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

BACKGROUND: There 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 RESULTS: In 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. CONCLUSION: Focal 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.

Cycle length statistics during human atrial fibrillation reveal refractory properties of the underlying substrate: a combined in silico and clinical test of concept study.

AIMS: The treatment of atrial fibrillation beyond pulmonary vein isolation has remained an unsolved challenge. Targeting regions identified by different substrate mapping approaches for ablation resulted in ambiguous outcomes. With the effective refractory period being a fundamental prerequisite for the maintenance of fibrillatory conduction, this study aims at estimating the effective refractory period with clinically available measurements. METHODS AND RESULTS: A set of 240 simulations in a spherical model of the left atrium with varying model initialization, combination of cellular refractory properties, and size of a region of lowered effective refractory period was implemented to analyse the capabilities and limitations of cycle length mapping. The minimum observed cycle length and the 25% quantile were compared to the underlying effective refractory period. The density of phase singularities was used as a measure for the complexity of the excitation pattern. Finally, we employed the method in a clinical test of concept including five patients. Areas of lowered effective refractory period could be distinguished from their surroundings in simulated scenarios with successfully induced multi-wavelet re-entry. Larger areas and higher gradients in effective refractory period as well as complex activation patterns favour the method. The 25% quantile of cycle lengths in patients with persistent atrial fibrillation was found to range from 85 to 190 ms. CONCLUSION: Cycle length mapping is capable of highlighting regions of pathologic refractory properties. In combination with complementary substrate mapping approaches, the method fosters confidence to enhance the treatment of atrial fibrillation beyond pulmonary vein isolation particularly in patients with complex activation patterns.

Activation Mapping With Integration of Vector and Velocity Information Improves the Ability to Identify the Mechanism and Location of Complex Scar-Related Atrial Tachycardias.

BACKGROUND: Activation mapping of scar-related atrial tachycardias (ATs) can be difficult to interpret because of inaccurate time annotation of complex electrograms and passive diastolic activity. We examined whether integration of a vector map can help to describe patterns of propagation to better explain the mechanism and location of ATs. METHODS: The investigational mapping algorithm calculates vectors and applies physiological constraints of electrical excitation in human atrial tissue to determine the arrhythmia source and circuit. Phase I consisted of retrospective evaluation in 35 patients with ATs. Phase II consisted of prospective validation in 20 patients with ATs. Macroreentry was defined as a continuous propagation in a circular path >30 mm; localized reentry was defined as a circular path ≤30 mm; a focal source had a centrifugal spread from a point source. RESULTS: In phase I, standard activation mapping identified 28 of 40 ATs (70%): 25 macroreentry and 3 focal tachycardias. In the remaining 12 ATs, the mechanism and location could not be identified by activation and required entrainment or empirical ablation for termination (radiofrequency time, 17.3±6.6 minutes). In comparison, the investigational algorithm identified 37 of 40 (92.5%) ATs, including 5 macroreentry, 3 localized reentry, and 1 focal AT not identified by standard mapping. It also predicted the successful termination site of all 37 of 40 ATs. In phase II, the investigational algorithm identified 12 macroreentry, 6 localized reentry, and 2 focal tachycardias that all terminated with limited ablation (3.2±1.7 minutes). It identified 3 macroreentry, 3 localized reentry, and 1 focal AT not well characterized by standard mapping. The diagnosis of localized reentry was supported by highly curved vectors, resetting with increasing curve and termination with limited ablation (22±6 s). CONCLUSIONS: Activation mapping integrating vectors can help determine the arrhythmia mechanism and identify its critical components. It has particular value for identifying complex macroreentrant circuits and for differentiating a focal source from a localized reentry.

Prospective, Tissue-Specific Optimization of Ablation for Multiwavelet Reentry: Predicting the Required Amount, Location, and Configuration of Lesions.

