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445
Effects of Stroke Volume and Velocity of Ejection
on End-Systolic Pressure of Canine Left Ventricle
End-Systolic Volume Clamping
HlROYUKI SUGA AND KEN-ICHI YAMAKOSHI
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SUMMARY To study the effects of contraction mode on ventricular end-systolic pressure-volume relationship, we compared
the end-systolic pressure of isovolumic contraction with that of
ejecting contraction at an identical end-systolic volume. The left
ventricle of excised cross-circulated canine hearts was fitted with a
water-filled balloon. The balloon was connected to a hydraulic
pump that allowed the ventricle to contract to a preset constant
end-systolic volume (19-37 ml) from a variable end-diastolic
volume. At each of control, enhanced, and depressed levels of
contractility, differences of end-systolic pressures of steady state
isovolumic and ejecting contractions were evaluated while stroke
volume and velocity of ejection were widely varied. The end-
systolic pressure in the ejecting contraction tended to decrease by
5-15% from that of the isovolumic beat with increases in either
stroke volume to 20-25 ml or peak velocity of ejection to about
800 ml/sec. There was no obvious difference in the results at
different levels of contractility. The magnitude of the end-systolic
pressure depression due to ejection was, however, relatively small
as compared to 4-fold changes in end-systolic pressure due to the
changes in contractility. We, therefore, conclude that the ventricular end-systolic pressure-volume relationship is affected
slightly by ejection, and that this effect is much smaller than
the maximal effect of changing contractility on the end-systolic
pressure-volume relationship.
NO AGREEMENT exists today as to whether the endsystolic pressure-volume relationship of the mammalian
ventricle is common to different modes of contraction
under a constant contractile state. There are many reports'"8 which indicate that this relationship is common.
However, these studies were conducted under conditions
in which the stability of the contractile state was not
rigorously assessed. We recently have found that the endsystolic pressure-volume relationship curve is virtually the
same for both entirely isovolumic contraction and auxobarically ejecting contraction under a stable contractile
state.9 In contrast, there are reports which indicate that
the end-systolic pressure-volume relationship depends on
the mode of contraction.l0> " However, one of these10 did
not deal with the pressure-volume relationship using a
direct method, and the other" merely indicated a speculative relationship derived from data on the frog heart.
Recently, Burns et al.12 reported that the end-systolic
pressure-volume relationship of isotonic contractions deviates from that of isovolumic contractions when the isotonic ventricular wall stress is relatively small and stroke
volume relatively large.
In relation to this problematic issue on the ventricle,
some studies'3'14 on papillary muscle preparations showed
that their force-length relationship at the end of contraction is independent of the history of contraction, whereas
others15"19 indicate its dependency. Recently, the degree
of this dependence was shown to be reduced by calcium
ions and/or caffeine or tetanus.19 However, these findings
were obtained in artificial experimental conditions. Therefore, it is still undetermined whether or not a similar
uependence on contraction mode may significantly affect
the end-systolic contractile force of the left ventricle ejecting under natural physiological conditions. The previous
finding of the uniqueness of the end-systolic pressurevolume relationship9 suggests that the dependence of the
end-systolic pressure-volume relationship on the history of
contraction, if any, may not be significant, in the canine
left ventricle. However, the design of this experiment9 is
not appropriate to permit a firm conclusion.
To study this problem we designed a pump that can
accurately control and measure the instantaneous intraventricular volume and precisely clamp the residual ventricular volume at the end of systole regardless of other
parameters of contraction. Connecting this pump to the
left ventricle of excised, metabolically supported canine
hearts, we studied whether and how much the end-systolic
pressure at a given identical end-systolic volume changes,
depending on stroke volume and velocity and timing of
ejection.
From the Department of Physiology, Faculty of Medicine. University of
Tokyo, and Institute for Medical and Dental Engineering. Tokyo Medical
and Dental University, Tokyo, Japan.
Dr. Suga's present address is: Department of Biomedical Engineering.
The Johns Hopkins University School of Medicine, Baltimore, Maryland
21205.
