Download Average Coronary Blood Flow Per Unit Weight and Without

Average Coronary Blood Flow Per Unit Weight
of Left Ventricle in Patients With
and Without Coronary Artery Disease
By FRANCIS J. KLOCKE, M.D., IVAN L. BUNNELL,
STEPHEN M. WITTENBERG, M.D.,
AND
M. D., DAVIDG GREENE, M.D.,
JOHN P. VISCO, M.D.
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SUMMARY
Average left ventricular flow per unit mass (F/W) has been evaluated at rest in 20 normal individuals and
26 patients with arteriographically proven, advanced coronary artery disease, using inert gas techniques
modified to take into account methodological problems presented by heterogeneous perfusion within the
ventricle. Preliminary studies in a canine model in which corornary flow could be measured directly before
and after coronary occlusion indicated (1) that inert gas techniques utilizing venous sampling are suitable
for abnormal situations when appropriately long periods of saturation and desaturation, and careful resolution of prolonged venous-arterial differences, are employed; and (2) that traditional inert gas methods are
not adequate when F/W is abnormally heterogeneous. Using helium as a tracer, coronary disease patients
showed a systematic reduction, in comparison to normal individuals, in average left ventricular F/W at rest
(54 ± 11 vs 70 ± 13 ml/min/100 g, P < 0.01). Simultaneous studies with traditional nitrous oxide and krypton techniques did not show this difference because of the methodological limitations of these techniques in
the presence of abnormally heterogeneous F/W. We conclude: (1) that useful, accurate measurements of
F/W can be obtained in coronary disease if appropriate methodological precautions are taken; and (2) that
appreciable portions of the left ventricle have an abnormally low F/W, even at rest, in patients with advanced coronary disease.
Additional Indexing Words:
Tissue-blood partition coefficients
Inert gas flow measurements
Validation of flow-measurement techniques
Coronary blood flow
Gas chromatography
Heterogeneous myocardial perfusion
developed by Kety and Schmidt for the cerebral circulation1 and subsequently modified by Eckenhoff et
al.2 for the coronary circulation. There has been
general agreement that average flow per unit weight
(F/W) for the left ventricle does not show a systematic
ALTHOUGH THE CLINICAL manifestations of
coronary atherosclerosis are agreed to be related to an imbalance between myocardial oxygen demand and supply, measurements of coronary blood
flow have been of limited value in clarifying specific
clinical situations and general pathophysiological
principles. Most existing measurements have been obtained using modifications of the inert gas technique
reduction in patients with coronary artery disease
studied at rest in the cardiac catheterization
laboratory.3 However, in view of the known
heterogeneity of flow in coronary disease, it has not
been clear that the reported measurements have been
methodologically adequate to ensure inclusion of
localized areas within the heart having a belowaverage perfusion. One difficulty in resolving this
question has been the lack of experimental data
validating specific inert gas techniques in situations in
which myocardial perfusion is abnormally
heterogeneous. The present investigation was intended (1) to examine the validity of measurements
employing three different inert gas techniques in an
animal model in which coronary flow could be
measured directly before and after coronary occlusion; and (2) to re-examine resting levels of average
F/W in conscious patients with and without coronary
disease. During the latter studies, measurements
From the Department of Medicine, State University of New York
Hospital and the E. J. Meyer
Memorial Hospital, Buffalo, New York.
Presented in part at the 1970 National Meeting of the American
Federation for Clinical Research, Atlantic City, New Jersey; the VI
World Congress of Cardiology, London, England; and a Symposium on Coronary Blood Flow sponsored by Laboratorio di
Fisiologia Clinica C.N. R. and the Council on Clinical Science of the
International Society of Cardiology, Pisa, Italy.
Supported by Grants HL-09587 and HL-15194 and contract PH
43-69-28 from the National Heart and Lung Institute, Bethesda,
at Buffalo and the Buffalo General
Maryland.
Address for reprints: Francis J. Klocke, M.D., Room C-169,
SUNYAB Clinical Center, E. J. Meyer Memorial Hospital, 462
Grider Street, Buffalo, New York 14215.
Received March 25, 1974; revision accepted for publication May
20, 1974.
Circutlation, Volutme 50, September
1974
.547
5-48
KLOCKE ET AL.
employing recent modifications of inert gas techniques were compared with simultaneous
measurements employing more traditional approaches. The findings indicate that traditional
methodology is not adequate in the presence of coronary disease and that there is indeed a systematic
reduction in average F/W in patients with
arteriographically advanced coronary disease studied
at rest in the cardiac catheterization laboratory.
Methods
Validation Studies
A right heart bypass preparation
was utilized so that total
outflow could be measured directly by timed
collection in a graduated cylinder during inert gas
measurements of average F/W (fig. 1). Seventeen mongrel
dogs were anesthetized with sodium pentobarbital, intubated and ventilated with a constant volume pump.
Atelectasis was minimized by 2-4 cm of continuous expiratory positive pressure. The chest was opened through a
median sternotomy, appropriate structures were isolated
and the heart suspended in a pericardial cradle. Sodium
heparin, 10,000 units, was administered intravenouslv and
supplemented with additional 5,000 unit doses at 30 min intervals. Systemic venous return drained through superior
and inferior vena caval cannulae into an external reservoir
primed with blood from a donor animal. An occlusive roller
pump passed blood at a constant rate from the reservoir
through a heat exchanger and a Bardic cannula inserted into
coronary
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PUMP
Figure
EJ
1
bypass preparation for validation studies.
pulmonary artery; LA = left atrium; LV = left
ventricle; SVC = superior vena cava; IVC = inferior vena cava;
RA = right atrium; RV= right ventricle; CS = coronary sinus;
LAD = left anterior descending coronary artery; RCA lig. = right
coronary artery ligature; CS samp. cath. = coronary sinus sampling
Canine
right
heart
(Ao = aorta; PA =
catheter; Res.
