Mechanisms of AF: Multiple Wavelet Hypothesis, Reentry, Spiral Waves, Rotational Activity, and Focal Triggers from the Pulmonary Veins and Other Sites
For many years, three concepts competed to explain the mechanism of AF: multiple reentrant wavelets (Figure 3A), rapidly discharging automatic foci (Figure 3B), and a single reentrant circuit with fibrillatory conduction (Figure 3C).194, 195,196 Considerable progress has been made in defining the mechanisms underlying initiation, perpetuation, and progression of AF (Figures 3, 4).16,17 A key breakthrough was the recognition that in some patients, AF is triggered and/or maintained by rapidly firing foci and can be “cured” by local catheter ablation.197 This crucial observation focused attention on the PV cardiomyocyte sleeves. Subsequent work confirmed the key role of the PVs in AF, particularly paroxysmal forms, and showed that the PVs have features that make them favored zones to harbor both focal automatic and microreentrant activity.157
The multiple wavelet concept was initially proposed by Garrey (Figure 3A), was later refined by Moe, and for at least 50 years became the dominant mechanistic framework for AF. Engelmann had earlier suggested that AF was maintained by rapidly discharging atrial ectopic foci,198,199,200 a notion that was subsequently rejected only to periodically resurface.201 Finally, Thomas Lewis suggested that a single rapidly rotating primary reentrant circuit (a “mother wave”) was the most likely mechanism underlying AF.202 For AF due to a single ectopic focus or a rapidly rotating single circuit, fibrillatory conduction is required to account for the irregular activation typical of AF.203 All three of these classical mechanisms were proposed in the early 20th century and continue to underlie much of the contemporary thinking about AF mechanisms.195
As mentioned above, the observations of early investigators who recognized the importance of the PVs in AF were critical. Their initial observations pointed to a critical role for very rapidly discharging PV foci in maintaining AF. Subsequent experimental studies indicated that the PVs could indeed represent sites of very rapid automatic activity, which is enhanced by the rapid activation caused by AF.204 Subsequent detailed studies of PV cardiomyocyte ion-current function84 and structure91 indicated that the PVs also have properties favoring local microreentry, which likely contribute to their participation in AF. Recent studies have implicated abnormal Ca2+ handling and DAD related to spontaneous ectopic activity of patients with paroxysmal or long-standing persistent AF.186,205 However, more recent studies strongly suggest that during long-term sustained AF, one should not expect an increase in the spontaneous release of Ca2+ from the SR, nor that DADs or triggered activity is involved in AF maintenance or in the progression to stable forms of the arrhythmia.158,206,207 Subsequent to recognition of the importance of the PVs, a variety of sites other than the PVs have been shown to potentially harbor AF-maintaining sources,208 but the critical importance of the PVs has withstood the test of time.
Allessie et al induced and mapped electrically induced tachycardia in isolated rabbit atria and documented the circular movement reentry in that model.209 Using a limited number of electrodes, the authors detected an activation sequence that suggested centripetal direction of wavelet propagation. The authors proposed that these centripetal wavelets activated tissue at the center of the circuit, resulting in double responses (double potentials) of subnormal amplitude. Because the centripetal wavelets were unable to propagate beyond the center, they prevented the impulse from shortcutting the circuit, resulting in the maintenance of reentry. This mechanism of reentry was named leading circle reentry by Allessie et al.209 Building on ideas put forward initially by Mines and later quantified by Wiener and Rosenblueth, Allessie et al suggested that functional reentry naturally establishes itself in the shortest circuit that can maintain reentry, defined by the distance a cardiac impulse travels during the RP.210,211,212 This distance determines the length of the shortest reentrant cardiac excitation wave (wavelength, WL) and is equal to the product of conduction velocity (CV) and RP (e.g., WL = CV × RP). If AF is maintained by multiple simultaneous reentrant waves, the likelihood of spontaneous termination is greatest when the atria are only large enough to maintain one reentrant wave; if the wavelength is shortened so that multiple waves can be maintained simultaneously, the chances of spontaneous termination will be greatly reduced and AF is likely to be sustained. Evidence to support this notion was obtained in a dog model by varying autonomic tone and administering antiarrhythmic drugs (AADs).211 However, some clinical observations were incompatible with the leading circle mechanism, notably the effectiveness of Na+ channel blockers in AF. According to the leading circle notion, Na+ channel blockers should decrease the wavelength by reducing CV and thereby promote, rather than terminate, AF. Furthermore, for many years, multiple numerical studies and high-density mapping studies in cardiac tissues have failed to confirm the idea of the leading circle or the presence of centripetal wavelets in the maintenance of reentrant excitation.
