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Detecting the threshold of anaerobic metabolism in cardiac patients during exercise
Detecting the Threshold of Anaerobic Metabolism in Cardiac Patients During Exercise* KARLMAN WASSERMAN,M.D.~ and MALCOLM B. MCILROY,
M.D.$
Palo Alto and San Francisco, California
H
ILL ET AL.l have shown that large quantities of lactic acid form when muscles lack oxygen. Formation of lactic acid during exercise permits oxidation to proceed anaerobically and accounts for most of the oxygen debt which Conseaccumulates during heavy exercise.2J quently, measurement of accumulated lactate has been used as an index of anaerobic metabolism.4s5 Because of the relatively high dissociation constant of lactic acid, virtually all of it is ionized in the physiologic range of pH. Therefore, when lactic acid is produced during anaerobic metabolism, it is completely buffered in the blood, and the level of bicarbonate is reduced,6-8 as in other metabolic acidoses. Pilcher and associates9 have shown that patients in acute heart failure have arterial pH values that are extraordinarily low, and Huckabeelo has reported an increased concentration of lactate in the blood of patients with circulatory failure. Harrison and Pilcher” found that patients with heart failure produced more carbon dioxide (CO*) during exercise than normal subjects performing the same exercise. Consequently, their gas exchange ratio (CO2 production to 02 consumption) was increased. They concluded that the excess CO2 could not be the end product of aerobic metabolism and must be evolved from CO2 stores. They reasoned that the excess CO2 was released from bicarbonate when acids formed during anaerobic metabolism were buffered : TISSUES 02
t-1
I
BLOOD 02
c---
1
While Harrison and Pilcher did not detect significant increases in the gas exchange ratio (R)$ of their normal subjects at the low loads they studied, metabolic acidosis does develop in normal subjects during work of greater intensity and R increases.‘j-8 The onset of anaerobic metabolism during exercise can thus be detected in three ways: (1) as an increase in the lactate concentration in blood, (2) as a decrease in arterial blood bicarbonate and pH and (3) as an increase in the In evaluatrespiratory gas exchange ratio (R). ing cardiovascular performance during work, a method which measures R has the advantage of avoiding blood sampling. Furthermore, equipment which is available in many cardiopulmonary laboratories can be used to measure R breath by breath. Thus, it is possible for the examiner to detect the threshold of anaerobic metabolism during the work test and to avoid exhaustive and potentially dangerous exercise of patients with heart disease under study. A method for the evaluation of cardiac performance by analysis of R breath by breath is reviewed in this paper. METHODS The method used has been described by Naimark and associates.’ It involves a standardized exercise test in which the subject pedals an ergometer or walks on a treadmill for four minutes at each of several graded workioads. Heart rate, minute ventilation, oxygen consumpti,on and end-tidal CO2 and Nt concentrations are measured. The respiratory gas exchange ratio can be calcuiated from the end-tidal gas
LUNGS __
02
+
Metabolic
j --t Lactic acid + NaHCOg + Na lactate f Hz0 + COZ-,+ p con --,+
$R
CO2 (excess) co*
=
CO2 production/Oz
consumption
=
+I,,,/
eo? = pulmonary respiratory quotient.
* From the Pulmonary Function Laboratory, Department of Medicine, Stanford University School of Medicine, Palo Alto, t and the Cardiovascular Research Institute, University of California Medical Center, San Francisco, Calif. 1 This investigation was supported in whole by U. S. Public Health Service Research Grants HE 06591 and HE 06285 from the National Institutes of Health. 844
THE AMERICANJOURNAL OF CARDIOLOOY
Anaerobic
Metabolism
1.0 R
F’N2
1.1 -
,.o-
1.2
-P.O-
13
-X0-
20
3.0
40
5:0
do
EN0 TIDALCOP W
do
FIG. 1. Nomogram for determining R from end-tidal NZ and COZ. FINKequals inspired NZconcentration. concentrations, using the following equation: R=
FACO~ 1.26 FAN2 - 1 + FAN2
where F,COz = the end-tidal COZ concentration and FAN2 = the end-tidal N2 concentration. This equation is derived from the alveolar ventilation and alveolar gas equations.7J2 R can be determined quickly by reference to a nomogram calculated from this equation (Fig. 1). RESULTS An example of the tracings of Nz, COs, heart rate and minute ventilation for the last 30 seconds of exercise at each workload during the test is shown in Figure 2. The values of R were determined from the nomogram. It will be seen that the increase in R is evident principally as a decrease in the end-tidal Nz concentration. When R, during the last 30 seconds of each workload, is plotted against oxygen consumption, a sigmoid curve is usually obtained (Fig. The steepest part of this curve indicates the 3). VOLUME14, DECEMBER1964
During
Exercise
845
level of oxygen consumption at which anaerobic metabolism becomes important, and we call this the “threshold” of anaerobic metabolism. It corresponds to the point at which the concentration of bicarbonate in the arterial blood decreases and the concentration of lactate rises.‘** Naimark et al. 7 found the threshold of anaerobic metabolism to be at a level of oxygen consumption of about 1.2 L./min. in normal sedentary men and about 0.8 in normal sedentary women. They also found that R increased at lower levels of work in patients with heart disease. The results of exercise tests in which the threshold of anaerobic metabolism was measured in 37 patients with heart disease are shown in Figure 4. The level of oxygen consumption at which the A R-Go, curve showed the steepest slope (anaerobic threshold) has been plotted in patients with different types of heart disease. In addition, the functional limitation of the patient is noted according to the New York Heart Association classification. The relation between the threshold of anaerobic metabolism and the “wedge” pressures at rest are plotted in In these patients patients with mitral stenosis. the discrepancies between the level of “wedge” pressure and the severity of symptoms are as numerous as those between the threshold of anaerobic metabolism and symptoms. This is not surprising in view of the multiplicity of factors determining exercise tolerance. In the other groups, only the severity of symptoms is In this limited series, the patients with shown. the less severe symptoms had higher thresholds of anaerobic metabolism. ILLUSTRATIVE CASES The clinical usefulnessof determining the threshold
of anaerobic metabolism is illustrated by the following case histories. CASE 1. Acromegaly. A 25 year old male insurance salesman was admitted to Stanford University Hospital, Palo Alto in May 1962 for evaluation of cardiomegaly. His past history revealed that he was the product of a normal delivery and had frequent colds in infancy. At the age of 14 months he was admitted to the hospital for the evaluation of hirsutism. At the age of 3 years he had a cardiac arrest during a tonsillectomy and required artificial respiration. At 7 years of age he was admitted to the hospital with an attack of lobar pneumonia, and a heart murmur was heard for the first time. Digitalis was started at this time. At the age of 14 he was in the hospital again because of the onset of ankle edema. Hirsutism, marked muscular development and a systolic murmur of variable quality, loudness and duration were
846
Wasserman 870
and McIlroy //oo
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i!
