Attenuation of stretch-induced arrhythmias following chemical ablation of Purkinje fibres, in isolated rabbit hearts

Purkinje fibres (PFs) play an important role in some ventricular arrhythmias and acute ventricular stretch can evoke mechanically-induced arrhythmias. We tested whether Purkinje fibres, play a role in these arrhythmias. Pseudo-ECGs were recorded in isolated, Langendorff-perfused, rabbit hearts in which the left ventricular endocardial surface was also irrigated with Tyrode, via an indwelling catheter placed in the left ventricular lumen. The number and period of ectopic activations was measured during left ventricular lumen inflation via an indwelling fluid-filled balloon (500 μL added over 2 s and maintained for 15 s in total). Mechanically-induced arrhythmias occurred in 70% of balloon inflations: they were maximal in the first 5 s and ceased within 15 s. Brief, (10 s) irrigation of the left ventricular lumen with Lugol solution (IK/I2), via the indwelling catheter, reduced inflation-induced ectopics by 98% (p < 0.05). Ablation of endocardial PFs by Lugol was confirmed by Triphenyltetrazolium Chloride staining. Optical mapping revealed the left ventricular epicardial activation patterns of ectopics could have PF-mediated and focal sources. In silico modelling predicted ectopic sources originating in the endocardial region propagate to and through the Purkinje fibres network. Acute distention-induced ectopics are multi-focal, their attenuation by Lugol, their activation patterns and in silico modelling indicate a participation of Purkinje fibres in these arrhythmias

Wavelength and Fibrosis Affect Phase Singularity Locations During Atrial Fibrillation

The mechanisms underlying atrial fibrillation (AF), the most common sustained cardiac rhythm disturbance, remain elusive. Atrial fibrosis plays an important role in the development of AF and rotor dynamics. Both electrical wavelength (WL) and the degree of atrial fibrosis change as AF progresses. However, their combined effect on rotor core location remains unknown. The aim of this study was to analyze the effects of WL change on rotor core location in both fibrotic and non-fibrotic atria. Three patient specific fibrosis distributions (total fibrosis content: 16.6, 22.8, and 19.2%) obtained from clinical imaging data of persistent AF patients were incorporated in a bilayer atrial computational model. Fibrotic effects were modeled as myocyte-fibroblast coupling + conductivity remodeling; structural remodeling; ionic current changes + conductivity remodeling; and combinations of these methods. To change WL, action potential duration (APD) was varied from 120 to 240ms, representing the range of clinically observed AF cycle length, by modifying the inward rectifier potassium current (IK1) conductance between 80 and 140% of the original value. Phase singularities (PSs) were computed to identify rotor core locations. Our results show that IK1 conductance variation resulted in a decrease of APD and WL across the atria. For large WL in the absence of fibrosis, PSs anchored to regions with high APD gradient at the center of the left atrium (LA) anterior wall and near the junctions of the inferior pulmonary veins (PVs) with the LA. Decreasing the WL induced more PSs, whose distribution became less clustered. With fibrosis, PS locations depended on the fibrosis distribution and the fibrosis implementation method. The proportion of PSs in fibrotic areas and along the borders varied with both WL and fibrosis modeling method: for patient one, this was 4.2–14.9% as IK1 varied for the structural remodeling representation, but 12.3–88.4% using the combination of structural remodeling with myocyte-fibroblast coupling. The degree and distribution of fibrosis and the choice of implementation technique had a larger effect on PS locations than the WL variation. Thus, distinguishing the fibrotic mechanisms present in a patient is important for interpreting clinical fibrosis maps to create personalized models

Leadless biventricular left bundle and endocardial lateral wall pacing versus left bundle only pacing in left bundle branch block patients

