Download The Contractile State of Cat and Dog Heart in Relation to the Interval

559
The Contractile State of Cat and Dog Heart
in Relation to the Interval between Beats
J.
PIDGEON,
M. LAB, A. SEED, G.
ELZINGA,
D. PAPADOYANNIS,
AND
M.I.M. NOBLE
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SUMMARY We induced atrioventricular dissociation and initiated ventricular pacing in intact dogs
and isolated cat hearts. Left ventricular pressure, its time derivative (dP/dt), and action potentials
were recorded. When a test pulse was introduced at varying intervals after a period of steady pacing,
an optimum contractile response was obtained at an average interval of 720 msec. A similar optimum
interval was obtained after pacing at various frequencies and after paired pulse stimulation but was
shortened to 560 msec after infusion of epinephrine. The magnitude of the optimum contractile response
increased with an increase in the frequency of prior pacing which was accompanied by an increase in
the time the cell membrane was depolarized. The optimum contractile response following paired pulse
stimulation was greater than that following regular pacing, with the same number of stimuli per minute
and the same time of membrane depolarization. The results are explicable in terms of intracellular
calcium ion recirculation with separate compartments for release to and uptake from the contractile
proteins. A negative feedback control of Ca2+ inflow to the cell by intracellular Ca2+ content is
postulated to explain the effect of paired pulse stimulation and shortening of action potential duration
following an increase in regular pacing frequency. Circ Res 47: 559-567, 1980
CONSIDERABLE insight has been gained in recent years into the relationship between the
strength of a cardiac muscle contraction and the
interval between beats. Studies of this topic have
been carried out on isolated strips of cardiac muscle
in which isometric tension can be measured and
action potentials recorded by intracellular microelectrodes (Koch-Weser and Blinks, 1963; Allen et
al., 1976; Edman and Johannsson, 1976). Anderson
et al. (1976) already have shown that patterns of
mechanical response observed in isolated muscle
hold for the intact ventricle.
These studies show a marked influence of the
preceding interval on the strength of a beat. In
particular, there is a partial refractoriness of the
mechanical response after a previous contraction
which takes a period of time to recover. Edman and
Johannsson (1976) first defined the time interval
after a priming period of steady state stimulation at
which a further stimulus would evoke an optimum
contraction, and then examined how the frequency
during the priming period influenced the force of
this optimum response. This optimum contractile
response proved to be a useful index of the potential
contractile force, which was assumed to be related
to the amount of activator calcium available.
We wished to establish whether this held in the
From the Departments of Medicine and Physiology, Charing Cross
Hospital, London, England; Department of Physiology, Free University,
Amsterdam, The Netherlands; and Midhurst Medical Research Institute,
Midhurst, Sussex, England.
This work was supported by grants from the Medical Research Council, the Wellcome Trust, the Mason Medical Research Foundation, and
N.A.T.O.
Address for reprints: Dr. W.A. Seed, Department of Medicine, Charing
Cross Hospital, London W6 8RF, England.
Original manuscript received June 5, 1979; accepted for publication
April 24, 1980.
intact heart. We therefore initially followed Edman
and Johannsson's experimental design and then
attempted to characterize the activation system in
some further detail. The experiments we describe
were performed in anesthetized open- or closedchest dogs with intact circulations and in isolated,
blood-perfused, and ejecting cat hearts.
Methods
Preparations
Closed-Chest Anesthetized Dogs
Six mongrel dogs were anesthetized with intravenous thiopental followed by 1% halothane in nitrous oxide and oxygen. A right thoracotomy was
performed under aseptic conditions. The pericardium was opened and epicardial pacing wires were
sewn to the right ventricle. To allow studies at
cardiac frequencies below the spontaneous heart
rate, we induced complete heart block by injecting
small quantities of formaldehyde into the interventricular septum in the vicinity of the bundle of His
while the electrocardiogram was monitored (Steiner
and Kovalik, 1968). When complete atrioventricular
dissociation had been established, an implantable
demand pacemaker (Devices 3821) was connected
to the pacing wires and buried under the skin at the
back of the neck. In two dogs, two piezoelectric
crystals were implanted into the left ventricle in
order to measure a cavity diameter with ultrasound.
The chest was closed and drained.
