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Approximate normal standards of maximal cardiac output during upright exercise in women
Approximate Normal Standards of Maximal Cardiac Output During Upright Exercise in Women KENNETH FUSAKO
F. HOSSACK, KUSUMI,
MD
MS
ROBERT A. BRUCE, MD, FACC
Seattle,
Washington
observed normal ranges of age- and weight-adjusted maximal oxygen uptake and age-adjusted maximal heart rate during wbrfghtexercise using the Bruce protocol are shown for 104 asymptomatic women. Cardiac output was measured during upright exercise in 11 normal women with the use of the direct Fick method. On the basis of the relation between oxygen uptake and cardiac output in these 11 women, the cardiac output and stroke volume were estimated by regression in the 104 women to provide normal ranges of age-adjusted values for cardiac output and stroke volume. The potential usefulness of these age-adjusted normal ranges is illustrated by analysis of 21 observations of maximal cardiac output in 16 women with heart disease. The
There is little information on the normal range of cardiac output during maximal exercise in sedentary women. Previous data, based on results of both cross-sectional’ and longitudinal studies,2 showed that maximal oxygen uptake decreases with age in both men and women. An extensive review by Sheppard3 indicated that a decrease in maximal oxygen uptake with advancing age had been reported from various countries. Recently, the ranges for maximal cardiac output, stroke volume, heart rate and oxygen uptake were provided for normal men.4 All four variables decreased with age. Maximal oxygen uptake showed the greatest and stroke volume the least decrease with age. The purpose of this study was to provide normal standards of ageadjusted values for maximal cardiac output, maximal oxygen uptake, maximal heart rate and maximal stroke volume in sedentary women. These normal standards provide a framework for evaluating the results of exercise testing in women with various cardiovascular diseases. Methods Study patients: A group of 104 asymptomatic sedentary women aged 20 to 70 years (mean 42) with no clinical evidence of heart disease performed symp-
From the Divislon of Cardiology, University of Washington, Seattle, Washington. This work was supported by Grants HL 23404 and NH RR-37 from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. Manuscript received October 13, 1980: revised manuscript received December 8.1980, accepted December 18, 1980. Address for reprints: Robert A. Bruce, MD, Division of Cardiology, RG20, University of Washington, Seattle, Washington 98195.
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tom-limited maximal exercise on a treadmill. During exercise, maximal oxygen uptake was measured. Another group of 11normal women aged 28 to 61 years (mean 50.5) underwent symptom-limited exercise testing on a treadmill. During the test, the direct Fick method was used to measure cardiac output at several submaximal work loads and at maximal exercise. These data provided a regression equation of the relation between oxygen uptake and cardiac output for women in our laboratory environment. Sikteen women with a spectrum of cardiac diseases underwent exercise testing with measurement of maximal cardiac output. Nine patients had coronary artery disease, five had valvular heart disease, one had hypertrophic cardiomyopathy and one was studied several years after an episode of adult respiratory distress syndrome. Five of the 16 underwent a second exercise test 6 months to 2 years after the first. In four of the five, the second test was performed after aortocoronary bypass surgery. Noninvasive test: After a preliminary history, physical examination and 12 lead electrocardiogram, each woman underwent an exercise test using the Bruce
The American Journal of CARDIOLOGY
Volume 47
protocol” to measure maximal heart rate and maximal oxygen uptake. Heart rate and rhythm were monitored using a modified V.5 chest lead, and blood pressure was measured with a sphygmomanometer. With the nose firmly occluded, expired air was collected at minute intervals through a mouthpiece and large bore tubes were connected to serial Neoprene@ bags. Subsequent analysis of samples for oxygen content and measurement of gas volumes were performed to calculate oxygen consumption. The methodology and reliability of these measurements were previously reported.’ Invasive test: Before undergoing invasive testing, each woman underwent a symptom-limited maximal exercise test as described. The t.echniques of performing cardiac catheterization and obtaining cardiac output measurements were previously described in detail.4 The study involved placing a Swan-Ganz catheter in the pulmonary artery and cannulating either the radial or the brachial artery. Simultaneous arterial and mixed venous blood samples were taken to measure oxygen content. Mean systemic arterial and mean pulmonary arterial pressures were measured. Observations were made with the subject at rest in the supine and sitting positions and then on several occasions during submaximal exertion and at maximal exercise. Measurements were then made at the 3rd and 5th minutes of recovery with the subject in the sitting position. The measurements of maximal heart rate and maximal oxygen uptake during an invasive exercise test are highly reproducible when compared with measurements made during a noninvasive exercise test.6 Cardiac output (literslmin) was obtained using the direct Fick method. Heart rate (beats/min) was obtained from 6 second strips of the electrocardiogram. Stroke volume (ml) was obtained by dividing cardiac output (ml/min) by heart rate. Pressure-rate product was the product of mean systemic arterial pressure and heart rate X 10e2.
5-
STE = 0.83 I
”
/ 1-d_ 0
0.5
I .o
I.5
48
m_m_,m~_p.t.I 20
25
30
i/O, (Ilters/mu7) FIGURE 1. The measurements of oxygen uptake (i/O,) (liters/min) and corresponding values of cardiac output (litersimin) are plotted for the 48 observations in the 11 normal women. There is a good correlation over the measured range. SEE = standard error of the estimate.
tions made during exercise gression equation is: Cardiac output (liters/min)
in these
women.
The re-
= 4.07 + 4.72 [oxygen uptake
(liters/min)].
