Rotors in Human Atrial Fibrillation

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Rotors in Human Atrial Fibrillation

Sanjiv M. Narayan and Wouter-Jan Rappel

Chapter Outline

Triggers Interact With Sustaining Mechanisms to Cause Human Atrial Fibrillation

Mapping Rotors During Human Atrial Fibrillation

Sustaining Rotors and Focal Impulses for Human Atrial Fibrillation

Clinical Implications

Conclusions

Mechanistic concepts for human atrial fibrillation (AF) have evolved substantially. In the past 15 years, meticulous mapping has established that human AF may be triggered by ectopic focal beats, while the combination of bioengineering analyses with detailed mapping has recently provided compelling evidence that AF, once triggered, is maintained by relatively few stable electrical rotors and focal sources that lie in patient-specific locations. These advances in our mechanistic understanding have already led to advances in therapy and improved outcomes for patients with AF.

In seminal work, Haïssaguerre ¹ reported that localized ectopy from the pulmonary veins (PVs) may trigger AF. This discovery launched the field of potentially curative AF ablation, with PV isolation as its cornerstone.² Nevertheless, the mechanisms that perpetuate AF, once triggered, remained undefined.^3,4 The multiwavelet hypothesis proposed that multiple spatially meandering electrical waves cause AF.⁵ However, this did not explain consistent patterns of propagation observed in patients with AF,^6,7 the termination of AF after localized ablation,^2,8 or the opposite finding—that extensive ablation to constrain wavelets may have little acute impact.^2,9 The alternative localized source hypothesis is based on animal and in silico experiments in which rapid localized spiral waves (rotors)^4,10 or focal sources⁷ directly cause AF. Although rotors in human AF have been disputed,⁵ and direct evidence has been lacking,⁴ rotors have been indirectly suggested at sites of high dominant frequency where ablation terminates paroxysmal AF^11,12 and, if interatrial rate gradients are abolished, improves outcome,¹¹ and by AF mapping.¹³

Recent data from our ¹⁴ and other laboratories¹⁵ show that human AF is indeed perpetuated by a small number of stable rotors or focal sources^14,15 in individuals with paroxysmal, persistent, and long-standing persistent AF. The mechanistic role of stable AF source rotors has been supported by the acute termination and subsequent non-reinducibility of AF by brief targeted ablation (focal impulse and rotor modulation [FIRM]) before any other intervention. Clinically, this approach has been shown to substantially improve the long-term elimination of AF compared with conventional ablation alone.¹⁶

In this chapter, we summarize the evidence for localized electrical rotors and focal sources for human AF, in the context of the historical background in this area. We then describe approaches to, and results from, mapping rotors and focal sources for human AF, and conclude with current clinical applications of this approach.

Triggers Interact With Sustaining Mechanisms to Cause Human Atrial Fibrillation

The fact that AF may be triggered by ectopic beats ¹ draws an intuitively attractive parallel with the mechanisms for “simple” supraventricular (SVT) and ventricular (VT) tachycardias, which are also triggered by ectopic beats. In those arrhythmias, triggers engage specific mechanisms of dual atrioventricular (AV) nodal physiology to maintain AV node reentry,¹⁷ an accessory pathway for maintaining AV reciprocating tachycardia,¹⁸ or a slowly conducting isthmus to maintain ventricular tachycardia.¹⁹

We hypothesized that AF may be caused when triggers engage specific AF-maintaining mechanisms that may be created dynamically via conduction block, leading to localized reentry, or by triggering repetitive focal beats. To address this hypothesis, we studied the rate dependence of monophasic action potential duration (APD) in the left and right atria, and bi-atrial patterns of rate-dependent bi-atrial conduction slowing in the left and right atria.20,21 and propagation en route to AF using multipolar basket catheters.