Biventricular endocardial (BIV-endo) pacing and left bundle pacing (LBP) are novel delivery methods for cardiac resynchronization therapy (CRT). Both pacing methods can be delivered through leadless pacing, to avoid risks associated with endocardial or transvenous leads. We used computational modelling to quantify synchrony induced by BIV-endo pacing and LBP through a leadless pacing system, and to investigate how the right-left ventricle (RV-LV) delay, RV lead location and type of left bundle capture affect response. We simulated ventricular activation on twenty-four four-chamber heart meshes inclusive of His-Purkinje networks with left bundle branch block (LBBB). Leadless biventricular (BIV) pacing was simulated by adding an RV apical stimulus and an LV lateral wall stimulus (BIV-endo lateral) or targeting the left bundle (BIV-LBP), with an RV-LV delay set to 5 ms. To test effect of prolonged RV-LV delays and RV pacing location, the RV-LV delay was increased to 35 ms and/or the RV stimulus was moved to the RV septum. BIV-endo lateral pacing was less sensitive to increased RV-LV delays, while RV septal pacing worsened response compared to RV apical pacing, especially for long RV-LV delays. To investigate how left bundle capture affects response, we computed 90% BIV activation times (BIVAT-90) during BIV-LBP with selective and non-selective capture, and left bundle branch area pacing (LBBAP), simulated by pacing 1 cm below the left bundle. Non-selective LBP was comparable to selective LBP. LBBAP was worse than selective LBP (BIVAT-90: 54.2 ± 5.7 ms vs. 62.7 ± 6.5, p < 0.01), but it still significantly reduced activation times from baseline. Finally, we compared leadless LBP with RV pacing against optimal LBP delivery through a standard lead system by simulating BIV-LBP and selective LBP alone with and without optimized atrioventricular delay (AVD). Although LBP alone with optimized AVD was better than BIV-LBP, when AVD optimization was not possible BIV-LBP outperformed LBP alone, because the RV pacing stimulus shortened RV activation (BIVAT-90: 54.2 ± 5.7 ms vs. 66.9 ± 5.1 ms, p < 0.01). BIV-endo lateral pacing or LBP delivered through a leadless system could potentially become an alternative to standard CRT. RV-LV delay, RV lead location and type of left bundle capture affect leadless pacing efficacy and should be considered in future trial designs

A comprehensive framework for evaluation of high pacing frequency and arrhythmic optical mapping signals

Introduction: High pacing frequency or irregular activity due to arrhythmia produces complex optical mapping signals and challenges for processing. The objective is to establish an automated activation time-based analytical framework applicable to optical mapping images of complex electrical behavior.Methods: Optical mapping signals with varying complexity from sheep (N = 7) ventricular preparations were examined. Windows of activation centered on each action potential upstroke were derived using Hilbert transform phase. Upstroke morphology was evaluated for potential multiple activation components and peaks of upstroke signal derivatives defined activation time. Spatially and temporally clustered activation time points were grouped in to wave fronts for individual processing. Each activation time point was evaluated for corresponding repolarization times. Each wave front was subsequently classified based on repetitive or non-repetitive events. Wave fronts were evaluated for activation time minima defining sites of wave front origin. A visualization tool was further developed to probe dynamically the ensemble activation sequence.Results: Our framework facilitated activation time mapping during complex dynamic events including transitions to rotor-like reentry and ventricular fibrillation. We showed that using fixed AT windows to extract AT maps can impair interpretation of the activation sequence. However, the phase windowing of action potential upstrokes enabled accurate recapitulation of repetitive behavior, providing spatially coherent activation patterns. We further demonstrate that grouping the spatio-temporal distribution of AT points in to coherent wave fronts, facilitated interpretation of isolated conduction events, such as conduction slowing, and to derive dynamic changes in repolarization properties. Focal origins precisely detected sites of stimulation origin and breakthrough for individual wave fronts. Furthermore, a visualization tool to dynamically probe activation time windows during reentry revealed a critical single static line of conduction slowing associated with the rotation core.Conclusion: This comprehensive analytical framework enables detailed quantitative assessment and visualization of complex electrical behavior

The Functional Role of Electrophysiological Heterogeneity in the Rabbit Ventricle During Rapid Pacing and Arrhythmias

Electrophysiological heterogeneity in action potential recordings from healthy intact hearts remains highly variable and, where present, is almost entirely abolished at fast pacing rates. Consequently, the functional importance of intrinsic action potential duration (APD) heterogeneity in healthy ventricles, and particularly its role during rapidly activating reentrant arrhythmias, remain poorly understood. By incorporating both transmural and apicobasal APD heterogeneity within a biventricular rabbit computational model and comparing with an equivalent homogeneous model, we directly investigated the functional importance of intrinsic APD heterogeneity under fast pacing and arrhythmogenic protocols. Although differences in APD were significantly modulated at the tissue level during pacing and further reduced as pacing frequency increased, small differences were still noticeable. Such differences were further marginally accentuated/attenuated via electrotonic effects relative to wavefront propagation directions. The remaining small levels of APD heterogeneity under the fastest pacing frequencies resulted in arrhythmia initiation via heterogeneous conduction block, in contrast to complete block in the homogeneous model. Such induction mechanisms were more evident during premature stimuli at slower paced rhythms where intrinsic heterogeneity remained to a greater degree. During sustained arrhythmias, however, intrinsic heterogeneity made little difference to overall reentrant behavior, either visually, or in terms of duration, metrics quantifying filament/phase singularity dynamics, and global electrocardiogram characteristics. These findings suggest that, despite being important during arrhythmia initiation, intrinsic electrophysiological heterogeneity plays little functional role during rapid pacing and sustained arrhythmia dynamics in the healthy ventricle and thus questions the need to incorporate such detail in computational models when simulating rapid arrhythmias