07.m
aa
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i
’
FIG. 2. End-tidal Nt and CO2 concentrations, heart rate and ventilation rate during graded exercise. 02 consumption and R are noted on top. The anaerobic threshold is between 1,100 and 1,385 ml. Oz/min. noted. A chest roentgenogram was interpreted as showing slight left ventricular hypertrophy. Circulation time, venous pressure and arterial blood pressure were normal. The electrocardiogram was normal except for evidence of digitalis effect. The drug was stopped at this time. At the age of 16 he was admitted to the hospital for cardiac catheterization. Normal intracardiac pressures and normal arterial oxygen saturation were found, and there was no evidence of intracardiac shunting. The cardiac output was increased, measurHe was cautioned against ing 6.5 L./min./Ms. overexertion, although the precise cardiac defect was not clear. At the age of 22 he was investigated again because of three episodes of hemoptysis. The hemoptysis was mild and associated with prolonged episodes of coughing. The heart was found to be enlarged, and there was a loud sound of pulmonary valve closure. An early systolic murmur was heard along the left sternal edge, and purplish mottling of the lower legs was noticed. Arterial and venous blood pressures were normal; hematocrit was 55 per cent. The chest x-ray film showed biventricular enlargement. The results of a second cardiac catheterization at this time were normal. The cardiac output was
4 L./min./M2. There was no change in the patient’s clinical condition in the next three years. The only symptom was mild intermittent ankle edema which responded to treatment with chlorothiazide. During the present admission there was no exertional dyspnea, and the electrocardiogram was normal, as were the third cardiac catheterization findings, except for the high cardiac output noted on the previous occasions. The cardiac output on this occasion was 7 L./min./Ms., with a stroke volume of 152 ml. The total blood volume was also increased at 4.3 L./MZ. Both the red cell mass and the (predicted, 2.5). plasma volume were increased. An extensive evaluation of the erythropoietic, endocrine, renal, skeletal and metabolic systems did not reveal the cause of the patient’s enlarged heart and high cardiac output. The patient exercised on a treadmill and was found to have a threshold of anaerobic metabolism of 3 L. Op/min. in contrast to the values of about 1.2 L./min. in untrained normal men. The patient’s heart rate reached only 138 during this exercise test, and linear extrapolation of his heart rate response gave a value for the oxygen consumption of 4.6 L./min. at a heart rate of 170. These measurements are similar to those seen in well trained athletes. The only hormone assay THE
AMERICAN
JOURNAL
OF CARDIOLOGY
Anaerobic
Metabolism
During
Exercise
1.0
0.9,
R
0.0
0.7
Fm. 3. The chanae in R and bicarbonate from rest during uninterrupted graded ergometer exercise in an asymptomatic 20 year old boy with a ventricular septal defect. which proved to be abnormal in this patient was that of growth hormone. The provisional diagnosis was that the patient had an unusual variant of acromegaly, possibly involving only the cardiovascular and muscular systems. The measurement of the threshold of anaerobic metabolism in this patient gave the clue to his supernormal exercise performance. CASE 2. Mitral stenosis. A 24 year old married woman was admitted to the hospital for evaluation of a heart murmur. Six weeks before, she had become short of breath and coughed up blood-tinged sputum while taking swimming lessons. She also noted chest pain and fatigue. Chest x-ray films showed cardiomegaly and evidence of pulmonary edema. She was treated with digoxin, chlorothiazide and penicillin. She improved with thii therapy; but when admitted for evaluation, she complained of dyspnea on mild exertion, fatigue and orthopnea and required two pillows at night. Her past history revealed that she had been slightly short of breath on exertion during childhood. She had had two pregnancies which she tolerated well except for some dyspnea and orthopnea during the second one. There was no history of previous rheumatic fever. The physical findings were normal except for the heart, which was slightly enlarged. A diastolic thrill was felt at the apex. There was a grade 4/6 harsh
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diastolic murmur, heard best between the apex and left lower sternal border throughout ,diastole with presystolic accentuation. The electrocardiogram was normal. Chest x-ray films showed no overall cardiac enlargement, although the left atrium appeared to be enlarged. Cardiac catheterization showed a mean pulmonary artery wedge pressure of 14 mm. Hg, with a cardiac output of 4.3 L./min. During exercise (oxygen consumption of 566 ml./min., with a heart rate of 150/ min.) her cardiac output increased to 5.8 L./min., while the mean pulmonary artery wedge pressure increased to 36 mm. Hg. Pulmonary vascular resistance was calculated to be normal. The mitral valve area was calculated to be 1.25 sq. cm. These results were interpreted as showing moderate mitral stenosis. Because of her severe symptoms, plans were made for surgical correction at an early date. Treadmill exercise studies before surgery and after optimal medical management revealed that this patient’s anaerobic threshold was between 550 and 620 ml. of oxygen/mm This is a low value and suggested that this patient had a reduced capacity for exercise without developing a metabolic acidosis. At surgery, severe mitral stenosis without calcification of the valve was found. The mitral valve orifice barely admitted the tip of the surgeon’s finger. The results of the exercise studies in thii patient were in keeping with her symptoms and seemed to give a better indication of
Wasserman and McIlroy
848
0 0
A
:
00
A
0.
I-
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0
0 f+
.
.
A
A
:
B
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0
00
A L
UITRAL
SrERosls
-I
,-
FIG. 4.
