LABORATORY INVESTIGATION
MYOCARDIAL OXYGEN SUPPLY
Effect of a reduction in blood viscosity on maximal
myocardial oxygen delivery distal to a moderate
coronary stenosis
ALBERT S. MOST, M.D., NICHOLAS A. Ruocco, JR., M.D.,
AND
HENRY GEWIRTZ, M.D.
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ABSTRACT This study tested the hypothesis that a reduction in blood viscosity by means of
isovolumetric hemodilution will permit an increase in maximal oxygen delivery to myocardium distal
to a moderate coronary arterial stenosis. It is known that blood viscosity is a determinent of resistance to
blood flow at both the stenotic and the arteriolar levels. Accordingly, a reduction in blood viscosity
could exert a favorable influence on maximal myocardial oxygen delivery in the setting of stenosis,
provided that the oxygen-carrying capacity of the blood is not compromised excessively. Closed-chest,
sedated domestic swine (n = 8) were instrumented with an artificial coronary arterial stenosis that
reduced vessel diameter by 64%. Measurements of hemodynamics, regional myocardial blood flow
(microspheres), lactate and oxygen metabolism, and whole blood viscosity were made at control and
after two successive 10 min intracoronary infusions of adenosine (400 and 800 ,ug/min) distal to the
stenosis. Next, albumin/saline solution was given intravenously to reduce the animal's hematocrit by
approximately 50%. Repeat measurements of all experimental variables were then made at a second
control and again after two successive 10 min intracoronary infusions of adenosine (400 and 800
gg/min) distal to the stenosis. Myocardial blood flow (ml/min/g) distal to the stenosis increased from
1.52 + 0.21 (mean 1 SD) to 4.10 0.86 in response to adenosine (peak dose) before hemodilution
(p < .01) and from 2.07 + 0.59 to 4.08 + 0.93 (p < .01) after hemodilution. Minimum resistance
(mm Hg/ml/min/g) distal to the stenosis, however, was approximately 33% lower (p < .05) during
infusion of adenosine after hemodilution than it was before hemodilution (endocardium 15.8 6.3 vs
24.5
14.1 and epicardium 9.0 ± 2.3 vs 14.0 ± 8.0). Maximal oxygen delivery (ml/min/lOOg) to
myocardium distal to the stenosis failed to improve and in fact was reduced (p < .01 vs before
hemodilution) after hemodilution (34.6 ± 9.5 vs 19.9 ± 6.8 to endocardium and 65.5 ± 16.4 vs 38.0
+ 10.5 to epicardium). Regional myocardial lactate metabolism, however, did not change vs initial
control during the study. Finally, hematocrit was reduced from 32 3% to 17 + 3% (p < .01) and
blood viscosity was reduced from 3.4 ± 0.2 to 2.4 0.3 centipoise (p < .01) by hemodilution. The
results of the study indicate that reducing blood viscosity by isovolumetric hemodilution may not
enhance maximal myocardial oxygen delivery in the setting of a moderate coronary arterial stenosis.
However, because minimal endocardial resistance is lowered by a reduction in blood viscosity, it is
likely that maximal oxygen delivery could be improved by this intervention if hemodilution were
accomplished with a fluid capable of transporting oxygen (e.g., perfluorocarbon emulsion).
Circulation 74, No. 5, 1085-1092, 1986.
±
DELIVERY OF OXYGENATED blood to the myocardium in the setting of a coronary arterial stenosis is
influenced by a number of factors. Many of these
(e.g., stenosis dimensions, heart rate, and perfusion
pressure) have been investigated in considerable detail
From the Division of Cardiology, Rhode Island Hospital, and Brown
University Program in Medicine, Providence, RI.
Supported in part by a grant from the NIH-NHLBI (HL 31664).
Address for correspondence: Henry Gewirtz, M.D., Division of Cardiology, Rhode Island Hospital, Providence, RI 02902.
Received March 4, 1986; revision accepted July 24, 1986.
