Download Oxygen Cost of Electrical Activation of the Heart

Oxygen Cost of Electrical Activation
of the Heart
By Francis J. Klocke, M.D., Eugene Braunwald, M.D., and
John Ross, Jr., M.D.
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• Although many previous studies have focused attention on the hemodynamic and
pharmacological determinants of myocardial
O2 consumption (MVO2), the O2 requirements
of electrical activation of the heart have not
been defined. Two major problems arise in
attempting to quantify the energy cost of this
process. 1) Since the amount of O2 required
probably constitutes only a small fraction of
the total MVO2, experimental techniques for
measuring MVO2 must be extremely sensitive
and capable of quantifying a relatively small
change of O2 uptake superimposed upon a
much larger basal O2 uptake. 2) Changes of
MVO2 caused by alterations of myocardial
electrical activity must be distinguished from
changes of MVO2 caused by associated variations of contractile activity.
A possible solution to the first of these problems is offered by the use of an O2 electrode
to measure small changes of MVO2 continuously in an isolated heart.1 A possible solution to the second problem was actually provided more than half a century ago by the
observation of Mines,2 that a heart's mechanical activity can be abolished while its electrical activity is preserved by perfusion with a
solution free of calcium. This "electro-mechanical dissociation" has subsequently been
studied by many workers (e.g.,3-6), sometimes using calcium-chelating agents in place
of a calcium-free perfusate. In some cases, a
minute fraction of the heart's mechanical activity was not eliminated and it is apparent,
as Mines clearly implied,2 that such small
amounts of contractile activity must not be
overlooked.
Methods
Whole blood was collected from donor animals and drained by gravity through ion exchange resin units,* one unit being employed for
each liter of blood. The resin was initially
charged in the sodium phase and served to reduce the total calcium concentration of the donor
blood to less than 0.3 mEq/ liter. Since preliminary experiments indicated that even this calcium concentration was sufficient to maintain
some mechanical activity, 6 mg/ liter disodium
EDTAt was added to the resin-treated blood. In
order to keep the spontaneous frequency of de-
From the Cardiology Branch, National Heart Institute, Bethesda, Maryland.
Accepted for publication September 7, 1965.
*JB-2 Ion exchange blood pack units, Fenwal Laboratories, Morton Grove, Illinois.
fEndrate, Abbott Laboratories, Chicago, Illinois.
Circulation Research, Vol. XVIII, April 1966
The present study was intended to define
the O2 requirements of myocardial depolarization and repolarization in a more precise manner than heretofore possible, and utilized an
isolated canine heart preparation. The basic
plans were: 1) to produce electromechanical
dissociation by perfusing the heart with whole
blood from which calcium had been removed
with an exchange resin and to which the
disodium salt of ethylenediaminetetraacetic
acid (EDTA) had been added; 2) to suppress
spontaneous depolarizations by elevating the
plasma K concentration slightly, and then to
induce propagated depolarizations at controlled frequencies by stimulating the heart
electrically; and 3) to measure changes of
MVO2 associated with increases of the frequency of depolarization by determining
changes of venous O2 content from a continuous recording of venous Po<> while arterial O2
content and coronary blood flow were held
constant. The findings indicate that the
amount of O2 required for electrical activity
of the heart is less than 1% of the total O2
consumption of the normally working heart.
357
358
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polarization low, 4.5 mEq KC1 was also added to
each liter of resin-treated blood. The resin treatment had removed K from the donor plasma
and this addition of KC1 produced a final plasma
concentration of 7.5 ± 0 . 4 (SEM) mEq/liter. The
final plasma Na concentration was 154 ± 1.6
mEq/liter.
