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Mechanistic Approaches for Persistent Atrial Fibrillation Ablation
Introduction
Atrial fibrillation (AF) is the most common sustained arrhythmia seen in clinical practice, and its prevalence is progressively increasing in developed countries. The highly successful catheter-based procedure, pioneered by Haissaguerre and colleagues, of ablating ectopic triggers that arise from the pulmonary veins in paroxysmal AF has evolved and progressively been extended to a much more heterogeneous population, in which unfortunately the success rate is significantly lower. New technical developments (“single shot” devices, mechanical and magnetic-based remote navigation, contact force-guided catheter ablation, etc.) have emerged during the last few years aiming to simplify pulmonary vein isolation (PVI) and increase safety. However, PVI is still associated with suboptimal clinical outcomes in persistent AF, which may be directly correlated with a progressively increased relevance of extrapulmonary vein regions in AF maintenance. For this reason, several empirical ablation strategies have been used in these patients in addition to PVI: linear ablations, posterior wall isolation, ablation of the ganglionic plexi, ablation of complex fractionated atrial electrograms (CFAEs), and stepwise methods combining some of them. Although initial series reported clinical benefit using some of these approaches, recurrences in the form of macroreentrant atrial arrhythmias have concurrently increased after targeting extrapulmonary vein regions. In addition, the effectiveness of these approaches has been called into question by larger, multicenter, randomized trials. Recently, left atrial appendage isolation has been proposed to increase this empirical armamentarium, although it has been associated with thrombus formation and increased risk for stroke. As a result of the foregoing, the optimal ablation strategy beyond PVI for persistent AF remains unclear. Such a disappointing scenario may be the result of the intrinsic limitations of approaches almost exclusively relying on anatomic landmarks and paying scant attention to the underlying mechanisms of persistent AF maintenance. Several approaches been developed to increase the specificity of persistent AF ablation procedures and their long-term outcomes. Such mechanistic approaches are based on further understanding of the mechanisms and patterns of activation underlying persistent AF. In fact, they can be considered a direct result of insights into the dynamic behavior of AF drivers initially obtained from experimental optical mapping studies and computer simulations of AF dynamics. For a revision of the competing theories attempting to explain the mechanisms underlying AF maintenance and the different experimental methodologies to map electrical activity during AF, the interested reader may consult our previous review. The purpose of this chapter is to specifically review the existing mechanistic mapping and ablation approaches aimed at targeting persistent AF drivers and their most recently reported outcomes.
Dominant Frequency Mapping
Spectral analysis is often used to localize the areas with the highest activation frequencies (DF max , shortest cycle lengths) during AF; such areas are supposed to host the fastest rotational or focal drivers (rotors or foci). Briefly, the spectrum of a signal during fibrillation represents the distribution of the energy/power of such a signal in the frequency domain. The frequency of the highest peak of the spectrum at one location is called dominant frequency (DF), which is often interpreted as a surrogate of the inverted average cycle length at that location. Spectral analysis enables investigators to perform an automated analysis of electrograms and is especially useful when the capability of accurately measuring the activation rate of the signal in the time domain is not available. In addition, the power spectrum is often used to quantify the aperiodic complexity of the signals based on the regularity index (RI), which ranges between 0 (completely aperiodical) and 1 (completely periodical). Atienza and colleagues performed ablation procedures guided by atrial DF maps of endocardial bipolar signals. These maps were obtained by means of electroanatomic mapping systems with embedded real-time spectral analysis capabilities. Only bipolar signals with RI of 0.2 or greater were used to create the DF maps. In an initial single-center study, Atienza and colleagues targeted DF max sites in addition to PVI. This procedure resulted in sinus rhythm maintenance in 56% of persistent AF patients after a follow-up of 9.3 ± 5.4 months. More recent data from the multicenter radiofrequency ablation of drivers of AF (RADAR-AF) trial showed that targeting DF max sites after PVI did not add additional value in 117 patients with persistent AF. In addition, this strategy trended toward more serious adverse events than PVI alone. These suboptimal results highlight the difficulty in identifying the dominant source(s) driving AF as atrial remodeling evolves. Moreover, sequential point-by-point acquisition of bipolar signals with a conventional ablation catheter (large electrode size) may be limited in its ability to properly identify high-frequency sources that often drift or meander over short periods of time.
