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Structure-function relationship in the AV junction.

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THE ANATOMICAL RECORD PART A 280A:952–965 (2004)
Structure-Function Relationship in
the AV Junction
IGOR R. EFIMOV,1* VLADIMIR P. NIKOLSKI,1
FLORENCE ROTHENBERG,1 IAN D. GREENER,2 JUE LI,2
HALINA DOBRZYNSKI,2 AND MARK BOYETT2
1
Department of Biomedical Engineering, Case Western Reserve University,
Cleveland, Ohio
2
School of Biomedical Sciences, University of Leeds, Leeds, United Kingdom
ABSTRACT
In the normal heart, the atrioventricular node (AVN) is part of the sole
pathway between the atria and ventricles. Under normal physiological conditions, the AVN controls appropriate frequency-dependent delay of contractions.
The AVN also plays an important role in pathology: it protects ventricles
during atrial tachyarrhythmia, and during sinoatrial node failure an AV junctional pacemaker can drive the heart. Finally, the AV junction provides an
anatomical substrate for reentry. Using fluorescent imaging with voltagesensitive dyes and immunohistochemistry, we have investigated the structurefunction relationship of the AV junction during normal conduction, reentry,
and junctional rhythm. We identified molecular and structural heterogeneity
that provides a substrate for the dual-pathway AVN conduction. We observed
heterogeneity of expression of three isoforms of connexins: Cx43, Cx45, and
Cx40. We identified the site of origin of junctional rhythm at the posterior
extension of the AV node in 79% (n ⫽ 14) of the studied hearts. This structure
was similar to the compact AV node as determined by morphologic and molecular investigations. In particular, both the posterior extension and the compact
node express the pacemaking channel HCN4 (responsible for the IF current)
and neurofilament 160. In the rabbit heart, AV junction conduction, reentrant
arrhythmia, and spontaneous rhythm are governed by heterogeneity of expression of several isoforms of gap junctions and ion channels. Uniform neurofilament expression suggests that AV nodal posterior extensions are an integral
part of the cardiac pacemaking and conduction system. On the other hand,
differential expression of Cx isoforms in this region provides an explanation of
longitudinal dissociation, dual-pathway electrophysiology, and AV nodal reentrant arrhythmogenesis. © 2004 Wiley-Liss, Inc.
Key words: atrio-ventricular junction; atrio-ventricular arrythmia; junctional rythm; optical mapping
“The AV node is the ‘soul’ of the heart, and whoever
understands its anatomy and electrophysiology will unlock the key to understanding the anatomic and electrical
workings of the heart itself.” So Douglas Zipes characterized the role of the AV node in his introduction to a recent
book, which provided the most comprehensive “view from
the millennium” on the atrial-AV nodal electrophysiology
(Mazgalev and Tchou, 2000). He also concluded, paraphrasing Winston Churchill’s famous characterization of
closed Stalinist Soviet society, that despite a century of
scientific inquiry by a constellation of the brightest minds
working in cardiac electrophysiology, the AV node remains “a riddle wrapped in a mystery inside an enigma”
©
2004 WILEY-LISS, INC.
(Mazgalev and Tchou, 2000). Despite publication of this
impressive volume, which summarized the results of a
century of AV nodal research, we hope to convince the
readers that recent progress in novel imaging modalities
*Correspondence to: Igor R. Efimov, Washington University,
St. Louis, MO. Fax: 314-935-8377.
E-mail: efimov@wustl.edu
Received 22 April 2004; Accepted 1 July 2004
DOI 10.1002/ar.a.20108
Published online 14 September 2004 in Wiley InterScience
(www.interscience.wiley.com).
STRUCTURE-FUNCTION RELATIONSHIP
in just 2 years yielded results that shed a new light on
many longstanding theories of AV conduction and offer a
plethora of novel insights worthy of further exploration.
These imaging modalities include fast fluorescent imaging
of electrical activity with voltage-sensitive dyes, structural optical coherence tomography imaging, and highresolution immunohistochemical imaging of protein expression. The aim of this review will be to place these new
insights in context with the vast body of literature that
already exists. Many of these findings have been made in
the rabbit model. While important differences in anatomy
do exist between the rabbit and human AV node, Mazgalev et al. (2001) described how findings in the rabbit
should be correlated to human AV node from a clinical
perspective.
PARADOXES OF STRUCTURE-FUNCTION
RELATIONSHIP OF AV JUNCTION
Since the discovery of the AV node by Tawara (1906),
this structure still mesmerizes new generations of investigators and has been at the center of highly emotional
debates between anatomists and electrophysiologists.
These debates focus on several major themes reflecting
duality of the electrophysiological nature of the AV node,
which is known to be both a conductor of impulses and an
oscillator: When does the AV node conduct impulses
(Lewis and Master, 1925) and when does it behave as an
oscillator perhaps under electronic (Meijler and Janse,
1988) or mechanical (Scherf and Cohen, 1964) modulation
from the atrial inputs? What are the anatomic (Inoue and
Becker, 1998) and functional substrates of the AV nodal
reentry, dual-pathway physiology (Moe et al., 1956), and
concealed (Langendorf, 1948) AV conduction?
