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Dobutamine Increases Cardiac Output
of the Total Artificial Heart
Implications for Vascular Contribution of Inotropic
Agents to Augmented Ventricular Function
Philip F. Binkley, MD; Kevin D. Murray, MD; Kim M. Watson, BS;
P. David Myerowitz, MD; and Carl V. Leier, MD
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Background. The synthetic catecholamine dobutamine increases stroke volume in normal
subjects and in patients with congestive heart failure. In addition to its direct influence on
myocardial contractility, dobutamine may significantly modulate vascular tone because of its a'
and ,B-adrenergic agonist activity.
Methods and Results. To test the hypothesis that such vasoactive properties significantly
contribute to the improved ventricular performance noted with this agent, hemodynamic
parameters were measured during stepped ascension infusion of dobutamine in a model that is
insensitive to positive inotropic stimulation. Administration of dobutamine in nine calves that
underwent replacement of the native right and left ventricles with pneumatically driven total
artificial hearts resulted in a significant (p=0.0001) increase in cardiac output from 7.0±+1.8
to 8.2±1.8 1/min and a significant (p=0.0001) decrease in total peripheral vascular resistance
from 1,224± 559 to 745 ±317 dyne-sec/cm5. A less marked influence was noted on the pulmonary
vasculature, with pulmonary vascular resistance exhibiting a significant (p<O.OS) decrease
from its baseline value only at the peak infusion. Consistent with an increase in venous return,
both left and right atrial pressures increased significantly (p<0.005) with dobutamine
administration.
Conclusions. These data demonstrate that the vasoactive properties of dobutamine significantly contribute to improved ventricular performance independent of direct myocardial
stimulation. This effect appears to result in part from a direct modulation of arterial and
venous tones rather than from a reflex response to primary changes in contractility.
(Circulation 1991;84:1210-1215)
obutamine is a synthetic catecholamine that
is known to increase cardiac output in
normal subjects and in patients with congestive heart failure.'-3 Although this effect is attributed in large part to direct stimulation of the myocardium and consequent increases in ventricular
contractility, dobutamine may influence the arterial
and venous vasculature because of a- and ,B-adrenergic agonist activity.3-10 Dobutamine exists as a
racemic mixture of two stereoisomers in which the
D
From the Divisions of Cardiology and Thoracic Surgery, The
Ohio State University Hospital, Columbus, Ohio.
Supported by a Grant-in-Aid from the American Heart Association, Central Ohio Affiliate, and Eli Lilly and Co., Indianapolis,
Ind. P.F.B. is the recipient of a Clinical Associate Physician Award
from the National Institutes of Health.
Address for reprints: Philip F. Binkley, MD, The Ohio State
University Hospital, Division of Cardiology, 1654 Upham Drive,
627 Means Hall, Columbus, OH 43210.
Received December 12, 1989; revision accepted April 9, 1991.
a-adrenergic activity is found to reside in the levo
isomer and 13-adrenergic activity is expressed by the
dextro isomer.'0 Varying degrees of peripheral vasodilation have been reported that have been ascribed
to either direct or reflex effects on the vasculature,
but the mechanism of this vascular response remains
incompletely described.6-9 The present investigation
used a model that is insensitive to the positive
inotropic influence of dobutamine to test the hypothesis that the vasoactive properties of this agent
significantly contribute to improved ventricular performance. The results indicate that dobutamine is
associated with a significant reduction of systemic
vascular resistance coincident with a significant increase in cardiac output that appears to be independent of its effects on myocardial contractility and may
be ascribed to its direct effects on the vasculature.
