Cardiovascular Research 2001 52(2):171-173; doi:10.1016/S0008-6363(01)00454-0
© 2001 by European Society of Cardiology
Copyright © 2001, European Society of Cardiology
Atrial fibrillation: from cells to computers
Kalyanam Shivkumara,* and
James N Weissb
aCardiac Electrophysiology Section, Division of Cardiology, Department of Medicine, University of Iowa Hospitals and Clinics, 4426 B, JCP, 200 Hawkins Drive, Iowa City, IA 52242-1081, USA
bUCLA Cardiovascular Research Laboratory, Departments of Medicine (Cardiology) and Physiology, UCLA School of Medicine, Los Angeles, CA 90095, USA
* Corresponding author. Tel.: +1-319-384-6105; fax: +1-319-384-6247 kalyanam-shivkumar{at}uiowa.edu
accepted 6 September 2001
See article by Workman et al. [11] (pages 226–235) in this issue.
Atrial fibrillation is one of the commonest arrhythmias encountered in clinical practice. The incidence of this arrhythmia increases with age and it is responsible for substantial morbidity, mortality [1]. Numerous studies have been performed to elucidate the cellular and molecular events associated with this rhythm. Our conceptual framework for understanding this rhythm disturbance is based on the pioneering work of Gordon Moe [2]. Atrial fibrillation is thought to be due to repetitive activation of the atria by multiple reentrant wavelets. Subsequent experimental work confirmed the key elements of the hypothesis of Moe [1]. The exact origin and the behavior of such wavelets is a source of intense ongoing investigation utilizing experimental and computational approaches.
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1. Cellular electrophysiological changes due to AF
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The cellular ionic changes that allow repetitive activation
of the atria at such high rates have been the focus of several
studies. Several investigators have demonstrated that the ERP
of the atrium shortens even after a brief duration of atrial
fibrillation. The demonstration of the phenomenon of ‘electrical
remodeling’ provided the impetus for some detailed studies
of atrial electrophysiology
[3]. Single cell recordings from
human atrial myocytes (from explanted hearts during orthotopic
cardiac transplantation and excised atrial appendages) have
been studied in great detail to determine the ionic currents
that regulate the atrial action potential. Electrical remodeling
is a dynamic phenomenon and reflects rapid physiological changes
in the electrical behavior of atrial cells
[3,4]. Ionic currents
that regulate the atrial action potential have been studied
in this setting to determine the mechanisms that are responsible
for the shortening of the atrial ERP. Changes in inward and
outward membrane currents have been characterized in both human
and animal studies of atrial fibrillation
[4,5]. Findings from
these studies include: (i) shortening of the ERP
[3,6,7], (ii)
shortening of the action potential duration (APD)
[8], (iii)
decreased shortening of ERP and APD with increasing frequency
of stimulation (rate adaptation), (iv) increased dispersion
of cellular refractoriness. Ionic current changes that have
been reported include: (i) reduction in
ICaL [8,9], (ii) reduction
in
INa [10], (iii) reduction in
Ito [8,9], and (iv) and very
little change in the inward rectifier K current (see Nattel
[5] for a detailed review).
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2. The present study
|
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Workman and colleagues
[11] have characterized cellular electrophysiological
data from isolated human atrial myocytes obtained from patients
with chronic atrial fibrillation and compared it to data from
patients in sinus rhythm. The data on normal myocytes adds to
the data from ‘control’ arms of similar studies.
The study aims to determine the relative contribution of changes
in inward and outward ionic currents to single cell electrophysiological
properties. Using standard voltage protocols and pharmacological
interventions, the contributions of
ICaL,
IK1,
IKSUS and
Ito to electrophysiological alterations were studied. There are
several important findings reported by the authors: (i) Fast-rate
induced depolarization and APD-shortening was attenuated in
AF, (ii) atrial ERP was shortened and its rate adaptation was
attenuated in myocytes from patients with AF, (iii)
ICaL was
reduced at physiological rates in atrial cells from patients
with AF, (iv) changes in
ICaL and
Ito are insufficient to completely
explain the ERP and MDP adaptations observed in myocytes from
patients with AF. An impressive finding of the study is the
ability to pace the cells so rapidly under whole cell clamp
conditions without loss of stability. A potential limitation,
however, is that the whole cell technique dialyzes the cytoplasm
and disturbs physiological intracellular signaling. The perforated
patch method has been suggested as a technique for better preservation
of normal intracellular signaling. An unavoidable limitation
of the study is the inability to assess how atrial fibrillation
affected regional electrophysiological heterogeneity, such as
dispersion of refractoriness, throughout the atrium. Since all
the cells were obtained from the RA appendage, it is possible
that the effects of AF on rate adaptation and other properties
may be different in other regions. This is relevant to the observation
that LA activations are typically more rapid than right atrial
activations during AF, suggesting that the engine of AF may
be typically located in the LA
[12]. It would have been interesting
to compare LA appendage myocytes to RA appendage myocytes. Obviously,
the role of PV sites and other ‘focal’ sites that
trigger AF are very important and relevant, although beyond
the scope of this study. The data using 4-AP need to be interpreted
with caution. The effects of this pharmacological intervention
cannot be completely ascribed to
Ito block. The effect of the
drug on other inward and outward currents needs to be considered.
