Download Chessboard of atrial fibrillation: reentry or focus? Single or multiple

Am J Physiol Heart Circ Physiol 289: H977–H979, 2005;
doi:10.1152/ajpheart.00456.2005.
Editorial Focus
Chessboard of atrial fibrillation: reentry or focus? Single or multiple
source(s)? Neurogenic or myogenic?
Igor R. Efimov and Vadim V. Fedorov
Department of Biomedical Engineering, Washington University, St. Louis, Missouri
The refractory period may be shortened to one-fifth or one-sixth
the normal, although vagus action is a necessary accompaniment
of such high-grade shortening. This change makes rapid reexcitation possible and the formation of circuits having diameters of but
a few millimetres. Since the refractory phase does not occur
simultaneously in all fibers, the circuits must be formed in different
and shifting locations.
ATRIAL FIBRILLATION (AF) is the most prevalent tachyarrhythmia in humans. AF continues to gain increasing prevalence
with the aging of the population, reaching 2.3% after 40 yr of
age and 10% after 80 yr of age (6). Despite more than a century
of research, the mechanisms of initiation and maintenance of
AF remain unclear, and the same principle issues have been
debated over and over again since the 1870s to the 1900s: 1) Is
AF myogenic or neurogenic in nature? 2) Is AF maintained by
reentry or by focal activity? 3) Is AF maintained by a single
source, or are multiple sources required? and 4) Is there a
critical mass of myocardium required to maintain AF?
Initial discovery of fibrillation produced by “faradization”
(electrical stimulation) in Ludwig’s laboratory (11) during
studies of autonomic control of the heart led to domination of
the neurogenic theory of fibrillation. Yet, the subsequent studies of Vulpian (28) and MacWilliam (18) laid to rest the
neurogenic theory. They put forward a myogenic theory of
fibrillation that remained dominant for over a century. The
triumph of this theory was imprinted in the term “fibrillation,”
coined by Vulpian. Yet, MacWilliam himself and many to
follow have demonstrated that unlike ventricular fibrillation
(VF), AF is strongly dependent on the autonomic nervous
system: “The movements excited by faradisation in the auricles
and ventricles differ very markedly in their relation to the
inhibitory influence of the vagus nerve” (18). More recently,
numerous studies have shown a prominent role played by the
autonomic nervous system in the initiation and maintenance of
AF (3, 4, 17, 24, 32). Thus it became generally accepted that
AF is not a purely myogenic phenomenon. Future studies will
undoubtedly uncover new neurogenic elements of AF. The
study of Zou et al. (33) published in this issue of the American
Journal of Physiology-Heart and Circulatory Physiology demonstrates one of such neurogenic elements, which appears to
play a critical role in the induction and maintenance of AF. The
study demonstrates how cholinergic effects may contribute to
the maintenance of microreentrant circuit sustaining AF.
In addition to the neurogenic-myogenic debates, focal and
reentrant theories of AF have been debated since the early days
of arrhythmia research. Seminal work of Garrey (8) and Lewis
et al. (15, 16) provided convincing and overwhelming support
Address for reprint requests and other correspondence: I. Efimov, Dept. of
Biomedical Engineering, Washington Univ., St. Louis, MO 63130 (E-mail:
[email protected]).
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H977
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W. E. Garrey. (Ref. 8, p. 240 –241).
for the reentrant theory of initiation and maintenance of AF, as
it was understood until recently. Garrey and Lewis et al. agreed
on the reentrant nature of AF, yet they disagreed on the number
of reentrant circuits that are required to maintain AF. Lewis et
al. (16) formulated a “mother ring” theory that suggested that
a single reentry circuit is sufficient to initiate and to sustain AF.
This theory has been further developed into the “mother rotor”
hypothesis and supported experimentally by Jalife’s group
(19). In contrast, Garrey (8) and subsequently Moe (21) suggested that multiple reentrant sources are required for AF
maintenance. Allessie et al. (2) provided compelling experimental evidence in support of a theory of multiple reentrant
sources for the initiation and maintenance of AF. Similarly, a
focal theory of AF has been reborn from the ashes by the
clinical observations of Haissaguerre et al. (10). Thus the
research community remains divided as it was in 1940 when
Carl Wiggers wrote: “As to the fundamental mechanisms of
fibrillation we have plenty of theories, but none is universally
accepted. Space is lacking to review the different hypotheses,
but we may note in passing that they all center around two
ideas, viz., (a) that the impulses arise from centers, or pacemakers, or (b) that the condition is caused by the re-entry of
impulses and the formation of circles of excitation. Each of
these views, again, has two groups of exponents, viz., (a) those
who believe that a single focus, or excitation ring, occurs, and
(b) those who favour the idea that multiple foci, or numerous
circus rings, are developed” (30). The study of Zou et al. (33)
provides an interesting theoretical support to microreentrant
theory of AF, showing that strong cholinergic discharges in a
small area of atrial myocardium can provide the substrate for a
microreentrant circuit as was initially proposed by Garrey (8).
