Introduction

Approaches for the ablation of atrial fibrillation (AF) have changed rapidly in the past two decades and are focused on eliminating triggers near and from the pulmonary veins (PVs), which may initiate AF. PV-guided ablation ameliorates AF in many patients , yet success remains suboptimal even in recent studies using force sensing catheters or cryoballoon ablation to minimize PV reconnection. Adding extensive ablation of complex fractionated electrograms or linear lesions have not improved the results of PV isolation (PVI) in recent multicenter trials.

Focal and rotational drivers for AF are increasingly studied ablation targets, whose mechanistic role has long been defined in translational studies and for which there is steadily increasing evidence in patients. Focal impulse and rotor mapping (FIRM), the most widely applied method to map AF drivers, reveals focal and rotational drivers, which may spatially overlap drivers in recent optical mapping studies of human AF and are similar to AF drivers described by other methods. Several important clinical questions currently exist. First, despite promising overall outcomes of AF driver ablation in a metaanalysis, it is unexplained why outcomes vary between centers. Second, there is a lack of practical guidance on how to optimally map and ablate AF drivers and avoid pitfalls. Third, it is unclear if different AF mapping methods would show similar or different features in the same patient. This chapter provides a practical clinical overview that attempts to address these topics.

Mechanistic Targets for Therapy: Rotational Drivers, Focal Drivers, and Disorganization

Despite decades of pharmacologic, surgical, and ablative therapy for AF, gaps in our mechanistic understanding of AF greatly limit ablation efficacy. Early mechanistic models suggested that AF was caused by the asynchronous discharge of numerous ectopic foci, but more recent studies have supported reentrant mechanisms. Fig. 18.1A shows classical reentry around an anatomic obstacle, with a fully excitable gap between leading and trailing edges ( head and tail ). In the leading circle hypothesis, functional reentry is maintained by a wave front encircling an area of tissue that remains refractory from constant centripetal activation, which in turn stabilizes the circuit ( Fig. 18.1B ). Disorganized models of AF have invoked either intermittent foci or meandering leading circle reentry, which suggests the need for extensive ablation to treat AF and largely reduce the importance of mapping.

Concepts of reentry applied to fibrillation. A, Reentry around a fixed anatomic obstacle. The wavelength (black) is shorter than the path length around the obstacle so that the activation wave front encounters excitable tissue (excitable gap, white) . B, Leading circle reentry. As an activation wave front propagates around a functionally refractory core, subthreshold centripetal forces (pointing inwards) depolarize the core slightly to maintain its refractory state. C, A 2-dimensional spiral wave, which, like a pinwheel, spins around a singular point in the center. D, A 3-dimensional scroll wave emanating from a filament. E, Electrophysiology of a spiral wave: Conduction velocity (arrow length) , reentry wavelength (wave front to wave tail) , and excitable gap (wave tail to wave front) diminish towards the center of the spiral wave. At a critical distance from the center, the wave front and tail meet, conduction velocity approaches zero, and a core is formed. If curvature is sufficient, activation will proceed around (dotted line) rather than into the core, forming a rotor. F, Computer simulation of reentry (56). Top, Snapshot of transmembrane voltage in AF. The wave front fuses with the tail creating a core of excitable yet unexcited tissue (core). Bottom, Snapshot of inactivation variables of sodium current; h.j, during reentry (see text)

From Pandit SV, Jalife J. Rotors and the dynamics of cardiac fibrillation. Circ Res. 2013; 112: 849-862. With permission.

Spiral wave reentry was first proposed in computer models, then revealed using optical mapping in isolated fibrillating ventricular muscle ( Fig. 18.1C ). A spiral wave rotates around a core in 2 dimensions, and a scroll wave rotates around a “filament” in 3 dimensions ( Fig. 18.1D ), each of which has a shorter path length than the periphery ( Fig. 18.1E ). At the core, the wave front (solid line in Fig. 18.1E ) encroaches upon the wave tail (dotted line), resulting in less depolarizing current, and slowed conduction velocity (arrows). Conduction slowing enables reentry near the core, where meeting of the wave front/tail meet reduce conduction velocities towards zero ( white asterisk , see Fig. 18.1C ). The core is thus unexcited yet potentially excitable. This differs fundamentally from leading circle reentry in which the center is excited and unexcitable. Fig. 18.1F depicts a snapshot of a computer-generated spiral wave. The spiral wave core and surrounding functional reentry form a “rotor.” This concept provides organizing centers for AF, whether one or multiple, which may in theory be ablation targets.

