Electrogram Morphology Recurrence for Mapping Persistent Atrial Fibrillation: Initial vs Redo Catheter Ablation.

BACKGROUND: Electrogram (EGM) morphology recurrence (EMR) mapping of persistent atrial fibrillation (AF) quantifies consistency of activation and is expected to be high and rapid near AF drivers. OBJECTIVES: The purpose of this study was to compare EMR in left atria (LA) and right atria (RA) in patients undergoing first vs redo ablation for persistent AF. METHODS: Multisite LA/RA mapping (LA: 281 ± 176 sites/patient; RA: 239 ± 166 sites/patient) before persistent AF ablation was performed in 42 patients (30 males, age 63 ± 9 years) undergoing first (Group 1, n = 32) or redo ablation (Group 2, n = 10). After cross-correlation of each automatically detected EGM with every other EGM per recording, the most recurrent electrogram morphology was identified and its frequency (Rec%) and recurrence cycle length (CLR) were computed. RESULTS: In Groups 1 and 2, minimum CLR was 172.8 ± 26.0 milliseconds (LA: 178.2 ± 37.6 milliseconds, RA: 204.4 ± 34.0 milliseconds, P = 0.0005) and 186.5 ± 28.3 milliseconds (LA: 196.1 ± 38.1 milliseconds vs RA: 199.0 ± 30.2 milliseconds, P = 0.75), with Rec% 94.7% ± 10% and 93.8% ± 9.2%. Group 2 minimum CLR was not different from Group 1 (P = 0.20). Shortest CLR was in the LA in 84% of Group 1 and 50% of Group 2 patients (P = 0.04). Only 1 of 10 patients in Group 2 had the shortest CLR in the pulmonary veins (PVs) compared with 19 of 32 in Group 1 (P = 0.01). Most sites (77.6%) had Rec% <50%. CONCLUSIONS: EMR identified the shortest CLR sites in the PVs in 59% of patients undergoing initial persistent AF ablation, consistent with reported success rates of ∼50% for PV isolation. The majority of sites have low recurrence and may reflect bystander sites not critical for maintaining AF. EMR provides a robust new method for quantifying consistency and rapidity of activation direction at multiple atrial sites.

Implementation of an intravenous sotalol initiation protocol: Implications for feasibility, safety, and length of stay.

INTRODUCTION: Oral sotalol initiation requires a multiple-day, inpatient admission to monitor for QT prolongation during loading. A 1-day intravenous (IV) sotalol loading protocol was approved by the United States Food and Drug Administration in March 2020, but limited data on clinical use and administration currently exists. This study describes implementation of an IV sotalol protocol within an integrated health system, provides initial efficacy and safety outcomes, and examines length of stay (LOS) compared with oral sotalol initiation. METHODS: IV sotalol was administered according to a prespecified initiation protocol to adult patients with refractory atrial or ventricular arrhythmias. Baseline characteristics, safety and feasibility outcomes, and LOS were compared with patients receiving oral sotalol over a similar time period. RESULTS: From January 2021 to June 2022, a total of 29 patients (average age 66.0 ± 8.6 years, 27.6% women) underwent IV sotalol load and 20 patients (average age 60.4 ± 13.9 years, 65.0% women) underwent oral sotalol load. The load was successfully completed in 22/29 (75.9%) patients receiving IV sotalol and 20/20 (100%) of patients receiving oral sotalol, although 7/20 of the oral sotalol patients (35.0%) required dose reduction. Adverse events interrupting IV sotalol infusion included bradycardia (seven patients, 24.1%) and QT prolongation (three patients, 10.3%). No patients receiving IV or oral sotalol developed sustained ventricular arrhythmias before discharge. LOS for patients completing IV load was 2.6 days shorter (mean 1.0 vs. 3.6, p < .001) compared with LOS with oral load. CONCLUSION: IV sotalol loading has a safety profile that is similar to oral sotalol. It significantly shortens hospital LOS, potentially leading to large cost savings.

A transient, closed-loop network of wireless, body-integrated devices for autonomous electrotherapy.

Temporary postoperative cardiac pacing requires devices with percutaneous leads and external wired power and control systems. This hardware introduces risks for infection, limitations on patient mobility, and requirements for surgical extraction procedures. Bioresorbable pacemakers mitigate some of these disadvantages, but they demand pairing with external, wired systems and secondary mechanisms for control. We present a transient closed-loop system that combines a time-synchronized, wireless network of skin-integrated devices with an advanced bioresorbable pacemaker to control cardiac rhythms, track cardiopulmonary status, provide multihaptic feedback, and enable transient operation with minimal patient burden. The result provides a range of autonomous, rate-adaptive cardiac pacing capabilities, as demonstrated in rat, canine, and human heart studies. This work establishes an engineering framework for closed-loop temporary electrotherapy using wirelessly linked, body-integrated bioelectronic devices.

