JACC: Clinical Electrophysiology

BackgroundStudies of VT mechanisms are largely based on a 2D portrait of reentrant circuits on one surface of the heart. This oversimplifies the 3D circuit that involves the depth of the myocardium. Simultaneous epicardial and endocardial (epi-endo) mapping was shown to facilitate a 3D delineation of VT circuits, which is however difficult via invasive mapping. ObjectiveThis study investigates the capability of noninvasive epicardial-endocardial electrocardiographic imaging (ECGI) to elucidate the 3D construct of VT circuits, emphasizing the differentiation of epicardial, endocardial, and intramural circuits and to determine the proximity of mid-wall exits to the epicardial or endocardial surfaces. Methods120-lead ECGs of VT in combination with subject-specific heart-torso geometry are used to compute unipolar electrograms (CEGM) on ventricular epicardium and endocardia. Activation isochrones are constructed, and the percentage of activation within VT cycle length is calculated on each surface. This classifies VT circuits into 2D (surface only), uniform transmural, nonuniform transmural, and mid-myocardial (focal on surfaces). Furthermore, the endocardial breakthrough time was accurately measured using Laplacian eigenmaps, and by correlating the delay time of the epi-endo breakthroughs, the relative distance of a mid-wall exit to the epicardium or the endocardium surfaces was identified. ResultsWe analyzed 23 simulated and in-vivo VT circuits on post-infarction porcine hearts. In simulated circuits, ECGI classified 21% as 2D and 78% as 3D: 82.6% of these were correctly classified. The relative timing between epicardial and endocardial breakthroughs was correctly captured across all cases. In in-vivo circuits, ECGI classified 25% as 2D and 75% as 3D: in all cases, circuit exits and entrances were consistent with potential critical isthmus delineated from combined LGE-MRI and catheter mapping data. ConclusionsECGI epi-endo mapping has the potential for fast delineation of 3D VT circuits, which may augment detailed catheter mapping for VT ablation.

Background: Accurate identification of macro-reentrant atrial tachycardia (AT) circuits is critical for successful ablation but remains challenging with conventional mapping techniques. The aim of this study was to automatically detect macro-reentrant AT loops from high-density local activation time (LAT) maps. Methods: We developed an algorithm for automated detection of macro-reentrant AT circuits using LAT-derived directed graphs. Compared to previous graph-based approaches, the algorithm is designed to identify the fastest-conducting reentrant pathways and cluster them by rotational orientation (clockwise vs. counterclockwise) to distinguish single- from dual-loop circuits. The algorithm was applied retrospectively to 60 macro-reentrant scar-related AT cases mapped with CARTO or Ensite from two institutions. The results were compared with blinded expert electrophysiologist annotations of loop location and single- vs. dual-loop classification. Results: The 60 cases included 16 right atrial and 44 left atrial ATs from 51 patients. Expert review identified 57% single-loop and 43% dual-loop circuits. Compared with expert annotation, the algorithm correctly identified anatomical loop locations with 88% accuracy and correctly distinguished single- vs. dual-loop ATs in 93% of cases. Conclusion: Our LAT graph-based algorithm automatically identified single- and dual-loop macro-reentrant AT circuits. Localizing these pathways may provide insight into circuit mechanisms and help guide ablation.

BackgroundWe performed high-density mapping of persistent atrial fibrillation (AF) in animals and patients (1) to test that AF is due to [&ge;]1 reentries, and (2) to characterize activation delay and reentries pre/ post pulmonary vein isolation (PVI). We determined electrophysiological characteristics that may predispose to the induction, maintenance, and reduction of AF. Methods and ResultsThis study includes 48 dogs and nine patients. 43 AF- and five sinus/ paced rhythm dogs (3-14 weeks rapid atrial pacing) were studied at open chest surgery with 117 epicardial electrograms (EGMs) (2.5mm dist.) in 6 bi-atrial regions. Rotational activity automatically detected with a new algorithm tracking the earliest and latest activation in all regions (5{+/-}2 per region) were stable over 424{+/-}505ms [120- 4940ms]. Reentry stability was highest in the right atrial appendage (RAA) (405{+/-}219ms) and the posterior left atrium (PLA) (267{+/-}115ms) and anchored between >=3 zones of activation delay (15{+/-}5ms, median 13ms) defined as >10ms per 2.5mm. Cycle length (CL) and degree of focal fibrosis were highest in the PLA and left atrial free wall (LAFW) with 94{+/-}7ms, 96{+/-}5ms, and 49{+/-}14%, 47{+/-}19%. Fiber crossing density correlated with the stability of rotational activity (R=0.6, P<0.05). Activation delay was 2x higher in AF compared to sinus rhythm/paced rhythm (interval 200-500ms). Activation delay zones > 10ms were at the same locations, but increased 4x during AF vs. SR and were located at fiber crossings, fibrosis/ fat zones. Stability of rotational activity correlated with Organization Index (OI), Fraction Index (FI), Shannons Entropy (ShEn), and CL (R>0.5, p< 0.0001). PVI in five hearts increased CL [2-14%] and reduced stability of rotational activity in nearly all regions remote to the pulmonary veins (PVs). Also in the clinical evaluation in nine patients using the HD-catheter (16 electrodes, 3mm dist.) activation delay at the reentrant trajectory was 2x higher at edges with maximal delay (20.5{+/-}8.1ms, median 19.6ms) vs (9.3{+/-}8.8ms, median 9.2ms) and 1.4 x higher during AF (13.0{+/-}18.7ms, median 7.2ms) compared to SR/ CS-pacing (18.0{+/-}11.6ms, median 17.7ms). ConclusionRotational activities in all bi-atrial regions anchored between small frequency-dependent activation delay zones in AF. PVI led to beneficial remodeling in bi-atrial regions remote to the PVs. These data may identify a new paradigm for persistent AF. Subject TermsArrhythmias, Atrial Fibrillation, Cardiac Electrophysiology, High-Density Mapping, Catheter Ablation, Pulmonary Vein Isolation, Fibrosis Clinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABSO_LIRotational activity trajectories based on high-resolution mapping follow propagation line patterns. C_LIO_LIRotational activities anchor frequently between small frequency-dependent slow conduction zones in all bi-atrial regions. C_LIO_LISlow conduction zones are fiber crossings zones and develop into fibrosis and fat regions over time. C_LIO_LIPVI reduces slow conduction zones and AF drivers in regions remote to the PVs in both atria. C_LI What Are the Clinical Implications?O_LIThe new method for the robust detection of rotational activity based on the earliest and latest activation may be useful for an improved AF treatment. C_LIO_LIStability of rotational activity may be predicted with the correlated substrate characteristic fiber crossings density, with slow conduction zones, and with established electrogram measures in the different atrial regions. C_LIO_LIPVI leads to beneficial remodeling in all regions remote to the PVs in the left atrium and right atrium. C_LI

