(Circulation. 1999;99:2806-2814.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Autonomic Modification of the Atrioventricular Node During Atrial Fibrillation
Role in the Slowing of Ventricular Rate
From the Department of Cardiology, the Cleveland Clinic Foundation, Cleveland, Ohio.
Correspondence to Todor N. Mazgalev, PhD, Department of Cardiology/Desk FF1, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195. E-mail mazgalt{at}cesmtp.ccf.org
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Abstract |
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Background—Postganglionic vagal stimulation (PGVS) by short bursts of subthreshold current evokes release of acetylcholine from myocardial nerve terminals. PGVS applied to the atrioventricular node (AVN) slows nodal conduction. However, little is known about the ability of PGVS to control ventricular rate (VR) during atrial fibrillation (AF).
Methods and Results—To quantify the effects and establish the mechanism of PGVS on the AVN, AF was simulated by random high right atrial pacing in 11 atrial-AVN rabbit heart preparations. Microelectrode recordings of cellular action potentials (APs) were obtained from different AVN regions. Five intensities and 5 modes of PGVS delivery were evaluated. PGVS resulted in cellular hyperpolarization, along with depressed and highly heterogeneous intranodal conduction. Compact nodal AP exhibited decremental amplitude and dV/dt and multiple-hump components, and at high PGVS intensities, a high degree of concealed conduction resulted in a dramatic slowing of the VR. Progressive increase of PGVS intensity and/or rate of delivery showed a significant logarithmic correlation with a decrease in VR (P<0.001). Strong PGVS reduced the mean VR from 234 to 92 bpm (P<0.001). The PGVS effects on the cellular responses and VR during AF were fully reproduced in a model of direct acetylcholine injection into the compact AVN via micropipette.
Conclusions—These studies confirmed that PGVS applied during AF could produce substantial VR slowing because of acetylcholine-induced depression of conduction in the AVN.
Key Words: atrioventricular node • atrium • vagus nerve • ventricles
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Atrial fibrillation (AF) has long been recognized as the most frequent chronic arrhythmia.1 Although the abnormal atrial function during AF and its consequences cannot be underestimated, it is important to note that AF is also associated with an elevated and irregular ventricular rate (VR).2 3 4 5 Mortality due to AF is limited, largely because of the filtering role played by the atrioventricular node (AVN).6 Because of the complexity of AV nodal function even at normal rates, our understanding of AVN conduction during AF remains limited.7 8 Thus, the relative roles of the atrial-AVN approaches versus the region of the compact node in the VR reduction during AF are not yet clear, although current clinical procedures are targeting either or both of these structures.
Slow-pathway modification attempts to achieve slower VR during AF,9 10 11 12 while preserving the AVN. AVN modification has shown some encouraging clinical results, but with inconsistent success rates among investigators.13 14 If this is unsuccessful, complete AVN destruction can be performed, rendering the patient pacemaker-dependent and undesirably altering the normal sequence of ventricular activation.13 15
It is conceptually more desirable to slow the VR during AF without requiring permanent ventricular pacing. One attractive idea is to take advantage of the rich supply of vagal nerves to the AVN.16 If these nerves are stimulated with weak, subthreshold currents, most atrial impulses would be blocked within the AVN. The impact of direct autonomic modulation of AVN conduction during AF has not been explored.
The goals of this study were (1) to compare the contribution of the atrial approaches and the region of the compact AVN in the VR-reducing process during AF and (2) to evaluate a new, nondestructive method to slow the VR during AF by applying postganglionic vagal stimulation (PGVS) directly onto the AVN.
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Methods |
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AVN Preparation
Experiments were performed in vitro on 11 isolated heart preparations obtained from New Zealand rabbits (body weight, 2 to 2.2 kg) after anesthesia with sodium pentobarbital injection (50 mg/kg). After a midsternal incision, the heart was excised, the ventricles and left atrium were discarded, and the final preparation contained right atrial tissues (Figure 1
).