The physical characteristics of the 104 normal women in whom measurements of maximal oxygen uptake were made are shown in Table II. Approximately 20 percent of these women smoked. Figure 2A plots the observed values of maximal oxygen uptake, corrected for weight, against age. The 95 percent confidence intervals are shown f2 standard deviations. At age 20, the normal range is 34.7 f 7.2 ml/kg per min and it decreases to 18.0 f 7.2 ml/kg per min at age 70. Maximal cardiac output was estimated by regression from the measured values of oxygen uptake (liters/min) using the equation from the 11 normal women (Fig. 2). The values are plotted with respect to age in Figure 2B. Maximal heart rate is
Results Normal women: Table I lists the physical characteristics and the results of values obtained during measurement of maximal cardiac output in the 11 normal women. Figure 1 plots the measurements of oxygen uptake and cardiac output for the 48 observa-
TABLE I Physical and Hemodynamic Variables in 11 Normal Women i/O*
Age Case
(yr)
Wt
Ht
max
max
HR max
SV max
CaOp
cvop
aCiOpD max
PsA max
& max
ta FAI
:
Sed
45 52
56.6 63.2
163 166
24.04 28.81
-12 -3
12.19 12.43
158 194
64
181 193
46
108 147
137 109
27
3 4
Sed Sed
43 ::
65.0 58.2
155 161
26.66 24.34
-1 1;
11.52 10.78
194 188
:3 63
212 173
;:
t:
151 132
154
;“o 15
z
Sed
69.0 74.1
167 161
21.42 26.72
-15
11.71 12.89
178 188
66
198 193
50
136 143
140 125
z”o
: 9
Sed Sed
z z:
66.0 50.9 66.0
166 158 165
23.74 28.72 20.77
-31 -15
10.94 13.93 10.25
164 184 166
81 ;:
160 188 171
42 52 53
118 136 118
1:: 102
f
z:
64.3 55.5
160 168
47.72 24.77
-G
14.36 11.98
200 176
:: 76
202 187
54 31
133 171
132 152
:: 25
50.5 9.3
62.6 6.7
163 4.1
27.07 7.34
-11 13
12.09 1.27
181 14
70 9
187 15
51 10
136 18
129 21
26 7
::
Mean SD
Activity
Act Sed
6
Y
Act = active; aa& max = arterial-mixed venous oxygen difference at maximal cardiac output (ml/liter): Ca02 = arterial oxygen content (ml/liter); C~OBZ mixed venous oxygen content (ml/liter); FAI = functional aerobic impairment (%); HR max = maximal heart rate (beats/min); Ht = height (cm); PPA m = mea” puimnary &erial pressure at the end of exercise (mm k!@; P% maX = m&m systemic arterial pressure at the end of exercise (mm Hg); Q Fax = maximal cardiac output (litersimin); SD = standard deviation: Sed = sedentary; SV max = stroke volume at maximal cardiac output (ml); VOp max = maximal oxygen uptake (ml/kg per min); Wt = weight (kg).
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MAXIMAL
CARDIAC
TABLE
II
OUTPUT IN WOMEN-HOSSACK
ET AL.
plotted against age in Figure 2C. Estimated stroke volume was obtained by dividing estimated cardiac output by maximal heart rate. These values are plotted against age in Figure 2D. Women with heart disease: The physical characteristics and the results of invasive exercise testing are shown for the patients with coronary heart disease and those with other cardiovascular diagnoses in Tables III and IV. Four of the patients had follow-up tests after coronary bypass surgery and the results are shown separately in Table III. In Figure 3, the respective values for maximal oxygen uptake, cardiac output, heart rate and stroke volume are plotted for these patients and the normal ranges are shown for reference.
Physical Characteristics and Exercise Responses of 104 Asymptomatic Sedentary Women (mean values f standard deviation)
Age Range
n
2034 35 49 5070
HR i/O* max Smoking max (%) (beatsimin) (ml/kg per min)
(Z,
(Z
22 59.2 165.2 f 5.9 f 5.0 59 62.8 166.4 & 10.0 f 6.2 23 64.5 166.3 f 11.1 f 7.0
22
Total 104 62.5 166.2 group f 10.0 f 6.1
22
22 21
192 f 11 180 f 11 176 f 12
32.3 f 5.9 26.7 + 3.5 24.5 f 3.1
181 f 13
27.4 f 4.9
Discussion Estimated maximal cardiac output in normal women: This study has confirmed the previously re-
HR max = maximal heart rate; Ht = height; n = number of observations; Wt = weight; VOa max = maximal oxygen uptake.
ported4>7-s high correlation
between
oxygen uptake
and
6
A 50
*5r
n=104
n=104
"Z41.3~0.333,
yzl5.0-0.071
I
r=,46
I
------4SO
40
30
20
60
50 Age
70
Iyears) I
20
C
100
I
40
I
50 Age (years)
I
I
60
70
D
250
Fz
30
‘y
n=104
I
y’206-0.5’3% r=.46
n=104
~‘74-0.172~ r z.20
30
I
20
t I
I
30
40
I
50 Age iyears)
I
I
I
60
70
20
I
30
I
40
I
50 Age (years)
I
6d
J
70
FIGURE 2. Derived values for observed and maximal cardiovascular variables in iO4 normal women. A, observed age- and weight-adjusted value of maximal oxygen uptake (VOa max). The regression line is shown and the normal range indicated by f2 standard deviations (SD). The standard deviation for oxygen uptake is 3.59 ml/(kg min). B, estimated age-adjusted values of maximal cardiac output (Q max). The standard deviation for cardiac output is 1.35 liters/min. C, observed age-adjusted values of maximal heart rate (HR max). The standard deviation for heart rate is 14 beats/min. D, estimated age-adjusted values of maximal stroke volume (SV). The standard deviation for stroke volume is 8 ml.