BackgroundIndependent investigations demonstrate greater radiofrequency (RF) ablation effects at left- sided left atrial posterior wall (LAPW) sites. ObjectiveTo investigate mechanisms underlying RF ablation heterogeneity during contact-force (CF) and VISITAG Module (Biosense Webster)-guided pulmonary vein isolation (PVI). MethodsConsecutive patients undergoing PVI during atrial overdrive pacing comprised 2 cohorts: intermittent positive pressure ventilation (IPPV, 14-16/min, 6-8ml/kg); high frequency jet ventilation (HFJV, 150/min, Monsoon III, Acutronic). Temperature-controlled (17ml/min, 48{degrees}C) RF data was retrospectively assessed at first-annotated (target 15s) LAPW sites: 30W during IPPV; 20W at left-sided sites during HFJV. ResultsTwenty-five and 15 patients underwent PVI during IPPV and HFJV, respectively. During IPPV, left versus right-sided median impedance drop (ImpD) was 13.6{Omega} versus 9.9{Omega} (p<0.0001) respectively and mean time to pure R unipolar electrogram (UE) morphology change 4.9s versus 6.7s (p=0.007) respectively. During HFJV, ImpD was greater at left-sided sites (9.7{Omega} versus 7.4{Omega}, p=0.21) and time to pure R UE significantly shorter: 4.3s versus 6.1s (p=0.02). Minimum case impedance subtracted from pre-RF baseline impedance (BI) generated site-specific {Delta}BI. Left-sided sites demonstrated significantly greater {Delta}BI, correlating strongly with Ln(ImpD) - IPPV r=0.84 (0.65 - 0.93), HFJV r=0.77 (0.35 - 0.93). At right-sided sites, {Delta}BI and Ln(ImpD) were without correlation during IPPV, but correlation was modest during HFJV (r=0.54, -0.007 - 0.84). Conclusions{Delta}BI may usefully indicate catheter-tissue contact surface area (SA). Consequently, greater left-sided LAPW RF effect may result from greater contact SA and in-phase catheter-tissue motion; HFJV may reduce right-sided out-of-phase catheter-tissue motion. Modifying RF delivery based on {Delta}BI may improve PVI safety and efficacy.

Atrial fibrillation (AF) is a major healthcare burden worldwide. For AF that is resistant to pharmacological intervention, the standard invasive treatment is a pulmonary vein isolation (PVI) procedure. Ganglionated plexuses (GP) ablation can be used as an adjunctive therapy to PVIs, together reducing the likelihood of AF recurrence. High-frequency stimulation (HFS) is a technique used to identify ectopy-triggering GP sites. However, to locate GP sites, sequential HFS must be delivered over the whole atria. Therefore, ensuring the safety of HFS delivery is integral to avoid causing irreversible damage from excessive pacing. We tested Tau-20 version 2 neural simulator, a prototype of a novel electrophysiological pacing and recording system that has the potential to guide intracardiac AF treatments. Using an ex vivo porcine Langendorff model that closely resembles the anatomy and physiology of a human heart, we confirmed that HFS can successfully trigger AF, indicating that HFS-positive locations contain GP sites. Additionally, we found that the HFS delivered via Tau-20 version 2 did not cause any damage to the heart. These findings evidence that once fully optimised, the Tau-20 system could be suitable for use in clinical settings.

