Download Sequence of Atrial Depolarization at Different Stages of

Sequence of Atrial Depolarization
at Different Stages of Development
of the Chick Embryo
By Gershon Hait, M.D., and Richard H. Licata, Ph.D.
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ABSTRACT
Simultaneous left and right atrial surface electrograms were obtained from
the right and left atria of 30 chick embryos. These were divided into 3 equal
groups that were studied at 15 to 16, 10 to 11, and 5 to 7 days of incubation.
The embryos were removed from the shell with their circulation intact and
temperature maintained constant. In an early stage of development (5 to 6
days), the left atrium and its appendage were larger than the right, and left
preceded right atrial depolarization. At and after 7 days of incubation, the
right atrium and its appendage were larger than the left, and right preceded
left atrial depolarization. The intervals for interatrial conduction and for atrioventricular conduction were about the same at all stages of development. Since
the length and width of the heart at 15 to 16 days of incubation were about
3 times those of a heart at 5 to 7 days of incubation, it is proposed that the
higher the stage of development of the chick embryo the greater must be the
conduction velocity between the two atria and from atrium to ventricle. This
was assumed to be related to the degree of development of the specialized
conduction pathways that are probably absent or underdeveloped in early
stages of development.
ADDITIONAL KEY WORDS
intact circulation and constant temperature
left atrial pacemaker
interatrial and atrioventricular conduction velocity
• Little information is available about possible pacemaking areas in the left atrium (16). Mindful of the ontogenic development of
the embryonic heart, we concerned ourselves
in the present study with the possibility that
the left atrium at some early stage of development could initiate its rhythm independently
and that its depolarization might precede
right atrial depolarization. At the conclusion
of our study we became aware of the interesting relationship between the interatrial and
From the Congenital Heart Disease Research and
Training Center of the Hektoen Institute, Chicago,
and the Department of Pediatric Cardiology, University of Illinois, and the Cook County Children's
Hospital, Chicago.
Dr. Hait's present address is Assistant Professor of
Pediatrics, Department of Pediatrics, Albert Einstein
College of Medicine, Bronx, New York.
Dr. Licata's present address is Professor and Chairman, Department of Anatomy, University of Nevada,
Reno, Nevada.
Accepted for publication December 12, 1966.
204
electrogram
sinoatrial pacemaker
left S-A node
the atrioventricular conduction velocity and
the various stages of development of the chick
embryo's heart and measured the intervals
for interatrial conduction and atrioventricular conduction.
Materials and Method
Simultaneous left and right atrial surface electrograms were recorded from 30 chick embryos.
Eggs were supplied from the same source weekly
and were uniformly incubated in our laboratory.
The allocation of 10 eggs for each of the 3
groups was done at random; one group of eggs
was incubated 5 to 7 days, another for 10 to 11
days and the third for 15 to 16 days. The embryo was removed from the ovum so as to preserve as much of the circulation as possible and
avoid hemorrhage. After cracking the shell, pieces
of shell were peeled carefully away from the
shell membrane. This procedure was best accomplished by immersing the entire egg in water
that had been heated to 98°F. After removal of
an adequate area of shell, the exposed shell
membrane was further carefully separated from
CircuUiion Risurcb, Vol. XX, Ftbnurj 1967
ATRIAL DEPOLARIZATION IN CHICK EMBYRO
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the remaining shell so that the entire embryo was
removed within its membrane. The membrane
was then incised along a line free of blood vessels, and the embryo and its chorioallantoic membranes and attached yolk sac were released.
The yolk sac was cut beyond the terminal venous
sinus and its contents were allowed to dissipate
in the water; the albumen sac or its remnant was
removed at the same time and the embryo and
its membranes were spread widely in the water
and carefully floated on a grid or a glass Maximow slide. In this manner the embryo with its
entire circulation was transported to the micromanipulator grid where it was spread out. The
amniotic membrane was then cut and the embryo
was placed on its back. The chest was opened by
incising the thoracic body wall laterally and by
removing the central part of the thoracic cage.
The embryo with its intact circulation was then
ready for placement of the exploring electrode
on the heart surface.
A mechanical micromanipulator consisting of
two unipolar electrodes and one indifferent electrode was constructed. This permitted coarse and
fine vertical, horizontal, and circular movements.
