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Circulation Research
NOVEMBER
1977
VOL.41
NO. 5
An Official Journal of the American Heart Attsociation
BRIEF REVIEWS
The Influence of the Parasympathetic Nervous
System on Atrioventricular Conduction
PAUL MARTIN
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IN THIS brief review I will attempt to amalgamate current
findings with important historical concepts about the influence of the parasympathetic nervous system on atrioventricular (AV) conduction. I first will describe the innervation of the AV nodal region. Then I will discuss the
influence of acetylcholine and associated cholinergic
agents, the effects of vagal stimulation, and the role of the
vagus in the genesis of arrhythmias. Finally, I will describe
briefly certain cardiovascular reflexes that affect AV conduction. I have not attempted to provide an exhaustive list
of references; rather, the most relevant works were arbitrarily selected to illustrate specific points. I regret that
many worthy contributions had to be omitted.
Innervation of the AV Node
It has been known since the early part of this century
that the autonomic nervous system can affect AV conduction profoundly.1"3 Anatomical studies during this era revealed that the AV node is richly innervated4-5 and that
the density of nerve fibers in this region exceeds that in the
myocardium.6 In subsequent years, it was found that ganglia, nerve fibers, and nerve nets lie in close proximity to
the AV node in the human heart7 and that the terminations on nodal tissue vary from fine fibrils to complex
reticular nets.8 It should be noted, however, that all of
these early works were based upon light microscopy and
variable staining techniques and, thus, not all of these
results were accepted conclusively.
Most of the definitive work in this area has been done
within the past 10-20 years. I first will review the neural
pathways to the AV node, and then describe the terminal
innervation of the node. Although the focus here is on the
vagus, the adrenergic innervation will also be mentioned
briefly for completeness.
Geis et al.9 recently have delineated the various autonomic pathways to the AV node of the dog. They found
that the left anterior limb of the ansa subclavia and the
From the Department of Investigative Medicine, Mt. Sinai Hospital,
Cleveland, Ohio.
This work was supported in part by Gram HL 10951 from the U.S.
Public Health Service and by a grant from the American Heart Association, Northeast Ohio Affiliate.
Address for reprints: Paul Martin, Ph.D., Department of Investigative
Medicine, University Circle, Cleveland, Ohio 44106.
ventrolateral cardiac nerves innervated the AV node in
each dog studied. The posterior ansa on the left side and
both limbs of the ansa on the right side innervated the A V
node in one-half to two-thirds of their dogs, whereas the
innominate, the recurrent cardiac, the craniovagal, and
the ventromedial cardiac nerves innervated the AV node
in less than one-fourth of the animals. The right-sided
sympathetic innervation of the AV node consisted of
nerve fibers that accompanied the great vessels to the
region where the inferior vena cava approximates the
inferior border of the left atrium. The sympathetic innervation on the left side followed similar pathways, but
additional fibers reached the node through the ventrolateral cardiac nerve. Both the left and right parasympathetic
innervations traversed pathways along the superior left
atrium and the region where the inferior vena cava lies
close to the inferior margin of the left atrium.
Thus it has been demonstrated that nerve fibers from
both sides of both autonomic divisions project onto the
AV node. The differential effects of neural activity from
the left and right sides is less clear, however. Historically it
was thought that the nerves on the left side primarily
control AV conduction, whereas those on the right side
govern heart rate.1"3-10 This differential distribution was
confirmed recently, both for the vagi""13 and for the sympathetic nerves.12 Others have reported, however, that at
submaximal stimulation levels, the right and left vagi produce an equal prolongation of AV conduction time.14
Also, with brief bursts of vagal stimulation, no consistent
pattern of left vagal dominance of the AV node was found.
However, equal efficacy of the right and left vagi was not
firmly established here because constant stimulation parameters were not used.15 Thus, most evidence favors the
dominance of the left- over the right-sided innervation of
the AV node, at least with maximal stimulus intensities.
The exceptions noted above make for some uncertainty,
however, especially when the interactions of neural activity with other factors are taken into account. This will be
discussed in more detail below.
