Download Determinants of Duration and Mean Rate of Ventricular Ejection

Determinants of Duration and Mean Rate of
Ventricular Ejection
By
E. BRAUXWALD, M.D.,
S. J. SABXOFF, M.D.
AXT> W.
X. STAIXSBY, SC.D.
The independent influences of stroke volume, heart rate, aortic pressure, hypothermia,
sympathoniiiuetic amines, metered mitral and aortic valvular regurgitation, and alterations in myocardial contractility on the duration and mean rate of ventricular ejection
and filling were studied. These observations were made in a metabolically supported,
isolated heart preparation with performance characteristics comparable to the nouisolated heart.
I
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T HAS long been recognized that the duration of mechanical ventricular systole is
inconstant and is modified by a variety of
hemodynamic, physical and humoral influences. It is generally held that mechanical
systole is abbreviated by tachycardia 1 " 3 and
the administration of sympathomimetic amines, 8 ' 4 and prolonged by an increase in
stroke volume 1 ' 8i 4 and by hypothermia. 5 " 7
The effects of an increase in aortic pressure
have been inconstant.s> 4> 8 However, in previous studies on the duration of ventricular
ejection, the effect of independently altering
each pertinent variable while holding the
others constant has not been accomplished.
The objectives of this investigation were to
ascertain the effect on the duration and mean
rate of left ventricular ejection of the independent alteration of stroke volume, heart
rate, aortic pressure, temperature, cardioactive sympathomimetic amines, and mitral and
aortic valvular regurgitation.
METHOD
The isolated supported heart preparation, the
performance characteristics and stability of which
have been described in detail elsewhere," was employed. This preparation consists of an isolated
dog heart from which all coronary venous blood
flows into the venous system of an intact, anesthetized dog which in turn continuously replaces
biochemically normal arterial blood into the reservoir of the isolated heart system. The independent
augmentation of stroke volume while heart rate
WJIH held constant by right atrial stimulation was
From the laboratory of Cardiovascular Physiology,
National Heart Institute, Bethesda, Md.
Received for publication January 3, 1958.
achieved by increasing left atrial inflow and adjusting the aortic resistance so as to keep mean
aortic pressure constant. Similarly, the independent effect of changes in aortic pressure while
maintaining stroke volume and heart rate constant was studied by appropi-iate adjustment of
left atrial inflow and of the aortic resistance. The
effects of heart rate changes were observed by
varying the atrial stimulation rate while maintaining mean aortic pressure and cardiac output
constant. The effects of hypothermia were studied
by cooling the blood in the reservoir of the isolated,
supported heart system while maintaining mean
aortic pressure, cardiac output and heart rate
constant.
The duration of left ventricular ejection was
measured from aortic pressure pulses obtained
through a catheter in the aortic arch with a Statham P-23D strain gage and generally recorded at
100 mm./sec. paper speeds on a direct-writing
oscillograph. Speeds of 50 mm./sec. were occasionally used. The interval between the onset
of the rise in aortic pressure and the incisura was
taken as the duration of ejection." The mean rate
of ventricular ejection in milliliters per second
was calculated as the stroke volume in milliliter
divided by the duration of systolic ejection in
seconds.
RESULTS
Effects of Changes in Stroke Volume. The
effects on the duration and mean rate of ventricular ejection of augmenting stroke volume
while holding heart rate, mean aortic pressure
and temperature constant are shown in figure
1. An increase in stroke volume was accompanied by an increase in the duration of ejection per beat and per minute. This observed
increase, however, was small relative to the
increase in stroke volume. Accordingly, the
mean rate of ejection was substantially augmented with increases in stroke volume. The
Circulation KrMr.areh, Volnmr VI. May 195!
BKAUXWALD, SAKXOFP AND STAINSBY
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Pia. 1 Top. Relationship between stroke volume
and tlio duration of systolic ejection per beat in msec.
(ordinate) and the consequent influence on the mean
rate of ejection {dashed lines) in 1 experiment. Heart
rate constant at 115. Mean aortic pressure constant
at 100 mm. Hg. Solid dots, value3 obtained at 36.2
C, open circles, values obtained at 30.0 C.
Flo. 2 Middle. Influence of heart rate on the
relationship between stroke volume and the duration
of systolic ejection per beat in msec, (ordinate).