A dissecting microscope was placed just above
the micromanipulator.
A heating chamber 4# X 3% inches was constructed from M-inch lucite. The roof of this
chamber was also the bottom of a bath. The
lucite was cut off the bottom of this bath (roof
of the heating chamber) and was replaced by
glass, which is a better heat conductor. The bath
was filled with Ringer's solution. A heating unit
and thermoregulator (Chatham Control Corp.)
were used to maintain the temperature at 98.9°
± 1°F. A pump provided constant circulation
of water. The entire chamber was attached to the
base of the micromanipulator.
A 3/32-inch copper wire frame 1 x 2 inches
with copper screen attached over it was used as
the indifferent electrode and was connected to
the indifferent electrode socket. This grid was
attached to the bottom of the bath by screws; it
was removable and easy to clean. The bath and
copper grid were cleaned before each new experiment.
Platinum wire, 0.0001 inch, was used for
studying embryos 15 to 16 and 10 to 11 days
old and 0.00005-inch wire for embryos 5 to 7
days old. One end of the platinum wire was
soldered to a shielded wire and, except for the
tip, was housed in a glass tube 3/16 inch in
diameter. To prevent injury to the epicardial surface, a club-shaped tip with a smooth end was
prepared. After each experiment, the platinum
electrode tip was cleaned by heating to bright
red in a flame.
Each of the two recording unipolar electrodes
CHCMUHO* Rtsurcb,
VoL XX, Ptkrtur) 1967
205
was connected to a preamplifier (Tektronix type
122), and both preamplifiers were connected
to a Dual Beam Oscilloscope (Tektronix type
502). Low frequency response of the preamplifiers was set at 0.2 cycle/sec and high frequency
response at 1 kc/sec. A gain of 1000 was used
in the preamplifiers. For obtaining permanent
records, a polaroid camera was used with type
47 3000 speed film. Each record was taken at
speeds of 0.2 sec/cm and at 50 msec/cm.
Each of the two type 122 preamplifiers was
powered by five 45-volt B batteries (Burgess
type M30) as well as a 6-volt storage battery.
Serial electrograms were recorded from one to
three points on each surface of the two atria. The
first recordings were obtained 1 to 12 min after the removal of the chick embryo from the egg.
The work area was enclosed by copper mesh.
Results
Left and right atrial surface electrograms
were always recorded simultaneously. In the
figures, the upper tracing was always recorded
from the right atrium and the lower tracing
from the left atrium.
The chick embryo's electrogram inscribed a
record similar to that of an adult mammalian
heart. Accordingly, the P wave was associated
with atrial depolarization, the QRS-T complex
with ventricular depolarization and repolarization, and the P-R interval with the period
commonly referred to as A-V nodal delay. In
man, repolarization of the atrium occurs during depolarization of the ventricles and is
therefore usually concealed. In the recording
from the chick embyro, one can usually see
the unconcealed atrial repolarization (Ta)
between the P wave and the QRS complex.
When the electrode was placed over the ventricular surface, the electrogram consisted of
small P and Ta waves followed by a QRS complex of high amplitude and a T wave (Fig.
la). Characteristically, there was a reverse
relationship of the amplitudes of the P wave
and QRS complex when the electrogram was
obtained from the atrial surface. Since the
electrode placed over the atrial surfaces was
relatively far from the ventricular mass, the
amplitude of depolarization of the atrium
(P wave) was greater than that of depolarization of the ventricle (QRS) (Fig. lc). The
electrode that was placed on the surface of
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HAIT, LICATA
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100 muc
I
QRS
FIGURE 1
Simtdtaneous electrograms obtained from various places over the heart of a 10-day-old chick
embryo: (a) 26 min after removal of the embryo from the egg. Upper tracing was obtained
from an electrode placed over the upper right side of the ventricular mass near the junction
with right atrium. Lower tracing was obtained from electrode placed over the upper left side of
the ventricle near the junction with left atrhun. In both tracings, note that the P wave was
followed by Ta, QRS, and T waves. In the lower tracing note the dome-and-dart shape
of the P waves, (b) 28 min after removal from the egg. Note that the PR in the upper
tracing preceded PL in the lower, hut the simultaneous electrical counterpart of PR
is clearly visible and seems to explain adequately the dome-and-dart configuration in P
in lower tracing of a. (c) 30 min after removal from the egg. In the upper tracing, the electrode was placed over the right atrium and in the lower, the second electrode was placed over
the left atrium. Note that when electrodes were placed over atrial surfaces and were therefore
far from the ventricular mass they recorded a much greater amplitude of atrial than of
ventricular depolarization. Also note that PR preceded Ptj. (d) 35 min after removal from the
egg. In the upper tracing, the electrode was placed over right side of the ventricle and in the
lower, was placed over the right atrium. In both upper and lower tracings atrial depolarization
appeared simultaneously.