BACKGROUND: Treatment of multiwavelet reentry (MWR) remains difficult. We previously developed a metric, the fibrillogenicity index, to assess the propensity of homogeneous, 2-dimensional tissues to support MWR. In this study, we demonstrate a method by which fibrillogenicity index can be generalized to heterogeneous tissues and validate an algorithm for prospective, tissue-specific optimization of ablation to reduce MWR burden. METHODS AND RESULTS: We used a computational model to simulate and measure the duration of MWR in tissues with heterogeneously distributed action potential durations and then assessed the relative efficacy of a variety of ablation strategies for reducing tissues' ability to support MWR. We then derived and tested a strategy in which multiple linear lesions partially divided a fibrillogenic tissue into functionally equivalent subsections. The composite action potential duration of heterogeneous tissue was well approximated by an inverse sum of cellular action potential durations (R(2)=0.82). Linear ablation more efficiently reduced MWR duration than branching ablation patterns and optimally reduced disease burden when positioned at a tissue's functional (rather than geometric) center. The duration of MWR after application of prospective, individually optimized ablation sets fell within 4.4% (95% confidence interval, 3-5.8) of the predicted target. CONCLUSIONS: We think that this study presents a novel approach for (1) quantifying the extent of a tissue's electric derangement, (2) prospectively determining the amount of ablation required to minimize the burden of MWR, and (3) predicting the most efficient distribution of these ablation lesions in tissue refractory to standard ablation strategies.

Structural defects lead to dynamic entrapment in cardiac electrophysiology.

Biological networks are typically comprised of many parts whose interactions are governed by nonlinear dynamics. This potentially imbues them with the ability to support multiple attractors, and therefore to exhibit correspondingly distinct patterns of behavior. In particular, multiple attractors have been demonstrated for the electrical activity of the diseased heart in situations where cardioversion is able to convert a reentrant arrhythmia to a stable normal rhythm. Healthy hearts, however, are typically resilient to abnormal rhythms. This raises the question as to how a healthy cardiac cell network must be altered so that it can support multiple distinct behaviors. Here we demonstrate how anatomic defects can give rise to multi-stability in the heart as a function of the electrophysiological properties of the cardiac tissue and the timing of activation of ectopic foci. This leads to a form of hysteretic behavior, which we call dynamic entrapment, whereby the heart can become trapped in aberrant attractor as a result of a transient change in tissue properties. We show that this can lead to a highly inconsistent relationship between clinical symptoms and underlying pathophysiology, which raises the possibility that dynamic entrapment may underlie other forms of chronic idiopathic illness.

Prospectively quantifying the propensity for atrial fibrillation: a mechanistic formulation.

The goal of this study was to determine quantitative relationships between electrophysiologic parameters and the propensity of cardiac tissue to undergo atrial fibrillation. We used a computational model to simulate episodes of fibrillation, which we then characterized in terms of both their duration and the population dynamics of the electrical waves which drove them. Monte Carlo sampling revealed that episode durations followed an exponential decay distribution and wave population sizes followed a normal distribution. Half-lives of reentrant episodes increased exponentially with either increasing tissue area to boundary length ratio (A/BL) or decreasing action potential duration (APD), resistance (R) or capacitance (C). We found that the qualitative form of fibrillatory activity (e.g., multi-wavelet reentry (MWR) vs. rotors) was dependent on the ratio of resistance and capacitance to APD; MWR was reliably produced below a ratio of 0.18. We found that a composite of these electrophysiologic parameters, which we term the fibrillogenicity index (Fb = A/(BL*APD*R*C)), reliably predicted the duration of MWR episodes (r2 = 0.93). Given that some of the quantities comprising Fb are amenable to manipulation (via either pharmacologic treatment or catheter ablation), these findings provide a theoretical basis for the development of titrated therapies of atrial fibrillation.

Digital resolution enhancement of intracardiac excitation maps during atrial fibrillation.

Atrial fibrillation (AF) is often successfully treated by catheter ablation. Those cases of AF that do not readily succumb to ablation therapy would benefit from improved methods for mapping the complex spatial patterns of tissue activation that typify recalcitrant AF. To this end, the purpose of our study was to investigate the use of numerical deconvolution to improve the spatial resolution of activation maps provided by 2-D arrays of intra-cardiac recording electrodes. We simulated tissue activation patterns and their corresponding electric potential maps using a computational model of cardiac electrophysiology, and sampled the maps over a grid of locations to generate a mapping data set. Following cubic spline interpolation, followed by edge-extension and windowing, we deconvolved the data and compared the results to the model current density fields. We performed a similar analysis on voltage-sensitive dye maps obtained in isolated sheep hearts. For both the synthetic data and the voltage-sensitive dye maps, we found that deconvolution led to visually improved map resolution for arrays of 10×10 up to 30×30 electrodes placed within a few mm of the atrial surface when the activation patterns included 3-4 features that spanned the recording area. Root mean square error was also reduced by deconvolution. Deconvolution of arrays of intracardiac potentials, preceded by appropriate interpolation and edge processing, leads to potentially useful improvements in map resolution that may allow more effective assessment of the spatiotemporal dynamics of tissue excitation during AF.