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Superfusing Solution
All solutions were prepared with deionized and subsequently
distilled water. The superfusing solution contained (in mmol/L)
NaCl 128.5, KCl 4.7, CaCl2 1.3,
MgCl2 1.05, NaHCO3 25,
NaH2PO4 1.19, and glucose
11.1. This was saturated with 95% O2/5%
CO2 and maintained at 35.5°C at a pH of 7.30 to
7.35. Propranolol (3x10-6 mol/L)
was added during experiments in which vagal stimulation or
acetylcholine (ACh) injections were used.
Electrodes and Recordings
Bipolar stimulation and recording electrodes were
custom-made from 0.20-mm Teflon-insulated platinum-iridium wire (0.5-mm
interelectrode distance). The high right atria were stimulated (2-ms
pulse, twice diastolic threshold) via optically isolated
stimulator units (WPI, A360) and an 8-channel programmable stimulator
(AMPI, Master-8). Surface bipolar electrograms were recorded at the
crista terminalis (CrT) and the interatrial septal (IAS) inputs of the
AVN and at the bundle of His (Figure 1
) via high-resistance,
differential-input probes and an 8-channel programmable signal
conditioner (Axon Instruments, CyberAmp 380). After amplification and
filtering (30 to 3000 Hz), signals were displayed on an oscilloscope
and simultaneously recorded on magnetic tape (Vetter
Digital, 4000A) for later computer analysis with AxoScope (Axon
Instruments) and Origin (Microcal) software programs.
Standard microelectrodes (15 to 30 M
) and a 2-channel amplifier
system (AxoProbe, Axon Instruments) were used to record action
potentials (APs) from distal and proximal AVN cells. The midnodal
(compact AVN) region was located in the anterior apex of the triangle
of Koch, about 2 mm posterior to the earliest His electrogram
recording site. Although the anatomic landmarks were
consistent, the approximate location of the compact nodal
region was further facilitated by recording of characteristic
N-type APs, as well as by the strong effects elicited by PGVS
and ACh (see later). Because morphological verification was not
attempted, the terms "compact node" and "midnode" will be used
to indicate the targeted region for positioning of pacing and/or
recording electrodes.
Pacing Protocols
The mean spontaneous sinus cycle length was 355±35 ms. The
basic paced cycle length was 300 to 320 ms in all preparations. The
mean basic conduction time (CrT-His) was 74±11 ms.
Basic-rate pacing was used during the initial 30 to 40 minutes of adaptation, during determination of vagal stimulation parameters (see below), and between repetitive periods of AF.
The term "AF" will be used to describe the randomized, high-rate atrial pacing and the resulting atrial responses. Custom-written software controlled an analog/digital board (MicroStar 3000A/111) that generated random numbers defining the interval between the subsequent driving stimuli (75- to 150-ms range). The same sequence could be generated multiple times, permitting repetitive initiation of the same AF pattern. In separate experiments (not included in this report), we evaluated the AF reproducibility. Each of the mean time intervals (ie, electrogram intervals measured at the posterior CrT AV nodal input [CrT-CrT], the anterior IAS AV nodal input [IAS-IAS], and the bundle of His recording site [H-H], see below in Data Acquisition) was measured in 2 consecutive trials performed from the same pacing site. Differences between mean interval measurements in trials 1 and 2 did not exceed 3 ms. The intraclass correlation coefficients for the mean intervals ranged from 0.97 to 0.99, confirming the high degree of reproducibility.
In 5 preparations, controlled cooling was applied to the posterior approach to the AVN, mimicking the clinical slow-pathway modification. A thermoelectric cooling probe (3.5-mm2 tip, Novoste Corp) was used to cool discrete areas of perinodal tissue.
Postganglionic Vagal Stimulation
The PGVS technique was based on the previously demonstrated high
density of vagal nerve terminals in the compact area of the
AVN.16 Importantly, the current threshold needed for nerve
excitation (ACh release) was lower than the threshold of myocardial
excitation.17 Therefore, subthreshold bursts elicited
vagal effects on AVN without impeding atrial or ventricular
(His) activation.