The pretreated blood was used to perfuse each
of 13 hearts which had been isolated from mongrel dogs, weighing between 19.1 and 27.7 kg,
and anesthetized with sodium pentobarbital, 30
mg/kg. The preparation is shown in figure 1,
and is similar to one employed previously." All
major vessels entering and leaving the heart
were ligated and an occlusive pump* was used
to perfuse the coronary arteries at a constant rate
of flow through the ascending aorta. The pump
was supplied with the pretreated blood from a
small bubble oxygenator,t in which the blood was
equilibrated with a 97% O2 and 3% CO 2 gas
mixture. Coronary venous blood returned to the
oxygenator through a cannula in the right heart
and a gravimetric flowmeter. A drainage tap in
the coronary venous line allowed blood to be
diverted from the oxygenator during the first
few minutes of the isolated perfusion, thereby
obviating any mixing of the animal's normocalcemic blood with the pretreated blood in the
oxygenator. A small cannula, not shown in figure
1, vented the left ventricle to the oxygenator and
ensured that ventricular volume did not change
during an experiment, even though there was
never measurable aortic regurgitation. Right ventricular temperature was monitored with a thermistor probe inserted into the right ventricle
through the right atrial appendage, and averaged 36.2°C (range 35.3 to 37.5°C).
The pH and PCOo of the arterialized blood
leaving the oxygenator averaged 7.36 (range 7.27
to 7.41) and 30 mm Hg (range 27 to 35 mm Hg)
respectively. Hematocrits average 37% (range 33
to 44%).
An O2 macroelectrodet inserted into the coronary venous line near the right atrium was used
with an appropriate electrical circuiti so that
the P 0 o of coronary venous blood could be recorded continuously. The O2 electrode was calibrated as described previously,8 at a temperature
within 1°C of that in the venous line. The latter
was monitored with a thermistor probe and
varied by no more than 0.2°C during any experimental period. The calibrating cuvette was
*Imico model 1009-P.
tModel 4546, Pulmo-Pak, Abbott Laboratories.
$Model 325812, Beckman Instruments, Fullerton,
California.
§Beckman model 160 gas analyzer.
KLOCKE, BRAUNWALD, ROSS
!o PT
lemp probe.
coronory return
loPT
FIGURE 1
Isolated canine heart preparation for studying Os
requirements for myocardial electrical activation. See
text for details. SVC: superior vena cava, 1VC: inferior vena cava, RA: right atrium, RV: right ventricle,
LA: left atrium, LV: left ventricle, BCA: brachiocephalic artery, LSA: left subclavian artery, PT: yrressure
transducer, SGA: strain gauge arch.
equipped with an automatic stirring device," and
values for P0,t obtained with the electrode in
the venous line agreed well with values obtained
when the same blood was withdrawn from the
venous line and analyzed in the cuvette.
High sensitivity strain gauge arches were sutured to both ventricles and used to verify the
absence of contractile activity. The arches were
calibrated at the completion of each experiment
by excising the muscle segments to which they
were sutured and by suspending known weights
from the feet of the arches while they were still
attached to the muscle segments. A conventional
Walton-Brodie strain gauge arch10 was employed
for the left ventricle and its signal was recorded
at the maximum sensitivity available with a carrier preamplifier;* this system allowed changes of
tension in the left ventricular segment of less
than 5 g to be detected. A specially designed11
•Model 1100B, Sanborn Company, Waltham, Massachusetts.
CircuUiion Rtsetrcb. Vol. XVIII, April 1966
359
OXYGEN COST OF MYOCARDIAL ELECTRICAL ACTIVATION
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strain gauge arch,* approximately ten times
more sensitive, was used for the right ventricle;
the accompanying carrier preamplifier and recording system were similar to those used with
the Walton-Brodie strain gauge arch and permitted detecting changes of tension in the right
ventricular segment of less than 0.5 g. The
choice of the right ventricle for the more sensitive strain gauge arch was based on preliminary
experiments in which it was noted that visible
contractions usually persisted longer in the right
ventricle than in the left ventricle when the perfusion with hypocalcemic blood was begun.
A clip electrode was attached to the right
ventricle near the inferior portion of the A-V
groove and was used with a laboratory stimulator,t a stimulus isolation unit, and an indifferent electrode to increase the frequency of
myocardial depolarization as desired. Stimuli
were applied for 3 to 5 millisecond periods at
currents slightly above threshold (0.5 to 6.0
ma). Ten of the 13 hearts were studied with
repetitive single stimuli applied in the conventional fashion; the remaining three hearts were
subjected to paired electrical stimulation.12 A
second clip electrode was attached to the right
ventricular epicardium and superficial myocardium just below the pulmonary valve and was
used to record myocardial electrical activity. In
a few experiments, the second electrode was intermittently transferred to the left ventricle to
verify that the induced depolarizations were
propagated throughout the ventricular myocardium. In one animal, electrical activity was recorded with both the superficial clip electrode
and a catheter electrode inserted into the right
ventricular cavity. Two direct-writing oscillographs were used to record propagated depolarizations, strain gauge arch activities, and coronary venous Po^ simultaneously at slow and
rapid paper speeds.