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No No No 60 9
64 :; 159 5
152 162 164
158
159 5
158 157
167
155
159
164
152 162
158
Ht (cm)
13.05 4.68
20.29 15.74
11.70
64.7 3.9
60.9 62.4 69.8
65.9
8.15
11.54
9.02
10.79 20.50
15.94 5.54
12.91 23.95 11.67
15.23
Postoperative
64.4 5.5
61.4 60.2
68.0
54.0
67.7
72.7
65.2 62.6
68.0
9.76
i/o, max
Preoperative
(G)
74 14
9”: 61
75
58 16
71
80
53
33
59
48
Z;:
47
% NVO,
7.79 2.23
7.56 10.38 4.96
8.25
6.89 2.04
10.60 a.54
7.04
4.19
6.31
5.13
5.45 8.73
6.08
b max
72 17
72 89 48
78
63 16
91 78
65
37
61
50
52 75
57
% ND
132 28
106 171 122
127
117 20
140 128
114
102
115
127
1:;
97
HR max
77 14
63 96 74
76
68 11
79 74
67
58
69
77
50 80
57
% NHR
60 13
71 61 41
65
59 12
76 67
62
41
55
40
65 61
63
SV max
94 20
113 :;
103
92 18 -__.__
116 104
97
63
a8
64
103 92
99
% NSV
195 25
202 195 219
160
181 17
175 184
154
171
182
187
208 202
164
CaOz
62 25
:7” 55
38
61 11
57 73
41
66
58
57
79 55
55
CvOz
133 26
104 144 164
122
120 13
120 111
113
105
124
128
129 147
109
avOzD
l
Treatment with beta receptor blocking agents was discontinued at least 48 hours before testing. + Percent narrowing of luminal diameter. AP = angina pectoris; avOOpD= arterial-mixed venous oxygen difference (ml/liter); bid = twice daily: C = complete revascularization; CaOz = arterial oxygen content (ml/liter); CvOz = mixed venous oxygen content (ml/liter); D = digoxin; F = furosemide; HR max = heart rate at maximal cardiac output (beatsjmin); H = hydrochlorothiazide; HT = hypertension; I = Isordil; IC = incomplete revascularization; LAD = left anterior descending coronary artery; LCx = left circumflex coronary artery; LMCA = left main coronary artery; M = metoprolol; Ml = myocardial infarction; %NHR = percent of age-predicted maximal heart rate; %NQ = percent of age-predicted maximal cardiac output; %NSV = percent of age-predicted maximal stroke volume: %NVOz = percent of age-predicted maximal oxygen uptake: P = propranolol; pm = as required; Q = quinidine; Q max = maximal observed cardiac output (liters/min); qid = four times daily: RCA = right coronary artery; SD = standard deviation: SV max = stroke volume at maximal cardiac output; tid = three times daily; VOz max = oxygen uptake at maximal cardiac output (ml/kg body weight per min).
Mean SD
Fatigue Fatigue Dyspnea
c c IC
No
48 57
2 3 4
Fatigue
LAD 60 LAD 50
58
50
65
63
D 0.25lday H 25Iday None H 25Iday None
Yes Yes
Yes
No
Yes
67
64 47
62
Age (yr)
c
Dyspnea Angina
Dyspnea
Dyspnea
Angina
LAD 100, LCX 90, RCA 100 RCA 90 LAD 50, LCx 90, RCA 50 LAD 90, LCX 90, RCA 100 LMCA 50, RCA 90 LAD 70, RCA 70 LAD 80, RCA 90
Coronary Anatomy (%)+
1
I 10 qid D 0.25lday F 40fday P 40 qid’ M 200 bid*
D 0.257day F 40 day 0 200 qid
Yes
Yes Yes
Angina Angina
P 40 tid’ I 10 qid P 40 tid’ H SC/day D 0.25/day P 40 tid’ Angina
Yes
Dyspnea
H 5OIday I 5 pm
Angina During Test
58 a
AP APIHT
APJMI
APIMI
AP
AP/HT
APIMI
Limiting Symptom
Mean SD
8 9
4
3’
1
Case Diagnosis
Drug Treatment (mg)
Results of Cardiac Output Measurements in Women with Coronary Heart Disease
TABLE Ill
MAXIMAL CARDIAC OUTPUT IN WOMEN-HOSSACK
ET AL
cardiac output. Because of this high correlation (r = 0.90), use of the equation to estimate maximal cardiac output in the 104 normal women is justified for the purpose of defining the normal range in relation to age (that is, f2 standard deviations from the regression line). The estimation of maximal cardiac output in the IO4 women using a regression equation based on maximal observations alone was not feasible because the range of maximal oxygen uptake in the 11 normal women did not encompass the range in the 104 women. The regression equation for maximal oxygen uptake and maximal cardiac output was calculated and the r value was 0.89 and the slope was not significantly different from that of the equation used. Effect of age: In the 104 normal women all variables decreased with increasing age. Maximal oxygen uptake showed the highest correlation with age. In terms of percent change with advancing age, maximal oxygen uptake showed the greatest decrease and stroke volume the least. Most other studies have reported a decrease in maximal oxygen uptake with increasing age.3,10J* Sheffield et a1.,12 using the Bruce protocol, showed a good correlation between age and maximal heart rate, but no relation between age and exercise duration, which reflects oxygen uptake.’ The normal range for heart rate from their study showed a more rapid decrease with increasing age than we found in this study. Comparison with previous studies of normal women: The previous reports of cardiac output measurements during exercise are of interest. Many of these observations were made in well trained athletes and thus do not reflect the cardiac output of an untrained woman. The interpretation of earlier results is further complicated by the use in some studies of indirect methods of cardiac output estimation and in others of observations made during supine or upright bicycle exercise. Astrand et a1.,7 using dye curves for estimation of cardiac output with bicycle exercise, found the mean maximal cardiac output in a group of active young women to be 18.5 liters/min and a stroke volume of 100 ml. Both values are higher than the normal ralues we propose. The values obtained by Kilbom and Astrand,13 in a group of untrained young and middle-aged women and a group of older women, are close to the normal range in our study. Other studies14s15 illustrate the problems in comparing cardiac output values. Raven et a1.14 found values of 27 liters/min in young female runners, but when the arterio-mixed venous oxygen difference was calculated, it was less than 100 ml/liters, which is a very low value and probably an unrealistic value for maximal exertion. The mean arterial-mixed venous oxygen difference of the 11 women in our study was 136 ml/li$er, which is identical to that reported by Kilbom and Astrand.i3 In the study of Astrand et a1.,7 mean arterial-mixed venous oxygen difference was 143 ml/liter which probably reflected the greater physical activity of those persons. Becklake et a1.,15 using bicycle exercise, found that cardiac output increased with age but that heart rate decreased, suggesting that stroke volume must have increased with age. This finding is
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50
25
Bb
A
I
I
I
20
30
40 Age
250
I
I
50
60
I
70
L,,,+r-
70
(years)
Age
(years)
150
C
D
I
Norma' Range
20
I
I
30
40 Age
(years
I
I
I
50
60
70
1
I
20
1
I
30
40
I
50 Age
1
I
60
70
(years)
FIGURE 3. Observed and derived values in women with heart disease. A, values for maximal oxygen uptake in the women with coronary artery disease before (closed circles), and after (open triangles) operation and in women with noncoronary heart disease (open circles) are shown in relation to age. Serial measurements in the same patient are connected by arrows. The normal range from Figure 2A is indicated. B, maximal cardiac output values. The normal range from Figure 28 is indicated. C, maximal heart rate values. The normal range from Figure 2C is indicated. D, maximal stroke volume values. The normal range from Figure 2D is indicated.