Each PGVS burst consisted of 16 rectangular current impulses (2-ms duration, 4-ms interimpulse interval). These 3 parameters were kept constant, resulting in a 92-ms burst.
Two other parameters were varied. The first parameter, timing of the PGVS delivery, was either nonsynchronized or triggered by the His electrogram. In the latter case, PGVS bursts could be initiated either by each trigger or by alternating triggers. For nonsynchronized delivery, PGVS bursts were generated at a constant rate of 1, 2, or 4 Hz.
The second parameter, current intensity, had 5 values
expressed as multiples of a threshold: x0.5, x0.75, x1, x2, and
x3. PGVS threshold was defined as the lowest intensity of a single,
synchronized burst delivered in the midnodal region during pacing at a
basic cycle length of 300 ms that produced complete AVN block (see
Figure 4C in the Results section). Thus, a total of 25 PGVS
combinations (5 timingsx5 intensities) were studied in random order in
each preparation.
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We compared PGVS with the direct effects of acetylcholine (ACh) by
injecting ACh into the compact region of the AVN with a 10-µm-tip
glass micropipette filled with 10 mmol/L ACh connected to a
pressure-impulse Pico-Pump (WPI). The pipette was impaled within
100 µm of the PGVS electrode. Using microscopic control and the
dial of the micromanipulator, we estimated the tip of the injector to
be 100 to 300 µm below the endocardial surface. Each picopulse
(duration, 50 or 100 ms) injected a droplet of
10-4 to 10-3 µL of
ACh. This technique mimicked the discrete release of ACh during PGVS
and was evaluated during both paced basic rates and AF. In 3
preparations, ACh picopulses were used along with
simultaneous recording of the AVN cellular AP. To
ensure that the picoinjection effects were due to ACh release rather
than to nonspecific artifacts, separate experiments confirmed that when
the pipette was empty or filled with Tyrode's solution containing low
concentrations of ACh (<10-6 mol/L), changes in
AVN conduction were negligible, eg, the basic conduction time at a
cycle length of 300 ms and the mean H-H interval during AF typically
remained within 5% of control.
Data Acquisition and Presentation
Electrograms from the CrT and IAS inputs and the bundle of His
were sampled at 1 kHz. Conduction times as well as consecutive CrT-CrT,
IAS-IAS, and H-H intervals were determined. Although AF episodes were
as long as several minutes, the above measurements were made on a
standardized number (100) of H-H intervals.
For simplicity of presentation, all analog records are organized in the following manner. The CrT, IAS, AP, and bundle of His (His) electrograms are displayed from top to bottom. In addition, the consecutive CrT-CrT, IAS-IAS, and H-H intervals were plotted as Lorenz plots. In this format, the abscissa of a given data point represents the value of the nth interval and the ordinate represents the next, nth+1, interval. This facilitates visualization of the range of intervals, as well as the degree of interval dispersion. Thus, a regular rhythm would translate into a single-point Lorenz plot, whereas irregular rates result in dispersed scattergrams.
Statistical Analysis
Coupling intervals (CrT-CrT, IAS-IAS, and H-H) were expressed as
mean±SD. H-H distribution data from the cooling experiments were
compared with control by the nonparametric paired
Wilcoxon test. H-H distributions obtained during AF were
compared with control by a 5-level repeated-measurements within-factor
analysis, ie, for every mode of PGVS delivery, the effects of 5
different intensities were evaluated. Linear, polynomial, and
logarithmic analyses of correlations were performed. A value of
P<0.05 was considered statistically significant.
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Results |
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Spatial Heterogeneity of AVN Conduction During AF: Cooling Modification of the Atrial-AVN Approaches and the Region of the Compact Node
Random, high-rate atrial stimulation resulted in chaotic activation of the posterior (CrT) and anterior (IAS) AVN inputs. Concomitant microelectrode recordings revealed that disorganized and decremental APs in the compact AVN region were the major substrate leading to blocks, ie, "filtering" of the atrial impulses. Figure 2
represents
traces obtained in the same heart during AF with microelectrodes
impaled in different locations. Recorded AF episodes were typically
much longer than the 5- to 10-second excerpts shown. Each trace starts
with several beats preceding initiation of AF.