One week after recovery, and in one case on later
occasions also, the dogs were anesthetized with
intravenous 1% thiopental followed by chloralose
(40 mg/kg), and the pacing wires at the back of the
neck were exposed. A Gaeltec (Gaeltec Ltd.) cath-
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CIRCULATION RESEARCH
eter tip micromanometer was introduced into the
left ventricle via a femoral artery.
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Open-Chest Anesthetized Dogs
Ten mongrel dogs were anesthetized with intravenous thiopental followed by 1% halothane in nitrous oxide and oxygen. This anesthetic plus intermittent positive-pressure ventilation with a Blease
Manley ventilator was maintained until the end of
the experiment; arterial Po2, Pco2, and pH were
monitored and kept normal. Each animal was positioned on its back, and a window consisting of the
sternum and some of the adjacent ribs was removed
to expose the anterior aspect of the heart. The
pericardium was incised and the edges were sutured
to the chest wall to form a pericardial cradle. Pacing
wires were sewn to the right ventricle, and heart
block was induced as described previously. A Gaeltec catheter-tip manometer was introduced as before. An electrode was applied to the surface of the
ventricles for action potential recording.
Isolated Ejecting Cat Heart
The preparation was set up as described by Elzinga and Westerhof (1978). Cat hearts were isolated in such a way that normal function of the left
heart was maintained. This was achieved by cannulating the aorta and left atrium while the pulmonary veins were tied off. The left atrial cannula
was connected to an overflow vessel providing a
constant filling pressure, and the cannula in the
aorta coupled the heart to a hydraulic model of the
input impedance of the cat's systemic arterial system. In the cannula connected to the aorta, an
occluder was mounted as described by Elzinga et
al. (1977) so that isovolumic beats could be interpolated. Electrodes were sewn on the right ventricle
for pacing, and heart block then was induced in the
same way as for the dog preparations.
Measurements
Pressure
Left ventricular (LV) pressure was measured in
the dogs with a Gaeltec catheter-tip pressure transducer used in conjunction with Hewlett-Packard
(8805B) or Devices (3552) carrier amplifiers. The
resonant frequency of the manometers was about
12 kHz. They showed no detectable gain change
between room and blood temperature (<0.5%) but
in some cases showed small baseline drifts. Therefore hydraulic calibrations at room temperature
were used to derive gain, and zero was taken as the
signal recorded at the moment of removal of the
catheter tip from the femoral artery.
The pressure signals were differentiated electronically to derive the rate of change of pressure (dP/
dt). The response of the differentiators was linear
for amplitude and phase to 100 Hz with a transit
VOL. 47, No. 4, OCTOBER 1980
time of 1 msec. The ventricular pressure signals
also were amplified to allow determination of enddiastolic values. Aortic pressure was measured
through a fluid-filled catheter in the carotid artery.
In the cat hearts, LV and aortic pressures were
measured through short fluid-filled cannulas; the
resonant frequencies were 80 Hz for aortic and 150
Hz for LV catheter manometer systems.
LV Diameter
The distance between the two implanted crystals
was calculated from the transit time between them
of ultrasound pulses generated via an Ekoline 20
(Smith Kline Instruments) echocardiograph. During the experiments, an analog signal of the diameter through the cardiac cycle was obtained from
the time analog module of the Ekoline. The linearity of this system was confirmed in vitro, and the
frequency response was shown to be flat to 30 Hz.
Epicardial Action Potentials
Measurements were made as described by Lab
and Woollard (1978). The open end of a polyethylene tube 2 mm in diameter was held in position on
the surface of one or other ventricle by the application of negative pressure to the other end of the
tube. Two silver-silver chloride electrodes were
used, one in contact with the heart within the lumen
of the tube and one on the outside of the tube which
made contact with the heart surface by means of a
saline-soaked cotton pledget.
The potential difference between the two electrodes was measured with a Devices 3461 preamplifier. The action potential duration (taken as the
time during which the myocardial cells were depolarized by more than 70%) was measured directly
from the records.
Recording
Signals were recorded on Brush 480, Devices M
19 or Elema Schonander EMT 81 pen recorders, or
a Micromovements M10-120A light-beam recorder.
In those experiments in which action potential measurements were made, the primary signals also were
recorded on a Racal Store 4 or a Hewlett-Packard
352A instrumentation tape recorder.