Address for reprints: Dr. Hiroyuki Suga, Department of Biomedical
Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Received February 17, 1976; accepted for publication October 21,
1976.
Methods
HEART PREPARATION
Fifteen pairs of mongrel dogs (10-19 kg) were anesthetized with sodium pentobarbital (30 mg/kg, iv). From each
pair, an excised, cross-circulated heart preparation [128 ±
7 (SE) g] was instituted without stoppage of coronary
flow.9 Briefly, a preparation dog was ventilated artificially
and a thoracotomy was performed. The left subclavian
artery and the right ventricle were cannulated and connected to the femoral arteries and veins, respectively, of a
support dog. The heart-lung section was isolated from the
446
CIRCULATION RESEARCH
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systemic circulation by ligature. The pulmonary hili then
were ligated and the lungs were cut off. The supported
heart was excised from the thorax and suspended over a
funnel. The right ventricular cannula was removed. The
coronary venous blood flowing out of the ventricle was
collected in the funnel and drained back to the support
dog's vein.
The left atrium was opened and all the chordae tendineae were freed from the mitral valves. A thin latex
balloon with an unstressed volume of about 70 ml was
placed within the left ventricle via the mitral annulus. A
miniature pressure transducer (Konigsberg P-22) was
placed inside the balloon, and its wire was pulled out
through a stab incision at the apex. The opening of the
balloon was fixed to a rigid connecting tube, and the roots
of the mitral valves were tied around the neck of the tube
with a purse-string suture. An appropriately shaped flange
protruding from the end of the connecting tube was positioned to prevent bulging of the balloon into the aorta.
The space between the balloon and the endocardium
was reduced to a minimum by applying continuous suction
through a catheter with multiple holes placed in this space.
Since the balloon's membrane was flabby and its unstressed volume was larger than the intraventricular volume, we assumed that the balloon could go into most of
the trabecular indentations.
Coronary perfusion pressure was kept at a constant level
between 75 and 120 mm Hg during each experimental
run. The temperature of the coronary perfusion blood was
kept at 37°C.
END-SYSTOLIC VOLUME CLAMP
The intraventricular balloon was connected via a semirigid tube [18-mm inside diameter (i.d.). 10 cm long] to a
pump that consisted of a hydraulic and an air housing
separated by a rolling seal diaphragm (effective area. 50
cm2) and a piston. The hydraulic housing was filled with
water without leaving air bubbles. Compressed air supplied to the air housing actuated the piston of the pump.
The movement of the piston was limited by an adjustable
mechanical stopper so that the piston sucked intraventricular water only to this stopper. Thus, end-systolic intraventricular volume always was clamped at a preset constant value. Peak velocity of ejection was controlled by
changing the compressed air pressure for pulling the piston. The electrocardiogram (ECG) signal from the left
ventricular epicardial lead was used to trigger the control
valve of the air flow to the pump with an adjustable delay
from the Q wave. The delay was varied to shift the onset of
ejection.
The movement of the piston, which was linearly proportional to changes in the intraventricular volume, was converted to an electric signal by a linear potentiometer installed across the piston rod and cylinder of the pump.
Total compliance of the volume measurement-control system including the connecting tube was 0.5 ml/100 mm Hg.
PRESSURE AND VOLUME CALIBRATION
The miniature pressure transducer was calibrated at the
beginning of each experiment against an extracorporeal
strain gauge pressure transducer.9 Thermal drift of the
VOL.
40, No. 5,
MAY
1977
miniature gauge was minimized by reducing the excitation
voltage to the strain gauge. In a preliminary test, no
thermal drift greater than 2 mm Hg was observed when
the gauge was suddenly subjected to a flow of a velocity of
600 cm/sec over a half second in a beaker containing 37°C
water.
