Competitive Drivers of Atrial Fibrillation: The Interplay Between Focal Drivers and Multiwavelet Reentry

BackgroundThere is debate whether human atrial fibrillation is driven by focal drivers or multiwavelet reentry. We propose that the changing activation sequences surrounding a focal driver can at times self-sustain in the absence of that driver. Further, the relationship between focal drivers and surrounding chaotic activation is bidirectional; focal drivers can generate chaotic activation, which may affect the dynamics of focal drivers.Methods and ResultsIn a propagation model, we generated tissues that support structural micro-reentry and moving functional reentrant circuits. We qualitatively assessed (1) the tissue’s ability to support self-sustaining fibrillation after elimination of the focal driver, (2) the impact that structural-reentrant substrate has on the duration of fibrillation, the impact that micro-reentrant (3) frequency, (4) excitable gap, and (5) exposure to surrounding fibrillation have on micro-reentry in the setting of chaotic activation, and finally the likelihood fibrillation will end in structural reentry based on (6) the distance between and (7) the relative lengths of an ablated tissue’s inner and outer boundaries. We found (1) focal drivers produced chaotic activation when waves encountered heterogeneous refractoriness; chaotic activation could then repeatedly initiate and terminate micro-reentry. Perpetuation of fibrillation following elimination of micro-reentry was predicted by tissue properties. (2) Duration of fibrillation was increased by the presence of a structural micro-reentrant substrate only when surrounding tissue had a low propensity to support self-sustaining chaotic activation. Likelihood of micro-reentry around the structural reentrant substrate increased as (3) the frequency of structural reentry increased relative to the frequency of fibrillation in the surrounding tissue, (4) the excitable gap of micro-reentry increased, and (5) the exposure of the structural circuit to the surrounding tissue decreased. Likelihood of organized tachycardia following termination of fibrillation increased with (6) decreasing distance and (7) disparity of size between focal obstacle and external boundary.ConclusionFocal drivers such as structural micro-reentry and the chaotic activation they produce are continuously interacting with one another. In order to accurately describe cardiac tissue’s propensity to support fibrillation, the relative characteristics of both stationary and moving drivers must be taken into account.

Bi-atrial high-density mapping reveals inhibition of wavefront turning and reduction of complex propagation patterns as main antiarrhythmic mechanisms of vernakalant

Aims Complex propagation patterns are observed in patients and models with stable atrial fibrillation (AF). The degree of this complexity is associated with AF stability. Experimental work suggests reduced wavefront turning as an important mechanism for widening of the excitable gap. The aim of this study was to investigate how sodium channel inhibition by vernakalant affects turning behaviour and propagation patterns during AF. Methods and results Two groups of 8 goats were instrumented with electrodes on the left atrium, and AF was maintained by burst pacing for 3 or 22 weeks. Measurements were performed at baseline and two dosages of vernakalant. Unipolar electrograms were mapped (249 electrodes/array) on the left and right atrium in an open-chest experiment. Local activation times and conduction vectors, flow lines, the number of fibrillation waves, and local re-entries were determined. At baseline, fibrillation patterns contained numerous individual fibrillation waves conducting in random directions. Vernakalant induced conduction slowing and cycle length prolongation and terminated AF in 13/15 goats. Local re-entries were strongly reduced. Local conduction vectors showed increased preferential directions and less beat-to-beat variability. Breakthroughs and waves were significantly reduced in number. Flow line curvature reduced and waves conducted more homogenously in one direction. Overall, complex propagation patterns were strongly reduced. No substantial differences in drug effects between right and left atria or between goats with different AF durations were observed. Conclusions Destabilization of AF by vernakalant is associated with a lowering of fibrillation frequency and inhibition of complex propagation patterns, wave turning, local re-entries, and breakthroughs.