the right atrium, and therefore was far from
the left atrium, recorded a greater amplitude
from the left than from the right atrium (Fig.
2b, upper tracing), and the electrode placed
on the left atrium recorded greater amplitudes
from the left than from the right atrium (Fig.
2b, lower tracing).
Analysis of the P wave in the electrogram
taken at a speed of 50 msec/cm demonstrated
the asynchronous activation of the two atria
(Fig. 2). In the upper tracing (right atrial
electrogram, Fig. 2b, c) the initial tallest component corresponded to right atrial depolarization. The second component, which was of a
Circulation Rtiurcb,
Vol. XX, Pebnury
1967
207
ATRIAL DEPOLARIZATION IN CHICK EMBYRO
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FIGURE 2
Electrograms obtained from one embryo in each of the three groups. Upper tracings were
obtained from the right atrium and lower tracings from the left atrium, except for the upper
tracing in a, which was obtained from the right upper ventricle, between the right and left
atrium, (a) From a 16-day-old chick embryo 49 min after removal from the egg. Note that
right atrial depolarization PR preceded left atrial depolarization. Since in the upper tracing the
electrode was on the right ventricle at abotit equal distance from both atria, both right and left
atrial depolarizations were of similar amplitudes, (b) From 10-day-old chick embryo 31 min
after removal from the egg. Note in the upper tracing that right atrial depolarization PK was
in synchrony with a small wave in the lower tracing. This PR was followed by a small elevation
(upper tracing) synchronous with left atrial depolarization, which was of higher amplitude
in the lower tracing PL. (c) From a 7-day-old chick embryo at 47 min after removal from the
egg. Note in the upper tracing that right atrial depolarization PH ivas followed by a prolonged
interatrial interval (interatrial block) and a small wave synchronous with left atrial depolarization Ph. In the lower tracing, a small wave synchronous with PR was followed by a large wave
P,. Also note absence of QRS complex (A-V block).
much smaller amplitude, corresponded to left
atrial depolarization. In the lower tracing
(left atrial electrogram), the small initial component represented the right atrial depolarization and the second tall component that of
the left atrial depolarization. Right preceded
left atrial depolarization in all 20 embryos 10
to 16 days old.
In 10 embryos 5 to 7 days old it was possible to distinguish microscopically two different stages of development. In five hearts at
an earlier stage of development, the left atrial
appendage was two to three times larger
than the right, and the ventricular apex was
rounded rather than pointed in the ventral
view. This corresponded approximately to 5
to 6 days of incubation. In histologic section
of these hearts we noted that the volume of the
CircmUtion RtlMrcb, Vol. XX. Fibnurj
1967
left atrium was greater than that of the right,
anteriorly. In four of these hearts, left preceded right atrial depolarization (Fig. 3b). In the
other five hearts at a more advanced development, the right atrial appendage was larger
than the left and the ventricular apex was
more conical in shape in the ventral view; this
stage corresponded approximately to 6 to 7
days of incubation. In four of these hearts the
sequence of atrial depolarization was right
preceding left (Fig. 3a). In two embryos,
one from the earlier stage (5 to 6 days) and
one from the more advanced stage of development (6 to 7 days), the initial depolarization was from the right atrium but reverted
to an initial left depolarization 4 and 12 min
after the beginning of the experiment (Fig.