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The cell in Figure 2A was impaled in the anterior atrial
approach just above the tendon of Todaro, and
APAN (2B) was recorded from an AN cell
located inferior to the tendon of Todaro. In both regions,
numerous APs were inscribed from more positive membrane potentials and
had smaller amplitudes and shorter durations than during slow, regular
rates. Electrotonic humps were rarely observed. These findings were
typical for cells in the atrial-AVN approaches and suggested a
reduction of the proximal driving force.
In contrast, rate-induced changes in the compact AVN region were more
complex (Figure 2C). APs with multiple humps, reduced and
variable amplitude and duration, low dV/dt of the upstroke, and
frequent electrotonic depolarizations (arrows) were
consistently observed. Although the mechanisms underlying these
observations remain unclear, factors such as delayed refractoriness of
the N cells that substantially outlasts the repolarization phase of
their AP,18 and the irregularity of the atrial input, may
be responsible.
The distal AVN was activated in a simpler manner (not shown). The rate was slower, and a steady 1:1 ratio was observed between the distal AP and the His electrogram. Only small AP amplitude variations were noticeable in the NH region, and the AP duration changes paralleled the duration of the diastolic coupling intervals.
The above observations strongly suggest that the filtering of atrial
impulses during AF started at the atrial approaches but was most
pronounced in the compact AVN region. We performed controlled and
reversible cooling (to 18°C) of the posterior AVN approach during AF
in 5 preparations. The cooling probe was first placed between the
ostium of the coronary sinus and the tricuspid valve 3
mm away from the compact AVN, similar to the lead location during
radiofrequency ablation procedures, and then moved anteriorly. As
demonstrated in Figure 3, during AF,
posterior-approach cooling (3A) produced only small slowing of cellular
rates and VRs. Moving the cooling probe close to the compact
nodal region (3B) produced dramatic effects. Multiple subthreshold
depolarizations (stars) not followed by His electrograms indicated only
partial penetration of the AVN. This situation resembled the high
degree of concealed conduction during AF.19 Similar
results were consistently observed in all preparations in which
cooling was applied. The degree of ventricular slowing was
proportional to the degree of nodal cooling. Thus, in conditions of
random, high-rate atrial bombardment, direct depression of conduction
in the compact AVN appears to be more effective in slowing VR than
modification of atrial engagements of the AVN.
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Effects of PGVS During AF
PGVS effects were highly spatially sensitive. As in the
above-described observations during cooling, the strongest depression
of AVN conduction was observed when vagal stimulation was applied
directly to the compact node. ACh released during PGVS induced
characteristic hyperpolarization associated with
depressed amplitude and duration of the AP (Figure 4). These effects were dependent on both
the intensity and the phase (ie, the timing versus the CrT electrogram)
of the vagal burst.20 Thus, an early PGVS (phase 0 ms, 4A)
had the strongest effect on the beat immediately after the burst,
whereas later PGVS (phase 220 ms, 4B) prolonged conduction of the
subsequent beat to a greater degree. A burst with proper timing could
exert a strong effect at lower intensity (phase 73 ms, 4C).
The above considerations were applicable for slow, regular heart rates.
During AF, however, synchronization of a PGVS burst with a random
atrial signal would not be warranted. Therefore, in subsequent studies,
vagal bursts were synchronized with His electrograms or nonsynchronized
at a predetermined frequency. In Figure 5, PGVS was delivered at 2 Hz and 1x
threshold (see Methods). Mean VR slowed from 235 bpm (mean coupling
interval, 212 ms) to 184 bpm (mean coupling interval, 325 ms). The
microelectrode was impaled in the compact nodal region. Note the abrupt
change in the cellular response immediately after the start of PGVS.
