Download Relation Between Left Ventricular Diastolic Pressure and Myocardial

Relation Between Left Ventricular Diastolic Pressure and
Myocardial Segment Length and Observations on the
Contribution of Atrial Systole
Bij R. J. LINDEN, M.B., CH.B., PH.D., AND J. H. MITCHELL, M.D.
and the pericardium incised widely and secured
to the chest wall. Short, wide bore (7.5 cm. long,
0.45 cm. internal diameter) metal cannulae were
inserted into the left atrium through the atrial
appendage and into the left ventricle through
the apical dimple.11 Aortic pressure was recorded
through a sound (13 cm. 1 :ii;r, 0.2 cm. internal
diameter) inserted through the left common carotid
artery. One end of a multi-angular clamp was
attached to each cannula as near to the heart
as possible and the other end fixed to a rigid
metal frame secured to the table so as to surround
the operating field. The pressure gages were then
attached to the eannulae and also clamped rigidly
to the frame.
A femoral artery and vein were cannulated
and connected to a reservoir of heparinized blood
which was thoroughly mixed with that of the
experimental animal by repeated infusion and
withdrawal of blood. Left ventricular diastolic
pressure was varied by increasing or decreasing
blood volume. All values were recorded on a multichannel direct-writing' Sanboru oscillograph. Statliam P-23 Gb gages were used to record pressure
in the left atrium and ventricle, a P-23 Db gage
in the aorta. With the cannulae used the whole
system had frequency responses flat (±5%) out
to 30 c.p.s. for the left atrial and left ventricular
systems and 25 c.p.s. for the aortic system when
tested using the method described by Linden."
In the ventricle, only the pressure changes below
40 cm. HoO were recorded so that the diastolic
pressure could be measured more accurately. Zero
baselines were obtained by opening the ventricle
and atrium at the end of the experiment and
exposing the cannula tips to atmospheric pressure.
Heart rate was reeorded with a Gilford cardiotachometer.
The instrument by means of which the changes
in length of the myocardial segment were reeorded
is shown in figure 1. It consists of 2 rotating
microtorque potentiometers (Giannini & Co., Inc.,
model no. 85111) to each of which is attached
a movable aluminum arm (0.38 6m.) by means
of a small hinge (0.5S Gin.). The potentiometer
shaft rotates on jeweled bearings and has a torque
rating of 0.003 to 0.008 oz.-in. The 2 potentiometers are fixed together in a metal yoke such
that the 2 rotating shafts are approximately
O
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NE OP THE fundamental characteristics of striated muscle is the augmentation of its contraction which results from a
longer initial length.1"3 It is thus of some importance to attempt to relate changes in
diastolic myocardial fiber length to other
parameters of the ventricle's performance
characteristics. Because of the complex arrangement of muscle fibers in the myocardium
it is not feasible at the present time to study
the behavior of any 1 fiber or any group of
fibers having the same orientation in space.
The problem of obtaining an indication of the
change in the length of the muscle fibers
therefore becomes one of obtaining au index
of the change in length of a segment of the
whole depth of myocardium. To this end an
instrument was designed to record the relative movements of 2 points in the left ventricular myocardium while simultaneously recording changes in left ventricular pressure.
In addition to establishing the curve describing the relation between left ventricular
diastolic pressure and myocardial segment
length, it was anticipated that such a method
might facilitate the estimation of the contribution of atrial systole to observed changes in
myocardial segment length.4 A preliminary
report of these experiments has been given.5
Methods
Experiments were performed on mongrel dogs
of botli sexes weighing 11.0 to 24.5 Kg., anesthetized with morphine sulfate (2 mg./Kg. intramuscularly) followed half an hour later by a
warmed mixture of chloralose (60 mg./Kg.) and
urethane (600 mg./Kg.) given intravenously.
Intermittent positive pressure ventilation was
maintained with a Starling pump. The chest was
opened through the fifth left intercostal space,
From the Laboratory of Cardiovascular Physiology,
National Heart Institute, Bethesdn, Md.
Received for publication Juno 13, 1960.
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Circulation Research, Volume VIII, September miSO
VENTRICULAR PRESSURE-LENGTH CURVE
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Figure 2
Instrument for calibrating the myocardial segment
length recorder. Each micrometer produces a movement of 0.5 mm. for each complete rotation (50
divisions.)