=
reservoir; Heat exc.
= heat
exchanger).
the main pulmonary artery through a right ventricular stab
wound. Retrograde leakage of blood into the right ventricle
was avoided by doubly ligating the main pulmonary artery
around the cannula. Total coronarv outflow drained to a second reservoir through another cannula, having multiple side
holes, which was inserted into the right ventricle through
the azygos vein. The contents of this reservoir were returned
to the systemic venous reservoir at 2-4 minute intervals.
WXhen coronary flow was to be measured directly, right heart
outflow was diverted to a graduated cylinder for timed 30-60
sec collections. Flow to the nonworking right ventricle was
minimized by ligating the right coronary artery high in the
A-V groove and its superficial branches to the conus as they
reached the anterior portion of the-ventricle. This procedure
produced obvious cyanosis of the right ventricular free wall
except for the few millimeters nearest the septum (supplied
by tributaries of the left coronary arterv). Surface gas
transfer, which is known to occur in open-chest
preparations,4 was minimized by enclosing the ventricles in
a closely fitting latex covering. Arterial pressure was
monitored through a catheter in the aortic arch, which was
also used to sample systemic arterial blood during inert gas
measurements. A left ventricular catheter was available for
injection of dissolved gas tracer. Coronarv venous blood was
sampled through a 7 or 8 F Sones catheter introduced into
the coronary sinus from the right atrial appendage and advanced 2-3 cm beyond the coronary sinus ostium. Systemic
arterial temperature was monitored with a thermistor inserted into the descending aorta and the heat exchanger adjusted to maintain aortic temperature constant within ±10
at 35-38°C. Prior to coronary ligation, systolic and diastolic
arterial pressures ranged from 80 to 175 mm Hg (average
121 mm Hg) and 60 to 110 mm Hg (average 74 mm Hg),
respectively. Corresponding values after coronary ligation
were 85 to 160 mm Hg (average 117 mm Hg) and 60 to 100
mm Hg (average 73 mm Hg). Heart rate varied from 75 to
165 beats/min (average 122 beats/min) before coronary
ligation, and from 80 to 145 beats/min (average 111
beats/min) after ligation.
Different inert gases were studied simultaneously to
evaluate the effects of varying periods of saturation and
desaturation on the measurement of average F/W.
Measurements employing helium (He) were particularly
designed to include areas of lOW flow5 while those employing
nitrous oxide (N2O) and krvpton (Kr) were intended to
duplicate techniques commonly used in other laboratories.
For He measurements, the inspirate was switched from
room air to a mixture containing 75Cc He, 4C N2, and 21%
02 twentv minutes prior to the onset of desaturation. For
N20 measurements, 4% N20 was substituted for the 4% N2
during the last 10 minutes preceding desaturation. For Kr
measurements, 5-10 ml of isotonic saline saturated with dissolved Kr was injected into the left ventricle at the onset of
desaturation. Fifteen to twentv pairs of 2.0 ml arterial and
coronary venous blood samples were drawn during the last
few minutes prior to desaturation and the 20-25 minutes immediately thereafter and analyzed for inert gas concentrations with a gas chromatograph. Helium analyses were
performed on alternate pairs using a unit described
previously.6 N20 and Kr analyses were performed on the
remaining pairs, using a similar unit. The carrier gas was
helium and the test gas sample passed successively through
an 8-10 foot column of Poropak Q (for isolation of N20 from
the remainder of the sample), a thermistor detector (for
measurement of N20), an 8-10 foot column of activated
charcoal (for isolation of Kr) and a second thermistor detecCirculatiorn
Volumne 50,
September 1974
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AVERAGE LV F/W WITH AND WITHOUT CAD
549
tor (for measurement of Kr). Tracer concentrations were
quantitated from the heights of the appropriate
chromatographic peaks and expressed in arbitrary units
(preliminary experiments having verified linear
relationships between tracer concentration and peak
height). Helium values for average F/W were obtained using the Kety-Schmidt formula5 and desaturation curves
covering the entire 20-25 minute period of observation. N20
values for F/W were obtained using the same formula and
curves covering only the initial 10 minutes of desaturation.
Kr values were calculated using a monoexponential
clearance constant derived from the initial 2-4 minutes of
desaturation.7 Tissue-blood partition coefficients were
calculated as described subsequently.
Measurements of average F/W were obtained before
and/or approximately one hour after production of a
localized myocardial infarction. The latter was accomplished by ligating several adjacent diagonal branches
of the left anterior descending coronary artery supplying the
anterior free wall of the left ventricle (fig. 1). Total coronary
outflow was measured repeatedly prior to the onset of tracer
administration to verify the existence of a stable state.
Timed outflow collections were obtained at 1-2 min intervals
throughout desaturation and average values for directly
measured outflow converted from total flow (ml/min) to
F/W (ml/min/100 g) by dividing measured outflow by the
postmortem weight of the left ventricle, septum and small
perfused segment of adjacent right ventricular free wall (the
latter averaging 7.5 ± 0.9 [sD]% of the total weight).
Clinical Studies
Forty-six patients were studied in conjunction with
diagnostic cardiac catheterization after having given informed consent. Twenty were classified as having normal
coronary circulations and are subsequently referred to as the
normal patient group. Thirteen of the 20 were studied
because of chest pain not thought clinically to represent
angina pectoris. All had normal coronary arteriograms. The
remaining seven individuals included five with functional
murmurs and no cardiac complaints, one with mild mitral
stenosis and a normal left ventricle, and one with mild
mitral regurgitation but a normal left ventricle (related to
the systolic click-late systolic murmur syndrome). Coronary
arteriograms were not performed in view of the absence of
evidence of coronary disease. Systolic and diastolic arterial
pressures for the entire group ranged from 95 to 135 mm Hg
(average 116 mm Hg) and 60 to 80 mm Hg (average 73 mm
Hg), respectively. Heart rates varied from 58 to 90 and
averaged 73 beats/min.