The volume signal was calibrated by the following two
steps: First, the gain of the volume signal was calibrated by
changing known amounts of water in the pump while the
connecting tube to the heart was temporarily closed. Then
the piston was pulled firmly to the stopper. Water was
sucked out of the intraventricular balloon with a graduated
syringe until the balloon was completely collapsed by a
highly negative pressure. The electrical signal at this volume of water in the pump was regarded as representing
zero intraventricular volume. The amount of water in the
syringe indicated the clamped value for end-systolic volume. As long as the total volume of water in the system
and the setting of the stopper were unchanged, the same
calibration held for the end-systolic volume. With these
sensitivity and zero calibrations, the volume tracing was
translated into intraventricular water volume. Since the
ventricle, even as collapsed as above, still contained the
sum of the volumes of such intraventricular devices as the
balloon, pressure gauge, etc.. this volume (7 ml) was
added to the measured intraventricular water volume to
obtain the real intraventricular volume.
EXPERIMENTAL PROTOCOL
After the preparation stabilized for about 30 minutes an
end-systolic volume was chosen such that the isovolumic
end-systolic pressure at this volume would be a constant
between 80 and 1 20 mm Hg. The end-systolic volume thus
chosen was kept unchanged throughout the rest of each
experiment regardless of any later change in the isovolumic end-systolic pressure due to a spontaneous change in
contractility. The end-systolic volume that was thus determined ranged from 19 to 37 ml among the preparations.
Contractility of the left ventricle preparation without
any additional inotropic intervention was considered
"control." After a series of control runs contractility was
enhanced by infusing 10% calcium chloride solution into
the coronary artery perfusion tube at such a rate that the
isovolumic end-systolic pressure would reach a steady
level about 50% higher than control. Contractility was
finally reduced by injecting an appropriate amount of
0.1% propranolol into the coronary artery so that the
isovolumic end-systolic pressure would fall to a steady
level about 50% less than control.
Under each of three contractile states, the following
three experimental runs were carried out while the endsystolic volume was clamped at the same constant value.
The order of these runs at each contractility was randomized.
1. Stroke volume run: Stroke volume was varied from 0
(isovolumic) to 20 or 25 ml in five or six steps by increasing the end-diastolic volume. However, end-diastolic pressure was never allowed to exceed 20 mm Hg. Peak velocity of ejection was set at about 200 ml/sec. The onset of
ejection from the Q wave was set at a value between 50
and 75 msec.
447
END-SYSTOLIC PRESSURE-VOLUME RELATIONSH IP/Saga and Yamakoshi
volume in the same run. These end-systolic pressures coincided in time from Q wave of ECG with each other (time
resolution = 10 msec). Note that the end-systolic pressure
of ejecting beats was not necessarily the peak (P,) of the
individual pressure curve which could occur before the end
of ejection.
Finally, the end-systolic pressures (P2) of the ejecting
beats were compared with the end-systolic pressure (Plv)
of the isovolumic beat in the same run. The velocity of
ejection was assessed from the maximal slope of the volume tracing.
Results
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FIGURE 1 Schematic illustration of ventricular pressure and volume curves of an isovolumic (solid) and an ejecting contraction
(dashed) in the same run. The two curves were superimposed with
respect to the time from Q wave of ECG. P, = an earlier peak or
hump of the pressure curve which was observed before the end of
ejection (T?) in contractions with relatively large stroke volume. P2
= another peak or hump of the pressure curve which was always
observed after the end of ejection. Either P, or P2 was the peak
pressure of the ejecting beat. Plv = peak isovolumic pressure. T[ =
onset of ejection. T 3 = end of systole, where the ejecting pressure
curve took P2 and the isovolumic pressure curve took P lv .
2. Ejection velocity run: Peak velocity of ejection was
varied from about 100 ml/sec to 700-1.000 ml/sec in four
or five steps, while stroke volume and the onset of ejection
were kept constant approximately at 15 ml and 50-75
msec, respectively.
3. Ejection timing run: The onset of ejection measured
from the Q wave was shifted from about 25 msec to 100125 msec, while stroke volume and peak ejection velocity
were kept constant at about 15 ml and 200 ml/sec, respectively.
