAPs recorded during sinus rhythm/atrial pacing are associated with areas of slow conduction during reentrant AT. The burden and distribution of AAPs may provide actionable insights into AT circuit features, including in cases in which ATs are difficult to map.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 20 Sep 2023:e012241; epub ahead of print</small></div>

<div><h4>Reversible Pulsed Electrical Fields as an In Vivo Tool to Study Cardiac Electrophysiology: The Advent of Pulsed Field Mapping.</h4><i>Koruth JS, Neuzil P, Kawamura I, Kuroki K, ... Aidietis A, Reddy VY</i><br /><b>Background</b><br />During electrophysiological mapping of tachycardias, putative target sites are often only truly confirmed to be vital after observing the effect of ablation. This lack of mapping specificity potentiates inadvertent ablation of innocent cardiac tissue not relevant to the arrhythmia. But if myocardial excitability could be transiently suppressed at critical regions, their suitability as targets could be conclusively determined before delivering tissue-destructive ablation lesions. We studied whether reversible pulsed electric fields (PF<sub>REV</sub>) could transiently suppress electrical conduction, thereby providing a means to dissect tachycardia circuits in vivo.<br /><b>Methods</b><br />PF<sub>REV</sub> energy was delivered from a 9-mm lattice-tip catheter to the atria of 12 swine and 9 patients, followed by serial electrogram assessments. The effects on electrical conduction were explored in 5 additional animals by applying PF<sub>REV</sub> to the atrioventricular node: 17 low-dose (PF<sub>REV-LOW</sub>) and 10 high-dose (PF<sub>REV-HIGH</sub>) applications. Finally, in 3 patients manifesting spontaneous tachycardias, PF<sub>REV</sub> was applied at putative critical sites.<br /><b>Results</b><br />In animals, the immediate post-PF<sub>REV</sub> electrogram amplitudes diminished by 74%, followed by 78% recovery by 5 minutes. Similarly, in patients, a 69.9% amplitude reduction was followed by 84% recovery by 3 minutes. Histology revealed only minimal to no focal, superficial fibrosis. PF<sub>REV-LOW</sub> at the atrioventricular node resulted in transient PR prolongation and transient AV block in 59% and 6%, while PF<sub>REV-HIGH</sub> caused transient PR prolongation and transient AV block in 30% and 50%, respectively. The 3 tachycardia patients had atypical atrial flutters (n=2) and atrioventricular nodal reentrant tachycardia. PF<sub>REV</sub> at putative critical sites reproducibly terminated the tachycardias; ablation rendered the tachycardias noninducible and without recurrence during 1-year follow-up.<br /><b>Conclusions</b><br />Reversible electroporation pulses can be applied to myocardial tissue to transiently block electrical conduction. This technique of pulsed field mapping may represent a novel electrophysiological tool to help identify the critical isthmus of tachycardia circuits.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 20 Sep 2023:e012018; epub ahead of print</small></div>

<div><h4>Hypoxia Promotes Atrial Tachyarrhythmias via Opening of ATP-Sensitive Potassium Channels.</h4><i>Specterman MJ, Aziz Q, Li Y, Anderson NA, ... Lambiase PD, Tinker A</i><br /><b>Background</b><br />Hypoxia-ischemia predisposes to atrial arrhythmia. Atrial ATP-sensitive potassium channel (K<sub>ATP</sub>) modulation during hypoxia has not been explored. We investigated the effects of hypoxia on atrial electrophysiology in mice with global deletion of K<sub>ATP</sub> pore-forming subunits.<br /><b>Methods</b><br />Whole heart K<sub>ATP</sub> RNA expression was probed. Whole-cell K<sub>ATP</sub> current and action potentials were recorded in isolated wild-type (WT), Kir6.1 global knockout (6.1-gKO), and Kir6.2 global knockout murine atrial myocytes. Langendorff-perfused hearts were assessed for atrial effective refractory period (ERP), conduction velocity, wavefront path length (WFPL), and arrhymogenicity under normoxia/hypoxia using a microelectrode array and programmed electrical stimulation. Heart histology was assessed.<br /><b>Results</b><br />Expression patterns were essentially identical for all K<sub>ATP</sub> subunit RNA across human heart, whereas in mouse, Kir6.1 and SUR2 (sulphonylurea receptor) were higher in ventricle than atrium, and Kir6.2 and SUR1 were higher in atrium. Compared with WT, Kir6.2 global knockout atrial myocytes had reduced tolbutamide-sensitive current and action potentials were more depolarized with slower upstroke and reduced peak amplitude. Action potential duration was prolonged in 6.1-gKO atrial myocytes, absent of changes in other ion channel gene expression or atrial myocyte hypertrophy. In Langendorff-perfused hearts, baseline atrial ERP was prolonged and conduction velocity reduced in both K<sub>ATP</sub> knockout mice compared with WT, without histological fibrosis. Compared with baseline, hypoxia led to conduction velocity slowing, stable ERP, and WFPL shortening in WT and 6.1-gKO hearts, whereas WFPL was stable in Kir6.2 global knockout hearts due to ERP prolongation with conduction velocity slowing. Tolbutamide reversed hypoxia-induced WFPL shortening in WT and 6.1-gKO hearts through ERP prolongation. Atrial tachyarrhythmias inducible with programmed electrical stimulation during hypoxia in WT and 6.1-gKO mice correlated with WFPL shortening. Spontaneous arrhythmia was not seen.<br /><b>Conclusions</b><br />K<sub>ATP</sub> block/absence leads to cellular and tissue level atrial electrophysiological modification. Kir6.2 global knockout prevents hypoxia-induced atrial WFPL shortening and atrial arrhythmogenicity to programmed electrical stimulation. This mechanism could be explored translationally to treat ischemically driven atrial arrhythmia.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 30 Aug 2023:e011870; epub ahead of print</small></div>

<div><h4>Sex and Gene Influence Arrhythmia Susceptibility in Murine Models of Calmodulinopathy.</h4><i>Wren LM, DeKeyser JM, Barefield DY, Hawkins NA, ... Wasserstrom JA, George AL</i><br /><b>Background</b><br />Pathogenic variants in genes encoding CaM (calmodulin) are associated with a life-threatening ventricular arrhythmia syndrome (calmodulinopathy). The in vivo consequences of CaM variants have not been studied extensively and there is incomplete understanding of the genotype-phenotype relationship for recurrent variants. We investigated effects of different factors on calmodulinopathy phenotypes using 2 mouse models with a recurrent pathogenic variant (N98S) in <i>Calm1</i> or <i>Calm2</i>.<br /><b>Methods</b><br />Genetically engineered mice with heterozygous N98S pathogenic variants in <i>Calm1</i> or <i>Calm2</i> genes were generated. Differences between the sexes and affected genes were assessed using multiple physiological assays at the cellular and whole animal levels. Statistical significance among groups was evaluated using 1-way ANOVA or the Kruskal-Wallis test when data were not normally distributed.<br /><b>Results</b><br /><i>Calm1</i><sup><i>N98S/+</i></sup> (<i>Calm1</i><sup><i>S/+</i></sup>) or <i>Calm2</i> <sup><i>N98S/+</i></sup> (<i>Calm2</i><sup><i>S/+</i></sup>) mice exhibited sinus bradycardia and were more susceptible to arrhythmias after exposure to epinephrine and caffeine. Male <i>Calm1</i><sup><i>S/+</i></sup> mice had the most severe arrhythmia phenotype with evidence of early embryonic lethality, greater susceptibility for arrhythmic events, frequent premature beats, corrected QT prolongation, and more heart rate variability after epinephrine and caffeine than females with the same genotype. <i>Calm2</i><sup><i>S/+</i></sup> mice exhibited a less severe phenotype, with female <i>Calm2</i><sup><i>S/+</i></sup> mice having the least severe arrhythmia susceptibility. Flecainide was not effective in preventing arrhythmias in heterozygous CaM-N98S mice. Intracellular Ca<sup>2+</sup> transients observed in isolated ventricular cardiomyocytes from male heterozygous CaM-N98S mice had lower peak amplitudes and slower sarcoplasmic reticulum Ca<sup>2+</sup> release following in vitro exposure to epinephrine and caffeine, which were not observed in cardiomyocytes from heterozygous female CaM-N98S mice.<br /><b>Conclusions</b><br />We report heterogeneity in arrhythmia susceptibility and cardiomyocyte Ca<sup>2+</sup> dynamics among male and female mice heterozygous for a recurrent pathogenic variant in <i>Calm1</i> or <i>Calm2</i>, illustrating a complex calmodulinopathy phenotype in vivo. Further investigation of sex and genetic differences may help identify the molecular basis for this heterogeneity.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 17 Aug 2023:e010891; epub ahead of print</small></div>

<div><h4>Temporal Trends and Lesion Sets for Persistent Atrial Fibrillation Ablation: A Meta-Analysis With Trial Sequential Analysis and Meta-Regression.</h4><i>Sau A, Kapadia S, Al-Aidarous S, Howard J, ... Peters NS, Ng FS</i><br /><b>Background</b><br />Ablation for persistent atrial fibrillation (PsAF) has been performed for over 20 years, although success rates have remained modest. Several adjunctive lesion sets have been studied but none have become standard of practice. We sought to describe how the efficacy of ablation for PsAF has evolved in this time period with a focus on the effect of adjunctive ablation strategies.<br /><b>Methods</b><br />Databases were searched for prospective studies of PsAF ablation. We performed meta-regression and trial sequential analysis.<br /><b>Results</b><br />A total of 99 studies (15 424 patients) were included. Ablation for PsAF achieved the primary outcome (freedom of atrial fibrillation/atrial tachycardia rate at 12 months follow-up) in 48.2% (5% CI, 44.0-52.3). Meta-regression showed freedom from atrial arrhythmia at 12 months has improved over time, while procedure time and fluoroscopy time have significantly reduced. Through the use of cumulative meta-analyses and trial sequential analysis, we show that some ablation strategies may initially seem promising, but after several randomized controlled trials may be found to be ineffective. Trial sequential analysis showed that complex fractionated atrial electrogram ablation is ineffective and further study of this treatment would be futile, while posterior wall isolation currently does not have sufficient evidence for routine use in PsAF ablation.<br /><b>Conclusions</b><br />Overall success rates from PsAF ablation and procedure/fluoroscopy times have improved over time. However, no adjunctive lesion set, in addition to pulmonary vein isolation, has been conclusively demonstrated to be beneficial. Through the use of trial sequential analysis, we highlight the importance of adequately powered randomized controlled trials, to avoid reaching premature conclusions, before widespread adoption of novel therapies.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 17 Aug 2023:e011861; epub ahead of print</small></div>

<div><h4>Electrical Resynchronization and Clinical Outcomes During Long-Term Follow-Up in Intraventricular Conduction Delay Patients Applied Left Bundle Branch Pacing-Optimized Cardiac Resynchronization Therapy.</h4><i>Chen X, Li X, Bai Y, Wang J, ... Su Y, Ge J</i><br /><b>Background</b><br />Left bundle branch-optimized cardiac resynchronization therapy (LOT-CRT) has shown encouraging results for QRS duration reduction and heart function improvement. However, the feasibility and efficacy of LOT-CRT have not been well established in intraventricular conduction delay patients. This study aims to assess and compare the efficacy and clinical outcome of CRT based on left bundle branch pacing, combined with coronary sinus left ventricular pacing (LOT-CRT) with CRT via biventricular pacing (BiV-CRT) in intraventricular conduction delay patients indicated for CRT.<br /><b>Methods</b><br />Consecutive patients with intraventricular conduction delay and CRT indications were assigned nonrandomized to LOT-CRT (n=30) or BiV-CRT (n=55). Addition of the left bundle branch pacing (or coronary venous) lead was at the discretion of the implanting physician guided by suboptimal paced QRS complex and on clinical grounds. Echocardiographic parameters and clinical characteristics were accessed at baseline and during 2-years\' follow-up.<br /><b>Results</b><br />Success rate for LOT-CRT and BiV-CRT was 96.8% and 96.4%. LOT-CRT had greater reduction of QRS duration compared with BiV-CRT (42.7±17.4 ms versus 21.9±21.5 ms; <i>P</i><0.001). Higher left ventricular ejection fraction was also achieved in LOT-CRT than BiV-CRT at 6-month (36.7±9.8% versus 30.5±6.4%; <i>P</i><0.05), 12-month (34.8±7.6% versus 30.3±6.2%; <i>P</i><0.05), 18-month (36.3±7.9% versus 28.1±6.6%; <i>P</i><0.005), and 24-month follow-up (37±9.5% versus 30.5±7%; <i>P</i><0.05). Adverse clinical outcomes including heart failure rehospitalization and mortality were lower in LOT-CRT group for 24 months follow-up (hazard ratio, 0.33; <i>P</i>=0.035).<br /><b>Conclusions</b><br />LOT-CRT improves ventricular electrical synchrony and may provide greater clinical outcomes as compared with BiV-CRT in intraventricular conduction delay patients. These findings need further evaluation in future randomized controlled trials.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 14 Aug 2023:e011761; epub ahead of print</small></div>