Mean aortic pressure constant at 118 mm. Hg. Dashed lines, mean rate of ejection. Heart weight, 209
Gm.
Fio. 3 Bottom. Influence of heart rate on the
relationship between minute cardiac output and the
total duration of systolic ejection in seconds per
minute (ordinate). Dashed lines, mean rate of ejection. Same experiment as figure 2.
data in figure 1 a r e representative examples
of the results in 12 of 13 hearts.
Effects of CJianges in Heart Bate. Figures
2 and 3 are representative examples of experiments in 6 hearts. Stroke volume was augmented at each of 3 different heart rates while
mean aortic pressure and temperature were
held constant. At any given heart rate the
duration of ejection per beat was prolonged
as stroke volume was augmented, as noted
above. However, as can be seen from figure 2,
at any given stroke volume, the duration of
ejection per beat was shorter at the higher
heart rates. The mean rate of ejection with
any given stroke volume was, therefore, greater at the higher heart rates. As the heart
rate was increased, the shortening of the duration of ejection, however, was small relative
to the increase in heart rate; thus, the total
duration of ejection per minute was prolonged. The data from the experiment shown
in figure 2 were then examined from the
point of view of the relationship between cardiac output and the total duration of ventricular ejection per minute (fig. 3). It was
observed that, as the heart rate was increased,
at any given cardiac output the shortening
of the duration of ejection per beat was small
relative to the increase in heart rate, and the
total duration of ejection per minute was
therefore prolonged. The mean rate of ejection was therefore diminished with any given
cardiac output at the higher heart rates.
Thus, while at any given stroke volume an
increased heart rate will shorten the duration
of ventricular ejection per beat, at any given
cardiac output an increased heart rate will
prolong the total duration of ventricular ejection per minute.
Comparison of Effects of Changes in Heart
Rate and Stroke Volume. Two sets of data
from 1 experiment are shown in figure 4. In
the first (solid dots), stroke volume was augmented by increasing cardiac output at a constant heart rate while mean aortic pressure
was held constant. In the second (open circles), stroke volume was augmented by lowering heart rate while cardiac output and
mean aortic pressure were held constant.
When stroke volume was augmented by low-
321
VENTRICULAR EJECTION
-i
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ering heart rate, the prolongation of the duration of ejection per beat was substantially
greater than when similar increases in stroke
volume were induced by augmenting cardiac
output at a constant heart rate. The difference iu the slopes of the two lines shown
in figure 4 indicates how changes in rate, per
se, may modify the relationship between stroke
volume and the duration of ejection. These
results are representative of those obtaiued
in 4 similar experiments.
Effects of Increasing Mean Aortic Pressure.
Substantial changes in mean aortic pressure
had little influence on the duration of ejection
in 6 of 7 hearts. As shown in figure 5, the
relationship between stroke volume and duration of ejection at a constant heart rate was
relatively constant at mean aortic pressures
of 75, 100, 125, and 150 mm. Hg. In this
range it was repeatedly observed that, when
mean aortic pressure was elevated at any
given stroke volume and heart rate, no significant change in the duration of ventricular
ejection occurred even though filling pressures varied substantially. These observations are not consonant with the views of Wiggers.4 However, it was observed in the 2 experiments in which such observations were
made (fig. 5) that when, at a given stroke
volume, mean aortic pressure was elevated
markedly (175 to 200 mm. Hg 3 ), a lengthening of the duration of ejection did occur.
Effects of Temperature. When temperature
was progressively decreased while stroke volume, heart rate, cardiac output and mean
aortic pressure were held constant, a progressive lengthening of the duration of ejection
and a progressive diminution of the mean
ejection rate were observed (fig. 6). These
data were representative of the experiments
in 3 hearts. The effect of temperature on the
relationship between stroke volume and the
duration of ejection is shown in figure 1. It
was observed in 2 experiments in which this
relationship was examined that, with mean
aortic pressure and heart rate held constant,
at any given stroke volume the duration of
ejection was substantially longer at the lower
temperature.
Effects on Duration of Ejection of a De-
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Fio. 4 Top. Eelative influence on the relationship
between stroke volume and duration of ejection per
beat in msec, (ordinate) of (a) increasing stroke
volume at a constant heart rate by augmenting cardiac output {solid dots) and of (b) increasing stroke
volume by lowering heart rate at a constant cardiac
output {open circles). Numbers contiguous to the
open circles, indicate heart rate. Dashed lines, mean
rate of ejection. Heart weight, 352 6m.