Vol. 74, No. 5, November 1986
in earlier studies. Rheologic factors, however, have
received relatively little attention. It is known that for
any given level of flow across a coronary stenosis the
pressure gradient required to maintain flow increases
as the viscosity of blood increases," 2 and that effective
resistance to flow also increases at the arteriolar level
as blood viscosity increases.3 4 At shear rates equal to
or greater than 100/sec (representative of values observed in the coronary circulation5' 6), blood viscosity
is independent of shear rate and is primarily a function
of hematocrit and fibrinogen concentration.3 4' 7 These
1085
MOST et al.
considerations suggest the hypothesis that maximal
oxygen delivery to myocardium distal to a coronary
stenosis may be improved by reducing blood viscosity,
particularly if the oxygen-carrying capacity of the
blood is not compromised excessively. We tested this
hypothesis in a series of closed-chest, sedated, domestic swine instrumented with an artificial coronary arterial stenosis that reduced luminal diameter of the vessel
by 64%. Isovolumetric hemodilution with albumin/saline solution was used to reduce blood viscosity. A
moderate reduction in coronary diameter was chosen
to create conditions in which a definite increase in
myocardial blood flow distal to the stenosis could occur. Each animal was studied both at rest and under
conditions of maximal coronary vasodilation (intracoronary adenosine) before and after hemodilution.
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Materials and methods
Animal preparation. Farm-bred pigs (n = 8, mean weight
= 42 kg, range = 37 to 51 kg) were anesthetized with ketamine
(25 mg/kg im), placed on a volume-cycled respirator, and ventilated with 0.5% to 1.5% halothane and nitrous oxide (60:40
mixture with oxygen). Respiratory tidal volume and frequency
were adjusted to maintain arterial blood gases and pH within the
physiologic range. Fluid-filled No. 7F catheters were positioned under fluoroscopic guidance in the descending aorta, left
atrium, and anterior interventricular vein (AIV). The latter was
carefully positioned in each case to lie adjacent or distal to the
stenosis (see below) to ensure selective sampling of venous
effluent from the zone of myocardium distal to the stenosis. A
rigid coronary arterial stenosis was placed in the left anterior
descending coronary artery (LAD) by use of a technique described in detail elsewhere.8 1 The stenosis reduced the diameter of the coronary lumen by 64%. A small fluid-filled catheter
was embedded in the stenosis and through this catheter pressure
distal to the stenosis was recorded and adenosine was infused
according to the experiment protocol. The results of a "pop" test
performed on the infusion catheter (reported previously9) demonstrated that 90% or more of the phasic information present in
the distal coronary pressure waveform could be registered by the
catheter. A single electrocardiographic lead was affixed to monitor heart rate. A pacing catheter was placed in the right atrium
to maintain a constant heart rate during each study. Finally, a
micromanometer-tipped catheter was placed in the left ventricle
and was balanced and calibrated with respect to the fluid-filled
catheter in the aorta.
After all catheters and the stenosis were placed, the animals
were allowed to partially awaken from anesthesia until they
were breathing spontaneously and had brisk corneal reflexes.
Subsequently, small doses of sodium thiamylol were administered intravenously to keep the animals quiet and free of pain.
Animals were fully anticoagulated with heparin and received
aspirin (325 mg iv) to sustain patency of the coronary stenosis.
Study protocol. The protocol consisted of two identical sets
of interventions, one under control conditions and the other
during hemodilution. In the control condition, aortic, left ventricular, and left atrial pressures were recorded in addition to
coronary arterial pressure distal to the stenosis. Arterial and
AIV blood samples were drawn for lactate and oxygen determination and blood flow was measured with radiolabeled microspheres (for methods see below). An intracoronary infusion of
1086
adenosine (distal to the stenosis) was initiated for 10 min at 400
,ug/min (0.34 ml/min), after which similar pressure measurements, flow determination, and blood sampling were repeated.
A 10 min, an 800 gg/min infusion followed (0.34 ml/min). and
repeat measurements and blood samples were obtained at its
conclusion. After this protocol, a phlebotomy was carried out in
each animal with equivolume replacement of blood with a saline-albumin solution. The solution consisted of 3 g bovine
serum albumin dissolved in 100 ml normal saline adjusted to pH
7.45 with sodium bicarbonate. Hematocrit was lowered by 40%
to 50%. Once hemodilution of this degree was achieved, the
same baseline and two adenosine infusion protocols were carried out. At the conclusion of the study protocol, marker microspheres were injected through the catheter to mark the region
perfused by the stenosed portion of LAD. This region of left
ventricular myocardium, the LAD zone. was therefore identified for subsequent comparison with a remote, unlabeled region
perfused by the left circumflex coronary artery (LCX). Once the
marker microsphere infusion was completed each animal was
given a large intravenous dose of sodium thiamylol and 5 min
later was killed with an intravenous injection of KCI.