A profound complexity of the AV junctional area has
presented a significant challenge to anatomists throughout the entire 20th century. Scientists have disagreed on
several major definitions of the components of the AV
junction. Janse et al. (2000) recently acknowledged the
“lack of a common terminology for the tissues of AV junction” as one of the five points highlighted to explain the
fact that there were arguments as to whether the atrium
was involved in nodal reentry. Attempts have been made
recently to clarify the terminology (Cosio et al., 1999). As
is often the case, however, it will likely take many years
before clinicians, anatomists, and electrophysiologists can
agree on application of this new system. Among the debated issues have been posterior-anterior (Inoue and
Becker, 1998) versus inferior-superior (Anderson and Ho,
2000) anatomical orientation of the AV conduction axis;
anatomic location and morphologic definition of the compact AV node itself (Anderson and Ho, 2000); existence
(Racker, 1989; Inoue and Becker, 1998; Medkour et al.,
1998) or nonexistence (Anderson and Ho, 2000; Bharati,
2000) of specialized conductive bundles, fibers, or approaches to the AV node; existence (Anderson and Ho,
2000) or nonexistence (Bharati, 2000) of the anatomically
defined triangle of Koch; and existence or nonexistence
(Bharati, 2000) of an isthmus, which is usually targeted
during ablation (Shah et al., 2002) of AV nodal reentry
and does exist from an electrophysiological point of view.
Due to the lack of consensus on such fundamental issues
of anatomy of the AV junction, electrophysiologists have to
choose between two distinctly different anatomic and potential approaches (Shah et al., 2002) during clinical evaluation of AV conduction and therapy of AV nodal reen-
953
trant tachycardia. The anatomic approach is based on
targeting the anatomical landmarks of the slow pathway,
such as the isthmus between the coronary sinus orifice
and the tricuspid valve. The potential approach is based
on targeting a characteristic slow-frequency electric potential signature of the slow pathway (Haissaguerre et al.,
1992; Jackman et al., 1992).
Anatomic and electrophysiological (potential) therapeutic approaches reflect the structure and function of the AV
junction. Yet, at the present time, due to an impossibility
of simultaneous application of anatomic and electrophysiological approaches that have adequate resolution, the
anatomic and electrophysiological approaches remain
somewhat disconnected in their interpretation and conclusions. The most striking reflection of this disconnect was
expressed by Meijler and Janse (1988), who concluded
that “we are faced with a paradoxical situation that the
most typical nodal action potential has not yet been linked
to the most typical nodal cell.” Thus, despite a century of
anatomic, electrophysiological, and clinical research, the
AV node remains, according to Zipes, “a riddle wrapped in
a mystery inside an enigma”.
MORPHOLOGIC AND
ELECTROPHYSIOLOGICAL HETEROGENEITY
OF AV JUNCTION
An unprecedented technological innovation of the 20th
century allowed a significant advancement of our understanding of the electrophysiological nature of AV conduction. Similar to the clinical arena, two major approaches of
research inquiry coexisted in the basic cardiac physiology
laboratories: anatomic (Tawara, 1906) and electrophysiological (Watanabe and Dreifus, 1965; Shah et al., 2002).
Attempts to combine the two approaches have yielded
limited results (Anderson et al., 1974). Both approaches
provided a significant body of evidence testifying to the
profound morphologic and electrophysiological heterogeneity of the AV junction.
The first description of the AV node was given by
Tawara (1906). He identified the knoten as the atrial
portion of the bundle connecting the atria and ventricles.
In this work, Tawara noted that the bundle become insulated as it passed from the atrial tissues into the central
fibrous body and suggested that the point of insulation be
taken as the boundary between the knoten and the atrioventricular bundle of His, since it was difficult in the
human to make this distinction using histological criteria.
When Anderson (1972a, 1972b) first illustrated the histological heterogeneity in the rabbit node, he was unaware
of the criterion proposed by Tawara (1906) and suggested
that the node in the rabbit could be divided into anterior
enclosed and posterior open regions, a concept subsequently endorsed by Petrecca and Shrier (2000). More
recently, there have been proposals that anatomists
should return to the original criterion suggested by
Tawara (1906) when making correlations with electrophysiology (Anderson and Ho, 2000; Mazgalev et al.,
2001). Other investigators, however, have proposed that
the AV junction should be defined to include all structures
contributing to atrial-His interval and associated ratedependent and dual-pathway properties (Billette, 2002).
In this review, we will use this physiological definition of
Billette’s (2002) that defines the AV junction as a heterogeneous structure, consisting of the nodal extensions and
954
EFIMOV ET AL.
Fig. 1. Anatomical location of the SA node, the AV junction, and the
His bundle structures in the AVN as determined by expression of neurofilament 160. SVC, superior vena cava; IVC, inferior vena cava; CS,
coronary sinus; PNE, posterior nodal extension; AVN, atrioventricular
node; His, bundle of His; TV, tricuspid valve; SAN, sinoatrial node. Areas
expressing neurofilament 160 are shown in green.
approaches within the triangle of Koch, along with the
heterogeneous component of the conduction axis in the
rabbit that is enclosed within the fibrous tissues of the
central fibrous body (Fig. 1). We will follow the zoological
orientation terminology, anterior/posterior, as opposed to
superior/inferior used by clinicians. It should be noted
that the rabbit is the most common animal model to study
AV conduction; despite the small size of the species, its
coronary sinus is large due to the existence of left precava
joining the coronary sinus (similar to the left superior
vena cava sometimes encountered in humans). It is also
worth noting that previous investigators showed that
nodal extension goes all round the tricuspid valve orifice,
crossing over the bundle behind the aorta (Anderson,
1972a). An important work of Mazgalev et al. (2001)
showed how studies in the rabbit could be correlated with
clinical findings in the human.
According to Bharati (2000), histologically the AV node
consists of three layers: superficial or subendocardial, intermediate or mid part, and the deep or innermost layer.
