Clinical usefulness of digital twin guided virtual amiodarone test in patients with atrial fibrillation ablation.

It would be clinically valuable if the efficacy of antiarrhythmic drugs could be simulated in advance. We developed a digital twin to predict amiodarone efficacy in high-risk atrial fibrillation (AF) patients post-ablation. Virtual left atrium models were created from computed tomography and electroanatomical maps to simulate AF and evaluate its response to varying amiodarone concentrations. As the amiodarone concentration increased in the virtual setting, action potential duration lengthened, peak upstroke velocities decreased, and virtual AF termination became more frequent. Patients were classified into effective (those with virtually terminated AF at therapeutic doses) and ineffective groups. The one-year clinical outcomes after AF ablation showed significantly better results in the effective group compared to the ineffective group, with AF recurrence rates of 20.8% vs. 45.1% (log-rank p = 0.031, adjusted hazard ratio, 0.37 [0.14-0.98]; p = 0.046). This study highlights the potential of a digital twin-guided approach in predicting amiodarone's effectiveness and improving personalized AF management. Clinical Trial Registration Name: The Evaluation for Prognostic Factors After Catheter Ablation of Atrial Fibrillation: Cohort Study, Registration number: NCT02138695. The date of registration: 2014-05. URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02138695.

Anti- and pro-fibrillatory effects of pulmonary vein isolation gaps in human atrial fibrillation digital twins.

Although pulmonary vein isolation (PVI) gaps and extrapulmonary vein triggers contribute to recurrence after atrial fibrillation (AF) ablation, their precise mechanisms remain unproven. Our study assessed the impact of PVI gaps on rhythm outcomes using a human AF digital twin. We included 50 patients (76.0% with persistent AF) who underwent catheter ablation with a realistic AF digital twin by integrating computed tomography and electroanatomical mapping. We evaluated the final rhythm status, including AF and atrial tachycardia (AT), across 600 AF episodes, considering factors including PVI level, PVI gap number, and pacing locations. Our findings revealed that antral PVI had a significantly lower ratio of AF at the final rhythm (28% vs. 56%, p = 0.002) than ostial PVI. Increasing PVI gap numbers correlated with an increased ratio of AF at the final rhythm (p < 0.001). Extra-PV induction yielded a higher ratio of AF at the final rhythm than internal PV induction (77.5% vs. 59.0%, p < 0.001). In conclusion, our human AF digital twin model helped assess AF maintenance mechanisms. Clinical trial registration: https://www.clinicaltrials.gov ; Unique identifier: NCT02138695.

Corrigendum: Computational modeling for antiarrhythmic drugs for atrial fibrillation according to genotype.

[This corrects the article DOI: 10.3389/fphys.2021.650449.].

Clinical Usefulness of Virtual Ablation Guided Catheter Ablation of Atrial Fibrillation Targeting Restitution Parameter-Guided Catheter Ablation: CUVIA-REGAB Prospective Randomized Study.

BACKGROUND AND OBJECTIVES: We investigated whether extra-pulmonary vein (PV) ablation targeting a high maximal slope of the action potential duration restitution curve (Smax) improves the rhythm outcome of persistent atrial fibrillation (PeAF) ablation. METHODS: In this open-label, multi-center, randomized, and controlled trial, 178 PeAF patients were randomized with 1:1 ratio to computational modeling-guided virtual Smax ablation (V-Smax) or empirical ablation (E-ABL) groups. Smax maps were generated by computational modeling based on atrial substrate maps acquired during clinical procedures in sinus rhythm. Smax maps were generated during the clinical PV isolation (PVI). The V-Smax group underwent an additional extra-PV ablation after PVI targeting the virtual high Smax sites. RESULTS: After a mean follow-up period of 12.3±5.2 months, the clinical recurrence rates (25.6% vs. 23.9% in the V-Smax and the E-ABL group, p=0.880) or recurrence appearing as atrial tachycardia (11.1% vs. 5.7%, p=0.169) did not differ between the 2 groups. The post-ablation cardioversion rate was higher in the V-Smax group than E-ABL group (14.4% vs. 5.7%, p=0.027). Among antiarrhythmic drug-free patients (n=129), the AF freedom rate was 78.7% in the V-Smax group and 80.9% in the E-ABL group (p=0.776). The total procedure time was longer in the V-Smax group (p=0.008), but no significant difference was found in the major complication rates (p=0.497) between the groups. CONCLUSIONS: Unlike a dominant frequency ablation, the computational modeling-guided V-Smax ablation did not improve the rhythm outcome of the PeAF ablation and had a longer procedure time. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02558699.