Cardiac Optogenetics in Atrial Fibrillation: Current Challenges and Future Opportunities

Although rarely life-threatening on short term, atrial fibrillation leads to increased mortality and decreased quality of life through its complications, including heart failure and stroke. Recent studies highlight the benefits of maintaining sinus rhythm. However, pharmacological long-term rhythm control strategies may be shadowed by associated proarrhythmic effects. At the same time, electrical cardioversion is limited to hospitals, while catheter ablation therapy, although effective, is invasive and is dedicated to specific patients, usually with low amounts of atrial fibrosis (preferably Utah I-II). Cardiac optogenetics allows influencing the heart’s electrical activity by applying specific wavelength light pulses to previously engineered cardiomyocytes into expressing microbial derived light-sensitive proteins called opsins. The resulting ion influx may give rise to either hyperpolarizing or depolarizing currents, thus offering a therapeutic potential in cardiac electrophysiology, including pacing, resynchronization, and arrhythmia termination. Optogenetic atrial fibrillation cardioversion might be achieved by inducing a conduction block or filling of the excitable gap. The authors agree that transmural opsin expression and appropriate illumination with an exposure time longer than the arrhythmia cycle length are necessary to achieve successful arrhythmia termination. However, the efficiency and safety of biological cardioversion in humans remain to be seen, as well as side effects such as immune reactions and loss of opsin expression. The possibility of delivering pain-free shocks with out-of-hospital biological cardioversion is tempting; however, there are several issues that need to be addressed first: applicability and safety in humans, long-term behaviour, anticoagulation requirements, and fibrosis interactions.

P6555A self-adaptive approach to antitachycardia pacing - a head to head comparison using advanced computational modeling

Background Antitachycardia pacing (ATP) for monomorphic VT (MVT) reduces painful defibrillation shocks. Most ICD-treated ventricular arrhythmias are MVT, suggesting an opportunity for improved ATP to decrease shocks. We report on a new algorithm (Yee, Circ AE 2017) that uses electrophysiologic (EP) first-principles to design ATP sequences in real-time. Heart-rate history is used to design the first ATP sequence, and failed ATP post-pacing interval is used to design later sequences. Purpose The purpose of this modeling study was to understand how this new ATP algorithm would perform in a head-to-head comparison with traditional burst ATP. Modeling allows direct comparison of the two algorithms in identical, realistic, patient-derived cardiac arrythmias. Methods Patient-specific late gadolinium enhanced MRI and EP data were used to build an adjudicated cohort of realistic numerical heart models with varied EP, infarct, border zone. Publicly available EP modeling software CARPentry was used to calculate sustained reentrant VT initiated with the programmed electrical stimulation used to induce VT clinically. The VTs were physician-adjudicated to validate models. Burst ATP was 3 sequences of 8 pulses at 88% of VT cycle length, each decremented by 10ms. The new ATP was limited to 3 automatically designed sequences. Results Three hundred unique VT scenarios were generated from 6 human hearts with multiple VT circuits, 5 electrophysiologic states, and 10 pacing locations. Burst ATP terminated 168/300 VTs (56%) and accelerated 2.7%. The new ATP terminated 234/300 VTs (78%) with the same acceleration. The two dominant ATP failure mechanisms were identified as 1) insufficient prematurity to close the excitable gap, and 2) failure to reach the critical isthmus of the VT circuit. For these mechanisms, the new ATP algorithm reduce failures from 64 to 28 (44% reduction) without increasing acceleration. Conclusion The new automated ATP algorithm successfully adapted ATP sequences for VT episodes that burst ATP failed to terminate. The new ATP was successful even with complex scar geometries and electrophysiology heterogeneity as seen in the real world.