Computer simulations and experiments in multiple mammalian species suggest that functional reentry is better explained by rotors or spiral waves (Figure 3D). This idea was first conceptualized by Russian scientists in the 1960s, and later popularized by Arthur Winfree to explain the reentry in all excitable media.213,214,215 The rotor is the organizing center of the reentrant excitation215; it spins at exceedingly high frequencies, radiating spiral wavefronts with outwardly decreasing curvature, forming an Archimedean spiral, and resulting in wave fragmentation in its periphery.216,217 Because CV decreases as the wavefront curvature becomes steeper toward the center tip, it follows that at that site (sometimes called the phase singularity [PS]) the curvature reaches a critical value, the velocity becomes zero, and the PS follows a circular trajectory.215,218 At each point the direction of propagation is perpendicular to the wavefront and the velocity increases toward the periphery. The PS is a unique point where the wavefront and the wavetail converge and velocity is zero, preventing the impulse from extending toward the center of the rotation. Instead, the PS becomes the rotor, circling around a small center of unexcited but excitable tissue.218 The concept of rotor can also be applicable to anatomical reentry in the atria; a pectinate muscle or the orifice of a PV can stabilize a reentrant rotor.156,219 Unlike leading-circle reentry, spiral-wave reentry is not determined by the wavelength, but rather by the source-sink relationship between the activation wavefront and the tissue that must be excited in front of it to maintain activity. The rotor concept has been applied to AF, and subsequent studies have confirmed its ability to account for the AF-suppressing actions of Na+ channel blockers.119
Recent advances in electrophysiological recording and analysis have led to important advances in appreciating AF-maintaining mechanisms in patients. Interestingly, they have also led to new controversies. The application of advanced computing technology to the definition of detailed intracardiac electrical activity based on highly sophisticated body surface mapping (BSM), a technique called electrocardiographic imaging (ECGI), has led to the noninvasive analysis of underlying mechanisms in patients with AF.220,221 Both focal and reentrant rotor sources were visualized and tended to become more numerous as AF was maintained for longer periods.221 Detailed analysis of patients undergoing AF ablation indicates that rotors are localized to specific atrial regions and tend to be short-lasting, with rotor cores tending to occur at the interface between fibrotic tissue and more normal atria.222 Investigators have also applied intra-atrial basket catheters and complex mathematical analysis to define AF mechanisms and target them in the electrophysiology laboratory with a technique called focal impulse and rotor modulation (FIRM).77 FIRM procedures have identified rotational activity in patients with AF. A number of studies have shown the superiority of FIRM-based ablation over conventional ablation strategies.223 However, the success of targeted rotational activity ablation, as well as the meaning of rotors detected by FIRM technology, have been disputed in recent clinical studies. A prospective randomized clinical trial is now underway. It is notable that conventional mapping techniques using isochronal mapping have not been able to identify continuous rotational activation.224,225 It is also notable that detailed human atrial mapping studies have not observed discrete rotors, but rather suggest that AF is maintained by dissociation between epicardial and endocardial layers, with mutual interaction producing multiplying activity that maintains the arrhythmia (Figure 3E).226,227,228,229 Investigators have recorded more than 500 epicardial electrograms from both atria during cardiac surgery in patients with persistent AF and were unable to identify reentrant activity.229 They interpreted their results as suggesting predominance of focal activity and breakthroughs. Potential unifying findings were recently presented by investigators, who performed high-resolution endocardial and epicardial optical mapping in explanted diseased human hearts.227 They noted that AF was driven by stable transmural reentrant sources anchored to anatomical complexities and fibrotic regions. One limitation of their studies was a need for an action potential abbreviating drug (pinacidil) to observe AF, limiting the applicability of their findings to spontaneous AF.
In summary, although the presently available data leave a number of questions open, they do indicate that both ectopic activity and reentry play important roles in AF. The specific mechanisms and determinants remain to be elucidated, along with their implications for therapy.