Methods
All investigations and procedures were reviewed
and approved by the animal use committee of the
Binkley et al Augmented Function of Artificial Heart
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Ohio State University. The model consisted of nine
calves that underwent replacement of the native right
and left ventricles with pneumatically driven total
artificial right and left ventricles (Jarvik 7, Symbion,
Inc., Salt Lake City, or Utah 100, University of Utah,
Salt Lake City). The procedure for implantation of
the artificial ventricles has been previously described.11-'3 Briefly, general anesthesia was maintained with halothane after pentobarbital induction
and endotracheal intubation. A right lateral thoracotomy was performed, and the animal was placed on
cardiopulmonary bypass. The native right and left
ventricles were excised along the atrioventricular
valve rings and above the semilunar valves. Atrial
quick-connect cuffs were sewn into the right and left
atria, and vascular grafts were anastomosed to the
pulmonary artery and aorta. The artificial right and
left ventricles were then positioned and secured
using the respective atrial quick-connect cuffs and
vascular grafts. The right and left ventricles were
connected via drive line tubing to the respective
pneumatic chambers of the heart driver. Control
parameters for each ventricle consisted of heart rate,
drive pressure, and percent time in systole. With
activation of the artificial ventricles, the animal was
weaned from total cardiopulmonary bypass. Device
parameters were adjusted to maintain physiological
pressures and ensure adequate cardiac output. The
wound was closed with running sutures, and drainage
tubes were inserted in the pleural space. The animal
was transported to a specially constructed cage that
optimized animal mobility while ensuring the integrity of the drive line connection to the heart driver.
All animals were extubated and pleural drainage
tubes were removed within 24 to 48 hours. A 4-day
recovery period preceded the study protocol.
All drug infusions were performed with the animal
in the sternal recumbent posture. Aortic, pulmonary
arterial, and left and right atrial pressures and cardiac outputs were monitored for a total of 20 minutes
to ensure hemodynamic equilibration, which was
defined as less than 10% variation in any of these
parameters. Device parameters were adjusted so that
the artificial ventricles were not completely filling at
baseline. Specifically, heart rate for the nine animals
ranged from 100 to 120 beats/min (mean+SD, 109 +7
beats/min), and percent time in systole ranged from
44% to 50% (mean+SD, 47+3%). Right ventricular
drive pressures ranged from 75 to 120 mm Hg
(mean±SD, 103 + 17 mm Hg), and left ventricular
drive pressures ranged from 235 to 285 mm Hg
(mean+SD, 262+16 mm Hg). These initial device
parameters were maintained constant throughout the
subsequent dobutamine infusions. Cardiac outputs
were measured using the cardiac output monitoring
and diagnostic unit (COMDU, Symbion) of the heart
driver. This device integrates diastolic exhaust air
flow and applies a volume conversion factor to calculate stroke volume on a beat-by-beat basis. Validation of this technique has been performed by com-
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parison with simultaneously measured cardiac
outputs using turbine flowmeters.14
After establishing hemodynamic equilibration,
dobutamine was administered for three consecutive
10-minute infusions at rates of 6,12, and 24 jig/kg/
min using a percutaneously inserted external jugular
line. Minute averages of cardiac output were printed
continuously by the COMDU, and atrial, pulmonary
arterial, and aortic pressures were recorded at the
peak of each infusion. After measurements were
acquired at peak dosing, the infusion was discontinued, and the animal was allowed to return to baseline
hemodynamic status.
Derived Hemodynamic Parameters and
Statistical Analysis
Cardiac output was averaged during the last 5
minutes of the baseline period and of each infusion
period and was used for assessment of dobutamine
effects on stroke volume. Total peripheral vascular
resistance (dyne.sec/cm5) was calculated as mean
systemic pressure (mm Hg) multiplied by 80 and then
divided by cardiac output (1/min). Similarly, total
pulmonary vascular resistance was calculated according to the same formula using mean pulmonary artery
pressure and cardiac output. Analysis of variance for
repeated measures was used to test for significant
changes in hemodynamic parameters associated with
dobutamine administration. Posttest comparisons
were performed to identify specific points that differed significantly from baseline. Statistical significance was defined as a probability of less than 0.05.
