<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>