Abundant terminals from both divisions of the autonomic nervous system innervate the AV node. The distribution of cholinergic terminals appears to be considerably
more dense than that to the surrounding regions of the
heart.16"21 The sympathetic innervation of the AV node
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also is extensive. However, the concentration of norepinephrine in the AV node is not significantly different from
that in the neighboring cardiac tissues.22'23 Cholinesterase
is abundant in the specialized conducting fibers in the right
atrium that bypass the crest of the node to enter it along its
convex surface. Vagal suppression of this bypass tract may
be one mechanism that prevents it from short-circuiting
the AV node under ordinary conditions.17
It was believed initially that the nerve supply to the AV
node is not distinct from that to the surrounding myocardium.19 It has been found, however, that small cardiac
branches of the vagus can affect atrial contractility, AV
conduction, and sinoatrial (SA) nodal rate independently.9'24 Furthermore, with focal excitation of intracardiac vagal fibers, axons stimulated near the SA node do
not affect AV conduction, and those stimulated near the
AV node do not affect heart rate.13-20 Normally, parasympathetic ganglia are not contained within the AV node
itself, but such ganglia are located at its posterior margin,
interposed between the node and the anterior wall of the
coronary sinus.18
It generally had been thought that nerve terminals do
not come into direct contact with AV nodal cells.18 It has
been reported more recently, however, that portions of
the node are supplied richly with neuromuscular contacts.25'26 Both granular (presumably adrenergic) and
agranular (presumably cholinergic) vesicular processes
were described, although the latter predominated. The
vesicular processes were found within sarcolemma-lined
tunnels inside nodal cells, as well as along grooves in the
cell surfaces.25 The functional significance of this pattern
of terminal innervation remains to be defined. However,
the incidence of such neuromuscular contacts varies tremendously from site to site within the node, and contact
sites were found quite rarely in the nodes of some vertebrate species.18
Cholinergic Effects
EFFECTS OF ACETYLCHOLINE AND RELATED
AGENTS
With the advent of microelectrode recording techniques, it became possible to elucidate the structural basis
for the autonomic effects on AV conduction. In a pioneering study, Cranefield et al.27 added acetylcholine (ACh) to
tissue baths containing preparations of isolated rabbit
hearts. They found that, when complete AV block ensued,
the transmission failure occurred at the atrial margin of the
AV node. The characteristic action potential changes in
these junctional fibers included slower depolarization,
notching, and slurring of the upstroke, and decreased
amplitude.27-28 It was concluded, however, that these effects were "secondary to the fragmentation of the action
potential into several asynchronous components."27 Furthermore, the amplitude and upstroke velocity of a nodal
action potential at the atrial margin depend, in part, on the
width of the atrial potentials that drive it; thus, the decrease in the duration of the atrial action potential induced
by ACh serves as a less effective driving stimulus and, per
se, inhibits AV conduction. Retrograde stimuli passing
first through lower nodal regions where action potential
VOL. 41, No. 5, NOVEMBER
1977
waveshape is relatively unaffected by ACh thereby elicit a
more normal action potential amplitude in the upper AV
nodal cells.29 An increase in heart rate exaggerates the
depressant effect of ACh on conduction in the atrionodal
marginal cells. There is little direct effect on the action
potentials of the lower node or His' bundle.29 Using similar preparations, however, others have found that ACh
exerts its principal effects on the action potentials in the
middle area of the AV node rather than at the atrionodal
junction.13-30 Furthermore, in these studies, the response
appeared to be independent of the direction of propagation.13 That ACh can result in the reduction of nodal
potential amplitudes has been a common finding by electrophysiologists, however. This effect is especially interesting since such graded action potential amplitudes seem
to violate the "all or one" law of most other myocardial
(and nerve) cell types, and thus indicates a fundamentally
different membrane behavior.
It now is clear that an important mechanism of ACh
action is to increase potassium conductance. This was
shown indirectly by holding the cell membrane at a potential more negative than the Nernst potential for K+; the
addition of ACh induced a partial depolarization rather
than the hyperpolarization that ordinarily is obtained at
the usual levels of resting potential.31 This shift toward the
Nernst potential for K+ is the result expected, of course, if
ACh increases K+ permeability. More direct evidence for
the effect of ACh on K+ conductance has been provided
by isotope experiments.31
If the permeability to K+ is sufficiently high, attempts to
elicit a propagated action potential in the AV node may
fail. Even a large increase in Na+ permeability may not be
able to shift the membrane sufficiently far from the resting
level to evoke a regenerative depolarization.32 Surprisingly, potassium infusions at concentrations of 4.8-6.9
mEq/liter alleviate the AV block induced by vagal activation, although, at higher K+ levels, parasympathominetic
actions are enhanced. Still higher concentrations of K+
cause AV block, even in the absence of vagal activity.33
The antagonizing effects of the lower K+ concentrations
are not mediated by catecholamine release. Instead, they
may act by reducing the resting potential, thereby bringing
it closer to the threshold level. Alternatively, the effect of
ACh on the amplitude and rate of rise of the action
potential may be inhibited, thereby allowing the cell to
depolarize more rapidly.