Hemodynamic measurements. All data were obtained with
a Hewlett-Packard eight-channel recorder (Model 7788A). In
addition, output from pressure transducers and the electrocardiographic amplifier were digitized on-line and subsequently
analyzed as previously described.9 A PDP 11/40 computer system was used for data acquisition and analysis. All hemodynamic measurements were made based on an average cardiac cycle
(10 sec data acquisition) constructed by the computer. Tensiontime index (mm Hg/sec) was taken as the area under the systolic
portion of the left ventricular pressure trace.
Regional myocardial blood flow. For each experimental
condition approximately 4 x 106 radiolabeled microspheres ( 15
gm diameter, 85 to 105 ,uCi total radioactivity) were injected
via the left atrial catheter to determine regional myocardial
blood flow. 10 A different radioisotope was chosen at random for
each flow determination. Microspheres were suspended in 2 ml
of 20% dextran with 0.01% Tween-80 and mechanically dispersed by repeated injection between stock vial and syringe for
2 min before each injection.
The anterior free wall along with the posterior and lateral
walls of the left ventricle were removed from the excised heart,
after which epicardial blood vessels and fat were carefully
trimmed away. Next, the ventricle was cut into cubes weighing
1 to 3 g and the location of each was carefully noted on a
diagram of the free wall of the ventricle. Each cube was divided
into endocardial and epicardial halves. Each endocardial and
epicardial half was again divided in half to obtain endocardial
and epicardial layers that represented the innermost and outermost quarters of the left ventricular wall, respectively. Each
quarter of the transmural cube weighed between 0.25 and 0.75
g. Radioactivity was measured in a gamma well counter (Packard Instruments, Downer Grove, IL). A computer was used to
correct for spillover of counts from one isotope into the window
of another and to calculate regional myocardial blood flow in
each tissue sample.
Tissue samples from the free wall of the left ventricle in the
distribution of the LAD that received the drug infusion were
designated as being from the distal zone. These samples were
readily identified because each contained a high concentration
(-7000/g) of marker microspheres. Tissue samples (n = 10 to
20 transmural cubes) obtained from myocardium at the posterobasal region of the left ventricle perfused by the nonstenosed
LCX also were analyzed. This region of the left ventricle (designated the circumflex zone) was used as a reference area because
it was physically remote from the distal zone and contained no
marker microsphere radioactivity.
CIRCULATION
LABORATORY INVESTIGATION-MYOCARDIAL OXYGEN SUPPLY
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Flow values in endocardial and epicardial layers of each zone
are based on data obtained from the innermost and outermost
quarters of the myocardial wall, respectively. Transmural flow
values, however, are based on activity of each isotope in all four
quarters of each transmural cube. The value of transmural flow
for each cube represents a weighted mean average of calculated
flows for each of the four quarters comprising the cube. Tissue
samples that exhibited control flow values greater than 2 SDs
below mean flow for the distal zone were considered to be
severely ischemic and were thus excluded from analysis.
Coronary arteriolar resistance in endocardium distal to the
stenosis was calculated by dividing distal coronary mean diastolic pressure minus mean left atrial pressure plus 7 mm Hg by
distal zone endocardial blood flow. Distal zone epicardial and
transmural resistances were calculated in the same fashion except for the fact that distal coronary mean pressure and distal
zone epicardial and transmural flows, respectively, were used in
the computation. Resistances in the circumflex zone were calculated with the use of aortic instead of distal coronary pressure.
Effective backpressure in the coronary circulation was taken as
mean left atrial pressure plus 7 mm Hg based on experimental
data of Pantley et al.' 1
Resistance at the level of stenosis was calculated as follows:
regional myocardial blood flow distal to the stenosis and the
arterial-AIV lactate difference.
Blood viscosity. Hematocrit of venous blood was determined
by the standard capillary tube/microcentrifuge technique at each
stage of the study protocol. Viscosity of whole blood was measured with a Wells-Brookfield microviscometer over a range of
shear rates (10 to 200/sec). Each determination was performed
at constant temperature (37° C) and in duplicate or triplicate if
duplicate values differed by more than 10%. The viscometer
was calibrated with oils of known viscosity. Values of blood
viscosity measured at shear rate of 90/sec were used in the data
analysis because (1) average shear rate in the coronary circulation is roughly of this order,5' 6 and (2) viscosity of blood is
essentially independent of shear rate above this level.3'' 7 Viscosity measurements were carried out at each stage of the protocol.