Results
Systemic Vascular Response
Cardiac output was noted to increase in each of the
nine calves beginning with the first infusion rate. For
the group as a whole, the mean cardiac output of
7.0±1.8 1/min significantly (p = 0.0001) increased over
the range of dosages tested, attaining a peak value of
8.2±1.8 1/min at the 24-,mg/kg/min infusion rate
(Figure 1A). Posttest comparison of values indicated
that all infusion rates were associated with cardiac
outputs significantly greater than baseline. Coincident with the increase in cardiac output, total peripheral vascular resistance significantly (p=0.0001) decreased from the baseline value of 1,224±559
dyne.sec/cm5 with each of the three infusion rates,
with the lowest value of 745 ±317 dyne-sec/cm5 noted
at the 24-,g/kg/min infusion (Figure 1B). This response was accompanied by a significant (p=0.001)
decrease in mean aortic pressure from 98±32 to
70±14 mm Hg at the peak infusion rate (Figure 1C).
Pulmonary Vascular Response
In contrast to the effect noted in the systemic
vasculature, less marked decreases in pulmonary
vascular resistance were observed (Figure 2). The
baseline value of 367±313 dyne-sec/cm' significantly
(p<0.05) decreased to a value of 280±261 dyne.sec/
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Circulation Vol 84, No 3 September 1991
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INFUSION RATE--MCGIKG/MIN
FIGURE 2. Plots of changes in pulmonary vascular hemodynamics with dobutamine administration. Panel A: Significant
decrease in pulmonary vascular resistance (PVR) noted with
peak dobutamine infusion rate only. Panel B: No change in
mean pulmonary artery (PA) pressure observed with dobutamine administration.
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FIGURE 1. Panel A: Plot of mean and standard deviation of
cardiac output for nine calves with total artificial hearts at
baseline and with dobutamine administered at 6, 12, and 24
pg/kg/min i.v. A significant increase in cardiac output is noted
compared with baseline with each dobutamine infusion rate.
Panel B: Plot of significant decrease in mean and standard
deviation total peripheral vascular resistance (TPR) with
dobutamine administration. A significant decrease is noted
with low- as well as high-dose infusion. Panel C: Plot of
significant decline in mean aortic pressure with dobutamine
infusion.
exhibited a moderate but statistically significant (p =0.004) increase from 9±4 to 13±3 mm Hg.
To test the specific role of the a- and fl-agonist
properties of dobutamine in mediating the observed
circulatory response, selective pharmacological stimulation of the vasculature was performed in a subset of
the experimental animals. The influence of a-adren-
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noted at peak infusion. Smaller decreases in
pulmonary vascular resistance were noted at intermediate infusion rates, and posttest comparisons
demonstrated that only the value at peak infusion
differed significantly from baseline. No significant
change in the baseline mean pulmonary artery pressure of 24±7 mm Hg was noted with dobutamine
administration (Figure 2B).
cm5
Right and Left Ventricular Filling Pressures
Both left and right atrial pressures increased with
dobutamine infusion (Figure 3). A progressive and
significant (p=0.0004) increase in left atrial pressure
was noted with the baseline value of 13±5 mm Hg
increasing to 18+7 mm Hg with peak infusion and
with left atrial pressure significantly greater than
baseline with each infusion rate. Similarly, right atrial
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FIGURE 3. Plots of changes in left (panel A) and right
(panel B) atrial pressures with dobutamine. A significant
increase in right atrialpressure is noted with peak infusion and
in left atrial pressure at all infusion rates.
Binkley et al Augmented Function of Artificial Heart
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ergic stimulation was established in one cow using a
1-mg i.v. bolus of phenylephrine, which resulted in an
increase in cardiac output from 9.6 to 11.1 1/min
despite increases in mean systemic pressure from 113
to 149 mm Hg and in total peripheral resistance from
942 to 1,074 dyne.sec/cm5. Having characterized the
influence of a-agonist stimulation on circulatory function in this model, the a-adrenergic properties of
dobutamine were isolated by ,B-blockade using 20 mg
propranolol administered intravenously in the same
cow before infusion of dobutamine. Dobutamine infusion after this pretreatment with propranolol resulted in an increase in cardiac output from 8.7 to 10.1
1/min with an increase in mean blood pressure from
112 to 131 mm Hg. The specific influence of the
a-adrenergic properties of dobutamine were further
examined in two different cows by infusion of the levo
isomer of dobutamine (Eli Lilly and Co., Indianapolis,
Ind.) in which reside the a-agonist properties of
racemic dobutamine.10 In these two cows, infusion of
the levo stereoisomer of dobutamine resulted in increases in cardiac output from 7.9±1.0 to 10.0±1.1
1/min, in mean systemic pressure from 77±4 to 148 ±3
mm Hg, in total peripheral resistance from 788±138
to 1,186±122 dyne.sec/cm5, in left atrial pressure from
14±7 to 28±1 mm Hg, and in right atrial pressure
from 7±7 to 11±8 mm Hg.