Twenty-six patients had typical clinical features of angina
pectoris and underwent coronary arteriography. All showed
greater than 50% occlusion of at least one of the three major
coronary arteries and most had abnormalities of two or three
of these vessels. Systolic and diastolic arterial pressures
ranged from 85 to 168 mm Hg (average 121 mm Hg) and 50
to 95 mm Hg (average 71 mm Hg), respectively. Heart rates
varied from 55 to 100 and averaged 74 beats/min.
Measurements of coronary flow utilized the principles
outlined in the validation studies. An arterial needle or small
arterial catheter was inserted percutaneously into a femoral
artery and a Sones catheter was advanced into the coronary
sinus from a venotomy in the right antecubital fossa. The tip
of the coronary sinus catheter was advanced at least 2 cm
beyond the coronary sinus ostium (as seen in the frontal
projection) to avoid right atrial admixture.5 The nostrils
were occluded and the patient breathed through a
mouthpiece and low resistance unidirectional valve. All
patients breathed helium (in concentrations ranging from
50-79%) throughout a 20-minute saturation period. Twentyfive patients had 2-5% N20 added to the inspirate for the
final ten minutes of test gas breathing. In thirteen patients
in whom a left ventricular catheter was available, 10-20 ml
of isotonic saline saturated with dissolved Kr was injected
into the left ventricle at the onset of desaturation. Arterial
and coronary sinus blood samples were drawn during the
final few minutes of test gas administration and for 20
minutes thereafter.
Circulation, Volume .50, September 197a1
Partition Coefficients
Partition coefficients were measured directly in additional
in vitro experiments. Twenty to sixty gram specimens of left
ventricular myocardium were obtained from human hearts
at the time of autopsy and from dog hearts immediately
following pentobarbital anesthesia. The human tissues were
from individuals in whom the primary cause of death was
not heart disease; a few specimens showed patchy myocardial fibrosis due to coronary atherosclerosis but results were
not demonstrably different from other specimens. All
specimens were initially stripped of epicardium and endocardium and cut into small slices, omitting visible blood
vessels and connective tissue. The slices were divided into
two or three portions, weighed, diluted on a 1:1, 1:2 or 1:3
basis with isotonic saline and homogenized with a small
Waring blender and an ultrasonic homogenizer. Each
homogenate was equilibrated in a Farhi tonometer8 at 37°C
with a gas mixture containing He, N20 or Kr, or a combination of these tracers. Isotonic saline was tonometered with
the same gas mixture and 2.0 ml aliquots of each
equilibrated homogenate and saline were analyzed
chromatographically as outlined above. A tissue-saline partition coefficient expressing the amount of tracer contained in
1 g of tissue as a fraction of that contained in 1 ml of saline
was calculated for each gas from the fraction of myocardium
in the homogenate and the chromatographic peak heights
for the test gas in the homogenate and saline (assuming
myocardial specific gravity to be 1.05). Coefficients for the 23 homogenates prepared from each tissue specimen were
averaged (the individual values always agreeing within
±10% of one another).
Since the solubilities of He, N,0 and Kr differ
significantly in plasma and erythrocytes, data were also
collected relating the relative solubility of each gas in blood
and saline to hematocrit. Blood specimens were collected
from six healthy laboratory workers as well as seven dogs
anesthetized with pentobarbital. A portion of each specimen
was centrifuged to obtain plasma and a high-hematocrit
concentrate. Isotonic saline, plasma, the original specimen
and the high hematocrit concentrate were equilibrated in a
Farhi tonometer with a gas mixture containing He, N20 and
Kr and analyzed as described above. The chromatographic
peak height of each plasma or blood sample was expressed
as a fraction of the peak height of the corresponding saline
sample, and human and canine data were each pooled to obtain least-squares regression lines relating blood-saline partition coefficient (the amount of tracer contained in 1 ml of
blood expressed as a fraction of that contained in 1 ml of
saline) to hematocrit.
Tissue-blood partition coefficients for individual
measurements of F/W were obtained by dividing the
average human or canine tissue-saline partition coefficient
bv the blood-saline partition coefficient appropriate to the
hematocrit.
KLOCKE ET AL.
550
Table 1
------- =
-
Partition Coefficient Determinations
=
z
Myocardium-Saline (370C):
8-
Canline
Human
He
Kr
N
11
7
11
N20
Blood-Saline (370C):
He
Human:
Canine:
Kr
Human:
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Canine:
N20
Human:
Canine:
mean
-
0.85
-
1.09
0.95
-
SD
0.04
0.07
0.06
N
13
10
7
SD
mean
0.05
1. 08 = t 0.04
0.96 -t 0.06
0.85
-
t
G
W
cv
4-
1-
z
0
U
0
Regression equation
SEE
P.C. = 0.96 - 0.17 (Hct)
P.C. = 0.95 - 0.17 (Het)
0.018
0.021
P.C. = 1.06 + 0.50 (Hct)
P.C. = 1.02 + 0.78 (Hct)
0.036
0.032
0.95 + 0.16 (Hct)
0.97 + 0.19 (Hct)
0.046
0.032
P.C.
P.C.
PRE - LIGATION
POST - LIGATION
=
=
Abbreviations: N = number of left ventricles tested; SD =
standard deviation; P.C. = partition coefficient; Hct =
hematocrit (ml/100 ml); SEE = standard error of estimate.
