EFFECT OF OBSERVATIONS AND ON EXERCISE ON ON TRAINED PATIENTS WITH AND BLOOD UNTRAINED WITH HEART PYRUVIC NORMAL DISEASE ACID SUBJECTS AND HYPERTENSION ZALE A. YANOF, M.D. CHICAGO An increase of lactic acid in the blood and tissues following exercise is one of the classic observations in physiology. Since this discovery an extensive literature has accumulated on changes in lactic acid as related to work, training and fatigue. More recently Dill and his group1 have suggested that it be employed as an index of cardiovascular fitness. However, it is now the considered opinion of most biochemists 2 that pyruvic acid, and not lactic acid, is the core of the carbohydrate metabolism of tissues. In the breakdown of dextrose by the tissues all reactions appear to revolve around pyruvic acid as the pivotal point. Further interest has been attached to pyruvic acid because of Peters'3 discovery that the presence of vitamin B1 is necessary for its oxidation. This displacement of lactic acid in the scheme of the carbohydrate metabolism of tissues by pyruvic acid led to the formulation of this work. METHOD AND MATERIAL A standard exercise of fifty ascents and descents in one hundred seconds over a two step contrivance,4 with the blood level of pyruvate determined while the subject was resting and ten and sixty minutes after the exercises, was performed by 11 wrestlers and track men aged 18 to 21 from the University of Chicago, 10 persons aged 19 to 54 engaged in sedentary occupa¬ tions, 10 patients aged 21 to 48 of functional classes II and III with cardiac disease and •enlargement and 9 hypertensive patients aged 31 to 51 of functional class I without cardiac enlargement or detectable renal involvement but with systolic blood pressures exceeding 200 mm. of mercury. Blood pyruvate was analyzed by Friedemann's modification 5 of Lu's method.6 Preliminary investigation revealed the ten and the sixty minute period to be optimum for study.7 From the Department of Medicine of the University of Chicago. This investigation was aided by a fellowship grant from the Jessie Horton Koessler Fund of the Institute of Medicine, Chicago, and by a grant from the Douglas Smith Fund of the University of Chicago. 1. Knehr, C. A.; Dill, D. B., and Neufeld, W.: Training and Its Effect on Man at Rest and at Work, Am. J. Physiol. 136:148 (March) 1942. 2. Barron, E. S. G.: Cellular Oxidation Systems, Physiol. Rev. 19:184 (April) 1939. Stern, K. G.: Biological Oxidations and Reductions, Ann. Rev. Biochem. 9:1, 1940. Cori, C. F., and Cori, G. T.: Carbohydrate Metabolism, ibid. 10:151, 1941. 3. Peters, R. A.: Biochemical Lesion in Vitamin B1 Deficiency\p=m-\Applicationof Modern Biochemical Analysis and Its Diagnosis, Lancet 1:1161 (May 23) 1936. 4. Master, A. M.: The Two-Step Test of Myocardial Function, Am. Heart J. 10:495 (April) 1935. 5. Friedemann, T. E., and Haugen, G. E.: Pyruvic Acid: I. Collection of Blood for the Determination of Pyruvic and Lactic Acids, J. Biol. Chem. 144:67 (June) 1942; II. Determination of Keto-Acids in Blood and Urine, ibid., to be published. 6. Lu, G. D.: Studies on the Metabolism of Pyruvic Acid in Normal and Vitamin Bi Deficient States : I. A Rapid Specific and Sensitive Method for the Estimation of Blood Pyruvate, Biochem. J. 33:249 (Feb.) 1939. 7. These time intervals were selected at the suggestion of Dr. Theodore E. Friedemann, of the Abbott Foundation for Medical Research, Northwestern University (personal com- munication). Downloaded From: http://archinte.jamanetwork.com/ by a University of Pittsburgh User on 06/20/2015 RESULTS Ten Minute Changes in Blood Pyruvate (tables 1 through 4).