<div><h4>Dynamics of High-Density Unipolar Epicardial Electrograms During PFA.</h4><i>Amorós-Figueras G, Casabella-Ramon S, Moreno-Weidmann Z, Ivorra A, Guerra JM, García-Sánchez T</i><br /><b>Background</b><br />Pulsed field ablation (PFA) is a novel nonthermal cardiac ablation technology based on irreversible electroporation (IRE). While areas of IRE lead to durable lesions, the surrounding regions, where reversible electroporation occurs, recover. The behavior of local electrograms in areas of different electroporation levels remains unknown. The goal of this study is to characterize electrogram dynamics after PFA in IRE and reversible electroporation areas.<br /><b>Methods</b><br />A total of 6 domestic swine were used. PFA was applied in the epicardium of the right and left ventricles using a focal monopolar catheter. Additional radiofrequency ablations were performed. Epicardial unipolar electrograms were acquired at baseline and for 60 minutes post PFA/radiofrequency ablation using a high-density electrode matrix attached to the epicardium. Electrogram dynamics were analyzed in areas corresponding to different levels of electroporation. Acute lesion formation was assessed after 3 to 5 hours by triphenyl tetrazolium chloride staining.<br /><b>Results</b><br />Electrogram analysis demonstrated a clear association between electrogram changes and the level of electroporation. Immediately after PFA, electrograms displayed the following: a significant decrease in R/S-wave amplitude; a large elevation of the ST-segment; and a large decrease in their |(dV/dt)|<sub>max</sub>. Marked changes in electrograms were observed beyond the lesion area. Thereafter, a gradual recovery was observed. The evolution of all the electrogram parameters throughout the 60 minutes after PFA was significantly different (<i>P</i><0.05) between the IRE and reversible electroporation areas. Acute lesion staining showed significantly larger depth for PFA lesions compared with radiofrequency ablation.<br /><b>Conclusions</b><br />This study shows that unipolar electrograms can differentiate between reversible electroporation and IRE areas during the first 30 minutes post ablation. Differences after the first 30 minutes are less evident. Our findings could result useful for immediate lesion assessment after PFA and warrant further investigation.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 14 Aug 2023:e011914; epub ahead of print</small></div>

<div><h4>Initial Experience With Intercostal Insertion of an Extravascular ICD Lead Compatible With Existing Pulse Generators.</h4><i>Burke MC, Knops RE, Reddy V, Aasbo J, ... Pepplinkhuizen S, Ebner A</i><br /><b>Background</b><br />This study assessed safety and feasibility of a novel extravascular implantable cardioverter defibrillator (ICD) lead when inserted anteriorly through a rib space and connected to various commercially available ICD pulse generators (PGs) placed in either a left mid-axillary or left pectoral pocket. Currently available or investigational, extravascular-ICDs include a subcutaneous or subxiphoid lead connected to customized extravascular-ICD PGs.<br /><b>Methods</b><br />This novel extravascular-ICD (AtaCor Medical Inc, San Clemente, CA) employs a unique intercostal implant technique and is designed to function with commercial DF-4 ICD PGs. In this nonrandomized, single-center, acute study, 36 de novo or replacement ICD (transvenous ICD) patients enrolled to receive a concomitant extravascular-ICD lead inserted through an intercostal space along the left parasternal margin. extravascular-ICD leads were connected to DF-4 compatible ICD PGs positioned in either a left mid-axillary or pectoral pocket for acute sensing and defibrillation testing. Defibrillation testing started at 30 Joules (J) and stepped up or down in 5 to 10 joule increments depending on the success and limitations of the generator used.<br /><b>Results</b><br />Successful acute defibrillation using ≤35 J was noted in 100% of left mid-axillary PG subjects (n=27, mean 16.3±8.6 J) and 83% of left pectoral PG subjects (n=6, mean 21.0±8.4 J). Furthermore, 24 of 27 (89%) of patients tested with a left, mid-axillary intermuscular PG had successful VF conversion with defibrillation energies at least 10 J below the maximum delivered output of the device. All evaluable episodes (n=93) were automatically sensed, detected, and shocked. No serious device-related intraoperative adverse events were observed.<br /><b>Conclusions</b><br />This first-in-human study documented the safe and reliable placement of a novel extravascular ICD lead with effective sensing and defibrillation of induced ventricular fibrillation using commercial DF-4 ICD PGs.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 01 Aug 2023; 16:421-432</small></div>

<div><h4>Ventricular Electrograms Duration Map to Detect Ventricular Arrhythmia Substrate: the VEDUM Project Study.</h4><i>Rossi P, Cauti FM, Niscola M, Magnocavallo M, ... Dallaglio P, Bianchi S</i><br /><b>Background</b><br />The analysis of the wave-front activation patterns is crucial for the comprehension and treatment of ventricular tachycardia (VT). The ventricular electrograms duration map (VEDUM) is a potential method to identify areas (VEDUM area) with slow and inhomogeneous activation. There is no available data on the characteristics and the arrhythmogenic role of VEDUM areas identified during sinus/paced rhythm.<br /><b>Methods</b><br />Patients referred for VT ablation were enrolled at 3 different centers. VEDUM maps during sinus/paced rhythm as well as substrate and functional maps were created; activation mapping was performed for all hemodynamically tolerated VT.<br /><b>Results</b><br />Thirty-two patients (mean age:70.1±9.4 years; males 93.8%) were enrolled. The VEDUM approach was achieved in all patients and the mean size of the VEDUM area was 12.1±6.9 cm<sup>2</sup> (interquartile range, 7.8-14.9 cm<sup>2</sup>). A significative difference was observed between the electrogram duration in the VEDUM area and the normal tissue (163.7 ms [interquartile range, 142.3-199.2 ms]; versus 65.5 ms [interquartile range, 59.5-76.2 ms]; <i>P</i><0.001). The VEDUM area was visualized in a dense scar (<0.5 mV) in 19 (59.4%) patients. A deceleration zone and late potentials were recorded inside the VEDUM area in 56.3% and 81.3%, respectively. When a complete VT activation mapping was available, the isthmus projected in the VEDUM area in 93.5% of patients; 8 of them had multiple VTs mapped and in the 87.5% all VT isthmuses were included in the VEDUM area.<br /><b>Conclusions</b><br />VEDUM maps allow the identification of discrete areas of inhomogeneous and slow conduction. They represent a potential target for VT ablation, including patients with multiple morphologies.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 24 Jul 2023:e011729; epub ahead of print</small></div>

<div><h4>Impact of Median Sternotomy on Safety and Efficacy of the Subcutaneous Implantable Cardioverter Defibrillator.</h4><i>Sugrue A, Ibrahim R, Lu M, Bhatia NK, ... Merchant FM, Frankel DS</i><br /><b>Background</b><br />Subcutaneous implantable cardioverter defibrillators (S-ICDs) are an attractive alternative to transvenous ICDs among those not requiring pacing. However, the risks of damage to the S-ICD electrode during sternotomy and adverse interactions with sternal wires remain unclear. We sought to determine the rates of damage to the S-ICD lead during sternotomy, inappropriate shocks from electrical noise due to interaction with sternal wires, and failure to terminate spontaneous or induced ventricular arrhythmias.<br /><b>Methods</b><br />Retrospective, multicenter study of patients undergoing sternotomy before or after S-ICD implantation. Clinical, procedural, and device-related data were collected by each center and analyzed by the coordinating center. These data were compared with a historical control cohort of nonsternotomy patients.<br /><b>Results</b><br />Of 196 identified patients (52±16 years, 47 females), 166 underwent S-ICD implantation after sternotomy and 30 sternotomy after S-ICD. There was no damage to any lead among those who underwent sternotomy after S-ICD. Defibrillation threshold testing was performed in 63% at implant, with 91% first shock success. During a median follow-up of 29 months (range, 1-188), S-ICD first shocks successfully terminated spontaneous ventricular arrhythmias in 31 of 32 patients (97%). Inappropriate shocks occurred in 22 patients, most commonly related to T wave oversensing (n=14). Compared with the nonsternotomy controls, there were no differences in rates of first shock success for induced or spontaneous arrhythmias or rate of inappropriate shocks.<br /><b>Conclusions</b><br />Sternotomy before or after S-ICD does not confer additional risk relative to a historical control group without sternotomy.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 24 Jul 2023:e011867; epub ahead of print</small></div>

<div><h4>Catheter Ablation of Atrial Fibrillation in Adult Congenital Heart Disease: Procedural Characteristics and Outcomes.</h4><i>Hu TY, Janga C, Amin M, Tan NY, ... Egbe AC, Madhavan M</i><br /><b>Background</b><br />The outcomes of catheter ablation for atrial fibrillation in adults with congenital heart disease are not well described.<br /><b>Methods</b><br />In a retrospective study of adult patients with congenital heart disease who underwent catheter ablation for atrial fibrillation between 2000 and 2020 at Mayo Clinic, procedural characteristics and outcomes were collected. The primary outcomes were atrial arrhythmia (AA) recurrence following a 3-month blanking period and repeat ablation. An arrhythmia clinical severity score was assessed pre- and post-ablation based on the duration of arrhythmia episodes, symptoms, cardioversion frequency, and antiarrhythmic drug use.<br /><b>Results</b><br />One hundred forty-five patients (age, 57±12 years; 28% female; 63% paroxysmal atrial fibrillation) underwent 198 ablations with a median follow-up of 26 months (interquartile range, 14-69). One hundred ten, 26, and 9 patients had simple, moderate, and complex congenital heart disease, respectively. All patients underwent pulmonary vein isolation, and non-pulmonary vein targets were ablated in 79 (54%). AA recurrence at 12 months was 37% (95% CI, 29%-45%). On univariate analysis, increasing left atrial volume index was associated with higher odds of AA recurrence (odds ratio, 1.03 [1.00-1.06] per 1 mL/m<sup>2</sup> increment; <i>P</i>=0.05). Noninducibility of atrial flutter was predictive of decreased odds of AA recurrence (odds ratio, 0.43 [0.21-0.90]; <i>P</i>=0.03). A second ablation was performed in 43 patients after a median of 20 (interquartile range, 8-37) months. Arrhythmia clinical severity scores improved following ablation, reflecting a decrease in symptoms, cardioversions, and antiarrhythmic drugs.<br /><b>Conclusions</b><br />Catheter ablation of atrial fibrillation is feasible and effective in patients with ACHD and reduces symptoms. Recurrence of AA frequently requires repeat ablation.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 24 Jul 2023:e011392; epub ahead of print</small></div>

