A Reproducible Protocol to Assess Arrhythmia Vulnerability in silico: Pacing at the End of the Effective Refractory Period

Abstract

In both clinical and computational studies, different pacing protocols are used to induce arrhythmia and non-inducibility is often considered as the endpoint of treatment. The need for a standardized methodology is urgent since the choice of the protocol used to induce arrhythmia could lead to contrasting results, e.g., in assessing atrial fibrillation (AF) vulnerabilty. Therefore, we propose a novel method-pacing at the end of the effective refractory period (PEERP)-and compare it to state-of-the-art protocols, such as phase singularity distribution (PSD) and rapid pacing (RP) in a computational study. All methods were tested by pacing from evenly distributed endocardial points at 1 cm inter-point distance in two bi-atrial geometries. Seven different atrial models were implemented: five cases without specific AF-induced remodeling but with decreasing global conduction velocity and two persistent AF cases with an increasing amount of fibrosis resembling different substrate remodeling stages. Compared with PSD and RP, PEERP induced a larger variety of arrhythmia complexity requiring, on average, only 2.7 extra-stimuli and 3 s of simulation time to initiate reentry. Moreover, PEERP and PSD were the protocols which unveiled a larger number of areas vulnerable to sustain stable long living reentries compared to RP. Finally, PEERP can foster standardization and reproducibility, since, in contrast to the other protocols, it is a parameter-free method. Furthermore, we discuss its clinical applicability. We conclude that the choice of the inducing protocol has an influence on both initiation and maintenance of AF and we propose and provide PEERP as a reproducible method to assess arrhythmia vulnerability.

Keywords: arrhythmia; atrial fibrillation; computational modeling; pacing protocol; reproducibility; vulnerability.

Figure 1

Posterior and anterior view of Utah stage II (UII) model in (A) and Utah stage IV (UIV) model in (B). Black regions indicate fibrotic tissue in which 50% of the elements were non-conductive and the remaining 50% electrophysiologically remodeled due to cytokine effects.

Figure 2

Example of stable llPS (A) and multiple wave fronts (B).

Figure 3

Model UIV partitioned into segments, the black dots represent the fibrotic elements.

Figure 4

First row: number of inducing points classified per induced arrhythmic mechanism: multiple wave fronts, flutter, non-stable and stable long living phase singularity. Second row: arrhythmic mechanisms induced by each protocol in the different atrial models.

Figure 5

Number of atrial segments in which inducing points were identified applying the various protocols in the different models.

Figure 6

(A) CI at which RP^B induced arrhythmia in each atrial model. (B) Number of beats per CI (N) needed to initiate arrhythmia in both RP^B and RP^E. (C) Total number of beats applied in the protocols PEERP, RP^B, and RP^E inducing arrhythmic episodes.

Figure 7

Simulated time required to entirely perform each protocol from one stimulation point in s.

Figure 8

Number of inducing points identified in the model UIV when decreasing the temporal resolution used to find the local effective refractory period in the PEERP method.

Figure 9

Number of maintaining atrial segments after applying each protocol in all the 227 stimulus locations. We simulated 1.5 s after the end of each protocol to observe the evolution of the arrhythmia.

Figure 10

Geodesic distance between inducing points and centers of the path covered by stable llPSs.

Figure 11

Number of stable llPSs per simulation with the different induction protocols.