The depressed amplitude and dV/dt of the AP during AF were further
reduced, a direct vagal effect on the N cells.20 Multiple
electrotonic responses (one marked by arrow) suggested that either the
cellular excitability, the driving force, or both were insufficient to
permit regenerative depolarization. Double-humped APs (star) were
frequently present. Although different mechanisms may be
responsible for this phenomenon, likely explanations include the
arrival of multiple, fragmented, anterograde wave fronts in the
same location or reentrant activation of the impaled fiber.
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Quantitative Assessment of Vagally Induced Slowing of VR
During AF
A consistent finding in each of the preparations studied
was the significant VR slowing during AF by PGVS applied directly to
the AVN. The Lorenz plots (Figure 6)
clearly illustrate this finding. The scattergrams represent the
corresponding intervals during control AF (6A, 6B, and 6C) and during
PGVS (6D, 6E, and 6F). Note that PGVS had no effect on the atrial
events: the mean value and distribution of both CrT-CrT (6A and 6D) and
IAS-IAS (6B and 6E) remained unchanged. Thus, the vagal effect was
confined only to the AVN region, although specific involvement of the
transitional and compact nodal regions cannot be delineated. A
significant prolongation of the H-H intervals can be seen (6C and 6F),
with mean H-H interval increasing almost 2-fold versus control (515
versus 272 ms).
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The Table summarized data obtained
from all hearts. Mean H-H intervals are shown during control-AF and
PGVS. The latter was delivered in 5 modes and with 5 intensities (see
Methods). Figure 7 shows that
higher-intensity and more frequent bursts were associated with
increased prolongation of the H-H intervals (correlation coefficients
were in the range 0.94 to 0.99, P<0.001).
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H-H Prolongation Versus Control H-H With Different PGVS
Configurations
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To confirm that PGVS effects were induced by ACh release, we compared
them with those of minute amounts of ACh injected directly into the
compact node (see Methods). Figure 8
represents excerpts from a long AF episode with delivery of ACh
every 500 ms (2 Hz). A comparison of Figure 8 with Figure 5 demonstrates the qualitative similarity between the effects of
PGVS and ACh. Note the progressively decremental effect on the AP
amplitude (8A through 8C) as well as the presence of multiple local
electrotonic responses and multihumped APs.
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Hundreds of ACh pulses could be delivered in this manner, without any
apparent fading of the effect. In contrast, prolonged PGVS was
associated with a progressive attenuation and even a reversal of the
effect on the VR. In these cases, we first initiated PGVS and then,
when fading became apparent, we replaced PGVS with ACh pulse injection.
Figure 9 demonstrates that a long-lasting
prolongation of the H-H intervals was immediately restored with the
delivery of ACh.
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Cholinergic Depression of Conduction and Multiple Wave
Fronts
Direct intranodal ACh injection provided an insight into the
nature of the multihumped AVN AP observed during AF and PGVS (Figures 2, 5, and 8). Figure 10 illustrates 1 preparation in which
ACh pulses were injected during constant pacing (300 ms) at IAS. Panels
A through C represent 4-second excerpts from a continuous
recording. The AP was recorded from a fiber in the compact
node. During ACh pulses (Figure 10A, 10B, and 10C), progressive
hyperpolarization (the dashed horizontal line marks
the level of the control diastolic membrane potential)
accompanied a splitting of the AP into 2 components (10A and 10B),
along with the gradual depression of the AVN conduction until 2:1 block
developed (10C). Note that AVN block was correlated with the missing
second component of the AP (arrows), although the first one, although
very low in amplitude, was always present.
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The 2 AP components evolved in a characteristic way. Figure 10D
shows superimposed traces obtained during control and 22 seconds after
the start of ACh injection (the thicker AP and His signals). The timing
of the first component (star) remained exactly the same as the control
AP, although its amplitude decreased rapidly during ACh injections and
soon became just a local electrotonus. The second component (dot)
appeared later in the subsequent beats in parallel with the
prolongation of the AVN delay (the IAS-His interval), from 88 ms in
control to 146 ms. In addition, the amplitude of the second component
gradually depressed and began to alternate between higher and lower
amplitudes (Figure 10B, arrows). Accordingly, the AVN
conduction delay was alternating between 140 and 146 ms in consecutive
conducted beats (10D, arrows).