4); this latter sequence of depolarization re-
208
HAIT, LICATA
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FIGURE 3
(a) Electrograms from, a 7-day-old-embryo 33 min after removal from the egg. Note in the
upper tracing PR was followed by a PL in the lower tracing. Also note presence of Ta and
absence of QRS complex (A-V block), (b) From an embryo S to 6 days old, 12 min after
removal from the egg. Note in the lower tracing that left atrial depolarization PL preceded right
atrial depolarization PB in the upper tracing.
mained throughout the experiment. A visual
confirmation of these findings could be made
under the microscope, especially toward the
end of each experiment, when the asynchronism between left and right atrial contraction
was more easily noticeable.
Intervals between the two atrial components
as well as the P-R intervals were measured in
all cases at the beginning of each experiment,
then 30 min after the removal of the embryo
from the egg, and at the end of each experiment (Table 1). The interval that separated
the two atrial components was taken to represent an interatrial conduction time during
which the electrical impulse was propagated
from one atrium to the other. The average
interatrial intervals were 8, 6, and 6 msec and
the average P-R intervals were 115, 104, and
114 msec in embryos 15 to 16, 10 to 11 and
5 to 7 days old respectively. These findings
were particularly significant, since the hearts
of embryos 15 to 16 days old were about three
times as long and as wide as those of embryos 5 to 7 days old. Both intervals increased
progressively throughout the experiment, thus
indicating interatrial and atrioventricular
blocks. However, although 30 min after removal of the embryo from the egg the average interatrial interval increased only by 1
msec in embryos 15 to 16 days old, it increased by 6 and 10 msec in those 10 to 11
and 5 to 7 days old. The increase in the average P-R interval 30 min after removal of the
embryo from the egg was 27, 31, and 65
msec in embryos 15 to 16, 10 to 11 and 5 to
7 days old respectively.
Discussion
It is not clear why left atrial depolarization
precedes that of the right at the early stage
(5 to 6 days) of development. In histologic
studies of the hearts we noted that the left
atrium was still larger than the right, anteriorly, at 4 to 6 days of incubation (7). It may
CircaUlion RtSHrcb, Vol. XX, Ftbrmtry 1967
209
ATRIAL DEPOLARIZATION IN CHICK EMBYRO
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FIGURE 4
Electrograms from embryo approximately 6 days old. In all three, upper tracing was obtained with the electrode over the right atrium and the lower tracing with the electrode over
the left atrium, (a) 11 min after removal from the egg. Note that the right atrial depolarization
PR preceded left atrial depolarization PL. A minute later (at 12 min), left preceded right atrial
depolarization, (b) 19 min after removal from the egg; left now preceded right atrial depolarization, (c) 41 min after removal from the egg. The sequence of left preceding right atrial
depolarization was maintained until the end of the experiment.
therefore be postulated that the pacemaking
cells of the sinus venosus which are incorporated in the atrium are distributed in proportion to the size of their respective atria, resulting in left atrial dominance at this stage of
development. Some time between 6 and 7 days
of incubation, with the outgrowth of the right
atrium, the sinus venosus with its pacemaking cells completes its shift to the right and
becomes submerged primarily in the right
atrium (8), resulting in right atrial dominance. Such a postulate may perhaps provide
an explanation for our observations in hearts of
two chick embryos belonging to this stage of
development (5 to 7 days). In these cases
(Fig. 4), initial right atrial depolarization
may have reverted to initial left atrial depolarization during a time when transition from
left to right atrial dominance had just taken
place, and because the right atrium at that
time was more vulnerable when the preparation deteriorated, left sided dominance was
reestablished.
Another possible explanation of why left
preceded right atrial depolarization during the
early stages of development may be related to
the left structural homologue of the right
sinoatrial node (9, 10). Although Patten (9)
CircuUtio* RiiMrcb, Vol. XX, Ftbriury 1967
suggested that the pacemaking tissue at the
left precaval vein was later carried downward
and inward to become the A-V node, Licata (10) believed that as the left caval vessels
dropped out, regression of the sinoatrial homologue followed. The two primordial nodes
had general structural similarity and were
both intimately supplied by homolateral blood
and innervation.