<div><h4>Dronedarone Versus Sotalol in Antiarrhythmic Drug-Naive Veterans With Atrial Fibrillation.</h4><i>Pundi K, Fan J, Kabadi S, Din N, ... Turakhia MP, Sandhu AT</i><br /><b>Background</b><br />Sotalol and dronedarone are both used for maintenance of sinus rhythm for patients with atrial fibrillation. However, while sotalol requires initial monitoring for QT prolongation and proarrhythmia, dronedarone does not. These treatments can be used in comparable patients, but their safety and effectiveness have not been compared head to head. Therefore, we retrospectively evaluated the effectiveness and safety using data from a large health care system.<br /><b>Methods</b><br />Using Veterans Health Administration data, we identified 11 296 antiarrhythmic drug-naive patients with atrial fibrillation prescribed dronedarone or sotalol in 2012 or later. We excluded patients with prior conduction disease, pacemakers or implantable cardioverter-defibrillators, ventricular arrhythmia, cancer, renal failure, liver disease, or heart failure. We used natural language processing to identify and compare baseline left ventricular ejection fraction between treatment arms. We used 1:1 propensity score matching, based on patient demographics, comorbidities, and medications, and Cox regression to compare strategies. To evaluate residual confounding, we performed falsification analysis with nonplausible outcomes.<br /><b>Results</b><br />The matched cohort comprised 6212 patients (3106 dronedarone and 3106 sotalol; mean [±SD] age, 71±10 years; 2.5% female; mean [±SD] CHA<sub>2</sub>DS<sub>2</sub>-VASC, 2±1.3). The mean (±SD) left ventricular ejection fraction was 55±11 and 58±10 for dronedarone and sotalol users, correspondingly. Dronedarone, compared with sotalol, did not demonstrate a significant association with risk of cardiovascular hospitalization (hazard ratio, 1.03 [95% CI, 0.88-1.21]) or all-cause mortality (hazard ratio, 0.89 [95% CI, 0.68-1.16]). However, dronedarone was associated with significantly lower risk of ventricular proarrhythmic events (hazard ratio, 0.53 [95% CI, 0.38-0.74]) and symptomatic bradycardia (hazard ratio, 0.56 [95% CI, 0.37-0.87]). The primary findings were stable across sensitivity analyses. Falsification analyses were not significant.<br /><b>Conclusions</b><br />Dronedarone, compared with sotalol, was associated with a lower risk of ventricular proarrhythmic events and conduction disorders while having no difference in risk of incident cardiovascular hospitalization and mortality. These observational data provide the basis for prospective efficacy and safety trials.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 24 Jul 2023:e011893; epub ahead of print</small></div>

<div><h4>Action Potential Morphology Accurately Predicts Proarrhythmic Risk for Drugs With Potential to Prolong Cardiac Repolarization.</h4><i>Lee W, Ng B, Mangala MM, Perry MD, ... Vandenberg JI, Hill AP</i><br /><b>Background</b><br />Drug-induced or acquired long QT syndrome occurs as a result of the unintended disruption of cardiac repolarization due to drugs that block cardiac ion channels. These side effects have been responsible for the withdrawal of a range of drugs from market and are a common reason for termination of the development of new drugs in the preclinical stage. Existing approaches to risk prediction are expensive and overly sensitive meaning that recently there have been renewed efforts, largely driven by the comprehensive proarrhythmic assay initiative, to develop more accurate methods for allocation of proarrhythmic risk.<br /><b>Methods</b><br />In this study, we aimed to quantify changes in the morphology of the repolarization phase of the cardiac action potential as an indicator of proarrhythmia, supposing that these shape changes might precede the emergence of ectopic depolarizations that trigger arrhythmia. To do this, we describe a new method of quantifying action potential morphology by measuring the radius of curvature of the repolarization phase both in simulated action potentials, as well as in action potentials measured from induced pluripotent stem cell-derived cardiomyocytes. Features derived from the curvature signal were used as inputs for logistic regressions to predict proarrhythmic risk.<br /><b>Results</b><br />Optimal risk classifiers based on morphology were able to correctly classify risk to drugs in the comprehensive proarrhythmic assay initiative panels with very high accuracy (0.9375) and outperformed conventional metrics based on action potential duration at 90% repolarization, triangulation, and charge movement (qNet).<br /><b>Conclusions</b><br />Analysis of action potential morphology in response to proarrhythmic drugs improves prediction of torsadogenic risk. Furthermore, morphology metrics can be measured directly from the action potential, potentially eliminating the burden of undertaking complex screens of potency and drug-binding kinetics against multiple cardiac ion channels. As such, this method has the potential to improve and streamline regulatory assessment of proarrhythmia in preclinical drug development.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 19 Jun 2023:e011574; epub ahead of print</small></div>

<div><h4>Efficacy and Safety of Adjunctive and Primary Use of the TightRail Mechanical Cutting Sheath for Lead Extraction.</h4><i>Sampognaro JR, Karatela M, Lewis RK, Black-Maier E, ... Hegland DD, Piccini JP</i><br /><b>Background</b><br />Rotational cutting tools are increasingly used in transvenous lead extraction. There are limited data on their safety and efficacy, particularly when used adjunctively for stalled progression. The aim of this study was to evaluate the utilization, safety, and effectiveness of mechanical rotational cutting tools for transvenous lead extraction.<br /><b>Methods</b><br />Patients undergoing transvenous lead extraction at a single tertiary center (April 2015 to January 2021, n=586) were included in this retrospective analysis. The study characterized the 251 patients (42.8%) whose cases involved the TightRail mechanical cutting tool.<br /><b>Results</b><br />Among 251 patients, 526 leads were extracted and TightRail was used for 70.5%. The TightRail was used adjunctively with the laser for 65.2% of leads, 97.8% of the time as the second tool after stalled progression. Using a multivariable logistic regression model, we found that active-fixation leads (odds ratio, 2.78 [95% CI, 1.62-4.78]; <i>P</i>=0.0002), dual-coil leads (odds ratio, 3.39 [95% CI, 1.87-6.16]; <i>P<0</i>.0001), and lead dwell time (odds ratio, 1.16 [95% CI for 1-year increase, 1.11-1.21]; <i>P<0</i>.0001) were factors independently associated with adjunctive TightRail use. Stalled progression requiring TightRail occurred most often in the innominate vein and superior vena cava (59.3%). The clinical success rate was 96.8%, and the rate of major adverse events was 2.8%. Only 1 major adverse event was observed during TightRail use.<br /><b>Conclusions</b><br />Rotational cutting with TightRail was used in 42.8% of transvenous lead extractions, predominantly in an adjunctive manner after stalled laser progression in the innominate vein and superior vena cava, and more frequently for dual-coil and leads with longer dwell times. Adjunctive TightRail use carries a low risk of major complications.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 02 Jun 2023:e011603; epub ahead of print</small></div>

<div><h4>Outcomes After Development of Ventricular Arrhythmias in Single Ventricular Heart Disease Patients With Fontan Palliation.</h4><i>Giacone HM, Chubb H, Dubin AM, Motonaga KS, ... Hanley FL, Chen S</i><br /><b>Background</b><br />With the advent of more intensive rhythm monitoring strategies, ventricular arrhythmias (VAs) are increasingly detected in Fontan patients. However, the prognostic implications of VA are poorly understood. We assessed the incidence of VA in Fontan patients and the implications on transplant-free survival.<br /><b>Methods</b><br />Medical records of Fontan patients seen at a single center between 2002 and 2019 were reviewed to identify post-Fontan VA (nonsustained ventricular tachycardia >4 beats or sustained >30 seconds). Patients with preFontan VA were excluded. Hemodynamically unstable VA was defined as malignant VA. The primary outcome was death or heart transplantation. Death with censoring at transplant was a secondary outcome.<br /><b>Results</b><br />Of 431 Fontan patients, transplant-free survival was 82% at 15 years post-Fontan with 64 (15%) meeting primary outcome of either death (n=16, 3.7%), at a median 4.6 (0.4-10.2) years post-Fontan, or transplant (n=48, 11%), at a median of 11.1 (5.9-16.2) years post-Fontan. Forty-eight (11%) patients were diagnosed with VA (90% nonsustained ventricular tachycardia, 10% sustained ventricular tachycardia). Malignant VA (n=9, 2.0%) was associated with younger age, worse systolic function, and valvular regurgitation. Risk for VA increased with time from Fontan, 2.4% at 10 years to 19% at 20 years. History of Stage 1 surgery with right ventricular to pulmonary artery conduit and older age at Fontan were significant risk factors for VA. VA was strongly associated with an increased risk of transplant or death (HR, 9.2 [95% CI, 4.5-18.7]; <i>P</i><0.001), with a transplant-free survival of 48% at 5-year post-VA diagnosis.<br /><b>Conclusions</b><br />Ventricular arrhythmias occurred in 11% of Fontan patients and was highly associated with transplant or death, with a transplant-free survival of <50% at 5-year post-VA diagnosis. Risk factors for VA included older age at Fontan and history of right ventricular to pulmonary artery conduit. A diagnosis of VA in Fontan patients should prompt increased clinical surveillance.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 31 May 2023:e011143; epub ahead of print</small></div>

<div><h4>Pulsed Field Versus Cryoballoon Pulmonary Vein Isolation for Atrial Fibrillation: Efficacy, Safety, and Long-Term Follow-Up in a 400-Patient Cohort.</h4><i>Urbanek L, Bordignon S, Schaack D, Chen S, ... Schmidt B, Chun KRJ</i><br /><b>Background</b><br />The cryoballoon represents the gold standard single-shot device for pulmonary vein isolation (PVI) in patients with atrial fibrillation (AF). Single-shot pulsed field PVI ablation (nonthermal, cardiac tissue selective) has recently entered the arena. We sought to compare procedural data and long-term outcome of both techniques.<br /><b>Methods</b><br />Consecutive AF patients who underwent pulsed field ablation (PFA) and cryoballoon-based PVI were enrolled. Cryoballoon PVI was performed using the second-generation 28-mm cryoballoon; PFA was performed using a 31/35-mm pentaspline catheter. Success was defined as no recurrence of atrial tachyarrhythmia after a 3-month blanking period.<br /><b>Results</b><br />Four hundred patients were included (56.5% men; 60.8% paroxysmal AF; age, 70 [interquartile range, 59-77] years), 200 in each group (cryoballoon and PFA), and baseline characteristics did not differ. Acute PVI was achieved in 100% of PFA and in 98% (196/200) of cryoballoon patients (<i>P</i>=0.123; 4 touch-up ablations). Median procedure time was significantly shorter in PFA (34.5 [29-40] minutes) versus cryoballoon (50 [45-60] minutes; <i>P</i><0.001), fluoroscopy time was similar. Overall procedural complications were 6.5% in cryoballoon and 3.0% in PFA (<i>P</i>=0.1), driven by a higher rate of phrenic nerve palsies using cryoballoon. The 1-year success rates in paroxysmal AF (cryoballoon, 83.1%; PFA, 80.3%; <i>P</i>=0.724) and persistent AF (cryoballoon, 71%; PFA, 66.8%; <i>P</i>=0.629) were similar for both techniques.<br /><b>Conclusions</b><br />PFA compared with cryoballoon PVI shows a similar procedural efficacy but is associated with shorter procedure time and no phrenic nerve palsies. Importantly, 12-month clinical success rates are favorable but not different between both groups.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 31 May 2023:e011920; epub ahead of print</small></div>

<div><h4>Atrial Fibrillation Ablation in Young Adults: Measuring Quality of Life Using Patient-Reported Outcomes Over 5 Years.</h4><i>Johnson BM, Wazni OM, Farwati M, Saliba WI, ... Nakagawa H, Hussein AA</i><br /><b>Background</b><br />Ablation is used for both rhythm control and improved quality of life (QoL) in atrial fibrillation (AF). It has been suggested that young adults may experience high recurrence rates after ablation and data remain lacking regarding QoL benefits. We aimed to investigate AF ablation outcomes and QoL benefits in young adults undergoing AF ablation using a large prospectively maintained registry and automated patient-reported outcomes (PRO).<br /><b>Methods</b><br />All patients undergoing AF ablation (2013-2016) at our center were prospectively enrolled. Patients aged 50 years or younger were included. For PROs, QoL measures and symptoms were assessed at baseline, 3 months after ablation, and every 6 months thereafter. The AF severity score served as the main assessment of QoL.<br /><b>Results</b><br />A total of 241 young adults (age, 16-50 years) were included (17% female, 40.3% persistent AF). In all, 77.2% of patients remained arrhythmia-free during the first year of follow-up (80% in nonstructural AF and 66% in structural AF). Using PROs, 90% of patients reported improvement in QoL throughout all survey time points up to 5 years postablation (<i>P</i><0.0001). The baseline median AF severity score was 14 and improved to between 2 and 4 on all follow-up after ablation (<i>P</i><0.0001). Patients also reported fewer and shorter AF episodes, fewer emergency room visits secondary to AF, and fewer hospitalizations (<i>P</i><0.0001).<br /><b>Conclusions</b><br />Ablation remains an effective rhythm-control strategy in young adults with AF. Young adults also experience significant improvement in QoL with reduction of the frequency and duration of AF episodes and AF-related healthcare utilization.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 15 May 2023:e011565; epub ahead of print</small></div>