The influence of p-adrenergic stimulation in this
model was characterized in two cows in which isoproterenol was infused. Isoproterenol infusion resulted in an increase in cardiac output from 7.0±0.1 to
8.3±0.2 1/min, a decrease in systemic vascular resistance from 1.132+6 to 609±23 dyne.sec/cm5, and an
increase in right and left atrial pressures of 50%. The
influence of the p-adrenergic stimulating properties of
dobutamine was then tested in two different cows by
infusion of the dextro isomer of dobutamine, which
imparts the p-agonist properties of racemic dobutamine.'0 Infusion of the dextro isomer resulted in an
increase in cardiac output from 6.7±0.8 to 8.3±1.1
1/min, a decrease in systemic vascular resistance from
845±262 to 611±96 dyne.sec/cm5, and an increase in
atrial pressures equal to those seen with isoproterenol.
Discussion
The present investigation demonstrates that in
addition to its positive inotropic properties, the vascular effects of dobutamine significantly contribute to
the enhanced cardiac output that results from its
administration. Dobutamine infusion resulted in significant increases in cardiac output despite the absence of any change in the drive parameters of the
artificial heart, indicating that the changes in cardiac
output must be solely ascribed to the influence of
dobutamine on the vasculature. This vasoactive augmentation of cardiac output appears to consist of a
reduction in ventricular afterload and potentially an
increase in venous return mediated by a reduction of
venous capacitance.
The model used in the present investigation is
uniquely suited to the analysis of mechanisms of
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vascular control. Because the total artificial heart is
devoid of any sensitivity to positive inotropic stimulus, the model may be viewed as one in which the
vascular response to a given perturbation may be
isolated from any coincident influence on myocardial
contractility. Observed vascular responses must
therefore be ascribed to the direct influence of an
intervention on the vasculature rather than to reflex
mechanisms arising from primary changes in myocardial contractility. Although the innate "contractility"
of the artificial heart is fixed once the initial functional parameters of the device have been set, the
performance of the artificial ventricle is sensitive to
preload and afterload, and its function may be modified by alterations in loading conditions. This has
been demonstrated in animal models at rest, during
exercise, and in response to various pharmacological
interventions.15-19 Thus, given the properties of this
model, the vascular determinants of ventricular and
overall circulatory performance may be segregated
and analyzed. Finally, this is an otherwise physiological model in that the animals are not anesthetized
and are alert and active in a manner resembling the
preoperative state.
That dobutamine may directly or indirectly modulate systemic vascular resistance has been noted in
prior investigations in human subjects and animal
models.4-9 However, none of these has completely
eliminated the direct positive inotropic effects of
dobutamine on the myocardium and the possible
attendant secondary vascular responses. Varying reductions in systemic vascular resistance have been
described and attributed to either direct p2-adrenergic stimulation of peripheral resistance vessels or to
reflex mechanisms. Using a canine model, Liang and
Hood6 reported that lower-dose infusions of dobutamine resulted in reductions in peripheral vascular
resistance that could be prevented by ganglionic
blockade.6 However, at higher doses, reductions in
vascular resistance could be prevented by p-adrenergic but not ganglionic blockade. It was concluded that
lower-dose infusions of dobutamine indirectly mediated vasodilation because of baroreceptor activation
resulting from enhanced ventricular contractility and
consequent increase in pulse pressure.
