Physiological Significance of Maximal Oxygen
Intake in "Pure" Mitral Stenosis
By JOHN R. BLACGKMON, M.D., LORING B. ROWELL, PH.D., J. WARD KENNEDY,
RICHARD D. Twiss, M.D.,
AND
M.D.,
ROBERT D. CONN, M.D.
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SUMMARY
Acute circulatory and respiratory adjustments to mild through maximal upright exercise were studied in seven patients with "pure" mitral stenosis. Maximal oxygen uptake
was determined objectively by demonstrating a plateau of oxygen uptake with increasing
workloads. Time to reach a plateau of oxygen uptake was normal (2 to 3 minutes) at
all workloads. At any given oxygen uptake, cardiac output and hepatic clearance of
indocyanine green (ICG) were abnormally low while total arteriovenous (A-V) oxygen
difference, heart rate, blood lactate, and ventilation were abnormally high. However,
with respect to relative oxygen uptake (per cent of maximal oxygen uptake), the reduction in cardiac output was exaggerated, but A-V oxygen difference, heart rate, blood
lactate, and hepatic clearance of ICG were essentially normal. RQ and VE/VO0 were
quantitatively abnormal even with respect to relative oxygen uptake, but the pattern
of changes from mild to maximal exercise was normal. Low maximal oxygen uptake
defined the reduction in stroke volume while other circulatory responses were normal
with respect to relative oxygen uptake.
Additional Indexing Words:
Mitral stenosis
Exercise, upright
Maximal oxygen uptake
IHepatic clearance of indocyanine green
I N NORMAL MAN the maximal oxygen
uptake is a measure of the functional
capacity of the cardiovascular system to transport oxygen.1 2 The measurement represents
the product of maximal heart rate, stroke
volume, and A-V oxygen difference. Accordingly, a significant reduction in any one of
these parameters as a result of disease or
other stress will be sensitively indicated by
an objective and highly reproducible technique for determining maximal oxygen uptake.
In this respect, the measurement provides a
far more sensitive and quantitative index of
impaired function than responses to impairment at rest or during submaximal exercise.
During the latter, heart rate, for example
(and probably stroke volume), is subject to
large and unpredictable variations.3 However,
the validity of the maximal oxygen uptake
in mitral stenosis has been questioned. There
is suspicion that time to reach a steady state
of oxygen uptake in these patients may be
prolonged beyond their endurance time.4
In this study, time required to achieve
a plateau of oxygen intake was determined
From the Department of Medicine, Division of
Cardiology, University of Washington School of Medicine, Seattle, Washington.
Supported in part by Grant HE-09773 from the
National Heart Institute, U. S. Public Health Service,
and by State of Washington Initiative 171 Funds
for Research in Biology and Medicine. A portion of
this work was conducted through the Clinical Research Center facility of the University of Washington, supported by the National Institutes of Health
(Grant FR-37).
Work done during Dr. Rowell's tenure of an
Established Investigatorship of the American Heart
Association.
Dr. Twiss is a Postdoctoral Fellow, U. S. Public
Health Service Grant HE-05281.
Dr. Conn is a Teaching and Research Scholar of
the American College of Physicians.
Circulation, Volume XXXVI, October 1967
497
BLACKMON ET AL.
498
Table 1
Physical Characteristics of the Subjects
Subject
Sex
BR
BG
HA
BB
BA
RB
BP
F
F
F
F
F
M
F
Age
(yr)
24
25
42
40
48
26
41
Age
~Ht
~
Ht
(cm)
Wt
Wt
(kg)
Body
surface
168
158
166
162
152
170
62.7
49.9
58.2
57.2
44.9
70.5
55.8
1.70
1.48
1.66
1.62
1.39
1.81
1.57
164
Maximal
Maximal
heart rate
02 uptake
(ml/kg X min) (beats/min)
(m2)
190
178
146
188
174
194
200
21.6
24.4
22.0
22.9
22.2
25.0
25.0
Cada
Fuctonal
Cardiac
mechanism
Functional
class*
RSR
RSR
AF
RSR
RSR
RSR
RSR
II
II
II-III
II
II
II
II
*Criteria of New York Heart Association.
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during exercise in upright posture. The subjects were cardiac patients with essentially
normal cardiac output and only moderately
elevated pulmonary arterial pressures at rest,
but with total blood flow limited during
exercise primarily by a reduced mitral valve
orifice. Total A-V oxygen difference and cardiac output were determined during upright
exercise requiring from 32 to 100% of maximal
oxygen uptake of these patients.