Statistical analysis. All data are expressed as the mean ±
SD. To facilitate analysis only data obtained at the dose of
adenosine that produced the maximal reduction in endocardial
resistance distal to the stenosis were analyzed. Before hemodilution, this was the 800 ,ug/min dose for six of eight animals and
after hemodilution this dose produced maximal reduction in five
of the eight animals. In five animals the dose level was the same
under each condition (800 ,rg/min in four of five). The significance of differences in group mean values was assessed by
means of blocked one-way analysis of variance and the Newman-Keuls multiple comparison test. 12 It should be noted, however, that stenosis resistance as well as minimal resistances
distal to the stenosis before and after hemodilution were directly
compared with one another after log transformation (to minimize variances) and without consideration of respective control
values. This is equivalent to performing a paired t test. The
same procedure (except for log transformation) also was used
for maximal oxygen delivery distal to the stenosis before and
after hemodilution. Values of p < .05 were considered statistically significant.
Stenosis resistance =
mean aortic pressure - mean distal coronary pressure
LAD transmural flow
Regional myocardial oxygen metabolism. Paired samples
(2 to 3 ml) of arterial and anterior interventricular venous blood
were obtained for determination of oxygen content (Lex-02CON Instrument, Lexington Instruments, Waltham, MA) during each phase of the study. Oxygen content (vol %) was determined in duplicate for each sample and values were accepted
only if the difference between them was 0.2 ml 02/dl or less.
Regional myocardial oxygen consumption was calculated as the
product of transmural regional myocardial blood flow distal to
the stenosis and the arterial-AIV oxygen difference.
Regional myocardial lactate metabolism. Lactate concentration in arterial and AIV blood was determined by a spectrophotometric method (Calbiochem Rapid Lactate Reagents, Calbiochem-Behring, La Jolla, CA). Samples of blood (5 ml) were
immediately deproteinized by placing them in cold perchloric
acid (8% vol/vol). The samples were centrifuged and the supernatant was frozen for subsequent analysis in duplicate. Regional
lactate consumption was calculated as the product of transmural
Results
Rheology. As intended, hematocrit of venous blood
was reduced from 32 + 3% to 17 ± 3% (p < .01) by
hemodilution. Blood viscosity (centipoise) at a shear
rate of 90/sec declined from 3.4 ± 0.2 to 2.4 + 0.3 (p
< .01) after hemodilution.
TABLE 1
Hemodynamic data (mean ± 1 SD)
Before hemodilution
Heart rate (min- )
Mean aortic pressure (mm Hg)
Distal coronary pressure (mm Hg)
Overall mean
Diastolic mean
Stenosis gradient (mm Hg)
LV end-diastolic pressure (mm Hg)
Tension-time index (mm Hg)
Control 1
Adenosine 1
Control 2
Adenosine 2
115 ±9
114 + 10
115 -+8
111 +10
117 +l10
93 ± 15B
117 +l13
90 ± 2lB
83+13B
75 + 19B
1l±+ 6
4 + 4B
27.0 ± 5.4B
55+17B
44_ qB,C
35+1 lB,C
4 + 4B
28.3 ± 5 9B
106± 13
103 ±-9
73+2lB
9+5
12 ± 5
35.4 + 3.1
39+14B
8 ± 4A
LV = left ventricular.
Ap < .05 vs control 1; Bp < .01 vs control 1; cp < .01
Vol. 74, No. 5, November 1986
Hemodilution
66± 2lB
34.0 + 5.0
vs
control 2.
1087
MOST et al.
TABLE 2
Data on regional myocardial blood flow (ml/min/g; mean ± 1 SD)
Before hemodilution
LAD zone
Endocardium
Epicardium
Transmural
EN/EP ratio
Circumflex zone
Endocardium
Epicardium
Transmural
EN/EP ratio
Hemodilution
Control 1
Adenosine 1
Control 2
1.52 + 0.18
1.38 +0.27
1.52± 0.21
1.13 + 0.20
2.64 + 0.65A
5.01±+ 1.16B
4.10 + 0.86B
0.55 ±+0.18B
2.06=+±0.67A
1.89 +0.49
2.07 + 0.59
1.08 + 0.17
2.56 0.85B
4.85 1 JOB-C
4.08 + 0.93B C
0-54 0 1qB,C
1.65 +±0.18
1.39 ± 0.17
1.57 ± 0.17
1.19±0.13
1.93 ± 0.54
1.61 ± 0.52
1.83 ± 0.55
1.21 +0.13
2.36 0.83B
1.99 0.54A
2.23 +0.65A
1.17+0.17
2.25 0.59A
l.90 ± 0.46A
2.15 ± 0.53A
1.19±0.14
Adenosine 2
EN/EP= endocardial/epicardial.
vs control 1; Bp < .01 vs control 1; cp < .01 vs control 2.