Threshold of anaerobic metabolism in 37 patients with heart disease.
the severity of her lesion than the resting cardiac catheterization data from which the valve area was calculated. CASE 3. Mitral insu&%iency. A 41 year old man was admitted to the hospital for the evaluation of a heart murmur. The murmur was first discovered eight years before when he applied for life insurance. He remained asymptomatic until 18 months before admission, when he began to have chest pain unrelated to exertion and increasing exertional dyspnea. His physician prescribed bed rest, a low salt diet, digitalis and diuretics. With this regimen the patient was symptom-free, having shortness of breath only after heavy drinking or hard exercise. There was no cough, hemoptysis, edema nor cyanosis and no past history of rheumatic fever. On physikal examination the heart was found to be enlarged, with a loud, blowing systolic murmur best heard at the apex and radiating to the axilla. There was no diastolic murmur, and the cardiac rhythm
was regular. The electrocardiogram was abnormal and showed prolonged A-V conduction with intraventricular conduction delay, large voltage in the left precordial leads suggesting left ventricular hypertrophy, and digitalis effect. Chest x-ray films showed mild left ventricular and possible left atria1 enlargement suggestive of mitral valve disease. Cardiac catheterization showed a cardiac output of 5.6 L./min., with a v wave in the “wedge” pressure of 43, a y of 14 and a mean pressure of 21 mm. Hg. With exercise during cardiac catheterization (90, = 795 ml./min. and heart rate = 98), the cardiac output increased to 7.3 L./min., while the wedge pressure increased to a mean of 54 mm. Hg with a v wave of 88. It was concluded that the patient had a marked degree of mitral insufficiency. Exercise studits on the treadmill showed normal results. The patients’ anaerobic threshold was about 1.3 L./min. VO,. The highest oxygen consumption at which the patient exercised was 1.59 L./min. (heart THE AMERICAN JOURNALOF CARDIOLOGY
Anaerobic Metabolism During Exercise
849
1.0
FIG. 5. The reproducibility of effect of workload on R measured during continuous exercise. The subject is exercised between each of the three series at work loads less than 800 ml./min. until a steady state in R is reached (recovery exercise). This required approximately 10 minutes. The numbers indicate the order of the tests.
0.9
R
0.8
I
I
400
800
I I200
I
I
1600
PO00
QO, (ML/M/N - StPD) rate 125). These results were inconsistent with the interpretation of the cardiac catheterization data but were in keeping with the patient’s relative lack of symptoms. At surgery a cleft was found in the aortic leaflet of the mitral valve, and the chordae tendineae appeared normal.
DISCUSSION The cases presented show the type of information that can be obtained from exercise tests in which the threshold of anaerobic metabolism is determined. The workload at which metabolic acidosis develops during exercise can be seen as the exercise test is being performed, and it is unnecessary to ask the patient to exercise until exhausted. An awareness of the changes in R during the test makes it possible to choose appropriate loads for the subject, and the discomfort of blood sampling is avoided. The results obtained provide an objective measure of an aspect of exercise performance which supplements the clinical and hemodynamic data. The test can be repeated at intervals to follow the patient’s progress. To demonstrate that the observed changes in R are not due to the duration of exercise or the total energy expended, we repeated the work test (ergometer exercise) three times without stopping following a 10 minute “warm-up” VOLUME
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DECEMBER
1964
(Fig. 5). Between each test the subject exercised continuously for about 10 minutes at a workload below the “knee” of the A R-30, curve-“recovery exercise”.13 Newman et a1.14 have shown that the rate of removal of lactic acid from the blood is more rapid if the subject exercises at a light load instead of resting during the recovery period. This also permits a more rapid recovery of R after work. The three R decreased when R-v,, curves were similar. the workload was reduced, despite the continuaFurthermore, the threshold of tion of exercise. anaerobic metabolism was approximately the same in the three exercise tests. This study shows that the R-Oo, curve was independent of the cumulative effects of a period of exercise lasting one and a half hours. Effect of Hyperventilation on R: Factors other than metabolic acidosis which may cause R to increase have been discussed elsewhere.’ The Its effect most troublesome is hyperventilation. on R is transientI and is also less during exercise when the rate of oxygen consumption is increased. We have calculated the order of magnitude of the increase in R caused by hyperFigure 6 shows the ventilation during exercise. change in R at various oxygen consumptions for different degrees of hyperventilation measured
Wasserman
850 +AR 0.4
-Ahco, 0.:
0.2
0.1
l
voptMLfMIn-
PlPD)
FIG. 6. The change in R at various 02 consumptions after two minutes of hyperventilation. The curves for hypoventilation are the same except the signs for AR and P*COz are reversed.
as decrease in alveolar PcoZ. We have arbitrarily assumed a period of hyperventilation lasting two minutes and used the dissociation curve of the CO2 stores in the body and the dissociation rate data of Fahri and Rahn.15 While their measurements were made on dogs, the values for the decrease in CO2 stores per kilogram of body weight for each millimeter of Hg reduction in alveolar CO2 tension are similar to those determined by Vance and Fowler in man.16 It can be seen from Figure 6 that hyperventilation increases R most at low levels of oxygen consumption. The one factor not considered in this calculation is the increase in cardiac output that occurs during exercise. It would tend to speed the rate of dissociation of CO2 stores and cause the curves in Figure 6 to be shifted down. We, as well as others, seldom find a decrease in arterial COZ tension during submaximal exercise $7J’ ~8 so hyperventilation is not a common problem. Certain patients with mitral stenosis In such may hyperventilate during exercise. instances it is necessary to determine how much the hyperventilation would increase R before
and
McIlroy
drawing any conclusions about the development of metabolic acidosis. Anaerobic Metabolism us. Oxygen Debt: Throughout this report we have spoken of the use of the gas exchange ratio (R) to detect the threshold of anaerobic metabolism. Anaerobic metabolism should be differentiated from oxygen debt. Oxygen debt includes not only the oxygen deficit due to anaerobic oxidative processes during the conversion of pyruvate to lactate but also the oxygen deficit which occurs during exercise and which has been called by Margaria et al. the “alactic acid” oxygen debt.lg It occurs at all workloads during the first few minutes of exercise and is rapidly repaid during recovery.13 ,20 This is probably not an oxygen debt resulting from anaerobic metabolism, but rather it is due to depletion of the oxygen stores in the body. Christensen et alzl have studied intermittent heavy work of short duration and showed that lactic acid did not increase in the blood in spite of the accumulation of an oxygen debt. When the rest period was sufficiently long and the exercise of short duration, the oxygen debt could be completely “alactic” and be repaid during the rest period. Dawsonz2 questioned the source of the creditors for the oxygen debt. Certainly lactic acid The crediis a creditor during heavy exercise. tors responsible for the “alactic” oxygen debt must be in part (1) the myoglobin which gives up its oxygenz3 (2) hemoglobin which gives up its oxygen when the mixed venous oxygen saturation decreases during exercisez4 and (3) the tissues which lose oxygen when oxygen tenThese sion in the tissues falls during exercise. creditors can account for approximately one half of the “alactic” oxygen debt estimated from the size of this debt reported by Dill.*O Replenishment of the stores of creatine phosphate and adenosine triphosphate during recovery also requires oxygen in excess of that required for The high energy phosphate acts basal needs. as stored energy which is used during exercise and is restored as a result of aerobic oxidation during recovery-another “alactic” creditor. A graph showing the relationship between oxygen debt and AR to oxygen consumption is shown in Figure 7. The subject exercised for 10 minutes
at each workload,
were allowed
for recovery.