Mapping multi-wavelet reentry without isochrones: an electrogram-guided approach to define substrate distribution.

AIMS: A key mechanism responsible for atrial fibrillation is multi-wavelet reentry (MWR). We have previously demonstrated that ablation in regions of increased circuit density reduces the duration of, and decreases the inducibility of MWR. In this study, we demonstrate a method for identifying local circuit density using electrogram frequency and validated its effectiveness for map-guided ablation in a computer model of MWR. METHODS AND RESULTS: We simulated MWR in tissues with variation of action potential duration and intercellular resistance. Electrograms were calculated using various electrode sizes and configurations. We measured and compared the number of circuits to the tissue activation frequency and electrogram frequency using three recording configurations [unipolar, contact bipolar, orthogonal closed unipolar (OCU)] and two frequency measurements (dominant frequency, centroid frequency). We then used the highest resolution electrogram frequency map (OCU centroid frequency) to guide the placement of lesions to high frequency regions. Map-guided ablation was compared with no ablation and random/blind ablation lesions of equal length. Electrogram frequency correlated with tissue frequency and circuit density as a function of electrode spatial resolution. Map-guided ablation resulted in a significant reduction in MWR duration (142 ± 174 vs. 41 ± 63 s). CONCLUSION: Electrogram frequency correlates with circuit density in MWR provided electrodes have high spatial resolution. Map-guided ablation is superior to no ablation and to blind/random ablation.

Principles of differential diagnostic pacing maneuvers: serial versus parallel conduction.

In this article we will review differential diagnostic pacing maneuvers. It is not meant to be an exhaustive review of all such maneuvers. Rather, we offer some general analytic principles as they apply to electrophysiology (EP) and illustrate their use through several examples. Our hope is to provide a framework for thinking about electrogram data that acts more like a compass and map than like a specific set of directions. Amongst the most helpful pieces of advice that we can offer the EP trainee is to actively try to picture the waves of electricity spreading through the heart, passing beneath the recording electrodes and generating the electrograms you seek to interpret. Digest the fact that more than one propagation pattern can result in the same electrogram pattern and that differential diagnostic pacing is aimed at distinguishing between these possibilities. A fundamental tenet of differential diagnostic maneuvers of any kind (not simply pacing) is to choose a test that maximizes the difference between possible explanations. This perspective and a careful and meticulous cataloguing of what you can unambiguously conclude from the electrograms versus what remains to be determined via pacing offers the best approach to succeeding at EP. We will discuss pacing maneuvers in three contexts: differential diagnosis of narrow complex tachycardia, mapping of accessory pathways, and Para-Hisian pacing.

Improved spatial resolution and electrogram wave direction independence with the use of an orthogonal electrode configuration.

To improve spatial resolution in recordings of intra-cardiac electrograms we characterized the utility of a novel configuration of two recording electrodes arranged perpendicularly to the endocardial surface. We hypothesized that this configuration denoted as orthogonal close unipolar (OCU) would combine advantages of conventional unipolar and contact bipolar (CBP) configurations. Electrical excitation was simulated in a computational model as arising from dipole current or from multi-wavelet reentry sources. Recordings were calculated for electrode tips 1 mm above the plane of the heart. Analogous recordings were obtained from swine hearts. Electrograms recorded with CBP showed strong dependence on orientation of the electrode pair with respect to the direction of spread of tissue excitation. By contrast, OCU recordings exhibited no directional dependence. OCU was significantly superior to CBP with respect to avoidance of far-field confounding of local tissue activity; the average far-field/near-field ratios for CBP and OCU were 0.09 and 0.05, respectively, for the simulated dipole current sources. In the swine hearts the ratios of ventricular to atrial signals for CBP and OCU were 0.15 ± 0.07 and 0.08 ± 0.09, respectively (p < 0.001). The difference between the actual dominant frequency in the tissue and that recorded by the electrodes was 0.44 ± 0.33 Hz for OCU, 0.58 ± 0.40 Hz for unipolar, and 0.62 ± 0.46 Hz for CBP. OCU confers improved spatial resolution compared with both unipolar and CBP electrode configurations. Unlike the case with CBP, OCU recordings are independent of excitation wave-front direction.

