Effectiveness of atrial fibrillation rotor ablation is dependent on conduction velocity: An in-silico 3-dimensional modeling study.

BACKGROUND: We previously reported that stable rotors are observed in in-silico human atrial fibrillation (AF) models, and are well represented by a dominant frequency (DF). In the current study, we hypothesized that the outcome of DF ablation is affected by conduction velocity (CV) conditions and examined this hypothesis using in-silico 3D-AF modeling. METHODS: We integrated 3D CT images of left atrium obtained from 10 patients with persistent AF (80% male, 61.8±13.5 years old) into in-silico AF model. We compared AF maintenance durations (max 300s), spatiotemporal stabilities of DF, phase singularity (PS) number, life-span of PS, and AF termination or defragmentation rates after virtual DF ablation with 5 different CV conditions (0.2, 0.3, 0.4, 0.5, and 0.6m/s). RESULTS: 1. AF maintenance duration (p<0.001), spatiotemporal mean variance of DF (p<0.001), and the number of PS (p = 0.023) showed CV dependent bimodal patterns (highest at CV0.4m/s and lowest at CV0.6m/s) consistently. 2. After 10% highest DF ablation, AF defragmentation rates were the lowest at CV0.4m/s (37.8%), but highest at CV0.5 and 0.6m/s (all 100%, p<0.001). 3. In the episodes with AF termination or defragmentation followed by 10% highest DF ablation, baseline AF maintenance duration was shorter (p<0.001), spatiotemporal mean variance of DF was lower (p = 0.014), and the number of PS was lower (p = 0.004) than those with failed AF defragmentation after DF ablation. CONCLUSION: Virtual ablation of DF, which may indicate AF driver, was more likely to terminate or defragment AF with spatiotemporally stable DF, but not likely to do so in long-lasting and sustained AF conditions, depending on CV.ope

A New Efficient Method for Detecting Phase Singularity in Cardiac Fibrillation

BACKGROUND: The point of phase singularity (PS) is considered to represent a spiral wave core or a rotor in cardiac fibrillation. Computational efficiency is important for detection of PS in clinical electrophysiology. We developed a novel algorithm for highly efficient and robust detection of PS. METHODS: In contrast to the conventional method, which calculates PS based on the line integral of the phase around a PS point equal to ±2π (the Iyer-Gray method), the proposed algorithm (the location-centric method) looks for the phase discontinuity point at which PS actually occurs. We tested the efficiency and robustness of these two methods in a two-dimensional mathematical model of atrial fibrillation (AF), with and without remodeling of ionic currents. RESULTS: 1. There was a significant association, in terms of the Hausdorff distance (3.30 ± 0.0 mm), between the PS points measured using the Iyer-Gray and location-centric methods, with almost identical PS trajectories generated by the two methods. 2. For the condition of electrical remodeling of AF (0.3 × ICaL), the PS points calculated by the two methods were satisfactorily co-localized (with the Hausdorff distance of 1.64 ± 0.09 mm). 3. The proposed location-centric method was substantially more efficient than the Iyer-Gray method, with a 28.6-fold and 28.2-fold shorter run times for the control and remodeling scenarios, respectively. CONCLUSION: We propose a new location-centric method for calculating PS, which is robust and more efficient compared with the conventionally used method.ope

The Spatiotemporal Stability of Dominant Frequency Sites in In-Silico Modeling of 3-Dimensional Left Atrial Mapping of Atrial Fibrillation

BACKGROUND: We previously reported that stable rotors were observed in in-silico human atrial fibrillation (AF) models, and were well represented by dominant frequency (DF). We explored the spatiotemporal stability of DF sites in 3D-AF models imported from patient CT images of the left atrium (LA). METHODS: We integrated 3-D CT images of the LA obtained from ten patients with persistent AF (male 80%, 61.8 ± 13.5 years old) into an in-silico AF model. After induction, we obtained 6 seconds of AF simulation data for DF analyses in 30 second intervals (T1-T9). The LA was divided into ten sections. Spatiotemporal changes and variations in the temporal consistency of DF were evaluated at each section of the LA. The high DF area was defined as the area with the highest 10% DF. RESULTS: 1. There was no spatial consistency in the high DF distribution at each LA section during T1-T9 except in one patient (p = 0.027). 2. Coefficients of variation for the high DF area were highly different among the ten LA sections (p < 0.001), and they were significantly higher in the four pulmonary vein (PV) areas, the LA appendage, and the peri-mitral area than in the other LA sections (p < 0.001). 3. When we conducted virtual ablation of 10%, 15%, and 20% of the highest DF areas (n = 270 cases), AF was changed to atrial tachycardia (AT) or terminated at a rate of 40%, 57%, and 76%, respectively. CONCLUSIONS: Spatiotemporal consistency of the DF area was observed in 10% of AF patients, and high DF areas were temporally variable. Virtual ablation of DF is moderately effective in AF termination and AF changing into AT.ope