BackgroundDuring radiofrequency (RF) ablation, lesion size increases with increasing contact force (CF), RF power and application time. The effects of CF and RF power on lesion size during high-power and short-duration (HP-SD) ablation have not been well-determined. This study aimed to, during HP-SD ablation: 1) examine the relationship between lesion size and CF, RF power and time, and 2) prospectively validate the ability of a novel logarithmic formula, incorporating CF, RF power and time (Force-Power-Time-Index, FPTI, gram x Watt x sec) to predict lesion size using a swine beating heart model. MethodsEight closed-chest swine were studied. A 7.5Fr CF ablation catheter with a 3.5mm irrigated-tip electrode containing 6 surface thermocouples (Qdot-Micro) was positioned in the right and left ventricles. In five swine (Phase1-Study), RF was delivered at [&le;]90Watts (modulated to maintain the surface electrode temperature<65{degrees}C) for 4sec to 103 ventricular sites with various CF (range 5-54g). Swine were sacrificed and lesion size was measured. A new logarithmic FPTI-Formula was created based on the relationship between lesion depth and CF, power and time. In the prospective validation study using the remaining three swine (Phase2-Study), RF(90W) was delivered for 4 sec at 72 sites with FPTI-Formula predicted lesion depths of 2-6mm. Actual lesion depth was compared to the predicted lesion depth. ResultsIn the Phase1-study, there was a close relationship between lesion depth and the product of Force x Power x Time (R=0.711, p<0.0001), creating a novel logarithmic FPTI-Formula to predict lesion depth. In the Phase2-study, lesion depth predicted by the FPTI-Formula correlated highly with actual lesion depth (1.9-6.1mm), with {+/-}1mm accuracy in 68/72(94%) lesions (R=0.867, p<0.0001). No steam pop or thrombus formation occurred. ConclusionDuring HP-SD ablation, the new FPTI-Formula prospectively predicted lesion depth with high accuracy while the surface electrode temperature control prevented steam pop and thrombus formation.

BackgroundAlthough atrial electrograms (EGMs) are thought to reflect pathophysiological substrate for atrial fibrillation (AF), it is not known which electrograms are suitable targets during AF ablation. We hypothesized that electrogram morphology recurrence (EMR) better reflects arrhythmogenic AF substrate than traditional frequency and complexity measures of AF. In a canine rapid atrial pacing (RAP) model of AF, we assessed the relationship between EMR and traditional AF electrogram measures, rotational activity in the atria, fibrosis, myofiber orientation and parasympathetic innervation. MethodsPersistent AF was induced in 13 dogs by RAP for 6-8 weeks. High-density epicardial mapping (117 electrodes) was performed in six atrial sub-regions. EMR measures Recurrence percentage (Rec%) and cycle length of the most frequent electrogram morphology (CLR), Fractionated Interval (FI), Organization Index (OI), Dominant Frequency (DF) and Shannons Entropy (ShEn) were analyzed before and after atropine administration. Myocyte fiber orientation, amount of fibrosis and spatial distribution of parasympathetic nerve fibers were quantified. ResultsRec% was greatest in the appendages, and CLR was lowest in the posterior left atrium. Rec%/CLR correlated with FI, OI and the complexity measure ShEn, but not with DF. All electrogram measures were poorly correlated with fibrosis and myofiber anisotropy. Rec% correlated closely with stability of rotational activity. Unlike other measures, Rec% correlated closely with spatial heterogeneity of parasympathetic nerve fibers; this was reflected in CLR response to atropine. ConclusionEMR correlates closely with stability of rotational activity and with the pattern of atrial parasympathetic innervation. CLR may therefore be a viable therapeutic target in persistent AF.

BackgroundElectrographic flow (EGF) mapping algorithms employing Horn-Schunck flow estimations can create temporospatial visualizations of atrial electrical wavefront propagations during atrial fibrillation (AF). Reproducible patterns of centrifugal EGF activation from discrete sites may represent sites of AF origin or sources. Our objectives were to assess the patterns and prevalence of AF sources using EGF mapping. MethodsUnipolar electrograms were recorded for 1-minute with 64-pole basket catheters. Flow estimates were constructed by passing consecutive frames through an algorithm to learn and then compare typical wave direction patterns to describe flow-field evolution. During each 2-second segment, sites initiating centrifugal activation patterns were defined as AF sources. Maps of source location/activity duration were generated. ResultsThe EGF method was applied to 405 prospective and retrospective patients with persistent or long-standing persistent AF. Mean age 62.5 years; mean LA size 54 mm; mean AF duration 4.6 years. EGF mapping found 6.6 {+/-} 2.4 AF sources/patient (range 1 to 17). Distribution was 55% LA and 45% RA. Dominant sources (prevalence [&ge;]20%) were demonstrated in 185 (45.7%) patients, but only 10.7% of all sources were dominant. While AF cycle length (CL) was not affected by source prevalence, CL variance significantly decreased as source prevalence increased. ConclusionsComplex AF conduction patterns make ablation challenging, but EGF mapping enables detection and organization of time-dependent AF behaviors. Although many low prevalence sources are detected, they may not be clinically relevant, while higher prevalence sources seem to modulate AF. Recording durations of 1 minute facilitate source discrimination.

BackgroundPulsed-field ablation (PFA) is becoming more widely used as its efficacy and safety. However, the durability of pulmonary vein isolation (PVI) is not necessarily satisfactory even with PFA. This study aimed to investigate whether post-PFA residual tiny pulmonary vein potentials (PVPs) on a high-resolution map may serve as a predictor of late-phase reconnection between the left atrium and pulmonary vein. MethodsFifteen patients who underwent PFA-based PVI, and the second ablation for recurrent atrial tachyarrhythmias were enrolled. The association between residual tiny PVPs ([&ge;] 0.03 mV) on a post-PFA high-resolution map and reconnected PVPs observed during the second ablation were studied. The presence or absence of PVPs in 270 pulmonary vein segments from 15 cases was compared between the post-PFA map of the initial ablation and the map from the second ablation. ResultsAmong 42 post-PFA residual tiny PVPs, 34 (81%) showed locational concordance with the late-phase reconnected PVPs identified at the second ablation. Thirty-four (52%) out of 66 late-phase reconnected PVPs at the second ablation were located at sites concordant with the post-PFA residual tiny PVPs. Post-PFA residual tiny PVPs defined as bipolar voltage of [&ge;] 0.03 mV well predicted late-phase reconnected PVPs (sensitivity=52%, specificity=96%, positive predictive value=81%, negative predictive value=86%). ConclusionThe presence of post-PFA residual tiny PVPs can be used as late-phase reconnection between the left atrium and pulmonary vein. Condensed abstractThis observational study aimed to investigate whether post-PFA residual tiny pulmonary vein potentials (PVPs) on a high-resolution map may serve as a predictor of late-phase reconnection between the left atrium and pulmonary vein. Fifteen patients were who underwent pulmonary vein isolation using pulse field ablation and the second ablation for recurrent atrial tachyarrhythmias were enrolled. Residual tiny PVPs defined as bipolar voltage of [&ge;] 0.03 mV well predicted late-phase reconnected PVPs (sensitivity=52%, specificity=96%, positive predictive value=81%, negative predictive value=86%). In conclusion, the presence of post-PFA residual tiny PVPs can be used as late-phase reconnection between the left atrium and pulmonary vein