With respect to drugs that affect autonomic function,
the cardiac vagus nerves are more susceptible to the blocking action of tetrodotoxin than are the sympathetic
nerves.34 This drug also has a direct effect on cardiac cell
membranes. The cardiac action potential appears to consist of relatively independent fast and slow components,
involving separate channels in the cardiac cell membranes.
The slow component predominates at the SA and AV
nodes.28 The slow channels are relatively insensitive to
tetrodotoxin, but the fast channels are very sensitive.32
The slow channels are effectively inhibited by verapamil
via a noncholinergic mechanism.35
Atropine slows SA nodal discharge rate in low doses,
but accelerates it at higher doses in humans.36 In the
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spontaneously beating heart, the curve of AV conduction
time as a function of atropine concentration is U-shaped;
i.e., it first decreases, as expected, but then surprisingly
increases again. However, all values of conduction time
are less than the control level.36 When the heart rate is
held constant, on the hand, there is a consistent doserelated shortening of the AV conduction time.36 Thus, the
lesser effect of higher doses of atropine on A V conduction
in the unpaced heart could be explained entirely by an
interaction with the depressant effect of the increased
heart rate at these doses.36
A comparison of the effects of ACh with those of local
anesthetics and adenosine triphosphate has been made by
selective perfusion of these agents into either the AV
nodal artery or the anterior septal artery that supplies the
bundle branches before the node. It was concluded that
ACh blocks conduction proximal to the bundle branches,
but procaine, lidocaine, and ATP impair conduction in the
AV node37 as well as in the proximal bundle branches. It
also was found that ACh infused into the anterior septal
artery slows an AV nodal rhythm but has no effect on
retrograde conduction, whereas ACh infused into the posterior septal artery has the opposite effect.38 It was concluded that AV nodal rhythms originate in the area supplied by the anterior septal artery. Conversely, the area
supplied by the posterior septal artery has low automaticity but is highly susceptible to ACh and norepinephrine.38
Finally, it was noted above that the SA and AV nodes
contain a rich supply of cholinesterase.17 The ratio of
cholinesterase distribution to nodal and non-nodal tissue
may be of the order of 100:1.39 Furthermore, a proteindeficient diet results in an increase in cardiac acetylcholinesterase activity and a decrease in cardiac butyrocholinesterase activity.40 The latter may be the more important of
the two for changes in the control of cardiac excitation.40
As expected, the cholinesterase inhibitors, neostigmine
and physostigmine, selectively perfused into the AV nodal
artery produce dose-related AV block, and the effect is
abolished by atropine.4'
EFFECTS OF VAGUS NERVE STIMULATION
In a discussion of the effects of vagal stimulation, it is
desirable to distinguish between those studies involving
protracted trains of stimuli and those with single or brief
bursts of stimuli. Continuous supramaximal trains of vagal
stimulation prolong AV conduction time with a latency of
less than 1 second.12 In some dogs, left vagus stimulation,
but not right, preferentially induces second degree heart
block.14 Thus, the vagi may innervate two functional areas
of the AV node; both vagi may be distributed to a site that
controls the AV conduction time, but the left vagus alone
may innervate an area with a considerably higher predilection to block. However, since heart rate was not kept
constant in this study and since right vagal stimulation has
a greater effect on SA nodal rate than does the left, the
interaction of simultaneously changing heart rate and vagal activity on AV conduction (to be discussed in detail
below) casts some doubt over this conclusion.