Ablation and antiarrhythmic drug effects on PITX2 +/- deficient atrial fibrillation: A computational modeling study.

Introduction: Atrial fibrillation (AF) is a heritable disease, and the paired-like homeodomain transcription factor 2 (PITX2) gene is highly associated with AF. We explored the differences in the circumferential pulmonary vein isolation (CPVI), which is the cornerstone procedure for AF catheter ablation, additional high dominant frequency (DF) site ablation, and antiarrhythmic drug (AAD) effects according to the patient genotype (wild-type and PITX2 +/- deficient) using computational modeling. Methods: We included 25 patients with AF (68% men, 59.8 ± 9.8 years of age, 32% paroxysmal AF) who underwent AF catheter ablation to develop a realistic computational AF model. The ion currents for baseline AF and the amiodarone, dronedarone, and flecainide AADs according to the patient genotype (wild type and PITX2 +/- deficient) were defined by relevant publications. We tested the virtual CPVI (V-CPVI) with and without DF ablation (±DFA) and three virtual AADs (V-AADs, amiodarone, dronedarone, and flecainide) and evaluated the AF defragmentation rates (AF termination or changes to regular atrial tachycardia (AT), DF, and maximal slope of the action potential duration restitution curves (Smax), which indicates the vulnerability of wave-breaks. Results: At the baseline AF, mean DF (p = 0.003), and Smax (p < 0.001) were significantly lower in PITX2 +/- deficient patients than wild-type patients. In the overall AF episodes, V-CPVI (±DFA) resulted in a higher AF defragmentation relative to V-AADs (65 vs. 42%, p < 0.001) without changing the DF or Smax. Although a PITX2 +/- deficiency did not affect the AF defragmentation rate after the V-CPVI (±DFA), V-AADs had a higher AF defragmentation rate (p = 0.014), lower DF (p < 0.001), and lower Smax (p = 0.001) in PITX2 +/- deficient AF than in wild-type patients. In the clinical setting, the PITX2 +/- genetic risk score did not affect the AF ablation rhythm outcome (Log-rank p = 0.273). Conclusion: Consistent with previous clinical studies, the V-CPVI had effective anti-AF effects regardless of the PITX2 genotype, whereas V-AADs exhibited more significant defragmentation or wave-dynamic change in the PITX2 +/- deficient patients.

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.

Restitution Slope Affects the Outcome of Dominant Frequency Ablation in Persistent Atrial Fibrillation: CUVIA-AF2 Post-Hoc Analysis Based on Computational Modeling Study.

Introduction: Although the dominant frequency (DF) localizes the reentrant drivers and the maximal slope of the action potential duration (APD) restitution curve (Smax) reflects the tendency of the wave-break, their interaction has never been studied. We hypothesized that DF ablation has different effects on atrial fibrillation (AF) depending on Smax. Methods: We studied the DF and Smax in 25 realistic human persistent AF model samples (68% male, 60 ± 10 years old). Virtual AF was induced by ramp pacing measuring Smax, followed by spatiotemporal DF evaluation for 34 s. We assessed the DF ablation effect depending on Smax in both computational modeling and a previous clinical trial, CUVIA-AF (170 patients with persistent AF, 70.6% male, 60 ± 11 years old). Results: Mean DF had an inverse relationship with Smax regardless of AF acquisition timing (p < 0.001). Virtual DF ablations increased the defragmentation rate compared to pulmonary vein isolation (PVI) alone (p = 0.015), especially at Smax <1 (61.5 vs. 7.7%, p = 0.011). In post-DF ablation defragmentation episodes, DF was significantly higher (p = 0.002), and Smax was lower (p = 0.003) than in episodes without defragmentation. In the post-hoc analysis of CUVIA-AF2, we replicated the inverse relationship between Smax and DF (r = -0.47, p < 0.001), and we observed better rhythm outcomes of clinical DF ablations in addition to a PVI than of empirical PVI at Smax <1 [hazard ratio 0.45, 95% CI (0.22-0.89), p = 0.022; log-rank p = 0.021] but not at ≥ 1 (log-rank p = 0.177). Conclusion: We found an inverse relationship between DF and Smax and the outcome of DF ablation after PVI was superior at the condition with Smax <1 in both in-silico and clinical trials.