Our purpose was to indicate whether cardiovascular adjustments involved in approaching and attaining maximal oxygen uptake in
these patients are similar to those of normal
subjects. Clearly, there are great differences in
total A-V oxygen difference and systemic partitioning of left ventricular output at a given
absolute oxygen uptake in normal and diseaselimited subjects during supine exercise.5 Although there is information regarding the
extent of redistribution of cardiac output in
normal subjects with upright exercise,6 similar
information is not available for patients. Perhaps differences between responses of normal
subjects and these patients to a given level
of submaximal exercise merely reflect differences in the fractions of their respective maximal oxygen uptakes. We have assessed the
extent of repartitionment of cardiac output
away from nonexercising tissues during upright exercise by measuring the magnitude
of total body oxygen extraction (total A-V
oxygen difference) and percentage decrements in rates of hepatic clearance of indocyanine green. The latter reflects percentage
decrements in hepatic-splanchnic blood flow
(HBF) when hepatic function is normal.7
These data were related to absolute and
relative (per cent of maximal oxygen uptake)
oxygen consumptions.
Materials and Methods
Subjects
The subjects
were one
male and six female
inpatients undergoing evaluation for mitral
com-
Table 2
Diagnostic-Hemodynamic Data from Subjects at Supine Rest on the Day of Experiment
02 uptake
Subject
(mllmin)
250
BR
BG
HA
BB
BA
RB
BP
188
277
204
Mean
215
SD
40
225
155
207
Arterial 02, mlI 100 ml
Content
Capacity
15.1
18.1
16.7
18.2
18.5
20.2
19.3
15.5
19.4
17.7
18.6
18.7
20.2
20.3
Cardiac
output
(L/min)
A-V 02
difference
(ml/100 ml)
Stroke
volume
(ml)
3.20
3.82
3.39
4.49
4.40
6.10
4.30
7.9
5.9
5.8
4.6
4.3
4.5
4.7
39
54
56
50
55
69
55
4.24
0.96
5.4
1.3
54
9
Circulation, Volume XXXVI, October 1967
OXYGEN INTAKE IN MITRAL STENOSIS
499
missurotomy (table 1). All
were characterized
work during a multistage exercise test to exhaustion on a treadmill.8
The criteria for selection of subjects for these
studies were absence of clinical pulmonary and
systemic venous congestion and normal liver
function as judged by lack of hepatomegaly
clinically, normal clearance of indocyanine green
(ICG), and normal right atrial pressures (table
2). Results of diagnostic catheterization (supine
rest) revealed an increased total A-V oxygen
difference and subnormal cardiac output in only
one subject (BR) (table 2). All had low stroke
volumes and elevated pulmonary arterial and
right ventricular pressures.
by
very
low tolerance
of exercise at known fractions of maximal oxygen
uptake that could be maintained for 15 minutes.
To assess the rate of rise of oxygen uptake,
expired air collections were made at 30-second
intervals from the start to 5 minutes of exercise,
at both maximal and submaximal levels during
the 3 days of standardization of the subjects.
These intervals of expired gas collection were
staggered at different intervals on each day so
that midpoints of collection covered 15-second
intervals. Expired air was collected through
specially constructed low-resistance "triple J"
valves (100 ml dead space) and tubing into
a 350 L balanced spirometer and a series of
120 L neoprene bags arranged on a low-resistance
manifold. Gas samples were analyzed for carbon
dioxide and oxygen within + 0.03 vol% by the
Scholander microtechnique.
On the fourth day subjects reported to the
laboratory at 8:00 a.m. in the fasting state.
Under local anesthesia a no. 7 Cournand catheter was inserted into a vein at the antecubital
fossa and directed into the pulmonary artery
under fluoroscopic control. A Cournand needle
was inserted into the radial artery of the same
arm. During supine rest cardiac output, oxygen
consumption, and systemic, pulmonary (arterial
and wedge), and right atrial pressures were measured. Pressures were measured with a Statham
P-23Db transducer, and oxygen consumption
was measured by the open-circuit technique.