Supramaximal stimulus trains to the vagi induce bradydysrhythmias, with fixed or changing degrees of heart
595
block." These responses are a monotonically increasing
function of the stimulus amplitude. A V conduction may be
prolonged by about 50-70% of control before block appears.12- l4' 42-43 Vagal stimulation will slow an AV junctional rhythm, just as it does an SA nodal rhythm.15 The
degree of prolongation of AV conduction depends
strongly on the concomitant degree of SA nodal slowing.42
This interaction of the direct vagal effect on the AV node
and the concomitant indirect effect of a lengthened cardiac
cycle increase the difficulty of deriving quantitative conclusions about A V conduction in those studies in which the
heart is not paced.11"14 This interaction will be discussed in
detail below.
The dynamics of the processes that occur at the vagal
nerve endings in the AV node are best studied with single
vagal stimuli or with brief bursts of stimuli. In our laboratory, the effects on AV conduction were extremely variable when we used unpaced dog-heart preparations. Either
an increase or a decrease in the AV conduction time was
obtained, depending upon the timing of the stimulus
within the cardiac cycle.44 This variability in the direction
of the response was ascribed mainly to the indirect effects
of the concomitant changes in cardiac cycle length on AV
conduction. In a subsequent study,45 single vagal stimuli
produced a consistent prolongation of AV conduction
when the heart was paced. In this study, "vagal effect
curves" were used to represent the total dynamic response
to a single stimulus. The responses from a series of separate stimuli, given at increasing increments of delay in the
cardiac cycle, were combined in a single curve, as originally devised by Brown and Eccles for the heart rate
responses.46 Such curves clearly show that the magnitude
of the AV conduction response is critically dependent on
the time in the cardiac cycle at which the stimulus is given.
Figure 1 shows two such curves from the same animal,
in which the heart was driven at two different atrial pacing
intervals (AA). The large circle, square, and triangle in
Figure 1 represent the effects of one vagal stimulus over
three consecutive cardiac cycles. The stimulus that caused
this set of responses was given in the cardiac cycle that just
preceded the cycle represented by the circle (precisely, at
t = 0 on the time axis). The figure shows that the vagal
.\AV%
45
AA,msec
o450
• 350
30
15
0.5
1.0
TIME, SEC
1.5
2.0
FIGURE 1 Vagal effect curves from the same dog at two different
atrial pacing intervals. The abscissa axis indicates the lime elapsed
from a single vagal stimulus burst given at I = 0. The ordinates are
the percent change in AV conduction time over a sequence of
consecutive cardiac cycles with the circles, squares, and triangles
being measured in the first, second, and subsequent beats after the
beat in which the stimulus is given. (Adapted, with permission,
from Martin.45)
596
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effects at the AV node are rapid and transitory. Most of
the response disappears in less than two seconds, just as in
the SA node.46 Efferent vagal activity in the intact animal
can occur as discrete bursts in the cardiac cycle.47-48 Thus,
a given burst can affect AV conduction in the very next
cardiac cycle, and it is therefore possible for AV conduction to be controlled on a beat-to-beat basis. This makes it
possible for the vagus to play a role in the genesis of
certain arrhythmias, a concept that is developed below.
Double peaks are found in curves derived from 62% of
the dogs studied.45 The points at the first and second peaks
are derived from the same stimulus. The peak of the curve
signifies that the AV interval is lengthened maximally.
Concomitantly, the effective refractory period is prolonged maximally. Hence, the AV node has less time to
recover before its next activation. Consequently, the next
atrial impulse arrives earlier in the relative refractory period of the AV junction. A given quantity of ACh released
at the nerve terminals is likely to have a greater effect on
AV conduction time if the node is in a more refractory
state.15'45 Therefore, the atrial impulse that arrives at the
AV junction when its ability to conduct is maximally
depressed (e.g., at the first peak) is likely also to be
conducted very slowly. Hence, it will be at or near the
second peak. A similar explanation has been advanced by
Spear and Moore,15 who also used a form of the vagal
effect curve. Rarely is a third peak evident, as in Figure 1,
but when it occurs, the mechanism is similar. This figure
also illustrates that the amplitude of the curve increases
with the pacing frequency when the vagal stimulation
parameters are constant. At more rapid heart rates, the
AV node is more refractory and, therefore, a given vagal
stimulus will have a greater effect.45
Brown and Eccles46 concluded that the shape of a vagal
effect curve for the SA node is related directly to the time
course of ACh concentration near the affected cells. The
vagal influence on AV conduction was simulated recently
with a mathematical model of the release, diffusion, and
inactivation of ACh, combined with a relaxation oscillator
model of AV nodal cells.45 It was concluded from this
analysis that, for the AV conduction system, the time
course of the tissue concentration of ACh need not correspond to the configuration of a vagal effect curve. Particularly, it was concluded that the second peaks are a property of the nodal cells per se, since the simulated ACh
concentration declines monotonically.