Corrigendum: Spatial changes in the atrial fibrillation wave-dynamics after using antiarrhythmic drugs: A computational modeling study.

[This corrects the article DOI: 10.3389/fphys.2021.733543.].

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.

Spatial Changes in the Atrial Fibrillation Wave-Dynamics After Using Antiarrhythmic Drugs: A Computational Modeling Study.

Background: We previously reported that a computational modeling-guided antiarrhythmic drug (AAD) test was feasible for evaluating multiple AADs in patients with atrial fibrillation (AF). We explored the anti-AF mechanisms of AADs and spatial change in the AF wave-dynamics by a realistic computational model. Methods: We used realistic computational modeling of 25 AF patients (68% male, 59.8 ± 9.8 years old, 32.0% paroxysmal AF) reflecting the anatomy, histology, and electrophysiology of the left atrium (LA) to characterize the effects of five AADs (amiodarone, sotalol, dronedarone, flecainide, and propafenone). We evaluated the spatial change in the AF wave-dynamics by measuring the mean dominant frequency (DF) and its coefficient of variation [dominant frequency-coefficient of variation (DF-COV)] in 10 segments of the LA. The mean DF and DF-COV were compared according to the pulmonary vein (PV) vs. extra-PV, maximal slope of the restitution curves (Smax), and defragmentation of AF. Results: The mean DF decreased after the administration of AADs in the dose dependent manner (p < 0.001). Under AADs, the DF was significantly lower (p < 0.001) and COV-DF higher (p = 0.003) in the PV than extra-PV region. The mean DF was significantly lower at a high Smax (≥1.4) than a lower Smax condition under AADs. During the episodes of AF defragmentation, the mean DF was lower (p < 0.001), but the COV-DF was higher (p < 0.001) than that in those without defragmentation. Conclusions: The DF reduction with AADs is predominant in the PVs and during a high Smax condition and causes AF termination or defragmentation during a lower DF and spatially unstable (higher DF-COV) condition.

Computational Modeling for Antiarrhythmic Drugs for Atrial Fibrillation According to Genotype.

Background: The efficacy of antiarrhythmic drugs (AAD) can vary in patients with atrial fibrillation (AF), and the PITX2 gene affects the responsiveness of AADs. We explored the virtual AAD (V-AAD) responses between wild-type and PITX2 +/--deficient AF conditions by realistic in silico AF modeling. Methods: We tested the V-AADs in AF modeling integrated with patients' 3D-computed tomography and 3D-electroanatomical mapping, acquired in 25 patients (68% male, 59.8 ± 9.8 years old, 32.0% paroxysmal type). The ion currents for the PITX2 +/- deficiency and each AAD (amiodarone, sotalol, dronedarone, flecainide, and propafenone) were defined based on previous publications. Results: We compared the wild-type and PITX2 +/- deficiency in terms of the action potential duration (APD90), conduction velocity (CV), maximal slope of restitution (Smax), and wave-dynamic parameters, such as the dominant frequency (DF), phase singularities (PS), and AF termination rates according to the V-AADs. The PITX2 +/--deficient model exhibited a shorter APD90 (p < 0.001), a lower Smax (p < 0.001), mean DF (p = 0.012), PS number (p < 0.001), and a longer AF cycle length (AFCL, p = 0.011). Five V-AADs changed the electrophysiology in a dose-dependent manner. AAD-induced AFCL lengthening (p < 0.001) and reductions in the CV (p = 0.033), peak DF (p < 0.001), and PS number (p < 0.001) were more significant in PITX2 +/--deficient than wild-type AF. PITX2 +/--deficient AF was easier to terminate with class IC AADs than the wild-type AF (p = 0.018). Conclusions: The computational modeling-guided AAD test was feasible for evaluating the efficacy of multiple AADs in patients with AF. AF wave-dynamic and electrophysiological characteristics are different among the PITX2-deficient and the wild-type genotype models.