In the present investigation, significant reductions
in total peripheral vascular resistance were observed
at low as well as high infusion rates. In this model,
which is insensitive to positive inotropic stimulation,
augmented contractility and subsequent increases in
pulse pressure would not be primary events initiating
reflex vasodilation. It would appear that in this
context, even low-dose infusion of dobutamine would
bring about vasodilation via direct p2-adrenergic
stimulation of peripheral resistance vessels.
In addition to its influence on the systemic arterial
vasculature, dobutamine may also modulate venous
capacitance and, consequently, venous return. Both aand p-adrenergic stimulations have been shown to
reduce venous capacitance in a variety of models.20-23
Because dobutamine possesses a- and p-adrenergic
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Circulation Vol 84, No 3 September 1991
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agonist activities, it may augment venous return by
stimulation of both of these receptor systems. Consistent with this hypothesis, Fuchs et al23 demonstrated a
decrease in venous capacitance accompanying dobutamine infusion as measured by splanchnic volume
and found that this decrease could be prevented by
a-blockade. Thus, both afterload reduction (via /2agonist effects) and augmentation of venous return
(resulting from a- and /3-agonist activities) may contribute to the increase in cardiac output mediated by
dobutamine's influence on the vasculature.
The subset of cows in which the responses to
specific a- and ,B-adrenergic stimulations were examined further substantiates these mechanisms. a-Adrenergic stimulation with phenylephrine resulted in an
increase in cardiac output similar in magnitude to that
observed with dobutamine infusion. This occurred
despite marked increases in systemic arterial pressure
and systemic vascular resistance. Because the pneumatically driven artificial heart operates at a driving
pressure greater than even the peak systemic pressure
achieved with phenylephrine, it will continue to eject
the volume of blood returned by the venous circulation despite such elevations in afterload. As such, the
artificial ventricle resembles the normally functioning
human heart in its capacity to maintain stroke volume
despite elevations in afterload.24 Therefore, although
the artificial ventricle has a demonstrated sensitivity to
afterload,16-19 in the setting of augmented venous
return, a net increase in stroke volume may result
despite an increase in afterload, especially if the
magnitude of increased venous return is relatively
greater than the increase in afterload. Thus, the only
mechanism by which a-adrenergic stimulation could
increase cardiac output in this model is through
augmentation of venous return. Similarly, this would
account for the observed response to dobutamine
infusion after /3-blockade with propranolol, in which
the a-adrenergic activity of dobutamine would be
unmasked, and with infusion of the levo isomer of
dobutamine, which possesses only a-agonist activity.
As with phenylephrine, an increase in cardiac output
was observed with infusion of these agents despite
substantial increases in systemic pressure. The increase in atrial pressures with the levo isomer infusion
further supports this mechanism.
That the ,/-agonist properties of dobutamine contribute to the increase in cardiac output in this model is
demonstrated by the responses to the dextro isomer of
dobutamine, which possesses only /3-adrenergic stimulating properties, and to the infusion of isoproterenol.
Infusion of the dextro isomer in two of the cows
resulted in an increase in cardiac output accompanied
by a reduction of systemic vascular resistance. Both
right and left atrial pressures increased with infusion of
this isomer. Similarly, isoproterenol infusion resulted in
an increase in cardiac output at all infusion rates and
was accompanied by a decrease in systemic vascular
resistance and an increase in atrial pressures. Whether
the increase in cardiac output associated with these
agents derives from the influence of /3-adrenergic stim-
ulation on afterload, from /-adrenergic-mediated reduction of venous capacitance and augmented venous
return, or from a combination of these mechanisms
cannot be completely resolved based on the current
data. However, an increase in atrial pressure similar to
that seen after the levo isomer suggests that a primary
influence on venous return is an important component
of this response.
The influence of dobutamine on the pulmonary
vasculature appears to be less marked than that noted
for the systemic vasculature. Although a decrease in
pulmonary vascular resistance was noted, this occurred
only at the maximal infusion rate. This contrasts with
the marked sensitivity of the systemic vasculature in
which significant decreases in resistance were noted at
even the lowest infusion rate. These differences may
arise because of variations in pulmonary and systemic
vascular adrenergic receptor populations and affinities
for dobutamine. Significant decreases in pulmonary
vascular resistance accompanying dobutamine administration have been reported in humans with congestive
heart failure.23,7 The present data suggest that such a
decline in pulmonary vascular resistance may result
from indirect influences such as reductions in ventricular filling pressures or reflex responses to increased
cardiac output rather than from a direct effect on the
pulmonary vasculature.
