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In a pivotal trial (NCT05252702), the AVEIR DR (Abbott) leadless pacemaker system was found to be safe and effective in delivering DDDR synchronous atrial and ventricular pacing. This dual-chamber system employs 2 leadless pacemakers with implant-to-implant communication. Although implantation of the ventricular device as a single-chamber pacemaker has been well described, there are additional considerations surrounding the dual-chamber implantation procedure. Herein, we review the dual-chamber leadless pacemaker implantation workflow while providing guidance to optimize safe and effective implantation procedures., Competing Interests: Disclosures P.N., R.N.D., V.Y.R., D.V.E., T.C., S.S., R.E.K., and J.E.I. report Abbott consulting fees. P.D., D.V.E., and R.E.K. report Abbott research grants. D.V.E., T.C., and S.S. report Abbott honoraria. R.N.D., M.S., M.G.B., G.H., R.E.K., and J.E.I. serve as Abbott steering committee members. Unrelated to this manuscript: V.Y.R. serves as a consultant for and has equity in Ablacon, Acutus Medical, Affera-Medtronic, Anumana, Apama Medical–Boston Scientific, APN Health, Aquaheart, Atacor, Autonomix, Axon Therapies, Backbeat, BioSig, CardiaCare, Cardiofocus, CardioNXT/AFTx, Circa Scientific, CoRISMA, Corvia Medical, Dinova-Hangzhou DiNovA EP Technology, East End Medical, EP Frontiers, Farapulse, Field Medical, Focused Therapeutics, HRT, Intershunt, Javelin, Kardium, Keystone Heart, Laminar Medical, LuxMed, Medlumics, Neutrace, Nuvera–Biosense Webster, Oracle Health, Pulse Biosciences, Restore Medical, Sirona Medical, SoundCath, Valcare; unrelated to this work, he has served as a consultant for Adagio Medical, Append Medical, AtriAN, BioTel Heart, Biosense Webster, Biotronik, Boston Scientific, Cairdac, Cardionomic, CoreMap, Fire1, Gore & Associates, Impulse Dynamics, Medtronic, Novartis, Novo Nordisk, and Philips; and unrelated to this work, he has equity in Atraverse, DRS Vascular, Manual Surgical Sciences, Newpace, Nyra Medical, Soundcath, Surecor, and Vizaramed. R.C. reports consulting fees from Medtronic. T.C. reports speaking and consulting fees from Medtronic, Philips, Boston Scientific, and ShockWave. S.S. holds an unrelated patent with Abbott. R.E.K reports research grants and consulting fees from and serves as a steering committee member of Boston Scientific and reports speaking fees from Medtronic. J.E.I. reports consulting fees from Medtronic and serves as a Data Safety Monitoring Committee member of Boston Scientific., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Disclosures Dr Ip reports consulting, steering committee, and speaking fees from Abbott; consulting fees from Medtronic; and data safety monitoring committee and speaking fees from Boston Scientific.

Background: Shock-reduction implantable cardioverter-defibrillator programming (SRP) was associated with fewer therapies and improved survival in randomized controlled trials, but real-world studies investigating SRP and associated outcomes are limited., Methods and Results: The BIOTRONIK CERTITUDE registry was linked with the Medicare database. We included all patients with an implantable cardioverter-defibrillator implanted between August 22, 2012 and September 30, 2021 in the United States. SRP was defined as programming to either a therapy rate cutoff ≥188 beats per minute or number of intervals to detection ≥30/40 for treatment. Among 6781 patients (mean 74±9 years; 27% women), 3393 (50%) had SRP. Older age, secondary prevention indication, and device implantation in the southern or western United States were associated with lower use of SRP. The cumulative incidence rate of implantable cardioverter-defibrillator shocks was lower in the SRP group (5.1% shocks/patient year) compared with the non-SRP group (7.2% shocks/patient year) (adjusted hazard ratio [HR], 0.83 [95% CI, 0.73-0.96]; P =0.005). Over a median follow-up of 2.9 years, 739 deaths occurred in the SRP group and 822 deaths occurred in the non-SRP group (adjusted HR, 0.97 [95% CI, 0.88-1.07]; P =0.569). SRP was associated with a lower all-cause mortality among patients without ischemic heart disease compared with patients with ischemic heart disease (adjusted HR, 0.64 [95% CI, 0.48-0.87] versus adjusted HR, 1.02 [95% CI, 0.92-1.14]; P interaction =0.004)., Conclusions: Adoption of SRP is low in real-world clinical practice. Age, clinical variables, and geographic factors are associated with use of SRP. In this study, SRP-associated decrease in mortality was limited to patients without ischemic heart disease.