and 50 minutes The
oxygen
debt
was measured during the first 15 minutes This graph shows that the “knee” recovery. the AR-G,,
curve
(B) approximately
THE AMERICAN
JOURNAL
of of
coincided
OF CARDIOLOGY
Anaerobic
Metabolism
During
Exercise
851
toot 02
DEBT
WLJ
moo
0
.I5
+AR
JO
.os,
0,
FIG. 7. A, the oxygen debt incurred for 10 minutes of exercise at the workloads indicated by the oxygen consumption on the abscissa. B, AR for uninterrupted graded exercise in the same subject.
with the onset of the steepest part of the oxygen debt curve (A). The oxygen debt for workloads below the “knee” of the curve was paid off within four minutes of stopping work, but repayment of oxygen debt was incomplete after 15 minutes of recovery for the workloads above the “knee.” Dill*O has pointed out that the bend in the oxygen-debt curve is the point at which the lactic acid oxygen debt becomes detectable. The studies presented here indicate that the measurement of the ventilatory gas exchange ratio during exercise is a useful test of cardiovascular function. It answers the question of VOLUME
14,
DECEMBER
1964
how much work a subject can do before the heart fails to meet the tissue oxygen requirements. The fact that this information can be obtained without blood sampling and at the time the exercise is being performed has great merit from both the patient’s and examiner’s viewpoint. SUMMARY The measurement of the respiratory gas exchange ratio (R) during a standard exercise test is used to detect the onset of anaerobic metabolism during exercise, which results from fail-
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852
ure of the cardiovascular system to supply the oxygen requirements of the tissues. The method described uses end-tidal gas concentrations to calculate R while the exercise test is taking place. Blood sampling is unnecessary, and the results can be determined during the test, thus avoiding exhaustive exercise. The method provides an objective measurement of one of the factors influencing exercise tolerance. ACKNOWLEDGMENT The authors wish to acknowledge the excellent assistance of Antonius L. van Kessel during most of this study and to thank Dr. Julius H. Comroe, Jr. and Dr. Herbert N. Hultgren for their helpful comments during the preparation of this paper. REFERENCES 1.
2. 3.
4. 5.
6.
7.
8.
9.
A. V., LONG, C. N. H. and LUPTON, H. Muscular exercise, lactic acid and the supply and utilisation of oxygen. Proc. Roy. Sot. London, s. B, 96: 438, 1924; 97: 84, 1924; 97: 155, 1924. HILL, A. V. The revolution in muscle physiology. Phyriol. Rev., 12: 56, 1932. MARGARIA, R., CERRETELLI,P., DI PRAMPERO,P. E., MASSARI, C. and TORELLI, G. Kinetics and mechanism of oxygen debt contraction in man. J. Appl. Physiol., 18: 371, 1963. HUCKABEE,W. E. Anaerobic energy metabolism in man. Boston M. Quart., 9: 1, 1958. WELLS, F. G., BALKE, B. and VON FOSSAU, D. D. Lactic acid accumulation during work. A suggested standardization of work classification. J. Appl. Physiol., 10: 51, 1957. DE LANNE, R., BARNES,J. R., BROUHA,L. and MASSART, F. Changes in acid-base balance and blood gases during muscular activity and recovery. J. Appl. Physiol., 14: 328, 1959. NAIMARK,A., WASSERMAN,K. and MCILROY, M. B. Continuous measurement of ventilatory exchange ratio during exercise: A test of cardiovascular function. J. Appl. Physiol., 19: 644, 1964. ISSEKUTZ, B., JR. and RODAHL, K. Respiratory quotient during exercise. J. Appl. Physiol., 16 : 606, 1961. PILCWER,C., CLARK, G. and HARRISON,T. R. The buffering power of the blood and tissues. J. Clin. Invest., 8: 317, 1930. HILL,
and McIlroy 10. IIUCKABEE,W. E. Abnormal resting blood lactate. I. The significance of hyperlactatemia in hospitalized patients. Am. J. Med., 30: 833. 1961. 1 1. I IARRISON,7’. R. and PILCHER, C. Studies in congestive heart failure. II. The respiratory exchange during and after exercise. J. Clin. Invest., 8: 291, 1930. 12. RAIIN, H. and FENN, W. 0. A Graphical Analysis of the Respiratory Gas Exchange, p. 19. Washington, D. C., 1955. American Physiological Society. 13. DILL, D. B. and SACKTOR, B. Exercise and the oxygen debt. J. Sports Med. @ Phys. Fitness, 2: 66, 1962. 14. NEWMAN, E. V., DILL, D. B., EDWARDS, H. T. and WEBSTER,F. A. The rate of lactic acid removal in exercise. Am. J. Physiol., 118: 457, 1937. 15. FAHRI, L. E. and RAHN, H. Gas stores of the body and the unsteady state. J. Appl. Physiol., 7: 472, 1955. 16. VANCE, J. W. and FOWLER, W. S. Adjustment of stores of carbon dioxide during voluntary hyperventilation. Dis. Chest, 37: 304, 1960. 17. MCILROY, M. B. and HOLMGREN,A. Arterial blood gas tensions during exercise in normal subjects. Fed. Proc., 20: 423, 1961. 18. RILEY, R. L. Pulmonary function in relation to exercise. In: Science and Medicine in Exercise and Sports, p. 162. Edited by JOHNSON,W. E. New York, 1960. Harper & Brothers. 19. MARGARIA, R., EDWARDS, H. T. and DILL, D. B. The possible mechanisms of contracting and paying the oxygen debt and the role of lactic acid in muscular contraction. Am. J. Physiol., 106: 689 1933. 20. DILL, D. B. Fatigue and physical fitness. In: Ref. 18, p. 387. 21. CHRISTENSEN,E. H., HEDMAY, R. and SALTIN, B. Intermittent and continuous running. Acta physiol. scandinou., 50: 269, 1960. 22. DAWSON, P. M. The Physiology of Physical Education. D. 365. Baltimore. 1935. Williams & Will&s. 23. ASTRAND, I., ASTRAND, P., CHRISTENSEN, E. H. and HEDMAN, R. Myohemoglobin as an oxygenstore in man. Acta physiol. scandinau., 48: 454, 1960. 24. DONALD, K. W., BISHOP, J. M., GUMMING,G., and WADE, 0. L. Effect of exercise on cardiac output and circulatory dynamics of normal subjects. Clin. SC., 14: 37, 1955.