Ablation of multiwavelet re-entry guided by circuit-density and distribution: maximizing the probability of circuit annihilation.

BACKGROUND: A key mechanism responsible for atrial fibrillation is multiwavelet re-entry (MWR). We have previously demonstrated improved efficiency of ablation when lesions were placed in regions of high circuit-density. In this study, we undertook a quantitative assessment of the relative effect of ablation on the probability of MWR termination and the inducibility of MWR, as a function of lesion length and circuit-density overlap. METHODS AND RESULTS: We used a computational model to simulate MWR in tissues with (and without) localized regions of decreased action potential duration and increased intercellular resistance. We measured baseline circuit-density and distribution. We then assessed the effect of various ablation lesion sets on the inducibility and duration of MWR as a function of ablation lesion length and overlap with circuit-density. Higher circuit-density reproducibly localized to regions of shorter wavelength. Ablation lines with high circuit-density overlap showed maximum decreases in duration of MWR at lengths equal to the distance from the tissue boundary to the far side of the high circuit-density region (high-overlap, -43.5% [confidence interval, -22.0% to -65.1%] versus low-overlap, -4.4% [confidence interval, 7.3% to -16.0%]). Further ablation (beyond the length required to cross the high circuit-density region) provided minimal further reductions in duration and increased inducibility. CONCLUSIONS: Ablation at sites of high circuit-density most efficiently decreased re-entrant duration while minimally increasing inducibility. Ablation lines delivered at sites of low circuit-density minimally decreased duration yet increased inducibility of MWR.

Ablation of multi-wavelet re-entry: general principles and in silico analyses.

AIMS: Catheter ablation strategies for treatment of cardiac arrhythmias are quite successful when targeting spatially constrained substrates. Complex, dynamic, and spatially varying substrates, however, pose a significant challenge for ablation, which delivers spatially fixed lesions. We describe tissue excitation using concepts of surface topology which provides a framework for addressing this challenge. The aim of this study was to test the efficacy of mechanism-based ablation strategies in the setting of complex dynamic substrates. METHODS AND RESULTS: We used a computational model of propagation through electrically excitable tissue to test the effects of ablation on excitation patterns of progressively greater complexity, from fixed rotors to multi-wavelet re-entry. Our results indicate that (i) focal ablation at a spiral-wave core does not result in termination; (ii) termination requires linear lesions from the tissue edge to the spiral-wave core; (iii) meandering spiral-waves terminate upon collision with a boundary (linear lesion or tissue edge); (iv) the probability of terminating multi-wavelet re-entry is proportional to the ratio of total boundary length to tissue area; (v) the efficacy of linear lesions varies directly with the regional density of spiral-waves. CONCLUSION: We establish a theoretical framework for re-entrant arrhythmias that explains the requirements for their successful treatment. We demonstrate the inadequacy of focal ablation for spatially fixed spiral-waves. Mechanistically guided principles for ablating multi-wavelet re-entry are provided. The potential to capitalize upon regional heterogeneity of spiral-wave density for improved ablation efficacy is described.

Effects of electrode size and spacing on the resolution of intracardiac electrograms.

BACKGROUND: Electrogram fractionation can result when multiple groups of cardiac cells are excited asynchronously within the recording region of a mapping electrode. The spatial resolution of an electrode thus plays an important role in mapping complex rhythms. METHODS: We used a computational model, validated against experimental measurements in vitro, to determine how spatial resolution is affected by electrode diameter, electrode length, interelectrode distance (in the case of bipolar recordings), and height of the electrode above a dipole current source. RESULTS: We found that increases in all these quantities caused progressive degradation in two independent measures of spatial resolution, with the strongest effect being due to changes in height above the tissue. CONCLUSION: Our calculations suggest that if electrodes could be constructed to have negligible dimensions compared with those in use today, we would increase resolution by about one order of magnitude at most.

Electrogram fractionation: the relationship between spatiotemporal variation of tissue excitation and electrode spatial resolution.