Background: A dual-chamber leadless pacemaker system has been designed for atrioventricular synchronous pacing using wireless, beat-to-beat, implant-to-implant (i2i) communication between distinct atrial and ventricular leadless pacemakers. The atrioventricular synchrony achieved across various ambulatory scenarios has yet to be systematically evaluated., Methods: A prospective, single-arm, unblinded, multicenter, international clinical trial of the leadless pacemaker system was conducted in patients with a conventional dual-chamber pacing indication enrolled from February 2022 to March 2023. Leadless pacemaker systems were implanted, and 12-lead Holter electrocardiographic recordings were collected 3 months after implantation over various postures/activities: sitting, supine, left lateral recumbent, right lateral recumbent, standing, normal walk, and fast walk. An independent Holter core laboratory performed a manual adjudication of the percent of atrioventricular synchronous beats using the standard 300-millisecond PR interval limit. Atrium-to-ventricle and ventricle-to-atrium i2i communication success rates were also assessed. Post hoc summary statistics describing the relationships between atrioventricular synchrony and i2i success, posture/activity, implantation indication, atrioventricular event, and heart rate were calculated., Results: In the evaluable population (n=384 of 464 enrolled [83%]; 61% male; age, 70 years; weight, 82 kg; 60% ejection fraction; 95% of beats evaluable), the mean atrioventricular synchrony of 98% of beats observed across all postures using the standard 300-millisecond limit was greater than both atrial-to-ventricular i2i (94%) and ventricular-to-atrial i2i (94%; P <0.001), exceeding both i2i values in 95% of patients. Atrioventricular synchrony was achieved in >95% of evaluable beats across all postures/activities, implantation indications, atrioventricular paced/sensed event combinations, and heart rate ranges (including >100 bpm)., Conclusions: This dual-chamber leadless pacemaker system demonstrated atrioventricular synchrony in 98% of evaluable beats at 3 months after implantation. Atrioventricular synchrony was maintained across postures/activities and remained robust for heart rates >100 bpm., Competing Interests: Dr Ip reports consulting fees from Abbott and Medtronic and serves as a Steering Committee member for Abbott and a Data Safety Monitoring Committee member for Boston Scientific. Dr Rashtian reports research grants and consulting fees from Abbott. Dr Exner reports consulting fees and research grants from Abbott and Medtronic and, unrelated to this article, reports consulting fees and research grants from Boston Scientific and GE Healthcare, as well equity in CorVista, Clarius, eMurmur, HelpWear, and ProtonIntel. Dr Reddy is a consultant to Abbott. Unrelated to this article, he serves as a consultant for and has equity in Ablacon, Acutus Medical, Affera-Medtronic, Apama Medical-Boston Scientific, Anumana, APN Health, Aquaheart, Atacor, Autonomix, Axon Therapies, Backbeat, BioSig, CardiaCare, CardioNXT/ AFTx, Circa Scientific, CoRISMA, Corvia Medical, Dinova-Hangzhou DiNovA EP Technology, East End Medical, EPD-Philips, EP Frontiers, Epix Therapeutics-Medtronic, EpiEP, Eximo, Farapulse-Boston Scientific, Field Medical, Focused Therapeutics, HRT, Intershunt, Javelin, Kardium, Keystone Heart, Laminar, LuxMed, Medlumics, Middlepeak, Neutrace, Nuvera-Biosense Webster, Oracle Health, Restore Medical, Sirona Medical, SoundCath, and Valcare; unrelated to this work, has served as a consultant for AtriAN, Biosense Webster, BioTel Heart, Biotronik, Boston Scientific, Cairdac, Cardiofocus, Cardionomic, CoreMap, Fire1, Gore & Associates, Impulse Dynamics, Medtronic, Novartis, Philips, Pulse Biosciences; and he has equity in DRS Vascular, Manual Surgical Sciences, Newpace, Nyra Medical, Surecor, and Vizaramed. Dr Doshi reports consulting fees from Abbott and serves as a steering committee member for Abbott. Dr Badie, J.R. Nevo, and A. Goil are employees of Abbott. Dr Defaye reports research grants from Abbott, Boston Scientific, and Medtronic. Dr Canby reports consulting fees from Medtronic. Dr Grazia Bongiorni serves as a steering committee member for Abbott. Dr Shoda serves as a Steering Committee member for Abbott. Dr Hindricks serves as a Steering Committee member for Abbott. Dr Knops reports research grants, consulting fees, and serving as a Steering Committee member for Abbott and Boston Scientific and speaking fees from Medtronic.

Background: Paroxysmal supraventricular tachycardia (PSVT) is a common episodic arrhythmia characterized by unpredictable onset and burdensome symptoms including palpitations, dizziness, chest pain, distress, and shortness of breath. Treatment of acute episodes of PSVT in the clinical setting consists of intravenous adenosine, beta-blockers, and calcium channel blockers (CCBs). Etripamil is an intranasally self-administered L-type CCB in development for acute treatment of AV-nodal dependent PSVT in a nonmedical supervised setting., Methods: This paper summarizes the rationale and study design of NODE-303 that will assess the efficacy and safety of etripamil. In the randomized, double-blinded, placebo-controlled, Phase 3 RAPID trial, etripamil was superior to placebo in the conversion of single PSVT episodes by 30 minutes post initial dose when administered in the nonhealthcare setting; this study required a mandatory and observed test dosing prior to randomization. The primary objective of NODE-303 is to evaluate the safety of symptom-prompted, self-administered etripamil for multiple PSVT episodes in real-world settings, without the need for test dosing prior to first use during PSVT. Secondary endpoints include efficacy and disease burden. Upon perceiving a PSVT episode, the patient applies an electrocardiographic monitor, performs a vagal maneuver, and, if the vagal maneuver is unsuccessful, self-administers etripamil 70 mg, with an optional repeat dose if symptoms do not resolve within 10 minutes after the first dose. A patient may treat up to four PSVT episodes during the study. Adverse events are recorded as treatment-emergent if they occur within 24 hours after the administration of etripamil., Results: Efficacy endpoints include time to conversion to sinus rhythm within 30 and 60 minutes after etripamil administration, and the proportion of patients who convert at 3, 5, 10, 20, 30, and 60 minutes. Patient-reported outcomes are captured by the Brief Illness Perception Questionnaire, the Cardiac Anxiety Questionnaire, the Short Form Health Survey 36, the Treatment Satisfaction Questionnaire for Medication and a PSVT survey., Conclusions: Overall, these data will support the development of a potentially paradigm-changing long-term management strategy for recurrent PSVT., Competing Interests: Conflicts of interest Sarah Omodele, Silvia Shardonofsky and David B. Bharucha are employees of Milestone Pharmaceuticals. Bruce S. Stambler received compensation as a consultant for Milestone Pharmaceuticals. Peter Noseworthy declares no conflict of interest. Hanh Bui declares no conflict of interest. A John Camm received compensation as a consultant for Milestone Pharmaceuticals; grants and personal fees from Boehringer Ingelheim, Bayer, Pfizer, Bristol-Myers Squibb, and Daiichi Sankyo; personal fees from Medtronic, Boston Scientific, Menarini, and Biotronik; and support from Anthos, Sanofi, Abbott, GlaxoSmithKline, and Johnson & Johnson. Benoit Coutu declares no conflict of interest. Maria Leonor Parody declares no conflict of interest. Samuel F Sears received compensation from Medtronic and Abbott as a consultant; he also received speaker compensation from Medtronic, Zoll, and Biotronik; serves as a quality-of-life consultant for Thyve, Tenaya, and Milestone Pharmaceutical. Narendra Singh declares no conflict of interest. Juan Agudelo Uribe declares no conflict of interest. John Vyselaar declares no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Competing Interests: Disclosures Dr Ip received consulting fees from Abbott, Medtronic and Boston Scientific. He serves on the steering committee of Abbott and on the data safety monitoring committee of Boston Scientific.