Resting clearance of ICG was determined from
six 3-ml arterial blood samples taken at 2-minute
intervals. Sampling began 5 minutes after injection of 12.5 mg of ICG into the pulmonary
artery. Absorbancy of ICG in separated plasma
was determined at 805 m,u in a Beckman DU
spectrophotometer. Details of these techniques
During rest and
were described previously.6'
exercise, cardiac output was determined by the
to
Procedures
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Each subject was studied (without catheterization) twice daily Monday through Wednesday
in an air-conditioned room maintained at 70 F.
The final experiments (with catheterization) were
completed on Thursdays. After familiarizing the
subjects with the treadmill and respiratory apparatus, they exercised repeatedly each morning
and afternoon (several hours of rest were interspersed) at various speeds and grades on the
treadmill. The objectives were (1) to establish
the time required to achieve a steady state of
oxygen consumption during work; (2) to determine maximal oxygen uptake by the criteria
of Taylor and associates1 but with speed reduced
to 3.5 mph,* and (3) to select moderate levels
*Since oxygen uptake increases in a predictable
manner with increments in treadmill grade, at constant speed, this approach was taken to determine
maximal oxygen uptake. When grade is held constant and speed increased, problems related to
changes in mechanical efficiency of fast walking or
running make maximal oxygen uptake difficult to
determine even in normal men.8
Right
ventricle
Right
atrium
Pulmonary
vascular
resistance
Mitral
valve
orifice
ICG
t 12
Arterial
lactate
(mean)
(dyne-cm sec-5)
(cm2)
(min)
(mg1llO ml)
43/3
3
34/6
54/4
47/4
50/5
49/2
46/4
7/1
4
5
5
350
147
236
107
206
118
316
0.8
0.8
0.8
1.0
0.9
1.1
1.0
3.1
2.3
4.0
3.0
3.4
2.8
2.8
6.3
7.7
9.3
7.2
6.6
4.4
4
1
211
30
0.9
0.1
3.1
0.5
6.7
1.6
Blood pressures, mm Hg
Pulmonary artery
Mean
Wedge
Radial
artery
112/65
90/54
106/54
130/65
110/56
100/69
90/50
105/59
14/7
25
17
29
18
37
22
25
31
28
38
35
20
5
31
6
23
15
15
Circulation, Volume XXXVI, October 1967
5.1
BLACKMON ET AL.
500
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Circulation, Volume XXXVI, October 1967
501
OXYGEN INTAKE IN MITRAL STENOSIS
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direct Fick method from duplicate pulmonary
and radial arterial blood samples.
After completion of measurements at rest,
subjects got up and walked on the treadmill
for 15 minutes at each previously established
speed and grade. During exercise, the catheterized
arm rested on an arm board adjusted to minimize
possible support. Fifteen- to 20-minute recovery
periods (seated) were interspersed between
workloads. During these experiments, 3-minute
expired air collections were made only during
the steady state for oxygen uptake, coincident
with cardiac output measurements at submaximal
levels. One-minute collections were obtained between 2 and 3 minutes at maximal exercise.
Pulmonary and radial arterial blood samples
were drawn during the seventh and thirteenth
minutes of submaximal exercise, and during 2.5
to 3 minutes of exercise at the level of maximal
oxygen uptake. Oxygen content of these blood
samples was determined by the manometric
technique of Van Slyke and Neill.
Rates of clearance of ICG during each level
of submaximal exercise were determined as described previously.6 7 Immediately after withdrawal of 3 ml of arterial blood (for spectrophotometric blank) at the third to fourth minutes
of exercise, 12.5 mg of ICG were injected
(pulmonary artery). Clearance rate was determined from five successive 3-ml samples drawn
at 2-minute intervals starting 3 to 4 minutes
after injection. ICG clearance could not be determined at the final workload, which lasted only
3 minutes. This "maximal" load was the lowest
workload that was previously shown to elicit
a maximal oxygen uptake.
One-milliliter arterial blood samples for lactate determination were drawn at the twelfth
minute of submaximal exercise and 1 to 2 minutes after completion of exercise at the level of
maximal oxygen uptake. Concentration of lactate
was determined according to Strom's modification of the Barker-Summerson technique.9 In
one patient (BR), systemic arterial blood P02,
pCO2, pH, and bicarbonate concentration were
determined at rest and during submaximal and
maximal exercise. P02 and pCO2 were determined by means of Clarke and Severinghaus
electrodes, respectively, calibrated with gases
standardized by Scholander microtechnique. Bicarbonate was calculated from pH (measured
by Astrup [Radiometer] pH electrode type
C-297) and pCO2 with the Henderson Hasselback nomogram.
