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.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.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).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.
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.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.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.We propose a new location-centric method for calculating PS, which is robust and more efficient compared with the conventionally used method.
Background: Although pulmonary vein isolation (PVI) is the basis of atrial fibrillation (AF) catheter ablation (AFCA), the conditional changes of an anti-AF effect and the wave-dynamic mechanism are poorly understood. Therefore, we compared the effects of PVI based on the ablation circumference, width, and number or locations of gaps with or without amiodarone at the same condition in realistic computational modeling of human AF. Hypothesis: An anatomical level of PVI and characteristics of the PVI gap would affect the anti-AF effects of the AFCA. Methods: We included 50 patients (76.0% persistent AF) who underwent AFCA. Realistic AF modeling reflecting the computed tomography (CT) and the electroanatomical map was performed on each patient. We compared the AF defragmentation rate (DeFR; change to atrial tachycardia (AT) or termination), termination rate (TnR), and changes in the dominant frequency (DF) and the number of phase singularities (PSs) based on the PVI level (antral vs. ostial), PVI width (single vs. 3х width), number and location of 2-mm PVI gaps with or without amiodarone (10mM). We randomly assigned the number and location of the PVI gaps to the AF models. Results: The antral PVI had a significantly higher DeFR (p for trend <0.001) and TnR (p for trend <0.001) than the ostial PVI, PVI gaps, or baseline AF. However, there was no difference depending on PVI width. Among the PVI gaps, the DeFR (p for trend<0.001) decreased as the gap number increased. Additional amiodarone increased DeFR (p=0.003) and TnR (p=0.034) and reduced DF (p<0.001) and the number of PSs (p<0.001) with PVI-gap, especially with a single PVI-gap. Conclusions: In this realistic computational modeling study with integrated patients’ atrial anatomy and electrophysiology, the atrial mass reduction depending on the anatomical PVI level, number of PVI gaps, and additional antiarrhythmic drug significantly affected the AF maintenance mechanisms.
Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): This research was supported by Basic Science Research Program through the National Research Foundation of Korea(NRF) funded by the Ministry of Education(2022R1I1A1A01071083). This work was also supported by the Korea Medical Device Development Fund grant funded by the Korea government (the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, the Ministry of Health & Welfare, the Ministry of Food and Drug Safety) (Project Number: RS-2022-00141473). Background In the planning of atrial fibrillation (AF)-related procedures, predicting left atrial (LA) anatomy and pulmonary vein (PV) diameter is important for the effectiveness and safety of the procedures but requires a labor-intensive measurement process. Here, we propose an artificial intelligence (AI) based PV diameter measurement algorithm for the computed tomogram (CT)-based automated PV evaluation. Methods We implemented a mesh-based convolutional neural network for the surface segmentation of four PVs and the LA appendage (LAA) in a 3D LA surface mesh. Our algorithm includes two originative methods of surface depth feature and cohesion loss function to improve the performance. We trained the model with the LA mesh of 210 AF patients’ CT scan and validated the accuracy of surface segmentation and PV diameter with independent 158 samples. Results Using an AI-based automated LA measurement model, we achieved an average Intersection over Union (IoU) of 83.4% and a regional IoU from 78.4 to 87.2 % in 158 LA meshes. When we added the surface depth feature, the IoU was improved by 31.7% compared to the conventional 3D feature. The cohesion loss function reduced the fragmentation rate of the surface label by 3.2%. Post-processed PV diameters did not differ from manually measured left (P=0.56) and right upper PV diameters (P=0.08) but differed in both lower PVs (p<0.001). The eccentricity variance of the PV ostia did not differ between AI-measured and manually measured PVs (P=0.68~0.84). Conclusion We proposed an AI-guided automated algorithm for surface segmentation and PV diameter measurement and validated it at both upper PVs and the eccentricity of the PV ostia. Our algorithm can be applied to the automated sizing of LA appendage and improve labor-intensive manual segmentation.
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.