Etripamil, a fast-acting nondihydropyridine L-type calcium channel blocker, is under investigation for potential self-administration for the acute treatment of supraventricular tachyarrhythmias in a medically unsupervised setting. We report detailed pharmacokinetics and pharmacodynamics of intranasally administered etripamil in healthy adults from 2 Phase 1, randomized, double-blind studies: Study MSP-2017-1096 (sequential dose-escalation, crossover study design, n = 64) and NODE-102 (single dose, 4-way crossover study, n = 24). Validated bioanalytical assays determined plasma concentrations of etripamil and its inactive metabolite. Noncompartmental pharmacokinetic parameters were calculated. Pharmacodynamic parameters were determined for PR interval, blood pressure, and heart rate. Etripamil was rapidly absorbed intranasally, with time to maximal plasma concentration of 5-8.5 minutes, corresponding to a rapid greater than 10% increase in mean maximum PR interval from baseline within 4-7 minutes of doses of 60 mg or greater. Following peak plasma concentrations, systemic etripamil levels declined rapidly within the first 15 minutes following dosing and decreased more gradually thereafter. PR interval prolongation greater than 10% from baseline was generally sustained for about 45 minutes at doses of 60 mg or greater. The mean terminal half-life ranged from about 1.5 hours with 60 mg to about 2.5-3 hours for the 70- and 105-mg doses. Etripamil was generally well tolerated without symptomatic hypotension. Adverse events were primarily mild to moderate and related to the administration site; no serious adverse events or episodes of atrioventricular block occurred. Intranasal etripamil administration, at doses of 60 mg or greater, produced rapidly occurring slowing of atrioventricular nodal conduction with a limited duration of effect without hemodynamic or electrocardiographic safety signals in healthy volunteers., (© 2024 Milestone Pharma. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Most forms of sustained ventricular tachycardia (VT) are caused by re-entry, resulting from altered myocardial conduction and refractoriness secondary to underlying structural heart disease. In contrast, VT caused by triggered activity (TA) is unrelated to an abnormal structural substrate and is often caused by molecular defects affecting ion channel function or regulation of intracellular calcium cycling. This review summarizes the cellular and molecular bases underlying TA and exemplifies their clinical relevance with selective representative scenarios. The underlying basis of TA caused by delayed afterdepolarizations is related to sarcoplasmic reticulum calcium overload, calcium waves, and diastolic sarcoplasmic reticulum calcium leak. Clinical examples of TA caused by delayed afterdepolarizations include sustained right and left ventricular outflow tract tachycardia and catecholaminergic polymorphic VT. The other form of afterpotentials, early afterdepolarizations, are systolic events and inscribe early afterdepolarizations during phase 2 or phase 3 of the action potential. The fundamental defect is a decrease in repolarization reserve with associated increases in late plateau inward currents. Malignant ventricular arrhythmias in the long QT syndromes are initiated by early afterdepolarization-mediated TA. An understanding of the molecular and cellular bases of these arrhythmias has resulted in generally effective pharmacologic-based therapies, but these are nonspecific agents that have off-target effects. Therapeutic efficacy may need to be augmented with an implantable defibrillator. Next-generation therapies will include novel agents that rescue arrhythmogenic abnormalities in cellular signaling pathways and gene therapy approaches that transfer or edit pathogenic gene variants or silence mutant messenger ribonucleic acid., Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Limited data exist about the origins and mechanisms of atypical atrial flutter that occurs in the absence of prior ablation or surgery., Objectives: The aims of this study were to report a large cohort of patients who presented for catheter ablation of de novo atypical flutters, to identify the most common locations and mechanisms of arrhythmia, and to describe outcomes after ablation., Methods: Demographic, electrophysiological, and outcome data were collected for patients who underwent ablation of de novo atypical flutter., Results: The mechanisms of 85 atypical flutters were identified in 62 patients and localized to the left atrium (LA) in 58 and right atrium (RA) in 27. In the LA, mechanisms were classified as macro-re-entry in 29 (50%) and localized re-entry in 29 (50%), whereas in the RA, mechanisms were macro-re-entry in 8 (30%) and localized re-entry in 19 (70%) (proportion of localized re-entry in the LA vs. RA, P = 0.08). Nine patients had both localized and macro-re-entrant atypical flutters. In the LA, localized re-entry was commonly found in the anterior LA, followed by the pulmonary veins and septum. In the RA, localized re-entry was found at various sites, including the lateral or posterior RA, septum, and coronary sinus ostium. During 39.4 months (Q1-Q3: 18.2-65.8 months) of follow-up, atrial arrhythmias occurred in 66% of patients after a single ablation and in 50% after >1 ablation. Among patients who underwent repeat ablation, compared with the index arrhythmia, different tachycardia circuits or arrhythmias were documented in 13 of 18 cases (72%)., Conclusions: Atypical atrial flutters in patients without prior surgery or complex ablation are often due to localized re-entry (approximately 50% in the LA and a higher frequency in the RA). Other atrial tachycardias commonly occur during long-term follow-up following ablation, suggesting progressive atrial myopathy in these patients., Competing Interests: Funding Support and Author Disclosures This work was supported by the Greenberg Institute for Cardiac Electrophysiology. Dr Markowitz has received consulting fees from Boston Scientific. Dr Liu has received honoraria from Biotronik. Dr Cheung has received consulting fees from Abbott and Boston Scientific; and has received fellowship grant support from Abbott Medical, Biosense Webster, Boston Scientific, and Medtronic. Dr Thomas has received honoraria from Biotronik and Acutus Medical. Dr Ip has received honoraria from Abbott Laboratories; and has received consulting fees from Boston Scientific. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: 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., Methods: Reduction of Ventricular Rate in Patients with Atrial Fibrillation evaluated the efficacy and safety of etripamil for the reduction of ventricular rate (VR) in patients presenting urgently with AF-RVR (VR ≥110 beats per minute [bpm]), was randomized, double-blind, placebo-controlled, and conducted in Canada and the Netherlands. Patients presenting urgently with AF-RVR were randomized (1:1, etripamil nasal spray 70 mg: placebo nasal spray). The primary objective was to demonstrate the effectiveness of etripamil in reducing VR in AF-RVR within 60 minutes of treatment. Secondary objectives assessed achievement of VR <100 bpm, reduction by ≥10% and ≥20%, relief of symptoms and treatment effectiveness; adverse events; and additional measures to 360 minutes., Results: Sixty-nine patients were randomized, 56 dosed with etripamil (n=27) or placebo (n=29). The median age was 65 years; 39% were female patients; proportions of AF types were similar between groups. The difference of mean maximum reductions in VR over 60 minutes, etripamil versus placebo, adjusting for baseline VR, was -29.91 bpm (95% CI, -40.31 to -19.52; P <0.0001). VR reductions persisted up to 150 minutes. 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%, versus 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 versus placebo. Serious adverse events were rare; 1 patient in the etripamil arm experienced transient severe bradycardia and syncope, assessed as due to hypervagotonia., Conclusions: 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., Registration: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT04467905., Competing Interests: Disclosures Dr Camm has received grants and personal fees from Boehringer Ingelheim, Bayer, Pfizer, Bristol-Myers Squibb, and Daiichi Sankyo; personal fees from Medtronic, Boston Scientific, Menarini, and Biotronik; and support from Anthos, Sanofi, Abbott, GlaxoSmithKline, and Johnson & Johnson. Dr Piccini has received grants for clinical research from Abbott, the American Heart Association, the Association for the Advancement of Medical Instrumentation, Bayer, Boston Scientific, iRhythm, and Philips and serves as a consultant to Abbott, AbbVie, ARCA biopharma, Bayer, Boston Scientific, Bristol-Myers Squibb (Myokardia), Element Science, Itamar Medical, LivaNova, Medtronic, ElectroPhysiology Frontiers, ReCor, Sanofi, Philips, and UpToDate. Dr Alings has no disclosures to report. Drs Dorian, Ip, and Stambler serve on the steering committee for Milestone Pharmaceuticals. Dr Gosselin has no disclosures to report. Drs Kowey and Mondésert are consultants for Milestone Pharmaceuticals. Drs Prins, Roux, van Eck, and Al Windy have no disclosures to report. Drs Thermil, Shardonofsky, and Bharucha are employees of Milestone Pharmaceuticals. Dr Roy has no disclosures to report.