Results
Partition Coefficients
Data for tissue/saline partition coefficients and
regression lines relating blood/saline partition
coefficients to hematocrit are shown in table 1.
Tissue/blood partition coefficients calculated for a
hematocrit of 40 in man were 0.95 for He, 0.94 for
N20 and 0.87 for Kr.*
Validation Studies
Representative sets of desaturation curves before
and after left anterior descending ligation are illustrated in figures 2 and 3. Data from all 17 animal
studies are given in table 2 and figure 4. Prior to left
anterior descending ligation, values for F/W obtained
from He desaturation curves averaged 99 ± 10 (SD)%
of directly measured F/W and the mean of the
differences between He and metered flow was 7% of
metered flow. Corresponding averages for N20 and Kr
were 104 ± 11% and 98 + 11%. Following left
anterior descending ligation, small prolonged venousarterial differences were apparent in the He desaturation curves, while differences from pre-ligation curves
could not be identified for N20 and Kr. He flows
averaged 96 ± 9% of directly measured flow and the
*Tissue-blood partition coefficients in this paper relate the
equilibrium concentrations of tracer in 1 g of myocardium and 1 ml
of blood. In some other studies, these coefficients have been expressed in terms of the relative concentrations of tracer in 1 ml of
myocardium and 1 ml of blood, with a value for myocardial specific
gravity being added subsequently in the calculation of F/W. The
present values would be 5% larger if expressed in this form.
0-
25
20
15
10
cv)
0
0
0
°
m
TIME (MIN)
Figure 2
Arterial and coronary sinus desaturation curves for He before and
after coronary ligation in a canine right heart bypass study (animal
7, table 2).
mean of the differences between He and metered flow
was 9% of metered flow. N20 and Kr flows exceeded
directly measured flow (N20 = 124 + 22% of directly
measured flow, P < 0.02 [paired t using absolute
values for F/W] and Kr = 122 ± 14% of directly
measured flow, P < 0.01 [also paired t using absolute
values for F/W]).
Clinical Studies
Data from all patients, including arteriographic
"scores" as described by Rowe et al.,3 are given in
--o-°-.--
ii
= PRE - LIGATION
-- =
POST - LIGATION
(I) R
z
z
cv
z
cr
0
0 10z
z
11
uJ
0
z
0
0
z
3-
0
0
0
0
0
C)
£0
-
2
4
6
8
10
10
i
2
4
6
TIME (MIN)
TIME (MIN)
Figure 3
Arterial and coronary sinus desaturation curves for N20 and
semilogarithmically plotted coronary sinus desaturation curves for
Kr in the same canine study illustrated in figure 2.
Circulation, Volume 50, September 1974
~~
AVERAGE LV F/W WITH AND WITHOUT CAD
551
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Circulation, Volume 50, September 1974
"..I
cq
m
11C
C: t- X
---- -P-4
m: 0
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LC_4 =
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KLOCKE ET AL.
552
Table 3
Data in Normal Patient Group
170o =
*-
CONTROL
AFTER LAD
LIGATION
150No.
% OF
130DIRECTLY
MEASURED
FLOW
1
2
3
4
110-
a
6
7
WS(N((NSf
8
90-
9
10
11
0
70
He
Kr
N20
Figure 4
Downloaded from http://circ.ahajournals.org/ by guest on April 29, 2017
Comparisons of
inert gas and
directly measured
flows in canine
inert gas flow ex-
validation studies. Each data point represents an
pressed as a percentage of the simultaneous directly measured flow.
Absolute values of flow are not shown. Lines connecting open and
closed circles indicate observations before and after coronary ligation in individual animals. Solid horizontal bars represent mean
values for each set of data; P values were calculated using paired ttests and absolute values of inert gas and directly measured F/W.
(NS = not significant).
tables 3 and 4 and figure 5. Representative studies
from a normal patient and a patient with coronary
artery disease are illustrated in figures 6 and 7. Values
for average F/W using He averaged 70 ± 13
ml/min/100 g in the normal patient group and
54 ± 11 ml/min/100 g in the coronary disease group
(P < 0.01). Measurements employing N20 averaged
70 ± 9 ml/min/100 g in 12 normal patients
(108 ± 16% of simultaneous measurements employing He) and 69 + 11 ml/min/100 g in 13 coronary
disease patients (138 ± 18% of simultaneous
measurements employing He, P < 0.01, paired t, fig.
8). Measurements employing dissolved Kr averaged
83 ± 19 ml/min/100 g in 12 coronary disease patients
(154 ± 29% of simultaneous measurements employing He, P < 0.01, paired t, fig. 8). Only one such comparison was available in a normal patient (figs. 6 and
8).
Discussion
Methodological Considerations and Previous
Validation of Inert Gas Measurements of F/W
These studies indicate
a
systematic difference in
with and without corfinding is at variance
with previous reports, it is pertinent to consider
methodological differences between this and other
studies and to review animal studies in which inert gas
average F/W at rest in patients
onary artery disease. Since this
12
13
14
15
16
17
18
19
20
Age
Sex
45
39
M
18
43
43
46
37
38
17
29
22
41
48
36
28
41
4,5
54
46
34
mI
AvI
mI
M
m
m
m
F
F
F
F
F
F
F
F
F
F
F
F
Arteriographic
score (3)
He
Inert gas flows
ml/min/100 g
78
275
300
52
71
67
60
54
a6
77
71
5)2
66
82
86
300
300
300
300
300
300
300
N20
Kr
75
.52
76
67
67
63
90
71
80
78
105
300
300
268
300
Mean:
90
70
62
65
67
69
70
SD:
13
66
69
64
70
9
Table 4
Data in Coronary Artery Disease Patients
No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15.