clearly at variance with our data, and a problem with the methodology of Becklake et al. was their failure to define adequately maximal exercise performance for each person. Application to women with heart disease: The inclusion of the data of the patients with heart disease illustrates the usefulness and importance of having normal standards for evaluation of exercise results. It also emphasizes the need to take into account changes that normally occur with age when assessing patients. The maximal cardiac output was similar in Patient 1 postoperatively (age 63) and in Patient 10 (age 36); however, the respective percent of the age-predicted normal values was 78 and 67 percent. This value was abnormally low in the younger patient, but a similar absolute value (8.2 liters/min) was within the age-predicted normal range in the postoperative patient. Measurement of Fick cardiac output during exercise gives additional insight into the mechanisms of cardiac impairment. With respect to the preoperative data in the patients with coronary artery disease, only three had a maximal oxygen uptake in the normal range. In Patient 3 maximal cardiac output was at the lower limit of the normal range (75 percent of normal), and the maximal oxygen uptake was relatively well preserved
(80 percent of normal). This woman was a participant in an exercise program and the effects of training are reflected by the wide arterial-mixed venous oxygen difference,16 which contributed to the preservation of maximal oxygen uptake. In only two of the preoperative patients (Patients 4 and 6) was the stroke volume significantly impaired, and both patient’s had the lowest values for cardiac output. Analysis of the postoperative results are of interest and adds to the documentation of the physiologic benefits of successful surgery. In the three cases of complete revascularization (Cases 1 to 3, Table II), there was a significant increase in the percent of average age-predicted normal cardiac output. The mean increase for these three patients was 18 percent. This increase was due mainly to an increase in heart rate. Treatment with beta receptor blocking agents was discontinued at the time of preoperative testing and the heart rate impairment in these cases was a reflection of coronary disease rather than a drug effect. In the evaluation of the patients without coronary disease, the deleterious effects of a rapid ventricular response associated with atria1 fibrillation are illustrated by the two patients (Case 10 and 13, Table IV) with mitral stenosis who had this rhythm disturbance.
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MAXIMAL
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ET AL.
Both had rapid ventricular responses during exercise with significant impairment of stroke volume. The effect of the mitral valve stenosis becomes relatively more important during exercise than at rest because of the limited diastolic filling associated with the rapid heart rate. The deterioration in Patient 10 with the development of atria1 fibrillation is apparent when serial comparisons are made. Several of the patients with mitral stenosis had a high arterial-mixed venous oxygen difference at maximal exercise, a finding reported by others.17 Such data have useful clinical applications, as illustrated by Patient 15. This woman’s symptoms were difficult to evaluate and the decision to treat her surgically or medically was being debated. However, with the knowledge of a relatively normal exercise capacity
and cardiac output, it was possible to delay intervention. Without some tentative guidelines for normal standards, evaluation of the testing results would be difficult. Implications: This study provides for healthy, sedentary women normal standards for age-adjusted values for maximal cardiac output, maximal oxygen uptake, maximal heart rate and maximal stroke volume during treadmill exercise. These data allow values obtained from studies performed in patients to be expressed as a percent of the age-predicted normal value and provide a framework for the evaluation of various interventions. The normal changes that take place with age are emphasized. These normal standards for women complement the previously reported normal values for men.4
References 1. Bruce RA, Kusumi F, Hosmer D. Maximal oxygen intake and nomographic assessment of functional aerobic impairment in cardiovascular disease. Am Heart J 1973;85:546-62. 2. Irving JB, Kusumi F, Bruce RA. Longitudinal variations in maximal oxygen consumption in healthy men. Clin Cardiol 1980;3:1346. 3. Sheppard RJ. World standards of cardiorespiratory performance. Arch Environ Health 1966; 13:664-72. 4. Hossack KF, Bruce RA, Green B, Kuwmi F, DeRouen TA, Trlmble S. Maximal cardiac output during upright exercise: approximate normal standards and variations with coronary heart disease. Am J Cardiol 1980;46:204-12. 5. Bruce RA. Exercise testing of patients with coronary heart disease. Ann Clin Res 1971;3:323-32. 6. Hossack KF, Bruce RA, Green B, Belanger L, Kusumi F. Comparison of results obtained with noninvasive and invasive sympt_om-limitedexercise testing. J Cardiac Rehab 1981: in press. 7. Astrand PO, Cuddy TE, Saftin B, Stenberg J. Cardiac output during submaximal and maximal work. J Appl Physiol 1964;19:26874. 8. Hanson JS, Tabakin BS. Comparison of the circulatory responses to upright exercise in 25 “normal” men and 9 distance runners. l3r Heart J 1965;27:211-9. 9. YcDonough JR, Danielson RA, Wills RE, Vine DL. Maximal cardiac output in patients with cardiac disease. Am J Cardiol 1974;33:
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23-9. 10. Bengtsson C, Vedin JA, Grlmby G, Tibblln G. Maximal work performance test in middle-aged women: results from a population study. Stand J Clin Lab Invest 1978;38:181-8. 11. Drinkwater BL. Physiological responses of women to exercise. Exercise Spot-l Sci Rev 1973; 1: 125-53. 12. Sheffield LT, Maloof JA, Sawyer JA, Roitman 0. Maximal heart rate and treadmill performance of healthy women in relation to age. Circulation_1978;57:79-84. 13. Kllbotn A, Astrand I. Physical training with submaximal intensities in women. II. Effect on cardiac output. Stand J Clin Lab Invest 1971;28:163-75. 14. Raven PB, Drinkwater BL, Harvath SM. Cardiovascular responses of young female track athletes during exercise. Med Sci Sports 1972;13:664-72. 15. Becklake MR, Frank H, Dagenais GR, Ostiguy FL, Guzman CA. Influence of age and sex on exercise cardiac output. J Appl Physiol 1968;20:938-47. 16. Detry JMR, Rousseau M, Vanderborche G, Kusumi F, Brasseur LA, Bruce RA. Increased arteriovenous oxygen difference after physical training in coronary heart disease. Circulation 197 1;44: 109-18. 17. Blackman JR, Rowell LB, Kennedy JW, Twiss RD, Corm RD. Physiological significance of maximal oxygen intake in “pure” mitral stenosis. Circulation 1967;36:497-510.