Ap < .05
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Hemodynamics (table 1). Heart rate was held constant
by atrial pacing throughout the study. The infusion of
adenosine caused a significant (p < .05) reduction vs
control in left ventricular end-diastolic pressure before
hemodilution. However, both aortic mean pressure
and tension-time index remained unchanged during the
initial infusion of adenosine. As anticipated the transstenotic gradient increased significantly vs that at control in response to adenosine before hemodilution.
After hemodilution had been accomplished, there
was a significant (p < .05) reduction vs prehemodilution levels in aortic mean pressure, tension-time index,
and left ventricular end-diastolic pressure. None of
these variables, however, changed significantly vs
those at control 2 in response to the second infusion of
adenosine. Finally, the transstenotic pressure gradient
increased significantly (p < .01) vs that at control 2 in
response to adenosine and did not differ significantly
from that observed during the infusion of adenosine
before hemodilution.
Regional myocardial blood flow (table 2). Before hemodilution, flow in all myocardial layers distal to the
stenosis increased in response to adenosine. Epicardial
flow, however, increased more than endocardial flow,
and as a result, the endocardial/epicardial flow ratio
declined significantly (p < .01) vs control. Flows in
the circumflex region did not change vs those at control during the infusion of adenosine.
At control 2 after hemodilution there was a significant (p < .05) increase vs the value at control 1 in
circumflex zone flow in all myocardial layers. Although flows in all layers of the myocardium distal to
the stenosis also tended to increase vs those at control 1
after hemodilution (i.e., at control 2), only the increase
in distal zone endocardial flow was statistically signifi1088
cant (p < .05). Infusion of adenosine distal to the
stenosis after hemodilution resulted in a substantial
increase in epicardial and transmural flow (p < .01),
but only a modest and statistically insignificant rise in
endocardial flow. Flow in all layers of the myocardium
distal to the stenosis during the trial of adenosine with
hemodilution was comparable to (but not greater than)
that observed during adenosine before hemodilution.
Stenosis and coronary vascular resistance (table 3). Be-
fore hemodilution both endocardial and epicardial resistance distal to the stenosis declined significantly (p
< .01) in response to adenosine. After hemodilution
both endocardial and epicardial resistance distal to the
stenosis declined (p < .01) vs control 1 levels. After
hemodilution the infusion of adenosine also resulted in
a significant (p < .01) reduction vs control 2 in both
endocardial and epicardial resistance. In addition, values of endocardial and epicardial resistance observed
during infusion of adenosine after hemodilution were
significantly (p < .05) less than those observed during
adenosine alone.
Stenosis resistance increased vs that at control 1 in
response to adenosine. After hemodilution stenosis resistance did not differ significantly from that at control
1. Similarly, the administration of adenosine after hemodilution was accompanied by a significant increase
in stenosis resistance. Stenosis resistances during
adenosine and hemodilution did not differ from that
observed during adenosine alone.
Myocardial oxygen delivery (table 4). Adenosine produced a substantial increase (p < .01) vs the control
value in myocardial oxygen delivery in both endocardium and epicardium distal to the stenosis. Myocardial
oxygen extraction during the infusion of adenosine
declined (p < .01) vs that at control, while oxygen
CIRCULATION
LABORATORY INVESTIGATION-MYOCARDIAL OXYGEN SUPPLY
TABLE 3
Data on coronary vascular resistance (mm Hg/ml/min/g; mean ± 1 SD)
Hemodilution
Before hemodilution
LAD zone
Endocardium
Epicardium
Transmural
Circumflex zone
Endocardium
Epicardium
Transmural
Stenosis
Adenosine 2
Control 1
Adenosine 1
Control 2
61.6±+ 7.8
70.5 ± 14.8
62.4± 8.7
24.5 + 14.1A
14.0± 8.OA
16.5 ±7.3
34.9+11.3A
41.7 ± lO.lA
38.4 ± 9.7A
15.8 ±6.3A,B
9.0+ 2 3A,B
11.6+ 2.A,B
60.8±8.0
74.9 ± 10.2
66.1±7.6
6.2 ±4.5
54.9± 13.5
69.6 ± 20.3
60.6± 16.1
9.7 ± 4.5A
37,3 ±9.4A
45.2 ± 9.3A
40.6± 8.5A
5.0 ± 2.8
35.2 ± 5.3A
44.0 ± 6.7A
38.7 + 5.3A
8.7 ± 3.OB
All LAD zone resistances (endocardial, epicardial, and transmural) at Adenosine 2 were less (p < .05) than respective values
at Adenosine 1.