BackgroundTranslation of knowledge of sinoatrial nodal "SAN" automaticity gleaned from animal studies to human dysrhythmias, e.g. "Sick Sinus" Syndrome (SSS) requiring electronic pacemaker insertion has been sub-optimal, largely because heart rate (HR) varies widely across species. ObjectivesTo discover regulatory universal mechanisms of normal automaticity in SAN pacemaker cells that are self-similar across species. MethodSub-cellular Ca2+ releases, whole cell AP-induced Ca2+ transients and APs were recorded in isolated mouse, guinea-pig, rabbit and human SAN cells. Parametric Ca2+ and Vm Kinetic Transitions (PCVKT) during phases of AP cycles from their ignition to recovery were quantified. ResultsAlthough both action potential cycle lengths (APCL) and PCVKT during AP cycles differed across species by ten-fold, trans-species scaling of PCVKT during AP cycles and scaling, of PCVKT to APCL in cells in vitro, EKG RR intervals in vivo, and BM were self-similar (obeyed power laws) across species. Thus, APCL in vitro, HR in vivo, and BM of any species can be predicted by PCVKT during AP cycles in SAN cells measured in any single species in vitro. ConclusionsIn designing optimal HR to match widely different BM and energy requirements from mice to humans, nature did not "reinvent pacemaker cell wheels", but differentially scaled kinetics of gears that regulate the rates at which the "wheels spin". This discovery will facilitate the development of novel pharmalogic therapies and biologic pacemakers featuring a normal, wide-range rate regulation in animal models and the translation of these to humans to target recalcitrant human SSS. Condensed AbstractStudies in animal models are an important facet of cardiac arrhythmia research. Because HR differs by over ten-fold between some animals and humans, translation of knowledge about regulatory mechanisms of SAN normal automaticity gleaned from studies in animal models to target human SSS has been sub-optimal. Our findings demonstrating that trans-species self-similarity of sub-cellular and cellular mechanisms that couple Ca2+ to Vm during AP cycles can predict heart rate in vivo from mice to humans will inform on the design of novel studies in animal models and facilitate translation of this knowledge to target human disease.

BackgroundFractionated potential (FP) ablation during atrioventricular nodal reentrant tachycardia (AVNRT), is an effective strategy that minimizes redundant radiofrequency (RF) applications. This study aimed to evaluate the utility of cryoablation targeting FPs to effectively terminate AVNRT while further minimizing redundant cryoapplications. Moreover, we observed what appeared to be compact AVN (cAVN) or proximal His potentials--tiny, dull potentials (TDPs) with continuity to the His potential during sinus rhythm (SR) and AVNRT--in the anteroseptal area. The second aim of this study was to explore the significance of those potentials. MethodsAnalyzed were 53 slow-fast AVNRT patients who underwent ablation procedures. Ultra-high resolution activation maps in the triangle of Koch were obtained during SR (n=34) and AVNRT (n=46). TDPs during SR and AVNRT in the anteroseptal area were identified and annotated using the LUMIPOINT Activation Search tool. ResultsFP areas were observed in 19 patients (56%) during SR and in 46 (100%) during AVNRT. This area corresponded to the AVNRT termination and/or successful ablation site in all, with peak numbers of 8.8{+/-}1.4 during AVNRT and 5.3{+/-}1.3 during SR. The number of ablation points was 3.6{+/-}1.5 for the FP-guided cryoablation (n=32) (Bonferroni corrected P<0.05 vs. anatomical RF; and P<0.05 vs. FP-guided RF), 5.4{+/-}2.1 for the FP-guided RF ablation (n=11) (P=0.0825 vs. anatomical RF), and 8.2{+/-}3.2 for the conventional RF ablation (n=10). Transient AV block occurred in 11 patients (21%). All AV block sites overlapped with the TDP area in the phase just before the His potential during AVNRT and SR, with a confidence setting of [&ge;]24% (35[24-60]%). Conversely, in 42 patients without AV block, no ablation was performed in this area. ConclusionThe FP-guided cryoablation strategy targeting AVNRT termination required fewer cryoapplications than RF ablation. The RF/cryo application in the TDP area during SR and AVNRT posed a risk of AV block.