Autonomic Dysfunction and Neurohormonal Disorders in Atrial Fibrillation.

Atrial fibrillation (AF) is the most commonly diagnosed arrhythmia and eludes an efficacious cure despite an increasing prevalence and a significant association with morbidity and mortality. In addition to an array of clinical sequelae, the origins and propagation of AF are multifactorial. In recent years, the contribution from the autonomic nervous system has been an area of particular interest. This review highlights the relevant physiology of autonomic and neurohormonal contributions to AF origin and maintenance, the current state of the literature on targeted therapies, and the path forward for clinical interventions.

Repeat pulmonary vein isolation with or without FIRM-guided ablation for recurrent atrial fibrillation with pulmonary vein reconnection.

INTRODUCTION: Focal impulse and rotor modulation (FIRM) ablation can be used to target nonpulmonary vein (PV) sources of atrial fibrillation (AF). No published studies have compared freedom from atrial fibrillation (FFAF) after pulmonary vein reisolation (PVRI) plus FIRM to PVRI alone in patients with reconnected PVs undergoing repeat ablation. METHODS: A 3:1 matched retrospective cohort study was performed on 21 patients with recurrent AF and PV reconnection who underwent PVRI plus FIRM-guided ablation and 63 patients with recurrent AF treated with PVRI alone at a single institution. All patients in the PVRI-alone cohort had cryoballoon PVRI at the time of repeat ablation without additional lesion sets for AF. Cases were matched based on the type of AF (paroxysmal vs nonparoxysmal), left atrial diameter (±4 mm), left ventricular ejection fraction (±10%), duration of AF (±18 months), and age (±5 years). The primary endpoint was FFAF after a 3-month blanking period. RESULTS: Out of 53 total FIRM cases performed at Northwestern Memorial Hospital between 2015 and 2017, 21 patients had PVRI plus FIRM for recurrent AF with PV reconnection. These patients had an average of 3.3 ± 2.1 rotors (60% left atrial) ablated. Over a median follow-up time of 24.7 months (interquartile range, 13-36 months), patients in the PVRI-alone cohort demonstrated a higher rate of FFAF (n = 35; 55.6%) than patients in the PVRI plus FIRM-guided ablation cohort (n = 7; 33.3%) (logrank P = .049). CONCLUSION: In patients undergoing repeat ablation for AF with PV reconnection, PVRI plus FIRM did not increase FFAF compared to PVRI alone.

Characterization of atrial flutter after pulmonary vein isolation by cryoballoon ablation.

PURPOSE: Pulmonary vein isolation (PVI) by cryoballoon ablation (CBA) has emerged as a commonly used technique for the treatment of atrial fibrillation. We sought to explore the incidence, risk factors for, and characterization of post-CBA-PVI atrial flutter. METHODS: We analyzed a prospective registry of patients who underwent CBA-PVI at a single institution. We included patients with more than 3 months of follow-up data and excluded those with a history of cavotricuspid isthmus (CTI) ablation. Locations of post-CBA-PVI atrial flutters were determined by analysis of intracardiac electrograms and electroanatomic maps. RESULTS: There were 556 patients included in the analysis. The mean age was 61.0 ± 10.6 years, 67.4% were male, the number of failed anti-arrhythmic medication trials was 1.2 ± 0.8, and the duration of atrial fibrillation pre-CBA was 54.3 ± 69.1 months. The 28-mm second-generation cryoballoon was used almost exclusively. Over a median follow-up time of 22.7 ± 17.9 months, 25 (4.5%) patients developed post-CBA-PVI atrial flutter after the 3-month blanking period. Of those 25 patients, 15 (60%) underwent subsequent ablation to eliminate the atrial flutter circuit, with 60% being CTI-dependent and the remainder left-sided (p value not significant). Risk factors for the development of atrial flutter included NYHA class ≥ 2 (OR 5.02, p < 0.001), presence of baseline bundle branch block (OR 4.33, p = 0.006), and left ventricular ejection fraction < 50% (OR 3.36, p = 0.007). CONCLUSIONS: The rate of post-CBA-PVI atrial flutter is low after the blanking period even with medium-term follow-up. The origin of atrial flutter is equally divided between the right and left atria.

Oxidative stress creates a unique, CaMKII-mediated substrate for atrial fibrillation in heart failure.