In order to translate coronary venous Po.( into coronary venous O2 contents, a blood oxygen
dissociation curve was constructed for each experiment.13 In view of the previously demonstrated constancy of arterial Po., in this preparation,1 arterial Oo content is known to have
been constant within 0.01 to 0.03 ml/100 ml for
the 10 to 15 minutes involved in an experimental
determination. Changes of venous O2 content
therefore reflected accurately changes in the ar*Myocardial force transducer, type 3106A-14S-5P,
manufactured by Honeywell, Inc., Minneapolis,
Minnesota, and adapted by the Instrumentation Section, National Institutes of Health.
tModel 104A, American Electronic Laboratories,
Philadelphia, Pennsylvania.
CircmUliOM Rtiarcb,
Vol. XVIII, April 1966
teriovenous O2 difference. The gravimetric flowmeter recordings indicated the absolute magnitude of the coronary blood flow and provided a
continuous check on its constancy. Detection of
extremely small changes of MV0 o were facilitated by initially adjusting coronary flow so that
the coronary venous P Oa was above 70 mm
Hg (i.e., on the "flat" portion of the oxygen dissociation curve). Stimulation was maintained for
a minimum of five minutes at any particular frequency, to ensure that the Po,, in the blood
passing the electrode reflected the new steady
state accurately.
Results
A total of 38 satisfactory experiments were
achieved in the 13 hearts (table 1). Coronary
blood flow ranged from 48 to 90 ml/min,
averaged 72 ml/min, and was constant for all
experiments in any given heart. Coronary
venous Po2values, prior to stimulation, were
between 71 and 159 mm Hg; the average value
for all 13 hearts was 120 mm Hg. The MVO2
prior to stimulation ranged from 0.49 to 1.08
ml/100 g/min, averaged 0.78 ml/100 g/min,
and returned to control levels when stimulation was discontinued (figs. 2 and 3) and
when multiple stimulations were carried out
in the same hearts. In ten of the 13 hearts,
spontaneous depolarization was absent; in the
other three hearts, the spontaneous frequency
of depolarization was no higher than 72/min.
The stepwise increments of the frequency of
depolarization induced by electrical stimulation ranged from 74 to 250 depolarizations/min; in eight of the 13 hearts the frequency of depolarization was increased more
than once.
In each of the 31 experiments in the ten
hearts studied with conventional stimulation
(table 1: 1 to 10), the increase of the frequency of myocardial depolarization was accompanied by a small but definite increase of
MVO2. Recordings from representative experiments are shown in figures 2 and 3. The average increase of MVO2 ranged from 0.22 to
0.62 /iliter/activation/100 g; the mean of these
averages was 0.40 ±0.04 (SEM) /xliter/activation/100 g (table 1). In no experiment did
either visual observation of the heart or the
strain gauge arch recordings suggest that the
KLOCKE, BRAUNWALD, ROSS
360
electrical activation induced any contractile
activity. In the hearts in which the frequency
of depolarization was increased more than
once, increased increments of MVO2 paralleled increased increments of the frequency of
depolarization, and the increment of
TABLE 1
Effects on Myocardial Oxygen Consumption (MVO^
Electrical Activation
Heart
weight
Coronary
flow
g
ml/min
1
162
72
2
3
240
210
48
67
4
5
6
7
233
218
196
247
75
78
74
84
Dog
no.