Ap < .01 vs control 1; Bp < .01 vs control 2.
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consumption and arterial oxygen content remained unchanged vs the control 1 level.
After hemodilution arterial oxygen content declined
(p < .01) vs that at control 1. Although myocardial
oxygen extraction at control 2 was unchanged vs that
of control 1, myocardial oxygen consumption at control 2 was reduced (p < .05) vs that at control 1.
Oxygen delivery to endocardial and epicardial layers
distal to the stenosis at control 2 did not differ significantly from levels observed at control 1. In response to
the infusion of adenosine there was no change vs control in arterial oxygen content or myocardial oxygen
consumption. Myocardial oxygen extraction again declined significantly (p < .01) vs the control 2 value
during the infusion of adenosine. Oxygen delivery to
endocardium distal to the stenosis failed to increase
compared with that at control 2 during adenosine, although oxygen delivery to the epicardium did increase
(p < .01). Oxygen delivery to both endocardium and
epicardium were lower during adenosine and hemodilution than during adenosine alone (both p < .01).
Regional myocardial lactate metabolism (table 5). Arterial and AIV lactate concentrations did not change vs
those at control in response to adenosine. Similarly,
regional myocardial lactate consumption did not
change vs that at control during administration of
adenosine.
After hemodilution (i.e., at control 2) arterial and
anterior interventricular vein lactate concentrations
(1.3 + 0.7 and 0.9 ± 0.8 mM) did not differ significantly from respective values measured before hemodilution. However, both arterial and AIV lactate concentrations tended to increase over those at control 2
during adenosine following hemodilution. The change
in arterial lactate was not significant, although the
change in AIV concentration was (p < .05). Regional
myocardial lactate consumption at control 2 did not
differ significantly from that at control 1 and also did
TABLE 4
Data on regional myocardial oxygen metabolism (mean ± 1 SD)
Before hemodilution
Arterial 02 content (vol %)
AIV 02 content (vol %)
Myocardial 02 extraction (%)
Myocardial 02 consumption (mlImin/100 g)
LAD zone 02 delivery (ml/min/l00 g)
Endocardium
Epicardium
Hemodilution
Control 1
Adenosine 1
Control 2
13.7±+1.2
2.2+0.8
84 + 6
17.6± 3.7
13.1 1.3
8.7 2.9B
27 + 4B
17.2± 8.1
7.8±0.7B
1.3 ±0.8
85 + 9
13.2 ± 3.8A
20.8 ± 3.6
19.0+4.8
34.6 ± 9.5B
65.5±16.4B
14.7±4.4
16.0±5.5
Adenosine 2
7.8+0. 9B
4.8+0 8B,C
39 + 7B,C
12.5 -+3.7A
19.9±+-6.8
38.0± 1o.5c
Values for oxygen delivery to endocardium and epicardium distal to the stenosis during Adenosine 2 were consistently less (p
< .01) than corresponding values during Adenosine 1.
Ap < .05 vs control 1; Bp < .01 vs control 1; cp < .01 vs control 2.
Vol. 74, No. 5, November 1986
1089
MOST et al.
TABLE 5
Data on regional myocardial lactate metabolism (mean ± 1 SD)
Before hemodilution
Arterial lactate (mM)
AIV lactate (mM)
Lactate utilization (mmol/minIl00 g)
Hemodilution
Control 1
Adenosine 1
Control 2
Adenosine 2
1.0 + 0.4
0.6±0.3
0.05 + 0.02
0.8 ± 0.2
0.7±0.2
0.04 + 0.02
1.3 + 0.7
0.9+0.8
0.07 + 0.02
1.6-+ 1.0
1.5+1.A
0.05 + 0.06
Ap < .05 vs control 2.
not change significantly during administration of adenosine after hemodilution.