Figure 1
Myocardial segment length recorder. P = microtorque potentiometer; Y = yoke; H = hinge. The
pointed end of each lever arm (L) is inserted
into the myocardium until stud rests on epicardial
surface. Insert sho-ws adjustable vertical mount
to which recorder is attached.
25 mm. apart. Each movable arm is 30 nun. long
from the center of the hinge to the epicardial
stud; the portion from the stud to the point is
12 mm. long and it is this portion which is thrust
into the myocardium until the stud is in contact
with the surface. Each lever arm stud can move
freely in all directions in the horizontal plane, but
the potentiometer shaft only rotates when the
motion of the stud has a component along a line
parallel to the line joining the centers of the 2
hinges. Both potentiometers are supplied by the
same 90 volt battery and the outputs are connected
so that the algebraic difference between the 2
angles of rotation is obtained. The output is led
through a D.C. carrier preamplifier to the Sanborn
recorder.
After 2 points on the myocardial surface through
which the lever arms are to be inserted are selected
(fig. 1), the lever arms, freed from the hinges, are
plunged into the myocardium until the studs rest
Circulation Research, Volnma VIII, September lilliO
on the myocardial surface. The lever arms are then
attached to the hinges. Bleeding does not occur if
the epicardial studs are kept approximated to the
epicardium.
The segment length recorder is calibrated by
moving the lever arms a. known distance with a
double micrometer constructed for this purpose
and observing the deflection on the recorder. The
calibrating device is shown in figure 2. For calibration, the lever arms were moved in steps of
0.5 mm. and the changes recorded. The sensitivity
usually used was such that 6 nun. deflection on
the paper represented 1 mm. movment along the
chord of the arc described by either lever arm.
In order to insure that the relation between
ventricular diastolic pressure and myocardial segment length was being examined at or near an
equilibrium state, it was desirable to have a slow
heart rate. Three technics for inducing ventricular
bradyeardia were used. In the first 2 methods a
preliminary right thoraetomy was performed and
either the SA node was crushed or a complete
heart block was obtained by sectioning the bundle
of His.8 The third method of maintaining a slow
heart rate was by a constant moderate vagal
stimulation throughout the course of an experiment.
To examine the relation between left ventricular
diastolic pressure and myocardial segment length
the procedure employed was the following: blood
volume was reduced until the left ventricular enddiastolie pressure was between 1 and 3 cm. H.,O.
In order to eliminate the baseline position change
of the heart induced by movement of the lungs
during respiration, the respiratory pump was
stopped and the lungs allowed to deflate by opening
a side-arm in the respiratory line. Then the epicardial studs of the lever arms were rapidly adjusted
by manipulation of the vertical adjustment knob
(fig. 1, insert). A high speed tracing (25, 50
or 100 mm./sec.) was obtained as soon as the
LINDEN, MITCHELL
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250
Ao.
nun
Hg
0
40
LV-Ct
cm
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Figure 3
Ao. = aortic pressure; L.V.-D. = left ventricular
diaslolic pressure; M.S.L. = changes in myocardial
segment length; + = elongation; — = shortening;
full scale deflection represents length change of
8 mm.; chart speed = 50 mm./sec. response to
stimulation of distal cut end of left vagus nerve;
heart rate = 43/min.
hemodynamie parameters were stable (6 to 10
seconds); the respiratory pump was then immediately restarted. Next, approximately 75 ml. of
blood was infused and another high speed tracing
obtained. This sequence of infusion and measurement was repeated until further infusions produced
little or no detectable increase in myocardial segment length. All values were monitored at a paper
speed of 0.5 mm./sec. in the intervals between the
high speed records.
In other experiments a rapid infusion of 300
to 400 ml. of blood was made in 20 to 40 seconds.
In some of these the heart was in complete asystole
as the result of intense vagal stimulation, and in
others heart block had caused a markedly decreased
ventricular rate. During these rapid infusion experiments the vertical height of the segment length
recorder was continuously adjusted so as to maintain the proper approximation of the cpicardial
studs to the surface of the ventricle. The data
obtained, using either the single, large rapid infusion, or the stepwise infusion technic, were
employed to plot left ventricular pressuremyocardial segment length curves. These will be
referred to as pressure-length curves.