Competing Interests: Funding Support and Author Disclosures Dr Ip has received consulting fees from Abbott and Medtronic; has served on a steering committee for Abbott; and has served on a data safety monitoring committee for Boston Scientific.

Competing Interests: Disclosures C. Iadecola serves on the scientific advisory board of Broadview Ventures. The other authors report no conflicts.

Background Self-administration of investigational intranasal L-type calcium channel blocker etripamil during paroxysmal supraventricular tachycardia (PSVT) appeared safe and well-tolerated in the phase 3 NODE-301 (Multi-Centre, Randomized, Double-Blind, Placebo-Controlled, Efficacy, and Safety Study of Etripamil Nasal Spray for the Termination of Spontaneous Episodes of Paroxysmal Supraventricular Tachycardia) trial of adults with sustained atrioventricular nodal-dependent PSVT. The NODE-302 open-label extension further characterized etripamil safety and efficacy. Methods and Results Eligible patients were monitored via self-applied cardiac monitoring system for 5 hours after etripamil self-administration. The primary end point was time-to-conversion of positively adjudicated PSVT to sinus rhythm after etripamil treatment. Probability of conversion to sinus rhythm was reported via Kaplan-Meier plot. Adverse events were based on self-reported symptoms and clinical evaluations. Among 169 patients enrolled, 105 self-administered etripamil ≥1 time for perceived PSVT (median [range], 232 [8-584] days' follow-up). Probability of conversion within 30 minutes of etripamil was 60.2% (median time to conversion, 15.5 minutes) among 188 PSVT episodes (92 patients) positively adjudicated as atrioventricular nodal dependent by independent ECG analysis. Among 40 patients who self-treated 2 episodes, 75% had a significantly consistent response by 30 minutes; 9 did not convert on either episode, and 21 converted on both episodes (χ 2 =8.09; P =0.0045). Forty-five of 105 patients (42.9%) had ≥1 treatment-emergent adverse event, generally transient and mild-to-moderate, including nasal congestion (14.3%), nasal discomfort (14.3%), or rhinorrhea (12.4%). No serious cardiac safety events were observed within 24 hours of etripamil. Conclusions In this extension study, investigational etripamil nasal spray was well tolerated for self-treating recurrent episodes of PSVT without medical supervision. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03635996.