The precise mechanisms by which oxidative stress (OS) causes atrial fibrillation (AF) are not known. Since AF frequently originates in the posterior left atrium (PLA), we hypothesized that OS, via calmodulin-dependent protein kinase II (CaMKII) signaling, creates a fertile substrate in the PLA for triggered activity and reentry. In a canine heart failure (HF) model, OS generation and oxidized-CaMKII-induced (Ox-CaMKII-induced) RyR2 and Nav1.5 signaling were increased preferentially in the PLA (compared with left atrial appendage). Triggered Ca2+ waves (TCWs) in HF PLA myocytes were particularly sensitive to acute ROS inhibition. Computational modeling confirmed a direct relationship between OS/CaMKII signaling and TCW generation. CaMKII phosphorylated Nav1.5 (CaMKII-p-Nav1.5 [S571]) was located preferentially at the intercalated disc (ID), being nearly absent at the lateral membrane. Furthermore, a decrease in ankyrin-G (AnkG) in HF led to patchy dropout of CaMKII-p-Nav1.5 at the ID, causing its distribution to become spatially heterogeneous; this corresponded to preferential slowing and inhomogeneity of conduction noted in the HF PLA. Computational modeling illustrated how conduction slowing (e.g., due to increase in CaMKII-p-Nav1.5) interacts with fibrosis to cause reentry in the PLA. We conclude that OS via CaMKII leads to substrate for triggered activity and reentry in HF PLA by mechanisms independent of but complementary to fibrosis.

Identifying initiation and elongation inhibitors of dengue virus RNA polymerase in a high-throughput lead-finding campaign.

Dengue virus (DENV) is the most significant mosquito-borne viral pathogen in the world and is the cause of dengue fever. The DENV RNA-dependent RNA polymerase (RdRp) is conserved among the four viral serotypes and is an attractive target for antiviral drug development. During initiation of viral RNA synthesis, the polymerase switches from a "closed" to "open" conformation to accommodate the viral RNA template. Inhibitors that lock the "closed" or block the "open" conformation would prevent viral RNA synthesis. Herein, we describe a screening campaign that employed two biochemical assays to identify inhibitors of RdRp initiation and elongation. Using a DENV subgenomic RNA template that promotes RdRp de novo initiation, the first assay measures cytosine nucleotide analogue (Atto-CTP) incorporation. Liberated Atto fluorophore allows for quantification of RdRp activity via fluorescence. The second assay uses the same RNA template but is label free and directly detects RdRp-mediated liberation of pyrophosphates of native ribonucleotides via liquid chromatography-mass spectrometry. The ability of inhibitors to bind and stabilize a "closed" conformation of the DENV RdRp was further assessed in a differential scanning fluorimetry assay. Last, active compounds were evaluated in a renilla luciferase-based DENV replicon cell-based assay to monitor cellular efficacy. All assays described herein are medium to high throughput, are robust and reproducible, and allow identification of inhibitors of the open and closed forms of DENV RNA polymerase.

Contribution of fibrosis and the autonomic nervous system to atrial fibrillation electrograms in heart failure.

BACKGROUND: Fibrotic and autonomic remodeling in heart failure (HF) increase vulnerability to atrial fibrillation (AF). Because AF electrograms (EGMs) are thought to reflect the underlying structural substrate, we sought to (1) determine the differences in AF EGMs in normal versus HF atria and (2) assess how fibrosis and nerve-rich fat contribute to AF EGM characteristics in HF. METHODS AND RESULTS: AF was induced in 20 normal dogs by vagal stimulation and in 21 HF dogs (subjected to 3 weeks of rapid ventricular pacing at 240 beats per minute). AF EGMs were analyzed for dominant frequency (DF), organization index, fractionation intervals (FIs), and Shannon entropy. In 8 HF dogs, AF EGM correlation with underlying fibrosis/fat/nerves was assessed. In HF compared with normal dogs, DF was lower and organization index/FI/Shannon entropy were greater. DF/FI were more heterogeneous in HF. Percentage fat was greater, and fibrosis and fat were more heterogeneously distributed in the posterior left atrium than in the left atrial appendage. DF/organization index correlated closely with %fibrosis. Heterogeneity of DF/FI correlated with the heterogeneity of fibrosis. Autonomic blockade caused a greater change in DF/FI/Shannon entropy in the posterior left atrium than left atrial appendage, with the decrease in Shannon entropy correlating with %fat. CONCLUSIONS: The amount and distribution of fibrosis in the HF atrium seems to contribute to slowing and increased organization of AF EGMs, whereas the nerve-rich fat in the HF posterior left atrium is positively correlated with AF EGM entropy. By allowing for improved detection of regions of dense fibrosis and high autonomic nerve density in the HF atrium, these findings may help enhance the precision and success of substrate-guided ablation for AF.