This three-layered structure has been associated with
three different electrophysiological responses observed in
the AV junction. Based on the morphology of action poten-
tials recorded with microelectrodes, the following three
distinct regions of the AV node have been identified (Hoffman et al., 1958; Paes de Carvalho and de Almeida, 1960):
the atrionodal (AN), true nodal or compact nodal (N), and
nodo-His (NH). The N response was characterized by a
relatively slow rate of rise during upstroke and a small
amplitude of the action potential. AN and NH action potentials showed an intermediate morphology between the
N region and the atrial muscle (AN) and the N region and
His bundle (NH), respectively. It is generally believed that
there is an association between the morphologically typical nodal cells and the electrophysiologically typical nodal
cells (N cells). Yet convincing proof of this association is
still lacking. Billette (1987) presented the most comprehensive microelectrode mapping of the AV node and identified six different cell types based on action potential
morphology, excitability, and refractoriness. Most importantly, Billette’s (1987) data provide convincing evidence
of the presence of various electrophysiological cell types
throughout almost the entire triangle of Koch, which
again emphasizes inseparable structure-function integrity
of the entire AV junctional area, well beyond the compact
AV node. Recently presented morphological (Inoue and
Becker, 1998) and electrophysiological (Medkour et al.,
1998; Nikolski and Efimov, 2001) evidence of the posterior
nodal extensions, which in some cases can reach coronary
sinus and perhaps connect directly to the Crista terminalis, could conceivably explain the presence of the nodal
and transitional cells at a significant anatomical distance
from the compact AV node. Yet purely morphologic analysis of the AV junction clearly has failed to explain the
complex electrophysiological behavior of the AV node. Recent progress in molecular and cellular biology research
provides highly promising insights, which could one day
explain normal and pathological AV conduction.
MERGING OF ANATOMIC AND
ELECTROPHYSIOLOGICAL APPROACHES
THROUGH IMAGING
So far, the major obstacle in the investigation of the
structure-function relationship of the AV node has been
an inability to assess simultaneously a profoundly heterogeneous ion channel expression, morphological structure,
and electrophysiological responses in 3D. The results of
histology and immunohistochemistry are difficult to correlate with the results of electrophysiological studies, usually conducted with a limited number of electrodes. Recent
application of fluorescent imaging with voltage-sensitive
dyes to the research of AV conduction (Efimov et al., 1997)
has provided a missing link between anatomy and electrophysiology (Choi and Salama, 1998; Efimov and Mazgalev, 1998; Nikolski and Efimov, 2001; Wu et al., 2001).
Fluorescent imaging with voltage-sensitive dyes has
revolutionized cardiac electrophysiology research during
the last decade (Rosenbaum and Jalife, 2002). This technology allows high-resolution mapping of transmembrane
voltage at various spatial scales ranging from subsubcellular to the whole heart (Rosenbaum and Jalife, 2002). In
the first application of fluorescent imaging to AV conduction (Efimov et al., 1997), we discovered that optical signals collected during normal sinus rhythm at the distal
AV node area contain two distinct components, which
could hypothetically correspond to activation of two separate layers of the rabbit AV node, similar to human tril-
STRUCTURE-FUNCTION RELATIONSHIP
Fig. 2. Three-dimensional (multilayer) imaging of the conduction
through the AV junction. A: The AV junctional preparation was paced at
atrial septum with a cycle length S1S1 ⫽ 280 ms (top) and 274 ms
(bottom), which caused Wenkebach AV block. Bipolar electrograms
were recorded from Crista terminalis (CrT) and bundle of His. Optical
traces (OAP) represent the superimposition of signals from the septum
and the distal AV nodal areas. B: Masson trichrome-stained section
through the distal AV node. Places of microelectrode recordings (MAPs)
are marked with black and white circles. Modified with permissions from
Efimov and Mazgalev (1998) and Dobrzynski et al. (2003).
aminar arrangement as described by the anatomists
(Tawara, 1906; Inoue and Becker, 1998; Anderson and Ho,
2000; Bharati, 2000). Our subsequent study provided
proof of this hypothesis (Efimov and Mazgalev, 1998).
Using simultaneous microelectrode and optical recordings, we demonstrated that the two components observed
in fluorescent optical recordings indeed correspond to
transmembrane voltage action potentials recorded with
microelectrodes from different layers: superficial and middle layers (Bharati, 2000). The two layers have distinctly
different morphological and electrophysiological properties. The superficial layers are composed of transitional
AN cells, which express sodium channels and Cx43, while
the middle compact node layer does not express sodium
channels and relies on low-conductance Cx45 for cell-tocell coupling. As a result, the two layers have markedly
dissimilar action potential morphologies, which correspond to AN and N regions, respectively. There is also a
large difference in the conduction velocity, ranging from
30 to 70 and 2 to 10 cm/sec, respectively.
FLUORESCENT IMAGING OF
MULTILAYERED CONDUCTION
Precise three-dimensional anatomic reconstruction of
electrical activity from fluorescent signals remains to be
developed. Rapidly evolving diffusive optical tomography
(Arridge, 1999) and optical coherence tomography (Huang
et al., 1991) could provide such methodologies in the near
future. Meanwhile, our experiments with the AV node
955
Fig. 3. Typical (slow-fast) AV node reentry induced by premature
stimulation of the Crista terminalis. A: Color map of conduction during
reentry produced by a single premature impulse. Only first 120-msec
interval of reentry is shown, illustrating activation of the posterior nodal
extension, the compact AV node, and the fast pathway. Map is superimposed with photograph of the preparation (see B for landmarks).
Diamonds illustrate position of recording sites, optical signal from which
are shown in C. B: Continuation of reentrant conduction: activation of the
transitional AN layer in 20 msec. The same field of view is shown. Notice
significant difference in activation times between the two panels. C:
Optical action potentials recorded along the reentry pathway. Solid-line
arrow illustrates conduction in the slow pathway and fast pathway.