Volume 47
F. HOSSACK, KUSUMI,
MD
MS
ROBERT A. BRUCE, MD, FACC
Seattle,
Washington
observed normal ranges of age- and weight-adjusted maximal oxygen uptake and age-adjusted maximal heart rate during wbrfghtexercise using the Bruce protocol are shown for 104 asymptomatic women. Cardiac output was measured during upright exercise in 11 normal women with the use of the direct Fick method. On the basis of the relation between oxygen uptake and cardiac output in these 11 women, the cardiac output and stroke volume were estimated by regression in the 104 women to provide normal ranges of age-adjusted values for cardiac output and stroke volume. The potential usefulness of these age-adjusted normal ranges is illustrated by analysis of 21 observations of maximal cardiac output in 16 women with heart disease. The
There is little information on the normal range of cardiac output during maximal exercise in sedentary women. Previous data, based on results of both cross-sectional’ and longitudinal studies,2 showed that maximal oxygen uptake decreases with age in both men and women. An extensive review by Sheppard3 indicated that a decrease in maximal oxygen uptake with advancing age had been reported from various countries. Recently, the ranges for maximal cardiac output, stroke volume, heart rate and oxygen uptake were provided for normal men.4 All four variables decreased with age. Maximal oxygen uptake showed the greatest and stroke volume the least decrease with age. The purpose of this study was to provide normal standards of ageadjusted values for maximal cardiac output, maximal oxygen uptake, maximal heart rate and maximal stroke volume in sedentary women. These normal standards provide a framework for evaluating the results of exercise testing in women with various cardiovascular diseases. Methods Study patients: A group of 104 asymptomatic sedentary women aged 20 to 70 years (mean 42) with no clinical evidence of heart disease performed symp-
From the Divislon of Cardiology, University of Washington, Seattle, Washington. This work was supported by Grants HL 23404 and NH RR-37 from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. Manuscript received October 13, 1980: revised manuscript received December 8.1980, accepted December 18, 1980. Address for reprints: Robert A. Bruce, MD, Division of Cardiology, RG20, University of Washington, Seattle, Washington 98195.
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tom-limited maximal exercise on a treadmill. During exercise, maximal oxygen uptake was measured. Another group of 11normal women aged 28 to 61 years (mean 50.5) underwent symptom-limited exercise testing on a treadmill. During the test, the direct Fick method was used to measure cardiac output at several submaximal work loads and at maximal exercise. These data provided a regression equation of the relation between oxygen uptake and cardiac output for women in our laboratory environment. Sikteen women with a spectrum of cardiac diseases underwent exercise testing with measurement of maximal cardiac output. Nine patients had coronary artery disease, five had valvular heart disease, one had hypertrophic cardiomyopathy and one was studied several years after an episode of adult respiratory distress syndrome. Five of the 16 underwent a second exercise test 6 months to 2 years after the first. In four of the five, the second test was performed after aortocoronary bypass surgery. Noninvasive test: After a preliminary history, physical examination and 12 lead electrocardiogram, each woman underwent an exercise test using the Bruce
The American Journal of CARDIOLOGY
Volume 47
protocol” to measure maximal heart rate and maximal oxygen uptake. Heart rate and rhythm were monitored using a modified V.5 chest lead, and blood pressure was measured with a sphygmomanometer. With the nose firmly occluded, expired air was collected at minute intervals through a mouthpiece and large bore tubes were connected to serial Neoprene@ bags. Subsequent analysis of samples for oxygen content and measurement of gas volumes were performed to calculate oxygen consumption. The methodology and reliability of these measurements were previously reported.’ Invasive test: Before undergoing invasive testing, each woman underwent a symptom-limited maximal exercise test as described. The t.echniques of performing cardiac catheterization and obtaining cardiac output measurements were previously described in detail.4 The study involved placing a Swan-Ganz catheter in the pulmonary artery and cannulating either the radial or the brachial artery. Simultaneous arterial and mixed venous blood samples were taken to measure oxygen content. Mean systemic arterial and mean pulmonary arterial pressures were measured. Observations were made with the subject at rest in the supine and sitting positions and then on several occasions during submaximal exertion and at maximal exercise. Measurements were then made at the 3rd and 5th minutes of recovery with the subject in the sitting position. The measurements of maximal heart rate and maximal oxygen uptake during an invasive exercise test are highly reproducible when compared with measurements made during a noninvasive exercise test.6 Cardiac output (literslmin) was obtained using the direct Fick method. Heart rate (beats/min) was obtained from 6 second strips of the electrocardiogram. Stroke volume (ml) was obtained by dividing cardiac output (ml/min) by heart rate. Pressure-rate product was the product of mean systemic arterial pressure and heart rate X 10e2.
5-
STE = 0.83 I
”
/ 1-d_ 0
0.5
I .o
I.5
48
m_m_,m~_p.t.I 20
25
30
i/O, (Ilters/mu7) FIGURE 1. The measurements of oxygen uptake (i/O,) (liters/min) and corresponding values of cardiac output (litersimin) are plotted for the 48 observations in the 11 normal women. There is a good correlation over the measured range. SEE = standard error of the estimate.
tions made during exercise gression equation is: Cardiac output (liters/min)
in these
women.
The re-
= 4.07 + 4.72 [oxygen uptake
(liters/min)].