Another relevant property of the AV conducting system
is that the response to a single vagal stimulus depends on
the time passed after the preceding vagal activity. In a
recent study in the paced heart, two identical, brief stimulus bursts were separated by an increasing time interval,
and each burst was given at the same point in its respective
cardiac cycle.49'50 To normalize the data, change in AV
conduction time (AAV) was expressed as the ratio of the
response to the second stimulus burst (AAv2) to that of the
first (AAV,). The results are shown in Figure 2, in which
the abcissae are the time intervals between bursts. The
mean minimum ratio was 0.67 and it occurred at a stimulus separation of about 5 seconds; i.e., when the two
stimuli were separated by about 5 seconds, the magnitude
VOL. 41, No. 5, NOVEMBER 1977
of the second response was only 67% of the magnitude of
the first response. The ratio did not return to unity until
about 1 minute had intervened between stimulus bursts.
When the left and right cervical vagi were stimulated
alternately over an equivalent range of delays, essentially
the same results were obtained (Fig. 2, open circles). This
indicates that the mechanism of the depression of the
second response probably is not associated with processes
governing the synthesis, release, or depletion of acetylcholine. These processes are independent for the two nerves;
stimulation of one side should not affect the synthesis,
release, or depletion of ACh from the terminals on the
other side. This would require, of course, that there be no
convergence of the left and right efferent fibers on common parasympathetic ganglia; such a lack of convergence
has been reported.51
One mechanism for the attenuation of the response to
the second vagal stimulus (Fig. 2) might involve a transient
enhancement of cholinesterase activity by the first stimulus. I could find no work to support this possibility. Alternatively, the burst of ACh released during the first stimulus might desensitize the receptor transiently to pulses of
ACh released during subsequent vagal bursts. This latter
concept has been used to explain vagal escape for the SA
node52 possibly associated with local changes in sodium
concentration.53 The results of Figure 2 similarly provide
an explanation of vagal escape at the AV node.
I also have studied the interaction of the direct effects of
single vagal stimuli on the AV node with the indirect
effects of concomitant changes in atrial cycle length (heart
period). To accomplish this, I subtracted the vagal effect
curve derived from the paced heart preparation from that
obtained in the unpaced heart preparation in the same
dog.54 The changes in cycle length produced by vagal
stimulation in the unpaced heart were stored in the memory of a digital computer. The SA node of the dog then
was crushed, and these sequences of changing cycle
lengths were "played back" in real time from the computer into pacing electrodes attached to the right atrium
near to the SA node. Thus, the AV conduction response
to the applied sequence of cycle lengths could be assessed
in the absence of the interacting effects of vagal stimulation. It was found that, over some portions of the vagal
effect curves, AV conduction time decreased more when
1.11.0-
AAV; . 9 -
o
.8-
•°
.7-
• —same
nerve
O - a I ternate
.6-
5
10
15
20
25
30
40
nerves
50
Time, s e c .
FIGURE 2 Plot of the ratio of the atrioventricular conduction
response to a second stimulus (&A V,) to the response of a control
stimulus (&A VJ vs. the amount of time separating A/4 Vl and
A/lVj. (Reprinted from Martin** by permission of the American
Heart Association, Inc.)
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both vagal activity and changing cycle length were simultaneously imposed than when the cycle length changes alone
were imposed; that is, the AV conduction time was actually less in the presence of vagal activity than in its
absence, a paradoxical response.