Dashed-line arrow illustrates rapid conduction in the superficial transitional layer. Time scale bars below show time intervals illustrated in A
and B as conduction maps. D: Conventional bipolar electrograms recorded during last basic stimulus (S1), premature stimulus (S2), and
reentrant beat. Electrograms were recorded from high Crista terminalis
(hiCrT), low Crista terminalis (loCrT), interatrial septum (IAS), and the
bundle of His (His). Reproduced with permission from Nikolski and
Efimov (2001).
provided a new estimate of the depth of penetration of
fluorescent techniques into the tissue. Previous assessments conducted by various groups suggested that optical
signals carry information from 100 to 500 ␮m of tissue
from the surface (Rosenbaum and Jalife, 2002). Experiments in the multilayered AV node provided evidence that
the depth could be as large as 1–2 mm (Efimov et al., 1997;
Choi and Salama, 1998; Efimov and Mazgalev, 1998; Wu
et al., 2001). Thus, multiphasic optical signal morphology
is easily explained by a longitudinal dissociation of electrical activity in the proximal but highly heterogeneous
layers of the AV junction, which was first described by
Mines (1913).
Figure 2 illustrates an example of characteristic signature of longitudinal dissociation: biphasic signal morphology recorded optically during conduction in the rabbit AV
junction (Nikolski and Efimov, 2001). It shows an example
of optical action potential (OAP) and microelectrode action
potential (MAP) recordings and histology from the distal
AV junctional area of the rabbit heart (Efimov and Mazgalev, 1998; Dobrzynski et al., 2003). These recordings were
conducted during Wenkebach periodicity: the first and
third beats documented in each panel of Figure 2A conducted from Crista terminalis (CrT) to the His bundle,
while the second beat failed, as evident from the His
956
EFIMOV ET AL.
bundle electrograms. Optical potentials were recorded
from the distal AV junction area. Figure 2B shows the
histological view of this region in another preparation
from the same apical area of triangle of Koch (Dobrzynski
et al., 2003), which clearly shows multilayered morphology of the AV junction. One can see the thin layer of AN
transitional tissue (closed circle), the compact AV node
(open circle), and loosely coupled deeper layer of NH transitional cells. OAP recordings during conducted beats contained two components, representing electrical activity in
the two layers. OAP recorded during AV block contained
only one component. Microelectrode recordings conducted
simultaneously provide evidence that the first component
of optical recording corresponds to the superficial transitional AN layer (closed circle in Fig. 2) of the AV junction,
while the second component represents electrical activity
of the deeper nodal layer (open circle in Fig. 2). Such
multiphasic optical signal morphology was recorded from
all studied rabbit preparations during both antegrade and
retrograde AV conduction. In our studies, we did not inject
dye to mark the cells from which we obtained the electrophysiological recordings. We are currently working on microelectrode recordings in parallel with optical coherence
tomography and fluorescent imaging, which will allow
precise 3D positioning of the microelectrode tip with accuracy of 1–3 micrometers within the studied tissue structure.
We estimated the depth of origin of the two components
using slow diffusion of the voltage-sensitive dye during
superfusion (Nikolski and Efimov, 2001). In this case, we
used 1 ␮mol/L solution of di-4-ANEPPS, which is 10 –20
times lower than the previously used concentration (Efimov et al., 1997). In the first 5–10 min, only the superficial
layer of tissue was stained because of the slow diffusion of
the dye into deeper layers. As a result, in the beginning of
staining, only the second (late) component of the optical
response was observed. During retrograde conduction,
this component represents activation of superficial AN
layer of the AV node. Activation of the deeper AV nodal
structure (first or early component) became distinguishable only after 20 min. The delivery of the dye was stopped
at 40 min and washout was started. The amplitude of the
first component continued to grow due to the maintained
diffusion of the dye from the superficial to deeper layers.
Meanwhile, the difference between the second and the
first peak started to decrease, reflecting dye washout from
the superficial layer (Nikolski and Efimov, 2001). Thus,
the direction of diffusion of the dye during superfusion is
consistent with the anatomic location of the two layers
contributing to the dual-component optical signal.
FLUORESCENT IMAGING OF
AV NODAL REENTRY
The first clear and elegant description of AV junctional
reentry belongs to Mines (1913), who described longitudinal dissociation preceding the onset of reentry and leading
to its initiation. More than half a century later, reentry
was induced by premature stimulation and documented
by Coumel et al. (1967) in humans and by Janse et al.
(1971) in the rabbit preparation. The study by Janse et al.
(1971) showed the results of the application of a brush of
10 microelectrodes during AV nodal reentry in the rabbit
preparation. Now, 31 years later, despite numerous attempts, nobody has been able to repeat this enormously
difficult experiment (Janse et al., 1971) and reproduce his
results. Microelectrode recordings, while remaining the
gold standard of cellular electrophysiology, present significant challenges to those in search of spatially resolved
electrical mapping of the heart.
Now we can present a detailed map of AV nodal reentry
using fluorescent mapping of AV nodal action potentials.
Figure 3 shows a map of a so-called typical AV nodal
reentry also known as slow/fast reentry, reflecting the fact
that reentrant beat propagates antegradely via the slow
pathway and then retrogradely via the fast pathway. Unlike the painstaking art of several-site microelectrode recordings, which was mastered only by a few (Janse et al.,
1971; Billette, 1987), optical techniques give us hundreds
of recordings, providing a thorough documentation of AV
nodal reentry (Nikolski and Efimov, 2001; Nikolski et al.,
2003). Figure 3A shows an activation color map during
conduction via the slow and fast pathways, which takes
120 msec. It is followed by rapid activation by the superficial AN layer (Fig. 3B), which covers the same distance
in only 20 msec, bringing activation back from the fast to
the slow pathway and allowing impulse to reenter the
slow pathway, completing the circuit. Thus, this map, to
the best of our knowledge, represents the first complete
map of activation during typical (slow/fast) AV nodal reentry. Figure 3C further illustrates these data by presenting 24 optical action potentials (out of 256 available recordings), which were selected along the reentry circuit.