Interaction of phase singularities on the spiral wave tail: reconsideration of capturing the excitable gap

The action mechanism of stimulation toward spiral waves (SWs) owing to the complex excitation patterns that occur just after point stimulation has not yet been experimentally clarified. This study sought to test our hypothesis that the effect of capturing excitable gap of SWs by stimulation can also be explained as the interaction of original phase singularity (PS) and PSs induced by the stimulation on the wave tail (WT) of the original SW. Phase variance analysis was used to quantitatively analyze the postshock PS trajectories. In a two-dimensional subepicardial layer of Langendorff-perfused rabbit hearts, optical mapping was used to record the excitation pattern during stimulation. After a SW was induced by S1–S2 shock, single biphasic point stimulation S3 was applied. In 70 of the S1-S2-S3 stimulation episodes applied on 6 hearts, the original PS was clearly observed just before the S3 point stimulation in 37 episodes. Pairwise PSs were newly induced by the S3 in 20 episodes. The original PS collided with the newly induced PSs in 16 episodes; otherwise, they did not interact with the original PS. SW shift occurred most efficiently when the S3 shock was applied at the relative refractory period, and PS shifted in the direction of the WT. In conclusion, quantitative tracking of PS clarified that stimulation in desirable conditions induces pairwise PSs on WT and that the collision of PSs causes SW shift along the WT. The results of this study indicate the importance of the interaction of shock-induced excitation with the WT for effective stimulation. NEW & NOTEWORTHY The quantitative analysis of spiral wave dynamics during stimulation clarified the action mechanism of capturing the excitable gap, i.e., the induction of pairwise phase singularities on the wave tail and spiral wave shift along the wave tail as a result of these interactions. The importance of the wave tail for effective stimulation was revealed.

Abstract 2137: Relationship between Duration of Basal QRS Complex and Effectiveness of Antitachycardia Pacing in Implantable Cardioverter-Defibrillator Patients

In re-entrant Monomorphic Ventricular Tachycardias (MVT), the ability of Antitachycardia Pacing (APT) to terminate the arrhythmia depends on the presence of an excitable gap (EG) and on the capability of the impulses to penetrate this EG. The main limiting factor for penetrating the EG is the distance and the obstacles between pacing site and circuit. Therefore, the duration of basal QRS complex (QRSd), as marker of left ventricle size, fibrosis and/or necrosis, could be related to the efficacy of ATP. Our aim is to determine the relationship between QRSd and the effectiveness of ATP in terminating MVT. In this prospective study we included 200 ICD patients with substrate for presenting MVT (LVEF: 31±11; pacing site: right ventricular apex). Detection and ATP therapies for MVT were programmed as follows: a) Fast-MVT : Cycle Length (CL): 250 –320 ms; 1 burst of 5 pulses at 84 % of CL, and: b) Slow MVT: CL > 320 ms; 3 bursts of 15 pulses at 91%. QRSd was determined on the surface ECG (50 mm/s) inmediatly before the device implant. During a follow-up of 602±368 days, 546 MVT (CL: 329±35 ms; fast MVT: 41 %; QRSd: 111±25 ms) were recorded in 64 patients. Overall success rate of APT was: 87%. MVT terminated with ATP were associated with QRSd values significantly lower: 109±24 vs. 121±29 (p<0.001). After classifying the events into 3 groups according to the QRSd tertiles (≤100, 101–119, ≥120 ms), the frequency of successful ATP (S-ATP) was higher in the first tertile: 96% vs. 80% (Odds Ratio: 5.8; 95% Confidence Interval: 2.9- 11.6; p<0.001). In a multivariate analysis which included LVEF, aetiology, indication, functional class, CL of MVT, beta-blocker therapy (mgs/day) and left ventricle end-diastolic diameter, QRSd (ms) remained as an independent predictor of S-ATP: Odds Ratio: 0.96 (95% Confidence Interval: 0.94 – 0.97; p<0.001). Patients with lower values of QRSd presented higher rates of S-ATP (mean±standard deviation): 98±4 (QRSd≤100) vs. 81±26 (QRSd: 101–120) vs. 72±40 (QRSd>120); p=0.01 (ANOVA). Among ICD patients, the duration of QRS complex is related to the effectiveness of ATP: for each ms of QRSd the adjusted probability of ATP terminating the episode decreases 4 points. Patients with QRSd≤100 ms have significantly higher rates of S-ATP.