Background: 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., Methods: 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., Results: 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., Conclusions: 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., Competing Interests: Disclosures Dr Banker reports consulting fees and research support from Abbott, Boston Scientific, and Medtronic. Dr Rippy reports consulting fees from Abbott. Dr Neužil reports consulting fees from Abbott. Dr Exner reports consulting fees and research grants from Abbott, Boston Scientific, and Medtronic. Dr Nair reports consulting fees, honoraria, research grants and support from and serving on advisory boards for Abbott, Adagio Medical, Biosense Webster, Boston Scientific, and Medtronic. Dr Knops reports consulting fees, research grants, and honoraria from Abbott, Boston Scientific, and Medtronic. Dr Ip reports honoraria, serving as a consultant and on a steering committee for Abbott; and consulting fees and honoraria for Medtronic; and serving on a data safety monitoring committee for Boston Scientific. Dr Doshi reports consulting fees and fellowship support from Abbott, Boston Scientific, and Medtronic. Dr Rashtian reports consulting fees and research grants from Abbott. Dr Reddy has served as a consultant to Abbott; in addition, unrelated to this article, Dr Reddy has served as a consultant for and has equity in Ablacon, Acutus Medical, Affera-Medtronic, Anumana, Apama Medical-Boston Scientific, APN Health, Aquaheart, Atacor, Autonomix, Axon Therapies, Backbeat, BioSig, CardiaCare, CardioNXT/AFTx, Circa Scientific, CoRISMA, Corvia Medical, Dinova-Hangzhou DiNovA EP Technology, East End Medical, EPD-Philips, EP Frontiers, Epix Therapeutics-Medtronic, EpiEP, Eximo, Farapulse-Boston Scientific, Field Medical, Focused Therapeutics, HRT, Intershunt, Javelin, Kardium, Keystone Heart, LuxMed, Medlumics, Middlepeak, Neutrace, Nuvera-Biosense Webster, Oracle Health, Restore Medical, Sirona Medical, SoundCath, Valcare; unrelated to this work, has served as a consultant for AtriAN, Biosense-Webster, BioTel Heart, Biotronik, Boston Scientific, Cairdac, Cardiofocus, Cardionomic, CoreMap, Fire1, Gore & Associates, Impulse Dynamics, Medtronic, Novartis, Philips, Pulse Biosciences; and has equity in Manual Surgical Sciences, Newpace, Nyra Medical, Surecor, and Vizaramed. N. Cooper, D.F. Booth, D. Ligon, Dr Badie, and M. Krans are all employees of Abbott. The other author report no conflicts.

Competing Interests: Funding Support and Author Disclosures Dr Ip has received consulting fees from and served on the steering committee of Abbott; has received consulting fees from Medtronic; and has served on the data safety monitoring committee for Boston Scientific.

Background: Dual-chamber leadless pacemakers (LPs) require robust communication between distinct right atrial (RA) and right ventricular (RV) LPs to achieve atrioventricular (AV) synchrony., Objective: The purpose of this preclinical study was to evaluate a novel, continuous implant-to-implant (i2i™) communication methodology for maintaining AV-synchronous, dual-chamber DDD(R) pacing by the 2 LPs., Methods: RA and RV LPs were implanted and paired in 7 ovine subjects (4 with induced complete heart block). AV synchrony (% AV intervals <300 ms) and i2i communication success (% successful i2i transmissions between LPs) were evaluated acutely and chronically. During acute testing, 12-lead electrocardiographic and LP diagnostic data were collected from 5-minute recordings, in 4 postures and 2 rhythms (AP-VP and AS-VP, or AP-VS and AS-VS) per subject. Chronic i2i performance was evaluated through 23 weeks postimplant (final i2i evaluation period: week 16-23)., Results: Acute AV synchrony and i2i communication success across multiple postures and rhythms were median [interquartile range] 100.0% [100.0%-100.0%] and 99.9% [99.9%-99.9%], respectively. AV synchrony and i2i success rates did not differ across postures (P = .59, P = .11) or rhythms (P = 1, P = .82). During the final i2i evaluation period, the overall i2i success was 98.9% [98.1%-99.0%]., Conclusion: Successful AV-synchronous, dual-chamber DDD(R) leadless pacing using a novel, continuous, wireless communication modality was demonstrated across variations in posture and rhythm in a preclinical model., (Copyright © 2023. Published by Elsevier Inc.)