Results
Data obtained during exercise are
presented
in table 3. In the figures that follow, these
Circulation,
Volume
XXXVI,
October 1967
BLACKMON ET AL.
502
100
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701-
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1
1
I
2
3
4
5
6
I
I
8
7
Minutes
I
9
10
11
12
___j
13
Figure 1
Times required for submaximal (o) and maximal (A) levels of oxygen uptake to reach the highest
value attained (100%) are shown. Each observation is expressed as a per cent of the highest
value noted for a given workload. Included between 95 and 100% is the variation of the method
and the subjects' responses once a steady state was achieved.
35 r
30p
r.
ch25
qj
20
V
Z1
za
'5
q01
0
2.5
5
7.5
10 12.5
Work intensity, percent grade (3.5mph)
Figure 2
Relation between oxygen uptake per kilogram of body
weight and work intensity at a given constant speed
and grade on the treadmill. Responses are contrasted
with values from 40 normal young subjects from this
laboratory (unpublished observations). The shaded
area represents the 95% confidence limits for normal
data have been contrasted with appropriate
regression lines computed from results from
normal men and women, recently published
by I. Astrand'0 and P. 0. Astrand and associates,1" and from data collected in this
laboratory during the past 3 years. Since
it is body weight-not surface area-that determines oxygen uptake and cardiac output
during exercise and since measurement of
body weight is more accurate, all values are
normalized for body weight.*
Oxygen Consumption
Oxygen comsumption during rest was well
within normal limits (table 2). Percentage
*Excellent reasons for discontinuing the use of
surface area in these conditions have been cited
previously.'2-15
subjects. The dashed line represents data from the only
subject who exercised at 3.0 mph. Maximal oxygen uptake was eventually achieved as evidenced by the plateau of oxygen uptake with increased workload.
Circulation, Volume XXXVI, October 1967
OXYGEN INTAKE IN MITRAL STENOSIS
50 A
503
0
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I
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20
40
60
l
I
7
I
80 100 '
20 40
Percent of maximal Vo2
I
I
I
60
80
100
Figure 3
(A) Ratio of pulmonary ventilation (VE STPD) to oxygen uptake (V02) and (B) respiratory exchange ratio (RQ), both in relation to relative metabolic rate. Solid circles show all observations made on each of the seven patients. The solid lines in A and B show the average responses
of 30 normal young men and the range of their values (shaded area).
0-@ o---0
A---A A ........ i
pH mmHg
7.50 r i
mmHg mM/L
PC02 BR
P02
[HCO3I
,1100120
35-
90
7.45 F
30 F
"80
25 F
7.40 L
ft
I
40
60
80
20
Percent of maximal V02
I
-i 70
100
Figure 4
Arterial blood gases and acid-base at rest and during
three intensities of work. Results from a single subject
(BR) reflecting the hyperventilation in mitral stenosis
with low pCO2 and HCO3-p and high pH during rest
and exercise.
Circulation, Volume XXXVI, October 1967
response times for oxygen uptake at the start
of exercise are shown in figure 1. The highest
oxygen uptake measured at any time during
a given intensity of exercise was set as 100%.
All other values during that test were expressed as a per cent of this value. Variation
of repeated measurements is illustrated by
inclusion of measurements made during a
steady state at later times during submaximal
exercise. The variation between 95 and 100%
is the sum of methodological errors including
expired gas concentration and volume measurement, and reproducibility in setting treadmill speed and grade plus variations in the
subjects' own responses. The 95 to 100% response time for oxygen uptake was almost
always 2 to 3 minutes. Accordingly, measurements of A-V oxygen difference, ICG clearance
rate, and so forth during submaximal exercise
BLACKMON ET AL.
504
20r
A
MS y=0.525x+3.89
-
MS
y =
O.
126 x + 3.75 (r =.96)
B
0
1-
Qj?
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0%.
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80.
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0
I
-L
1
30 40
50
20
Oxygen uptake, ml /kg x min.
I-A
25
50
75
100
Percent of maximal V02
10
Figure 5
Total body A-V oxygen diference at rest and during exercise. Regression lines for the seven
patients (solid lines) with individual data (solid circles) are contrasted with regression lines
(dashed lines) for 11 normal young women (9) and 12 normal young men (8) (calculated
from data of Astrand and co-workers. I') Regression equations are shown for normal subjects and
for the patients (MS, upper left). These data are plotted with respect to absolute oxygen uptake
(ml/kg X min) (A) and relative oxygen uptake (B). Regression lines were terminated at observed
average maximal A-V oxygen diferences. In B, open circles (o) are from data of Rowell and
colleagues-16 from six normal young men (at 25.6 C).
were obtained during a steady state of oxygen
uptake.