Fio. 5 Middle. Influence of aortic pressure on
the relationship between stroke volume and the duration of ejection per beat in msec, (ordinate). Numbers, the mean aortic pressure at which each set of
values was obtained. Heart rate constant at 150.
Heart weight, 271 Gm.
Fio. 6 Bottom. Relationship between the blood
temperature and the duration of ejection per beat
in msec, (ordinate) and mean ejection rate. Stroke
volume constant at 18.2 ml. Heart rate constant at
115. Mean aortic pressure constant at 100 mm. Hg.
BRAUXWALD, SARXOFF AXD STAIXSBY
322
STROKE
VOLUME
cc
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Fio. 7. Eelationship between stroke volume and
the duration of ejection per beat in msec, (ordinate)
(a) in the prosonce of a descending limb on the ventricular function curve (open circles) and (b) after
the administration of 5 mg. mephentermine sulfate
{solid dots). Xumbers contiguous to points, left
ventricular end-diastolie pressure in cm. HiO. Heart
rate constant at 160. Mean aortic pressure constant
:it 100 nun. Hg. Dashed lines, mean rate of ejection.
Heart woight, 222 Gm.
scendiiig Limb on the Ventricular Function
Curve. In ] experiment evidence of failure
was manifest by a depressed ventricular function curve with a descending limb.10 An increase in the duration of ejection accompanied
the elevation of filling pressure in spite of
the decrease in stroke volume which occurred
on the descending limb of the curve. Following the administration of 5 mg. of mephentermine sulfate, an agent which elevates the
ventricular function curve and abolishes the
descending limb,11 the above noted reversal of
the relationship between stroke volume and
duration of ejection was abolished; the range
of filling pressures was also lowered (fig. 7).
Effects of Sympathomimetic
Amines.
Figure 7 also demonstrates that following the
administration of mephentermiue sulfate, at
any given stroke volume, the duration of
ejection is shorter and mean rate of ejection
higher with heart rate and mean aortic pressure constant. This has been treated in detail
elsewhere.11 Similar observations were also
made with norepiuephrine and nietaraminol.
Studies on Duration of Ventricular Ejection in the Xoirisolated Heart. A previously
described preparation1- in which the independent control of the pertinent hemodynamic
parameters of the in situ heart's performance
could be obtained was also employed for the
type of analysis illustrated above. In the 4
such nonisolated heart experiments, observations were made on the influence of stroke volume, aortic pressure, heart rate and sympathomimetic drugs. The results were found
to be similar to those described.
A summary of all results is shown in table 1.
Effect of Mitral and, Aortic Regurgitatwn
un Duration of Systolic Aortic Ejection. An
analysis of data was made from experiments
on acutely induced and continuously metered
mitral and aortic regurgitation.13'14 In 3
experiments on dogs weighing an average of
25 Kg., mitral regurgitant flows of 2.0 to 4.0
L./min. were induced while forward cardiac
output was held constant. This did not influence the duration of ventricular ejection into
the aorta. In contrast, in 3 other dogs of
similar weight, aortic regurgitant flows of 2.2
to 3.5 L./M. were accompanied by substantial
increases in the duration of systolic ejection
which were comparable to those observed
when total ventricular stroke volume was increased by similar amounts in the absence of
regurgitation.
DISCUSSION
The interpretations derived from previous
investigations on the determinants of the
duration of systolic ejection are complicated
by: (a) the instability of the preparations
employed and the consequent difficulty in the
use of sequentially obtained data,s (b) lack
of direct measurement of stroke volume,1"1
and (c) the lack of independent control of
the pertinent hemodynamic parameters.1'7
The isolated, supported heart preparation employed in the above studies is one in which stability, nonfailing performance characteristics,
simultaneous measurement and independent
control of the required hemodynamic parameters could be achieved.0 In addition, the performance of the isloated heart under study
was uninfluenced by neural and humoral factors which, in an intact dog preparation, may
be evoked by interventions such as infusion
VENTRICULAR EJECTION
323
TABLE 1.—Summary of Observations on Factors Which Modify Duration and Mean Bate
of Ventricular Ejection
Experimental conditions
Intervention
Mean aortic
pressure
Increased stroke volume
Increased heart rate
Increased heart rate
Increased mean aortic pressuret
Hypothermia
Descending limb V. F. curve
Sympathomimetic amines
*
*
A
•
+
Heart
rate
Stroke
volume
*
A
A
*
*
*
*
*
*
*
*
Observation*Cardiac
output
A
A
*
*
*
V
*
Duration
ejection
(m«eo /beat)
A
—
A
A
Duration
Mean rat**
ejection
ejection
(see./min.) (mJ./syst-sec.)