<div><h4>Early Impact of Proton Beam Therapy on Electrophysiological Characteristics in a Porcine Model.</h4><i>Imamura K, Deisher AJ, Dickow J, Rettmann ME, ... Foote RL, Packer DL</i><br /><b>Background</b><br />Particle therapy is a noninvasive, catheter-free modality for cardiac ablation. We previously demonstrated the efficacy for creating ablation lesions in the porcine heart. Despite several earlier studies, the exact mechanism of early biophysical effects of proton and photon beam delivery on the myocardium remain incompletely resolved.<br /><b>Methods</b><br />Ten normal and 9 infarcted in situ porcine hearts received proton beam irradiation (40 Gy) delivered to the left ventricular myocardium with follow-up for 8 weeks. High-resolution electroanatomical mapping of the left ventricular was performed at baseline and follow-up. Bipolar voltage amplitude, conduction velocity, and connexin-43 were determined within the irradiated and nonirradiated areas.<br /><b>Results</b><br />The irradiated area in normal hearts showed a significant reduction of bipolar voltage amplitude (10.1±4.9 mV versus 5.7±3.2, <i>P</i><0.0001) and conduction velocity (85±26 versus 55±13 cm/s, <i>P</i>=0.03) beginning at 4 weeks after irradiation. In infarcted myocardium after irradiation, bipolar voltage amplitude of the infarct scar (2.0±2.9 versus 0.8±0.7 mV, <i>P</i>=0.008) was significantly reduced as well as the conduction velocity in the infarcted heart (43.7±15.7 versus 26.3±11.4 cm/s, <i>P</i>=0.02). There were no significant changes in bipolar voltage amplitude and conduction velocity in nonirradiated myocardium. Myocytolysis, capillary hyperplasia, and dilation were seen in the irradiated myocardium 8 weeks after irradiation. Active caspase-3 and reduction of connexin-43 expression began in irradiated myocardium 1 week after irradiation and decreased over 8 weeks.<br /><b>Conclusions</b><br />Irradiation of the myocardium with proton beams reduce connexin-43 expression, conduction velocity, and bipolar conducted electrogram amplitude in a large porcine model. The changes in biomarkers preceded electrophysiological changes after proton beam therapy.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 15 May 2023:e011179; epub ahead of print</small></div>

<div><h4>Effects of Atrioventricular Optimization on Left Ventricular Reverse Remodeling With Cardiac Resynchronization Therapy: Results of the SMART-CRT Trial.</h4><i>Gold MR, Ellenbogen K, Leclercq C, Lowy J, ... Stein KM, Auricchio A</i><br /><b>Background</b><br />The role of atrioventricular optimization (AVO) to improve cardiac resynchronization therapy outcomes remains controversial. Previous post hoc analyses of a multicenter trial showed that measures of electrical dyssynchrony (right ventricular-left ventricular [LV] or QLV durations) are associated with patients who benefit from AVO.<br /><b>Methods</b><br />This was a global, multicenter, prospective, randomized trial of de novo cardiac resynchronization therapy implant patients with an right ventricular-LV duration ≥70 ms to determine whether AVO results in greater reverse remodeling. Patients were randomized 1:1 for either an AVO algorithm (SmartDelay) that determines atrioventricular delay and pacing chamber, biventricular or LV only, or a fixed atrioventricular delay of 120 ms with biventricular pacing. Paired echocardiograms performed at baseline and 6 months were evaluated. The primary end point was echocardiographic cardiac resynchronization therapy response, defined dichotomously as a >15% reduction in LV end-systolic volume.<br /><b>Results</b><br />A total of 310 patients (n=120 women) were randomized and had completed 6 months of follow-up. The echocardiographic cardiac resynchronization therapy response rate did not statistically differ between the groups (SmartDelay, 74.8%; fixed, 67.7%; <i>P</i>=0.17). Analyses of prespecified secondary end points demonstrated significant improvements in the absolute (median: SmartDelay, -41.0 mL; fixed, -33.0 mL; <i>P</i>=0.01) and relative change in LV end-systolic volume (SmartDelay, -38.3%; fixed, -27.8%; <i>P</i>=0.03) for patients with SmartDelay optimization. Similar results were observed for the relative improvement in LV ejection fraction (SmartDelay, 46.7%; fixed, 32.1%; <i>P</i>=0.050); absolute improvement in LV ejection fraction trended to be higher with SmartDelay (<i>P</i>=0.06).<br /><b>Conclusions</b><br />Analysis of reverse remodeling parameters demonstrated that AVO via SmartDelay, relative to the nonoptimized fixed atrioventricular delay comparator group, improved absolute and relative changes in LV function in patients with longer right ventricular-LV duration.<br /><b>Registration</b><br />URL: https://www.<br /><b>Clinicaltrials</b><br />gov; Unique identifier: NCT03089281.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 15 May 2023:e011714; epub ahead of print</small></div>

<div><h4>Systematic Electrophysiological Study Prior to Pulmonary Valve Replacement in Tetralogy of Fallot: A Prospective Multicenter Study.</h4><i>Waldmann V, Bessière F, Gardey K, Bakloul M, ... Khairy P, Combes N</i><br /><b>Background</b><br />Ventricular arrhythmias and sudden death are recognized complications in tetralogy of Fallot. Electrophysiological studies (EPS) before pulmonary valve replacement (PVR), the most common reintervention in tetralogy of Fallot, could potentially inform therapy to improve arrhythmic outcomes.<br /><b>Methods</b><br />A prospective multicenter study was conducted to systematically assess EPS with programmed ventricular stimulation in patients with tetralogy of Fallot referred for PVR from January 2020 to December 2021. A standardized stimulation protocol was used across all centers.<br /><b>Results</b><br />A total of 120 patients were enrolled, mean age 39.2±14.5 years, 53.3% males. Sustained ventricular tachycardia was induced in 27 (22.5%) patients. When identifiable, the critical isthmus most commonly implicated (ie, in 90.0%) was between the ventricular septal defect patch and pulmonary annulus. Factors independently associated with inducible ventricular tachycardia were history of atrial arrhythmia (OR, 8.56 [95% CI, 2.43-34.73]) and pulmonary annulus diameter >26 mm (OR, 5.05 [95% CI, 1.47-21.69]). The EPS led to a substantial change in management in 23 (19.2%) cases: 18 (15.0%) had catheter ablation, 3 (2.5%) surgical cryoablation during PVR, and 9 (7.5%) defibrillator implantation. Repeat EPS 5.1 (4.8-6.2) months after PVR was negative in 8 of 9 (88.9%) patients. No patient experienced a sustained ventricular arrhythmia during 13 (6.1-20.1) months of follow-up.<br /><b>Conclusions</b><br />Systematically performing programmed ventricular stimulation in patients with tetralogy of Fallot referred for PVR yields a high rate of inducible ventricular tachycardia and carries the potential to alter management. It remains to be determined whether a standardized treatment approach based on the results of EPS will translate into improved outcomes.<br /><b>Registration</b><br />URL: https://www.<br /><b>Clinicaltrials</b><br />gov; Unique identifier: NCT04205461.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 12 May 2023:e011745; epub ahead of print</small></div>

<div><h4>Heterogeneity of Repolarization and Cell-Cell Variability of Cardiomyocyte Remodeling Within the Myocardial Infarction Border Zone Contribute to Arrhythmia Susceptibility.</h4><i>Amoni M, Vermoortele D, Ekhteraei-Tousi S, Doñate Puertas R, ... Claus P, Sipido KR</i><br /><b>Background</b><br />After myocardial infarction, the infarct border zone (BZ) is the dominant source of life-threatening arrhythmias, where fibrosis and abnormal repolarization create a substrate for reentry. We examined whether repolarization abnormalities are heterogeneous within the BZ in vivo and could be related to heterogeneous cardiomyocyte remodeling.<br /><b>Methods</b><br />Myocardial infarction was induced in domestic pigs by 120-minute ischemia-reperfusion injury. After 1 month, remodeling was assessed by magnetic resonance imaging, and electroanatomical mapping was performed to determine the spatial distribution of activation-recovery intervals. Cardiomyocytes were isolated and tissue samples collected from the BZ and remote regions. Optical recording allowed assessment of action potential duration (di-8-Anepps, stimulation at 1 Hz, 37 °C) of large cardiomyocyte populations while gene expression in cardiomyocytes was determined by single nuclear RNA sequencing.<br /><b>Results</b><br />In vivo, activation-recovery intervals in the BZ tended to be longer than in remote with increased spatial heterogeneity evidenced by a greater local SD (3.5±1.3 ms versus remote: 2.0±0.5 ms, <i>P</i>=0.036, n<sub>pigs</sub>=5). Increased activation-recovery interval heterogeneity correlated with enhanced arrhythmia susceptibility. Cellular population studies (n<sub>cells</sub>=635-862 cells per region) demonstrated greater heterogeneity of action potential duration in the BZ (SD, 105.9±17.0 ms versus remote: 73.9±8.6 ms; <i>P</i>=0.001; n<sub>pigs</sub>=6), which correlated with heterogeneity of activation-recovery interval in vivo. Cell-cell gene expression heterogeneity in the BZ was evidenced by increased Euclidean distances between nuclei of the BZ (12.1 [9.2-15.0] versus 10.6 [7.5-11.6] in remote; <i>P</i><0.0001). Differentially expressed genes characterizing BZ cardiomyocyte remodeling included hypertrophy-related and ion channel-related genes with high cell-cell variability of expression. These gene expression changes were driven by stress-responsive TFs (transcription factors). In addition, heterogeneity of left ventricular wall thickness was greater in the BZ than in remote.<br /><b>Conclusions</b><br />Heterogeneous cardiomyocyte remodeling in the BZ is driven by uniquely altered gene expression, related to heterogeneity in the local microenvironment, and translates to heterogeneous repolarization and arrhythmia vulnerability in vivo.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 02 May 2023:e011677; epub ahead of print</small></div>

<div><h4>Causes of Early Mortality After Catheter Ablation of Atrial Fibrillation.</h4><i>Tan MC, Rattanawong P, Karikalan S, Deshmukh AJ, ... Munger TM, Lee JZ</i><br /><b>Background</b><br />Recognition of the causes of early mortality after atrial fibrillation (AF) catheter ablation is essential for the improvement of patient safety. This study sought to determine the causes of early mortality (≤90 days) after AF ablation.<br /><b>Methods</b><br />We performed a retrospective analysis of AF ablation from January 1, 2013, to December 1, 2021 at the Mayo Clinic (Rochester, Phoenix, and Jacksonville). Causes of death were identified through a comprehensive chart review of the electronic health record from within the Mayo Clinic system and outside records when available.<br /><b>Results</b><br />A total of 6723 patients were included in the study. The 90-day all-cause mortality rate was 0.22% (n=15). Among all 90-day deaths, majority of the deaths (73.3%) did not have a direct relationship with the procedure. Sudden death was the most common cause of early death (20%), followed by peri-procedural stroke (13%), respiratory failure (13%), atrioesophageal fistula (13%), infection (7%), heart failure (7%), and traumatic brain injury (7%). The 90-day mortality rate directly due to AF ablation procedural complications was 0.06% (n=4).<br /><b>Conclusions</b><br />AF ablation procedure has a 90-day mortality of 0.22%, and the most common cause of early mortality was sudden death. The majority (73.3%) of early mortality was not directly associated with a procedural complication, and the mortality rate due to complications associated with the AF ablation procedure was low at 0.06%. Further studies are required to investigate causes and risk factors associated with sudden death in this patient population.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 21 Apr 2023:e011365; epub ahead of print</small></div>