THE
AMERICAN
JOURNAL
OF CARDIOLOGY
M.D.$
Palo Alto and San Francisco, California
H
ILL ET AL.l have shown that large quantities of lactic acid form when muscles lack oxygen. Formation of lactic acid during exercise permits oxidation to proceed anaerobically and accounts for most of the oxygen debt which Conseaccumulates during heavy exercise.2J quently, measurement of accumulated lactate has been used as an index of anaerobic metabolism.4s5 Because of the relatively high dissociation constant of lactic acid, virtually all of it is ionized in the physiologic range of pH. Therefore, when lactic acid is produced during anaerobic metabolism, it is completely buffered in the blood, and the level of bicarbonate is reduced,6-8 as in other metabolic acidoses. Pilcher and associates9 have shown that patients in acute heart failure have arterial pH values that are extraordinarily low, and Huckabeelo has reported an increased concentration of lactate in the blood of patients with circulatory failure. Harrison and Pilcher” found that patients with heart failure produced more carbon dioxide (CO*) during exercise than normal subjects performing the same exercise. Consequently, their gas exchange ratio (CO2 production to 02 consumption) was increased. They concluded that the excess CO2 could not be the end product of aerobic metabolism and must be evolved from CO2 stores. They reasoned that the excess CO2 was released from bicarbonate when acids formed during anaerobic metabolism were buffered : TISSUES 02
t-1
I
BLOOD 02
c---
1
While Harrison and Pilcher did not detect significant increases in the gas exchange ratio (R)$ of their normal subjects at the low loads they studied, metabolic acidosis does develop in normal subjects during work of greater intensity and R increases.‘j-8 The onset of anaerobic metabolism during exercise can thus be detected in three ways: (1) as an increase in the lactate concentration in blood, (2) as a decrease in arterial blood bicarbonate and pH and (3) as an increase in the In evaluatrespiratory gas exchange ratio (R). ing cardiovascular performance during work, a method which measures R has the advantage of avoiding blood sampling. Furthermore, equipment which is available in many cardiopulmonary laboratories can be used to measure R breath by breath. Thus, it is possible for the examiner to detect the threshold of anaerobic metabolism during the work test and to avoid exhaustive and potentially dangerous exercise of patients with heart disease under study. A method for the evaluation of cardiac performance by analysis of R breath by breath is reviewed in this paper. METHODS The method used has been described by Naimark and associates.’ It involves a standardized exercise test in which the subject pedals an ergometer or walks on a treadmill for four minutes at each of several graded workioads. Heart rate, minute ventilation, oxygen consumpti,on and end-tidal CO2 and Nt concentrations are measured. The respiratory gas exchange ratio can be calcuiated from the end-tidal gas
LUNGS __
02
+
Metabolic
j --t Lactic acid + NaHCOg + Na lactate f Hz0 + COZ-,+ p con --,+
$R
CO2 (excess) co*
=
CO2 production/Oz
consumption
=
+I,,,/
eo? = pulmonary respiratory quotient.
* From the Pulmonary Function Laboratory, Department of Medicine, Stanford University School of Medicine, Palo Alto, t and the Cardiovascular Research Institute, University of California Medical Center, San Francisco, Calif. 1 This investigation was supported in whole by U. S. Public Health Service Research Grants HE 06591 and HE 06285 from the National Institutes of Health. 844
THE AMERICANJOURNAL OF CARDIOLOOY
Anaerobic
Metabolism
1.0 R
F’N2
1.1 -
,.o-
1.2
-P.O-
13
-X0-
20
3.0
40
5:0
do
EN0 TIDALCOP W
do
FIG. 1. Nomogram for determining R from end-tidal NZ and COZ. FINKequals inspired NZconcentration. concentrations, using the following equation: R=
FACO~ 1.26 FAN2 - 1 + FAN2
where F,COz = the end-tidal COZ concentration and FAN2 = the end-tidal N2 concentration. This equation is derived from the alveolar ventilation and alveolar gas equations.7J2 R can be determined quickly by reference to a nomogram calculated from this equation (Fig. 1). RESULTS An example of the tracings of Nz, COs, heart rate and minute ventilation for the last 30 seconds of exercise at each workload during the test is shown in Figure 2. The values of R were determined from the nomogram. It will be seen that the increase in R is evident principally as a decrease in the end-tidal Nz concentration. When R, during the last 30 seconds of each workload, is plotted against oxygen consumption, a sigmoid curve is usually obtained (Fig. The steepest part of this curve indicates the 3). VOLUME14, DECEMBER1964
During
Exercise
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level of oxygen consumption at which anaerobic metabolism becomes important, and we call this the “threshold” of anaerobic metabolism. It corresponds to the point at which the concentration of bicarbonate in the arterial blood decreases and the concentration of lactate rises.‘** Naimark et al. 7 found the threshold of anaerobic metabolism to be at a level of oxygen consumption of about 1.2 L./min. in normal sedentary men and about 0.8 in normal sedentary women. They also found that R increased at lower levels of work in patients with heart disease. The results of exercise tests in which the threshold of anaerobic metabolism was measured in 37 patients with heart disease are shown in Figure 4. The level of oxygen consumption at which the A R-Go, curve showed the steepest slope (anaerobic threshold) has been plotted in patients with different types of heart disease. In addition, the functional limitation of the patient is noted according to the New York Heart Association classification. The relation between the threshold of anaerobic metabolism and the “wedge” pressures at rest are plotted in In these patients patients with mitral stenosis. the discrepancies between the level of “wedge” pressure and the severity of symptoms are as numerous as those between the threshold of anaerobic metabolism and symptoms. This is not surprising in view of the multiplicity of factors determining exercise tolerance. In the other groups, only the severity of symptoms is In this limited series, the patients with shown. the less severe symptoms had higher thresholds of anaerobic metabolism. ILLUSTRATIVE CASES The clinical usefulnessof determining the threshold