AimsEarly discharge after electrophysiological procedures has gained increasing attention. However, definition of patient- and procedure-related prerequisites for successful and safe discharge strategies after atrial tachycardia (AT) ablation remains unknown. We therefore evaluated patient characteristics, procedural features, and outcomes according to index length of stay (LOS) following AT ablation. Methods and resultsThe multicenter observational SATELLITE registry enrolled consecutive patients undergoing AT rhythm control. Patients were stratified by LOS ([&le;]1, 2 and >2 nights) after catheter ablation. Among 670 patients (67 [IQR 56-75] years, 54.9% male), LOS was [&le;]1 night in 13.9%, 2 nights in 41.9% and >2 nights in 44.2%. LOS was only modestly predictable from clinical characteristics including age, sex, atrial fibrillation and prior atrial ablation (AUC 0.73). Discrimination improved after inclusion of procedural variables and early post-procedural events (AUC 0.77; P=0.0300), consistent with an increase in left atrial procedures (26.5% vs. 76.0% vs. 80.8%; P<0.0001), acute minor complications (3.2% vs. 2.5% vs. 14.5%; P<0.0001) and early recurrences of atrial arrhythmia (2.2% vs. 6.8% vs. 21.3%; P<0.0001). During 2.8{+/-}3.0 years of follow-up, LOS did not predict long-term outcomes including subsequent cardiovascular hospitalization (HR 1.19, 95% CI 0.78-1.81; P=0.4175). ConclusionDespite multiple comorbidities, most patients undergoing AT ablation need up to 2 nights of hospitalization. However, prolonged hospital stays before successful and safe discharge are common and associated with acute minor complications and early recurrences of atrial arrhythmia rather than comorbidities. Accordingly, discharge timing largely reflects the immediate peri-procedural clinical course, therefore challenging purely logistics-driven planning. Key Learning PointsO_ST_ABSWhat is already knownC_ST_ABSO_LIEarly discharge after electrophysiological procedures has gained increasing attention. C_LIO_LIDefinition of patient- and procedure-related prerequisites for successful and safe discharge strategies after atrial tachycardia (AT) ablation remains unknown. C_LI What this study addsO_LIDespite multiple comorbidities, most patients undergoing AT ablation need up to 2 nights of hospitalization. C_LIO_LIProlonged hospital stays before successful and safe discharge are common and associated with acute minor complications and early recurrences of atrial arrhythmia rather than comorbidities. C_LIO_LIDischarge timing largely reflects the immediate peri-procedural clinical course, therefore challenging purely logistics-driven planning C_LI Structured Graphical AbstractO_LIDespite multiple comorbidities, most patients undergoing AT ablation need up to 2 nights of hospitalization. However, prolonged hospital stays before successful and safe discharge are common and associated with acute minor complications and early recurrences of atrial arrhythmia rather than comorbidities. Accordingly, discharge timing largely reflects the immediate peri-procedural clinical course, therefore challenging purely logistics-driven planning. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=130 SRC="FIGDIR/small/26345799v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@200309org.highwire.dtl.DTLVardef@1a745fcorg.highwire.dtl.DTLVardef@e3cd45org.highwire.dtl.DTLVardef@1b98c3e_HPS_FORMAT_FIGEXP M_FIG C_FIG

BackgroundAdditional linear ablation for persistent atrial fibrillation (PerAF) still has limited evidence-based medical proof. ObjectivesWe probed into the mechanisms of intermediate atrial tachycardia (AT) during PerAF termination by catheter ablation and provided evidence for it. Methods136 patients who converted to organized AT after PerAF termination in the Extent-AF study were analyzed. Bi-atrial activation mapping combined with entrainment mapping were performed to identify the mechanisms and critical isthmus of these ATs. ResultsA total of 164 ATs in 136 patients were identified (average 1.2 per patients) and 143 (87%) ATs in 113 patients (average 1.3 per patient) were successfully mapped. The mechanisms of intermediate ATs were macro-reentry in 110 (77%), micro-reentry in 21 (15%), and focal AT in 12 (8%). Among the macro-reentrant ATs, the most common were perimitral ATs (PM-AT) 52 (47%), followed by roof dependent ATs (RF-AT) in 40 (36%) and typical atrial flutter (AFL) in 18 (16%). 98 (72%) patients had successfully ablated intermediate ATs. Among these patients, 88 (90%) required at least one of the perimitral line, roofline, or peritricuspid line to finally restore sinus rhythm. At the end of 12 months of follow-up, 63 (64.3%) patients with successful ablative ATs were free of any arrhythmia. ConclusionThe majority of intermediate ATs after PerAF termination were macro-reentrant ATs. Linear ablation targets the mitral isthmus, roof, and tricuspid isthmus was a critical step of PerAF ablation to restore sinus rhythm in up to 90% patients, suggesting the importance of additional linear ablation.