Background: Whole exome sequencing may identify rare pathogenic/likely pathogenic variants (LPVs) that are linked to atrial fibrillation (AF). The impact of LPVs associated with AF on a population level on outcomes is unclear., Objectives: This study sought to examine the association of LPVs with AF and their impact on clinical outcomes using the UK Biobank, a national repository of participants with available whole exome sequencing data., Methods: A total of 200,631 individuals in the UK Biobank were studied. Incident and prevalent AF, comorbidities, and outcomes were identified using self-reported assessments and hospital stay operative, and death registry records. LPVs were determined using arrhythmia and cardiomyopathy gene panels with LOFTEE and ClinVar to predict variants of functional significance., Results: Compared with control subjects, there was a modestly increased prevalence of LPVs among 9,585 patients with AF (2.0% vs 1.7%, respectively; P = 0.01). Among those with prevalent AF at <45 years of age, 4.2% were LPV carriers. LPVs in TTN and PKP2 were associated with AF with adjusted odds ratios of 2.69 (95% CI: 1.57-4.61) and 2.69 (95% CI: 1.54-4.68), respectively. There was no significant difference in combined ischemic stroke, heart failure hospitalization, and mortality among patients who have AF with and without LPVs (25.1% vs 23.8%; P = 0.49). Among participants with AF and available cardiac magnetic resonance imaging data, LPV carriers had lower left ventricular ejection fractions than non-LPV carriers (42% vs 52%; P = 0.027)., Conclusions: Patients with AF had a modestly increased prevalence of LPVs. Among reference arrhythmia and cardiomyopathy genes, the contribution of rare variants to AF risk at a population level is modest and its impact on outcomes appears to be limited, despite an association of LPVs with reduced left ventricular ejection fraction among patients with AF., Competing Interests: Funding Support and Author Disclosures This work was supported by grants from the Michael Wolk Heart Foundation, the New York Cardiac Center, Inc, and the New York Weill Cornell Medical Center Alumni Council. The Michael Wolk Heart Foundation, the New York Cardiac Center, Inc, and the New York Weill Cornell Medical Center Alumni Council had no role in the design and conduct of the study, the collection, analysis, and interpretation of the data, or the preparation, review, or approval of the manuscript. Dr Cheung has received consulting fees from Abbott, Biotronik, and Boston Scientific; research grant support from Boston Scientific; and fellowship grant support from Abbott, Biosense Webster, Biotronik, Boston Scientific, and Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Introduction: Leadless cardiac pacemakers (LCPs) are becoming more commonly utilized because of their potential advantages (i.e., reduced short and long-term complications, improved patient comfort) and may be the preferred option for patients with venous access problems, high-risk for infection, previous lead fractures, or skin erosion. There are currently two types of LCP fixation mechanisms that have been FDA approved-Medtronic's Micra system has a tine-based fixation and Abbott's Aveir system has a helix-fixation design. This article highlights important tips and tricks for a successful implant of a helix-fixation LCP, particularly when difficulties are encountered, and provides precautions to avoid potential complications., Methods: Cases of single chamber Aveir LCP implantation were reviewed to highlight examples of procedural pitfalls and suggested methods to circumnavigate them., Results: There are unique procedural considerations regarding the Aveir LCP implant as well as challenges that that may be occasionally encountered. Techniques to address these-such as avoiding air embolism, maneuvering difficult entry into the right ventricle, handling complicated positioning/repositioning, evaluating proper fixation, and releasing difficult tethers-are illustrated in detail. Advice to reduce risks of perforation and to position optimally for potential retrieval and communication for dual chamber pacing are also described., Conclusions: The advanced teaching concepts described and emphasized in this article may help improve success and prevent procedural complications, especially when physicians are learning how implant these novel helix-fixation LCPs., (© 2023 Wiley Periodicals LLC.)

Background: Percutaneous endocardial left atrial appendage occlusion (LAAO) is an alternative therapy for stroke prevention in patients with atrial fibrillation who are poor candidates for oral anticoagulants. Oral anticoagulation is generally discontinued 45 days following successful LAAO. Real-world data on early stroke and mortality following LAAO are lacking., Methods: Using International Classification of Diseases, Tenth Revision , Clinical-Modification codes, we performed a retrospective observational registry analysis to examine the rates and predictors of stroke, mortality, and procedural complications during index hospitalization and 90-day readmission among 42 114 admissions in the Nationwide Readmissions Database for LAAO between 2016 and 2019. Early stroke and mortality were defined as events occurring during index admission or 90-day readmission. Data on timing of early strokes post-LAAO were collected. Multivariable logistic regression modeling was used to ascertain predictors of early stroke and major adverse events., Results: LAAO was associated with low rates of early stroke (0.63%), early mortality (0.53%), and procedural complications (2.59%). Among patients who had readmissions with strokes after LAAO, the median time from implant to readmission was 35 days (interquartile range, 9-57 days); 67% of readmissions with strokes occurred <45 days postimplant. Between 2016 and 2019, the rates of early stroke after LAAO significantly decreased (0.64% versus 0.46% P -for-trend <0.001), while early mortality and major adverse event rates were unchanged. Peripheral vascular disease and a history of prior stroke were independently associated with early stroke after LAAO. Early post-LAAO stroke rates were similar between low, medium, and high LAAO volume tertile centers., Conclusions: In this contemporary real-world analysis, the early stroke rate after LAAO was low, with the majority occurring within 45 days of device implantation. Despite an increase in LAAO procedures between 2016 and 2019, there with a significant decline in early strokes after LAAO during that period.