Oxygen uptake and ventilation were abnormally high at lower workloads. Slopes
relating oxygen uptake to work intensity were
flatter than normal and fell to (or below)
normal values as maximal oxygen uptake was
approached (fig. 2). Even when ventilatory
equivalent (VE/VO2) was related to the fraction of the maximal oxygen uptake (relative
oxygen uptake )-excessive ventilation was evident in most (fig. 3A). Respiratory exchange
ratio (RQ) was quite variable, tending toward
lower than normal values at lower workloads,
with no trend away from normal values at
greater exertion, when related to maximal
oxygen uptake (fig. 3B). Acid-base data indicating the extent of hyperventilation at rest
and during exercise are shown in subject
BR (fig. 4).
The low maximal oxygen uptake of 21.6
to 25.0 (average 23.3) ml per kg per minute
resulted from reduced circulatory transport
of oxygen rather than from a delayed response
time for oxygen uptake.
Arteriovenous Oxygen Differences
At any absolute level of oxygen uptake,
A-V oxygen difference was very much higher
than equivalent values for normal young men
and women (fig. 5A). However, at any given
relative oxygen uptake the response was midway between the values of normal young
men and women (fig. 5B ) .16 As maximal
oxygen uptake was approached, maximal A-V
oxygen difference (average 16.3 ml/ 100 ml
at 90 to 100% of maximum oxygen uptake)
rose close to maximal values in normal young
men (average 17.0 ml/ 100 ml) but was slightly higher than maximal values for normal
women."
Cardiac Output
With
output
one
was
exception (BR) resting cardiac
within the 95% confidence limits
Circulation, Volume XXXVI, October 1967
505
OXYGEN INTAKE IN MITRAL STENOSIS
350r
200r
A
300[
180
.f
-b
250F
"' 160
- A
200
Q3
/A
-
150h
*
,b
Mitral s -nosis
y-3.?5x4 '2.29
14C
rI:
k 120
Q 100
I3
\- 1~5&l'
10
0
z
20
30
40
Oxygen uptake, ml/kg x min.
350
B
Z3
,,
Normal
o-.o.Age
io10
50
60
A---
*
A1
Ref (10)
20-29yr.
Age 40-49 yr
* MS patients
A
30
-'A
300
60 70
40 50
Percent of maxi ma
80
90
100
V02
.G
o
250
Figure 7
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A ~~~~~~~A
200
150
,~~
100I
50
0
female patients during the final experiment are contrasted with normal values from women in appropriate
age groups (data of Astrand10).
,C
~
0
20
Heart rates during mild to maximal exercise in the six
y-0.90 x + 61.04
60
40
Percent of maximal
1%
80
100
2
Figure 6
Cardiac output in relation to absolute (A) and relative
oxygen uptake (B) at rest and during exercise. Regression lines for the seven patients (solid lines) with individual data (solid circles) are contrasted with regression lines (dashed lines) for normal young men (3)
and women (9) (calculated from data of Astrand and
co-workers."l) Regression lines were terminated at
observed average maximal oxygen uptakes. Each line
is accompanied by appropriate regression equations.
to relative oxygen uptake during exercise was
in the low-normal range. As in normal subjects,"1 17 the rise in lactate occurred between
50 and 70% of maximal oxygen uptake (fig.
8). Lactate concentrations at 88 to 100% of
maximal oxygen uptake range from 49.5 to
0
loo1
$ 75
of normal values.6 During exercise, cardiac
output was always subnormal (fig. 6A). This
was accentuated when cardiac output was
related to relative oxygen uptake (fig. 6B).
Average cardiac output at 88 to 100% of
maximal oxygen uptake was only 8.31 1.21
L per minute, or 150 ml per kg per minute
in contrast to values of 350 and 300 ml per
kg per minute for normal young men and
women, respectively." Since heart rates were
close to normal for appropriate age groups
in women (fig. 7), low cardiac output resulted
from very low stroke volumes (table 2).