BackgroundPulmonary vein isolation (PVI) constitutes the established strategy for atrial fibrillation (AF) ablation. With the advent of PV stenosis risk-free pulsed field ablation (PFA), we explored the feasibility and safety of additional ablation within PV sleeves (PVA). Moreover, we assessed the durability of PVI through PFA in a deep sedation setting, comparing a 3D Electroanatomical Mapping (3D-EAM)-based navigation approach with the standard fluoroscopy-based one. MethodsIn this single-center, first-in-human study (NCT07035288), 40 AF patients underwent first time PFA-based PVI+PVA (4 additional applications inside the PVs) between November 2024 and April 2025 using a circular array PFA catheter (PulseSelect, Medtronic, Minneapolis, MN), randomized to either 3D-EAM-based (Carto3 prime, J&J, Irvine, CA) or fluoroscopy-based navigation, in a propofol-based deep sedation setting. Rate of conversion from 3D-EAM to fluoroscopy-based navigation was recorded. First-pass isolation was assessed immediately post-ablation. Venography and 3D-EAM were performed at remapping at 2 to 3 months after the index procedure. ResultsNo major procedure-related adverse events were noted, as well as no acute kidney injury, significant hemolysis or phrenic nerve palsy. First-pass isolation was successfully achieved in 95% of patients (3D-EAM: 95%, fluoroscopy: 95%, p=NS) and in 98.7% of PVs. Venography performed at remapping revealed no PV stenosis. PVI durability per patient was 92.5% (3D-EAM: 90%, fluoroscopy: 95%, p=NS) and per vein was 97.5% (3D-EAM: 97.5%, fluoroscopy: 97.5%, p=NS between navigation methods). Half of 3D-EAM cases were converted to fluoroscopy due to map shift. ConclusionsPFA-based PVA is safe. Catheter performance, as depicted by 97.5% durable PVI, was such that adding a 3D-EAM system was not associated with improved efficacy and exhibited high conversion rate to fluoroscopy-based navigation in a deep sedation setting. Categories: electrophysiology Special Sections: Original article Randomized clinical trial: NCT07035288

Atrial fibrosis promotes atrial fibrillation by stabilizing spiral waves, with focal fibrosis causing strong anchoring that resists termination. Optogenetics offers a low-energy alternative for rhythm control, but its efficacy in human atrial tissue remains under investigation. Here, we developed a two-dimensional computational model of human atrial tissue expressing the light-sensitive protein GtACR1, coupled with fibroblasts, to simulate spiral wave dynamics under varying degrees (0%-100%) and types (focal vs. diffuse) of fibrosis. We examined the effects of subthreshold illumination area (0%-100%) and spatial intensity profiles (uniform, parabolic, linear, exponential) on termination efficiency, and tested low-intensity periodic stimulation for wave drift induction. Results show that the minimum light area required for termination increases with fibrosis degree. At 25%-50% fibrosis, focal substrates require larger illumination areas than diffuse ones, confirming stronger anchoring. Crucially, the relationship between illumination area and termination time is non-monotonic. An "optimal light range" exists: smaller areas fail to eliminate the wave, while excessively large areas suppress wavefront collisions, prolonging termination. In diffuse fibrosis, low-intensity periodic illumination successfully induces drift and boundary collision, enabling self-termination. In contrast, in focal fibrosis, the spiral wave core remains anchored, and drift cannot be initiated by modulating stimulation frequency or intensity alone. Our findings demonstrate that fibrosis type and extent critically influence optogenetic control efficacy. The existence of an optimal illumination strategy highlights the need for spatially tailored interventions. These results provide a mechanistic basis for developing individualized, low-energy optogenetic defibrillation protocols. Author summaryAtrial fibrillation, a common heart rhythm disorder, is often sustained by rotating electrical waves in the heart muscle. Scarring (fibrosis) in the atria can anchor these waves, making them harder to eliminate. Optogenetics -- a technique that uses light to control genetically modified heart cells--offers a promising low-energy approach to stop these dangerous rhythms. However, how different patterns of scarring affect the success of optical interventions remains unclear. In this study, we developed a computational model of human atrial tissue expressing a light-sensitive protein (GtACR1) to investigate how two major types of fibrosis--localized "focal" scars versus widespread "diffuse" scarring -- influence the effectiveness of light-based rhythm control. We found that focal fibrosis strongly anchors spiral waves, requiring larger illuminated areas for termination, while diffuse fibrosis allows more efficient disruption with smaller light zones. Crucially, we discovered an "optimal light range": too little light fails to stop the wave, but too much can paradoxically prolong termination by suppressing wavefront collisions. Furthermore, we show that low-intensity periodic light can induce drift and self-termination in diffuse fibrotic tissue, but fails in focal substrates due to structural anchoring. Our findings highlight that one-size-fits-all optical strategies are suboptimal, and that personalized illumination protocols--tailored to individual fibrosis patterns--could enable safer, lower-energy defibrillation in the future.

BackgroundHeart rhythm relies on complex interactions between electrogenic membrane proteins and intracellular Ca2+ signaling in sinoatrial node (SAN) myocytes; however, mechanisms underlying the functional organization of proteins involved in SAN pacemaking and its structural foundation remain elusive. Caveolae are nanoscale, plasma membrane pits that compartmentalize various ion channels and transporters, including those involved in SAN pacemaking, via binding with the caveolin-3 scaffolding protein, but the precise role of caveolae in cardiac pacemaker function is unknown. Our objective was to determine the role of caveolae in SAN pacemaking and dysfunction (SND). MethodsBiochemical co-purification, in vivo electrocardiogram monitoring, ex vivo optical mapping, in vitro confocal Ca2+ imaging, and immunofluorescent and electron microscopy analyses were performed in wild type, cardiac-specific caveolin-3 knockout, and 8-weeks post-myocardial infarction heart failure (HF) mice. SAN tissue samples from donor human hearts were used for biochemical studies. We utilized a novel 3-dimensional single SAN cell mathematical model to determine the functional outcomes of protein nanodomain-specific localization and redistribution in SAN pacemaking. ResultsIn both mouse and human SANs, caveolae compartmentalized HCN4, Cav1.2, Cav1.3, Cav3.1 and NCX1 proteins within discrete pacemaker signalosomes via direct association with caveolin-3. This compartmentalization positioned electrogenic sarcolemmal proteins near the subsarcolemmal sarcoplasmic reticulum (SR) membrane and ensured fast and robust activation of NCX1 by subsarcolemmal local SR Ca2+ release events (LCRs), which diffuse across [~]15-nm subsarcolemmal cleft. Disruption of caveolae led to the development of SND via suppression of pacemaker automaticity through a 50% decrease of the L-type Ca2+ current, a negative shift of the HCN current (If) activation curve, and a 40% reduction of Na+/Ca2+-exchanger function, along with [~]2.3-times widening of the sarcolemma-SR distance. These changes significantly decreased the SAN depolarizing force, both during diastolic depolarization and upstroke phase, leading to bradycardia, sinus pauses, recurrent development of SAN quiescence, and significant increase in heart rate lability. Computational modeling, supported by biochemical studies, identified NCX1 redistribution to extra-caveolar membrane as the primary mechanism of SAN pauses and quiescence due to the impaired ability of NCX1 to be effectively activated by LCRs and trigger action potentials. HF remodeling mirrored caveolae disruption leading to NCX1-LCR uncoupling and SND. ConclusionsSAN pacemaking is driven by complex protein interactions within a nanoscale caveolar pacemaker signalosome. Disruption of caveolae leads to SND, potentially demonstrating a new dimension of SAN remodeling and providing a newly recognized target for therapy.