Results
The first 16 experiments attempted were
devoted to modifying the apparatus and gaining experience in its use. The results reported
are those obtained from the subsequent experiments in 25 dogs in which 1 or more of
the procedures described below were carried
out.
In order to estimate the accuracy with
which, induced changes in myocardial segment
length could be reproducibly recorded when
all the other recorded parameters remained
the same, the following experiment was done.
The instrument was set so that the studs on
each of the 2 levers just rested on the heart's
surface and a record of myocardial segment
length was taken together with a record of
left ventricular pressure (control). Next, the
potentiometer assembly was vertically displaced, and the operator then attempted to
return the lever to is original position with
respect to the heart and another record obtained (experimental). Then, this displacement and attempted correction were repeated
about 10 times in each dog. The difference between the measurements of myocardial segment length under control and experimental
conditions was expressed as the mean deviation from the control measurement. Of 46
comparisons in 5 dogs, in only 1 comparison
was the deviation from the control measurement more than 0.2 mm. between the lever
arms. The mean deviation from the control
measurement was 0.1 mm.
We could not be certain that the events of
the cardiac cycle throughout ventricular systole and early diastole were recorded accurately because of apparent artefacts sometimes
caused by the roll of the heart as it contracted
and relaxed. In the absence of such apparent
artefacts, the records merit qualitative examination. Such an examination is facilitated by
the bradycardia induced by vagal stimulation
as shown in figure 3. The changes in myocardial segment length throughout the cardiac
cycle can be readily followed. During the
period of diastasis there is a gradual increase
in the myocardial segment length. With the
onset of the pressure rise in the ventricle as
a result of atrial contraction there is a further increase in segment length. The onset of
the rise in ventricular pressure due to ventricular contraction occurs with no concomitant change in segment length. At or just
prior to the beginning of the rise in aortic
Circulation Research, Volume VIII, September 1960
VENTRICULAR PRESSURE-LENGTH CURVE
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pressure, the segment begins to shorten. This
shortening continues until the time of closure
of the aortic valves (incisura). For a brief
period after this point little change in length
occurs. It is assumed that this represents the
isometric relaxation phase. After this point
segment length increases rapidly during the
rapid inflow phase and more gradually once
again during the following period of diastasis.
In figure 3 the relatively small end-diastolic
increment in segment length coincident with
atrial systole is attributable to the high ventricular diastolic pressure (see fig. 4) and the
diminished atrial contractility induced by
vagal stimulation.9
Rarely in these records is there any indication of an "initial systolic expansion."10 Occasionally, however, in records taken during
stimulation of the stellate ganglion, a sharp
pointed wave is seen during the isometric
contraction phase. Generally this disturbance
is over and another plateau is reached before
the abrupt decrease in myocardial segment
length which results from the ejection of
blood into the aorta.11 More commonly, a
shortening of the segment being recorded is
observed at some period during the isometric
contraction phase (fig. 6).
Effect of Infusion on Relation Between Left Ventricular Pressure and Myocardial Segment Length
During Diastasis
Three types of experiment were performed. A. In those dogs in which the heart
rate was such as to provide a recognizable
period of diastasis, the heart rate was maintained constant throughout successive stepwise infusions by pacing the atrium at a rate
just above the spontaneous heart rate. B. In
the second group the heart rate was slowed
by stimulating the peripheral cut end of a
vagus nerve while blood was rapidly infused.
C. In the third group, bradycardia was induced by prior crushing of the SA node or
section of the bundle of His. In each series
of experiments the dog was bled after each
run and a repeat experiment was performed.
Representative results are shown in figure 4.
When the diastolic pressure in the ventricle
was low, a small increment in pressure proCirculation Research, Volume VIII, September I960
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3
4
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INDICATED CHANGES IN DIASTOLIC SEGMENT LENGTH: MM
Figure 4
Iioo successive runs (circles and squares) in
which left ventricular diastolic pressure was elevated
by the stepioise infusion of blood. The plot shows
the relation between diastolic pressure and changes
in myocardial segment length during diastasis
(prior to atrial systole).
duced a relatively large increase in myocardial
segment length (sensitive part). Conversely,
at the higher ventricular diastolic pressures
only small increases in segment length were
produced by a similar or even greater pressure increment (insensitive part). Figure 4
also demonstrates the reproducibility of the
full range of the diastolic pressure-length relation obtainable with the technic used.