Stability of the preparation during each run is a prerequisite for the present analysis. Therefore, we produced
steady state beats of isovolumic contraction before and
after each of the three runs to examine whether there was
any change in peak isovolumic pressure. When we found a
difference less than 5 mm Hg in steady state isovolumic
end-systolic pressure values before and after the run. we
judged that the preparation was reasonably stable during
the run. About 75% of total runs proved to be stable and
were subjected to the following analysis.
DATA ANALYSIS
First, the steady state peak pressure values of the entirely isovolumic contraction was read from strip chart
tracings, being designated as the end-systolic pressure (Plv
in Fig. 1).
Second, in the steady state ejecting beats with different
loading conditions in the same run. peak pressure values
(P2 in Fig. 1) after the end of ejection (T2 in Fig. 1) were
read, and designated as the end-systolic pressure of the
ejecting beats. Figure 1 schematically illustrates the relationship between the end-systolic pressures of an isovolumic and an ejecting beat with a relatively large stroke
Figure 2 (Panels A. B. and C) shows examples of the
simultaneous recordings of left ventricular pressure, volume, and ECG in three different runs under different
levels of contractility. The end-systolic volume was always
kept constant accurately, as is evident in the second chan^
500 msec
LV
16
B
Lv
PRESSURE
(mmHg)
500 msec
100h-
LV
VOLUME
(ml)
J
V--
60
LV
PRESSURE 100h
(mmHg)
0
LV
VOLUME
(ml)
20
m
60
i,0Y
LV
ECG
ONSET OF
EJECTION
(msec)
ISV
30
50
70
100
FIGURE 2 Simultaneous tracings of the left ventricular pressure,
volume, and ECG. Arrows indicate the end of systole. Panel A
shows the data in a stroke volume run under control contractile
state. Panel B shows an ejection velocity run under an enhanced
contractile state. Panel C shows an ejection timing run under a
depressed contractile state. ISV = isovolumic contraction.
CIRCULATION RESEARCH
448
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net of each panel. Heart rate did not change with changes
in the mode of contraction. Note that the contour of
intraventricular pressure changed markedly with changes
in the mode of contraction. As we indicated in previous
papers.7- 9 these changes in pressure contour again seem to
be largely explainable by the ventricular instantaneous
pressure-volume relationship. Therefore, these phenomena were not analyzed in the present study, but the endsystolic pressure-volume relationship was analyzed as follows.
Although the contour of the intraventricular pressure
was thus markedly altered, the end-systolic pressure values in the ejecting beats changed only slightly with increases in stroke volume, as shown in Figure 2A. Similar
trends were generally observed at all the levels of contractility in each preparation. Maximal depression of the endsystolic pressure was observed with stroke volume of 2025 ml. where the percent magnitude of the pressure depression. 100-(Piv - P2)/Piv, varied from 5% to 15%
among preparations.
Figure 2B shows the recordings in the ejection velocity
run. The end-systolic pressure in ejecting beats generally
decreased by about 10% when ejection velocity exceeded
200 ml/sec. Figure 2C shows that the end-systolic pressure
changed little despite the shift of the onset of ejection over
a wide range.
Figure 3 is a representative plot of the end-systolic
pressures against the three varied parameters under three
different levels of contractility in one preparation. In these
panels, the isovolumic end-systolic pressure is plotted
against the zeros of the abscissas. Similar decreases in the
end-systolic pressure with increases in stroke volume and
ejection velocity were observed at all three different levels
of contractility.
Figure 4 is a su.nmary of statistical analyses of the data
from all the preparations. End-systolic pressure values in
ejecting beats were converted to percentage with respect
to the isovolumic end-systolic pressure in each run. Data
from different levels of contractility were pooled together.
Since abscissa values for a given type of run were not
always identical among separate runs, the abscissa was
divided into several ranges and corresponding data within
a given range were pooled together. Each data point
represents the mean percent value of the end-systolic pressure ± 1 SEM of all the preparations at a specified abscissa
range of parameter. The plots show that in general endsystolic pressure decreased with increases in stroke volume
and peak velocity of ejection, and the decrease is on an
average about 10% at most. The shift of onset of ejection
had little effect on the end-systolic pressure except when
the onset was very early or very late during systole.