16
17
18
19
20
21
22
23
24
25
26
Age
Sex
47
M
m
m
m
m
m
m
42
54
48
59
42
53
63
45
56
57
37
33
53
53
61
59
56
42
42
53
44
44
37
62
48
AM
M
m
m
m
m
M
m
m
M
m
m
m
m
M
F
F
F
F
Arteriographic
score (3)
He
15.5
58
1735
58
115
163
125
210
95
188
115
43
62
40
45
95
49
58
49
.58
2.5
217
8.5
Inert gas flows
ml/min/100 g
N20
Kr
S.5
84
85
-
88
62
74
79
69
77
62
122
55
118
64
105a
53
125
47
210
200
98
52
42
69
225
54
193
62
125
.i.
210
200
150
238
200
173
Mean:
44
57
56
52
38
46
SD:
62
60
80
84
51
J56
75
85
.54
65
75
68
70
69
83
11
11
19
Circutlation, 'oluime 50, September 1974
AVERAGE LV F/W WITH AND WITHOUT CAD
110-
55.3
of myocardium being evaluated. In addition, the rate
of exchange of tracer between tissue and capillaries
must not be limited by the physical process of diffusion.
90-
0
(A) Techniques Employing Sampling of
Coronary Venous Outflow
0
0
of8
AVERAGE
F/W
70(ml/min/lOOg)
0
v
0
0
0
00
50-
Downloaded from http://circ.ahajournals.org/ by guest on April 29, 2017
30-
NORMAL
TT
C000
CAD
Figure 5
Individual values of average LV F/W in normal individuals and
disease patients. Solid horizontal bars represent mean
values for the two groups. Note reasonably good separation of
groups ebove 70 and below 50 ml/min/100 g, but large overlap
between 50 and 70 ml/min/100 g. As discussed in the text, the
group means differ significantly (P < 0.01).
coronary
measurements have been compared with direct
measurements of coronary flow. As discussed in more
detail previously,9 three requirements are especially
important for commonly used inert gas techniques:
(1) Concentration of tracer must be uniform
throughout the myocardium at both the onset and
completion of the flow measurement. If F/W is truly
homogeneous, this requirement can be achieved with
any duration of saturation or desaturation. When flow
is not homogeneous, venous outflow originates
predominantly from areas having a higher-thanaverage F/W and changes in average tissue gas concentration (the numerator of the Kety-Schmidt equation) which are inferred from changes in venous (or
arterial) gas concentration are incorrectly high until a
uniform tissue gas concentration has been achieved.
(2) Analytical methods for measuring changes in
tissue or blood gas concentration must be sufficiently
sensitive to quantitate small changes in tracer concentration reflecting areas of below-average F/W. These
changes become evident only after the initial portion
of the measurement and appear as small but
prolonged venous-arterial (or tissue-arterial) test gas
differences.
(3) For calculation of F/W from a monoexponential
rate constant of desaturation following bolus injection
of tracer, F/W must be uniform throughout the area
Circttlation, volurme .50, September 1974
Previous comparisons of inert gas measurements of
F/W and direct measurements of F/W have been
limited in number and have not included circumstances in which heterogeneity of F/W has been
increased to an abnormal degree. Direct validation of
techniques employing coronary sinus sampling rests
heavily on the careful work of Gregg and co-workers
with N2O.4 After defining problems related to surface
gas loss and other factors, N20 measurements during
10-15 minute saturation periods were compared to
values of F/W obtained from measurements of left
coronary inflow and postmortem left coronary injection. In nine animals, N20 flows averaged 101 ± 14%
of directly measured flows (range 78-121%). The initial work of Eckenhoff et al.2 also attempted this type
of comparison but, for reasons outlined by Gregg, a
definitive conclusion was not possible. More recently,
Aukland et al.10 reported 19 comparisons of directly
measured venous outflow and F/W calculated from
monoexponential clearance constants following
several minutes of dissolved H2 infusion in six isolated,
nonworking hearts. H2 values for F/W averaged
97 ± 7% (range 72-105%) of directly measured F/W,
the latter being expressed as cc/min/100 g of total
heart. The successful use of the monoexponential
clearance constant implied that flow was relatively
homogeneous in the particular experimental preparation. This conclusion was supported by the similarity
of additional curves following bolus injection of H2 to
those following the more prolonged H2 infusion.
The present observations in the right heart bypass
preparation prior to coronary ligation support the
validity of measurements employing conventional
N20 techniques and bolus injection of tracer with coronary sinus sampling in the working heart when
regional variations in F/W are small. However, in
view of the findings after coronary ligation, conventional techniques have important limitations when
coronary perfusion is abnormally heterogeneous. The
overestimates of average F/W with Kr seem readily
understandable. When employing bolus injection, distribution of tracer corresponds to distribution of total
flow and it is impossible to achieve the requisite uniformity of tissue tracer concentration when regional
F/W varies. The use of a monoexponential rate constant reduces the likelihood of even partial representation of areas of below-average F/W in the value for
average F/W and, when employed in conjunction
KLOCKE ET AL.
554
100-
11
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0
0
4
8
12
20
16
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24
5
10
0
4
TIME
(MINUTES)
Figure 6
Arterial and coronary sinus desaturation curves for He and N,0 and semilogarithmically p.lotted desaturation curve for Kr
in a normal individual (case 1, table 3).
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100-
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ARTERIAL
CORONARY
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TIME
(MINUTES)
Figure 7
Arterial and coronary sinus desaturation curves for He and N20 and semilogarithmically plotted desaturation curve for Kr
in a coronary disease patient (case 9, table 4).
Circulation, Volume 50, September
1974
AVERAGE LV F/W WITH AND WITHOUT CAD
220
o
=
* =
admixture.5 This no doubt minimized the contribution
to our measurements of the postero-medial left ventricular free wall and the posterior portion of the interventricular septum and values for "average" F/W
should be interpreted with this in mind. It happened
that our coronary patient group included only one individual with isolated right coronary artery disease.