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8
219
75
9
154
57
10
209
63
of Increases of the Frequency of
Frequency of <depolarixatkm
Daring
Itlmulation
Control
_j J' depolarizations/mtn
0
0
0
44
54
72
45
0
35
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
192
100
136
196
196
196
186
136
176
94
94
94
156
126
158
158
126
126
126
126
126
188
250
250
126
126
128
126
126
126
126
AMVOi
Single
values
Averages
/illter/activatioa/100 g
0.28
0.22
0.40
0.44
0.50
0.43
055
0.29
0.29
0.47
0.58
054
0.52
0.35
0.41
0.46
0.29
0.26
0.32
0.24
0.18
0.14
0.15
0.16
0.74
0.55
0.84
057
0.60
0.49
0.57
0.25
0.40
0.46
055
0.29
0.29
0.53
0.41
0.22
0.62
Mean:
SEM:
11*
12#
239
148
90
78
13*
157
70
0
0
0
0
0
0
0
124
74
74
86
102
86
86
0.40
0.04
0.18
0.18
050
050
0.55
0.21
0.47
0.56
0.44
0.52
Mean:
0.38
"Hearts studied with paired electrical stimulation rather than single stimulation. Each pair
of stimuli produced two propagated depolarizations, e.g., in heart 11, stimulation was at a
frequency of 62 pairs per min.
CircmUliom Rticrcb,
Vol. XVIII, April 1966
OXYGEN COST OF MYOCARDIAL ELECTRICAL ACTIVATION
361
120-J
CORONARY
VENOUS Pn
(mrnHQ)
OO-
8O
RV
STRAIN GAUGE A R C H 1 2 5 ]
A FORCE - g
0J
LV
STRAIN GAUGE ARCH 30A FORCE-g
0-
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ECG
DEPOLARIZATIONS
PER MIN
END STIM.
BEGIN STIM.
FIGURE 2
Recording at slow paper speed from a representative experiment in a heart studied with single
stimulation (dog no. 3, table 1). Full scale (50 mm) deflections on the right and left ventricular
strain gauge arch recordings would have resulted from increments of isometric tension of 42
and 150 g, respectively. The spontaneous frequency of depolarization was 54/min and the
control venous Po was 113 mm Hg. When the frequency of dejwlarization was increased to
196/min by electrical stimulation, venous Po decreased to 97 mm Hg, corresponding to a
decrease of venous O, content of 0.22 ml/100 vd. Coronary flow was 67 ml/min and the
total increase of MS/O, of 0.15 ml/min corresponded to an increase per activation of 0.50
iditer/100 g. When electrical stimulation was discontinued, the sjiontaneous frequency of
depolarization briefly increased, to an average value of 86/min, before returning to the control
value of 54/min.
per activation was reasonably constant. Thus,
the On required for a single activation did not
appear to change over the relatively wide
range of frequencies examined, i.e., 0 to
250/min.
Increases of the frequency of depolarization
were also associated with small increases of
MVO; in each of the seven trials in the three
hearts studied with paired electrical stimulation (table 1: 11 to 13). Considering each pair
of depolarizations as having resulted in two
activations, these increases averaged 0.18,
0.44, and 0.52 ^liter/activation/100 g. The
mean of these averages was 0.38 ^iliter/activation/100 g. Electrical stimulation at currents which produced a recordable stimulus
CirctUliom Rcifjrch, Vol. XV1I1, April 1966
artifact without a propagated depolarization
never caused a change of MVOL..
In four of the 13 hearts, satisfactory recordings of coronary venous Po., were obtained
when ventricular fibrillation occurred as the
intensity of electrical stimulation was being
adjusted. The increases of MVO-.. resulting
from the change from no electrical activation
to ventricular fibrillation were 45, 60, 71, and
113 /xliters/min/100 g. When the fibrillation
was terminated with electrical countershock,*
MV02 consistently exhibited a further increment for several minutes. These increments
*D-72 Defibrillator, Electrodyne Company, Norwood, Massachusetts.
362
KLOCKE, BRAUNWALD, ROSS
3 MIN
PRIOR TO
STIMULATION
NEAR END
OF
STIMULATION
BEGINNING
OF
STIMULATION
END
OF
STIMULATION
6 MIN
AFTER END OF
S T IMULA X 'ON
162
CORONARY
VENOUS Ffcj
(mmHa)
I4Z
H
„
is:
RV
0
STRAIN GAUGE ARCH
a FORCE-q
LV
STRAIN GAUGE ARCH
A FORCE-g
INTRAVENTRICULAR
ECG
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EPICARDIAL
ECG
DEPOLARIZATIONS
PLh M , \
FIGURE 3
Recording at rapid paper speed from a representative experiment in a heart studied with single
stimulation (dog no. 10, table 1). Time markers indicate one-second intervals. Full-scale (50
mm) deflections on the right and left ventricular strain gauge arch recordings would again
have resulted from increments of isometric tension of 42 and 150 g, reflectively. Spontaneous
depolarizations were absent and the control venous Po was 154 mm Hg. When propagated
depolarizations were produced at a rate of 126/min, venous Po decreased to 131 mm Hg,
corresponding to a decrease of venous Oe content of 0.21 ml/100 ml. Coronary flow was 63
ml/min and the total increase of MVOt of 0.13 ml/min corresponded to an increase per
activation of 0.49 pliter/100 g.