<div><h4>Novel Approaches for the Diagnosis of Concealed Nodo-Ventricular and His-Ventricular Pathways.</h4><i>Higuchi S, Gerstenfeld EP, Hsia HH, Wong CX, ... Belhassen B, Scheinman MM</i><br /><b>Background</b><br />Confirming the presence and participation of concealed nodo-ventricular (cNV) or His-ventricular (cHV) pathways in tachyarrhythmias is challenging. We describe novel observations to aid in diagnosing cNV or cHV pathways.<br /><b>Methods</b><br />We present 7 cases of cNV and cHV pathway-mediated arrhythmias and focus on several laboratory observations: (1) differential ventricular overdrive pacing (VOD) from the base versus apex, (2) response to His refractory premature ventricular complexes, (3) paradoxical atriohisian response (shorter atriohisian interval during tachycardia than that during sinus rhythm) in long RP tachycardia, and (4) the role of adenosine to aid in the diagnosis.<br /><b>Results</b><br />Three cases underwent differential VOD during tachycardia. All demonstrated a shorter postpacing interval minus tachycardia cycle length during basal pacing than apical pacing with one case exhibiting apical VOD results compatible with atrioventricular nodal reentrant tachycardia. Basal VOD was useful for localizing the ventricular connection in a case with cHV pathway. In 3 cases, His refractory premature ventricular complexes reset the tachycardia without conduction to the atrium, which excluded the involvement of an atrioventricular pathway or atrial tachycardia, or atrioventricular nodal reentrant tachycardia alone. One case had His refractory premature ventricular complexes followed by subsequent constant AA interval and then tachycardia termination, suggesting a bystander cNV pathway involvement. Two cNV pathway cases presented with long RP tachycardia had paradoxical atriohisian shortening of >15 ms, suggesting parallel activation of the atrium and the atrioventricular node. Adenosine terminated the tachycardia with retrograde block in 2 cases with cNV pathways but had no response on a cHV pathway.<br /><b>Conclusions</b><br />cNV and cHV pathways mediated tachyarrhythmias can present with variable clinical presentations. We emphasize the important role of differential VOD sites, His refractory premature ventricular complexes that reset or terminate the tachycardia without conduction to the atrium, paradoxical atriohisian response in long RP tachycardia, and the use of adenosine for diagnosing cNV and cHV pathways.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 21 Apr 2023:e011771; epub ahead of print</small></div>

<div><h4>Transcatheter Leadless Pacing in Children: A PACES Collaborative Study in the Real-World Setting.</h4><i>Shah M, Borquez AA, Cortez D, McCanta A, ... Ramesh Iyer V, Williams MR</i><br /><b>Background</b><br />Transcatheter Leadless Pacemakers (TLP) are a safe and effective option for adults with pacing indications. These devices may be an alternative in pediatric patients and patients with congenital heart disease for whom repeated sternotomies, thoracotomies, or transvenous systems are unfavorable. However, exemption of children from clinical trials has created uncertainty over the indications, efficacy, and safety of TLP in the pediatric population. The objectives of this study are to evaluate clinical indications, procedural characteristics, electrical performance, and outcomes of TLP implantation in children.<br /><b>Methods</b><br />Retrospective data were collected from patients enrolled in the Pediatric and Congenital Electrophysiology Society TLP registry involving 15 centers. Patients ≤21 years of age who underwent Micra (Medtronic Inc, Minneapolis, MN) TLP implantation and had follow-up of ≥1 week were included in the study.<br /><b>Results</b><br />The device was successfully implanted in 62 of 63 registry patients (98%) at a mean age of 15±4.1 years and included 20 (32%) patients with congenital heart disease. The mean body weight at TLP implantation was 55±19 kg and included 8 patients ≤8 years of age and ≤30 kg in weight. TLP was implanted by femoral (n=55, 87%) and internal jugular (n=8, 12.6%) venous approaches. During a mean follow-up period of 9.5±5.3 months, there were 10 (16%) complications including one cardiac perforation/pericardial effusion, one nonocclusive femoral venous thrombus, and one retrieval and replacement of TLP due to high thresholds. There were no deaths, TLP infections, or device embolizations. Electrical parameters, including capture thresholds, R wave sensing, and pacing impedances, remained stable.<br /><b>Conclusions</b><br />Initial results from the Pediatric and Congenital Electrophysiology Society TLP registry demonstrated a high level of successful Micra device implants via femoral and internal venous jugular approaches with stable electrical parameters and infrequent major complications. Long-term prospective data are needed to confirm the reproducibility of these initial findings.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 11 Apr 2023:e011447; epub ahead of print</small></div>

<div><h4>Randomized Trial of Stand-Alone Use of the Antimicrobial Envelope in High-Risk Cardiac Device Patients.</h4><i>Ellis CR, Greenspon AJ, Andriulli JA, Gould PA, ... Amaral AP, Mittal S</i><br /><b>Background</b><br />Cardiac implantable electronic device (CIED) infection has a high mortality. Previous investigations showed reduced postoperative infections using skin preparation with chlorhexidine, preoperative intravenous antibiotics, and a TYRX-a antibacterial envelope. The additional benefit of antibiotic pocket wash and postoperative antibiotics has not been systematically studied.<br /><b>Methods</b><br />ENVELOPE was a prospective, multicenter, randomized, controlled trial enrolling patients undergoing CIED procedures with ≥2 risk factors for infection. The control arm received standard chlorhexidine skin preparation, intravenous antibiotics, and the TYRX-a antibiotic envelope. The study arm received pocket wash (500 mL antibiotic solution) and postoperative antibiotics for 3 days along with the prophylactic control measures. The primary end point was CIED infection and system removal at 6 months.<br /><b>Results</b><br />One thousand ten subjects (505 per arm) were enrolled and randomized. Patients were seen in person for a wound check with digital photo 2 weeks postimplant and at 3 and 6 months. CIED infection rate was low in both groups (1.0% control arm and 1.2% study arm, <i>P</i>=0.74). In the 11 subjects with infection and system removal, the time to study end point was 107±92 days with a PADIT (Prevention of Arrhythmia Device Infection Trial) score of 7.4 and a 64% 1-year mortality. Prior history of CIED infection independently predicted CIED system removal at 6 months in all subjects (odds ratio, 9.77, <i>P</i>=0.004). Of 11 infections requiring system removal, 5 were in the setting of pocket hematoma.<br /><b>Conclusions</b><br />The use of antibiotic pocket irrigation and postoperative oral antibiotics provides no additional benefit to the prophylactic measures of chlorhexidine skin preparation, preoperative intravenous antibiotics, and an antibiotic envelope in reducing CIED infection. Postoperative hematoma is a major risk factor for infection, driven by the use of antiplatelet and anticoagulant medications. The strongest predictor of CIED removal at 6 months, regardless of intervention, was prior CIED infection.<br /><b>Registration</b><br />URL: https://www.<br /><b>Clinicaltrials</b><br />gov; Unique identifier: NCT02809131.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 24 Mar 2023:e011740; epub ahead of print</small></div>

<div><h4>Outcomes of Early Rhythm Control Therapy in Patients With Atrial Fibrillation and a High Comorbidity Burden in Large Real-World Cohorts.</h4><i>Dickow J, Kany S, Roth Cardoso V, Ellinor PT, ... Yao X, Rillig A</i><br /><b>Background</b><br />A recent subanalysis of the EAST-AFNET 4 (Early Treatment of Atrial Fibrillation for Stroke Prevention Trial) suggests a stronger benefit of early rhythm control (ERC) in patients with atrial fibrillation and a high comorbidity burden when compared to patients with a lower comorbidity burden.<br /><b>Methods</b><br />We identified 109 739 patients with newly diagnosed atrial fibrillation in a large United States deidentified administrative claims database (OptumLabs) and 11 625 patients in the population-based UKB (UK Biobank). ERC was defined as atrial fibrillation ablation or antiarrhythmic drug therapy within the first year after atrial fibrillation diagnosis. Patients were classified as (1) ERC and high comorbidity burden (CHA<sub>2</sub>DS<sub>2</sub>-VASc score ≥4); (2) ERC and lower comorbidity burden (CHA<sub>2</sub>DS<sub>2</sub>-VASc score 2-3); (3) no ERC and high comorbidity burden; and (4) no ERC and lower comorbidity burden. Patients without an elevated comorbidity burden (CHA<sub>2</sub>DS<sub>2</sub>-VASc score 0-1) were excluded. Propensity score overlap weighting and cox proportional hazards regression were used to balance patients and compare groups for the primary composite outcome of all-cause mortality, stroke, or hospitalization with the diagnoses heart failure or myocardial infarction as well as for a primary composite safety outcome of death, stroke, and serious adverse events related to ERC.<br /><b>Results</b><br />In both cohorts, ERC was associated with a reduced risk for the primary composite outcome in patients with a high comorbidity burden (OptumLabs: hazard ratio, 0.83 [95% CI 0.72-0.95]; <i>P</i>=0.006; UKB: hazard ratio, 0.77 [95% CI, 0.63-0.94]; <i>P</i>=0.009). In patients with a lower comorbidity burden, the difference in outcomes was not significant (OptumLabs: hazard ratio, 0.92 [95% CI, 0.54-1.57]; <i>P</i>=0.767; UKB: hazard ratio, 0.94 [95% CI, 0.83-1.06]; <i>P</i>=0.310). The comorbidity burden interacted with ERC in the UKB (interaction- <i>P</i>=0.027) but not in OptumLabs (interaction-<i>P</i>=0.720). ERC was not associated with an increased risk for the primary safety outcome.<br /><b>Conclusions</b><br />ERC is safe and may be more favorable in a population-based sample of patients with high a comorbidity burden (CHA<sub>2</sub>DS<sub>2</sub>-VASc score ≥4).<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 21 Mar 2023:e011585; epub ahead of print</small></div>

<div><h4>Intracardiac Echocardiography-Guided Implantation for Proximal Left Bundle Branch Pacing.</h4><i>Kuang X, Zhang X, Cui Y, Wei F, ... Huang W, Fan J</i><br /><b>Background</b><br />Multiple screw-in attempts under fluoroscopy are often needed to place the pacing lead tip near or at the left bundle branch (LBB). This study was conducted to evaluate the feasibility of implanting an LBB pacing lead in the proximal LBB (PLBB) guided by intracardiac echocardiography (ICE).<br /><b>Methods</b><br />The distribution of the LBB was initially determined by ICE anatomic imaging and 3-dimensional electrical mapping of His and LBB potentials in 20 patients in the first parts of the study. In the second part, 101 consecutive pacemaker-indicated patients were randomized into the ICE-guided and non-ICE groups for LBB pacing implantation. The procedural details and electrophysiological characteristics of the 2 groups were compared.<br /><b>Results</b><br />In the first part of the study, PLBB was identified at 10 to 20 mm from the tricuspid annulus toward the apex with an area of 4.5±1.1 cm<sup>2</sup>. In the second part, the number of lead screw-in attempts in the septum was fewer in the ICE group than in the non-ICE group (1.43±0.62 versus 1.98±0.75, <i>P</i>=0.0002). The duration of the procedure (26±8 versus 43±9 minutes, <i>P</i><0.001) and fluoroscopy for LBB pacing implantation (7.4±1.8 versus 10.7±2.4 minutes, <i>P</i><0.001) in the ICE group was significantly shorter than those in the non-ICE group. LBB pacing in the ICE group generated a lesser QRS duration with more cases of LBB trunk pacing (46.8% versus 25%, <i>P</i>=0.031) and PLBB (91.5% versus 72.7%, <i>P</i>=0.0267) pacing compared with that in the non-ICE group.<br /><b>Conclusions</b><br />The basal left ventricular septum can be better visualized using ICE. ICE-guided PLBB pacing is feasible and safe, with a shorter duration required for the procedure and fluoroscopy, and generates greater LBB trunk pacing and PLBB pacing.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 16 Mar 2023:e011408; epub ahead of print</small></div>