A
A
A
—
A
A
—
A
A
A
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* Hemodynamic parameters held constant.
t See text and figure 5 regarding the effects of markedly elevated mean aortic pressure.
and vena caval and aortic compression, maneuvers used in previous investigations.4
These data are of interest in the interpretation of observations on the splitting of the second heart sound in the normal and diseased
state. During inspiration the augmentation
of right ventricular stroke volume,16 is accompanied by a widening of the interval between aortic and pulmonic valve closure.10'1T
This may be bast explained by the effect of
such an increase in stroke volume on the demonstrated increase in the duration of ventricular ejection (fig. 1). Similarly, in patients
with atrial septal defects, the widened splitting of the second sound is compatible with
the known discrepancy between right and left
ventricular stroke volumes. Further, the fixation of the interval between aortic and pulmonic valve closure during respiration, a sign
detectable by auscultation,17 suggests that in
such patients the respiratory phase has little
influence on right ventricular stroke volume.
In contrast, in patients with patent ductus
arteriosus, in whom the stroke volume of the
left ventricle exceeds that of the right, abolition or reversal of the normal splitting has
been observed.18 The data shown in figure 6
indicate that pronounced elevation of resistance to ventricular pjection results in its prolongation and may help to explain the wideuing of the normal splitting in pulmonic stenosis19 and the observed abolition and even reversal of the normal splitting in aortic steno18
sis.
It is self-evident that, with the exception of
the slight changes in the duration of isometric
contraction and relaxation which might occur,4 those factors modifying the duration and
mean rate of ventricular ejection have a reciprocal influence on the duration and mean rate
of ventricular filling. One interesting implication of this relates to the dynamic alterations accompanying mitral or tricuspid stenosis. In addition to the well-appreciated effect
of heart rate on the time available for mitral
valve flow, it becomes evident that an increase
in stroke volume at any given heart rate will
produce an elevation of the pressure gradient
across the valve. This would result not only
from the increased flow, per se, but also because of the encroachment on the length of
diastole resulting from the increased duration
of ventricular ejection (fig. 1).
The experiments described may also be helpful in the analysis of factors influencing
coronary flow in the presence of coronary artery disease. Under these circumstances the
influence of the metabolic factors which normally regulate coronary vascular resistance12' 20' 21 would seem to be largely obviated
by the change in the locus of the critical resistance element from the adjustable arteriole
to an artery with a fixed orifice. When this
is the case, coronary flow is determined principally or solely by hydraulic factors, prominent among which is the time available for
flow, i.e., the duration of diastole.20
It would appear that tachycardia, an in-
BRAUNWALD, SARNOFF AND STAINSBY
324
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crease in stroke volume, the presence of a depressed ventricular function curve and/or a
descending limb, hypothermia and markedly
elevated systolic pressures each prolong the
duration of ventricular ejection per minute
and thereby reciprocally diminish the time per
minute available for coronary flow. Although
it has been demonstrated that an isolated increase in stroke volume does not, of itself,
substantially augment the myocardial oxygen
requirement21 or coronary flow,12 the manifestations of myocardial hypoxia with an increased stroke volume when coronary artery
disease is present can be at least partially
explained by the decrease in time available
for coronary flow (fig. 1). An accompanying
tachycardia not only augments the myocardial
oxygen requirement21 but would also intensify
the flow time limitation by further prolonging
the duration of systole per minute (fig. 3).