These AP changes accompanying ACh injections were reproduced many
times, with impalements in different fibers from the compact nodal
region. The splitting of the AP into 2 components was a
consistent finding. When ACh injection was terminated, the
return toward control mirrored the process just described. Initially,
the second component began to increase in amplitude (Figure 11A, dashed arrow), and its amplitude
alternations gradually disappeared (11B, arrows). The strongly
depressed first component recovered more slowly (11C, dashed arrow),
during which time the ACh-induced membrane
hyperpolarization gradually disappeared. Finally, a
fusion of the 2 components into a single AP (11D, arrow) completed the
recovery.
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Different AP dissociation dynamics were observed outside the compact
nodal region. Figure 12 illustrates
typical traces obtained from an AN (transitional) fiber located just
inferior to the tendon of Todaro. During ACh infusion, the
AP again dissociated into 2 components (12B and 12C), as in Figure 10. However, the process developed differently. First, the
ACh-induced hyperpolarization was less pronounced
than in the N fibers. This can be explained by the facts that the fiber
was farther from the ACh-injecting pipette and that the ACh effect was
different on atrial-cell–like cells. Second, the first component
maintained 75% of the amplitude of the original (12A) but
progressively shortened. Third, the secondary component was first
detected as a late hump (12B, arrow) and eventually was inscribed as a
very-low-amplitude depolarization that was present only when there
was a successful propagation to the bundle of His (12C, stars).
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These observations strongly suggested the presence of 2 wave
fronts (Figure 12, inset). According to this model, the earlier
wave front should be associated with the anterior septal activation
(the putative "fast pathway") and was dominant (detectable, in both
the transitional and compact regions) before the infusion of ACh. The
latter led to block of the earlier wave front at the compact nodal
region entrance, so that its "signature" on the level of the
compact node deteriorated to small electrotonic humps (Figure 10) but could still be detected outside the compact node
(Figure 12). Successful conduction to the bundle of His was
then maintained by a second, delayed wave front that was apparently
more resilient to the ACh effect. The signatures of this now
predominant wave front were the second components in the recorded
APs and the successful activation of the bundle of His during the ACh
infusion. In addition, a retrograde turnaround of the delayed wave
front toward the septum cannot be ruled out (Figure 12B and 12C), although it did not result in atrial echo-beats.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Major Findings
Reversible autonomic modulation of the AVN during AF substantially slowed VR. This effect probably resulted from ACh-induced hyperpolarization of the compact nodal region and was manifest in both depressed conduction and increased inhomogeneity with multiple wave fronts. Rich vagal innervation of the compact node provides the unique opportunity to use subthreshold PGVS during AF as an effective tool for slowing VR while preserving the integrity of all anatomic structures and the anterograde pattern of conduction.
Modification of the Atrial-AVN Approaches Versus Depression of the
Compact Node
Localized cooling of the posterior approaches, a procedure similar
to posteroseptal radiofrequency ablation, had limited
effect on the VR during AF (Figure 3A). In contrast, when the
cooling was applied close to the compact node (Figure 3B), the
H-H intervals prolonged dramatically. The lower efficiency of the VR
control obtained with modification of one atrial approach can be
explained by the persistent high-rate bombardment of the compact node
via the remaining atrial approaches. It may be speculated that only an
arch of ablation along the boundaries of the triangle of Koch, rather
than only localized posterior modification, may result in a successful
VR slowing during AF. Alternatively, direct depression of the compact
AVN by cooling invariably resulted in a dramatic slowing of the VR
without alteration of the pattern of atrial bombardment.