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Discussion
We tested the hypothesis that reducing blood viscosity by isovolumetric hemodilution may improve maximal myocardial oxygen delivery distal to a moderate
coronary arterial stenosis by reducing the effective resistance to blood flow both at the stenosis and the
arteriolar level. The hypothesis in effect proposes that
the loss in oxygen-carrying capacity of the blood
caused by hemodilution will be more than offset by
improved flow resulting from the reduction in blood
viscosity. The results of the study, however, indicate
that even in the face of a moderate stenosis flow may
not increase sufficiently to offset the loss of oxygencarrying capacity caused by hemodilution. This conclusion holds even allowing for the possibility that
after hemodilution peak blood flow and maximal oxygen delivery to myocardium distal to the stenosis
would likely have been roughly 20% greater than observed had aortic mean pressure not declined by 20%
during hemodilution.
It is important to emphasize, however, that under
basal conditions in the present study hemodilution sufficient to reduce hematocrit by roughly 50% did not
cause any evidence of impairment of myocardial oxygenation. This reflects the fact that vasodilator reserve
distal to the stenosis, particularly in the endocardium,
was adequate to permit flow to increase sufficiently to
satisfy prevailing levels of myocardial oxygen demand. Hemodilution and associated loss of oxygencarrying capacity of the blood presumably provided
the stimulus for coronary vasodilation under control 2
conditions before the administration of adenosine.
However, the fact that endocardial and epicardial resistances distal to the stenosis were roughly 33% lower
during adenosine after hemodilution than before (table
3) indicates that reduced blood viscosity per se can
augment the flow reserve of the arteriolar bed and
thereby contribute to maintenance of adequate myocardial oxygenation.
1090
Since conclusions regarding the influence of hemodilution on coronary flow reserve are based primarily
on calculated values of coronary vascular resistance, it
is appropriate to consider potential limitations of such
calculations. In the present study, all of the variables
used in making the calculations were directly measured at each phase of the experiment, with one exception. Since it was impossible to measure zero flow
pressure at every phase of the study, we used measured
left ventricular end-diastolic pressure plus 7 mm Hg
based on data obtained by Pantely et al.11 in fully
vasodilated (intracoronary adenosine) domestic swine.
While it is true that zero flow in the coronary circulation may be influenced importantly by changes in coronary tone,'3' 14 data from two previous studies"' 15 indicate that, under conditions of maximal coronary
vasodilation, zero flow pressure changes very little
over the range of left ventricular diastolic pressures
(average 4 to 12 mm Hg) encountered during administration of adenosine in the present study. Furthermore,
previous studies also have shown that under conditions
of maximal coronary vasodilation a decline in coronary perfusion pressure may be associated with a decline in coronary conductance or an increase in resistance'5' 16 compared with levels observed at higher
perfusion pressures. In light of the above considerations it is reasonable to conclude that (1) calculated
resistance values likely provide appropriate estimates
of resistance to flow in the coronary circulation in the
present study, and (2) the estimate of the extent to
which hemodilution improved the vasodilative reserve
of the distal coronary bed may be conservative since
coronary perfusion pressure during adenosine plus hemodilution was reduced vs that after adenosine infusion but before hemodilution.
Unfortunately, as long as hemodilution is accomplished with fluids devoid of oxygen-carrying capacity, enhanced flow reserve resulting from reduced
blood viscosity may be offset by a reduction in oxygen
transport. It is not immediately obvious, however, at
what point an unfavorable balance will develop. In the
present study it was demonstrated that, in the setting of
CIRCULATION
LABORATORY INVESTIGATION-MYoCARDIAL OXYGEN SUPPLY
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a moderate stenosis (85% to 90% cross-sectional area
reduction), myocardial oxygen demand on the order of
20 to 40 ml/min/100 g can be met with an hematocrit as
low as 17%. It is not likely that higher levels of myocardial oxygen demand would have been as well tolerated.'7 Similarly, different (and possibly more favorable) results might have been obtained if the
oxygen-carrying capacity of the blood had been reduced less or if hemodilution had been undertaken
from a substantially higher baseline hematocrit (e.g.,
60% to 70%).