In a series of studies, we recently demonstrated that human AF onset is consistently preceded by alternans and complex oscillations in APD, which create a milieu of heightened repolarization dispersion immediately before AF onset. In patients with persistent and paroxysmal AF, we have found that sustained rapid rates produce marked alternans and complex oscillations in APD ²² preceding AF,²³ independently of APD restitution. In parallel, bi-atrial conduction velocity slows dynamically (restitution) just before AF onset at the location where AF is initiated.²⁴

In summary, these observations show that the onset of human AF is preceded by dynamic localized conduction slowing and exaggerated repolarization dispersion, both of which may be subtle or concealed at baseline. These conditions favor reentry and have provided the functional underpinnings for our studies of human AF mechanisms.

Mapping Rotors During Human Atrial Fibrillation

Prior Mapping Studies of Human AF

Several mechanisms for the maintenance of human AF have been proposed, including disorganized multiwavelet reentry,5,25 spatially localized reentrant²⁶ or focal⁷ sources, and mixed patterns.¹³ Divergence in these hypotheses in large part may reflect mapping that has not always met “classical” requirements: to broadly map chambers of interest, at sufficient spatiotemporal resolution to identify varying patterns, over long enough periods to capture variability, then to use interventions to demonstrate that proposed mechanisms are causal and are not bystanders. Failure to apply these criteria even to simple supraventricular^17,18,27 and ventricular¹⁹ arrhythmias is a well-recognized cause of incorrect diagnosis and potentially undesirable therapy.

Many clinical studies over the past decade show that human AF is spatially non-uniform. For instance, human AF exhibits consistent activation patterns,²⁸ consistent rate, or dominant frequency gradients within and between atria,^6,29 as well as electrocardiographic (ECG) spectra suggesting conserved global spatiotemporal organization for at least days³⁰ within and between patients. These data have long supported the notion that human AF is maintained by spatially localized mechanisms, further supported by the fact that human AF may terminate with ablation at defined triggers, drivers,¹ and other localized regions.^12,31 Such regions may arise in either atrium³² and are difficult to identify a priori, but can be ablated in both atria by a systematic stepwise approach.⁸

Higher-resolution mapping, on the other hand, has produced surprisingly inconsistent results. In seminal intraoperative mapping studies in AF patients, Cox, Schuessler, et al 33,34 found stable reentry within disordered AF that were interrupted by lesions that formed the basis for the Maze procedure³⁵ and that still underpin many current ablation lesion sets.² Conversely, in separate human AF studies,³⁶ Allessie et al found no consistency within disordered AF and concluded that AF was attributed to multiple reentrant waves (as in early computer models³⁷) with “focal” events reflective of transmural breakthrough. However, these studies mapped <20% of the dilated atria in these patients, and did not apply interventions to prove causality of disordered activation. More recent epicardial mapping has revealed localized high-frequency regions in AF patients consistent with sources.^7,38 Schilling et al³⁹ and more recently Cuculich et al¹³ used mathematical inverse solutions to map the atria via noncontact approaches (Ensite 3000™, St Jude Medical, Minneapolis, Minnesota, and EcVue™, Cardioinsight, Cleveland, Ohio, respectively) in AF.¹³ However, such studies have yet to use focused ablation to establish causality of each proposed mechanism and exclude bystanders.

Requirements to Map Human AF

Without a priori knowledge of the spatiotemporal organization of human AF, it has been difficult to propose “design” requirements for mapping. In 2001, we set out to study human AF by designing an approach suitable for mapping spatially meandering multiple wavelets or for identifying potential localized sources (rotors or focal sources). Our initial hypothesis was that localized sources do not exist in human AF.