Similar documentation of reentry was produced in our
experiments with retrograde stimulation.
Figure 4 shows the preparation schematics with the
trajectories of impulse conduction and 3D stack plots of
dF/dt corresponding to the three types of reentry: slowfast, fast-slow, and intranodal. Stackplots are shown in
projection along the main axis of the triangle of Koch and
time. From this 3D projection, the rapid atrial excitation
that follows S1 stimuli is seen as almost a horizontal slab
while conduction through nodal structures to His bundle
is presented as a sloped filament. During slow-fast pathway reentry initiation after an S2 stimulus, there was
conduction block in the A/AN layer, so the horizontal slab
representing atrial excitation is missing (see the left 3D
stack plot in Fig. 4). Only the 3D filament corresponding to
the slow-pathway conduction is present. The slope of the
filament reflects the conduction velocity: the steeper the
slope, the slower the propagation. The conduction velocity
in the A/AN layer within the triangle of Koch was 35.1 ⫾
17.2 cm/sec following S1 stimuli and 30.7 ⫾ 14.0 cm/sec
following S2 stimuli (n ⫽ 6; P ⬎ 0.5). We were unable to
measure conduction velocity in the AV node and the posterior nodal extension during basic beat propagation accurately due to superimposition of optical signals from the
AV node and the A/AN layer. During premature stimulation and reentry, the conduction velocity in the AV node
and the posterior nodal extension (the SP) was slower and
permitted measurements. Premature beat H2 resulted
from an impulse propagating at 7.9 ⫾ 3.4 cm/sec. The
reentrant beat propagated at 6.9 ⫾ 2.4 cm/sec (n ⫽ 6; P ⬎
0.5).
FLUORESCENT IMAGING OF AV
JUNCTIONAL AUTOMATICITY
Since the first discovery of AV nodal automaticity, the
site of initial pacemaker was sought by many investigators. They found that the sites of impulse formation are
located in the compact AV node (Paes de Carvalho et al.,
STRUCTURE-FUNCTION RELATIONSHIP
957
Fig. 4. Visualization of AV nodal reentry. Reentry trajectories obtained for the cases presented in Figure 2 together with space-time
stack plots of the dual-pathway AVN conduction are shown. Data were
collected from a square field of view containing the triangle of Koch as
shown on the schematics. Three-dimensional volumes were built by
stacking the sequentially recorded two-dimensional plots of dF/dt (Nikolski and Efimov, 2001). An isosurface was built using a density threshold, which was adjusted with time in order to preserve the continuity of
conduction along the pathways. Three-dimensional stack plot is visualized in a projection perpendicular to the preparation plane so that
horizontal axis of the stack plot corresponds to the horizontal axis of the
preparation schematic and vertical axis corresponds to time that increases from top to bottom. Arrows S1 and S2 show the times of the last
basic and premature stimuli. H1, H2, H3, and H4 show the times of His
signal appearances. Quick A/AN layer activation corresponds to almost
horizontal areas on the plot. Solid lines represent conduction trajectory
for basic and premature pacing. Dashed lines show reentry pathways.
Bold arrows on schematics and 3D stack plots indicate quick transmittance of the activation between dual-pathway inputs through A/AN layer.
SP and FP, slow and fast pathways. Reproduced with permission from
Nikolski and Efimov (2001).
1961) or in the NH region (Watanabe and Dreifus, 1968).
Fluorescent imaging provides a unique opportunity for
locating the site of origin of the junctional heartbeat. Our
data show that such sites could be found not only in the
compact N region or NH region, but also in the posterior
nodal extensions (PNE).
Figure 5 illustrates the optical mapping of the AV nodal
area during spontaneous activity when the sinus node was
surgically removed. Figure 5A and B show a preparation
in which the AV node drives the atrium and His bundle.
As seen from Figure 5A, the impulse originates in the
isthmus below the coronary sinus. Then it slowly spreads
in both directions along the posterior nodal extension until
it reaches a breakthrough point in the middle of the triangle of Koch. Rapid excitation of the atrium follows (see
right map in Fig. 5B). Optical traces and their derivatives
in Figure 5B show examples of optical action potentials
recorded from the site of origin (circle and solid trace) and
958
EFIMOV ET AL.
Fig. 5. Automaticity of the AV junction. A: Photograph of the preparation. White rectangle shows field of view of the optical mapping
system. The white curve circles the location of the site of the earliest
excitation during junctional AV rhythm. B: Maps of activation in the
deeper cell layers of AV node and posterior nodal extension (left map)
and the superficial AV layer (right map), following the breakthrough from
the deeper layer. The traces below show optical signals and their first
derivative at the location of pacemaker (white circle) and the break-
through to the surface layer (black triangle) as well as bipolar electrical
recordings at the bundle of His (His) and interatrial septum (Septum).
Corresponding electrodes are indicated in A with arrows. C: Map of
activation during spontaneous AV junctional rhythm in the preparation
with a retrograde conduction block. Only excitation of the deeper cell
layers is present. The trace below shows the unfiltered optical signal at
the location of the pacemaker (white triangle). Reproduced with permission (Dobrzynski et al., 2003).
the site of the breakthrough (triangle and dashed trace). One
can see that the location of the earliest excitation anatomically corresponds to the posterior AV node bundle extension.