The position of our coronary sinus catheters also
makes it unlikely that the observed decreases in F/W
in coronary artery disease were due to sampling a
larger than usual portion of right ventricular drainage.
NORMAL
CAD
180
% OF
SIMULTANEOUS
He FLOW
A
140(p<
0.01)
a
a
100-
(NS)
555
-
ooo..cm-
(C) Techniques Employing Precordial Counting
N20
60
Kr
Figure 8
Comparisons of N20 and Kr values of F/W with simultaneous He
values of F/ Win human studies. Each data point represents an N20
Downloaded from http://circ.ahajournals.org/ by guest on April 29, 2017
or Kr flow expressed as a percentage of the simultaneous He flow.
Absolute values of F/W are not shown. Solid horizontal bars represent mean values for each set of data; P values were calculated using
paired t-tests and absolute values of F/W.
with bolus injection,
assumes
that F/W is uniform
throughout the heart. Overestimates of flow with N20
after coronary ligation were more variable than those
with Kr, though statistically significant as a group.
While the reasons for the greater variability are not
clear, it is noted that N20 F/W constituted a larger
percentage of directly measured F/W after coronary
ligation than before in each of the seven animals in
which N20 and directly measured F/W were compared in both circumstances (fig. 4). This was not the
case for measurements employing He, where agreement of inert gas F/W with directly measured F/W
was as good after ligation as before. The He data indicate that inert gas techniques utilizing venous outflow sampling are suitable for abnormal situations
when appropriately long periods of saturation and
desaturation and resolution of prolonged venousarterial differences are employed.
(B) Coronary Sinus Drainage
as an
Index of LV Perfusion
As pointed out by Gregg and Fisher,"` the use of
sinus blood samples as an index of F/W for
the left ventricle and septum is less well established in
man than in dog. The postmortem injection studies of
Hood'2 are encouraging in demonstrating (1) drainage
into the coronary sinus of 96% of veins >1.0 mm in
diameter originating in the left ventricular free wall
and septum; and (2) only 17% of veins entering the
coronary sinus originating from other structures. In
the present studies, the coronary sinus catheter was inserted at least 2 cm beyond the coronary sinus ostium
(as seen in the frontal projection) to avoid right atrial
coronary
Circulation, Volume 50, September 1974
Although measurements employing coronary sinus
sampling differ in important respects from those
employing precordial counting,9 our reductions in
average F/W in coronary patients are also at variance
with findings of several groups using bolus injection of
Xe'33 into the left coronary artery and a monoexponential rate constant derived from a conventional
scintillation crystal. While an area of below-average
F/W has a potentially larger representation in a
precordial desaturation curve than a coronary sinus
desaturation curve,9 the basic requirements of even
saturation and resolution of prolonged tissue-arterial
differences again apply. As with Kr, bolus injection
results in distribution of tracer according to flow
rather than volume and the monoexponential calculation assumes homogeneity of F/W. Special problems
are also presented by the slower rate of Xe clearance
noted after the first minute or two of desaturation.
This appears related to the movement of the highly
lipid-soluble tracer into adipose tissue and/or delayed
elimination of tracer from alveolar gas spaces included
within the field " seen" by the external crystal.
Calculations of F/W which include this latter portion
of a desaturation curve give values which are patently
unreasonable and have no doubt influenced the decision of several groups to resort to monoexponential
calculation. The difficulties in fitting monoexponential
clearance constants to Xe data have been emphasized
by, among others, Zierler'3 and Bassingthwaighte. "
Sampling of adipose tissue during Xe washout and
simultaneous studies with antipyrine and Xe'4 both
suggest that even "early" rate constants are affected
by movement of Xe into adipose tissue, and delayed
clearance therefrom. These various potential
problems were pointed out and considered carefully
by Ross and his colleagues in their original description
of Xe'33 technique.'5 In addition to a number of
studies relating rate constants of clearance to
variations of flow in relative terms, they demonstrated
agreement between directly measured flow and 14
values obtained with Kr85 and Xe'33 in three animals.
The validity of measurements employing Kr85 and
5056
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precordial counting had also been considered by Herd
and his colleagues in 1962.16 A close correlation was
found between metered left coronary inflow and Kr8'
F/W in each of four dogs, although measured inflow
was not converted into F/W because of uncertainty
about the volume of tissue perfused. Additional comparisons of Xe"' F/W and directly measured flow
have been reported by Bassingthwaighte et al.'4 and
Shaw et al.17 However, validation of the most commonly used Xe methodology is not available in circumstances in which heterogeneity of perfusion has
been increased to an abnormal degree. The pitfalls
demonstrated by Shaw et al. using autoradiographic
techniques after canine coronary occlusion17
emphasize the importance of further validation if the
Xe technique is to continue to be used in coronary disease. While some of the difficulties related to
heterogeneity of F/W can be obviated by the ingenious use of detector systems to examine localized
areas within the heart,'8' 19 the general limitations of
bolus injection and monoexponential extrapolation
apply to the localized area. In view of the increasing
evidence for transmural variation of flow in abnormal
hemodynamic states,20 21 caution seems advisable in
translating Xe rate constants into specific values for
F/W even in topographically localized areas. Directionally incorrect conclusions about changes in
average F/W related to interventions seem at least
theoretically possible.