Detection Design Requirements

We reasoned that the factor most relevant to mapping spatial resolution is the length scale of the mapped event. Figure 43-1 illustrates a rotor with limited movement of the rotor tip (in a locus of migration) and wavebreak to fibrillation, generated in a computer simulation. Electrophysiological model parameters were chosen such that the spiral breaks down far from the migration locus.^3,4,23 The rotor controls activation in a “coherent domain” in 1 : 1 fashion with length scale R_rotor, beyond which activation breaks down into complex spatiotemporal patterns. A coherent rotor domain surrounded by incoherent activity can also be generated in simulations of heterogeneous tissue.^40,41 To map the rotor core, the required spatial resolution is comparable with the length scale of the reentrant path R_locus. It is important to note, however, that to simply detect rotational activity around the core (the rotor), the required spatial resolution is coarser and is comparable with its wavelength, λ, which is much larger than R_locus.

Figure 43-1 Snapshot of a Computer Simulation in Homogeneous Tissue
A rotor, the locus of migration of its tip, and its coherent domain of rotational activity (i.e., tissue controlled in a 1 : 1 fashion by the rotor). The model parameters were chosen such that beyond this region of tissue, the rotor breaks down into other spatiotemporal structures as the result of discordant alternans. The relevant length scales in the problem are the size of the domain of locus migration of the rotor tip, R_locus, the coherent domain (of detectable rotational activation), R_rotor, and the wavelength of the rotor, λ.

Figure 43-1 also illustrates the importance of mapping a sufficiently large field-of-view. Attempting to map a rotor with a field-of-view smaller than its trajectory of migration (using a small mapping plaque) may lead to results that are difficult to interpret. Hence, if the locations of putative AF sources are unknown, then as much of the atrial surface as possible should be mapped. Finally, the temporal resolution must be able to distinguish activation between neighboring recording sites and thus can be found by dividing the spatial resolution by the dynamic conduction velocity. For example, for a spatial resolution of 5 mm and a range of conduction velocity of 50 to 150 cm/s,⁴² the required temporal resolution is 3.3 to 10 ms.

We estimated the length scales λ, R_locus, and R_rotor, and thus the required spatial resolution, to map potential localized sources of human AF, based on animal studies and observations of human AF. Animal models of AF show varying mechanisms, including localized spiral waves (rotors),43,44 focal sources,⁴⁵ or nonlocalized waves.¹⁰ In experiments showing rotors, the length scale for the reentrant path (R_locus) ranges from 1 cm to >3 cm,^10,46,47 requiring a minimum resolution of 0.5 cm for mapping. Spatial organization in some models controlled tissue areas >5 cm²,⁴⁴ corresponding to a rotor length scale and wavelength >2 cm. Thus, once the location of a rotor is identified, reentry requires mapping a field-of-view of at least 2.5 × 2.5 cm, with a resolution of ≈1 cm.

In humans, the length scale of the reentrant path may be estimated from the concept of tissue wavelength ⁴⁸ as the product of minimum conduction velocity and the shortest refractory period. In AF patients, minimum (dynamic) conduction velocity in left and right atria is ≈40 cm/s⁴² and the minimum atrial refractory period ≈100 to 110 ms,^20,23 resulting in a minimum wavelength of ≈4 to 5 cm, diameter of ≈1.5 cm, and minimum required spatial resolution of ≈1 cm.

Numeric Validation of Design Requirements for AF Mapping

To test these design criteria for mapping human AF, we performed in silico data validation using an electrophysiological model. The model simulates wave propagation using the monodomain equation:

where V is the membrane voltage, C_m represents the membrane capacitance, D is the diffusion tensor, and I_ion represents the membrane currents. For the purposes of illustrating propagation in silico, we computed membrane currents using the 3- and 4-variable Fenton-Karma (FK) model.^49,50

Figure 43-2 illustrates spiral wave reentry in a 200 × 200-node simulation area with a physical size of 5 × 5 cm, corresponding to a spatial resolution Δx of 0.25 mm (Figure 43-2, A). The spiral is single-armed with a wavelength larger than L_rotor/2 and a period of 90 ms. The computed locus of migration of the rotor tip is illustrated in red in Figure 43-2, A, and consists of a complex meandering trajectory with a length scale of ≈1 cm. Thus, this simulated rotor has L_locus ≈1 cm, L_rotor >5 cm, and λ >2.5 cm.