—In the trained group the mean ten minute change in blood pyruvate was 3.6 per cent, and the blood pyruvate of only 3 subjects of 11 showed a rise after ten minutes. These increases were small and insignificant, as compared with the ten minute increases for the other groups. All the subjects in the untrained group showed marked rises in blood pyruvate after ten minutes, as evidenced by a mean rise of + 53.3 per cent and a range of + 28 to + 101 per cent. — Table 1.—Absolute and Percentage Changes in Pyruvate in the Blood of Trained Ten and Sixty Minutes After Moderate Exercise Subjects Blood Pyruvate, Mg./100 Cc. Subject No. Age, Yr. During 1. 18 Rest 0.50 3. 20 0.71 2. 4. 6. 7. 8. 9. 10. 11. 20 0.63 21 0.75 0.91 1.00 1.15 1.23 1.51 1.78 0.86 20 20 20 19 19 20 20 10 Minutée After Exercise 0.56 0.56 0.78 0.75 60 Minutes After Exercise 0.50 0.51 0.71 0.63 0.90 0.71 0.85 0.78 0.90 0.90 1.05 1.16 1.45 1.58 1.20 1.70 0.66 0.90 % 10 Minutes +12 —11 +10 0 % 60 Minutes 0 —19 0 —16 1 1 —29 26 —37 —10 — — —9 —6 — —21 —5 + 5 —4 —11 —23 Table 2.—Absolute and Percentage Changes in Pyruvate in the Blood of Untrained Ten and Sixty Minutes After Moderate Exercise Blood Pyruvate, Subject No. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. Mg./lOO Cc. Age, During 0.60 35 19 10 Minutes After Exercise 1.00 0.71 1.43 Tr. 45 28 54 24 24 28 20 30 Rest 0.60 0.75 0.80 0.86 0.90 0.90 0.91 0.90 0.86 1.06 1.30 1.10 1.36 1.38 1.21 1.38 Subjects 60 Minutes After Exercise 0.63 0.53 0.80 0.80 0.90 0.56 0.86 1.00 0.60 0.71 % 10 Minutes +67 % 60 Minutes +5 +43 —12 +41 + 7 +101 +63 +28 +51 +53 +33 +53 +13 +13 —35 4 +11 —34 —21 — In the group of subjects with heart disease the ten minute values for blood pyruvate were also all substantially elevated, with a mean of -\- 46 per cent and a range of -j- 23 to + 86 per cent. Again, in the hypertensive group there were definite increases at ten minutes. This group had the highest ten minute mean, -f- 63.6 per cent, and the highest single ten minute value, +131 per cent. The range of the ten minute values was + 26 to -f- 131 per cent. Sixty Minute Changes in Blood Pyruvate (tables 1 through 4).—At the end 1 to of an hour all subjects in the trained group had decreases ranging from 37 per cent, with the exception of 2 who had no change from the initial level. The mean sixty minute change was —15.1 per cent. Four of the trained sub¬ jects had significantly higher pyruvate levels while they were resting than that previously reported as normal. The significance of this is not clear, other than — — Downloaded From: http://archinte.jamanetwork.com/ by a University of Pittsburgh User on 06/20/2015 that it may in some way accompany the chemical changes of training, but it makes conclusions regarding the changes for these 4 subjects difficult to draw. In the untrained group the range of the sixty minute differences was + 13 to 5.7 per cent. 35 per cent, with a mean of The patients with heart disease had a sixty minute mean of + 16.8 per cent, and this is probably a real difference, as only 2 of 10 patients showed negative one hour values (and these were small) and 3 had values higher than +40 per cent. The mean of the sixty minute values of the hypertensive subjects was + 0.3 per cent, or for all practical purposes 0. — — Table 3.