In several preparations, we observed complete dissociation
of the AV node from the atrium following 3– 4 hr of the
experiment. Figure 5C shows an example of such activity.
Despite a complete cessation of communication between the
atrium and AV node, the posterior nodal extension continued robust pacemaking, which safely propagated throughout
the AV nodal extension, the compact AV node, and reached
His bundle. Yet no conduction was observed toward the
atrium. The optical trace shown below demonstrates clear
diastolic depolarization and nodal-like action potentials. We
were able to record these clean nodal potentials only in such
dissociated preparations, because otherwise optical action
potential from the superficial AN layer would mask most of
the nodal action potential.
needed 3D resolution. Figure 6 shows the first attempt of
the morphological 3D reconstruction of the AV nodal area
by OCT. As clearly seen in Figure 6B, the OCT images are
capable of visualizing the different anatomical structures
in the AV junction to a depth of 1 mm or more. An advantage OCT is that this methodology can be applied in clinical electrophysiology laboratory using catheter-based
OCT imagers. For example, a radio frequency ablation
catheter, which will carry the OCT imager, can be developed. This will allow precise anatomic localization of the
slow pathway and safe ablation of the site. At the present
time, OCT is available only for structural 3D imaging
without any dyes or contrast agents. Consequently, a
mapping of the transmembrane voltage or other electrophysiological parameters using this technology is not presently feasible. Yet the development of such absorbance dyes
is underway and we hope that 3D functionally modulated
optical coherence tomography will be available within 5
years for intravascular mapping of the AV node and the slow
pathway. Now OCT technology provides a bridge between
the optically recorded functional electrophysiological data
discussed above and new molecular approaches to characterize the anatomical data, establishing precise correspondence between the electrical activity and immunohistological images collected after cryosectioning.
OPTICAL COHERENCE TOMOGRAPHY
OF AV NODE
Despite the impressive success of fluorescent imaging
with voltage-sensitive dyes, this technology remains limited in its ability to gain insights into the depth of cardiac
tissue. Our data clearly indicate that optical signals carry
information about the deeper layers of tissue, but precise
anatomic location of the layers contributing to specific
optical action potentials and perhaps reconstruction of
electrical activity in 3D remains to be achieved. We have
recently introduced (Gupta et al., 2002) a novel optical
imaging modality, optical coherence tomography (OCT)
(Huang et al., 1991), which might be able to provide
MOLECULAR BASIS OF
ELECTROPHYSIOLOGICAL HETEROGENEITY
OF AV JUNCTION
The AV node is the Cinderella of mathematical cardiology, being the only major cell type or major structure of
STRUCTURE-FUNCTION RELATIONSHIP
959
Fig. 6. Optical coherence tomography of the AV junction. Optical coherence tomography was applied to
isolated AV junction of the rabbit heart in vitro. A shows 3D structure of the AV junction was reconstructed
from stack of 2D scans, one of which is shown in B.
the heart that has not yet been characterized within a
framework of an accurate mathematical model. This is in
contrast to its luckier counterpart, the sinoatrial (SA)
node, which inspired numerous mathematical modeling
studies (Demir et al., 1999). Several attempts to explain
AV conduction mathematically were based on the empirical modifications of existing models of the SA node. Molecular data suggest that electrophysiological heterogeneity of the AV node is due to heterogeneity of ion channel
and gap junction expression (Petrecca and Shrier, 2000).
Sodium Channels
Petrecca et al. (1997) provided convincing evidence of
lower levels of expression of sodium ion channels in the
compact AV node region and in ovoid-type isolated cells,
which exhibit an N-type electrophysiological response, including the lack of prominent INa current. Lack of INa
explains characteristic slow-rising tetrodotoxin-resistant
(Zipes and Mendez, 1973) upstroke of nodal cells. In addition, they presented evidence that cells lacking INa also
lack Ito, but have prominent IF, which is consistent with
the documented pacemaking ability of N cells (Paes de
Carvalho et al., 1961). Transitional cells of AN and NH
types, on the other hand, have more abundant expression
of INa (Petrecca et al., 1997; Petrecca and Shrier, 2000),
which explains their fast upstroke velocity and speed of
conduction.
Calcium Channels
Calcium channels play an important role in the conduction through the AV node (Zipes and Mendez, 1973; Noma
et al., 1980), thought to be responsible for impulse transmission in the absence of sodium channels. Both L-type
(Munk et al., 1996) and T-type calcium channels, ICa,L and
ICa,T, have been found in the AV node (Liu et al., 1993).
Pharmacology of these channels has been well characterized. However, no spatial mapping of ion channel expression has been presented so far. Such data are highly
desirable, because possible heterogeneity of calcium channel expression can clarify structure-function relationship
of the AV node, properties of which are known to be
Ca-dependent.
Potassium Channels
Potassium channels also appear to be nonuniformly expressed in the AV node. Transient outward current Ito,
similar to INa, appears to reside primarily in the transitional layers of the AV node (Munk et al., 1996), while
being more scarcely expressed in the N region (Munk et
al., 1996). The classic study of Noma et al. (1980) demonstrated that the delayed rectifier current IK is the major
repolarizing current in the AV node. More recent studies
suggested that rapid component of IKr is the predominant
if not the only component (Habuchi et al., 1995; Howarth
960
EFIMOV ET AL.