Atrial fibrillation (AF) is a progressive disease involving both structural and functional remodeling. To investigate the contribution of cell-scale functional remodeling to AF pathogenesis, we combined personalized 3D anatomical models with pathology-specific ionic models. The latter were developed using recordings in myocytes isolated from patients in sinus rhythm, paroxysmal, postoperative, and persistent AF. To quantify AF dynamics, we developed a novel algorithm for locating RDs by backtracking the conduction velocity field from the wavebreak regions. We demonstrate that our novel algorithm is at least 700 times faster than the traditional phase singularity analysis. The inducibility of simulated AF was not pathology-dependent, but pathological models demonstrate a more extensive arrhythmogenic substrate compared to the sinus rhythm. AF driver locations depend on electrophysiological remodeling; differences between pathology-specific models are explained by differences in wavebreak patterns. Specifically, RDs tend to dwell in the regions with the highest wavebreak probability.

Atrial fibrillation is the most common heart rhythm disorder in adults and a major cause of stroke. Unfortunately, current treatments of AF are suboptimal as they are not targeted to the molecular mechanisms underlying AF. In this study, we demonstrated using a novel gene-based strategy in a clinically relevant large animal of AF that oxidative injury is a key mechanism underlying the onset and perpetuation of AF. First, we demonstrated that generation of oxidative injury in atrial myocytes is a frequency-dependent process, with rapid pacing in canine atrial myocytes inducing oxidative injury through induction of NADPH oxidase 2 (NOX2) and generation of mitochondrial reactive oxygen species. We show that oxidative injury likely contributes to electrical remodeling in AF by upregulating a constitutively active form of acetylcholine-dependent K+ current (IKACh) - called IKH - by a mechanism involving frequency-dependent activation of protein kinase C epsilon (PKC{varepsilon}). To understand the mechanism by which oxidative injury promotes the genesis and/or maintenance of AF, we performed targeted injection of NOX2 shRNA in atria of normal dogs followed by rapid atrial pacing. The time to onset of non-sustained AF increased by more than 5-fold in NOX2 shRNA treated dogs. Furthermore, animals treated with NOX2 shRNA did not develop sustained AF for up to 12 weeks. The electrophysiological mechanism underlying AF prevention was prolongation of atrial effective refractory periods, with attenuated activation of PKC{varepsilon}, a likely molecular mechanism underlying this beneficial electrophysiological remodeling. Future optimization of this approach may lead to a novel, mechanism-guided therapy for AF.\n\nOne Sentence SummaryTargeted disruption of NOX2-dependent oxidative injury with a novel gene therapy approach prevents onset as well as perpetuation of atrial fibrillation.

BackgroundPulmonary vein isolations (PVI) are being performed using a high-power, short duration (HPSD) strategy. The purpose of this study was to compare the clinical efficacy and safety outcomes of a HPSD vs low-power long duration (LPLD) approach to PVI in patients with paroxysmal atrial fibrillation (AF). MethodsPatients were grouped according to a HPSD ([&ge;]40 W) or LPLD ([&le;] 35 W) strategy. The primary endpoint was the one-year recurrence of any atrial arrhythmia lasting [&ge;] 30 seconds, detected using three 14-day ambulatory continuous ECG monitoring. Procedural and safety endpoints were also evaluated. The primary analysis were regression models incorporating propensity scores yielding adjusted relative risk (RRa) and mean difference (MDa) estimates. ResultsOf the 398 patients included in the AWARE Trial, 173 (43%) underwent HPSD and 225 (57%) LPLD ablation. The distribution of power was 50 W in 75%, 45 W in 20% and 40 W in 5% in the HPSD group, and 35W with 25W on the posterior wall in the LPLD group. The primary outcome was not statistically significant at 30.1% vs 22.2% in HPSD and LPLD group with RRa 0.77 (95% confidence interval [CI]) 0.55-1.10; p=0.165). The secondary outcome of repeat catheter ablation was not statistically significant at 6.9% and 9.8% (RRa 1.59 [95% CI 0.77-3.30]; p=0.208) respectively. The incidence of any ECG documented AF during the blanking period was numerically lower in the HPSD group: 1.7% vs 8.0% (RRa 3.95 [95% CI 1.00-15.61; p=0.049). The total procedure time was significantly shorter in the HPSD group (MDa 97.5 minutes [95% CI 84.8-110.4)]; p<0.0001) with no difference in adjudicated serious adverse events. ConclusionsA HPSD strategy was associated with significantly shorter procedural times with similar efficacy in terms of clinical arrhythmia recurrence. Importantly, there was no signal for increased harm with a HPSD strategy. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=164 SRC="FIGDIR/small/23291526v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@915125org.highwire.dtl.DTLVardef@6684a4org.highwire.dtl.DTLVardef@8e3679org.highwire.dtl.DTLVardef@9a54ae_HPS_FORMAT_FIGEXP M_FIG C_FIG Non-standard Abbreviations and AcronymsHPSD: High-Power Short Duration; LPLD: Low-Power Long Duration; QOL: Quality of Life; WACA: wide area circumferential ablation; PVI: Pulmonary Vein Isolation; AF: Atrial Fibrillation Clinical PerspectiveO_ST_ABSWhat is knownC_ST_ABS-The optimal power and duration of ablation lesions to produce durable pulmonary vein isolation remain unclear. -Nonrandomized studies have suggested clinical efficacy with high-power short duration radiofrequency ablation vs low-power long duration. What this study adds-In this large substudy of the AWARE Trial, a high-power short duration radiofrequency ablation strategy was found to be similarly effective as a low-power long duration strategy with no difference in time to first recurrence of any AF lasting [&ge;] 30 seconds. -Procedural were substantially reduced with high-power short duration ablation with no significant difference in overall complication rates.