Electrophysiological significance of the interatrial conduction including cavo-tricuspid isthmus during atrial fibrillation.

KEY POINTS: The interatrial conduction, including Bachmann's bundle, the posterior septal conduction, the anterior septal conduction, and the cavo-tricuspid isthmus, contributes to the maintenance mechanisms of atrial fibrillation in a 3D biatrial model. The interatrial conduction ablation including a cavo-tricuspid isthmus ablation significantly affects the wave dynamics of atrial fibrillation (AF) and facilitates the AF termination or atrial tachycardia conversion of the AF after the circumferential pulmonary vein isolation. Additional cavo-tricuspid isthmus ablation after the circumferential pulmonary vein isolation improves long-term rhythm outcome after clinical AF catheter ablation. ABSTRACT: Although it is known that atrial fibrillation (AF) is mainly a left atrial (LA) disease, the role of the right atrium (RA) and interatrial conduction (IAC), including the cavo-tricuspid isthmus (CTI), has not been clearly defined. We tested AF wave dynamics with or without IAC in computational modelling and the rhythm outcome of AF catheter ablation (AFCA) including CTI ablation in clinical cohort data. We evaluated the dominant frequency (DF) in 3D biatrial AF simulations integrated with 3D-computed tomograms obtained from 10 patients. The IAC was implemented at Bachmann's bundle, posterior septum and the CTI. After virtual circumferential PV isolation (CPVI), we disconnected IACs one by one, and observed the wave dynamics. We compared the long-term rhythm outcome after CPVI alone and additional CTI ablation in 846 patients with AFCA. LA-DF was higher than RA-DF in AF (P < 0.001). After CPVI, the DF decreased significantly by additional IAC ablation (P = 0.003), especially in the LA (P = 0.016). The amount of DF reduction (P = 0.020) and rates of AF termination (P < 0.001) or AT conversion (P = 0.021) were significantly higher after IAC ablations including CTI than those without. In clinical AFCA, the AF recurrence rate was significantly lower in patients with additional CTI ablation than CPVI alone during 25 ± 20 months' follow-up (hazard ratio 0.60 [0.46-0.79], P < 0.001, Log rank P < 0.001). IAC contributes to the maintenance mechanism of AF, and IAC including CTI ablation affects AF wave dynamics, facilitating AF termination in 3D biatrial modelling. Additional CTI ablation after CPVI improves the long-term rhythm outcome in clinical AFCA, potentially in a paroxysmal type with accompanying atrial flutter, or atrial dimension close to normal.

In situ procedure for high-efficiency computational modeling of atrial fibrillation reflecting personal anatomy, fiber orientation, fibrosis, and electrophysiology.

We previously reported the feasibility and efficacy of a simulation-guided clinical catheter ablation of atrial fibrillation (AF) in an in-silico AF model. We developed a highly efficient realistic AF model reflecting the patient endocardial voltage and local conduction and tested its clinical feasibility. We acquired > 500 endocardial bipolar electrograms during right atrial pacing at the beginning of the AF ablation procedures. Based on the clinical bipolar electrograms, we generated simulated voltage maps by applying fibrosis and local activation maps adjusted for the fiber orientation. The software's accuracy (CUVIA2.5) was retrospectively tested in 17 patients and feasibility prospectively in 10 during clinical AF ablation. Results: We found excellent correlations between the clinical and simulated voltage maps (R = 0.933, p < 0.001) and clinical and virtual local conduction (R = 0.958, p < 0.001). The proportion of virtual local fibrosis was 15.4, 22.2, and 36.9% in the paroxysmal AF, persistent AF, and post-pulmonary vein isolation (PVI) states, respectively. The reconstructed virtual bipolar electrogram exhibited a relatively good similarities of morphology to the local clinical bipolar electrogram (R = 0.60 ± 0.08, p < 0.001). Feasibility testing revealed an in situ procedural computing time from the clinical data acquisition to wave-dynamics analyses of 48.2 ± 4.9 min. All virtual analyses were successfully achieved during clinical PVI procedures. We developed a highly efficient, realistic, in situ procedural simulation model reflective of individual anatomy, fiber orientation, fibrosis, and electrophysiology that can be applied during AF ablation.