There is now considerable direct evidence that rotors sustain fibrillation, using optical mapping in isolated hearts from multiple species including human AF. Optical mapping ( Fig. 18.2 ) uses video imaging of voltage-sensitive dye imaging, coupled with phase, activation, or other signal-processing approach, to produce high spatial and temporal resolution maps of AF. Fig. 18.2A illustrates rapid irregular action potentials at one point mapped optically. Fig. 18.2B plots such action potentials across the cardiac surface in fibrillation. Each color represents phase (from activation to repolarization) such that rotations can be traced through the color spectrum (from red to blue). Points in the atrium where activation and repolarization meet, that is, around which an entire cycle can be traced, have undefined phase and are termed phase singularities (PS), which may represent rotor cores. Rotors are not fixed like reentry around an obstacle but may precess in limited areas with complex trajectories ( Fig. 18.2C ). Fibrillation may thus terminate when the rotor collides with a boundary, does not have enough elbow room to spin, or via other mechanisms.

Optical mapping of fibrillatory conduction from an atrial fibrillation source. A, High resolution optical action potentials obtained from explanted fibrillating tissue. B, Snapshot of phase movie of a fibrillating rabbit ventricle, showing rotors as red to blue phase angles, and phase singularities (PS) as dark black dots where all phases (colors) converge. C, Rotor meandering and fractionation during AF in isolated sheep heart. On the left, a left atrial phase snapshot demonstrates reentry in the left atrium (LA) free wall. The inset shows the time–space trajectory of the tip (PS) , while the x and y coordinate signals are shown on the right.

Modified from Gray RA, Pertsov AM, Jalife J. Spatial and temporal organization during cardiac fibrillation. Nature . 1998; 392:75-78; and Zlochiver S, Yamazaki M, Kalifa J, Berenfeld O. Rotor meandering contributes to irregularity in electrograms during atrial fibrillation. Heart Rhythm. 2008;5:846-854. With permission.

Rotors were not consistently shown during clinical AF ablation until recent advances in mapping. Nevertheless, early work by Schuessler, Cox, and colleagues revealed stable reentrant sources that Maze surgery was designed in part to interrupt. Moreover, localized sources for AF have long been supported by observations including termination of persistent AF by localized ablation, detection of localized high dominant frequency suggesting rapid drivers, and spatially consistent activation vectors in AF that contradict disordered waves.

Historically, it was considered that AF resulted from the multi-wavelet and related models, which posit that disorganized activity generates new wavelets. This model requires no driver region per se , and hence that AF can be eliminated only by limiting critical mass, for example, extensive ablation or surgery. However, extensive ablation that limits atrial mass did not improve the elimination of AF in recent clinical trials, and the disorganized AF model does not readily explain the now routine termination of persistent AF by targeting identified regions in multiple studies in at least some patients. Work is needed to better reconcile the source and disorganized models of AF.

The terms spiral wave and rotor are often used interchangeably in the context of cardiac arrhythmias, yet nomenclature in this field is highly controversial. The term rotor is typically applied to the singular spatial point of rapid rotational activity, while spiral waves refers to the curvilinear emanating wave fronts of activation. Clinically the terms rotational activity, rotational driver, or even reentry are equally effective to describe the phenomena now mapped by multiple approaches.

Rationale for Mapping Human Atrial Fibrillation: Applying Basic Science to Patients

The mechanistic debate in AF has been amplified because it has only recently been appreciated that different mapping methods yield different mechanisms. This is not true for organized rhythms (e.g., atrial flutter), and which most systems basically agree. One specific difficulty with fibrillatory waves is that an electrode antenna may capture several local and far-field waves. There are few means of separation except knowledge, which falls within the refractory period, yet whose inclusion or exclusion may dramatically alter perceived mechanisms. Another difficulty is that temporospatial activity changes rapidly within AF, which challenges mapping.

Our laboratory commenced studies of human AF in the early 2000s using monophasic action potentials (MAPs) to reveal repolarization and multipolar catheters to measure conduction velocity in human atria during pacing and AF, and targeted ablation. It became clear in early studies that unipolar, bipolar, and MAP signals in AF differ dramatically, with examples of signals that appeared local in bipolar recordings actually being far field–that is, they lay within repolarization indicated uniquely by the MAP. This may explain why optical maps of AF, which are based on local action potentials, generally show rotational drivers of AF, whereas traditional AF activation maps show only disordered activity.

We set out to physiologically approximate optical maps in the electrophysiology laboratory, using signal processing to exclude far-field based on repolarization data from MAPs, followed by analyses of conduction velocity, and by validation of mechanisms by patient-specific targeted ablation. This led to focal impulse and rotor mapping/modulation (FIRM).