On the basis of considerations deriving from
Laplace's law,21'22 it is clear that, with any
given rate of development of myocardial wall
tension, the rate of development of intraventricular pressure will be a function of the
ventricular radius. The duration of ejection
at any given stroke volume is, in the final
analysis, a function of the rate of development
of the intraventricular pressure. "When the
ventricle is on the ascending limb of its ventricular function curve,10 an increase in the
end-diastolic fiber length is accompanied not
only by an increase in the force of contraction8 but also by an increase in its rate. This
is evidenced by the higher mean ejection rates
that accompany augmented stroke volumes
(fig. 1) and tends to counteract any prolongation of ejection brought about by the increase
in radius, per se. However, should a further
increase in radius and fiber length bring the
ventricle onto the descending limb of its function curve and a decline in both the force of
contraction and mean rate of ejection occur,
a consequent substantial prolongation of the
duration of ventricular ejection takes place
even though stroke volume declines (fig. 7).
SUMMAHT
A systematic investigation of factors influencing the duration and mean rate of both
left ventricular ejection and filling was made
in a stable, isolated heart preparation with
performance characteristics comparable to
those of the in situ heart. An increase in
stroke volume alone lengthens the duration of
ventricular ejection and increases the mean
rate of ejection. An increase in heart rate
alone at any given stroke volume shortens the
duration of ejection per beat, prolongs the
duration of ejection per minute and increases
the mean rate of ejection. An increase in heart
rate at a constant cardiac output greatly
shortens the duration of ejection per beat,
lowers the rate of ejection but prolongs the
duration of ejection per minute. An increase
in mean aortic pressure alone has little influence on either the duration of ventricular
ejection until markedly elevated mean aortic
pressures are reached. Under such circumstances, duration of ejection is lengthened
and the mean rate of ejection decreased.
Hypothermia alone prolongs the duration of
ejection while sympathoniimetic amines have
the opposite effect. Unlike the nonfailing
heart, the failing heart exhibits an increase in
the duration of ejection as stroke volume declines on the descending limb of its ventricular function curve. The clinical implications
of these observations were discussed.
SUMMABtO IN INTERLINGUA
Un investigation systematic del factores
que influentia le duration e le intensitate
medie del ejection e del replenation sinistroventricular esseva excutate in un stabile prcparato de corde isolate con characteristicas de
performance comparabile a illos de un corde
in sito. Un augmento del volumine per pulso
sol prolonga le duration del ejection ventricular e accelera le valor medie del ejection. Un
augmento del frequentia del corde so, a non
importa qual volumine per pulso, reduce le
duration del ejection per pulso, prolonga le
duration del ejection per minuta, e accelera
le valor medie del ejection. Un augmento
del frequentia del corde a nn constante rendimento cardiac reduce grandemente le duration
del ejection per pulso, relenta le intensitate
del ejection, sed prolonga le duration del ejection per minuta. Un augmento del pression
VEXTRICULAR EJECTION
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aortic medie sol ha pauc influentia super le
duration e super le intensitate del ejection
ventricular usque marcate elevationes del
pression aortic medie es attingite. Alora le
duration del ejection es prolongate e le intensitate medie del ejection es reducite.
Hypothermia sol prolonga le duration del
ejection durante que aminas sympathomimetic
ha un effecto contrari. Per contrasto con le
corde in stato de non-fallimento, le corde in
stato de fallimento exhibi un augmento del
duration del ejection quando le voluuiine per
pulso se reduce al latere descendente de su
curva de function ventricular. Le signification clinic de iste observationes es discutite.
325
I. Starling's law of the heart studied by
means of simultaneous right and left ventricular function curves in the dog. Circulation 9: 706, 1954.
11. WELCH, G. H., JR., BRAUNWALD, E., CASE, R.
B., AND SABNOFF, S. J.: The effect of
mephentermine sulfate (Wyamine) on myocardial oxygen consumption, myocardial
efficiency and peripheral vascular resistance.
Am. J. Med. In press.
12. BRAUNWALD, E., SARNOFF, S. J., CASE, R. B.,
STAINSBY, W. N., AND WELCH, G. H., JR.
Hemodynamic determinants of coronary
flow: Effects of changes in aortic pressure
and cardiac output on the relationship between myocardial oxygen consumption and
coronary flow. Am. J. Physiol. 192: 157163, 1958.
13. BRAUNWALD, E., WELCH, G. H., JR., AND
SABNOFF, S. J.: The hemodynamic effects of
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Determinants of Duration and Mean Rate of Ventricular Ejection
E. BRAUNWALD, S. J. SARNOFF and W. N. STAINSBY
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Circ Res. 1958;6:319-325
doi: 10.1161/01.RES.6.3.319
Circulation Research is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1958 American Heart Association, Inc. All rights reserved.
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