VOL.
0
500
1000
PEAK VELOCITY OF EJECTION
ml /sec
SIBOKE VOLUME
40. No. 5.
MAY
ONSET OF EJECTION
1977
msec
FIGURE 3 Graphs showing the changes in end-systolic pressure
with stroke volume (A), peak velocity of ejection (B), and onset of
ejection (C) under three levels of contractile state in the same
preparation.
The present analysis indicated that the end-systolic intraventricular pressure that was developed at a constant
end-systolic intraventricular volume slightly decreased
with increases in either stroke volume or peak velocity of
ejection. This is the first direct experimental evidence
showing this dependency. The observation of Burns et
al.12 may appear somewhat similar to the present findings.
However, they converted their ventricular pressure and
volume data into ventricular wall force and fiber length
and observed similar dependence of end-systolic contractile force on the amount of shortening. Therefore, it is
difficult to evaluate the end-systolic pressure and volume
relationship from their published data. Nevertheless, it is
interesting to note that their degree of depression of endsystolic contractile force by ejection was about 11 % at
most, which is close to our present observation. They
compared the end-systolic contractile force of a steady
state ejecting contraction with that of a steady state isovolumic contraction at a given end-systolic fiber length or
volume. They did not compare end-systolic contractile
100
90
5
10 15
20 25
STROKE VOLUME ml
LU
% 100
in
lU
or,
tr
so
Q.
100 200
400
800
PEAK dV/dt ml/sec
10
• 100
z
UJ
Discussion
The design of the present experiments enabled us to
study precisely whether the end-systolic pressure at a given
constant end-systolic volume depends on the mode of the
contraction of the ventricle. Since the end-systolic pressure of the ejecting mode was compared with that of the
isovolumic mode at the same end-systolic volume (paired
experiment) we could use the paired f-test which improved
the precision of comparison.20
90
0
25 50
75 100 125
ONSET OF EJECTION msec
FIGURE 4 Summary of statistical analyses of the percentile
changes of end-systolic pressure at the same end-systolic volumes
vs. stroke volume, peak velocity of ejection, and onset of ejection.
The abscissas show the ranges and their central values where the
end-systolic pressure data were pooled together. Solid circles and
bars indicate the mean and the standard error of the mean. Asterisks show P < 0.05 by t-test as compared to 100%.
END-SYSTOLIC PRESSURE-VOLUME RELATIONSHIP/Suga and Yamakoshi
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forces at the same end-systolic fiber length or volume
among several ejecting beats with different stroke volumes. Therefore, it cannot be concluded from their data
that the depression of end-systolic contractile force is dependent on stroke volume. Our study demonstrates this
dependence.
Here we discuss several possible mechanisms responsible for the observed depression of the end-systolic pressure in ejecting beats. Quick shortening of heart muscle
has an uncoupling effect and this is one of the possible
mechanisms. Brady21 found that in rabbit papillary muscle
the peak isometric tension is substantially (30%) greater
than the isotonic force level at the same end-systolic muscle length. He ascribed this to the uncoupling effect. Taylor15 observed a similar phenomenon in cat papillary muscle. However. Downing and Sonnenblick13 found that the
isotonic and isometric length-tension relations could be
superimposed in cat papillary muscle. Sonnenblick.14
Brutsaert and Sonnenblick.17 and Brutsaert et al.22 observed only a minor difference among the end-systolic
fiber lengths of different beats loaded with the same isotonic force and shortening from different initial lengths.
More recently. Bodem and Sonnenblick19 reported that
the degree of mechanical damping and the sarcoplasmic
calcium level critically affected the magnitude of the uncoupling effect. Temperature seems to be another factor
which modifies the effect.19 These observations were,
however, obtained in excised, artificially perfused papillary muscle preparations contracting under unphysiological conditions that were different among the investigators.
Although it remains to be known whether such an uncoupling effect has any significant role for natural ventricular
contraction, we cannot deny this possibility as a mechanism of the present findings.