of anaerobic metabolism is illustrated by the following case histories. CASE 1. Acromegaly. A 25 year old male insurance salesman was admitted to Stanford University Hospital, Palo Alto in May 1962 for evaluation of cardiomegaly. His past history revealed that he was the product of a normal delivery and had frequent colds in infancy. At the age of 14 months he was admitted to the hospital for the evaluation of hirsutism. At the age of 3 years he had a cardiac arrest during a tonsillectomy and required artificial respiration. At 7 years of age he was admitted to the hospital with an attack of lobar pneumonia, and a heart murmur was heard for the first time. Digitalis was started at this time. At the age of 14 he was in the hospital again because of the onset of ankle edema. Hirsutism, marked muscular development and a systolic murmur of variable quality, loudness and duration were
846
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and McIlroy //oo
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FIG. 2. End-tidal Nt and CO2 concentrations, heart rate and ventilation rate during graded exercise. 02 consumption and R are noted on top. The anaerobic threshold is between 1,100 and 1,385 ml. Oz/min. noted. A chest roentgenogram was interpreted as showing slight left ventricular hypertrophy. Circulation time, venous pressure and arterial blood pressure were normal. The electrocardiogram was normal except for evidence of digitalis effect. The drug was stopped at this time. At the age of 16 he was admitted to the hospital for cardiac catheterization. Normal intracardiac pressures and normal arterial oxygen saturation were found, and there was no evidence of intracardiac shunting. The cardiac output was increased, measurHe was cautioned against ing 6.5 L./min./Ms. overexertion, although the precise cardiac defect was not clear. At the age of 22 he was investigated again because of three episodes of hemoptysis. The hemoptysis was mild and associated with prolonged episodes of coughing. The heart was found to be enlarged, and there was a loud sound of pulmonary valve closure. An early systolic murmur was heard along the left sternal edge, and purplish mottling of the lower legs was noticed. Arterial and venous blood pressures were normal; hematocrit was 55 per cent. The chest x-ray film showed biventricular enlargement. The results of a second cardiac catheterization at this time were normal. The cardiac output was
4 L./min./M2. There was no change in the patient’s clinical condition in the next three years. The only symptom was mild intermittent ankle edema which responded to treatment with chlorothiazide. During the present admission there was no exertional dyspnea, and the electrocardiogram was normal, as were the third cardiac catheterization findings, except for the high cardiac output noted on the previous occasions. The cardiac output on this occasion was 7 L./min./Ms., with a stroke volume of 152 ml. The total blood volume was also increased at 4.3 L./MZ. Both the red cell mass and the (predicted, 2.5). plasma volume were increased. An extensive evaluation of the erythropoietic, endocrine, renal, skeletal and metabolic systems did not reveal the cause of the patient’s enlarged heart and high cardiac output. The patient exercised on a treadmill and was found to have a threshold of anaerobic metabolism of 3 L. Op/min. in contrast to the values of about 1.2 L./min. in untrained normal men. The patient’s heart rate reached only 138 during this exercise test, and linear extrapolation of his heart rate response gave a value for the oxygen consumption of 4.6 L./min. at a heart rate of 170. These measurements are similar to those seen in well trained athletes. The only hormone assay THE
AMERICAN
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Anaerobic
Metabolism
During
Exercise
1.0
0.9,
R
0.0
0.7
Fm. 3. The chanae in R and bicarbonate from rest during uninterrupted graded ergometer exercise in an asymptomatic 20 year old boy with a ventricular septal defect. which proved to be abnormal in this patient was that of growth hormone. The provisional diagnosis was that the patient had an unusual variant of acromegaly, possibly involving only the cardiovascular and muscular systems. The measurement of the threshold of anaerobic metabolism in this patient gave the clue to his supernormal exercise performance. CASE 2. Mitral stenosis. A 24 year old married woman was admitted to the hospital for evaluation of a heart murmur. Six weeks before, she had become short of breath and coughed up blood-tinged sputum while taking swimming lessons. She also noted chest pain and fatigue. Chest x-ray films showed cardiomegaly and evidence of pulmonary edema. She was treated with digoxin, chlorothiazide and penicillin. She improved with thii therapy; but when admitted for evaluation, she complained of dyspnea on mild exertion, fatigue and orthopnea and required two pillows at night. Her past history revealed that she had been slightly short of breath on exertion during childhood. She had had two pregnancies which she tolerated well except for some dyspnea and orthopnea during the second one. There was no history of previous rheumatic fever. The physical findings were normal except for the heart, which was slightly enlarged. A diastolic thrill was felt at the apex. There was a grade 4/6 harsh
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diastolic murmur, heard best between the apex and left lower sternal border throughout ,diastole with presystolic accentuation. The electrocardiogram was normal. Chest x-ray films showed no overall cardiac enlargement, although the left atrium appeared to be enlarged. Cardiac catheterization showed a mean pulmonary artery wedge pressure of 14 mm. Hg, with a cardiac output of 4.3 L./min. During exercise (oxygen consumption of 566 ml./min., with a heart rate of 150/ min.) her cardiac output increased to 5.8 L./min., while the mean pulmonary artery wedge pressure increased to 36 mm. Hg. Pulmonary vascular resistance was calculated to be normal. The mitral valve area was calculated to be 1.25 sq. cm. These results were interpreted as showing moderate mitral stenosis. Because of her severe symptoms, plans were made for surgical correction at an early date. Treadmill exercise studies before surgery and after optimal medical management revealed that this patient’s anaerobic threshold was between 550 and 620 ml. of oxygen/mm This is a low value and suggested that this patient had a reduced capacity for exercise without developing a metabolic acidosis. At surgery, severe mitral stenosis without calcification of the valve was found. The mitral valve orifice barely admitted the tip of the surgeon’s finger. The results of the exercise studies in thii patient were in keeping with her symptoms and seemed to give a better indication of
Wasserman and McIlroy
848
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FIG. 4.