Histologic sections of our present material
showed that at the point of discharge of the
right superior vena cava there was a thickening of muscle anteriorly which could be the
precursor of the sinoatrial node. A minimal
concentration of such a precaval musculature
mass was also seen in a similar location on the
left superior vena cava. The area comparable
to the S-A node as we saw it in the human
on the right side was difficult to distinguish
from the remainder of the atrial musculature
since very little connective tissue separated
them, whereas in the human embryo, the separation of the nodal mass from atrial musculature was well defined. Furthermore, in
the chick the musculature of this nodelike
area spiraled some distance headward within
the adventitia of the superior vena cava.
However, the vascular and neural relationship
210
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to this area was comparable to that in man.
Throughout, we have assumed that the impulse arose somewhere in the right atrium
and after reaching the right atrial electrode
propagated through the left atrium, finally
reaching the left atrial electrode. In the younger age group (5 to 6 days) we assumed that
the impulse traveled in the opposite direction.
This assumption is, however, not the only one
possible. It is possible that the impulse arose
somewhere in the right atrium between the
two electrodes and yet reached the left electrode sooner than it reached the right electrode and therefore seemed to have arisen
from the left atrium. However, we believe
that even if the impulse had originated between the two electrodes, it most probably
originated somewhere in the left sinoatrial
region since left preceded right atrial depolarization no matter where or how medially over
the surface of the left atrium the left electrode was placed.
However one may explain the fact that left
preceded right atrial depolarization in the early stages of development, the ultimate answer requires the identification of a diffuse or
localized pacemaking area in the sinoatrial
region, especially between 2 and 5 days of
incubation. To date, localization of tissue with
pacemaker potentiality in the right atrium by
microelectrode methods (11) shows a remarkable agreement with the ontogenic and
morphologic development of the sinus venosus (11-14). Localization of primary pacemaker activity somewhere in the sinus venosus in the early stages of embryo development
has been demonstrated by Lewis et al. (15);
its exact location has apparently been defined
in the turtle heart but in other species has
been reported to vary (16). No information,
however, is yet available about localization of
pacemaking areas in the left sinoatrial region
by microelectrode methods during early or
late stages of development.
Observations of occasional spontaneous contractions have been made in the isolated left
atrium of the chick embyro by Cohn (6)
and in the adult animal by Erlanger and
Blackman (1), Demoor (2, 4), and Hermann
HAIT, LICATA
et al. (5). Rothberger and Sacks (3) noted
that automaticity of left atrium occurred irregularly in the rabbit's heart, but histologic examination of their material by Aschoff did not
reveal accumulation of specialized tissue in
the left atrium. Serge (17) pointed out that
in ruminants the sinus node is shaped like a
horseshoe, ending with two nodular formations, one of which is located at the junction
between the two atria. In four human hearts,
he also found a horseshoe-shaped mass in
which the left nodular mass occupied the
groove between the musculature of the superior wall of the right atrium and that of the
left. Bruni (18) also found an extension of
sinus node tissue into the interatrial septum in
embryos of the sheep and ox. However, investigations and conclusions about an additional
sinus node were not confirmed (19). Clinical
evidence to confirm left atrial pacemaker sites
is also absent. In 1920 Schrumpf (20) published an electrocardiogram he thought was
a "double sinus rhythm"; one group of P
waves had a regular rate of 64/min of sinus
origin and a second, independent, set of P
waves had a rate of 109 beats/min. Marcel
and Exchaquet (21) demonstrated a double
atrial rhythm in one human fetus of 2'A months
gestation 11 min after hysterotomy. As in our
chick embryos 5-6 days old, they observed
left preceding right atrial depolarization. The
possibility of a left atrial ectopic focus has
been mentioned on a few occasions in connection with an abnormal direction of the P
wave (22-27). More recently, Mirowski et
al. (28), in an attempt to explain abnormal
configuration of the P wave in eight patients
with mirror-image dextrocardia and in four
normally placed hearts that were not in sinus
rhythm, suggested that a dome-and-dart-like
P wave might represent left atrial ectopic
rhythm.