had maximum values which ranged from 41 to
533 /tliters/min/100 g, and averaged 181
/iliters/min/lOOg.
Discussion
In the present study, increases of the frequency of electrical activation of an isolated
canine heart were consistently accompanied
by increases of MVO*, which averaged 0.40
filiter/activation/100 g. The experimental design was intended to ensure, as far as possible,
that the measured increments of MVO2 accurately represented the O2 utilized in the
heart's electrical activity. Possible changes of
MVO2 related to alterations of coronary flow14
were obviated by maintaining coronary flow
constant. Although alterations of myocardial
action potentials and the electrocardiogram do
occur with hypocalcemia,15 the recordings ob-
tained with the epicardial and endocardia]
electrodes (fig. 3) did not suggest that the observed increments of MVO^ were misleading
because of grossly abnormal patterns of depolarization. Since the induced depolarizations were propagated over both ventricles, it
also seems unlikely that the total On requirements were underestimated unless, of course,
more O2 is somehow needed for the heart's
electrical activation when it is contracting
than when it is not. Of greater concern is the
possibility that some portion of the measured
increments of MVO2 was due to minute increases of myocardial contractile activity induced by the electrical activity. The necessity
for searching carefully for such activity has
already been emphasized. That it was not
present is suggested by the high-sensitivity
strain gauge arch recordings and the visual
CircmUliom Research, Vol. XVIII, April 1966
OXYGEN COST OF MYOCARDIAL ELECTRICAL ACTIVATION
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observations in all 13 hearts, and the additional observation in two hearts that the increase of MVOo produced by a given frequency of stimulation did not diminish as
additional disodium EDTA was added to the
perfusing blood. However, since even these
techniques could conceivably have failed to
detect minute amounts of localized or abortive contractile activity, the possibility remains
that the O2 requirements for the heart's electrical activation are slightly less than the present results indicate.
It is of interest to consider the order of magnitude of the present findings in relation to a
previous investigation in isolated rabbit hearts
by Kohn.16 In that study hearts were perfused
with a calcium-free Chenoweth's solution, inflow and outflow O2 contents were measured
with Van Slyke techniques, and no statistically
significant difference of total MVO2 was found
between nine hearts in which electrical activity was maintained and four hearts in which
electrical activity had been abolished by KC1
infusion. It was concluded that if membrane
electrical activity did require O2, the quantity
was undetectable with the methods employed.
This conclusion is consistent with the findings
of the present investigation, in which the absolute increases of MVOo which were observed were significantly smaller than the
variations of total MVOo within each of
Kohn's two groups of hearts.
The order of magnitude of the present findings is also of interest in relation to studies of
monovalent cation transport. The observed
increment of MVO2 per activation, 0.40
/diter/100 g, can be expressed as 0.075 X 10-°
//.mole O2 per cm2 cell membrane surface area,
if it assumed that the myocardial cells comprise 60% by weight of the total heart,17 and
have the geometric form of cylinders 10 //, in
diameter18 and a specific gravity of 1.0. Extrapolating from studies in noncardiac tissues,19
each fimo\e of O2 would be expected to provide energy for the active transport of 4 to
24 //.moles of monovalent cations and, if the
O2 utilized for electrical activation served
solely to provide energy for transmembrane
cation transport during repolarization, the obCirculation Research, Vol. XVIII, April 1966
363
served O2 increment per activation, 0.075 X
10"° //mole per cm2, would correspond to the
active transport of between 0.3 X 10"° and
1.8 X 10"° //.mole of cation per cm2 membrane
surface area. Although the assumptions involved in these calculations are certainly gross
ones, these figures approach those obtained
experimentally in cephalopod axons in determinations of the net quantity of Na and K
crossing each cm2 of membrane with an electrical activation (3-4 X 10"° /xmole).-°
The hearts subjected to paired electrical
stimulation were studied to determine whether the altered rhythm and frequency of depolarization inherent in this intervention could
play a role in the marked increases of MVOo
which they are known to produce in the intact
heart.21 That this is not the case is indicated
by the finding that the average increase of
MVOo in the hearts studied with paired electrical stimulation (0.38 //.liter/activation/100
g) corresponded well to the average figure
observed in the hearts stimulated in the conventional fashion (0.40 //.liter/activation/100
g). The fact that the absolute increases of
MV02 were so small in the conventionally
stimulated hearts would, by itself, have also
suggested this conclusion.