<div><h4>Bronchial Safety After Pulsed-Field Ablation for Paroxysmal Atrial Fibrillation.</h4><i>Füting A, Reinsch N, Brokkaar L, Hartl S, ... Rausch E, Neven K</i><br /><b>Background</b><br />Thermal left atrial ablation can cause bronchial damage. Pulsed-field ablation (PFA) is a novel, nonthermal ablation modality for paroxysmal atrial fibrillation. We report on bronchial effects after pulmonary vein isolation using PFA for paroxysmal atrial fibrillation.<br /><b>Methods</b><br />A computed tomography scan showing the respiratory tract adjacent to the left atrial was obtained. Oral anticoagulation was interrupted on procedure day. Peri-procedurally, patients received heparin with an activated clotting time goal of >350 seconds. All pulmonary veins were individually isolated with a 13F steerable sheath and a pentaspline PFA catheter using either a straight-tip or J-tip guide wire. The J-tip guide wire patients were added to test the hypothesis that the straight-tip guidewire was associated with bleeding complications. One day afterward, bronchoscopy was performed. Serial hemoglobin levels were measured during 30-day follow-up.<br /><b>Results</b><br />In 2 series of 30 patients, PFA was performed, with all pulmonary veins acutely isolated. Clinical course was uneventful, no patient had chest discomfort, coughing, or hemoptysis. All patients underwent uncomplicated bronchoscopy, without thermal lesions or ulcers. In 12 out of 30 (40%) straight-tip guide wire patients, small amounts of old blood without active bleeding were seen in multiple segments. All hemoglobin levels remained clinically stable. At 30-day follow-up, all patients were asymptomatic.<br /><b>Conclusions</b><br />Pulmonary vein isolation using PFA for paroxysmal atrial fibrillation does not cause thermal lesions in the bronchial system. Use of a straight-tip, extrastiff guide wire for the over-the-wire PFA catheter can lead to asymptomatic bleeding in the bronchial system without clinical relevance at 30-day follow-up, opposite to use of a J-tip guide wire.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 13 Mar 2023:e011547; epub ahead of print</small></div>

<div><h4>Ablation of Ventricular Preexcitation to Cure Preexcitation-Induced Dilated Cardiomyopathy in Infants: Diagnosis and Outcome.</h4><i>Zhang Y, Jiang H, Cui J, Li MT, Zhou HM, Li XM</i><br /><b>Background</b><br />To investigate the clinical features of preexcitation-induced dilated cardiomyopathy in infants and evaluate safety and efficacy of radiofrequency ablation (RFCA) in these patients.<br /><b>Methods</b><br />This study included 10 infants (4 males and 6 females) with mean age of 6.78±3.14 months, mean weight of 8.11±1.71 kg, and mean left ventricular ejection fraction (LVEF) was 32.6±10.34%. Tachycardiomyopathy has been excluded and all patients were refractory to the drugs. All of these 10 patients underwent RFCA. All 10 patients underwent RFCA.<br /><b>Results</b><br />All the accessory pathways in these patients were located on right free wall and the acute success rate was 100%. No complication associated with the procedure occurred. In one case preexcitation recurred and was ablated successfully during the second attempt. There were 3 patients with mild cardiac dysfunction (LVEF, 40≤LVEF<50%), 3 with moderate (30≤LVEF<40%), and 4 with severe cardiac dysfunction (LVEF<30%, the ages were 3, 6, 7, and 10 months, respectively). The time for LVEF normalization was 1 week, 1 to 3 months, and ≥3 months, respectively. In 3 of the 4 severe cardiac dysfunction patients, the LVEF normalized at 3, 6, and 12 months after ablation, the LVEF of the remaining case did not recover at 3 months and is still being followed.<br /><b>Conclusions</b><br />Ventricular preexcitation could lead to severe cardiac dysfunction during infancy. RFCA may be a safe and effective treatment option in right free wall accessory pathways, even in infants with cardiac dysfunction. Cases of more severe cardiac dysfunction might require a longer time for LVEF recovery after RFCA.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 09 Mar 2023:e011569; epub ahead of print</small></div>

<div><h4>Economic and Health Value of Delaying Atrial Fibrillation Progression Using Radiofrequency Catheter Ablation.</h4><i>Berman AE, Kabiri M, Wei T, Galvain T, Sha Q, Kuck KH</i><br /><b>Background</b><br />Radiofrequency catheter ablation (RFCA) is an established treatment for atrial fibrillation (AF) refractory to antiarrhythmic drugs. The economic value of RFCA in delaying disease progression has not been quantified.<br /><b>Methods</b><br />An individual-level, state-transition health economic model estimated the impact of delayed AF progression using RFCA versus antiarrhythmic drug treatment for a hypothetical sample of patients with paroxysmal AF. The model incorporated the lifetime risk of progression from paroxysmal AF to persistent AF, informed by data from the ATTEST (Atrial Fibrillation Progression Trial). The incremental effect of RFCA on disease progression was modeled over a 5-year duration. Annual crossover rates were also included for patients in the antiarrhythmic drug group to mirror clinical practice. Estimates of discounted costs and quality-adjusted life years asssociated with health care utilization, clinical outcomes, and complications were projected over patients\' lifetimes.<br /><b>Results</b><br />From the payer\'s perspective, RFCA was superior to antiarrhythmic drug treatment with an estimated mean net monetary benefit per patient of $8516 ($148-$16 681), driven by reduced health care utilization, cost, and improved quality-adjusted life years. RFCA reduced mean (95% CI) per-patient costs by $73 (-$2700 to $2200), increased mean quality-adjusted life years by 0.084 (0.0-0.17) and decreased the mean number of cardiovascular-related health care encounters by 24%.<br /><b>Conclusions</b><br />RFCA is a dominant (less costly and more effective) treatment strategy for patients with AF, especially those with early AF for whom RFCA could delay progression to advanced AF. Increased utilization of RFCA-particularly among patients earlier in their disease progression-may provide clinical and economic benefits.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 09 Mar 2023:e011237; epub ahead of print</small></div>

<div><h4>Novel Calmodulin Variant p.E46K Associated With Severe Catecholaminergic Polymorphic Ventricular Tachycardia Produces Robust Arrhythmogenicity in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes.</h4><i>Gao J, Makiyama T, Yamamoto Y, Kobayashi T, ... Horie M, Kimura T</i><br /><b>Background</b><br />CaM (calmodulin) is a ubiquitously expressed, multifunctional Ca<sup>2+</sup> sensor protein that regulates numerous proteins. Recently, CaM missense variants have been identified in patients with malignant inherited arrhythmias, such as long QT syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT). However, the exact mechanism of CaM-related CPVT in human cardiomyocytes remains unclear. In this study, we sought to investigate the arrhythmogenic mechanism of CPVT caused by a novel variant using human induced pluripotent stem cell (iPSC) models and biochemical assays.<br /><b>Methods</b><br />We generated iPSCs from a patient with CPVT bearing <i>CALM2</i> p.E46K. As comparisons, we used 2 control lines including an isogenic line, and another iPSC line from an patient with long QT syndrome bearing <i>CALM2</i> p.N98S (also reported in CPVT). Electrophysiological properties were investigated using iPSC-cardiomyocytes. We further examined the cardiac RyR2 (ryanodine receptor) and Ca<sup>2+</sup> affinities of CaM using recombinant proteins.<br /><b>Results</b><br />We identified a novel de novo heterozygous variant, <i>CALM2</i> p.E46K, in 2 unrelated patients with CPVT accompanied by neurodevelopmental disorders. The E46K-cardiomyocytes exhibited more frequent abnormal electrical excitations and Ca<sup>2+</sup> waves than the other lines in association with increased Ca<sup>2+</sup> leakage from the sarcoplasmic reticulum via RyR2. Furthermore, the [<sup>3</sup>H]ryanodine binding assay revealed that E46K-CaM facilitated RyR2 function especially by activating at low [Ca<sup>2+</sup>] levels. The real-time CaM-RyR2 binding analysis demonstrated that E46K-CaM had a 10-fold increased RyR2 binding affinity compared with wild-type CaM which may account for the dominant effect of the mutant CaM. Additionally, the E46K-CaM did not affect CaM-Ca<sup>2+</sup> binding or L-type calcium channel function. Finally, antiarrhythmic agents, nadolol and flecainide, suppressed abnormal Ca<sup>2+</sup> waves in E46K-cardiomyocytes.<br /><b>Conclusions</b><br />We, for the first time, established a CaM-related CPVT iPSC-CM model which recapitulated severe arrhythmogenic features resulting from E46K-CaM dominantly binding and facilitating RyR2. In addition, the findings in iPSC-based drug testing will contribute to precision medicine.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 03 Mar 2023:e011387; epub ahead of print</small></div>

<div><h4>Recurrences of Atrial Fibrillation Despite Durable Pulmonary Vein Isolation: The PARTY-PVI Study.</h4><i>Benali K, Barré V, Hermida A, Galand V, ... Macle L, Martins RP</i><br /><b>Background</b><br />Recurrences of atrial fibrillation (AF) after pulmonary vein isolation (PVI) are mainly due to pulmonary vein reconnection. However, a growing number of patients have AF recurrences despite durable PVI. The optimal ablative strategy for these patients is unknown. We analyzed the impact of current ablation strategies in a large multicenter study.<br /><b>Methods</b><br />Patients undergoing a redo ablation for AF and presenting durable PVI were included. The freedom from atrial arrhythmia after pulmonary vein-based, linear-based, electrogram-based, and trigger-based ablation strategies were compared.<br /><b>Results</b><br />Between 2010 and 2020, 367 patients (67% men, 63±10 years, 44% paroxysmal) underwent a redo ablation for AF recurrences despite durable PVI at 39 centers. After durable PVI was confirmed, linear-based ablation was performed in 219 (60%) patients, electrogram-based ablation in 168 (45%) patients, trigger-based ablation in 101 (27%) patients, and pulmonary vein-based ablation in 56 (15%) patients. Seven patients (2%) did not undergo any additional ablation during the redo procedure. After 22±19 months of follow-up, 122 (33%) and 159 (43%) patients had a recurrence of atrial arrhythmia at 12 and 24 months, respectively. No significant difference in arrhythmia-free survival was observed between the different ablation strategies. Left atrial dilatation was the only independent factor associated with arrhythmia-free survival (HR, 1.59 [95% CI, 1.13-2.23]; <i>P</i>=0.006).<br /><b>Conclusions</b><br />In patients with recurrent AF despite durable PVI, no ablation strategy used alone or in combination during the redo procedure appears to be superior in improving arrhythmia-free survival. Left atrial size is a significant predictor of ablation outcome in this population.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 20 Feb 2023:e011354; epub ahead of print</small></div>

<div><h4> Knockout Induces Key Findings of Electrical Remodeling as Seen in Persistent Atrial Fibrillation.</h4><i>Schulz C, Lemoine MD, Mearini G, Koivumäki J, ... Eschenhagen T, Christ T</i><br /><b>Background</b><br />Electrical remodeling in human persistent atrial fibrillation is believed to result from rapid electrical activation of the atria, but underlying genetic causes may contribute. Indeed, common gene variants in an enhancer region close to <i>PITX2</i> (paired-like homeodomain transcription factor 2) are strongly associated with atrial fibrillation, but the mechanism behind this association remains unknown. This study evaluated the consequences of PITX2 deletion (PITX2<sup>-/-</sup>) in human induced pluripotent stem cell-derived atrial cardiomyocytes.<br /><b>Methods</b><br />CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) was used to delete <i>PITX2</i> in a healthy human iPSC line that served as isogenic control. Human induced pluripotent stem cell-derived atrial cardiomyocytes were differentiated with unfiltered retinoic acid and cultured in atrial engineered heart tissue. Force and action potential were measured in atrial engineered heart tissues. Single human induced pluripotent stem cell-derived atrial cardiomyocytes were isolated from atrial engineered heart tissue for ion current measurements.<br /><b>Results</b><br />PITX2<sup>-/-</sup> atrial engineered heart tissue beats slightly slower than isogenic control without irregularity. Force was lower in PITX2<sup>-/-</sup> than in isogenic control (0.053±0.015 versus 0.131±0.017 mN, n=28/3 versus n=28/4, PITX2<sup>-/-</sup> versus isogenic control; <i>P</i><0.0001), accompanied by lower expression of CACNA1C and lower L-type Ca<sup>2+</sup> current density. Early repolarization was weaker (action potential duration at 20% repolarization; 45.5±13.2 versus 8.6±5.3 ms, n=18/3 versus n=12/4, PITX2<sup>-/-</sup> versus isogenic control; <i>P</i><0.0001), and maximum diastolic potential was more negative (-78.3±3.1 versus -69.7±0.6 mV, n=18/3 versus n=12/4, PITX2<sup>-/-</sup> versus isogenic control; <i>P</i>=0.001), despite normal inward rectifier currents (both I<sub>K1</sub> and I<sub>K,ACh</sub>) and carbachol-induced shortening of action potential duration.<br /><b>Conclusions</b><br />Complete PITX2 deficiency in human induced pluripotent stem cell-derived atrial cardiomyocytes recapitulates some findings of electrical remodeling of atrial fibrillation in the absence of fast beating, indicating that these abnormalities could be primary consequences of lower PITX2 levels.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 10 Feb 2023:e011602; epub ahead of print</small></div>