(D) Partition Coefficients
Direct measurements of partition coefficients have
previously been reported for N20 by Kozam et al.22
The findings were similar to those reported in table 1
and there was verification that N20 solubility did not
differ significantly in hearts with and without coronary
artery disease. Since we were unable to measure the
solubility of helium in scarred myocardium directly,
we have assumed that partition coefficients for He also
do not differ systematically in patients with and
without coronary disease. The slope of our N20
regression line relating relative blood and saline
solubilities to hematocrit is positive but small and the
routine use of a tissue-blood partition coefficient of
0.94 ml/g would seem suitable. The slope of the corresponding regression line for helium is negative
(because He is less soluble in erythrocytes than
plasma), and 0.95 ml/g might be a reasonable value
for routine use as tissue-blood partition coefficient. In
the case of Kr, myocardial solubility is not known to
have been measured directly previously. The usual
procedure has been to assume a tissue-blood partition
coefficient of 1.0, pointing out that this value has been
measured directly for brain tissue. The present data
suggest that the solubility of Kr in myocardium is
KLOCKE ET AL.
systematically less than in blood and that tissue-blood
partition coefficients for Kr vary significantly with
hematocrit.
(E) Other Considerations
From the practical point of view, the greatest
limitation in obtaining a methodologically satisfactory
measurement of F/W is the time involved (40 minutes
after preliminary positioning of catheters, etc.). The
standard deviations of directly measured F/Ws in
table 2 indicate the degree to which the requirement
of "' stationarity"23 was met in the present animal
studies. Comparable informati-on is not available in
the patient studies, although there seems no reason to
suspect a selectively unsteady state in the coronary
disease group. Also of potential concern is the contribution to the measured exchange of extracardiac
structures. While the amount of superficial adipose
tissue is greater in the human heart than the canine
heart, measurements of oil-water solubility ratios in
our laboratory indicate that this parameter is 50%
greater for N20 than He. This is against the possibility
that the observed differences between He and N20
F/Ws in coronary disease were due to an increased
representation of adipose tissue in the He curves.
Since He is inherently more diffusible than N20, the
possibility of a measurable contribution to He data
from non-adipose structures near the heart cannot be
excluded, although this circumstance would not
provide an explanation for the observed differences in
He F/Ws in patients with and without coronary disease. In any event, the volume of tissue represented in
the present measurements is the volume of distribution of the sampled tracer.
Comparisons of He Values for F/W with N20 and
Kr Values for F/W
Even though direct measurements of F/W are not
possible in man, it is of interest to compare He, N20
and Kr values of F/W in the present human studies
with each other and with previous measurements from
other laboratories.* The absolute values of F/W obtained with He and N20 in normal patients agree
reasonably with those summarized by Rowe,24 particularly when differences in assumed values for
myocardial specific gravity and tissue-blood partition
coefficients are taken into account. In addition, when
*Average values for F/W reported in this paper differ slightly
from those given in preliminary publications. The differences are
the result of (1) the use of a value for myocardial specific gravity of
1.05 (instead of 1.00); (2) the calculation of individual tissue-blood
partition coefficients from the data in table 1; (3) the inclusion of the
small segment of perfused right ventricular free wall adjacent to the
septum in the calculation of directly measured F/W in the right
heart bypass studies; and (4) the inclusion of a few more cases in the
human studies.
Circuilation, X oluinie 50, September 1974
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AVERAGE LV F/W WITH AND WITHOUT CAD
15.57
present N20 flows in normal individuals are expressed
as percentages of simultaneous He flows (fig. 8), the
two measurements do not differ significantly. This is
compatible with the thesis that both techniques are
satisfactory in man when flow is not abnormally
heterogeneous. In the presence of coronary artery disease, absolute values for F/W with He averaged 23%
lower than values obtained with He in normal
patients, a reduction approximately similar in
magnitude to that recently reported using the same
technique in acute myocardial infarction by Hodges
et al.25 and in depressed inotropic states by Henry et
al.26 Our simultaneous N20 and He flows differed
significantly in coronary disease, N20 flows exceeding
He flows by an average of 38% (fig. 8). The absolute
N20 levels for F/W are similar to those obtained in
coronary disease by others but presumably reflect an
inability to include localized areas of reduced F/W in
the measurement of average F/W. Comparisons of Kr
and He flows were not performed systematically in
patients with arteriographically normal coronary
arteries but, in coronary patients, Kr flows showed
even larger discrepancies from He flows, averaging
154 ± 29% of He flows (fig. 8). The reasons for this
discrepancy are no doubt the same as described above
for the animal studies after coronary ligation. The
magnitude of the discrepancy would have been even
greater had the tissue-blood partition coefficient for
Kr been assumed to be 1.00.
with and without coronary disease appear not to be a
methodological artifact, we conclude that average left
ventricular F/W was decreased at rest in our coronary
group. These individuals all had histories of angina
pectoris and/or myocardial infarction and their
arteriographic abnormalities were rather advanced. It
seems reasonable that groups of individuals with less
severe disease may have an abnormality of average
F/W only during stress. Attempts were made to correlate the present values for F/W with the degree of
arteriographic abnormality, as indicated by the Rowe
"arteriographic score."3 A statistically significant correlation coefficient (r = 0.39, P < 0.01) could be obtained only if the seven patients in the normal group
not subjected to arteriography were assumed to have
normal coronary vessels. Thus, while there probably is
a "weak" correlation between average left ventricular
F/W in the cardiac catheterization laboratory and the
degree of arteriographic abnormality, the correlation
has limited usefulness in attempts to derive information about average F/W from individual arteriograms.
More useful correlations might well result if the
regional reductions in F/W which cause the diminution in average F/W could be related more specifically
to localized arteriographic abnormalities.