The physical characteristics of the 104 normal women in whom measurements of maximal oxygen uptake were made are shown in Table II. Approximately 20 percent of these women smoked. Figure 2A plots the observed values of maximal oxygen uptake, corrected for weight, against age. The 95 percent confidence intervals are shown f2 standard deviations. At age 20, the normal range is 34.7 f 7.2 ml/kg per min and it decreases to 18.0 f 7.2 ml/kg per min at age 70. Maximal cardiac output was estimated by regression from the measured values of oxygen uptake (liters/min) using the equation from the 11 normal women (Fig. 2). The values are plotted with respect to age in Figure 2B. Maximal heart rate is
Results Normal women: Table I lists the physical characteristics and the results of values obtained during measurement of maximal cardiac output in the 11 normal women. Figure 1 plots the measurements of oxygen uptake and cardiac output for the 48 observa-
TABLE I Physical and Hemodynamic Variables in 11 Normal Women i/O*
Age Case
(yr)
Wt
Ht
max
max
HR max
SV max
CaOp
cvop
aCiOpD max
PsA max
& max
ta FAI
:
Sed
45 52
56.6 63.2
163 166
24.04 28.81
-12 -3
12.19 12.43
158 194
64
181 193
46
108 147
137 109
27
3 4
Sed Sed
43 ::
65.0 58.2
155 161
26.66 24.34
-1 1;
11.52 10.78
194 188
:3 63
212 173
;:
t:
151 132
154
;“o 15
z
Sed
69.0 74.1
167 161
21.42 26.72
-15
11.71 12.89
178 188
66
198 193
50
136 143
140 125
z”o
: 9
Sed Sed
z z:
66.0 50.9 66.0
166 158 165
23.74 28.72 20.77
-31 -15
10.94 13.93 10.25
164 184 166
81 ;:
160 188 171
42 52 53
118 136 118
1:: 102
f
z:
64.3 55.5
160 168
47.72 24.77
-G
14.36 11.98
200 176
:: 76
202 187
54 31
133 171
132 152
:: 25
50.5 9.3
62.6 6.7
163 4.1
27.07 7.34
-11 13
12.09 1.27
181 14
70 9
187 15
51 10
136 18
129 21
26 7
::
Mean SD
Activity
Act Sed
6
Y
Act = active; aa& max = arterial-mixed venous oxygen difference at maximal cardiac output (ml/liter): Ca02 = arterial oxygen content (ml/liter); C~OBZ mixed venous oxygen content (ml/liter); FAI = functional aerobic impairment (%); HR max = maximal heart rate (beats/min); Ht = height (cm); PPA m = mea” puimnary &erial pressure at the end of exercise (mm k!@; P% maX = m&m systemic arterial pressure at the end of exercise (mm Hg); Q Fax = maximal cardiac output (litersimin); SD = standard deviation: Sed = sedentary; SV max = stroke volume at maximal cardiac output (ml); VOp max = maximal oxygen uptake (ml/kg per min); Wt = weight (kg).
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The American Journal of CARDIOLOGY
Volume 47
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MAXIMAL
CARDIAC
TABLE
II
OUTPUT IN WOMEN-HOSSACK
ET AL.
plotted against age in Figure 2C. Estimated stroke volume was obtained by dividing estimated cardiac output by maximal heart rate. These values are plotted against age in Figure 2D. Women with heart disease: The physical characteristics and the results of invasive exercise testing are shown for the patients with coronary heart disease and those with other cardiovascular diagnoses in Tables III and IV. Four of the patients had follow-up tests after coronary bypass surgery and the results are shown separately in Table III. In Figure 3, the respective values for maximal oxygen uptake, cardiac output, heart rate and stroke volume are plotted for these patients and the normal ranges are shown for reference.
Physical Characteristics and Exercise Responses of 104 Asymptomatic Sedentary Women (mean values f standard deviation)
Age Range
n
2034 35 49 5070
HR i/O* max Smoking max (%) (beatsimin) (ml/kg per min)
(Z,
(Z
22 59.2 165.2 f 5.9 f 5.0 59 62.8 166.4 & 10.0 f 6.2 23 64.5 166.3 f 11.1 f 7.0
22
Total 104 62.5 166.2 group f 10.0 f 6.1
22
22 21
192 f 11 180 f 11 176 f 12
32.3 f 5.9 26.7 + 3.5 24.5 f 3.1
181 f 13
27.4 f 4.9
Discussion Estimated maximal cardiac output in normal women: This study has confirmed the previously re-
HR max = maximal heart rate; Ht = height; n = number of observations; Wt = weight; VOa max = maximal oxygen uptake.
ported4>7-s high correlation
between
oxygen uptake
and
6
A 50
*5r
n=104
n=104
"Z41.3~0.333,
yzl5.0-0.071
I
r=,46
I
------4SO
40
30
20
60
50 Age
70
Iyears) I
20
C
100
I
40
I
50 Age (years)
I
I
60
70
D
250
Fz
30
‘y
n=104
I
y’206-0.5’3% r=.46
n=104
~‘74-0.172~ r z.20
30
I
20
t I
I
30
40
I
50 Age iyears)
I
I
I
60
70
20
I
30
I
40
I
50 Age (years)
I
6d
J
70
FIGURE 2. Derived values for observed and maximal cardiovascular variables in iO4 normal women. A, observed age- and weight-adjusted value of maximal oxygen uptake (VOa max). The regression line is shown and the normal range indicated by f2 standard deviations (SD). The standard deviation for oxygen uptake is 3.59 ml/(kg min). B, estimated age-adjusted values of maximal cardiac output (Q max). The standard deviation for cardiac output is 1.35 liters/min. C, observed age-adjusted values of maximal heart rate (HR max). The standard deviation for heart rate is 14 beats/min. D, estimated age-adjusted values of maximal stroke volume (SV). The standard deviation for stroke volume is 8 ml.
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The American Journal of CARDIOLOGY
Volume 47
No No No 60 9
64 :; 159 5
152 162 164
158
159 5
158 157
167
155
159
164
152 162
158
Ht (cm)
13.05 4.68
20.29 15.74
11.70
64.7 3.9
60.9 62.4 69.8
65.9
8.15
11.54
9.02
10.79 20.50
15.94 5.54
12.91 23.95 11.67
15.23
Postoperative
64.4 5.5
61.4 60.2
68.0
54.0
67.7
72.7
65.2 62.6
68.0
9.76
i/o, max
Preoperative
(G)
74 14
9”: 61
75
58 16
71
80
53
33
59
48
Z;:
47
% NVO,
7.79 2.23
7.56 10.38 4.96
8.25
6.89 2.04
10.60 a.54
7.04
4.19
6.31
5.13
5.45 8.73
6.08
b max
72 17
72 89 48
78
63 16
91 78
65
37
61
50
52 75
57
% ND
132 28
106 171 122
127
117 20
140 128
114
102
115
127
1:;
97
HR max
77 14
63 96 74
76
68 11
79 74
67
58
69
77
50 80
57
% NHR
60 13
71 61 41
65
59 12
76 67
62
41
55
40
65 61
63
SV max
94 20
113 :;
103
92 18 -__.__
116 104
97
63
a8
64
103 92
99
% NSV
195 25
202 195 219
160
181 17
175 184
154
171
182
187
208 202
164
CaOz
62 25
:7” 55
38
61 11
57 73
41
66
58
57
79 55
55
CvOz
133 26
104 144 164
122
120 13
120 111
113
105
124
128
129 147
109
avOzD
l
Treatment with beta receptor blocking agents was discontinued at least 48 hours before testing. + Percent narrowing of luminal diameter. AP = angina pectoris; avOOpD= arterial-mixed venous oxygen difference (ml/liter); bid = twice daily: C = complete revascularization; CaOz = arterial oxygen content (ml/liter); CvOz = mixed venous oxygen content (ml/liter); D = digoxin; F = furosemide; HR max = heart rate at maximal cardiac output (beatsjmin); H = hydrochlorothiazide; HT = hypertension; I = Isordil; IC = incomplete revascularization; LAD = left anterior descending coronary artery; LCx = left circumflex coronary artery; LMCA = left main coronary artery; M = metoprolol; Ml = myocardial infarction; %NHR = percent of age-predicted maximal heart rate; %NQ = percent of age-predicted maximal cardiac output; %NSV = percent of age-predicted maximal stroke volume: %NVOz = percent of age-predicted maximal oxygen uptake: P = propranolol; pm = as required; Q = quinidine; Q max = maximal observed cardiac output (liters/min); qid = four times daily: RCA = right coronary artery; SD = standard deviation: SV max = stroke volume at maximal cardiac output; tid = three times daily; VOz max = oxygen uptake at maximal cardiac output (ml/kg body weight per min).