BACKGROUND: Fractionated electrograms are used by some as targets for ablation in atrial and ventricular arrhythmias. Fractionation has been demonstrated to result when there is repetitive or asynchronous activation of separate groups of cells within the recording region of a mapping electrode(s). METHODS AND RESULTS: Using a computer model, we generated tissue activation patterns with increasing spatiotemporal variation and calculated virtual electrograms from electrodes with decreasing resolution. We then quantified electrogram fractionation. In addition, we recorded unipolar electrograms during atrial fibrillation in 20 patients undergoing atrial fibrillation ablation. From these we constructed bipolar electrograms with increasing interelectrode spacing and quantified fractionation. During modeling of spatiotemporal variation, fractionation varied directly with electrode length, diameter, height, and interelectrode spacing. When resolution was held constant, fractionation increased with increasing spatiotemporal variation. In the absence of spatial variation, fractionation was independent of resolution and proportional to excitation frequency. In patients with atrial fibrillation, fractionation increased as interelectrode spacing increased. CONCLUSIONS: We created a model for distinguishing the roles of spatial and temporal electric variation and electrode resolution in producing electrogram fractionation. Spatial resolution affects fractionation attributable to spatiotemporal variation but not temporal variation alone. Electrogram fractionation was directly proportional to spatiotemporal variation and inversely proportional to spatial resolution. Spatial resolution limits the ability to distinguish high-frequency excitation from overcounting. In patients with atrial fibrillation, complex fractionated atrial electrogram detection varies with spatial resolution. Electrode resolution must therefore be considered when interpreting and comparing studies of fractionation.

The impact of pharmacologic sympathetic and parasympathetic blockade on atrial electrogram characteristics in patients with atrial fibrillation.

BACKGROUND: Ablation of atrial autonomic inputs exerts antifibrillatory effects. However, because ablation destroys both myocardium and nerve cells, the effect of autonomic withdrawal alone remains unclear. We therefore examined the effects of pharmacologic autonomic blockade (PAB) on frequency and fractionation in patients with atrial fibrillation (AF). METHODS: Esmolol and atropine were administered and electrograms were recorded simultaneously from both atria and the coronary sinus. In 17 patients, AF was recorded for 5 minutes and dominant frequency (DF) and continuous activity (CA) were compared before and during PAB. RESULTS: Examination of the pooled data (537 sites, 17 patients) revealed a statistically significant decrease in mean DF (5.61­5.43Hz, P < 0.001) during PAB. Site-by-site analysis showed that 67% of sites slowed (0.45 ± 0.59 Hz), whereas 32% accelerated (0.49 ± 0.59Hz). Fractionation was reduced: median CA decreased from 31% to 26% (P < 0.001). In patient-by-patient analysis, mean DF/median CA decreased in 13 of 17 patients and increased in four. The spatial heterogeneity of DF decreased in nine of 17 patients (spatial coefficient of variation of DF at "nondriver sites" decreased by a mean of 2%). CONCLUSION: PAB decreases DF and CA in the majority of sites. Given the complexity of interactions between atrial cells during AF, the effects of PAB on DF and fractionation are more heterogeneous than the effects of PAB on isolated cells.

The temporal variability of dominant frequency and complex fractionated atrial electrograms constrains the validity of sequential mapping in human atrial fibrillation.

BACKGROUND: It has been proposed that sequential mapping of dominant frequency (DF) and complex fractionated atrial electrograms (CFAE) can identify target sites for ablation of atrial fibrillation (AF). These mapping strategies are valid only if DF and CFAE are temporally stable on the timescale of the mapping procedure. We postulate that DF and CFAE are temporally variable; consequently, sequential mapping can be misleading. OBJECTIVE: To make prolonged spatially stable multielectrode recordings to assess the temporal stability of DF and CFAE. METHODS: We recorded electrical activity for 5 minutes with the use of a 64-electrode basket catheter placed in the left atrium of 18 patients presenting for AF ablation. DF and CFAE were determined off-line, and their temporal variability was quantified. Maps created from simultaneous versus sequentially acquired data were compared. RESULTS: DF was temporally variable: the average temporal coefficient of variation was 22.7% +/- 5.4%. DF sites were transient, meeting criteria for only 22.1 seconds out of 5 minutes. Similarly, CFAEs were transient (average duration of CFAE 8.8 +/- 11.3 seconds). DF and CFAE sequential maps failed to identify 93.0% +/- 12.4% and 35.9% +/- 14.9% of DF and CFAE sites, respectively. CONCLUSION: Because of temporal variability, sequential DF and CFAE maps do not accurately reflect the spatial distribution of excitation frequency during any given sampling interval. The spatial distribution of DF and CFAE sites on maps created with sequential point acquisition depends upon the time at which each site is sampled.