Long-Term Outcome of Additional Superior Vena Cava to Septal Linear Ablation in Catheter Ablation of Atrial Fibrillation.

Background We previously reported the benefit of linear ablation from the superior vena cava to the right atrial septum (SVC-L) within a year after circumferential pulmonary vein isolation (CPVI) in patients with paroxysmal atrial fibrillation (AF). We explored the long-term effects of SVC-L and its potential related mechanisms. Methods and Results Among 2140 consecutive patients with AF ablation, we included 614 patients (73.3% male, aged 57.8±10.7 years, 13.7% with persistent AF) who did not undergo an extra-pulmonary vein left atrial ablation after propensity score matching; of those, 307 had additional SVC-L and 307 had CPVI alone. We evaluated the heart rate variability and computational modeling study to explore mechanisms. Although the procedure time was longer in the SVC-L group than the CPVI group (P<0.001), the complication rates did not differ (P=0.560). During 40.5±24.4 months of follow-up, the rhythm outcome was significantly better in the SVC-L group than the CPVI group (log rank, P<0.001). At 2-year follow-up of heart rate variability, a significantly higher mean heart rate (P=0.018) and a lower ratio of low/high-frequency components (P=0.011) were found with SVC-L than CPVI alone. In realistic in silico biatrial modeling, which reflected the electroanatomies of 10 patients, SVC-L significantly reduced biatrial dominant frequency compared with CPVI alone (P<0.001) and increased AF termination and defragmentation rates (P=0.033). Conclusions SVC-L ablation in addition to CPVI significantly improved the long-term rhythm outcome over 2 years after AF catheter ablation by mechanisms involving autonomic modulation and AF organization.

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.

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.

Pro-Arrhythmogenic Effects of Heterogeneous Tissue Curvature　- A Suggestion for Role of Left Atrial Appendage in Atrial Fibrillation.

BACKGROUND: The arrhythmogenic role of complex atrial morphology has not yet been clearly elucidated. We hypothesized that bumpy tissue geometry can induce action potential duration (APD) dispersion and wavebreak in atrial fibrillation (AF). Methods and Results: We simulated a 2D-bumpy atrial model by varying the degree of bumpiness, and 3D-left atrial (LA) models integrated by LA computed tomographic (CT) images taken from 14 patients with persistent AF. We also analyzed wave-dynamic parameters with bipolar electrograms during AF and compared them with LA-CT geometry in 30 patients with persistent AF. In the 2D-bumpy model, APD dispersion increased (P<0.001) and wavebreak occurred spontaneously when the surface bumpiness was greater, showing phase transition-like behavior (P<0.001). The bumpiness gradient 2D-model showed that spiral wave drifted in the direction of higher bumpiness, and phase singularity (PS) points were mostly located in areas with higher bumpiness. In the 3D-LA model, PS density was higher in the LA appendage (LAA) compared with other parts of the LA (P<0.05). In 30 persistent-AF patients, the surface bumpiness of LAA was 5.8-fold that of other LA parts (P<0.001), and exceeded critical bumpiness to induce wavebreak. Wave dynamics complexity parameters were consistently dominant in the LAA (P<0.001). CONCLUSIONS: Bumpy tissue geometry promoted APD dispersion, wavebreak, and spiral wave drift in in-silico human atrial tissue, and corresponded to clinical electroanatomical maps.

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.

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.