Effect of Atrial Contraction on Myocardial Segment Length
Shown in figure 5 is a record obtained from
a dog with heart block in which there were 4
atrial contractions for each ventricular contraction. The results of these atrial contractions could be readily observed in the absence
of disturbances produced by ventricular activity. The tracing at the left is 25 mm./sec.;
the right tracing is 100 mm./sec. Each atrial
contraction, which produced only a small
pressure rise in the ventricle, caused a substantial increase in myocardial segment
length. The observed increases in segment
length thus induced were an appreciable proportion of the total indicated segment shortening which had taken place during systole.
An example of the extent to which the level
of ventricular diastolic pressure will modify
the myoeardial elongation due to atrial systole is shown in figure 6, which shows 2 beats
LINDEN, MITCHELL
1096
^AJ?^
Ir
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TFigure 5
Dog with surgically induced heart block. L.A. = left atrial pressure; other symbols as
in figure 3. Chart speed at left is 25 mm./sec. At right is 100 mm./sec. Ventricular
rale = 50/viin.; atrial rate (paced) = 200/min. Note rise in left •ventricular diastolic
•pressure and increased myocardial segment length consequent to each atrial systole.
at the beginning and 2 beats at the end of a
rapid infusion of blood. At the beginning of
the infusion, when ventricular diastolic pressure was low, the small increment in enddiastolic pressure consequent to atrial systole
was accompanied by a substantial segment
length elongation. At the end of the infusion
when the ventricular diastolic pressure was
high, atrial systole caused a greater rise in
pressure but little increase in segment length.
This effect is also shown in figure 7, which
is a record from a dog with heart block and
a spontaneous atrial rate of 420/min. Each
small atrial contraction caused an increase in
ventricular pressure and a lengthening of the
myocardial segment; the length change relative to the pressure change was greater at
the beginning than at the end of diastole.
Discussion
Basically, the device described above represents an extension of the Cushny lever12'13
and the subsequent modifications made by
other investigators.4' 14~16 The 2 advantages
which this instrument is believed to have
are the following: 1. The mass of those parts
of the recording device which are moved by
the ventricle is low. While it has not been
found possible to test the natural frequency
of the fully assembled heart-lever system, the
rapidity of the response it is capable of yielding must be high (fig. 7). 2. The heart does
not impart momentum to the bulk of the system because both lever arms are free to move.
There are, nevertheless, Limitations to the
use of this technic: 1. The vertical distance
between the potentiometer shafts and the surface of the myocardium at the points of entry
of the lever arms (effective lever length)
should remain constant. This requires careful
attention to the vertical adjustment when recordings are being made. 2. Assuming the left
ventricle to be spheroid, it is necessary to
estimate the error with which the change in
distance between the studs of the lever arms
expresses the change in length of the arc of
ventricular muscle between the studs. Analysis revealed that with the effective length of
the lever arms used (30 mm.) the change in
chord length is a maximum of only 1 per cent
less than the simultaneous change in arclength when changes in chord length of no
more than 10 mm. occurred. The latter change
in chord length was not exceeded in the experiments described above. 3. During systole
when the heart exhibits a certain rotational
motion which moves the ventricular myocarCirculation Research, Volume VIII, September 1000
VENTRICULAR PRESSURE-LENGTH CURVE
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Figure 6
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L.V.—D. = left ventricular diastolic -pressure;
M.S.L. = change in myocardial segment length;
+ = elongation; — = shortening. Tivo beats at
the beginning and 2 beats at the end of a rapid
infusion of blood; 15 sees, between the left and
right tracings.