Abstract Background Although the dominant frequency (DF) may localize the reentrant drivers of atrial fibrillation (AF), its meandering nature makes it difficult to localize as an extra-pulmonary vein (extra-PV) target. Purpose We explored and quantified the spatiotemporal stability of DF by sophisticated digital-twin maps and the association with the rhythm outcome of clinical AF catheter ablation (AFCA). Methods We retrospectively examined the DF sites in the digital twin integrated by high-density electroanatomical maps (EAM) of 170 patients previously included in the CUVIA-AF2 trial (male 70.6%, 59.2±11.3 years old, 100% persistent AF). We monitored 34 seconds of virtual AF and analyzed DF sites in 10 different left atrial (LA) regions at 3 consecutive periods (6 seconds each after 16sec induction and blanking periods). The spatiotemporal stability index (STSI) was calculated to quantify mean DF's spatial and temporal variability. During protocol-based rhythm follow-up, we assessed the atrial arrhythmia recurrence rate by dividing patients into two groups based on STSI 0.75. Results During the simulation, 108 out of 170 (63.5%) patients obtained mean DF values in all three consecutive periods. There were 26 (24.1%) patients in the stable DF group (STSI ≥0.75, Stable group) and 82 (75.9%) patients in the unstable DF group (STSI <0.75, Unstable group). Although the proportion of patients with hypertension (73.1 vs. 47.6%, p=0.041) was higher and left ventricular end-diastole diameter (51.3±3.9 vs. 49.0±4.4 mm, p=0.020) was larger in the stable DF group than in the unstable DF group, other parameters, including LA size, LA voltage, or AF ablation targets, did not differ between two groups. During the median 19 [15-22] months follow-up, the atrial arrhythmia recurrence rate of the Stable group is higher than that of the Unstable group (log-rank p=0.031, HR = 2.06, CI [1.06-4.01]) Conclusions We found that the temporally stable DF in EAM-integrated virtual AF, the potential extra-PV AF drivers, is a surrogate marker of the adverse rhythm outcome of AFCA. A prospective clinical trial targeting the spatiotemporally stable DF will be warranted.
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.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.
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.
Introduction: We previously reported that a computational modeling-guided antiarrhythmic drug (AAD) test was feasible for assessing diverse AADs in patients with atrial fibrillation (AF). In this study, we took the virtual AAD test (V-AAD) in patients who took AADs after AF catheter ablation (AFCA). Hypothesis: Patients using an effective drug in the VAAD test will have fewer AF recurrences than patients using an ineffective drug. Methods: This single-center retrospective study included 246 patients (72.8% male, 60.7±10.2 years of age, 38.6% paroxysmal AF) prescribed AADs within 3 months after AFCA. Using realistic computational modeling, we evaluated the effects of five AADs (amiodarone, sotalol, dronedarone, flecainide, and propafenone; 2 doses for each drug). Clinical AADs (C-AAD) were chosen at the discretion of the physicians blinded to the V-AAD test. We defined the effective V-AAD as the V-AAD that terminated AF or converted AF to atrial tachycardia (AT) and the best V-AAD as the V-AAD that ended virtual AF the fastest. We compared AF recurrence rates after the AAD prescription depending on the results of the V-AAD test. Results: The ineffective and best V-AAD were administered in 64 (26.0 %) and 70 patients (28.5%). The recurrence rate within a year after using the ineffective, effective, and best V-AAD were 46.9%, 35.7%, and 25.7%, respectively (log-rank p=0.013). The recurrence rate within a year in patients with at least one V-AAD terminating AF and those without was 33.9% and 50.0%, respectively (log-rank p=0.034). The use of best V-AAD (OR 0.43, 95% CI [0.18-0.96]; p=0.042, vs. ineffective V-AAD) is an independent predictor of AF recurrence within a year of using AAD after AFCA. Conclusions: The digital twins-guided V-AAD test was feasible for evaluating the efficacy of multiple AADs in patients with AF who had a high chance of recurrence after AFCA. We need a prospective randomization study to assess the prediction power of the V-AAD test.
Background: Catheter ablation of persistent atrial fibrillation (AF) is still challenging and is characterized by a significant AF recurrence rate; however, no optimal extra-pulmonary vein lesion set is known. We previously reported the clinical feasibility of in silico simulation-guided AF catheter ablation. Methods: We randomly assigned 118 patients with persistent AF (77.8% men, age 60.8 ± 9.9 years) to the simulation-guided ablation group (53 patients) and the empirical ablation group (55 patients) based on the operators' experience. For in silico 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 simulation-guided ablation group. The primary outcome was freedom from atrial tachyarrhythmias lasting longer than 30 seconds after a single procedure. The duration of the follow-up was 31.5 ± 9.4 months.Findings: Virtual in silico ablation procedures were successful in 95.2% of the patients (108/118). The clinical recurrence rate was significantly lower after a simulation-guided ablation than after an empirical ablation (20.8% vs. 40.0%, log-rank p = 0.042). Simulation-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 superiority of the rhythm outcome of the simulation-guided ablation was more significant 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).Interpretation: Among patients with persistent AF, the simulation-guided ablation was superior to the empirical catheter ablation regarding the rhythm outcome. Trial Registration Number: This study was registered with the ClinicalTrials.gov number NCT02171364Funding Statement: This work was supported by a grant [HI18C0070] from the Korea Health 21 R&D Project, Ministry of Health and Welfare and a grant [NRF-2017R1A2B4003983] from the Basic Science Research Program run by the National Research Foundation of Korea (NRF), which is funded by the Ministry of Science, ICT & Future Planning (MSIP). Declaration of Interests: The authors declare that they have no conflicts of interest.Ethics Approval Statement: The study protocol adhered to the Declaration of Helsinki and was approved by the institutional review board of each participating center. Written informed consent was obtained from all patients.
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