Peak isovolumic pressures at the same ventricular volume were the same before and after each experimental
run. However, the contractility may have been altered in
ejecting beats even in such stable preparations for the
following reason: Contractility is known to change to another level when a mode of contraction.23"25 fiber length.26
or shortening velocity23 is altered in excised myocardium.
These effects have been suspected to be due to changes in
sarcoplasmic calcium level or to viscoelastic properties of
myocardium.23"26 A similar phenomenon could be responsible for the present findings. However, there is no study
in which the end-systolic fiber length of myocardium was
clamped at a constant length and effects of a history of
contraction on the steady state level of contractility was
assessed.
A third possibility is that cardiac oxygen consumption
increases with increases in stroke volume or ejection velocity and consequently oxygen supply becomes inadequate for load. However, this possibility seems less likely
since coronary vessels haye marked autoregulatory capability under constant perfusion pressure, as shown by
Monroe et al.27
A fourth possibility is that there is some viscous resistance againt deformation among myocardial fibers and
layers and this may impede their shortening and cause the
depression of pressure. Such an effect may not be a serious
factor in papillary muscles, where the fibers are in parallel
449
and contract synchronously. Within the ventricular wall,
however, fibers and layers are arranged in a complex
manner28 and contract asynchronously.29 producing shear
and bending force among them. Although there is no more
volume change at the end of systole, the ventricular dimensions may still be changing because of the asynchrony.
We cannot evaluate this possibility quantitatively at present because of the lack of published data.
If ejection per se increased asynchrony of ventricular
contraction, it could cause the pressure depression. However, the observed depression was not accompanied by a
widening of the pressure curve which would be expected as
a result of a greater asynchrony.29 Therefore, we probably
can negate this possibility. It also is unlikely that the
ventricular wall inertia causes the observed depression of
pressure .30
The ejection had already been completed and there was
no more net flow out of the ventricle at the end of systole
in ejecting beats. Therefore, kinetic energy of the ejected
flow could not reduce the measured pressure at the end of
systole. However, if there remained some local flow within
the ventricular cavity, especially in the vicinity of the
miniature pressure transducer, even after the end of ejection, it could reduce the measured pressure by the amount
equal to the kinetic energy of the flow (Bernoulli principle).31 However, it is difficult to consider the existence of
such a local flow that holds kinetic pressure large enough
to explain the observed pressure depression, since a kinetic pressure of 10 mm Hg requires a flow velocity of
about 300 cm/sec.31
Whatever the underlying mechanism might be, the degree of the end-systolic pressure depression in ejecting
contraction was at most 10% on the average. The range of
stroke volume examined in this experiment is wide enough
to cover the physiological range of the stroke volume in
dogs of comparable size (10-25 ml in 10- to 20-kg dogs).30
The range of velocity of ejection is more than the physiological range, according to the measured value (571 ml/
sec) under maximal stimulation of cardiac sympathetic
nerves.30 The onset of ejection was also varied widely
enough to cover the physiological range. Consequently,
we speculated that the degree of the depression of endsystolic pressure in ejecting beats in normal physiological
circumstances will not exceed the present observation.
The depression of the end-systolic pressure is. however,
relatively small as compared to changes in the end-systolic
pressure due to experimentally attainable changes in contractility. In the present experiment, the end-systolic pressure with the same volume was varied easily by ±50%
around control level by calcium and propranolol. respectively. In our previous studies7-9l32 the end-systolic pressure at the same end-systolic volume increased by as much
as 300% from control with administration of catecholamines to the heart or a nearly maximal stimulation of the
cardiac sympathetic nerves. Compared with these percentages, the percentile change in end-systolic pressure due to
ejection is almost negligible.
Acknowledgments
We are indebted to Dr. Kiichi Sagawa for critical comments and encouraging advice in the preparation of this manuscript.
CIRCULATION RESEARCH
450
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Circ Res. 1977;40:445-450
doi: 10.1161/01.RES.40.5.445
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