Stimulation
Timing of stimuli used to drive the ventricles was
achieved with, a Digitimer (Devices, 3290) which
provided two adjustable cycle times, each of which
contained one or more trigger pulses. This system
provided pulses for steady single or paired pacing
and abrupt changes of rate by switching between
cycle times. The trigger pulses from the Digitimer
were used to drive a Devices 2538 stimulator, the
voltage of which was adjusted to be 10-15% above
threshold.
INTERVAL-STRENGTH RELATION OF INTACT HEART'/Pidgeon et al.
PROTOCOL 1
PROTOCOL 2
TEST PULSE INTERVAL
PRIMING PERIOD
OPTIMUM TEST PULSE
INTERVAL
PROTOCOL 3
TEST PULSE INTERVAL
PROTOCOL 4
OPTIMUM TEST PULSE
INTERVAL
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FIGURE
1 Patterns of pacing used in this study.
Stimulation Protocols
Determination of Optimum Interval (Fig. 1,
Protocol 1)
During the period prior to the introduction of a
test pulse (the "priming period"), the heart was
paced at a fixed frequency until ventricular pressure, dP/dtmax, and action potential duration had
reached a steady state. Then a test pulse was introduced by switching briefly to a different cycle time
on the Digitimer pulse generator. This new interval
(test pulse interval) then was switched out, usually
after one beat, and reset to a new duration. After a
further priming period had ensured recovery of the
original steady state, it again was switched in. This
procedure was repeated until a range of test pulse
intervals had been explored. LV dP/dt^x of the test
beat, either as an absolute value or as a ratio of the
preceding steady state value, then was plotted
against the test pulse interval to derive by eye the
optimum test pulse interval. In six experiments, the
test pulse interval curve at a given priming frequency was determined before and during an infusion of epinephrine.
At very long intervals, the aortic diastolic pressure falls to low levels at which the maximum rate
of rise of LV pressure is no longer an isovolumic
event (Van den Bos et al., 1973). The possible
occurrence of this situation was monitored from the
561
aortic and LV pressure records; in none of the
experiments was it seen. In the cat hearts, the beat
after the test pulse interval was an isovolumic one
against a closed shutter.
Influence of Priming Frequency (Fig. 1, Protocol
2)
The procedure described above was repeated
with a number of different priming frequencies
ranging from 1 to 4 Hz. The effect of the steady
state heart rate on the entire test pulse interval
curve thus was determined. The optimum values
from each curve then were plotted against the priming (steady state) frequency (Edman and Johannsson, 1976).
To obtain more points on this plot, additional
tests were performed using many values of priming
frequency and a test pulse interval fixed at the
optimum value determined during the previous
runs. Experimental records from such a test are
shown in Fig. 2.
Paired Pulse Stimulation (Fig. 1, Protocols 3 and
4)
With the Digitimer set to generate paired pulses,
test pulse interval curves were determined (protocol
3) from which the optimum test pulse interval was
estimated.
In addition, in six experiments, protocol 4 was
followed. Stimuli at the optimum test pulse interval
(previously determined) were applied after periods
of single pacing at a given frequency and of paired
pulse pacing at half that frequency. The process
was repeated at several priming frequencies, and
plots of optimum contractile response against priming frequency were constructed for both single and
paired pacing.
Volume Infusion
To determine the effect of changes in heart size
upon dP/dtmax, saline at 37 °C was rapidly infused
intravenously in all the experiments reported. LV
end-diastolic pressure or diameter was used to monitor the changes in heart size, and dP/dtmax was
measured at a number of different steady state
priming frequencies. In addition, in five dogs, test
pulse interval curves (Fig. 1, protocol 1), performed
at the same priming frequency before and after the
saline infusion, were examined. In isolated cat
hearts, we raised the left atrial reservoir instead of
infusing saline. Observations were made at a variety
of steady state priming intervals over the range of
heart size explored.
Results
Effect of Ventricular Volume on Contractile
Indices
A change of heart size had no effect on LV dP/
max in the majority of experiments (Table 1). In
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CIRCULATION RESEARCH
VOL. 47, No. 4, OCTOBER 1980
38 —,
L. V. DIAMETER
mm
30
_
5000
_,
L V . dP dt
mm Hg sec.
0
—'
150
—,
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r\
r\
L. V. PRESSURE
mm.Hg.