Fig. 7. Coexpression of Cx43 and NF160 in the AV junction: posterior nodal extension, compact AV node,
and the bundle of His. Histological staining and immunolabeling was applied to 16 ␮m neighboring
cryosections from the entire AV junction. Three areas are represented: posterior nodal extension at the site
of junctional pacemaker, the compact AV node, and the bundle of His. AS, atrial septum; VS, ventricular
septum.
et al., 1996) of the delayed rectifier potassium current. In
contrast to the SA node (Habuchi et al., 1995), there is
little evidence of the presence of the slow component, IKs,
in the AV node (Habuchi et al., 1995). The role of the
inward rectifying potassium channels remains unclear.
IK1 channel plays a major role in maintenance of resting
potential in the atrial and ventricular cells. However, it is
almost absent from the AV node (Petrecca and Shrier,
2000). On the other hand, a well-documented vagal control
(Clemo and Belardinelli, 1986; Mazgalev et al., 1986) of
STRUCTURE-FUNCTION RELATIONSHIP
961
Fig. 8. AV junctional rhythm originates in a neurofilament 160-positive area. Top: Cryosection of the AV node dual-labeled with NF160
(green) and Cx43 (red) antibodies. NF160 labeling was used for 3D
reconstruction of NF160-positive area of the AV nodal extension. AS,
atrial septum; VS, ventricular septum. Bottom: Photograph of the prep-
aration overlapped with the image NF160-positive area (dark gray) and
an activation map of the AV junctional rhythm (colored). TT, tendon of
Todaro; IAS, intra-atrial septum; TVA, tricuspid valve; CS, coronary
sinus; VM, ventricular muscle; PB, penetrating bundle; BB, bundle
branches; PNE, posterior nodal extension; CN, compact node.
the AV node suggests a role for IK,Ach (Clemo and Belardinelli, 1986). The presence and the important role of a
pacemaker “funny” current, IF, was firmly established by
Noma et al. (1980) and other investigators (Habuchi et al.,
1995; Petrecca et al., 1997). We have recently demonstrated that predominant isoform of genes encoding IF
current (HCN4) is expressed in the AV node and posterior
nodal extension of the rabbit heart (Dobrzynski et al.,
2003).
Gap Junctional Channels
Gap junctional channels appear to play an especially
prominent role in AV conduction. Three major isoforms of
gap junctional channel proteins, connexins Cx43, Cx40,
and Cx45, have been mapped to specific regions of the
mammalian heart. Presently available data suggest that
all three isoforms are expressed in the triangle of Koch
and play a role in the AV conduction. The compact node (N
962
EFIMOV ET AL.
most of the myocardium, specifically in the atrial and
ventricular myocardium. On the other hand, transitional
layers of the AV node, including both AN and NH, exhibit
greater levels of expression. Our data suggest that spatial
heterogeneity of Cx43 expression might be related to the
dual-pathway electrophysiology of the AV node, forming
cell-to-cell communication pathways, which correspond to
the slow and fast pathways (Nikolski et al., 2003). Two
other connexin isoforms have been reported to play a role
in the conduction through the compact node (Cx45) and
NH region (both Cx40 and Cx45) (Gourdie et al., 1993).
CONNEXIN HYPOTHESIS OF DUALPATHWAY ELECTROPHYSIOLOGY
OF AV JUNCTION
Fig. 9. Summary of Cx and HCN isoforms expression in the AV
junction. HCN4 and NF160 are expressed throughout the conduction
system of the rabbit heart. Densities of connexins vary from area to area
of the CPCS.
region) has been shown to have low level of expression of
the major cardiac isoform, Cx43 (Gourdie et al., 1993;
Petrecca et al., 1997; Coppen and Severs, 2002), which is
responsible for cell-to-cell communication throughout
Fig. 10. NF160 (green) and antisarcomeric actin (red) labeling in a
day 13 rabbit embryo heart. Frontal sections, left section is most posterior in the heart. Arrows indicate NF160 labeling. High-magnification
images confirm colocalization of both markers (not shown). Left image
shows labeling in the AV junction. Sections between the left and middle
sections reveal additional labeling at the leading edge of the atrial
primum septum (not shown). This fuses with the positively labeled region
between the atria in the middle panel. Middle image shows extensive
The results of the immunohistochemical studies have
provided a vast amount of information that has shaped
our understanding of AV conduction and junctional
rhythm, based on significant heterogeneity of expression
of various proteins, including ion channels, receptors, gap
junctions, signaling molecules, etc. In particular, we have
recently demonstrated that our previous findings of bifurcation in the functional reentry pathway have a molecular
basis (Nikolski and Efimov, 2001; Nikolski et al., 2003).
Using immunolabeling of Cx43, we found Cx43-positive
bundles approaching the AV node from the coronary sinus
orifice, surrounded by Cx43-negative tissue. Correlation
with fluorescent data suggested that these Cx43-positive
bundles are the substrate for dual pathway and for reentry. In some preparations, we observed bifurcation of the
slow pathway in the middle of the triangle of Koch (Figs.
2 and 3). Immunolabeling showed that this functionally
labeling between the atria in the AV junction, at the crest of the developing interventricular septum, and on the endocardial surface of the
ventricular trabeculae. Additionally, there is labeling of cardiomyocytes
between the atrium and ventricle on the right atrioventricular junction.
Right image shows what has been termed the retroaortic limb of the
cardiac pacemaking and conduction system, which regresses in the
human but is maintained in the chick.