Figure 43-2 Effect of Mapping Resolution on a Simulated Clockwise Rotor
Simulation on a 200 × 200 grid. A, Spatial resolution Δx = 0.25 mm, corresponding to a 5 × 5-cm domain. The activation is plotted using a gray scale, with white corresponding to depolarized and black corresponding to repolarized tissue. The tip of the rotor meanders as shown in red. The green symbols are isochrones superimposed onto the snapshots. These isochrones are 20 ms apart and are computed as all grid points activated within 1 ms. Scalebar = 1 cm. B, Isochrones computed on a 20 × 20 grid obtained by coarsening the original grid. Isochrones are again 20 ms apart with the order green, blue, purple, and red; scalebar represents spatial resolution (Δx = 2.5 mm). C, Isochrones computed on an 8 × 8 grid providing spatial resolution Δx = 6.25 mm. D, Isochrones computed on a 4 × 4 grid providing spatial resolution Δx = 12.5 mm. Note that rotational activity (organized domain) of the rotor remains detectable at all resolutions.

Activation times for each node were determined using a voltage threshold (10% maximal) and were stored at temporal resolution Δt = 1 ms. Activation times were used to compute isochrones separated by 20 ms (Figure 43-2, B, green). To simulate coarser recording resolution, we coarsened stored activation time intervals but did not rerun simulations. Figure 43-2, B-D illustrates isochrones for the same rotor at resulting spatial resolutions of Δx = 2.5 mm (20 × 20 grid), Δx = 6.25 mm (8 × 8 grid), and Δx = 12.5 mm (4 × 4 grid), corresponding to isochronal intervals of 3 ms, 7 ms, and 18 ms, respectively. Notably, all values of Δx preserved rotational activity of the organized domain of the rotor.

Summary of Design Requirements for Human AF Mapping

These estimates and numeric simulations suggest that a spatial resolution of ≈0.5 cm may be able to resolve rotor migration, and a spatial resolution of ≈1 cm may capture rotational activity of a rotor in human AF. The corresponding temporal resolution should be at least 6 ms. These considerations laid the foundation for our direct contact focal impulse and rotor mapping (FIRM) approach,¹⁴ which we recently described to identify patient-specific sustaining rotors and focal sources for human AF. Localized AF sources were identified at electrophysiological study and their causal role verified by AF termination by patient-specific targeted ablation alone.

Sustaining Rotors and Focal Impulses for Human Atrial Fibrillation

Recently, our group ¹⁶ and others¹⁵ showed that human paroxysmal, persistent, and long-standing persistent AF are predominantly sustained by localized rotors or focal sources. In a multicenter experience that currently includes more than 200 patients, stable rotor or focal sources were identified in >98% of patients, in diverse bi-atrial locations that were stable for prolonged periods in each individual. Direct targeted ablation was applied to each mapped source (FIRM) before any other intervention, which led acutely to the termination or substantial organization of AF in the vast majority of cases. Patients who received FIRM together with conventional ablation had substantially greater freedom from AF on rigorous long-term follow-up compared with those receiving conventional ablation alone.

Identification of Rotors and Focal Impulses in Human AF: Focal Impulse and Rotor Mapping

We designed FIRM mapping on the basis of the above considerations including the requirement to apply ablation to prove proposed AF mechanisms.¹⁴ Accordingly, FIRM mapping is performed during clinical electrophysiology study by advancing 64-pole basket catheters to the right atrium and, after transseptal puncture, to the left atrium. Contact electrodes provide spatial resolution of 4 to 6 mm along each spline, and ≈4 to 10 mm between splines (higher resolution at the poles than at the equator). Heparin is infused to maintain activated clotting time >350 ms. In early work, we mapped both atria simultaneously (Figure 43-3

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