Threshold of anaerobic metabolism in 37 patients with heart disease.
the severity of her lesion than the resting cardiac catheterization data from which the valve area was calculated. CASE 3. Mitral insu&%iency. A 41 year old man was admitted to the hospital for the evaluation of a heart murmur. The murmur was first discovered eight years before when he applied for life insurance. He remained asymptomatic until 18 months before admission, when he began to have chest pain unrelated to exertion and increasing exertional dyspnea. His physician prescribed bed rest, a low salt diet, digitalis and diuretics. With this regimen the patient was symptom-free, having shortness of breath only after heavy drinking or hard exercise. There was no cough, hemoptysis, edema nor cyanosis and no past history of rheumatic fever. On physikal examination the heart was found to be enlarged, with a loud, blowing systolic murmur best heard at the apex and radiating to the axilla. There was no diastolic murmur, and the cardiac rhythm
was regular. The electrocardiogram was abnormal and showed prolonged A-V conduction with intraventricular conduction delay, large voltage in the left precordial leads suggesting left ventricular hypertrophy, and digitalis effect. Chest x-ray films showed mild left ventricular and possible left atria1 enlargement suggestive of mitral valve disease. Cardiac catheterization showed a cardiac output of 5.6 L./min., with a v wave in the “wedge” pressure of 43, a y of 14 and a mean pressure of 21 mm. Hg. With exercise during cardiac catheterization (90, = 795 ml./min. and heart rate = 98), the cardiac output increased to 7.3 L./min., while the wedge pressure increased to a mean of 54 mm. Hg with a v wave of 88. It was concluded that the patient had a marked degree of mitral insufficiency. Exercise studits on the treadmill showed normal results. The patients’ anaerobic threshold was about 1.3 L./min. VO,. The highest oxygen consumption at which the patient exercised was 1.59 L./min. (heart THE AMERICAN JOURNALOF CARDIOLOGY
Anaerobic Metabolism During Exercise
849
1.0
FIG. 5. The reproducibility of effect of workload on R measured during continuous exercise. The subject is exercised between each of the three series at work loads less than 800 ml./min. until a steady state in R is reached (recovery exercise). This required approximately 10 minutes. The numbers indicate the order of the tests.
0.9
R
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I
I
400
800
I I200
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PO00
QO, (ML/M/N - StPD) rate 125). These results were inconsistent with the interpretation of the cardiac catheterization data but were in keeping with the patient’s relative lack of symptoms. At surgery a cleft was found in the aortic leaflet of the mitral valve, and the chordae tendineae appeared normal.
DISCUSSION The cases presented show the type of information that can be obtained from exercise tests in which the threshold of anaerobic metabolism is determined. The workload at which metabolic acidosis develops during exercise can be seen as the exercise test is being performed, and it is unnecessary to ask the patient to exercise until exhausted. An awareness of the changes in R during the test makes it possible to choose appropriate loads for the subject, and the discomfort of blood sampling is avoided. The results obtained provide an objective measure of an aspect of exercise performance which supplements the clinical and hemodynamic data. The test can be repeated at intervals to follow the patient’s progress. To demonstrate that the observed changes in R are not due to the duration of exercise or the total energy expended, we repeated the work test (ergometer exercise) three times without stopping following a 10 minute “warm-up” VOLUME
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(Fig. 5). Between each test the subject exercised continuously for about 10 minutes at a workload below the “knee” of the A R-30, curve-“recovery exercise”.13 Newman et a1.14 have shown that the rate of removal of lactic acid from the blood is more rapid if the subject exercises at a light load instead of resting during the recovery period. This also permits a more rapid recovery of R after work. The three R decreased when R-v,, curves were similar. the workload was reduced, despite the continuaFurthermore, the threshold of tion of exercise. anaerobic metabolism was approximately the same in the three exercise tests. This study shows that the R-Oo, curve was independent of the cumulative effects of a period of exercise lasting one and a half hours. Effect of Hyperventilation on R: Factors other than metabolic acidosis which may cause R to increase have been discussed elsewhere.’ The Its effect most troublesome is hyperventilation. on R is transientI and is also less during exercise when the rate of oxygen consumption is increased. We have calculated the order of magnitude of the increase in R caused by hyperFigure 6 shows the ventilation during exercise. change in R at various oxygen consumptions for different degrees of hyperventilation measured
Wasserman
850 +AR 0.4
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0.2
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FIG. 6. The change in R at various 02 consumptions after two minutes of hyperventilation. The curves for hypoventilation are the same except the signs for AR and P*COz are reversed.
as decrease in alveolar PcoZ. We have arbitrarily assumed a period of hyperventilation lasting two minutes and used the dissociation curve of the CO2 stores in the body and the dissociation rate data of Fahri and Rahn.15 While their measurements were made on dogs, the values for the decrease in CO2 stores per kilogram of body weight for each millimeter of Hg reduction in alveolar CO2 tension are similar to those determined by Vance and Fowler in man.16 It can be seen from Figure 6 that hyperventilation increases R most at low levels of oxygen consumption. The one factor not considered in this calculation is the increase in cardiac output that occurs during exercise. It would tend to speed the rate of dissociation of CO2 stores and cause the curves in Figure 6 to be shifted down. We, as well as others, seldom find a decrease in arterial COZ tension during submaximal exercise $7J’ ~8 so hyperventilation is not a common problem. Certain patients with mitral stenosis In such may hyperventilate during exercise. instances it is necessary to determine how much the hyperventilation would increase R before
and
McIlroy
drawing any conclusions about the development of metabolic acidosis. Anaerobic Metabolism us. Oxygen Debt: Throughout this report we have spoken of the use of the gas exchange ratio (R) to detect the threshold of anaerobic metabolism. Anaerobic metabolism should be differentiated from oxygen debt. Oxygen debt includes not only the oxygen deficit due to anaerobic oxidative processes during the conversion of pyruvate to lactate but also the oxygen deficit which occurs during exercise and which has been called by Margaria et al. the “alactic acid” oxygen debt.lg It occurs at all workloads during the first few minutes of exercise and is rapidly repaid during recovery.13 ,20 This is probably not an oxygen debt resulting from anaerobic metabolism, but rather it is due to depletion of the oxygen stores in the body. Christensen et alzl have studied intermittent heavy work of short duration and showed that lactic acid did not increase in the blood in spite of the accumulation of an oxygen debt. When the rest period was sufficiently long and the exercise of short duration, the oxygen debt could be completely “alactic” and be repaid during the rest period. Dawsonz2 questioned the source of the creditors for the oxygen debt. Certainly lactic acid The crediis a creditor during heavy exercise. tors responsible for the “alactic” oxygen debt must be in part (1) the myoglobin which gives up its oxygenz3 (2) hemoglobin which gives up its oxygen when the mixed venous oxygen saturation decreases during exercisez4 and (3) the tissues which lose oxygen when oxygen tenThese sion in the tissues falls during exercise. creditors can account for approximately one half of the “alactic” oxygen debt estimated from the size of this debt reported by Dill.*O Replenishment of the stores of creatine phosphate and adenosine triphosphate during recovery also requires oxygen in excess of that required for The high energy phosphate acts basal needs. as stored energy which is used during exercise and is restored as a result of aerobic oxidation during recovery-another “alactic” creditor. A graph showing the relationship between oxygen debt and AR to oxygen consumption is shown in Figure 7. The subject exercised for 10 minutes
at each workload,
were allowed
for recovery.