In addition to considering group differences in
average LV F/W at rest, it is also pertinent to consider
the usefulness, and the limitations, of measurements
of this parameter in individual patients. As illustrated
in figure 5, nine of 10 cases in which F/W was 70
ml/min/100 g or more were normal individuals, while
all 10 cases in which F/W was below 50 ml/min/100 g
were coronary patients. However, the two groups
showed considerable "overlap" in the range between
50 and 69 ml/min/100 g and it is clear that the
measurement of average LV F/W at rest has limited
sensitivity and specificity in defining the status of the
coronary circulation in individual patients. A better
separation between "normal" and "abnormal" perfusion might well be accomplished by additional
measurements during a stressful intervention, or by
measurements of regional F/W.
Increased heterogeneity of F/W has been illustrated in a small series of coronary disease patients
in a previous report from our laboratory using
semilogarithmic plots of venous-arterial test gas
differences against time.5 Figure 9 shows a summary
plot for all individuals in the present study. While
there is significant overlap among individual curves in
normal and coronary patients, venous-arterial
differences for He are systematically more prolonged
in the coronary group, thus again confirming the increased heterogeneity of F/W in this condition.
Although individual curves are not shown in figure 9,
there was a reasonably good separation between nor-
F/W vs "Total" Flow in Man
When initial measurements of F/W did not reflect a
systematic reduction in coronary artery disease, it was
suggested that measurements of total flow (ml/min)
might be more useful. Measurements of total flow for
the entire heart (or, more specifically, that portion of
the heart "seen" by four-inch external scintillation
crystals) have been performed by several groups using
Rb84 and coincidence counting. Results have conflicted, the data of some groups showing no difference
at rest between individuals with and without coronary
disease27 and the data of other groups indicating a 2535% reduction in coronary disease.28 30 Measurements
of total left ventricular flow using a continuous thermodilution measurement of coronary sinus outflow3'
have not shown a difference between individuals with
and without coronary disease. The present data for
F/W do not resolve the differences among these
various measurements of " total" flow. However, as
discussed below, a reduction in F/W and a normal
"'total" flow in coronary disease would be compatible
if left ventricular size were increased systematically.
Implications of Present Measurements in
Coronary Artery Disease
Since the differences in He F/Ws between patients
Circuilation, Voltume 50, September
1974
KLOCKE ET AL.
558
30U
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L
8cr
O
LL ir
c:] z
=
* =
LL F-
hJOMAL
C
10-
Iz0
w1 5.0-o
W >
Iz
z D
D
3.0-
>
Z
1.0
>-)
0.5
0
.
1
.
4
8
12
16
'
20
TIME (MIN)
Figure 9
Downloaded from http://circ.ahajournals.org/ by guest on April 29, 2017
Semilogarithmic plot of average venous-arterial He differences vs
time in normal individuals and coronary patients. Sim ilar plots were
constructed for each study in tables 3 and 4 and ind!ividual values
tabulated from the smoothed curves at two-minute intrvals
points shown here are the resulting mean values (+1 sEmL Jor eacn
group.
T"he
mal and coronary patients in the later stages of
desaturation. At 20 minutes, for example, venousarterial differences were less than 1 % of initial He concentrations in all normal patients, but greater than 1 %
in 20 of 26 coronary patients. Attempts to construct
more specific equivalent models of coronary perfusion
using the information in figure 9 are complex and involve additional assumptions about diffusion
equilibrium, constancy of arterial inert gas concentration, etc., and are beyond the scope of this paper.
Although definitive information concerning the
nature of the areas of reduced flow in coronary disease
patients is not available, the volume of these areas
must be appreciable. Scar tissue related to previous
ischemic episodes no doubt constitutes at least a portion of the "low-flow'" tissue. We cannot exclude the
possibility that the reduction in F/W in coronary
patients is due entirely to scar tissue but were unable
to document previous myocardial infarction by
clinical, electrocardiographic, enzyme or angiographic data in four of the 10 coronary patients in
whom F/W was below 50 ml/min/100 g. Areas of
viable but "underperfused" muscle may also deserve
consideration. Reports of normal values for total flow
(ml/min) in coronary patients would be compatible
with the present data for F/W (ml/min/100 g) if left
ventricular size were increased systematically in
patients with coronary disease. Interesting data in this
regard are provided by recent pathological observations. While reviewing cases of cardiac rupture dur-
ing myocardial infarction, Naeim et al.32 noted heart
weights to average 20-25% more in infarction patients
without rupture than in a control group of noninfarction patients. In addition, Scott and Briggs33 reported
cardiac weights exceeding 450 grams in males and 400
grams in females in 83 of 183 patients dying suddenly
from. coronary atherosclerosis in Albany County, New
York. A similar incidence of cardiomegaly was
reported by Titus et al.34 in a series of 86 autopsied
cases of sudden unexpected death secondary to
ischemic heart disease in Rochester, Minnesota.
Finally, the finding of a reduction in average F/W
at rest in arteriographically advanced coronary disease
in no way diminishes the importance of evaluating the
coronary circulation in localized regions of the left
ventricle, and during stress as well as at rest. The major challenge in measurements during atrial pacing
and muscular exercise, and in efforts to quantitate
topographical and transmural variations in flow in
man, is still the development of methodologically
adequate, widely applicable technology.
Acknowledgment
The authors are indebted to Drs. D. T. Arani, A. Drakonakis, H.
L. Falsetti, P. Gandel, R. E. Mates, R. A. Oliveros and R. Tandon
for their participation in various phases of these studies, and to the
staffs of the Cardiac Catheterization and Angiology Laboratories of
the Buffalo General and E. J. Meyer Memorial Hospitals for their
superb assistance during the studies in man.
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Average Coronary Blood Flow Per Unit Weight of Left Ventricle in Patients With and
Without Coronary Artery Disease
FRANCIS J. KLOCKE, IVAN L. BUNNELL, DAVID GREENE, STEPHEN M.
WITTENBERG and JOHN P. VISCO
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Circulation. 1974;50:547-559
doi: 10.1161/01.CIR.50.3.547
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