963
STRUCTURE-FUNCTION RELATIONSHIP
defined bifurcating conduction pathways correlate with
bifurcating Cx43-positive bundles. Recently, our observation of Cx43-positive bundles at the AVN area was confirmed by Ko et al. (2004). These AV nodal data agree with
the previously observed Cx43-postive bundles in the SA
node (Joyner and van Capelle, 1986; Kwong et al., 1998;
Coppen et al., 1999) that had previously been suggested as
a mechanism of enhanced safety of the conduction from
the small SA nodal area that has to drive the large atrium
against an unfavorable source-sink relationship. It is
worth mentioning that the pathways delineated by the
connexins and NF160 immunostaining satisfy two out of
the three criteria of Aschoff (1910) and Monckeberg (Monckeberg, 1910) for conducting tracts. The criteria are as
follows: the cells are (immuno)histologically discrete; it is
possible to follow them from section to section; and they
should be insulated by fibrous sheaths from nonspecialized adjacent working myocardium. The pathways we describe do not fulfill the third criterion because their cells
intermingle with the working myocardium.
Rabbits in comparison to the other animals have a
unique property: cells of their cardiac pacemaking and
conduction system (CPCS) express neurofilament 160
(NF160). Figure 7 shows double labeling of distal AV node
with immunoprobes raised against Cx43 and NF160. It
shows that NF160 is expressed at high density throughout
the entire AV junction, including the AV nodal extension,
compact AV node, and the bundle of His.
We used NF160 staining in order to determine the tissue of the cardiac pacemaking and conduction system
within the AV junctional area (Fig. 8, top) and His-Purkinje network. The top panels of Figure 8 show that
NF160 is expressed throughout the entire cytosol of characteristically rounded compact nodal cells. Figure 8 shows
the distribution of neurofilament-positive conduction tissue (dark gray) in the triangle of Koch. The posterior
nodal extension corresponds to the position of the slow
pathway. Cx43 immunolabeling was abundant in the
working myocardium, but sparse or absent in the conduction tissue. Our data show two different tissue types in the
AV node region: neurofilament-negative/Cx43-positive tissue (atrial and ventricular muscle) and neurofilamentpositive/(mostly Cx43-negative) tissue (conduction tissue).
The color-coded activation map for the AV junctional
rhythm was optically recorded for this preparation and it
shows that the NF160-positive tissue provides the channel
for slow conduction due to the significant reduction of
Cx43 expression in myocytes of the PNE and compact
node structures. More distantly located NF160-positive
myocytes show a much higher degree of Cx43 expression
and it correlates with the conduction speed increase as
excitation approaches the central fibrous body where
NF160-positive myocytes form a penetrating (His) bundle.
Further investigation of the expression of other connexin
isoforms in the rabbit AV junction (Dobrzynski et al.,
2003; Ko et al., 2004) revealed that available Cx40 antibodies, being traditionally accepted as marker for AV
nodal structures in mouse and rat hearts, cannot be successfully applied to rabbit tissue. Dobrzynski et al. (2003)
reported the weak Cx40 staining and Ko et al. (2004)
concluded that Cx40 cannot be detected in the rabbit AV
nodal myocytes at all, while the same antibodies gave
abundant signal in the vascular endothelium (Ko et al.,
2004). Cx45 expression in the rabbit AV node follows the
pattern reported for rat and mouse hearts (Dobrzynski et
al., 2003). The relative role of different connexin isoforms
in heterogeneous conduction in the AV node is yet to be
determined.
Figure 9 summarizes our current knowledge about connexins distribution in the AV junctional area. Figure 9
also shows that the same area expresses HCN4 —predominant isoform of IF—pacemaker “funny” current. These
data correlate well with the known cellular heterogeneity
of the atrioventricular node in the rabbit as described by
Anderson (1972b).
CONCLUSION
An impressive success of fluorescent imaging in visualization of the entire circuit of AV nodal reentry, the
location of pacemaker during junctional rhythm, and
the activation during antegrade and retrograde dualpathway conduction has already provided evidence of
the strength of new imaging technology. Progress in AV
nodal research achieved in just a few years (Efimov et
al., 1997; Choi and Salama, 1998; Efimov and Mazgalev,
1998; Wu et al., 2001) will be further developed with
rich new methodologies, including optical coherence tomography and diffusive optical tomography. We believe
that these new extensions of voltage-sensitive imaging
methodologies will allow truly three-dimensional realtime imaging of electrical activity in the AV junction, as
well as in other structures of the heart. Such novel
methodology will allow reconstruction of entire 3D wave
fronts during various modes of conduction in the AV
junction.
At the same time, a rapid development of highthroughput immunohistochemistry sustains impressive
stream of discoveries of different aspects of molecular
mechanisms of AV conduction in normal and pathological states. An increased level of understanding of a
profound complexity of heterogeneous three-dimensional structure of the AV node [initially described by
Anderson (1972a), with Janse et al. (1974) later providing functional correlations] is likely to produce a theoretical basis for a comprehensive mathematical model of
the AV junction. Such a model will allow an exploration
of the structure-function relationship of the AV node in
the near future. We believe that this is the last major
piece of a puzzle that is being built by cardiac electrophysiologists within an international project known as
the virtual heart. Our present findings have cast further
light on the controversies described in the introduction.
However, we are still far from resolving all controversies.
Recently, we also applied NF160 and fluorescence
imaging with voltage-sensitive dye to developing rabbit
hearts. Our data confirm earlier findings that NF160 is
expressed as early as day 9.5 (Gorza et al., 1988). Interestingly, Figure 10 shows that NF160 is a marker of
the developing cardiac pacemaking and conduction system, which is already functional prior to completion of
septation as early as day 13 (data not shown). At this
stage of development, SA and AV junction are connected
with NF160-positive conduction pathway, which disappears at later stages of development and is undetectable
in the adult rabbit heart. Perhaps the structure that is
known as posterior AV nodal extension is a remnant of
this atrial conduction system.
964
EFIMOV ET AL.
ACKNOWLEDGMENTS
Supported by National Institutes of Health grant
HL58808 (to I.R.E.).
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