V-J
I 1 Second I
2 Experimental records demonstrating the frequency dependence of optimum contractile response. Top
record shows LV diameter measured with ultrasound crystals. Bottom record shows LV pressure and middle record
shows its rate of change (dP/dt). The priming frequency increases in steps (Fig. 1, protocol 2). The last beat on each
record is the test pulse. Note constant (optimum) test pulse interval and progressive increase in amplitude of the test
pulse dP/dtmax.
FIGURE
those experiments in which dP/dtmax was affected,
we eliminated volume-dependent changes in dP/
dtmax by excluding from analysis all those observations in which LV dimensions or end-diastolic pressure at the onset of the test contraction exceeded
those during the priming period. In the five dogs in
which test pulse interval curves were examined
1 The Effect of Elevation ofLV End-Diastolic
Pressure on Steady State
TABLE
Experiment no.
1
3
4
5
7
8 (i)
8 (ii)
9
10
12
13
14
15
16
19
20
21
Increase in
LV end-diastolic
pressure (mm Hg)
9.0
0.8*
10.0
6.0
6.4
9.7
n.q
2.8
10.7
5.7
18.0
2.1
5.4
6.6
14.8
7.4
5.5
•increase in end-diastoiic diameter (cm).
t Significant rise (p < o.oi).
% Change of
LV dP/dt™.
115.8
115.4
145.4
0.0
1 6.4
T22.0|
1 4.5
114.9
1 3.1
T 15.8|
117.6
0.0
1 9.4
T12.0f
143.4
1 9.8
t 3.9
before and after volume expansion, no changes in
shape or optimum test pulse interval were observed.
Optimum Test Pulse Interval
As the test pulse interval was increased (Fig. 1,
protocol 1), the strength of the contraction increased and reached a maximum. The interval at
which this maximum occurred was: 665 msec (range
500-800) for six closed - chest dogs; 750 msec (range
500-1000) for 10 open-chest dogs; and 795 msec
(range 700-1000) for six isolated, ejecting cat hearts.
Under control conditions, there was little further
change or a gradual decay in contractile strength at
intervals longer than these. Results from an individual experiment on a dog are shown in Figure 3a and
from an experiment on a cat in Figure 3b. There
was a tendency for the optimum test pulse interval
to shorten with increasing priming frequency. In six
dogs studied over the widest range of priming frequencies (1-4 Hz), optimum test pulse interval
shortened significantly ( P = 0.02) when values at 1
and 4 Hz were compared but not when intermediate
values were compared.
Figure 3 also shows that the entire test pulse
interval curve shifted upward when the priming
frequency was increased (priming interval decreased). There is one point on each curve at which
the test pulse interval is the same as the priming
interval. In Figures 3a and 3b, these points have
been joined by a solid line to indicate that the
INTERVAL-STRENGTH RELATION OF INTACT
HEART/Pidgeonetal.
563
LV dP/dt max 2200
ImmHg/secl
2000
LV aP/dt nax 4000
fnnHg/seci
1800
1600
3000
140L> -
1200
1000
2000
STEADY STATE
INTERVAL (msl
800
600
1000
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STEADY STATE
INTERVAL ims)
400
200
B
0
200
400
600
800
1000
TEST PULSE INTERVAL
1200
1400 1600
200
400
imsi
600
800
1000
1200
1400
1600
TEST PULSE INTERVAL (ms)
LV dP/dt max 4000
(mmHg/seci
3000
RATIO TP/SS 1.4
1.4
LV dP/dt max
1.2 -
1.0 -
2000
c
/
/
INTERVAL 333ms
0.8
AControl
x Epinephrine infusion
/•
0.6 -
Before heart block •
After heart block •
/
1000
0.4
STEADY STATE
INTERVAL 333 ms
/•
0.2
/
D
0
400
800
TEST PULSE INTERVAL
1200
1600
imsi
0
100
200
TEST P U L S E
300
400
500
INTERVAL (msl
3 A: Test pulse interval curves for a dog heart, constructed at three different steady state frequencies. The
curves in this and subsequent figures were drawn by hand through the data points. The optimum test pulse interval is
about 550 msec and shows little change with increasing steady state frequency. The solid line shows how the steady
state response changes with changing priming frequency. B: Test pulse interval curves at three frequencies for an
isolated cat heart. C: Test pulse interval curves before and during epinephrine infusion at 1 fig/kg per min in a dog.