Previous investigators have studied the effects of
abrupt changes in hematocrit on coronary flow and
resistance. In the nonstenosed canine coronary circulation it has been demonstrated that (1) minimal coronary vascular resistance increases as hematocrit is
raised from 30% to 70%,1s and (2) changes in blood
viscosity induced by alterations in hematocrit over a
wide range (20% to 60%) can account almost entirely
for observed changes in vascular resistance."9 The results obtained in the present study are consistent with
and also extend these observations. In the nonstenosed
coronary circulation the principal resistance to flow
resides at the arteriolar level. Under these conditions
lowering arteriolar resistance by hemodilution does
not carry with it the risk of reducing coronary perfusion pressure, which could occur in the stenosed coronary circulation as a result of increased turbulence
generated at the site of the stenosis. Since pressure loss
across a coronary arterial stenosis changes linearly
with viscosity but geometrically with turbulence,1 2 it
is not easy to know a priori how hemodilution will
affect myocardial blood flow and oxygen delivery in
the setting of stenosis. Any gain made in terms of
decreasing pressure loss across the stenosis as a result
of reducing blood viscosity in theory could be offset by
simultaneous enhancement of turbulence as blood exits the stenosis. * In the present study there was no
difference in stenosis resistance during adenosine before and after hemodilution, despite the fact that blood
viscosity was reduced by one-third (i.e., from roughly
3 to 2 centipoise at shear rate of 90/sec) and transstenotic flow was nearly identical with each trial. Thus,
marked hemodilution, even when accompanied by a
substantial increase in transstenotic blood flow, may
not be accompanied by an increase in the transstenotic
pressure gradient (compared with prehemodilution vasodilation) and hence an added reduction in perfusion
*The critical velocity (Vc) at which fluid flow in a cylindrical tube
becomes turbulent is directly proportional to the viscosity of the fluid.20
Thus, Vc = ReN/pD, where Re = Reynolds number; N = viscosity; p
= fluid density; D = tube diameter.
Vol. 74, No. 5, November 1986
pressure to the distal bed. This could reflect the fact
that development of turbulent flow is influenced more
by stenotic geometry than by fluid viscosity. In summary, the effects of a reduction in blood viscosity tend
to cancel each other out at the level of stenosis rather
than either increasing or decreasing the pressure gradient required for a given level of flow.
Clinical implications. Since hemodilution may reduce
the thrombogenicity of blood,2' it is possible that, in
the setting of a moderate coronary arterial stenosis, this
intervention would be useful in preventing or delaying
recurrent coronary thrombosis in patients who have
been treated with thrombolytic agents for acute myocardial infarction. In addition, the principal limitation
of hemodilution (i.e., loss of oxygen-carrying capacity) could be overcome by dilution with perfluorocarbon or other oxygen-transporting fluids instead of albumin/saline solution. Indeed, recent experiments in
canine preparations of myocardial infarction demonstrate that size of infarction can be reduced by use of
perfluorocarbon emulsions.22'23 Maintenance of the
oxygen-carrying capacity of diluted blood by administration of artificial blood substitutes and supplemental
oxygen would, in principle, expand the range of clinical conditions in which the intervention could be applied, since patients with more severe stenoses and/or
higher myocardial oxygen demands than modeled in
this study could be treated. Additional animal experiments will be required before such interventions can be
applied to humans.
In conclusion, this study tested the hypothesis that
reduction of blood viscosity by isovolumetric hemodilution will result in an overall improvement in maximal
myocardial oxygen delivery distal to a moderate coronary arterial stenosis. We demonstrated under basal
conditions that substantial hemodilution did not compromise myocardial oxygenation, even though the intervention failed to improve the maximal oxygen transport capability of the stenosed coronary circulation.
Hemodilution did not alter stenotic resistance either at
rest or after adenosine-induced coronary vasodilation.
It did, however, lower minimal arteriolar resistance by
approximately 33% after intracoronary administration
of adenosine. Accordingly, the data suggest that maximal oxygen transport may be improved by hemodilution in the setting of stenosis, provided that systemic
arterial pressure and oxygen-carrying capacity of the
blood are maintained at near-control levels. Artificial
blood substitutes such as perfluorocarbon emulsions
could be used to accomplish these ends.24
We thank Mrs. Christine Abatiello for her assistance in the
preparation of this manuscript. We also express our apprecia-
1091
MOST et al.
tion to the members of the Cardiac Research Laboratory for
expert technical assistance.
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CIRCULATION
Effect of a reduction in blood viscosity on maximal myocardial oxygen delivery distal to a
moderate coronary stenosis.
A S Most, N A Ruocco, Jr and H Gewirtz
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Circulation. 1986;74:1085-1092
doi: 10.1161/01.CIR.74.5.1085
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