Unlike previous investigations in humans with congestive heart failure, dobutamine administration in
this model is associated with significant increases in
right and left atrial pressures.2,37 This is consistent
with the increase in forward flow and venous return
observed in this setting. Unlike the native ventricle,
which can shift both to new pressure-volume relations and to different points within a given relation in
response to positive inotropic influence, the artificial
ventricle will operate along a relatively fixed pressure-volume curve; this will tend to increase filling
pressures in the setting of augmented venous return.
These changes in atrial pressures and volumes may
themselves contribute to the increase in cardiac
output through potentiation of atrial contractility by
an effect similar to the Starling mechanism of ventricular muscle contraction. Alternatively, dobutamine may directly influence contractility of the
atria and in this manner augment ventricular filling.
However, the importance of atrial systole is uncertain
in this model in which atrioventricular synchrony is
not preserved and, consequently, atrial filling occurs
at random intervals relative to ventricular filling.
The observed increase in cardiac output in this
model was noted to occur with the first infusion rate
and increase less markedly with subsequent infusions
(Figure 1). This phenomenon is most likely a result of
the fact that the maximal filling volume of the
artificial ventricle was approached with the increase
in cardiac output resulting from the first infusion,
leaving little margin for further increase with subsequent infusions. It is conceivable that if a greater
margin for increased filling were allowed, the cardiac
output would continue to increase with further infu-
Binkley et al Augmented Function of Artificial Heart
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sions rather than achieving the observed plateau.
However, operating the artificial ventricle at filling
volumes below those used in the present study would
result in inappropriately low cardiac outputs that
would not be tolerated by the animal.
The relevance of these observations to the clinically observed hemodynamic response to dobutamine
infusion in patients with congestive heart failure
provides a focus for future investigation. Although
direct comparisons of the afterload sensitivity of the
normal or failing ventricle with that of the artificial
heart have not been made, extrapolation from prior
studies in humans suggests that the artificial heart
resembles the normal ventricle in terms of its sensitivity to afterload.24 In a report by Ross and Braunwald,24 decreases in stroke volume were not seen in
ventricles with normal contractility until levels of
afterload approaching the drive pressure of the artificial ventricle were achieved. The failing ventricle is
known to have a much greater sensitivity to afterload;
thus, it may be speculated that in the setting of
ventricular failure, the vasoactive properties of dobutamine may have an even more profound effect on
circulatory performance because of their modulation
of loading conditions. This principle must be further
tested in humans with congestive heart failure and in
animal models of circulatory failure such as those
that may be adapted from the present model.
Conclusions
The present data indicate that the vasoactive properties of dobutamine contribute significantly to the
improved ventricular performance and augmentation
of cardiac output associated with its administration.
The model used in the present study effectively
eliminates the inotropic influence of this agent and
thus allows an analysis of the direct vascular effects of
dobutamine distinct from its influence on myocardial
contractility and attendant reflex vascular changes.
Further elucidation of the mechanisms of vascular
response to dobutamine and related positive inotropic agents may be provided through this model by
comparing and contrasting the hemodynamic response to agents that vary in their adrenergic receptor affinity and activity.
Acknowledgments
The authors wish to thank Anne Brandt and
Trichia Zavilla for their invaluable assistance in the
preparation of this manuscript.
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KEY WORDS
positive inotropic agents * vascular mechanisms
* congestive heart failure
.
Dobutamine increases cardiac output of the total artificial heart. Implications for
vascular contribution of inotropic agents to augmented ventricular function.
P F Binkley, K D Murray, K M Watson, P D Myerowitz and C V Leier
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Circulation. 1991;84:1210-1215
doi: 10.1161/01.CIR.84.3.1210
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