Although the electrodes were placed approximately in the same places on the surface
of both atria in all our experiments, their tips
were larger in the studies done on hearts of
chick embryos 15 to 16 days old than on those
5 to 7 days old. Nevertheless, the impulse
traveled between the two atria at about the
CircuUlion Rtsatrcb, Vol. XX, Ftbrmin
1967
ATRIAL DEPOLARIZATION IN CHICK EMBYRO
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same time in all groups even though the distance between the two atria at 16 to 17 days
was about three times the distance at 6 to 7
days (29). We assumed that the impulse
traveled from one end of an atrium to the
other atrium and the time elapsing between
the two action potentials (PR-PL ) was an index of conduction velocity. As already pointed out, the possibility that in the earliest stage
of development particularly, the impulse may
have arisen somewhere between the two electrodes, thus indicating even slower conduction time, could not be ruled out. Pending
verification by more critical techniques, it is
reasonable to assume that the more the heart
develops, the quicker the impulse travels from
the right to the left atrium. This is most likely
due to the developing speciahzed conducting
pathways between the two atria, such as the
Bachman bundle (12, 30). Whether a more
rapid conduction in such specialized tissue
is due to structural or chemical differences or
both is not known. It was interesting that 30
min after an embryo was removed from the
egg, the younger the embryo, the greater was
the tendency for interatrial block. All degrees
of interatrial blocks were encountered at the
end of each experiment: first degree interatrial block (Fig. 2), second degree interatrial block (Fig. 5) and, in one, a complete
interatrial block. This was probably due to the
deterioration of the preparation, which was
greater in younger embryos.
The P-R interval that we measured (Table
1) was not the "period of A-V nodal delay"
commonly referred to. The first part of the
ventricle to be excited was rather nearer the
apex, and the P-R interval therefore represented the time required for the impulse to
traverse through the A-V node, bundle of His,
and the Purkinje fibers. The measured P-R
intervals in the earliest possible tracings were
almost the same in all three groups (Table
1), even though hearts at 16 to 17 days were
about three times as long as hearts at 5 to 7
days. The slower conduction velocity in the
5- to 7-day-old hearts may be due to a cell-tocell conduction or to underdeveloped conduction pathways that linked the atrium and the
HAIT, LICATA
212
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FIGURE 5
Electrogram from 7-day-old chick embryo 60 min after removal from the egg. Upper tracing
was obtained from right atrium and lower tracing simultaneously from left atrium. Note
absence of QRS in both tracings (A-V block). Upper tracing shows first and third right atrial
depolarization PR followed by a small wave synchronous with left atrial depolarization P^,
which is well seen in the lower tracing. Second and fourth right atrial depolarization PR was
not followed by left atrial depolarization. This 2:1 interatrial block was maintained for a few
minutes; many such records were obtained to document its occurrence.
ventricle at that early stage of development.
Histologic verification of such a hypothesis
is difficult in the chick embryo, since it is not
known when the conduction system differentiates. Although the conduction system, S-A,
and A-V node have been well described in
human and in a few other mammalian species, they have been identified in the adult
chicken by some but not by others (31). In
histologic sections of our present material, the
interventricular septum, which contains the
A-V conducting bundle, was not complete
before the fifth to sixth incubation day. It was
thus reasonable to assume that conduction,
at least before this time, was not through a
complete conduction system and therefore its
velocity was slower. As in interatrial block,
the degree of atrioventricular block was in
direct relationship to the age of the embryo
and to the duration of the experiment (Table 1).
Acknowledgment
We are deeply indebted to Dr. Maurice Lev,
Director of the Congenital Heart Disease and Training Center in Chicago, for his continuous interest
and encouragement throughout this work.
References
1. ERLANGER, J., AND BLACKMAN, J. R.: Study of
relative rhythmicity and conductivity in various
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2. DEMOOR, J.: Contribution a la physiologie
generate du coeur: IV. Les manifestations de
l'automatisTn dans les differentes parties des
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3.
ROTHBERCER, C. J., AND SACHS, A.: Rhythmicity
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Quart. J. Exptl. Physiol. 29: 69, 1939.
4. DEMOOR, J.: Le reglage humoral dans le coeur:
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HERMANN, H., CORNUT, P., AND GUIRAN, J. B.: A
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Sequence of Atrial Depolarization at Different Stages of Development of the Chick Embryo
GERSHON HAIT and RICHARD H. LICATA
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Circ Res. 1967;20:204-213
doi: 10.1161/01.RES.20.2.204
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