It is interesting that APD restitution was flattened by chronic
AF (at least in the RA appendage), suggesting that either APD
restitution steepness
[13] might be less important in maintenance
of AF than other effects, such as wavelength shortening, anatomical/electrophysiological
heterogeneity, and/or left atrial changes.
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3. Intra-atrial and inter-atrial heterogeneity in action potential characteristics
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Several studies have shown that atrial action potential shapes
are pleomorphic and are ‘sculpted’ by relative differences
in the strength of inward and outward currents (at any given
point in time the membrane potential reflects the net balance
between inward and outward currents). Even normal atrial myocytes
have different action potential shapes, analogous to ventricular
myocytes. Nattel and colleagues demonstrated three types of
action potential morphologies in human atrial myocytes
[14].
They characterized cells as Type I, Type II and Type III based
on the relative ratios of
IK and
Ito. Cells with only
Ito showed
a triangular action potential waveform. LeGrand and co-workers
observed two types of AP morphologies in atrial cells in their
study
[15]. Thus normal atrial myocardium is likely to have
cells with differing ERP and APD rate adaptation properties.
Cells with different repolarization characteristics (due to
differences in ionic currents) may respond with dramatic differences
in APD and ERP when exposed to interventions that augment outward
currents, for example adenosine or vagal stimulation. Intuitively
‘all or none’ repolarization response (abrupt shortening
of the APD) could be observed in cells with a prominent
Ito analogous to cells in the epicardial regions of the ventricle
[16]. Thus, small differences in refractoriness (between cells
with slightly different repolarization characteristics) may
set the stage for reentry within the atrium. Once atrial fibrillation
starts ‘electrical remodeling’ perhaps perpetuates
the process. Cells from patients with chronic AF (after a period
of remodeling), not surprisingly, show significant differences
in APD morphologies between individual cells. Further, the etiology/underlying
disease that resulted in AF seems to have different ionic changes
(heart failure vs. pacing-induced AF)
[17].
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4. What are the implications of such studies?
|
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The obvious importance of such studies is identification of
potential ionic current targets for drug therapy to prevent
atrial fibrillation and help maintain sinus rhythm. In addition
to this, data along these lines are valuable for refining mathematical
models of atrial action potentials. A continuing challenge in
modern electrophysiology is the integration of knowledge gained
in cellular and molecular studies to improve our understanding
of arrhythmias in the whole organ. An important aspect of such
integrative research is mathematical modeling of cardiac arrhythmias.
Such models allow us to understand how cellular characteristics
of individual cells/ionic currents contribute to the behavior
of excitatory electrical waves in the atria as a whole.
Mathematical modeling of atrial activation is now being attempted in ‘anatomically accurate’ mathematical models which incorporate key anatomical structures such as the crista terminalis and the pectinate bundles. Recently, Harrild and Henriquez have used a complex model of the atrium (taking into account anatomic structures) and assigned different conduction velocities to each region to study atrial activation in three dimensions [18]. Future studies that incorporate functional differences between different regions of the atria will undoubtedly provide a framework to improve our understanding of atrial arrhythmias. For instance, areas of the atrium that display marked anisotropy related to structural characteristics have been shown to play an important role in the behavior of reentrant waves in animal experiments and mathematical models. ‘Anchoring’ of reentrant spiral waves to anatomic ‘obstacles’ has been shown to create a flutter like activation pattern resulting in conversion of fibrillation to flutter in combined mapping and modeling studies [19].
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5. Future questions
|
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Recently, focal triggers of atrial fibrillation have received
a lot of attention and in a subset of patients these triggers
can be ablated using catheter techniques to provide some meaningful
clinical benefit
[20]. We still do not understand the cellular
behavior of ‘triggers’ of atrial fibrillation. Further,
the exact reason why fibrillation persists in some settings
and is self limiting in others is also poorly understood. Clearly
triggers have to be incorporated into pathophysiological paradigms
of atrial fibrillation. The normal atrium, perhaps due to physiological
heterogeneity, has the potential to fibrillate. Triggers of
AF in this setting are likely to result in brief paroxysms of
fibrillation. If such triggers are frequent enough, AF may sustain
due to electrical remodeling analogous to the pacing model of
AF. In a diseased atrium, triggers may very well result in prolonged
episodes of AF due to accentuated heterogeneities in electrical
function (and ultrastructural changes such as fibrosis). Remodeling
during AF in this setting is likely to set the stage for permanent
AF (
Fig. 1). These questions are likely to be answered by a
combination of approaches (cellular, molecular, mapping, human
and mathematical modeling) to improve our understanding of the
complex pathophysiological mechanisms of this common arrhythmia.
An opportunity now exists to build stronger bridges from cells
to computers!
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References
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