Background: Improved ablation catheter-tissue contact results in more effective ablation lesions. Respiratory motion causes catheter instability, which impacts durable pulmonary vein isolation (PVI)., Objectives: This study sought to evaluate the safety and efficacy of a novel ablation strategy involving prolonged periods of apneic oxygenation during PVI., Methods: We conducted a multicenter, prospective controlled study of 128 patients (mean age 63 ± 11 years; 37% women) with paroxysmal atrial fibrillation undergoing PVI. Patients underwent PVI under general anesthesia using serial 4-minute runs of apneic oxygenation (apnea group; n = 64) or using standard ventilation settings (control group; n = 64). Procedural data, arterial blood gas samples, catheter position coordinates, and ablation lesion characteristics were collected., Results: Baseline characteristics between the 2 groups were similar. Catheter stability was significantly improved in the apnea group, as reflected by a decreased mean catheter displacement (1.55 ± 0.97 mm vs 2.25 ± 1.13 mm; P < 0.001) and contact force SD (4.9 ± 1.1 g vs 5.2 ± 1.5 g; P = 0.046). The percentage of lesions with a mean catheter displacement >2 mm was significantly lower in the apnea group (22% vs 44%; P < 0.001). Compared with the control group, the total ablation time to achieve PVI was reduced in the apnea group (18.8 ± 6.9 minutes vs 23.4 ± 7.8 minutes; P = 0.001). There were similar rates of first-pass PVI, acute PV reconnections and dormant PV reconnections between the two groups., Conclusions: A novel strategy of performing complete PVI during apneic oxygenation results in improved catheter stability and decreased ablation times without adverse events. (Radiofrequency Ablation of Atrial Fibrillation Under Apnea; NCT04170894)., Competing Interests: Funding Support and Author Disclosures Dr Cheung has received consulting fees from Abbott and Boston Scientific; research support from Boston Scientific; and fellowship grant support from Abbott, Biosense Webster, Boston Scientific, and Medtronic. Dr Patel has received consulting fees from Biosense Webster. Dr Markowitz has received fees from Boston Scientific for serving on a data safety monitoring board. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Limited real-world data exist on early outcomes in patients with heart failure with preserved ejection fraction (HFpEF) undergoing atrial fibrillation (AF) ablation., Objectives: The purpose of this study was to examine and compare rates of index procedural complications and 30-day readmissions after AF ablation in patients with HFpEF, with heart failure with reduced ejection fraction (HFrEF), and without heart failure., Methods: Using the Nationwide Readmissions Database (NRD), we examined 50,299 admissions of adults with heart failure undergoing AF catheter ablation between 2010 and 2014. Using ICD-9-CM codes, we identified procedural complications and causes of readmission after AF ablation., Results: From 2010 to 2014, the prevalence of HFpEF among patients undergoing AF ablation increased from 3.05% to 7.35% ( P for trend <.001). Compared to patients without heart failure, patients with HFpEF had significantly increased procedural complications and index mortality (8.4% vs 6.2% and 0.30% vs 0.08%, respectively; P = .016 and P = .010, respectively). Index complication rates between patients with HFpEF and HFrEF were similar. All-cause 30-day readmissions occurred in 18.3% of patients with HFpEF compared to 9.5% of patients without heart failure ( P <.001). Compared to no heart failure, the presence of HFpEF was independently associated with all-cause readmissions (adjusted odds ratio 1.52; 95% confidence interval 1.15-1.96; P = .002), but not with procedural complications, cardiac readmissions, or early mortality., Conclusion: Rates of 30-day readmissions after AF ablation are high in patients with HFpEF. However, after adjustment for age and comorbidities, complications and early mortality after AF ablation between patients with HFpEF and those without heart failure are comparable., (© 2022 Heart Rhythm Society. Published by Elsevier Inc.)

Background: Electrocardiographic (ECG) criteria have been proposed to localize the site of origin of outflow region ventricular arrhythmias (VAs). Many factors influence the QRS morphology of VAs and may limit the accuracy of these criteria., Objective: The purpose of this study was to assess the accuracy of ECG criteria that differentiate right from left outflow region VAs and localize VAs within the aortic sinus of Valsalva (ASV)., Methods: One hundred one patients (mean age 52 ± 16 years; 55 [54%] women) undergoing catheter ablation of right ventricular outflow tract (RVOT) or ASV VAs with a left bundle branch block, inferior axis morphology were studied. ECG measurements including V 2 transition ratio, transition zone index, R-wave duration index, R/S amplitude index, V 2 S/V 3 R index, V 1-3 QRS morphology, R-wave amplitude in the inferior leads were tabulated for all VAs. Comparisons were made between the predicted site of origin using these criteria and the successful ablation site., Results: Patients had successful ablation of 71 RVOT and 38 ASV VAs. For the differentiation of RVOT from ASV VAs, the positive predictive values and negative predictive values for all tested ECG criteria ranged from 42% to 75% and from 71% to 82%, respectively, with the V 2 S/V 3 R index having the largest area under the curve of 0.852. Morphological QRS criteria in leads V 1 through V 3 did not localize ASV VAs. The maximum R-wave amplitude in the inferior leads was the sole criterion demonstrating a significant difference between right ASV, right-left ASV commissure, and left ASV sites., Conclusion: ECG criteria for differentiating right from left ventricular outflow region VAs and for localizing ASV VAs have a limited accuracy., (Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Objectives: The goal of this study was to characterize the location and electrophysiological properties of left atrial appendage (LAA) atrial tachycardia (AT)., Background: The LAA has been reported to be a source of AT and atrial fibrillation (AF) triggers., Methods: This study retrospectively reviewed ATs mapped to the LAA. Activation and entrainment mapping were used to determine the mechanism and localize each AT circuit/origin., Results: From 2014 to 2018, a total of 45 patients (mean age 65 ± 10 years; 69% male) had 51 LAA ATs: 43 (84%) after AF ablation and 8 de novo (no prior AF). Overall, 50 (98%) were due to localized re-entry/micro-re-entry, whereas only 1 was a focal triggered AT. All 50 micro-re-entrant LAA ATs were mapped to the anterior base (70%) or LAA ridge (30%), and all were successfully treated with focal ablation; no case required LAA isolation. After successful ablation of the initial AT at the LAA base, 23 (62%) of 37 patients with AF also had inducible macro-re-entrant peri-mitral flutter, but none had AF triggers from inside the LAA., Conclusions: LAA ATs are almost always micro-re-entrant in mechanism and originate from either the anterior base or LAA ridge. AT originating from inside the LAA body is very rare. The anterior and ridge aspects of the LAA-left atrium junction seem to be arrhythmogenic hotspots prone to localized re-entry. These ATs are treatable with focal ablation without LAA isolation but are frequently associated with macro-re-entrant peri-mitral flutter., Competing Interests: FUNDING SUPPORT AND AUTHOR DISCLOSURES The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The use of insertable cardiac monitors (ICM) has been increasing because of their ability to provide long-term electrocardiographic monitoring and symptom correlation. Indications for implantation include evaluation of cryptogenic stroke, unexplained syncope, intermittent palpitations, and atrial fibrillation. When the ICM needs to be removed because of battery depletion and/or diagnostic revelation, its removal can be challenging because of its small size and the capsule that forms around the proximal end of the device. A simple technique is described that takes advantage of the ICM design to facilitate its successful extraction.