The top panel of Figure 3 shows the effects of vagal
stimulation in the presence and absence of pacing in one
dog. It is evident that the curve for the unpaced heart (U)
has substantial troughs of decreased conduction times,
whereas the curve for the paced heart (P) displays purely
inhibitory responses. The dashed curve (D) in the bottom
panel was obtained by subtracting these two curves. When
the identical sequences of cycle lengths recorded from the
unpaced heart were used to trigger the pacing stimulator,
the dynamic effect on AV conduction appears as the
"playback curve" (PB) in Figure 3. If there were a linear
summation of the direct vagal effects and the indirect cycle
length effects, the difference curve and playback curve
would have coincided. That is, the difference represents
the linear subtraction of the direct vagal component from
the vagal effect curves. It represents the effect of the
changing cycle lengths and of the interaction of cycle
length and vagal activity on AV conduction. The disparity
P-AAV paced
U-AAV unpaced
PB • A AV playback
20
D- DIFFERENCE
(-U-P)
P
597
between curves D and PB reflects the magnitude of the
interaction between the direct and indirect effects of vagal
activity. Changing atrial activation patterns and cardiac
pacemaking sites with vagal stimulation were found to be
important contributors to the paradoxical effect. Mechanisms residing in AV nodal (or lower) structures also
contributed importantly, being possibly related in part to
the facilitory effect of ACh on some His' bundle fibers.55-56
The paradoxical effect described above illustrates the
problem of the interpretation of A V conduction responses
to vagal stimulation when the heart is permitted to beat
spontaneously. The mechanisms of such responses clearly
are complex and not ascribable to direct vagal effects on
AV nodal cells alone. Similarly, studies in the unpaced
heart that purport to assess the functional dominance of
the left over the right vagus on AV conduction also must
be interpreted carefully. The right-sided vagal dominance
over the SA node seems indisputable.3>4-6- 8~14 Hence, a
given stimulus to the right vagus produces a greater
lengthening of the heart period than does that same stimulus applied to the left vagus. Thus, there will be a greater
interaction between the direct and indirect effects at the
AV node during right than during left vagal stimulation.
Therefore, in order to compare the responses to left and
right vagal stimulations, these interactions must be assessed properly.
ARRHYTHMIAS AND THE VAGUS
The important contribution of the autonomic nervous
system to the genesis of arrhythmias has been reviewed
1
recently.57 It was noted that nearly every clinically ob1 ii
-10 1
served arrhythmia can be reproduced by stimulation of
1
1
1
_
1
sites in the diencephalon and mesencephalon.58 The ar1
1
1
rhythmias
resulting from hypothalamic stimulation can be
1
-30
> 1
\ 11
abolished by autonomic blockade.59 Disruption of the normal balance between sympathetic and parasympathetic
TIME. sec.
influences may result in the shifting of cardiac pacemakers.60 Stimulation of the ventrolateral cardiac nerve,
"150
which is predominantly a sympathetic link from the central
nervous
system to the heart, but which also includes vagal
/
/ - v AAA
fibers in the dog, leads to various degrees of heart block,
f^
total AV dissociation, and AV junctional rhythms.61
These nodal effects are probably secondary to the sympathetically induced increase in cardiac rate, but vagal fibers
may also be involved.
\
1
>
-20
An emerging concept is that vagal activity may help to
1
1
i
|
1
1
i
!
allay certain arrhythmias, (e.g., extrasystoles and paroxysmal tachycardias), especially under such pathological con-40 ditions as ischemia and drug intoxication.57 Atropine, in
fact, contributes to AV nodal reentry in man, supposedly
FIGURE 3 Top panel: vagal effect curves from the same preparation in which the vagus was stimulated and the heart was paced (P) by providing the prerequisite balance between nodal conand unpaced (U). Bottom panel: the effect of vagal stimulation on duction velocity and refractoriness within reentrant pathatrial rate (bAA) measured simultaneously with the unpaced heart ways.62 Atropine also shortens the functional and effective
curve (U) above. When these same sequences of changing atrial
refractory periods of the AV node. Consequently Hisrates are used to pace the atrium without vagal stimulation, the
Purkinje block and aberrant ventricular conduction may
effect on AV conduction is measured as the curve labeled PB. The
emerge
during premature atrial stimulation.63 However,
curve labeled D is the arithmetic difference between the unpaced
atropine also shortens AV conduction time and increases
and paced heart curves at each point in time. See text for discusthe atrial pacing rate at which AV nodal Wenckebach
sion. (Reprinted from Martin*4 by permission of the American
rhythms occur.63
Heart Association, Inc.)
