<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>