Purpose: Left atrial thrombus (LAT) may be detected by transesophageal echocardiography (TEE) in patients with atrial fibrillation (AF) or flutter (AFL) despite continuous anticoagulation therapy. We sought to examine the rates and timing of LAT resolution in response to changes in anticoagulation regimen., Methods: A retrospective study of 1517 consecutive patients on ≥ 4 weeks continuous oral anticoagulation (OAC) undergoing TEE prior to either direct current cardioversion or catheter ablation for AF or AFL was performed. Patients who had LAT on index TEE imaging and had follow-up TEEs were analyzed., Results: Despite ≥ 4 weeks of continuous anticoagulation therapy, 63 (4.2%) patients had LAT. Forty-four patients (median age 67 [IQR 58, 74]; 33 [75%] male; 25 [57%] on direct oral anticoagulant [DOAC]) had follow-up TEEs performed. Upon detection of LAT on index TEE, 8 patients switched from warfarin to a DOAC, 21 patients switched from a DOAC to warfarin or another DOAC, and 15 patients remained on the same OAC. Over median 4.2 months (IQR 2.9, 6.6), LAT resolution was seen in 25 (57%) patients. Of the 25 patients who had LAT resolution, 7 (28%) required TEE imaging > 6 months after index TEE to show clearance of thrombus. Rates of LAT resolution were similar between patients who had alterations in OAC and those who did not (52 vs. 60%; P = 0.601)., Conclusions: After initial detection of left atrial thrombus despite uninterrupted anticoagulation for atrial fibrillation or flutter, > 40% patients have persistent clot despite additional extended anticoagulation.

The presence of premature ventricular contractions (PVCs) in patients with structurally normal hearts was once considered a benign phenomenon. However, in susceptible patients, these "benign" or idiopathic PVCs may develop malignant potential and trigger ventricular fibrillation and result in sudden cardiac death. Alternatively, idiopathic PVCs can also induce cardiomyopathy. Clinical recognition of these entities can lead to effective targeted therapy. In the first instance, treatment consists of ablating the PVC source and implanting a defibrillator, whereas in the second scenario, ablating the PVC origin can normalize left ventricular function., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Aims: Due to the complex anatomy of the left ventricular (LV) and right ventricular (RV) papillary muscles (PMs), PM ventricular arrhythmias (VAs) can be challenging to target with ablation. We sought to compare the outcomes of robotic magnetic navigation-guided (RMN) ablation and manual ablation of VAs arising from the LV and RV PMs., Methods and Results: We evaluated 35 consecutive patients (mean age 65 ± 12 years, 69% male) who underwent catheter ablation of 38 VAs originating from the LV and RV PMs as confirmed by intracardiac echocardiography. Catheter ablation was initially performed using RMN-guidance in 24 (69%) patients and manual guidance in 11 (31%) patients. Demographic and procedural data were recorded and compared between the two groups. The VA sites of origin were mapped to 20 (53%) anterolateral LV PMs, 14 (37%) posteromedial LV PMs, and 4 (11%) RV PMs Acute successful ablation was achieved for 20 (74%) VAs using RMN-guided ablation and 8 (73%) VAs using manual ablation (P = 1.000). Fluoroscopy times were significantly lower among patients undergoing RMN ablation compared to patients undergoing manual ablation [median 7.3, interquartile range (IQR) 3.9-18 vs. 24 (16-44) min; P = 0.005]. Retrograde transaortic approach was used in 1 (4%) RMN patients and 5 (46%) manual patients (P = 0.005). No procedural complications were seen in study patients., Conclusion: Use of an RMN-guided approach to target PM VAs results in comparable success rates seen with manual ablation but with lower fluoroscopy times and decreased use of transaortic retrograde access.

Recent evidence has demonstrated the importance of bone marrow-derived mesenchymal stem cells (BM-MSCs) in the repair of damaged myocardium. The molecular mechanisms of engraftment and migration of BM-MSCs in the ischemic myocardium are unknown. In this study, we developed a functional genomics approach toward the identification of mediators of engraftment and migration of BM-MSCs within the ischemic myocardium. Our strategy involves microarray profiling (>22,000 probes) of ischemic hearts, complemented by reverse transcription-polymerase chain reaction and fluorescence-activated cell sorting of corresponding adhesion molecule and cytokine receptors in BM-MSCs to focus on the coexpressed pairs only. Our data revealed nine complementary adhesion molecules and cytokine receptors, including integrin beta1, integrin alpha4, and CXC chemokine receptor 4 (CXCR4). To examine their functional contributions, we first blocked selectively these receptors by preincubation of BM-MSCs with specific neutralizing antibodies, and then we administered these cells intramyocardially. A significant reduction in the total number of BM-MSC in the infarcted myocardium was observed after integrin beta1 blockade but not integrin alpha4 or CXCR4 blockade. The latter observation is distinctively different from that reported for hematopoietic stem cells (HSCs). Thus, our data show that BM-MSCs use a different pathway from HSCs for intramyocardial trafficking and engraftment.