Another important consideration is the size of tissue needed
to sustain AF. After the initial observations of MacWilliam
related to VF (18), Garrey experimentally determined that a
certain minimal size of atrial tissue is required for the induction
and maintenance of AF (7). This hypothesis, known as the
“critical mass of fibrillation” theory, remained commonly accepted for nearly a century for both AF and VF. The theoretical
basis of the critical mass theory was developed using the
concept of wavelength (14), which is the product of the
refractory period and the conduction velocity of an impulse.
Allessie et al. (1) presented compelling evidence in support of
a “leading circle” hypothesis, which is based on the wavelength theory. They showed that the reentrant circuit cannot be
shorter than the wavelength (22). Yet again, recently, several
groups challenged that and showed what seemed impossible:
fibrillation in the mouse heart (9, 27, 29). These data seemed to
challenge the critical mass hypothesis. However, one could
argue that there is no conflict between these findings and the
critical mass hypothesis. The wavelength of the atrial myocardium can change significantly in response to pharmacological
intervention, autonomic effects, structural remodelling, and
genetic manipulations in mouse models. Thus the existence of
Editorial Focus
H978
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tion. New optical coherence tomography (12, 13) in combination with second harmonic-based transmembrane voltage sensing (20) may provide such a future technology.
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microreentry reflects the fact that cholinergic effects include
dramatic shortening of wavelength as was shown by Lewis et
al. and Garrey. The study of Zou et al. provides further insight
into the importance of cholinergic modulation of wavelength
and critical mass theory.
Experimental validation of the competing theories remains
challenging due to limited spatiotemporal resolution of the
experimental technologies and the profound complexity of
atrial myocardium. Zou et al. constructed, elegant in its simplicity, a chessboardlike model of the atria, which contains
regions rich in cholinergic receptors intermingled with myocardium void of them. They showed that specific anatomic
details of cholinergic heterogeneity are not essential for creating the substrate for microreentry circuits. The model predicts
the coexistence of several scales of reentrant patterns that dwell
on a heterogeneous substrate in their model: either single
dominant rotors or multiple unstable rotor-based reentry can
underlie persistent fibrillatory activity in their atrial model.
Their model shows that treatment with a high mean concentration of acetylcholine sets the stage for single primary rotors
anchored in low-acetylcholine concentration zones, which
maintains AF. Surrounding cholinergic rich areas stabilize the
leading source of AF. At lower mean concentrations of acetylcholine, extensive spiral waves meander (5, 34) and prevented the emergence of single stable rotors.
These observations provide a clear explanation for several
experimental findings in cholinergic AF. Sharifov et al. (26)
showed that in most cases of AF onset, a single leading and
stable source of excitation was established after the second to
third beats. Sustained cholinergic AF associated with a single
stable reentrant source was also observed in the isolated canine
right atrium (25). Early studies have shown that acetylcholinemediated reentry can be three dimensional, revealing simultaneously focal and reentrant activation patterns, respectively, on
epicardial and endocardial surfaces of the isolated canine right
atrium (31). The transition from macroreentrant to microreentrant patterns has been observed in a similar preparation, in
which AF was induced by electric stimulation in the presence
of incremental concentrations of acetylcholine resulting in
drastic shortening of atrial refractoriness and a decreasing
reentrant circuit beyond the mapping system’s spatial resolution. Stable microreentrant sources as a mechanism of electrically induced cholinergic AF were also documented in an
optical mapping study of the isolated sheep heart (19).
The spatial resolution of existing mapping systems is often
insufficient to distinguish microreentry from focal activity in
the heterogeneous three-dimensional structure of the atria.
Theoretically, the diameter of the microreentrant circuit
induced in the atria during cholinergic stimulation can be ⬍1
mm (23). Thus it is still unclear whether focal activity, which
was observed in the human (10) and animal models (25, 26), is
in fact due to microreentry. New imaging modalities are
needed to assess spatial anatomic heterogeneity with temporal
complexity of the microreentrant pattern. This controversy is
likely to drive experimental research in the near future. This
work, however, will require the development of novel imaging
modalities that will provide high-resolution three-dimensional
mapping of electrical activity in the three-dimensional mammalian atria, with a spatial resolution that enables accurate
quantitation of the changes in wave propagation parameters
produced by the cholinergic input and causing reentry initia-
Editorial Focus
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