Background and AimsSubstantial sex-based differences have been reported in atrial fibrillation (AF), with female patients experiencing worse symptoms, increased complications from drug side effects or ablation, and elevated risk of AF-related stroke and mortality. Recent studies revealed sex-specific alterations in AF-associated Ca2+ dysregulation, whereby female cardiomyocytes more frequently exhibit potentially proarrhythmic Ca2+-driven instabilities compared to male cardiomyocytes. In this study, we aim to gain a mechanistic understanding of the Ca2+-handling disturbances and Ca2+-driven arrhythmogenic events in males vs females and establish their responses to Ca2+-targeted interventions. Methods and ResultsWe incorporated known sex differences and AF-associated changes in the expression and phosphorylation of key Ca2+-handling proteins and in ultrastructural properties and dimensions of atrial cardiomyocytes into our recently developed 3D atrial cardiomyocyte model that couples electrophysiology with spatially detailed Ca2+-handling processes. Our simulations of quiescent cardiomyocytes show increased incidence of Ca2+ sparks in female vs male myocytes in AF, in agreement with previous experimental reports. Additionally, our female model exhibited elevated propensity to develop pacing-induced spontaneous Ca2+ releases (SCRs) and augmented beat-to-beat variability in action potential (AP)-elicited Ca2+ transients compared with the male model. Parameter sensitivity analysis uncovered precise arrhythmogenic contributions of each component that was implicated in sex and/or AF alterations. Specifically, increased ryanodine receptor phosphorylation in female AF cardiomyocytes emerged as the major SCR contributor, while reduced L-type Ca2+ current was protective against SCRs for male AF cardiomyocytes. Furthermore, simulations of tentative Ca2+-targeted interventions identified potential strategies to attenuate Ca2+-driven arrhythmogenic events in female atria (e.g., t-tubule restoration, and inhibition of ryanodine receptor and sarcoplasmic/endoplasmic reticulum Ca{superscript 2}-ATPase), and revealed enhanced efficacy when applied in combination. ConclusionsOur sex-specific computational models of human atrial cardiomyocytes uncover increased propensity to Ca2+-driven arrhythmogenic events in female compared to male atrial cardiomyocytes in AF, and point to combined Ca2+-targeted interventions as promising approaches to treat AF in female patients. Our study establishes that AF treatment may benefit from sex-dependent strategies informed by sex-specific mechanisms. Translational perspectiveAccumulating evidence demonstrates substantial sex-related differences in atrial fibrillation (AF), which is the most common arrhythmia, with female patients faring worse with the condition. By integrating known sex-differential components into our computational atrial cardiomyocyte model we found that female atrial cardiomyocytes in AF exhibit greater propensity to develop Ca2+-driven arrhythmia than male cardiomyocytes. Model analyses provided novel mechanistic insights and suggested strategies such as t-tubule restoration, correction of Ca2+-handling disturbances, and the combination of both, as promising approaches to treat AF in female patients. Our study uncovers and validate sex-specific AF mechanisms and inform the development of targeted anti-AF strategies. O_FIG O_LINKSMALLFIG WIDTH=184 HEIGHT=200 SRC="FIGDIR/small/583217v2_figa1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@d3ec3borg.highwire.dtl.DTLVardef@13a2c7borg.highwire.dtl.DTLVardef@3e4605org.highwire.dtl.DTLVardef@6726b4_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstract:C_FLOATNO Sex-specific 3D spatiotemporal models of human atrial cardiomyocyte Ca2+ signaling reveal a greater propensity to develop Ca2+-driven arrhythmic events in female vs male atrial cardiomyocytes in AF. Model analysis links sex-specific AF remodeling to arrhythmogenic mechanisms. AF, atrial fibrillation; SCR, spontaneous Ca2+ release; CaT, cytosolic Ca2+ transient; RyR2-P, phosphorylated ryanodine receptor type 2 (RyR2); CSQ, calsequestrin; LTCC, L-type Ca2+ channel; PLB, phospholamban; SERCA, sarcoendoplasmic reticulum Ca2+ ATPase; SR, sarcoplasmic reticulum. C_FIG