Figure 7
Spontaneous atrial tachycardia in dog irith surgically induced heart block. Ventricular rate of
•iO/min; atrial rate = 420/min; Symbols as in
previous figures.
diurn on an axis at right angles to the effective
recording movement of the levers, 1 lever arm
could be moved more than the other in this
direction and thus cause an actual change in
distance between the sampled ventricular
points which is larger than the change recorded. The same considerations apply during
the rapid changes in early diastole. Although
the error attributable to this consideration is,
upon visual inspection, thought to be small in
many experiments, we have been unable to
estimate the degree of inaccuracy thus introduced and the instrument cannot be depended
upon to give quantitatively reliable results
during the active ventricular phase of the
cardiac cycle. 4. The presence of the levers in
the myocardium may produce local myocardial hemorrhage. While the recording instrument described cannot be depended upon to
give quantitatively reliable results during
systole and early diastole, it does do so during
diastole when a recognizable equilibrium period is present such as exists at the end of
the period of diastasis.
In these experiments the length changes of
the ventricular segment being studied were
not necessarily quantitatively the same as
those occurring in other segments of the myocardium. However, we believe we can safely
assume that when the segment under study is
increased in length during diastole, other
myocardial segments also are increased in
length. With this in view the curve describing
the relation between pressure and length adds
to the knowledge gained from the curve describing the relation between end-diastolic
pressure and stroke work. In the latter relation, when ventricular pressure is low, a small
increase in pressure produces a marked increase in stroke work." It is on this portion
(sensitive part) of the pressure-length curve
that a small increase in pressure also produces
a large increase in myocardial segment length
(fig. 4). When ventricular end diastolic pressure is high, i.e., on the insensitive part of
the pressure-length curve, a substantial increase in pressure produces little increase in
either segment length or in stroke work."
These experimental observations lend further
support to the view that, if the contractile
characteristics of ventricular muscle are unaltered, the ventricle's contraction varies directionally with the initial length from which
the contraction takes place.
The importance of atrial systole for ventricular filling was shown by Gesell4 and by Wiggers and Katz.17 The extent to which atrial
systole can contribute to the lengthening of
ventricular myocardial fibers can be seen in
figures 5, 6, and 7. In the interesting and
painstaking study of Lind, Wegelius and
Lichtenstein,18 who used contrast media for
demonstrating the atrial contribution to ven-
Circulation Research, Volume VIII, September 1960
LINDEN, MITCHELL
1098
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tricular filling in human heart block, it was
suggested that the atrial beats which occurred
early in diastole made a substantial contribution to ventricular filling while those which
occurred late in diastole contributed little
"because the atrioventricular pressure difference is small." It would appear from the
data shown above that the more likely explanation is the position of the ventricle at that
time (late diastole) on a higher part of its
pressure-volume as well as its pressure-length
curve.
The dependence of the ventricle's stroke
•work upon initial length while it is in any
given state of contractility, when taken together with the contribution of atrial systole
to initial length, indicates the substantial extent to which atrial systole can provide the
stimulus for greater or lesser amounts of ventricular stroke work. The available reflex
pathways by means of which the vigor of
atrial systole can be modified will be described
elsewhere.9'19
Summary
A method is described for the continuous
recording of changes in the length of a segment of left ventricular myocardium, and its
advantages and limitations are discussed. The
curve depicting the relation between ventricular diastolie pressure and simultaneous
changes in the length of a myocardial segment
is presented. For a given increment in pressure, the myocardial segment length increases
more at low ventricular diastolie pressure than
at high pressure. Atrial systole causes a substantial increase in myocardial segment length
when the ventricle is on the sensitive part of
its pressure-length curve.
Acknowledgment
The continued advice and help of Mr. Frank W.
Noble, M.E.E., Laboratory of Technical Development,
in the design of the segment length recorder is most
gratefully acknowledged by the authors.
Summario in Interlingua
Es describite un methodo pro le continue registration de alterationes in le longor de un segmento de
myocardio sinistro-ventricular, e le avantages e le
limitationes del methodo es discutite. Es presentate
le curva que representa le relation inter pression ven-
tricular diastolie e simultanee alterationes in le longor
de un segmento myocardial. Pro un date augmento
in pression, le longor del segmento myocardial se
augmenta plus a basse que a alte pressiones ventricular diastolie. Le systole atrial causa un considerabile
augmento in longor de segmento myocardial durante
le sensibile parte del curva de pression e longor in le
ventriculo.
References
1. BLIX, M.: Die Lange und die Spannung des
Muskels. Skandin. Arch. Physiol. 5: 173, 1895.