Mean SD
Fatigue Fatigue Dyspnea
c c IC
No
48 57
2 3 4
Fatigue
LAD 60 LAD 50
58
50
65
63
D 0.25lday H 25Iday None H 25Iday None
Yes Yes
Yes
No
Yes
67
64 47
62
Age (yr)
c
Dyspnea Angina
Dyspnea
Dyspnea
Angina
LAD 100, LCX 90, RCA 100 RCA 90 LAD 50, LCx 90, RCA 50 LAD 90, LCX 90, RCA 100 LMCA 50, RCA 90 LAD 70, RCA 70 LAD 80, RCA 90
Coronary Anatomy (%)+
1
I 10 qid D 0.25lday F 40fday P 40 qid’ M 200 bid*
D 0.257day F 40 day 0 200 qid
Yes
Yes Yes
Angina Angina
P 40 tid’ I 10 qid P 40 tid’ H SC/day D 0.25/day P 40 tid’ Angina
Yes
Dyspnea
H 5OIday I 5 pm
Angina During Test
58 a
AP APIHT
APJMI
APIMI
AP
AP/HT
APIMI
Limiting Symptom
Mean SD
8 9
4
3’
1
Case Diagnosis
Drug Treatment (mg)
Results of Cardiac Output Measurements in Women with Coronary Heart Disease
TABLE Ill
MAXIMAL CARDIAC OUTPUT IN WOMEN-HOSSACK
ET AL
cardiac output. Because of this high correlation (r = 0.90), use of the equation to estimate maximal cardiac output in the 104 normal women is justified for the purpose of defining the normal range in relation to age (that is, f2 standard deviations from the regression line). The estimation of maximal cardiac output in the IO4 women using a regression equation based on maximal observations alone was not feasible because the range of maximal oxygen uptake in the 11 normal women did not encompass the range in the 104 women. The regression equation for maximal oxygen uptake and maximal cardiac output was calculated and the r value was 0.89 and the slope was not significantly different from that of the equation used. Effect of age: In the 104 normal women all variables decreased with increasing age. Maximal oxygen uptake showed the highest correlation with age. In terms of percent change with advancing age, maximal oxygen uptake showed the greatest decrease and stroke volume the least. Most other studies have reported a decrease in maximal oxygen uptake with increasing age.3,10J* Sheffield et a1.,12 using the Bruce protocol, showed a good correlation between age and maximal heart rate, but no relation between age and exercise duration, which reflects oxygen uptake.’ The normal range for heart rate from their study showed a more rapid decrease with increasing age than we found in this study. Comparison with previous studies of normal women: The previous reports of cardiac output measurements during exercise are of interest. Many of these observations were made in well trained athletes and thus do not reflect the cardiac output of an untrained woman. The interpretation of earlier results is further complicated by the use in some studies of indirect methods of cardiac output estimation and in others of observations made during supine or upright bicycle exercise. Astrand et a1.,7 using dye curves for estimation of cardiac output with bicycle exercise, found the mean maximal cardiac output in a group of active young women to be 18.5 liters/min and a stroke volume of 100 ml. Both values are higher than the normal ralues we propose. The values obtained by Kilbom and Astrand,13 in a group of untrained young and middle-aged women and a group of older women, are close to the normal range in our study. Other studies14s15 illustrate the problems in comparing cardiac output values. Raven et a1.14 found values of 27 liters/min in young female runners, but when the arterio-mixed venous oxygen difference was calculated, it was less than 100 ml/liters, which is a very low value and probably an unrealistic value for maximal exertion. The mean arterial-mixed venous oxygen difference of the 11 women in our study was 136 ml/li$er, which is identical to that reported by Kilbom and Astrand.i3 In the study of Astrand et a1.,7 mean arterial-mixed venous oxygen difference was 143 ml/liter which probably reflected the greater physical activity of those persons. Becklake et a1.,15 using bicycle exercise, found that cardiac output increased with age but that heart rate decreased, suggesting that stroke volume must have increased with age. This finding is
1084
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The American Journal of CARDIOLOGY
Volume 47
50
25
Bb
A
I
I
I
20
30
40 Age
250
I
I
50
60
I
70
L,,,+r-
70
(years)
Age
(years)
150
C
D
I
Norma' Range
20
I
I
30
40 Age
(years
I
I
I
50
60
70
1
I
20
1
I
30
40
I
50 Age
1
I
60
70
(years)
FIGURE 3. Observed and derived values in women with heart disease. A, values for maximal oxygen uptake in the women with coronary artery disease before (closed circles), and after (open triangles) operation and in women with noncoronary heart disease (open circles) are shown in relation to age. Serial measurements in the same patient are connected by arrows. The normal range from Figure 2A is indicated. B, maximal cardiac output values. The normal range from Figure 28 is indicated. C, maximal heart rate values. The normal range from Figure 2C is indicated. D, maximal stroke volume values. The normal range from Figure 2D is indicated.
