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

Abstract

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.

Fig. 1. The scheme and process of creating an AF digital twin and conducting a virtual AMD test.

a Creation of a patient-specific digital twin for patients with AF who underwent catheter ablation. b Construction of a 3D geometry with over 400,000 nodes arranged in a triangular mesh. Virtual maps were generated to characterize electrophysiological properties, including voltage, fibrosis, fiber orientation, and local activation time. c Virtual PVI procedure, with green lines representing ablation sites, pink areas indicating early activation sites, and yellow denoting pacing locations. d Virtual AMD testing under different conditions: no AMD (control), low dose, high dose, and toxic dose. e During constant 500 ms pacing across various AMD concentrations, surface EGMs were recorded, with time and voltage plotted to calculate human APD and dV/dt. f Segmentation method employed for the extra-pulmonary vein area of the LA. g Observation of AF post-ramp pacing over 32 seconds, with the creation of Smax maps using APD and diastolic interval, and DF maps during the maintenance phase of AF or AT between 17 and 23 seconds. EGMs show AF/AT maintenance until 32 seconds and termination before 16 seconds. AF atrial fibrillation, AMD amiodarone, AT atrial tachycardia, APD action potential duration, APD₉₀ 90% of action potential duration, CL cycle length, DF dominant frequency, dV/dt: peak upstroke velocity, EGM electrogram, Smax the maximal restitution slope of action potential duration, LA left atrium, PVI pulmonary vein isolation.

Fig. 2. Flow chart of the study.

We included a total of 115 patients and performed pacing at different AMD concentration settings. We observed changes in electrophysiological parameters and induced AF to assess virtual rhythm outcomes. AF termination at least once at any therapeutic dose was classified as Effective, while ongoing AF or AT was classified as Ineffective. Based on the results of virtual outcomes, we compared the clinical rhythm outcomes one year after clinical AMD usage. AAD antiarrhythmic drug, AF atrial fibrillation, AFCA atrial fibrillation catheter ablation, AMD amiodarone, APD₉₀ 90% of action potential duration, AT atrial tachycardia, DF dominant frequency, Smax the maximal restitution slope of action potential duration.

Fig. 3. Effects of virtual AMD on electrophysiological parameters and virtual AF outcomes.

a Action potential duration (APD) curves plotted under constant 500 ms pacing at various AMD concentrations. b A significant increase in APD₉₀ is observed with both low and high doses of AMD, with a slight decrease at the toxic dose, although still higher than the baseline (No AMD). c The peak upstroke velocity decreases significantly in a dose-dependent manner as the concentration of AMD increases. d Low-dose AMD increases Smax compared to baseline, while high-dose and toxic-dose AMD significantly reduce Smax. e There is a significant reduction in DF as the dose of AMD increases, indicating decreased AF driver activity. f As the dose of AMD increases, the rate of AF termination increases, showing the drug’s effectiveness at higher concentrations. g The AF maintenance rate decreases significantly with increasing AMD concentration, reflecting the enhanced likelihood of AF termination at higher doses. AF atrial fibrillation, AMD amiodarone, AT atrial tachycardia, APD action potential duration, DF dominant frequency, dV/dt: peak upstroke velocity, Smax the maximal restitution slope of action potential duration.

Fig. 4. Kaplan–Meier analysis of AF recurrence after AMD use according to virtual AMD response and mean Smax values.

a Graph divided by virtual AMD response (b) Baseline (No AMD): Graph divided by median value of mean Smax (1.5). AF atrial fibrillation, AMD amiodarone, Smax the maximal restitution slope of action potential duration.

Fig. 5. Mean, highest, lowest, and Δ regional Smax and DF according to LA region and virtual rhythm outcomes.

All variables shown are expressed as mean and standard deviation. a Regional mean Smax and Mean Smax according to virtual rhythm outcomes. b The Highest Smax according to virtual rhythm outcomes. c The Lowest Smax according to virtual rhythm outcomes. d Δ Regional Smax according to virtual rhythm outcomes. e Mean Smax according to virtual rhythm outcomes and region. f Mean DF according to virtual rhythm outcomes. g The Highest DF according to virtual rhythm outcomes. h The Lowest DF according to virtual rhythm outcomes. i Δ Regional DF according to virtual rhythm outcomes. j Mean DF value according to virtual rhythm outcomes and region. *denotes that the p-value of difference between the two groups (AF/AT vs. Termination) is below 0.05. †denotes that the p-value of difference between the two groups (AF vs. AT) is below 0.05. AF atrial fibrillation, AT atrial tachycardia, DF dominant frequency, LA left atrial, Smax the maximal restitution slope of action potential duration.