Blood Lactate Concentration
Blood lactate concentrations were high with
respect to absolute oxygen uptake. However,
the relationship of blood lactate concentration
Circulation, Volume XXXVI,
October 1967
0
E 50
t3
t3
.,4
25
F
0
.
0
___j
50
Percent of maximal Vo2
100
Figure 8
Arterial blood lactate concentration in relation to relative metabolic rate. This relationship in the seven patients was very similar to that observed in normal
young men.6 The solid line represents an average response for normal subjects.
BLACKMON ET AL.
506
q100Q
K
A
B
' .,
75
.
%q3.
\'\
*
Se 50
sXr=
0
t; 25
7
77/
MS y = -0.80 x + 110.1
r = -0.84
MS'C
r - -0.84
IS
d'y=-1.16 x +127.89
r =-0.89
a
Downloaded from http://circ.ahajournals.org/ by guest on July 31, 2017
10
20 30 40 50
Oxygen uptake, mI /kg x min.
0
II
25
50
75
Percent of maximal V02
-.,-
100
Figure 9
Correlation between fractional clearance rate of ICG as per cent of the resting value (1O(ff)
and absolute (A) and relative (B) metabolic rates. Regression lines with appropriate regression
equations and correlation coefficients (r) are shown for the seven patients (solid lines [MS]) and
for normal young men (8) from data of Rowell, Blackmon, and Bruce.7 In part B the shaded
area revresents the 95% confidence interval for normal subjects.7
107 mg per 100 ml. The average lactate concentration at 94% of maximal oxygen uptake
was 68.6 mg per 100 ml. The value previously
noted at maximal oxygen uptake in normal
older women (40 to 49 years) was 86 mg
per 100 ml.10 The equivalent value for normal
younger women (20 to 29 years) was 121 mg
per 100 ml.'0
Hepatic Clearance of ICG
Resting clearance of ICG at rest was
normal at a half-time (ti½) of 3.1 + 0.5
minutes.0' 718,19 With increments in oxygen
uptake, ICG clearance rate fell much more
steeply than normal (fig. 9A). However, when
the reduction in ICG clearance was related
to the per cent of maximal oxygen uptake
required (fig. 9B), the response was similar
to that of normal young men.6'7
Discussion
Circulatory
supine exercise in
patients with mitral stenosis have been studied
extensively,20 and were recently reviewed by
Wade and Bishop.5 However, these authors
responses to
had difficulty in relating cardiac responses
of different patients with different degrees
of functional limitation and exercise tolerance.
Further complication has resulted from the
predominant use of supine exercise. In this
posture, heart rate and A-V oxygen difference
are decreased, and cardiac output and stroke
volume are increased above values for upright work at a given oxygen uptake; thus,
a given quantity of oxygen is supplied by
a smaller total blood flow and greater oxygen
extraction by the tissues in upright exercise.
Chapman and co-workers,4 on the other hand,
saw the advantage of determining maximal
oxygen uptake during upright exercise in these
patients as an objective but approximate guide
to the degree of functional disability.
Allegedly a major problem in establishing
the functional limits of the cardiovascular
system in cardiac patients has been the slow
response time of oxygen uptake at the onset
of exercise.4' 21 Evidence supporting this contention has come from other studies on patients with myocardial failure and other
Circulation, Volume XXXVI, October 1967
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OXYGEN INTAKE IN MITRAL STENOSIS
50'i
complicating factors (valvular incompetence,
and others). Furthermore, results from nonstandardized forms of exertion22 lacking wellregulated intensity are impossible to interpret.
Despite these problems, Meakins and Long23
found no outstanding abnormality in the rapidity of the response of oxygen uptake in
patients with cardiac failure. Indeed, Donald,
and associates24 observed a steady state within
2 to 3 minutes in 10 of 16 patients during
supine cycling at regulated, constant loads.
Only the severely disabled patients showed
a delayed response. Accordingly, our patients,
who manifested no clinical evidence of myocardial failure or venous congestion, responded to increased demands for oxygen
with an essentially normal time lag of about
2 minutes for upright exercise. This was also
true at maximal exertion. Occasionally a slight
rise in submaximal oxygen uptake with time
was observed in a given subject but not
repeatedly (this has been noted occasionally
in normal subjects, also).
Although the response time for oxygen uptake was normal, values for oxygen uptake
and ventilation were abnormally high at lower
workloads. Since there is marked hyperventilation and reduced pulmonary compliance
in mitral stenosis,25 higher costs of breathing
may have been contributory. Otherwise the
elevation in oxygen uptake was unexplained.