Virtual In-Silico Modeling Guided Catheter Ablation Predicts Effective Linear Ablation Lesion Set for Longstanding Persistent Atrial Fibrillation: Multicenter Prospective Randomized Study

Objective: Radiofrequency catheter ablation for persistent atrial fibrillation (PeAF) still has a substantial recurrence rate. This study aims to investigate whether an AF ablation lesion set chosen using in-silico ablation (V-ABL) is clinically feasible and more effective than an empirically chosen ablation lesion set (Em-ABL) in patients with PeAF. Methods: We prospectively included 108 patients with antiarrhythmic drug-resistant PeAF (77.8% men, age 60.8 ± 9.9 years), and randomly assigned them to the V-ABL (n = 53) and Em-ABL (n = 55) groups. Five different in-silico ablation lesion sets [1 pulmonary vein isolation (PVI), 3 linear ablations, and 1 electrogram-guided ablation] were compared using heart-CT integrated AF modeling. We evaluated the feasibility, safety, and efficacy of V-ABL compared with that of Em-ABL. Results: The pre-procedural computing time for five different ablation strategies was 166 ± 11 min. In the Em-ABL group, the earliest terminating blinded in-silico lesion set matched with the Em-ABL lesion set in 21.8%. V-ABL was not inferior to Em-ABL in terms of procedure time (p = 0.403), ablation time (p = 0.510), and major complication rate (p = 0.900). During 12.6 ± 3.8 months of follow-up, the clinical recurrence rate was 14.0% in the V-ABL group and 18.9% in the Em-ABL group (p = 0.538). In Em-ABL group, clinical recurrence rate was significantly lower after PVI+posterior box+anterior linear ablation, which showed the most frequent termination during in-silico ablation (log-rank p = 0.027). Conclusions: V-ABL was feasible in clinical practice, not inferior to Em-ABL, and predicts the most effective ablation lesion set in patients who underwent PeAF ablation.ope

Multiple factors influence the morphology of the bipolar electrogram: An in silico modeling study

Although bipolar electrograms (Bi-egms) are commonly used for catheter mapping and ablation of cardiac arrhythmias, the accuracy and reproducibility of Bi-egms have not been evaluated. We aimed to clarify the influence of the catheter orientation (CO), catheter contact angle (CA), local conduction velocity (CV), scar size, and catheter type on the Bi-egm morphology using an in silico 3-dimensional realistic model of atrial fibrillation. We constructed a 3-dimensional, realistic, in silico left atrial model with activation wave propagation including bipolar catheter models. Bi-egms were obtained by computing the extracellular potentials from the distal and proximal electrodes. The amplitude and width were measured on virtual Bi-egms obtained under different conditions created by changing the CO according to the wave direction, catheter-atrial wall CA, local CV, size of the non-conductive area, and catheter type. Bipolar voltages were also compared between virtual and clinically acquired Bi-egms. Bi-egm amplitudes were lower for a perpendicular than parallel CO relative to the wave direction (p<0.001), lower for a 90° than 0° CA (p<0.001), and lower for a CV of 0.13m/s than 0.48m/s (p<0.001). Larger sized non-conductive areas were associated with a decreased bipolar amplitude (p<0.001) and increased bipolar width (p<0.001). Among three commercially available catheters (Orion, Pentaray, and Thermocool), those with more narrowly spaced and smaller electrodes produced higher voltages on the virtual Bi-egms (p<0.001). Multiple factors including the CO, CA, CV, and catheter design significantly influence the Bi-egm morphology. Universal voltage cut-off values may not be appropriate for bipolar voltage-guided substrate mapping.ope

Clinical Usefulness of Computational Modeling-Guided Persistent Atrial Fibrillation Ablation: Updated Outcome of Multicenter Randomized Study