Focal Impulse And Rotor Modulation Mapping
The focal impulse and rotor modulation (FIRM) mapping approach has the merit of being one of the first mechanistically based approaches to AF ablation that derives from the translation of basic science knowledge into the clinical arena. Narayan and associates used two basket catheters to obtain simultaneous endocardial unipolar electrograms from 128 locations at both atria in patients undergoing AF ablation ( Fig. 45.1A ). In addition, they developed a computational mapping system (RhythmView) based on such atrial electrograms, which enabled them to generate and visualize isopotential movies of the electrical activity and isochronal maps from individual cycles, based on bilinear interpolation of the phase state between each electrode and its nearest neighbors. Rotational activities (early meets late, i.e., red meets blue) around a center of rotation were identified as rotors, whereas focal activations were identified as activated areas that propagated centrifugally from the site of origin (see Fig. 45.1B ). From the start, the technology presented some inherent limitations that have been reviewed in detail elsewhere. For example, basket catheters often enable suboptimal electrode-tissue contact at many poles, their splines are sometimes not equidistantly separated once they are deployed in the atria, and their raw interspline spatial resolution is poor. In addition, focal activation might be interpreted as rotational activity if the wavefront reaches the surrounding electrodes sequentially. In fact, after highly promising initial single-center and multicenter nonrandomized studies that strongly supported the use of the methodology to detect and target rotors and focal sources to treat persistent AF, recent results of the larger Randomized Evaluation of AF Treatment With Focal Impulse and Rotor Modulation (REAFFIRM) multicenter trial have tempered the initial expectations. In this trial, 350 patients with persistent AF were randomized to either conventional PVI or FIRM-guided ablation followed by PVI. Although effectiveness in both arms was higher than historically reported, the study failed to provide evidence for FIRM + PVI superiority over PVI alone. The authors of the study reported that after a blanking period of 3 months, single procedure freedom from AF and atrial tachycardia recurrences at 12 months was 69.3% in the FIRM + PVI group and 67.5% in the PVI group ( P = .96).
Electrocardiographic Imaging And Phase Mapping
Recent studies have used a noninvasive electrocardiographic imaging (ECGI) system in which the body surface potentials recorded with 252 electrodes and the geometrical information provided by computed tomography are combined by algorithms that solve the electrocardiographic inverse problem to noninvasively obtain estimated epicardial electrograms (see Fig. 45.1C ). This approach is also subject to relevant limitations discussed elsewhere in detail. There are two important drawbacks: (1) With the exception of some specific systems, ECGI is limited to providing estimated electrograms of the atrial epicardium. Therefore the technology is not suited to provide the electrical activity on the interatrial septum, pulmonary vein–left atrial appendage ridge, coronary sinus, and so forth. (2) The torso geometry is obtained by computed tomographic imaging, so the patient is exposed to a considerable radiation dose. Haissaguerre and coworkers used the ECVUE system (CardioInsight), which added phase mapping capabilities to ECGI, to detect and target for ablation rotational and focal drivers in a series of 103 patients with persistent AF. Intervals of spontaneous or induced AF free from ventricular activity were selected for analysis. Phase mapping movies displayed over the biatrial epicardial geometry showed focal breakthroughs and/or rotors alongside their meandering/drifting trajectory paths (see Fig. 45.1D ). The system also revealed hot regions with high spatiotemporal density of focal or rotational drivers (see Fig. 45.1E ). The authors of the studies reported that rotors moved over wide regions of the atria, but recurred periodically in the same region. Eighty percent of drivers were rotors and 20% focal breakthroughs. Interestingly, most of them colocalized. Ablation of driver domains alone terminated AF in 63% of patients (75% of persistent and 15% of long-lasting AF patients) after 35 ± 21 minutes of radiofrequency delivery. Importantly, a marked reduction in termination rate was observed in AF episodes lasting 6 months or longer. Seventeen percent of patients required additional linear lesions to terminate AF after driver ablation. In total, AF terminated in 80% of patients (34% of them with direct conversion to sinus rhythm and 66% to atrial tachycardia, which required further ablation). After a 12-month follow-up and redo ablation in 18% of patients (three-fourths of them for atrial tachycardia), 64% patients were in stable sinus rhythm, 16% in atrial tachycardia, and 20% in AF. Of note, because mapping was performed bedside within 24 hours preceding the invasive procedure, the onset or extinction of drivers during ablation was not assessed. Therefore there may be room for improving the ablation results if real-time data were used during the procedure. A more recent study from the same group reported data from 135 patients with persistent AF. The authors of the study showed that the complexity of AF dynamics increased with longer AF durations, as reflected by an increased number of rotations, focal events, and regions hosting them. Indeed, with increased AF duration, a higher proportion of patients had multiple extra-PV driver regions, especially in the inferoposterior left atrium (LA) and superior and inferior right atrium (RA). In a recent multicenter study from eight European centers enrolling 118 patients with continuous AF for less than 1 year, ablation targeted drivers detected by the ECVUE system, followed by PVI and finally LA linear ablation if AF persisted. Driver ablation alone resulted in AF termination in 64% of patients with a mean time of radiofrequency delivery of 46 ± 28 minutes. In an additional 8% of patients, PVI or LA lines were required for acute AF termination. Total radiofrequency delivery was 75 ± 27 minutes. At 1-year follow-up, 78% of the patients were off antiarrhythmic drugs (AADs) and 77% of the patients were free from AF recurrence. However, 49% of the patients with no AF recurrence experienced one or more episode of atrial tachycardia during follow-up. Therefore it could be concluded that targeting drivers identified by the ECVUE system can result in high rates of AF termination (after a considerably large amount of radiofrequency delivery) and freedom from AF recurrence, but with the added cost of frequent recurrent atrial tachycardias that require further management.
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