<div><h4>Paroxysmal AF Ablation Using a Novel Variable-Loop Biphasic Pulsed Field Ablation Catheter Integrated With a 3D Mapping System: 1-Year Outcomes of the Multicenter inspIRE Study.</h4><i>Duytschaever M, De Potter T, Grimaldi M, Anic A, ... Jaïs P, Reddy VY</i><br /><AbstractText><br /><b>Background:</b><br/>- The inspIRE study evaluated safety and effectiveness of a fully integrated biphasic pulsed field ablation (PFA) system with a variable loop circular catheter for the treatment of drug-refractory paroxysmal atrial fibrillation (AF). <b>Methods</b> - Subjects underwent pulmonary vein isolation (PVI) with the PFA system, using at least 12 applications per vein; adenosine/isoproterenol was administered to confirm entrance block. Wave I assessed initial safety, including for esophageal lesions, silent cerebral lesions (SCLs), and PV stenosis. Wave II (pivotal phase) tested i) primary safety - incidence of early onset primary adverse events (PAEs), and primary effectiveness - confirmed PVI with freedom from documented atrial arrhythmia at 12-months (12M). The study design specified an interim analysis to determine early success once 30 subjects reached 12M follow-up (FU) and all subjects reached 3M FU. <b>Results</b> - Across 13 centers in Europe/Canada, 226 subjects were enrolled, met criteria for safety and effectiveness evaluations and received PFA (Wave I: 40; Wave II: 186). Wave I demonstrated no esophageal thermal lesions or PV stenosis. Among 39 subjects with cerebral MRI, SCLs were detected in 4 of the first 6 subjects, after which workflow enhancements, including a 10s pause between PFA applications was implemented; subsequently, only 4 of 33 subjects had SCLs. In the Wave II phase, no PAE was reported. Upon declaring early success, 83 subjects reached 12M FU. With 100% entrance block, PVI without acute reconnection was achieved in 97.1% of targeted veins. For Wave II, the primary effectiveness endpoint per Kaplan Meier at the time of interim analysis was 70.9%; 12M freedom from symptomatic AF/atrial flutter/atrial tachycardia recurrence and repeat ablation was 78.9% and 92.3%, respectively. Total procedure and transpired PFA times were 70.1 ± 27.7 min and 26.7 ± 14.0 min, respectively. <br /><b>Conclusions:</b><br/>- The inspIRE trial confirmed the safety and effectiveness of the novel mapping-integrated PFA system.</AbstractText><br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 03 Feb 2023; epub ahead of print</small></div>

<div><h4>Clinical Features, Genetic Findings, and Risk Stratification in Arrhythmogenic Right Ventricular Cardiomyopathy: Data From a Brazilian Cohort.</h4><i>Olivetti NQS, Sacilotto L, Wulkan F, Pessente GD, ... da Costa Pereira A, da Costa Darrieux F</i><br /><b>Background</b><br />Arrhythmogenic right ventricular cardiomyopathy (ARVC), a rare inherited disease, causes ventricular tachycardia, sudden cardiac death, and heart failure (HF). We investigated ARVC clinical features, genetic findings, natural history, and the occurrence of life-threatening arrhythmic events (LTAEs), HF death, or heart transplantation (HF-death/HTx) to identify risk factors.<br /><b>Methods</b><br />The clinical course of 111 consecutive patients with definite ARVC, predictors of LTAE, HF-death/HTx, and combined events were analyzed in the entire cohort and in a subgroup of 40 patients without sustained ventricular arrhythmia before diagnosis.<br /><b>Results</b><br />The 5-year cumulative probability of LTAE was 30%, and HF-death/HTx was 10%. Predictors of HF-death/HTx were reduced right ventricle ejection fraction (HR: 0.93; <i>P</i>=0.010), HF symptoms (HR: 4.37; <i>P</i>=0.010), epsilon wave (HR: 4.99; <i>P</i>=0.015), and number of leads with low QRS voltage (HR: 1.28; <i>P</i>=0.001). Each additional lead with low QRS voltage increased the risk of HF-death/HTx by 28%. Predictors of LTAE were prior syncope (HR: 1.81; <i>P</i>=0.040), number of leads with T wave inversion (HR: 1.17; <i>P</i>=0.039), low QRS voltage (HR: 1.12; <i>P</i>=0.021), younger age (HR: 0.97; <i>P</i>=0.006), and prior ventricular arrhythmia/ventricular fibrillation (HR: 2.45; <i>P</i>=0.012). Each additional lead with low QRS voltage increased the risk of LTAE by 17%. In patients without ventricular arrhythmia before clinical diagnosis of ARVC, the number of leads with low QRS voltage (HR: 1.68; <i>P</i>=0.023) was independently associated with HF-death/HTx.<br /><b>Conclusions</b><br />Our study demonstrated the characteristics of a specific cohort with a high prevalence of arrhythmic burden at presentation, male predominance, younger age and HF severe outcomes. Our main results suggest that the presence and extension of low QRS voltage can be a risk predictor for HF-death/HTx in ARVC patients, regardless of the arrhythmic risk. This study can contribute to the global ARVC risk stratification, adding new insights to the international current scientific knowledge.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 31 Jan 2023:e011391; epub ahead of print</small></div>

<div><h4>Reduction in Junctophilin 2 Expression in Cardiac Nodal Tissue Results in Intracellular Calcium-Driven Increase in Nodal Cell Automaticity.</h4><i>Landstrom AP, Yang Q, Sun B, Perelli RM, ... Kim JJ, Wehrens XHT</i><br /><b>Background</b><br />Spontaneously depolarizing nodal cells comprise the pacemaker of the heart. Intracellular calcium (Ca<sup>2+</sup>) plays a critical role in mediating nodal cell automaticity and understanding this so-called Ca<sup>2+</sup> clock is critical to understanding nodal arrhythmias. We previously demonstrated a role for Jph2 (junctophilin 2) in regulating Ca<sup>2+</sup>-signaling through inhibition of RyR2 (ryanodine receptor 2) Ca<sup>2+</sup> leak in cardiac myocytes; however, its role in pacemaker function and nodal arrhythmias remains unknown. We sought to determine whether nodal Jph2 expression silencing causes increased sinoatrial and atrioventricular nodal cell automaticity due to aberrant RyR2 Ca<sup>2+</sup> leak.<br /><b>Methods</b><br />A tamoxifen-inducible, nodal tissue-specific, knockdown mouse of Jph2 was achieved using a Cre-recombinase-triggered short RNA hairpin directed against Jph2 (Hcn4:shJph2). In vivo cardiac rhythm was monitored by surface ECG, implantable cardiac telemetry, and intracardiac electrophysiology studies. Intracellular Ca<sup>2+</sup> imaging was performed using confocal-based line scans of isolated nodal cells loaded with fluorescent Ca<sup>2+</sup> reporter Cal-520. Whole cell patch clamp was conducted on isolated nodal cells to determine action potential kinetics and sodium-calcium exchanger function.<br /><b>Results</b><br />Hcn4:shJph2 mice demonstrated a 40% reduction in nodal Jph2 expression, resting sinus tachycardia, and impaired heart rate response to pharmacologic stress. In vivo intracardiac electrophysiology studies and ex vivo optical mapping demonstrated accelerated junctional rhythm originating from the atrioventricular node. Hcn4:shJph2 nodal cells demonstrated increased and irregular Ca<sup>2+</sup> transient generation with increased Ca<sup>2+</sup> spark frequency and Ca<sup>2+</sup> leak from the sarcoplasmic reticulum. This was associated with increased nodal cell AP firing rate, faster diastolic repolarization rate, and reduced sodium-calcium exchanger activity during repolarized states compared to control. Phenome-wide association studies of the <i>JPH2</i> locus identified an association with sinoatrial nodal disease and atrioventricular nodal block.<br /><b>Conclusions</b><br />Nodal-specific Jph2 knockdown causes increased nodal automaticity through increased Ca<sup>2+</sup> leak from intracellular stores. Dysregulated intracellular Ca<sup>2+</sup> underlies nodal arrhythmogenesis in this mouse model.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 27 Jan 2023:e010858; epub ahead of print</small></div>

<div><h4>Abnormal Conduction Zone Detected by Isochronal Late Activation Mapping Accurately Identifies the Potential Atrial Substrate and Predicts the Atrial Fibrillation Ablation Outcome After Pulmonary Vein Isolation.</h4><i>Kuo MJ, Ton AK, Lo LW, Lin YJ, ... Hsu CY, Chen SA</i><br /><b>Background</b><br />The presence of abnormal substrate of left atrium is a predictor of atrial fibrillation (AF) recurrence after pulmonary vein isolation. We aimed to investigate the isochronal late activation mapping to access the abnormal conduction velocity for predicting AF ablation outcome.<br /><b>Methods</b><br />Forty-five paroxysmal AF patients (30 males, 57.8±8.7 years old) who underwent pulmonary vein isolation were enrolled. Isochronal late activation mapping was retrospectively constructed with 2 different windows of interest: from onset of P wave to onset of QRS wave on surface electrocardiography (W1) and 74 ms tracking back from the end of P wave (W2). Deceleration zone was defined as regions with 3 isochrones (DZa) or ≥4 isochrones (DZb) within a 1 cm radius on the isochronal late activation mapping, and the estimated conduction velocity (ECV) are 0.27 m/s and <0.20 m/s for DZa and DZb, respectively in W2. The distribution of deceleration zone was compared with the location of low-voltage zone (bipolar voltage ≤0.5 mV). Any recurrence of atrial arrhythmias was defined as the primary end point during follow ups after a 3-month blanking period.<br /><b>Results</b><br />Pulmonary vein isolation was performed in all patients, and there were 2 patients (4.4%) received additional extrapulmonary vein ablation. After a mean follow-up of 12.7±4.5 months, recurrence of AF occurred in 14 patients (31.1%). Patients with the presence of DZb in W2 had higher AF recurrence (Kaplan-Meier event rate estimates: HR, 9.41 [95% CI, 2.61-33.90]; log-rank <i>P</i><0.0001). 52.6% of the DZb locations in W2 were comparable to the distributions of low-voltage zone, and 47.4% DZb were distributed in the area without low-voltage zone.<br /><b>Conclusions</b><br />Deceleration zone detected by isochronal late activation mapping represents a critical AF substrate, it accurately predicts the AF recurrence following ablation in patients with paroxysmal AF.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 23 Jan 2023:e011149; epub ahead of print</small></div>