PGVS as a Tool for VR Slowing During AF
Subthreshold PGVS produces transient
hyperpolarization and subsequent depression of AVN
conduction.17 20 21 As this study has demonstrated, PGVS
applied directly over the AVN during AF resulted in a substantial
slowing of the VR (Figures 5 and 6). This effect was not
associated with a modification of the rate of atrial bombardment
(Figure 6) but rather was confined to the AVN region. We
speculate that PGVS worked by increasing the inhomogeneity of
conduction (producing fragmented and desynchronized wave fronts) and by
decreasing AP amplitude. This would result in a decremental proximal
driving force associated with multiple local electrotonic events and an
overall high rate of concealed conduction. However, this speculation
involves very complex mechanisms that are not inclusive and/or directly
supported by the experimental results.
The effects of PGVS on AVN conduction have been shown to be dependent
on the phase of the bursts in the cardiac cycle.21
Although phasic effects were probably present during AF as well,
the random arrival of the atrial impulses made it difficult to evaluate
their role. We investigated several different synchronized and
nonsynchronized modes of application of PGVS (Table 1) and found
that the VR slowing was proportional to both the intensity of the
current and the frequency of the PGVS bursts.
Fading of the PGVS Effects
The hyperpolarizing and depressive effects of ACh on the AVN
transmembrane potentials during regular slow atrial rhythms are well
known from classic works.22 23 Later
studies24 demonstrated that prolonged, high-frequency
stimulation of the intramural vagal nerves, but not exposure to ACh,
was associated with fading effects on the sinus node. In this study,
persistent application of strong PGVS bursts during AF in the isolated
rabbit heart preparation saturated vagal effects on the AVN. Because
direct ACh pulses reversed the fading effect over prolonged periods of
time (Figures 8 and 9), desensitization of the muscarinic
receptors25 was an unlikely underlying mechanism. An
alternative possibility is the release of neuropeptide Y from
sympathetic terminals. Neuropeptide Y attenuates the global vagal
effects26 but is evoked by strong and long neural
stimulation, in contrast to the brief and subthreshold PGVS used in our
studies. Thus, the most likely mechanism for the fading phenomenon is
the limited pool of choline in our in vitro experiments. Because
choline uptake in the synaptic cleft is a slow process and because this
is the main source of choline in vitro,27 repetitive PGVS
may have resulted in more released than synthesized ACh per second. In
vivo, where normally an unlimited pool of choline is provided by the
plasma,28 the synthesis of ACh during repetitive PGVS
would be less hampered.
Are Dual Pathways Involved in Conduction Through the Depressed
AVN?
The dynamic development of 2 distinct components of the AVN AP
during direct ACh injection (Figures 8 and 10 through 12) and during PGVS (Figure 5) is compatible
with the presence of fast and slow wave fronts with different ACh
sensitivities. Although unproven, a reasonable hypothesis can be
considered. The fast wave front may have produced the earlier component
of the cellular responses (Figures 10 through 12) and was readily depressed by ACh, whereas the later
slow wave front was more resilient. This later wave front was not
detectable in the microelectrode recordings during control,
because it arrived when the area of impalement was already depolarized
by the fast wave front. However, the presence of the slow wave front
was revealed during the ACh injection, and it was this delayed wave
front that maintained the conduction to the bundle of His.
Limitations of the Study
Random, high-rate atrial pacing was used in these studies to mimic
AF. The major advantage of this model was the possibility to repeatedly
reproduce nearly identical patterns of random atrial activation.
However, further in vivo studies are needed to evaluate the autonomic
modulation of the AVN during spontaneous AF. The reported observations
must be extrapolated cautiously to humans, even though direct
parasympathetic effects on the AVN in humans can be evoked by
PGVS29 30 or stimulation of 1 of the fat
pads.31 In addition, recent reports indicated that the
autonomic control of the AVN is preserved after radiofrequency ablation
of AVN reentrant tachycardia32 and that
electrical stimulation of parasympathetic fibers near the
posteroseptal and anteroseptal areas could induce a
negative dromotropic effect.33 These observations, along
with those from our study, suggest the need for further systematic
evaluation of the effects of long-lasting PGVS on the human AVN during
AF.
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Acknowledgments |
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This research was supported in part by grant 9807701 from the American Heart Association (Northeast Ohio Affiliate).
Received September 18, 1998; revision received February 10, 1999; accepted February 23, 1999.
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