At high workloads the gradual approach of
oxygen uptake toward normal values (the
slope decreased) merely represents the normal
asymptotic approach to maximal oxygen uptake.26 This merely occurred at a much lower
work intensity than that seen in normal subjects.26 The respiratory exchange ratios are
difficult to interpret. The low values during
mild exercise suggest chronic hyperventilation.
Data from BR (fig. 4) substantiate marked
hyperventilation both at rest and during exer-
duction of the measurement due to disease.
For female age groups 20 to 29 years and 40
to 49 years, maximal oxygen uptake in
Astrand's study averaged 39.9 + 1.66 and 32.5
+ 0.96 ml per kg per minute, respectively.
In contrast, values for women in our study
of 21.6 and 24.4 per kg per minute (age, 24
and 25 years) and 22.0 and 25.0 (average,
23.0) ml per kg per minute (age, 41 to 48
years) indicate a large reduction. Also, the
maximal oxygen uptake of the only male in
the study (RB) was reduced approximately
50% below a normal average.1 4 6, 7
In a qualitative sense, normal subjects and
patients with pure mitral stenosis approached
maximum oxygen uptake in the same manner;
that is, at a given relative oxygen uptake or
percentage of maximal oxygen uptake relative
increments in heart rate, A-V oxygen difference, blood lactate concentration, and decrements in hepatic clearance of ICG were
normal. Although increments in ventilatory
equivalent (VE/ Vo2) and RQ were exaggerated, even with respect to relative oxygen
uptake, these data still tended to follow normal curves.
Unfortunately, four patients were not able
to reach maximal oxygen uptake during the
final experiment (three were at 88 to 90%
and one at 94% of maximal oxygen uptake).
This probably resulted from our failure to
prevent the patients from leaning slightly
upon the arm rest supporting the catheterized
arm. However, Astrand and colleagues noted
that maximal oxygen uptake was slightly lower
with catheters even without the problem of
arm support.1' Accordingly, the average maximal A-V oxygen difference of 16.35 ml per
100 ml in our patients was actually a slightly
submaximal value in four cases. The magnitude of A-V oxygen difference at or near
maximal oxygen uptake indicates that total
extraction of oxygen approached limits that
are normal for young adults. However, these
limits vary with age,27 28 sex,1 and physical
conditioning,29 and are highest in well-conditioned young men. Average maximal A-V
oxygen difference was 18.5 ml per 100 ml in
five well-trained endurance athletes.30 Values
cise.
Since publication of the work of Chapman
and his colleagues, Astrand10 has provided
values for maximal oxygen uptake in normal
men and women with respect to age. These
studies have provided a broader frame of
reference for assessing the magnitude of reCirculation, Volume XXXVI, October 1967
508
17.0 and 14.3 ml per 100 ml in physically
young men and women, respectively.1"
Physical conditioning increased maximal A-V
oxygen difference from 15.4 to 16.4 ml per
100 ml in six sedentary young men.29 The
A-V oxygen difference during exercise appears to decrease with age in both men and
women.27' 28 "Maximal" A-V oxygen differences were well within the normal range
for our three younger subjects. However, values of 14.2 to 16.3 (average 15.3) ml per 100
ml at 88 to 100% (average 94%) of maximal
oxygen uptake in the four older subjects
could be abnormally high. Unfortunately,
maximal A-V oxygen differences have not
been determined in normal women in this
age range (that is, 40 to 48 years). Maximal
values for well-trained older men (45 to 55
years) averaged 13.3 (range 12.1 to 15.8)
ml per 100 ml.28 Indeed, in mitral stenosis
extreme widening of A-V oxygen difference
is an exaggeration of a normal mechanism
for oxygen transport at any given level of
oxygen uptake. However, when this response
is related to percentages of the maximal
oxygen uptake required, this conclusion is
still unfounded. Furthermore, the average
femoral venous oxygen content of 3.0 ml per
100 ml at maximal oxygen uptake in two of
Chapman and colleagues' subjects is higher
than equivalent values of 2.7 (1.8 to 3.4) ml
per 100 ml in six normal young men,31 again
suggesting normal oxygen extraction.