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Three distinct periodicities in vagal activity have been
observed in cats. One of the periods corresponds to the
respiratory rate,64 and it may play a role in the oscillatory
changes in AV conduction time. As noted above, some
vagal traffic occurs as discrete bursts within each cardiac
cycle.47' 48 These phasic changes in activity may play a role
in "supernormal" AV conduction; i.e., in better conduction than would be expected in a depressed node, but
which is still more depressed than in a normal node.65 It is
likely that periodic bursts of vagal activity produce overlapping vagal effect curves (Fig. 1). If the cardiac cycle
lengths are not constant, or if these periodic bursts do not
occur at the same point in each cardiac cycle, the peak of
each overlapping vagal effect curve will appear at different
times in subsequent cardiac cycles. For some cardiac cycles, the peak will occur at or just prior to the time at
which the AV node is excited, thus causing a prolongation
or even a block of AV conduction. For other cardiac
cycles, the vagal effect curve will begin its steep ascent just
after the AV node has been excited. AV conduction will
then be relatively unaffected, and the AV conduction time
will be less than for other beats. Hence AV conduction for
that beat would appear to be "supernormal." Similar
mechanisms may be involved in other arrhythmias, as has
already been suggested for the AV nodal Wenckebach
phenomenon.15
Cardiovascular Reflexes and AV Conduction
The arrhythmogenic effects of discrete bursts of vagal
activity discussed above suggest that such arrhythmias
might appear in the course of certain cardiac reflexes.
Repetitive bursts of vagal activity are induced reflexly by
the pulsatile pressure sensed by the arterial baroreceptors.
Carotid sinus massage may induce a decrease in atrial rate
and a Mobitz type II AV block, as recently documented in
patients with myocardial infarction.66 In dogs with chronic,
complete AV block, the changes in heart rate and arterial
blood pressure evoked by the carotid sinus reflex are twice
as great as those in normal dogs. Such differences are
abolished after vagotomy.67 Heart block often is associated with an increase in stroke volume and pulse pressure
and a decrease in ventricular rate. These changes may
alter the baroreceptor input in such a manner as to enhance the gain of the baroreceptor reflexes.67 The increased reflex gain, if also present in humans with heart
block, may serve a protective function by allowing a more
complete and rapid cardiovascular response to the fluctuations in blood pressure that occur in complete heart
block.68
It has been shown recently that the dye employed during
angiocardiography exerts both a direct and a reflexly mediated depression of cardiac excitation and conduction.69
It was thought that the reflex effects are mediated by left
ventricular chemoreceptors via vagal afferent and efferent
pathways, possibly the counterpart of the Bezold-Jarisch
reflex. The effects on AV conduction are not precisely
defined, due to the interaction of the direct vagal effect
with the indirect effect of the concomitant increase in
heart period. The existence of a vagovagal reflex influence
on AV conduction time and heart rate has been confirmed
by the detailed study of the responses to stimulation of
VOL. 41, No. 5, NOVEMBER
1977
various small cardiac nerves." It now is appreciated that
cardiac reflexes are extremely complex, since the simultaneous effects on contractile force, heart rate, AV conduction, and peripheral resistance may be highly specific. For
example, with both vagi intact, heart rate may be only
slightly affected by stimulation of the left cervical vagosympathetic trunk, while the AV node may be blocked
and right atrial force markedly diminished.70
Conclusions
The parasympathetic nervous system plays a significant
role in the normal process of AV excitation. The AV node
is innervated richly by vagal fibers. Even relatively low
levels of brief or sustained vagal stimulation may alter AV
conduction profoundly. However, the effect of autonomic
activity on the overall AV conduction process is not dependent solely on the direct response of the AV node to
neural activity. Neural activity also has appreciable effects
on cardiac rate, pacemaker location, and atrial activation
patterns. Furthermore, neurally induced changes in the
action potential from higher AV nodal regions can markedly alter the conduction time through the lower elements
of the conducting system. Each of these indirect responses
also has an effect on AV conduction time, some in a
direction just opposite to those of the direct neural influences. The overall effect of vagal activity on AV conduction, then, is the summated resultant of the direct and the
many indirect effects.
There will undoubtedly be a much better definition in
the future of the neural effects on discrete elements of the
AV conduction system and of the interactions among the
various elements. Perhaps such work will lead to an enhanced understanding of the functional significance of
discrete bursts of vagal activity in a cardiac cycle and of the
role of the autonomic nervous system in the genesis of
arrhythmias. These areas have not received sufficient attention.
Acknowledgments
The extensive assistance in the editorial preparation of this work by Dr.
Matthew N. Levy is gratefully acknowledged.
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Circ Res. 1977;41:593-599
doi: 10.1161/01.RES.41.5.593
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