2. FRANK,
O.:
Zur
Dynamik
des
Herzmuskels.
Ztschr. Biol. 32: 370, 1895.
3. STARLING, E. H.: Linacre Lecture on the Law of
the Heart. Delivered at Cambridge, 1915,
London, Longmans, Green and Co., 1918.
4. GESELL, R. A.: Cardiodynamics in heart block
as affected by auricular systole, auricular
fibrillation and stimulation of the vagus nerve.
Am. J. Physiol. 40: 267, 1916.
5. MITCHELL, J., LINDEN, R. J., AND SARNOFF, S. J.:
Teclmic for estimating changes in ventricular myocardial fiber length: Observations on
the effect of stellate ganglion stimulation
(abstr.) Fed. Proc. 18: 105, 1959.
6. SARNOFF, S. J., DONOVAN, T. J., AND CASE, R. B.:
Surgical relief of aortic stenosis by means of
apical-aortic valvular anastomosis. Circulation
11: 564, 1955.
7. LINDEN, R. J.: Method of determining the dy-
namic constants of liquid-containing membrane
manometer systems. Journal of Scientific Instruments 36: 137, 1959.
8. STARZL, T. E., AND GAERTNER, R. A.: Chronic
heart block in dogs: Method for producing
experimental heart failure. Circulation 12:
259, 1955.
9. SARNOFF, S. J., BROCKMAN, S. K., GILMORE, J. P.,
LINDEN, R. J., AND MITCHELL, J. H.: Regu-
lation of ventricular contraction: Influence
of cardiac sympathetic and vagal nerve stimulation on atrial and ventricular dynamics.
Circulation Research 8: 1108, 1960.
10. RTJSHMER, R. F . : Initial phase of ventricular
systole: Asynchronous contraction. Am. J.
Physiol. 184: 188, 1956.
11. MITCHELL, J. H., LINDEN, R. J., AND SABNOFF,
S. J.: Influence of cardiac sympathetic and
vagal nerve stimulation on the relation between
left ventricular diastolie pressure and myocardial segment length. Circulation Res. 8:
1100, 1960.
12. CUSHNT, A. R., AND MATTHEWS, S. A.: On the
effects of electrical stimulation of the mammalian heart. J. Physiol. 21: 213, 1897.
13. —: On periodic variations in the contractions
of the mammalian heart. J. Physiol. 25: 49,
1900.
Circulation Research, VoluvlG VUI, September I960
VENTRICULAR PRESSURE-LENGTH
1099
Effect of
17. WIGGERS, C. J., AND J£ATZ, L. N.: Contour of
coronary occlusion on myocardial contraction.
Am. J. Physiol. 112: 351, 1935.
ventricular volume curves under different conditions. Am. J. Physiol. 58: 439, 1921-22.
15. WALTON, E. P., AND BEODIE, 0. J . : Effect of
18. LIND, J., WEGELIUS, C, AND LICHTENSTEIK, H.:
14. TENNANT, E., AND WIGGEES, C. J.:
Dynamics of the heart in complete A-V block:
Angiocardiographic study. Circulation 10: 195,
1954.
drugs on contractile force of a section of
right ventricle under conditions of intact circulation. J. Pharmacol. & Exper. Therap. 90
26, 1947.
19. SARNOFF, 8. J., GILMORE, J. P., BEOCKMAN, S. K.,
10. COTTEN, M. DEV., AND MALING, H. M.: Eelation-
MITCHELL, J. H., AND LINDEN, R. J . : Regula-
ships among stroke work, contractile force and
fiber length during changes in ventricular
function. Am. J. Physiol. 189: 580, 1957.
tion of ventricular contraction by the carotid
sinus: Its effect on atrial and ventricular
dynamics. Circulation Research 8: 1123, 1960.
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Circulation Research, Volume VIII, September 1960
Relation Between Left Ventricular Diastolic Pressure and Myocardial Segment Length and
Observations on the Contribution of Atrial Systole
R. J. LINDEN and J. H. MITCHELL
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Circ Res. 1960;8:1092-1099
doi: 10.1161/01.RES.8.5.1092
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Copyright © 1960 American Heart Association, Inc. All rights reserved.
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