D: Test pulse interval curves for the same animal before and after heart block. Test pulse amplitude in each case
normalized by preceding steady state amplitude. The curve is incomplete because the spontaneous beat-to-beat interval
before block was 500 msec.
FIGURE
contractile strength of the priming beats (steady
state strength-interval response) changes little with
increasing frequency.
The effect of epinephrine on the test pulse inter-
val curve was studied in nine dogs. After control
studies, epinephrine was infused at a rate (1-2 jug/
kg per min) sufficient to produce an increase of
more than 50% in LV dP/dtma,, and that rate was
564
CIRCULATION RESEARCH
maintained while the test pulse interval curve was
remeasured. In all nine experiments, epinephrine
caused a shortening of the optimum test pulse interval and a steeper decline of contractile strength
at intervals longer than the optimum. The mean
test pulse intervals were: control, 740 ± 100 (mean
± SD) msec; and epinephrine, 560 ±110 msec (P <
0.01, Student's paired t-test).
VOL. 47, No. 4, OCTOBER 1980
Normalized 160 LV dP/dt max
n-6
(Results + SEMI
i
• Test pulse contraction IOCR)
/
O Steady state contraction
/
140
/
120
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Effect of Ventricular Pacing (Asynchronous
Contraction) on Contractile Indices
Activation of the ventricles by ventricular pacing
differs from normal activation, and this might influence the strength-interval behavior of the heart. To
examine this possibility, we constructed test pulse
interval curves in five dogs before and after the
induction of heart block. Before heart block, the
heart was paced via right atrial epicardial electrodes, using a priming frequency just above the
spontaneous heart rate and test pulse intervals up
to this frequency. After heart block, the process was
repeated with right ventricular pacing. Because of
the high spontaneous heart rate, the preblock experiment yielded only truncated test pulse interval
curves. In one animal, the results before and after
block were indistinguishable. In the remainder, absolute values of dP/dtmax were reduced after block,
but when the results were normalized against dP/
dtmax during the priming periods to allow for this,
the test pulse interval curves were indistinguishable
(Fig. 3d). Thus, although heart block reduced absolute values of dP/dt,nax in most instances, it did
not change its relation to test pulse interval.
Effect of Changing Priming Interval (Fig. 1,
Protocol 2)
As described above, the strength of the priming
beats changed little with increasing priming frequency. However, the contractile strength of the
test contraction at the optimum interval increased
progressively over the range of priming frequencies,
as can be seen in Figures 2 and 3a and 3b. In Figure
4, optimum contractile response and steady state
response are plotted against steady state frequency,
for the isolated cat heart (Fig. 4a) and the intact
dog heart (Fig. 4b). In both species, there was a
progressive rise in optimum contractile response, in
contrast to the steady state response.
An increase of priming frequency caused a decline in action potential duration to a new steady
state value (Fig. 5a). However, with each increase
in priming frequency, because of the greater number of action potentials per unit time, the heart
spent a progressively greater proportion of time
depolarized. Under these circumstances, there was
a correlation between optimum contractile response
and the percentage of time the membrane was
depolarized (Fig. 5b).
100
•
A
1.0
Normalized
LVdp/dt max
3.0
2.0
FREQUENCY
IHzl
IW
DOC
150
n •6
(Results
;
SEM)
140 . o Test pulse contraction (OCR I
A Steady state contraction
130
120
110
100
B
"1
2
3
Frequency
4
IHzl
FIGURE 4
Behavior of steady state and optimum contractile responses with frequency of steady state stimulation. Optimum contractile response (OCR; ordinate)
expressed as a ratio ofdP/dtma% for that beat divided by
dP/dtmai for steady state response at lowest frequency
tested. Data pooled from six isolated cat hearts (A) and
six dog experiments (B).
Paired Pulse Stimulation
Paired pulse stimulation during the priming period (Fig. 1, protocol 3) was performed at coupling
intervals between 210 and 300 msec; the interval
was kept constant within a given experiment. This
produced augmented responses to both priming and
test pulses compared to single pacing. The optimum
test pulse interval following paired pulse stimula-
INTERVAL-STRENGTH RELATION OF INTACT HEART/Pidgeon et al.