Comparing Different Atrial Fibrillation Mapping Methods

Differences in mapping methods must be reconciled, yet few studies have compared methods in the same patient data. We assembled an international registry to compare mapping methods in patients in whom ablation terminated persistent AF (NCT02997254), for which we will make data available online. Fig. 18.3 shows termination of persistent AF to sinus rhythm AF in a 65-year-old man (panels A , B ). In panel C , AF maps using traditional methods showed only partial and transient rotations (shown), which do not explain the site of termination. In panel D , an independent phase mapping approach shows consistent rotations at this site, corroborated by FIRM maps (panel E ), which show gray-scale activation maps and phase singularities (in red). Both of the latter methods explain AF termination. In one report, sites of AF termination showed rotational AF drivers by phase and activation, plus phase (FIRM), yet these sites were missed by traditional maps. In a preliminary study that directly visualized human atria, AF drivers using FIRM overlapped by drivers from simultaneous optical maps.

Comparing atrial fibrillation mapping methods in the same patient, where ablation terminates persistent atrial fibrillation. In a 65-year-old man, localized ablation (A) near the right superior pulmonary vein carina prior to PVI (B) terminates persistent AF to sinus rhythm. (C, D) Traditional activation maps show only a partial rotation (75% of cycle, orange to light blue) , which may not explain AF termination by ablation in this region. Notably, (E) phase maps by an independent method, and (F) activation plus phase maps (FIRM; activation in gray scale, phase in red) each revealed sustained rotations at the site where ablation terminates AF. Ablation site was identified prospectively by map (F).

Modified from Alhusseini M, Vidmar D, Meckler GL, et al. Two independent mapping techniques identify rotational activity patterns at sites of local termination during persistent atrial fibrillation. J Cardiovasc Electrophys . 2017;28(6):615-622; Zaman JAB, Baykaner T, Swarup V, et al. Recurrent post ablation paroxysmal atrial fibrillation shares substrates with persistent atrial fibrillation: an 11 center study. JACC: Clinical Electrophysiology. 2017;3:393-402.

This approach is limited since termination of persistent AF by ablation is not equivalent to elimination. On the other hand, it is rare to terminate persistent AF by ablation of a few cm ² of tissue before PVI, and other than termination there are few acute end points for ablation. Conversely, while long-term outcomes are the ultimate goal, they are not ideal for assessing the acute accuracy of AF maps since they include the effect of additional lesion sets including PVI, lesion recovery, disease progression, and other factors. Moreover, this approach to comparing maps eliminates apples-to-oranges comparisons of patient populations and recording electrodes, focuses on the mapping method/algorithm, and can introduce comparisons to ablation response.

In summary, different AF mapping methods show different mechanisms. Rudy et al. suggest that activation plus phase is optimal for mapping AF in electrocardiographic imaging (ECGI), which is the approach used by FIRM endocardially. Further comparative mapping studies are needed, particularly those that compare methods in the same patient data sets.

Clinical Outcomes of Focal Impulse and Rotor Mapping-Guided Ablation

Multiple studies now exist on the outcomes from AF driver ablation. Table 18.1 lists outcomes from AF-driver guided ablation studies to April 2017 comprising 1258 patients in 17 distinct populations. FIRM is the most widely applied technique (14/17 studies), and multicenter randomized trials are pending. As with most new approaches, although initial reports were promising, some recent reports have been disappointing. Nevertheless, in a systematic review of the entire population, 68% had persistent AF, with single procedure freedom from AF and from AF/all atrial arrhythmias of 73% and 61%, respectively. Small studies suggest that patients with comorbidities associated with lower PVI success, such as obstructive sleep apnea and obesity, may have more sources often away from PVs that may be targeted by FIRM mapping.

Overall there are many similarities in results between the AF mapping methods in Table 18.1 . Studies of FIRM typically show two to four biatrial AF drivers. ECGI showed three to five, and other techniques by Lin et al. showed two to three. When biatrial mapping is performed, about two-thirds of AF drivers lie in the left atrium and one-third in the right atrium. This distribution may explain ablation outcomes, in which various lesion sets may coincidentally hit AF drivers and contribute to the 70% ceiling of success for extensive left atrium (LA) ablation (i.e., because 30% of AF drivers lie in the right atrium [RA]).

In FIRM studies from multiple groups, AF sources arise in diverse locations, overall with 25% to 40% near pulmonary veins, 25% to 40% elsewhere in the left atrium, and 25% to 40% in the right atrium ( Fig. 18.4 and Table 18.2 ). Body surface mapping and ECG imaging show similar AF driver distributions but in larger regions, which may represent greater meander in projecting from the heart to the torso. In multiple studies right atrial drivers occur mostly in the free wall, posterolateral to the right atrial appendage, and rarely near the superior vena cava (SVC) or cavotricuspid isthmus (see Fig. 18.4 ). AF drivers are present in higher numbers and more widely distributed in patients with persistent rather than paroxysmal AF. The wavelet similarity mapping approach of Lin et al. showed fewer AF drivers, which may reflect mapping after PVI or their point-by-point strategy, and may uncover sites with less spatial precession/meander.

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