clearly at variance with our data, and a problem with the methodology of Becklake et al. was their failure to define adequately maximal exercise performance for each person. Application to women with heart disease: The inclusion of the data of the patients with heart disease illustrates the usefulness and importance of having normal standards for evaluation of exercise results. It also emphasizes the need to take into account changes that normally occur with age when assessing patients. The maximal cardiac output was similar in Patient 1 postoperatively (age 63) and in Patient 10 (age 36); however, the respective percent of the age-predicted normal values was 78 and 67 percent. This value was abnormally low in the younger patient, but a similar absolute value (8.2 liters/min) was within the age-predicted normal range in the postoperative patient. Measurement of Fick cardiac output during exercise gives additional insight into the mechanisms of cardiac impairment. With respect to the preoperative data in the patients with coronary artery disease, only three had a maximal oxygen uptake in the normal range. In Patient 3 maximal cardiac output was at the lower limit of the normal range (75 percent of normal), and the maximal oxygen uptake was relatively well preserved
(80 percent of normal). This woman was a participant in an exercise program and the effects of training are reflected by the wide arterial-mixed venous oxygen difference,16 which contributed to the preservation of maximal oxygen uptake. In only two of the preoperative patients (Patients 4 and 6) was the stroke volume significantly impaired, and both patient’s had the lowest values for cardiac output. Analysis of the postoperative results are of interest and adds to the documentation of the physiologic benefits of successful surgery. In the three cases of complete revascularization (Cases 1 to 3, Table II), there was a significant increase in the percent of average age-predicted normal cardiac output. The mean increase for these three patients was 18 percent. This increase was due mainly to an increase in heart rate. Treatment with beta receptor blocking agents was discontinued at the time of preoperative testing and the heart rate impairment in these cases was a reflection of coronary disease rather than a drug effect. In the evaluation of the patients without coronary disease, the deleterious effects of a rapid ventricular response associated with atria1 fibrillation are illustrated by the two patients (Case 10 and 13, Table IV) with mitral stenosis who had this rhythm disturbance.
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The American Journal of CARDIOLOGY
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MAXIMAL
CARDIAC
OUTPUT IN WOMEN-HOSSACK
ET AL.
Both had rapid ventricular responses during exercise with significant impairment of stroke volume. The effect of the mitral valve stenosis becomes relatively more important during exercise than at rest because of the limited diastolic filling associated with the rapid heart rate. The deterioration in Patient 10 with the development of atria1 fibrillation is apparent when serial comparisons are made. Several of the patients with mitral stenosis had a high arterial-mixed venous oxygen difference at maximal exercise, a finding reported by others.17 Such data have useful clinical applications, as illustrated by Patient 15. This woman’s symptoms were difficult to evaluate and the decision to treat her surgically or medically was being debated. However, with the knowledge of a relatively normal exercise capacity
and cardiac output, it was possible to delay intervention. Without some tentative guidelines for normal standards, evaluation of the testing results would be difficult. Implications: This study provides for healthy, sedentary women normal standards for age-adjusted values for maximal cardiac output, maximal oxygen uptake, maximal heart rate and maximal stroke volume during treadmill exercise. These data allow values obtained from studies performed in patients to be expressed as a percent of the age-predicted normal value and provide a framework for the evaluation of various interventions. The normal changes that take place with age are emphasized. These normal standards for women complement the previously reported normal values for men.4
References 1. Bruce RA, Kusumi F, Hosmer D. Maximal oxygen intake and nomographic assessment of functional aerobic impairment in cardiovascular disease. Am Heart J 1973;85:546-62. 2. Irving JB, Kusumi F, Bruce RA. Longitudinal variations in maximal oxygen consumption in healthy men. Clin Cardiol 1980;3:1346. 3. Sheppard RJ. World standards of cardiorespiratory performance. Arch Environ Health 1966; 13:664-72. 4. Hossack KF, Bruce RA, Green B, Kuwmi F, DeRouen TA, Trlmble S. Maximal cardiac output during upright exercise: approximate normal standards and variations with coronary heart disease. Am J Cardiol 1980;46:204-12. 5. Bruce RA. Exercise testing of patients with coronary heart disease. Ann Clin Res 1971;3:323-32. 6. Hossack KF, Bruce RA, Green B, Belanger L, Kusumi F. Comparison of results obtained with noninvasive and invasive sympt_om-limitedexercise testing. J Cardiac Rehab 1981: in press. 7. Astrand PO, Cuddy TE, Saftin B, Stenberg J. Cardiac output during submaximal and maximal work. J Appl Physiol 1964;19:26874. 8. Hanson JS, Tabakin BS. Comparison of the circulatory responses to upright exercise in 25 “normal” men and 9 distance runners. l3r Heart J 1965;27:211-9. 9. YcDonough JR, Danielson RA, Wills RE, Vine DL. Maximal cardiac output in patients with cardiac disease. Am J Cardiol 1974;33:
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23-9. 10. Bengtsson C, Vedin JA, Grlmby G, Tibblln G. Maximal work performance test in middle-aged women: results from a population study. Stand J Clin Lab Invest 1978;38:181-8. 11. Drinkwater BL. Physiological responses of women to exercise. Exercise Spot-l Sci Rev 1973; 1: 125-53. 12. Sheffield LT, Maloof JA, Sawyer JA, Roitman 0. Maximal heart rate and treadmill performance of healthy women in relation to age. Circulation_1978;57:79-84. 13. Kllbotn A, Astrand I. Physical training with submaximal intensities in women. II. Effect on cardiac output. Stand J Clin Lab Invest 1971;28:163-75. 14. Raven PB, Drinkwater BL, Harvath SM. Cardiovascular responses of young female track athletes during exercise. Med Sci Sports 1972;13:664-72. 15. Becklake MR, Frank H, Dagenais GR, Ostiguy FL, Guzman CA. Influence of age and sex on exercise cardiac output. J Appl Physiol 1968;20:938-47. 16. Detry JMR, Rousseau M, Vanderborche G, Kusumi F, Brasseur LA, Bruce RA. Increased arteriovenous oxygen difference after physical training in coronary heart disease. Circulation 197 1;44: 109-18. 17. Blackman JR, Rowell LB, Kennedy JW, Twiss RD, Corm RD. Physiological significance of maximal oxygen intake in “pure” mitral stenosis. Circulation 1967;36:497-510.
Volume 47