The average increase of MVO2 of 72
//.liters/min/100 g during ventricular fibrillation represents approximately 2% of the total
Oo utilization of the empty fibrillating dog
heart.22 This figure is of the same order of
magnitude as would be expected for a heart
being depolarized in the usual fashion at a
rate of approximately 200 per minute. The
further increases of MVOo which occurred
when the episodes of fibrillation were terminated with electrical countershock were
presumably related to the electrical effects of
the countershock.
In conclusion, the observed average increment of MVOo of 0.40 /iliter/activation/100 g
seems to define at least the order of magnitude of the Oo requirements for electrical
activation of the heart. Since this figure represents less than 1% of total myocardial O2
consumption per beat in the resting unanesthetized dog,23 it appears that the O2 required
364
KLOCKE, BRAUNWALD, ROSS
for electrical activation constitutes less than
1% of the total
Summary
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The present study was undertaken to define
the Oo requirements of electrical activation of
the heart. Thirteen isolated canine hearts
were perfused with whole blood from which
calcium had been removed with an exchange
resin and to which the disodium salt of ethylenediaminetetraacetic acid had been added.
Spontaneous depolarizations were suppressed
by raising the plasma potassium to an average concentration of 7.5 mEq/liter, and the
right ventricle was stimulated electrically at
controlled frequencies. Although the stimuli
produced propagated depolarizations, neither
high-sensitivity strain gauge arches sutured to
both ventricles, nor careful visual observation,
showed any evidence of associated contractile activity. Ten of the hearts were studied
with repetitive single stimuli applied in the
conventional fashion, while the remaining
three hearts were subjected to paired electrical stimulation. Changes of myocardial CK
consumption (MVOL>) were measured at a
constant coronary blood flow and arterial O2
content by determining changes of venous O^
content from a continuous recording of venous
Po.,. Increases of the frequency of depolarization were uniformly accompanied by small
increases of MVO*, averaging 0.40 ±0.04
(SEM) ju,liter/activation/100 g. The increases
were of the same order of magnitude in the
hearts subjected to paired electrical stimulation as in the hearts studied with single stimulation, suggesting that the altered frequency
and rhythm of depolarization in paired electrical stimulation cannot account for the
marked increase of MVO^ which this intervention produces in the intact heart. It is concluded that the amount of OL- required for
electrical activation of the heart is less than
1% of the total O2 consumption of the normally
working heart.
References
1. KLOCKE, F. J., KAISER, G. A., Ross, J., JR., AND
BBAUNWALD, E.: Mechanism of the increase
of myocardial oxygen uptake produced by
catecholamines. Am. J. Physiol. 209: 913, 1965.
2. MINES, G. R.: On functional analysis by the
action of electrolytes. J. Physiol. 46: 188, 1913.
3. EINTHOVEN, W.: The relation of mechanical and
electrical phenomena of muscular contraction,
with special reference to the cardiac muscle.
Harvey Lectures 20: 111, 1924.
4. CARB, S.: The effects of potassium, ammonium,
calcium, strontium and magnesium on the electrogram and myogram of mammalian heart
muscle. J. Pharmacol. Exptl. Therap. 101:
317, 1951.
5. KOHN, R. M.: Dissociation of electrocardiographic activity from myocardial contractility by
ionic alterations. Clin. Res. 6: 209, 1958.
6. LEE, Y. C. P., RICHMAN, H. C., AND VISSCHER,
M. B.: The roles of citrate and potassium ion
in cardiac arrest. Physiologist 5: 173, 1962.