Objective: Catheter ablation of persistent atrial fibrillation (AF) is still challenging, no optimal extra-pulmonary vein lesion set is known. We previously reported the clinical feasibility of computational modeling-guided AF catheter ablation. Methods: We randomly assigned 118 patients with persistent AF (77.8% men, age 60.8 ± 9.9 years) to the computational modeling-guided ablation group (53 patients) and the empirical ablation group (55 patients) based on the operators' experience. For virtual ablation, four virtual linear and one electrogram-guided lesion sets were tested on patient heart computed tomogram-based models, and the lesion set with the fastest termination time was reported to the operator in the modeling-guided ablation group. The primary outcome was freedom from atrial tachyarrhythmias lasting longer than 30 s after a single procedure. Results: During 31.5 ± 9.4 months, virtual ablation procedures were available in 95.2% of the patients (108/118). Clinical recurrence rate was significantly lower after a modeling-guided ablation than after an empirical ablation (20.8 vs. 40.0%, log-rank p = 0.042). Modeling-guided ablation was independently associated with a better long-term rhythm outcome of persistent AF ablation (HR = 0.29 [0.12-0.69], p = 0.005). The rhythm outcome of the modeling-guided ablation showed better trends in males, non-obese patients with a less remodeled atrium (left atrial dimension < 50 mm), ejection fraction ≥ 50%, and those without hypertension or diabetes (p < 0.01). There were no significant differences between the groups for the total procedure time (p = 0.403), ablation time (p = 0.510), and major complication rate (p = 0.900). Conclusion: Among patients with persistent AF, the computational modeling-guided ablation was superior to the empirical catheter ablation regarding the rhythm outcome. Clinical trial registration: This study was registered with the ClinicalTrials.gov, number NCT02171364.ope

Ganglionated plexi stimulation induces pulmonary vein triggers and promotes atrial arrhythmogenecity: In silico modeling study

BACKGROUND: The role of the autonomic nervous system (ANS) on atrial fibrillation (AF) is difficult to demonstrate in the intact human left atrium (LA) due to technical limitations of the current electrophysiological mapping technique. We examined the effects of the ANS on the initiation and maintenance of AF by employing a realistic in silico human left atrium (LA) model integrated with a model of ganglionated plexi (GPs). METHODS: We incorporated the morphology of the GP and parasympathetic nerves in a three-dimensional (3D) realistic LA model. For the model of ionic currents, we used a human atrial model. GPs were stimulated by increasing the IK[ACh], and sympathetic nerve stimulation was conducted through a homogeneous increase in the ICa-L. ANS-induced wave-dynamics changes were evaluated in a model that integrated a patient's LA geometry, and we repeated simulation studies using LA geometries from 10 different patients. RESULTS: The two-dimensional model of pulmonary vein (PV) cells exhibited late phase 3 early afterdepolarization-like activity under 0.05μM acetylcholine (ACh) stimulation. In the 3D simulation model, PV tachycardia was induced, which degenerated to AF via GP (0.05μM ACh) and sympathetic (7.0×ICa-L) stimulations. Under sustained AF, local reentries were observed at the LA-PV junction. We also observed that GP stimulation reduced the complex fractionated atrial electrogram (CFAE)-cycle length (CL, p<0.01) and the life span of phase singularities (p<0.01). GP stimulation also increased the overlap area of the GP and CFAE areas (CFAE-CL≤120ms, p<0.01). When 3 patterns of virtual ablations were applied to the 3D AF models, circumferential PV isolation including the GP was the most effective in terminating AF. CONCLUSION: Cardiac ANS stimulations demonstrated triggered activity, automaticity, and local reentries at the LA-PV junction, as well as co-localized GP and CFAE areas in the 3D in silico GP model of the LA.ope

Role of atrial wall thickness in wave-dynamics of atrial fibrillation

BACKGROUND/AIMS: Atrial anatomy and thickness may affect the electrical wave-dynamics of atrial fibrillation (AF). We explored the relationship between left atrial (LA) wall thickness (LAWT) or LA geometry and AF wave-dynamics. METHODS: We included 15 patients with persistent AF (age, 62.3 ± 11.9 years) who underwent AF catheter ablation. We measured the LAWT, LA endocardial curvature, and SD-curvature (surface bumpiness) from preprocedural computed tomography images. We compared those anatomical characteristics with electrophysiologic parameters such as dominant frequency (DF), Shannon entropy (ShEn), or complex fractionated atrial electrogram (CFAE)-cycle length (CL), calculated from intracardiac bipolar electrograms (300-500 points, 5 s), acquired during ablation procedures. RESULTS: 1. LAWT (excluding fat) varied widely among patients, locations, and types of AF. LAWT was inversely correlated with LA volume (r = -0.565, p = 0.028) and positively correlated with SD-curvature (r = 0.272, p < 0.001). 2. LAWT was positively correlated with ShEn (r = 0.233, p < 0.001) and negatively correlated with CFAE-CL (r = -0.107, p = 0.038). 3. In the multivariate linear regression analyses for AF wave-dynamics parameters, DF (β = -0.29 [95% CI -0.44--0.14], p < 0.001), ShEn (β = 0.19 [95% CI 0.12-0.25], p < 0.001), and CFAE-CL (β = 7.49 [95% CI 0.65-14.34], p = 0.032) were independently associated with LAWT. CONCLUSION: Regional LAWT is associated with LA structural features, and has significant correlations with the wave-dynamics parameters associated with electrical wavebreaks or rotors in patients with persistent AF.ope