Paradoxical change in atrial fibrillation dominant frequencies with baroreflex-mediated parasympathetic stimulation with phenylephrine infusion.

INTRODUCTION: Parasympathetic stimulation is known to promote atrial fibrillation (AF) through shortening of atrial refractory periods. We hypothesized that baroreflex-mediated parasympathetic stimulation via phenylephrine (PE) infusion would increase AF rate as measured by dominant frequency (DF). METHODS AND RESULTS: The protocol was performed in 27 patients (24 M, 59 ± 1 years old) prior to AF ablation. For 10 patients in AF, PE was infused until systolic blood pressure increased ≥30 mmHg. Electrograms were recorded in the left atrium before and after PE. DFs of each recording were calculated offline. Atrial effective refractory periods (ERPs) were measured before and after PE in 11 patients who were in sinus rhythm during the procedure. DFs were also measured in 6 patients in AF before and after complete parasympathetic blockade with atropine (0.04 mg/kg). PE resulted in increased RR intervals during sinus rhythm (1,170 ± 77 to 1,282 ± 85 ms, P = 0.03) and AF (743 ± 32 to 826 ± 30 ms, P = 0.03), consistent with parasympathetic effect on the sinus and AV nodes, respectively. DFs were decreased by PE in the left atrium (6.2 ± 0.2 to 6.0 ± 0.2 Hz, P = 0.004). Correspondingly, atrial ERPs significantly increased from 218 ± 13 to 232 ± 11 ms (P = 0.04). Atropine resulted in a decreasing trend in DF in the left atrium (5.9 ± 0.1 to 5.8 ± 0.1 Hz, P = 0.07). CONCLUSIONS: Despite baroreflex-mediated parasympathetic effect, PE produced a slowing of AF along with lengthening of ERP, while parasympathetic blockade also slowed DF. It is therefore likely that the direct and indirect adrenergic effects of PE on atrial electrophysiology are more prominent than its parasympathetic effects.

Early development of intracellular calcium cycling defects in intact hearts of spontaneously hypertensive rats.

Defects in excitation-contraction coupling have been reported in failing hearts, but little is known about the relationship between these defects and the development of heart failure (HF). We compared the early changes in intracellular Ca(2+) cycling to those that underlie overt pump dysfunction and arrhythmogenesis found later in HF. Laser-scanning confocal microscopy was used to measure Ca(2+) transients in myocytes of intact hearts in Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs) at different ages. Early compensatory mechanisms include a positive inotropic effect in SHRs at 7.5-9 mo compared with 6 mo. Ca(2+) transient duration increased at 9 mo in SHRs, indicating changes in Ca(2+) reuptake during decompensation. Cell-to-cell variability in Ca(2+) transient duration increased at 7.5 mo, decreased at 9 mo, and increased again at 22 mo (overt HF), indicating extensive intercellular variability in Ca(2+) transient kinetics during disease progression. Vulnerability to intercellular concordant Ca(2+) alternans increased at 9-22 mo in SHRs and was mirrored by a slowing in Ca(2+) transient restitution, suggesting that repolarization alternans and the resulting repolarization gradients might promote reentrant arrhythmias early in disease development. Intercellular discordant and subcellular Ca(2+) alternans increased as early as 7.5 mo in SHRs and may also promote arrhythmias during the compensated phase. The incidence of spontaneous and triggered Ca(2+) waves was increased in SHRs at all ages, suggesting a higher likelihood of triggered arrhythmias in SHRs compared with WKY rats well before HF develops. Thus serious and progressive defects in Ca(2+) cycling develop in SHRs long before symptoms of HF occur. Defective Ca(2+) cycling develops early and affects a small number of myocytes, and this number grows with age and causes the transition from asymptomatic to overt HF. These defects may also underlie the progressive susceptibility to Ca(2+) alternans and Ca(2+) wave activity, thus increasing the propensity for arrhythmogenesis in HF.

Magnetic electroanatomic mapping of an atrial tachycardia requiring ablation within the coronary sinus.

We describe a focal atrial tachycardia (AT) originating from the region of the inferoposterior mitral annulus in which ablation at the site of earliest endocardial activation during AT was unsuccessful. Three-dimensional electroanatomic mapping identified the earliest atrial activation within the coronary sinus. Radiofrequency energy delivered at this site within the CS terminated this tachycardia without any complications, suggesting an origin within the CS. To our knowledge, this is the first time a three-dimensional, high-density activation map of such a tachycardia has been reported.