Characterizing the arrhythmogenic substrate in personalized models of atrial fibrillation: sensitivity to mesh resolution and pacing protocol in AF models

Abstract

Aims: Computationally guided persistent atrial fibrillation (PsAF) ablation has emerged as an alternative to conventional treatment planning. To make this approach scalable, computational cost and the time required to conduct simulations must be minimized while maintaining predictive accuracy. Here, we assess the sensitivity of the process to finite-element mesh resolution. We also compare methods for pacing site distribution used to evaluate inducibility arrhythmia sustained by re-entrant drivers (RDs).

Methods and results: Simulations were conducted in low- and high-resolution models (average edge lengths: 400/350 µm) reconstructed from PsAF patients' late gadolinium enhancement magnetic resonance imaging scans. Pacing was simulated from 80 sites to assess RD inducibility. When pacing from the same site led to different outcomes in low-/high-resolution models, we characterized divergence dynamics by analysing dissimilarity index over time. Pacing site selection schemes prioritizing even spatial distribution and proximity to fibrotic tissue were evaluated. There were no RD sites observed in low-resolution models but not high-resolution models, or vice versa. Dissimilarity index analysis suggested that differences in simulation outcome arising from differences in discretization were the result of isolated conduction block incidents in one model but not the other; this never led to RD sites unique to one mesh resolution. Pacing site selection based on fibrosis proximity led to the best observed trade-off between number of stimulation locations and predictive accuracy.

Conclusion: Simulations conducted in meshes with 400 µm average edge length and ∼40 pacing sites proximal to fibrosis are sufficient to reveal the most comprehensive possible list of RD sites, given feasibility constraints.

Keywords: Atrial fibrillation; Convergence analysis; Fibrosis; Patient-specific computational modelling; Reentry.

Figure 1

Activation maps showing RDs induced in the same atrial location in low- and high-resolution versions of each patient-specific model (left and right frames within each panel, respectively). For all eight cases shown, the pacing sites used to induce reentry in the two models were also identical. Spacing between isochrone lines is 20 ms. (A) Patient 1, RD1: left lateral wall of posterior LA, inferior to LIPV. (B) Patient 1, RD4: lateral side of SVC. (C) Patient 2, RD2: upper part of SVC, opposite anterior wall of LA. (D) Patient 2, RD3: inferior RA along cusp of TCV, figure-of-eight morphology. (E) Patient 3, RD2: posterior LA, directly between common left PV trunk and RIPV. (F) Patient 3, RD3: adjacent to RIPV on posterior side. (G) Patient 4, RD1: anterior wall of LA, near septal connection to RA. (H) Patient 4, RD6: lateral RA on lower part of IVC. See Supplementary material online, Video S1 for dynamic illustrations of V_m over time for all eight cases shown here. IVC, inferior vena cava; LA, left atrial; LIPV, left inferior PV; PV, pulmonary vein; RA, right atrial; RD, re-entrant driver; RIPV, right inferior PV; SVC, superior vena cava; TCV, tricuspid valve.

Figure 2

Analysis of the instants at which electrophysiological behaviour diverges during simulated pacing of low- and high-resolution models. Top rows show maps of V_m in low- and high-resolution models (left and right, respectively) at relevant time points before, during, and after conduction block events leading to divergence. Time intervals before and after the peak positive d|DI|(t)/dt are shown. (A) In Patient 1, pacing from Site #7 led to initiation of RD1 in low-resolution model and RD4 in high-resolution model. Following the delivery of the final stimulus (at t = 2950 ms), critical conduction block occurred in the low-resolution model leading to divergence at t = 3180 ms. See Supplementary material online, Video S2 for a dynamic illustration of V_m over time for this case. (B) In Patient 4, pacing from Site #3 led to initiation of RD3 in low-resolution model and RD1 in high-resolution model. The instant of relevant conduction block in the low-resolution model was at t = 3880 ms. See main text for anatomical descriptions of rotor locations. RD, re-entrant driver.

Figure 3

Analysis of aggregated |DI| values across all simulations in low- and high-resolution versions of all patient-specific models. (A) |DI| values are presented for several different groups of results; data shown are medians, lower/upper quartiles, and 10th/90th percentiles. RD(±) match (Column 1) includes |DI| values [median (inter-quartile range) = 0.0292 (0.0114–0.0718)] for all simulation pairs (n = 43 cases, from 0 to 7500 ms) in which rapid pacing from a particular site led to the initiation of the same RD in both meshes. RD(–) match (Column 2) shows |DI| values [0.0140 (0.00650–0.0279)] for cases where pacing did not induce any reentry in either the low- or high-resolution model (n = 197, from 0 to time of first ST). Inducibility mismatch (Column 3) shows |DI| values [0.0173 (0.00801–0.0361)] for cases where pacing led to RD initiation in one mesh and ST in the other (n = 61; from 0 to ST time in the non-inducible model). Finally, RD mismatch (pre/post) (Columns 4/5) show |DI| values from the intervals preceding [0.0170 (0.00824–0.0328)] and following [0.0973 (0.0403–0.193)] the instant of largest increase (i.e., peak positive d|DI|/dt) in simulations where pacing from the same site led to initiation of RDs in different locations (n = 61); Pre-/post-intervals correspond to the same-coloured areas in |DI|(t) plots from Figure 2. As indicated by asterisks, data sets in the first four columns all differ significantly from the 5th column (P < 0.0001, Dunn’s multiple comparisons test). (B) Summary plots (same box-and-whisker settings as A) of non-normalized DI(t) during and after rapid pacing. Data are subdivided into cases where an RD only occurred in the low-resolution model (top rows; n = 43) or the high-resolution model (bottom rows; n = 18). RD, re-entrant driver; ST, spontaneous termination.

Figure 4

Analysis of pacing sites reordering to reduce computational burden while retaining predictive accuracy of simulation-based substrate characterization. (A) Schematic illustrating reordering Scheme #1, which prioritized ES of pacing sites. In this example, three different views of the same model (Patient 1) are shown: postero-anterior (left), right-lateral (middle), and antero-posterior (right). For visual clarity, each pacing site is shown as a golden yellow sphere and its sequence in the reordered ranking is indicated by the colour of surrounding atrial tissue. Fibrotic tissue regions are also shown in silhouette. (B) Same as (A) but for Scheme #2, which prioritized pacing site FP. Earlier sites are clustered near fibrotic regions (lateral parts of the posterior and anterior LA in the example shown); later sites are distributed in relatively fibrosis-free areas (here, the lateral RA). (C) Minimum number of pacing sites required to reveal all known RD locations (i.e., results of simulated pacing from all 80 locations) for ES vs. FP reordering in low- and high-resolution versions of all four patient-specific models. ES, even spacing; FP, fibrosis proximity; LA, left atrial; RA, right atrial; RD, re-entrant driver.