Anti-atrial Fibrillation Effects of Pulmonary Vein Isolation With or Without Ablation Gaps: A Computational Modeling Study

Background: Although pulmonary vein isolation (PVI) gaps contribute to recurrence after atrial fibrillation (AF) catheter ablation, the mechanism is unclear. We used realistic computational human AF modeling to explore the AF wave-dynamic changes of PVI with gaps (PVI-gaps). Methods: We included 40 patients (80% male, 61.0 ± 9.8 years old, 92.5% persistent AF) who underwent AF catheter ablation to develop our realistic computational AF model. We compared the effects of a complete PVI (CPVI) and PVI-gap (2-mm × 4) on the AF wave-dynamics by evaluating the dominant frequency (DF), spatial change of DF, maximal slope of the action potential duration restitution curve (Smax), and AF defragmentation rate (termination or change to atrial tachycardia), and tested the effects of additional virtual interventions and flecainide on ongoing AF with PVI-gaps. Results: Compared with the baseline AF, CPVIs significantly reduced extra-PV DFs (p < 0.001), but PVI-gaps did not. COV-DFs were greater after CPVIs than PVI-gaps (p < 0.001). Neither CPVIs nor PVI-gaps changed the mean Smax. CPVIs resulted in higher AF defragmentation rates (80%) than PVI-gaps (12.5%, p < 0.001). In ongoing AF after PVI-gaps, the AF defragmentation rates after a wave-breaking gap ablation, extra-PV DF ablation, or flecainide were 60.0, 34.3, and 25.7%, respectively (p = 0.010). Conclusion: CPVIs effectively reduced the DF, increased its spatial heterogeneity in extra-PV areas, and offered better anti-AF effects than extra-PV DF ablation or additional flecainide in PVI-gap conditions.ope

Clinical Outcomes of Computational Virtual Mapping-Guided Catheter Ablation in Patients With Persistent Atrial Fibrillation: A Multicenter Prospective Randomized Clinical Trial

Background: Clinical recurrence after atrial fibrillation catheter ablation (AFCA) still remains high in patients with persistent AF (PeAF). We investigated whether an extra-pulmonary vein (PV) ablation targeting the dominant frequency (DF) extracted from electroanatomical map-integrated AF computational modeling improves the AFCA rhythm outcome in patients with PeAF. Methods: In this open-label, randomized, multi-center, controlled trial, 170 patients with PeAF were randomized at a 1:1 ratio to the computational modeling-guided virtual DF (V-DF) ablation and empirical PV isolation (E-PVI) groups. We generated a virtual dominant frequency (DF) map based on the atrial substrate map obtained during the clinical AF ablation procedure using computational modeling. This simulation was possible within the time of the PVI procedure. V-DF group underwent extra-PV V-DF ablation in addition to PVI, but DF information was not notified to the operators from the core lab in the E-PVI group. Results: After a mean follow-up period of 16.3 ± 5.3 months, the clinical recurrence rate was significantly lower in the V-DF than with E-PVI group (P = 0.018, log-rank). Recurrences appearing as atrial tachycardias (P = 0.145) and the cardioversion rates (P = 0.362) did not significantly differ between the groups. At the final follow-up, sinus rhythm was maintained without any AADs in 74.7% in the V-DF group and 48.2% in the E-PVI group (P < 0.001). No significant difference was found in the major complication rates (P = 0.489) or total procedure time (P = 0.513) between the groups. The V-DF ablation was independently associated with a reduced AF recurrence after AFCA [hazard ratio: 0.51 (95% confidence interval: 0.30-0.88); P = 0.016]. Conclusions: The computational modeling-guided V-DF ablation improved the rhythm outcome of AFCA in patients with PeAF. Clinical Trial Registration: Clinical Research Information Service, CRIS identifier: KCT0003613.ope