<div><h4>Substrate Mapping Alters Ventricular Tachycardia Inducibility.</h4><i>Aboud AA, Davogustto G, Adeola O, Richardson TD, ... Stevenson WG, Kanagasundram A</i><br /><b>Background</b><br />Initiation of ventricular tachycardia (VT) by programmed electrical stimulation (PES) has an important role to allow mapping and assess ablation end points. We hypothesized that substrate mapping may alter VT inducibility by mechanical bumping of critical sites.<br /><b>Methods</b><br />Subjects with left ventricular scar-related VT that was inducible by PES who were undergoing ablation were included. PES was repeated after substrate mapping (Group I) or after time under sedation/anesthesia during which additional imaging and transeptal puncture were performed without substrate mapping (Group II). The response to the second PES was categorized as type I if the same VT was induced, type II if a different VT was induced, and type III if VT was not inducible.<br /><b>Results</b><br />Twenty-eight patients (median age 66 years, 61% ischemic cardiomyopathy), 14 in Group I and 14 in Group II, were included. Age, time between initial and second PES, type of cardiomyopathy, ejection fraction, and anesthesia methods were not different between the 2 groups. Initial VT cycle length, however, was shorter in Group I (305 millisecond [range, 235-600] versus 350 millisecond [range, 235-600], <i>P</i>=0.016). Also, Group I required more extrastimuli to induce VT in PES 1 (2 [1-4] versus 2 [1-3], <i>P</i>=0.022). In Group I, following substrate mapping, the second PES induced the same VT in 3 patients (21%), a different VT in 9 (64%), and no VT in 2 (14%) patients. In contrast, in Group II the same VT was induced in 10 (71%) patients, a different VT in 3 (21%) and no VT in 1 (7%) patient (<i>P</i>=0.017).<br /><b>Conclusions</b><br />Mechanical effects of substrate mapping commonly alter inducibility of VT. This has important implications for catheter ablation procedure planning and acute assessment of outcome and can potentially account for some recurrent VTs that are not recognized at the time of the procedure.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 05 Jan 2023:e010889; epub ahead of print</small></div>

<div><h4>Pleomorphic Ventricular Tachycardia in Dilated Cardiomyopathy Predicts Ventricular Tachycardia Recurrence After Ablation Independent From Cardiac Function: Comparison With Patients With Ischemic Heart Disease.</h4><i>Kimura Y, de Riva M, Ebert M, Glashan C, ... Trines SA, Zeppenfeld K</i><br /><b>Background</b><br />In dilated cardiomyopathy (DCM), outcome after catheter ablation of ventricular tachycardia (VT) is modest, compared with ischemic heart disease (IHD). Pleomorphic VT (PL-VT) has been associated with fibrotic remodeling and end-stage heart failure in IHD. The prognostic role of PL-VT in DCM is unknown.<br /><b>Methods</b><br />Consecutive IHD (2009-2016) or DCM (2008-2018) patients undergoing ablation for monomorphic VT were included. PL-VT was defined as ≥1 spontaneous change of the 12-lead VT-morphology during the same induced VT episode. Patients were followed for VT recurrence and mortality.<br /><b>Results</b><br />A total of 247 patients (86% men; 63±13 years; IHD n=152; DCM n=95) underwent ablation for monomorphic VT. PL-VT was observed in 22 and 29 patients with IHD and DCM, respectively (14% versus 31%, <i>P</i>=0.003). In IHD, PL-VT was associated with lower LVEF (28±9% versus 34±12%, <i>P</i>=0.02) and only observed in those with LVEF<40%. In contrast, in DCM, PL-VT was not related to LVEF and induced in 27% of patients with LVEF>40%. During a median follow-up of 30 months, 79 (32%) patients died (IHD 48; DCM 31; <i>P</i>=0.88) and 120 (49%) had VT recurrence (IHD 59; DCM 61; <i>P</i><0.001). PL-VT was associated with mortality in IHD but not in DCM. In IHD, VT recurrence was independently associated with LVEF, number of induced VTs, and procedural noncomplete success. Of note, in DCM, PL-VT (HR, 2.62 [95% CI, 1.47-4.69]), pathogenic mutation (HR, 2.13 [95% CI, 1.16-3.91]), and anteroseptal VT substrate (HR, 1.75 [95% CI, 1.00-3.07]) independently predicted VT recurrence.<br /><b>Conclusions</b><br />In IHD, PL-VT was associated with low LVEF and mortality. In DCM, PL-VT was not associated with mortality but a predictor of VT recurrence independent from LVEF. PL-VT in DCM may indicate a specific arrhythmic substrate difficult to control by current ablation techniques.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 03 Jan 2023:e010826; epub ahead of print</small></div>

<div><h4>Alternating Early Afterdepolarizations Underlying Bradycardia-Dependent Macroscopic T Wave and Discordant Mechanical Alternans.</h4><i>Qi D, Li W, Quan XQ, Gao Y, ... Gao C, Yan GX</i><br /><b>Background</b><br />Macroscopic T wave alternans (macro-TWA) often heralds the onset of Torsades de Pointes in patients with QT prolongation. However, the mechanisms underlying macro-TWA remain unclear. We examined the cellular and ionic basis for macro-TWA in rabbits with left ventricular hypertrophy (LVH).<br /><b>Methods</b><br />The renovascular hypertension model was used to induce LVH in rabbits. Action potentials were simultaneously recorded from epicardium and endocardium together with a transmural ECG and isometric contractility in arterially perfused left ventricular wedges. Late sodium current (I<sub>Na</sub>-L) was recorded in single-isolated left ventricular myocytes with the whole cell patch-clamp technique.<br /><b>Results</b><br />Macro-TWA and accompanied mechanical alternans occurred spontaneously in 8 of 33 LVH rabbits (<i>P</i><0.05, versus 0/15 in controls) and were induced by an I<sub>Na</sub>-L enhancer ATX-II at 1 to 3 nM in additional 7. Macro-TWA and mechanical alternans occurred discordantly, that is, that longer QT interval and larger T wave were associated with weaker isometric contractility. Alternating early afterdepolarizations in the endocardium caused macro-TWA in 12 of 15 LVH rabbits and, therefore, early afterdepolarization-dependent R-from-T extrasystoles and Torsades de Pointes always originated from the beats with longer QT and larger T wave during macro-TWA. I<sub>Na</sub>-L density was significantly larger in LVH myocytes than that of control myocytes. Macro-TWA, mechanical alternans, R-from-T extrasystoles, and Torsades de Pointes were all abolished by I<sub>Na</sub>-L blocker ranolazine or mexiletine.<br /><b>Conclusions</b><br />LVH enhances I<sub>Na</sub>-L density and promotes alternating early afterdepolarizations in the left ventricular endocardium that manifest as macro-TWA with discordant mechanical alternans. I<sub>Na</sub>-L blockade abolishes macro-TWA, mechanical alternans, early afterdepolarization-dependent R-from-T extrasystoles, and Torsades de Pointes.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 03 Jan 2023:e011453; epub ahead of print</small></div>

<div><h4>Chronic Kidney Disease Induces Proarrhythmic Remodeling.</h4><i>King BMN, Mintz S, Lin X, Morley GE, ... Khodadadi-Jamayran A, Fishman GI</i><br /><b>Background</b><br />Patients with chronic kidney disease (CKD) are at increased risk of developing cardiac arrhythmogenesis and sudden cardiac death; however, the basis for this association is incompletely known.<br /><b>Methods</b><br />Here, using murine models of CKD, we examined interactions between kidney disease progression and structural, electrophysiological, and molecular cardiac remodeling.<br /><b>Results</b><br />C57BL/6 mice with adenine supplemented in their diet developed progressive CKD. Electrocardiographically, CKD mice developed significant QT prolongation and episodes of bradycardia. Optical mapping of isolated-perfused hearts using voltage-sensitive dyes revealed significant prolongation of action potential duration with no change in epicardial conduction velocity. Patch-clamp studies of isolated ventricular cardiomyocytes revealed changes in sodium and potassium currents consistent with action potential duration prolongation. Global transcriptional profiling identified dysregulated expression of cellular stress response proteins RBM3 (RNA-binding motif protein 3) and CIRP (cold-inducible RNA-binding protein) that may underlay the ion channel remodeling. Unexpectedly, we found that female sex is a protective factor in the progression of CKD and its cardiac sequelae.<br /><b>Conclusions</b><br />Our data provide novel insights into the association between CKD and pathologic proarrhythmic cardiac remodeling. Cardiac cellular stress response pathways represent potential targets for pharmacologic intervention for CKD-induced heart rhythm disorders.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 03 Jan 2023:e011466; epub ahead of print</small></div>

<div><h4>Electrophysiology, Pathology, and Imaging of Pulsed Field Ablation of Scarred and Healthy Ventricles in Swine.</h4><i>Kawamura I, Reddy VY, Santos-Gallego CG, Wang BJ, ... Dukkipati SR, Koruth JS</i><br /><b>Background</b><br />Pulsed field ablation (PFA) has recently been shown to penetrate ischemic scar, but details on its efficacy, risk of arrhythmias, and imaging insights are lacking. In a porcine model of myocardial scar, we studied the ability of ventricular PFA to penetrate scarred tissue, induce ventricular arrhythmias, and assess the influence of QRS gating during pulse delivery.<br /><b>Methods</b><br />Of a total of 6 swine, 5 underwent coronary occlusion and 1 underwent radiofrequency ablation to create infarct scar and iatrogenic scar models, respectively. Two additional swine served as healthy controls. An 8 Fr focal PFA catheter was used to deliver bipolar, biphasic PFA (2.0 kV) lesions guided by electroanatomical mapping, fluoroscopy, and intracardiac echocardiography over both scarred and healthy myocardium. Swine underwent magnetic resonance imaging 2-7 days post-PFA.<br /><b>Results</b><br />PFA successfully penetrated scar without significant difference in lesion depth between lesion at the infarct border (5.9±1.0 mm, n=41) and healthy myocardium (5.7±1.3 mm, n=26; <i>P</i>=0.53). PFA penetration of both infarct and iatrogenic radiofrequency abalation scar was observed in all examined sections. Sustained ventricular arrhythmias requiring defibrillation occurred in 4 of 187 (2.1%) ungated applications, whereas no ventricular arrhythmias occurred during gated PFA applications (0 of 64 [0%]). Dark-blood late-gadolinium-enhanced sequences allowed for improved endocardial border detection as well as lesion boundaries compared with conventional bright-blood late-gadolinium-enhanced sequences.<br /><b>Conclusions</b><br />PFA penetrates infarct and iatrogenic scar successfully to create deep lesions. Gated delivery eliminates the occurrence of ventricular arrhythmias observed with ungated porcine PFA. Optimized magnetic resonance imaging sequences can be helpful in detecting lesion boundaries.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 03 Jan 2023:e011369; epub ahead of print</small></div>

<div><h4>Atrial Endocardial Unipolar Voltage Mapping for Detection of Viable Intramural Myocardium: A Proof-of-Concept Study.</h4><i>Yavin H, Younis A, Zilberman I, Krywanczyk A, ... Barkagan M, Anter E</i><br /><b>Background</b><br />Endocardial bipolar voltage amplitude is largely derived from endocardial and subendocardial wall layers. This may result in situations of low bipolar voltage amplitude despite the presence of mid-myocardial including epicardial (ie, intramural-epicardial) viable myocardium. This study examined the utility of endocardial unipolar voltage mapping for detection of viable intramural-epicardial atrial myocardium.<br /><b>Methods</b><br />In 15 swine, an atrial intercaval ablation line with an intentional gap was created. Animals survived for 6 to 8 weeks before electroanatomical mapping followed by sacrifice. Gaps were determined by the presence of electrical conduction and classified based on the histopathologiclly layer(s) of viable myocardium into the following: (1) transmural, (2) endocardial, and (3) intramural-epicardial. Voltage data from healthy, scar, and gap points were exported into excel. The sensitivity and specificity of bipolar and unipolar voltage amplitude to detect intramural-epicardial gaps were compared using receiver operating characteristic analysis.<br /><b>Results</b><br />In 9 of 15 (60%) swine, a focal ablation gap was detected in the intercaval line, while in the remainder 6 of 15 (40%), the line was complete without gaps. Gaps were classified into transmural (n=3), endocardial (n=3), or intramural-epicardial (n=3). Intramural-epicardial gaps were characterized by very low bipolar voltage amplitude that was similar to areas with transmural scar (<i>P</i>=0.91). In comparison, unipolar voltage amplitude in intramural-epicardial gaps was significantly higher compared to transmural scar (<i>P</i><0.001). Unipolar voltage amplitude had higher sensitivity (93% versus 14%, respectively) and similar specificity (95% versus 98%, respectively) to bipolar voltage for detection of intramural-epicardial gaps.<br /><b>Conclusions</b><br />Atrial unipolar voltage mapping may be a useful technique for identifying viable intramural-epicardial myocardium in patients with endocardial scar.<br /><br /><br /><br /><small>Circ Arrhythm Electrophysiol: 03 Jan 2023:e011321; epub ahead of print</small></div>