and 50 minutes The
oxygen
debt
was measured during the first 15 minutes This graph shows that the “knee” recovery. the AR-G,,
curve
(B) approximately
THE AMERICAN
JOURNAL
of of
coincided
OF CARDIOLOGY
Anaerobic
Metabolism
During
Exercise
851
toot 02
DEBT
WLJ
moo
0
.I5
+AR
JO
.os,
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FIG. 7. A, the oxygen debt incurred for 10 minutes of exercise at the workloads indicated by the oxygen consumption on the abscissa. B, AR for uninterrupted graded exercise in the same subject.
with the onset of the steepest part of the oxygen debt curve (A). The oxygen debt for workloads below the “knee” of the curve was paid off within four minutes of stopping work, but repayment of oxygen debt was incomplete after 15 minutes of recovery for the workloads above the “knee.” Dill*O has pointed out that the bend in the oxygen-debt curve is the point at which the lactic acid oxygen debt becomes detectable. The studies presented here indicate that the measurement of the ventilatory gas exchange ratio during exercise is a useful test of cardiovascular function. It answers the question of VOLUME
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how much work a subject can do before the heart fails to meet the tissue oxygen requirements. The fact that this information can be obtained without blood sampling and at the time the exercise is being performed has great merit from both the patient’s and examiner’s viewpoint. SUMMARY The measurement of the respiratory gas exchange ratio (R) during a standard exercise test is used to detect the onset of anaerobic metabolism during exercise, which results from fail-
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ure of the cardiovascular system to supply the oxygen requirements of the tissues. The method described uses end-tidal gas concentrations to calculate R while the exercise test is taking place. Blood sampling is unnecessary, and the results can be determined during the test, thus avoiding exhaustive exercise. The method provides an objective measurement of one of the factors influencing exercise tolerance. ACKNOWLEDGMENT The authors wish to acknowledge the excellent assistance of Antonius L. van Kessel during most of this study and to thank Dr. Julius H. Comroe, Jr. and Dr. Herbert N. Hultgren for their helpful comments during the preparation of this paper. REFERENCES 1.
2. 3.
4. 5.
6.
7.
8.
9.
A. V., LONG, C. N. H. and LUPTON, H. Muscular exercise, lactic acid and the supply and utilisation of oxygen. Proc. Roy. Sot. London, s. B, 96: 438, 1924; 97: 84, 1924; 97: 155, 1924. HILL, A. V. The revolution in muscle physiology. Phyriol. Rev., 12: 56, 1932. MARGARIA, R., CERRETELLI,P., DI PRAMPERO,P. E., MASSARI, C. and TORELLI, G. Kinetics and mechanism of oxygen debt contraction in man. J. Appl. Physiol., 18: 371, 1963. HUCKABEE,W. E. Anaerobic energy metabolism in man. Boston M. Quart., 9: 1, 1958. WELLS, F. G., BALKE, B. and VON FOSSAU, D. D. Lactic acid accumulation during work. A suggested standardization of work classification. J. Appl. Physiol., 10: 51, 1957. DE LANNE, R., BARNES,J. R., BROUHA,L. and MASSART, F. Changes in acid-base balance and blood gases during muscular activity and recovery. J. Appl. Physiol., 14: 328, 1959. NAIMARK,A., WASSERMAN,K. and MCILROY, M. B. Continuous measurement of ventilatory exchange ratio during exercise: A test of cardiovascular function. J. Appl. Physiol., 19: 644, 1964. ISSEKUTZ, B., JR. and RODAHL, K. Respiratory quotient during exercise. J. Appl. Physiol., 16 : 606, 1961. PILCWER,C., CLARK, G. and HARRISON,T. R. The buffering power of the blood and tissues. J. Clin. Invest., 8: 317, 1930. HILL,
and McIlroy 10. IIUCKABEE,W. E. Abnormal resting blood lactate. I. The significance of hyperlactatemia in hospitalized patients. Am. J. Med., 30: 833. 1961. 1 1. I IARRISON,7’. R. and PILCHER, C. Studies in congestive heart failure. II. The respiratory exchange during and after exercise. J. Clin. Invest., 8: 291, 1930. 12. RAIIN, H. and FENN, W. 0. A Graphical Analysis of the Respiratory Gas Exchange, p. 19. Washington, D. C., 1955. American Physiological Society. 13. DILL, D. B. and SACKTOR, B. Exercise and the oxygen debt. J. Sports Med. @ Phys. Fitness, 2: 66, 1962. 14. NEWMAN, E. V., DILL, D. B., EDWARDS, H. T. and WEBSTER,F. A. The rate of lactic acid removal in exercise. Am. J. Physiol., 118: 457, 1937. 15. FAHRI, L. E. and RAHN, H. Gas stores of the body and the unsteady state. J. Appl. Physiol., 7: 472, 1955. 16. VANCE, J. W. and FOWLER, W. S. Adjustment of stores of carbon dioxide during voluntary hyperventilation. Dis. Chest, 37: 304, 1960. 17. MCILROY, M. B. and HOLMGREN,A. Arterial blood gas tensions during exercise in normal subjects. Fed. Proc., 20: 423, 1961. 18. RILEY, R. L. Pulmonary function in relation to exercise. In: Science and Medicine in Exercise and Sports, p. 162. Edited by JOHNSON,W. E. New York, 1960. Harper & Brothers. 19. MARGARIA, R., EDWARDS, H. T. and DILL, D. B. The possible mechanisms of contracting and paying the oxygen debt and the role of lactic acid in muscular contraction. Am. J. Physiol., 106: 689 1933. 20. DILL, D. B. Fatigue and physical fitness. In: Ref. 18, p. 387. 21. CHRISTENSEN,E. H., HEDMAY, R. and SALTIN, B. Intermittent and continuous running. Acta physiol. scandinou., 50: 269, 1960. 22. DAWSON, P. M. The Physiology of Physical Education. D. 365. Baltimore. 1935. Williams & Will&s. 23. ASTRAND, I., ASTRAND, P., CHRISTENSEN, E. H. and HEDMAN, R. Myohemoglobin as an oxygenstore in man. Acta physiol. scandinau., 48: 454, 1960. 24. DONALD, K. W., BISHOP, J. M., GUMMING,G., and WADE, 0. L. Effect of exercise on cardiac output and circulatory dynamics of normal subjects. Clin. SC., 14: 37, 1955.
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