Since 25 to 30% of the cardiac output is
normally partitioned to the hepatic-splanchnic
circulation at rest, extreme widening of total
A-V oxygen difference could only be achieved
in patients with low cardiac output in exercise by marked diversion of blood flow from
this region to working muscle. Heretofore,
Donald and associates24 used percentage
changes in hepatic A-V oxygen difference to
assess percentage changes in hepatic blood
flow. Splanchnic oxygen uptake was assumed
to remain constant during exercise (this was
approximately true during the brief periods
of exercise used7" 3:1). Since hepatic venous
catheterization was not possible in the present
study, our experimental design necessitated
were
active
BLACKMON ET AL.
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reliance upon changes in hepatic clearance
of ICG to assess changes in hepatic-splanchnic
blood flow. Accordingly, our assumption was
that hepatic extraction efficiency for ICG does
not decrease during exercise. Actually the
efficiency of extraction of ICG increases
slightly from rest to exercise. The tendency
is for percentage changes in clearance rates
of ICG to underestimate changes in estimated
hepatic blood flow by about 9%.7 Recent studies from this laboratory have corroborated
this finding.32 It can be assumed that patients
in this study responded similarly as all had
normal hepatic function.
As with total A-V oxygen difference, percentage decrements in ICG clearance were
exaggerated at a given absolute oxygen uptake
but not at relative oxygen uptake. All but
three measurements of ICG clearance fell
within the 95% confidence limits for normal
young male subjects when related to relative
oxygen uptake. However, the slopes of the
regression lines were slightly different. This
relationship has never been established for
normal women-young or old. The flatter slope
for these patients, if real, could reflect a
normally smaller reduction in hepatic blood
flow in women with exercise. This might
contribute to their normally narrower A-V
differences during exercise. Although these
quantitative differences indeed may exist,
qualitatively left ventricular output appears
to be partitioned normally to visceral organs,
and working skeletal muscle as well, during
exercise in pure mitral stenosis. Appearance
of increments in blood lactate concentration
in normal subjects" 17 and in our patients
at 50 to 70% of maximal oxygen uptake suggests that oxygen supply to working muscle
becomes limited at the same fraction of maximal oxygen uptake in both groups. Furthermore, the rates at which this limitation proceeds as maximal oxygen uptake is approached
are similar.
Mitchell and associates1- concluded that
the maximal oxygen uptake is a measure of
cardiac capacity and the ability to increase
A-V oxygen difference rather than the ability
Circulation, Volume XXXVI, October 1967
OXYGEN INTAKE IN MITRAL STENOSIS
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of the peripheral vasculature to receive cardiac output. Our data suggest that the
physiological significance of maximal oxygen uptake as defined by these authors is
applicable to our patients. Arterial oxygen
saturation is well maintained (even though
it may have been somewhat reduced to start
with) even at maximal oxygen uptake.4 Our
results confirm this finding. Alveolar-arterial
oxygen transport was not a limiting factor
for total oxygen transport in these patients.
When mechanisms of increasing oxygen uptake are examined in the rearrangement of
the Fick equation where oxygen uptake=
heart rate x stroke volume x A-V oxygen
difference, stroke volume stands out as the
only factor limiting maximal oxygen uptake,
since the remaining factors increase over a
normal range to essentially normal limits.
Thus, when oxygen uptake is set at maximum
and stroke volume is only one half that of
a normal subject, maximal cardiac output is
similarly subnormal. As this study has shown
in pure mitral stenosis, this defect is quantitatively reflected in an equivalent reduction
in maximal oxygen uptake. The physiological
significance of the reduction in maximal oxygen uptake in these patients was the reduction
in stroke volume resulting from mechanical
obstruction imposed by a diseased mitral
valve.
We conclude that the measurement of maximal oxvgen uptake provides the most information for the least amount of clinical procedure in assessing the restriction imposed
upon cardiovascular functional capacity by
pure mitral stenosis. Since other circulatory
adaptations to increased demands for oxygen
transport appear to be normal, the test defines the extent to which stroke volume has
been restricted.
Acknowledgment
The assistance of Mrs. Fusako Kusumi and Mrs.
Evelyn Steen, R.N., is gratefully acknowledged.
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Circulation, Volume XXXVI, October 1967
Physiological Significance of Maximal Oxygen Intake in "Pure" Mitral Stenosis
JOHN R. BLACKMON, LORING B. ROWELL, J. WARD KENNEDY, RICHARD
D. TWISS and ROBERT D. CONN
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Circulation. 1967;36:497-510
doi: 10.1161/01.CIR.36.4.497
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
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