565
LV dP/dt max
(mmHg/sec)
40 mV
40 mV
STEADY •
STATE
o
Normal Pacing (Interval 500ms)
Paired Pacing (Interval looomsl
0.5s
Normalised
LVtfc/cfl max
(OCR)
I
Results with SEM
n-6
140
0
400
800
1200
TEST PULSE INTERVAL
1600
(ms)
OCR tnmHq/secl
3d
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2200
r
120
110
T
100
*
.
0 1
B
,,
25
30
35
45
Fraction of time membrane > 70% depolarised
45
1200
(%l
5 A: Epicardial action potentials recorded at
the same paper speed in the dog during steady state
stimulation at 1.25 and 2.1 Hz. The broken line indicates
70% depolarization, the level at which action potential
duration was measured. Note shortening with increased
heart rate. B: Relationship between percentage of time
spent depolarized by membrane and optimum contractile response. Optimum contractile response normalized
as in Figure 4. Results pooled from six dogs.
1000
FIGURE
tion was similar to or shorter than that observed
with single pacing (Fig. 6a).
In order to explore further the relationship between optimum contractile response and the percentage of time during the priming period which
the muscle spent depolarized, we examined optimum contractile responses for both single and
paired pulse pacing using protocol 4 (Fig. 1). The
results of such an experiment, performed at several
priming frequencies, are shown in Figure 6b. The
behavior with single pacing is the same as that
described earlier (Fig. 4). With paired pacing, however, the optimum contractile response is consistently higher for any given percentage of time the
membrane spends depolarized and shows little augmentation as depolarization time increases.
Discussion
This study shows that the ability of the heart to
contract reaches an optimum 500-1000 msec after
the previous beat and that this optimum contractile
B
40
Fraction of time me Drane
FIGURE 6 A: Test pulse interval curves for the same
dog heart paced singly (protocol 1) and paired (protocol
3). B: Optimum contractile responses of a dog heart for
single and paired pacing as illustrated in Figure 1,
protocol 4.
response increases with increasing frequency of the
preceding beats.
Recent analyses (see for example, Kaufmann et
al., 1974; Allen et al., 1976; Edman and Johannsson,
1976) have interpreted the strength-interval relationship in terms of calcium ion movements. The
concept has evolved that contractile force is determined by the amount of ionic calcium released in
the immediate vicinity of the contractile proteins
from stores within the cell. These stores trap Ca2+
which moves into the cell during the action potential, and release it for activation during subsequent
action potentials. Thus, the Ca2+ content of the
stores, which determines the inotropic state of the
muscle at any instant, is labile and depends on the
preceding history of activity. Studies on isolated
cardiac muscle suggest that the Ca2+ released to
activate the contractile proteins is re-stored during
relaxation and requires a finite time to come into a
state where it can be released again. If one beat
follows another after an interval which is shorter
566
CIRCULATION RESEARCH
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than this recycling time, only a fraction of the Ca2+
taken up during relaxation is released. This results
in a negative inotropic effect and masks the effect
of the change in interval on the total amount of
Ca2+ in the storage system, which can be considered
to determine the potential contractile performance
achieved if the total Ca2+ is released. Edman and
Johannsson (1976) examined this potential by inserting stimuli after test intervals equal in time to
the recycling time and found that the resulting
contractions (termed "optimum contractile response") increased progressively over the entire
range of steady state frequencies studied. This is
the positive inotropic effect of increased frequency.
In the present study of the intact heart, we
followed the experimental protocols of Edman and
Johannsson. To control the interval between beats
over a wide range, heart block was induced and the
right ventricle was paced. The sequence and synchrony of activation were therefore abnormal, and
in most cases the magnitude of dP/dt max fell after
block. However, this should not affect the analysis
of the underlying mechanisms in the blocked heart,
especially as the early part of the test pulse interval
curve up to 500 msec had an identical form before
and after block (Fig. 3d). A major potential problem
is the fact that indices of contractile strength may
be dependent on end-diastolic volume, and enddiastolic volume varies with the interval between
beats. LV dP/dtmax sometimes can be independent
of end-diastolic volume (Van den Bos et al., 1973),
and this proved to be the case more often than not
in this study (Table 1). Therefore, we consider that
the plot of dP/dtmax against test pulse interval (Fig.
3) is relatively free from distortion from this cause.
We conclude that the optimum interval obtained,
500-1000 msec (Figs. 3 and 6), is a valid indication
of the true optimum of the intrinsic mechanism in
the muscle which controls the contractile response.