7. KLOCKE, F. J., KAISER, G. A., Ross, J., JR., AND
BRAUNWALD, E.: An intrinsic adrenergic vasodilator mechanism in the coronary vascular
bed of the dog. Circulation Res. 16: 376, 1965.
8. Ross, J., JR., KAISER, G. A., AND KLOCKE, F. J.:
Observations on the role of diminished oxygen
tension in the functional hyperemia of skeletal
muscle. Circulation Res. 15: 473, 1964.
9. SEVERINGHAUS, J. W., AND BRADLEY, A. F.: Elec-
trodes for blood pO,, and pCO., determination.
J. Appl. Physiol. 13:*515, 1958."
10.
BONIFACE, K. J., BRODIE, O. J., AND WALTON,
R. P.: Resistance strain gauge arches for direct
measurement of heart contractile force in animals. Proc. Soc. Exptl. Biol. Med. 84: 263,
1953.
11.
WILLIAMS, J. F., JR., SONNENBLICK, E. H., AND
BRAUNWALD, E.: Determinants of atrial contractile force in the intact heart. Am. J. Physiol. 209: 1061, 1965.
12. FROMMER, P. F.: Studies on coupled pacing
technique and some comments on paired electrical stimulation. Bull. N. Y. Acad. Med. 41:
670, 1965.
13.
HAAB, P. E., PIIPEH, J., AND RAHN, H.: Simple
method for rapid determination of an O.,
dissociation curve of the blood. J. Appl. Physiol. 15: 1148, 1960.
14.
KAHLEB, R. L., BRAUNWALD, E., KELMINSON,
L. L., KEDES, L., CHIDSEY, C. A., AND SEGAL,
S.: Effect of alterations of coronary blood
flow on the oxygen consumption of the nonworking heart. Circulation Res. 13: 501, 1963.
15.
SURAWICZ, B., LEPESCHKIN, E., HERRLICH, H. C.,
AND HOFFMAN, B. F.: Effect of potassium and
calcium deficiency on the monophasic action
potential, electrocardiogram and contractility
of isolated rabbit hearts. Am. J. Physiol. 196:
1302, 1959.
16. KOHN, R. M.: Myocardial oxygen uptake during
ventricular fibrillation and electromechanical
Circulation Research, Vol. XVlll, April 1966
OXYGEN COST OF MYOCARDIAL ELECTRICAL ACTIVATION
dissociation. Am. J. Cardiol. 11: 483, 1963.
17. JOHNSON, J. A., AND SIMONDS, M. A.: Chemical
21. Ross, J., JR., SONNENBLICK, E. H., KAISER, C. A.,
FROMMER, P. L., AND BRAUNWALD, E.: Elec-
and histological space determinations in rabbit
heart. Am. J. Physiol. 202: 589, 1962.
troaugmentation of ventricular performance and
oxygen consumption by repetitive application
of paired electrical stimuli. Circulation Res.
16: 332, 1965.
18. SPIRO, D., AND SONNENBLICK, E. H.: Structure
and function of the heart muscle cell. Cyclopedia of Medicine, Surgery and Specialties,
Philadelphia, F. A. Davis Company, 1964.
22. MCKEEVER, W. P., GREGG, D. E., AND CANNEY,
P. C : Oxygen uptake of the nonworking left
ventricle. Circulation Res. 6: 612, 1958.
19. WHITTAM, R., AND WILLIS, J. S.: Ion movements
and oxygen consumption in kidney cortex
slices. J. Physiol. 168: 158, 1963.
20. HODCKIN, A. L.: Ionic movements and electrical
activity in giant nerve fibers. Proc. Roy. Soc.
London, B: 148: 1, 1958.
Downloaded from http://circres.ahajournals.org/ by guest on June 17, 2017
Circulation Research, Vol. XVUI, April 1966
365
23.
GREGG, D. E., KHOURI, E. M., AND RAYFORD,
C. R.: Systemic and coronary energetics in
the resting unanesthetized dog. Circulation
Res. 16: 102, 1965.
Oxygen Cost of Electrical Activation of the Heart
Francis J. Klocke, Eugene Braunwald and John Ross., Jr.
Downloaded from http://circres.ahajournals.org/ by guest on June 17, 2017
Circ Res. 1966;18:357-365
doi: 10.1161/01.RES.18.4.357
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