According to Edman and Johannsson, this is the
time for Ca2+ (both entering during the previous
action potential and sequestered from relaxation)
to come into the releasable state. Effects similar to
those shown in the present study can be observed
in the records of KiLz et al. (1969), Anderson et al.
(1976), and Arentzen et al. (1978).
The problem of variable end-diastolic volume has
less effect on the relationship between the priming
frequency and the optimum contractile response
(Fig. 4) because the test pulse interval (and therefore filling time) is fixed. Thus, the optimum contractile response increases progressively with heart
rate over the entire range studied. This confirms
Edman and Johannsson's findings for rabbit papillary muscle.
Edman and Johannsson attributed the increase
in optimum contractile response with increased
stimulation rate (Fig. 4) to increased Ca2+ entry
into the cell accompanying the increased number of
action potentials per unit time. They found a close
correlation between the fraction of time the cell
VOL. 47, No. 4, OCTOBER 1980
membrane is depolarized and the optimum contractile response, a result which we have confirmed in
the intact dog heart (Fig. 5b). In both their study
and this one, an increase in heart rate produced its
effect on optimum contractile response within a few
beats. Therefore, a new balance between Ca2+ entry
and efflux from the cell must be established rapidly
in such circumstances since, in the steady state,
Ca2+ inflow during the action potential of each beat
must be balanced by an equal loss of Ca2+ from the
cell. Evidence for such a beat-dependent effect is
available from several studies (Hoffman et al., 1956;
Koch-Weser and Blinks, 1963; Braveny and Sumbera, 1970; Wohlfart, 1979).
When the heart rate is increased, there is an
increase in Ca2+ influx due to the greater time the
membrane is depolarized. Initially, this exceeds
Ca2+ efflux so that Ca2+ accumulates but, subsequently, influx and efflux equalize to produce a new
steady state with a higher intracellular Ca2+ as
indicated by the greater optimum contractile response. This equalization could be due to increased
efflux, resulting from the greater amount of Ca2+
within the cell. Alternatively, or in addition, the
higher intracellular Ca2+ could reduce influx by
shortening the action potential (Fig. 5a). Thus, we
would not expect an obligatory relationship between the amount of Ca2+ in the intracellular pool
and the steady state influx rate. Indeed, with paired
pacing (Fig. 6b), for any given proportion of time
that the membrane spent depolarized (time available for Ca2+ influx), the optimum contractile response is much greater than for single pacing.
Our finding that catecholamines shorten the optimum interval (Fig. 3c) may be due to their property of producing faster relaxation, i.e., faster uptake of Ca2+ from the contractile proteins. If this
calcium is passed to the releasable store, it might
be expected to be available for release in a shorter
time, thus shortening the optimum interval as observed.
The best known analysis of the strength-interval
relation is that of Koch-Weser and Blinks (1963)
who assumed that the effect of a change in interval
between beats depended on a summation between
a positive inotropic effect, a negative inotropic effect, and the basal "rested state" level of contractility of the unstimulated or infrequently stimulated
muscle.
We now would interpret the positive inotropic
effect of increased frequency, demonstrated by the
increase in optimum contractile response, as following from a transient increase in calcium influx over
efflux, leading to an increased s- •:? of the calcium
pool. However, if successive l«eats at the higher
frequency occur at less than the optimum interval,
their contractility is reduced because of inadequate
time between beats for Ca2+ to come into a releasable state; this reduction of contractility is the
negative inotropic effect. Thus, the steady state
contractile response results from a balance between
INTERVAL-STRENGTH RELATION OF INTACT HEART/Pidgeon et al.
the pool size of calcium and the time available for
its recycling.
The behavior of beats immediately following a
step change in frequency can be interpreted in the
same way. Thus, the beat obtained immediately
after a change to higher frequency is weak because
the interval is shorter than the optimum. With a
sudden reduction of frequency, the first interval is
lengthened, allowing greater filling of the releasable
store, so the first beat is strong, reflecting the
greater amount of Ca2+ in the system during the
preceding period of high-frequency stimulation.
These effects have been shown to occur in the
intact heart (Kilz et al., 1969; Noble et al., 1969) as
well as in isolated preparations.
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Circ Res. 1980;47:559-567
doi: 10.1161/01.RES.47.4.559
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