—Absolute and Percentage Changes in Pyruvate in the Blood of Patients with Heart III) Ten and Sixty Minutes After Moderate Exercise * Disease (Functional Classes II and Blood Pyruvate, Mg./lOO Cc. Subject Age, Yr. 22 23 24 25 26 27 23 No. 21 37 34 24 48 Type of Heart Disease RV RV RV RV RV 28 29 RV RV 30 47 HA 29 RV 23 35 31 Functional Class During II II 0.63 Rest 0.80 0.86 II-III III III III 10 Minutes After Exercise 0.86 1.30 0.98 1.00 1.06 1.31 1.76 1.86 1.23 0.71 1.20 0.90 0.90 1.00 1.10 II III II II-III 60 Minutes After % Exercise 10 Minutes 0.63 +37 +63 +23 +46 +80 +86 +23 +33 +27 +42 0.90 0.98 1.33 1.46 1.43 1.03 1.06 0.70 1.23 1.46 1.70 % 60 Minutes 0 +13 +14 +48 +49 +43 + 3 — 4 1 + 3 — The following abbreviations have been employed: RV, rheumatic valvular heart disease; H, hyperteneion, and HA, hypertension with angina. * Percentage Changes in Pyruvate in the Blood of Patients with Hypertensive Vascular Disease (Functional Class I) Ten and Sixty Minutes After Moderate Exercise Table 4.—Absolute and Blood Pyruvate, Subject Age, 32 33 51 51 49 No. 34 35 .'it: 37 40 Yr. Punetional Class 47 42 31 41 During Rest 1.13 0.75 1.03 1.13 1.10 0.63 0.56 0.75 0.78 Mg./100 Cc. 10 Minutes After 60 Minutes Exercise Exercise 10 Minutes 1.46 1.73 0.90 0.86 +29 +131 +42 +76 +91 +64 +79 +35 +26 1.46 1.95 2.10 1.03 1.00 1.01 0.98 After 0.90 0.95 1.10 0.83 0.63 0.76 0.70 % % 60 Minutes. —24 +20 —IS —16 0 +32 +13 +1 —10 COMMENT Statistical and Correlative Analysis.—-All the data were subjected to statistical analysis.8 The trained subjects were of approximately the same age and of equal degree of training. As a group their ten and sixty minute changes in blood pyruvate were not statistically significant. But on an individual basis the varied responses of pyruvate of this group, as well as those of the untrained subjects, may be indicative of various degrees of cardiovascular fitness. Correlation of results of individual physical endurance tests with the changes in blood pyruvate could possibly have been revealing in this respect, but it was not attempted in this study. The track men and the wrestlers showed no difference as a group in either their ten or their sixty minute response of blood pyruvate to the exercise. me 8. Dr. Frederic T. Jung, of the in the statistical calculations. Department of Physiology, Northwestern University, aided Downloaded From: http://archinte.jamanetwork.com/ by a University of Pittsburgh User on 06/20/2015 The ten minute changes in blood pyruvate of the untrained subjects and of the patients with heart disease and with hypertension were found to be statistically significant. None of the groups, with the exception of the patients with heart disease, could be shown to have statistically significant sixty minute changes. Fisher's rule 9 stipulates that a critical ratio of 2 represents statistical significance. The calculated critical ratio of the sixty minute changes of the patients with heart disease was 1.42, and this is close enough to 2 to place the sixty minute changes of the patients with cardiac disease in the realm of "practical" significance. In the untrained group the subjects were all closely alike in daily physical activity, but there was a purposeful wide age variation to match the age range of the patients with heart disease and with hypertension. That the ten minute changes were significant would indicate that age was not a modifying factor in these changes. The ten and sixty minute changes of the other groups were simi¬ larly not influenced by age. In the patients with heart disease and with hypertension there were individual differences based on such variables as duration, type and magnitude of symptoms ; functional capacity ; cardiac enlargement ; degree of cardiac damage and stress ; number of failures, and lability of blood pressure. It is usually impossible to select a group of patients who are standardized on all the variables of clinical experimentation. In the main these variables were related to the changes in blood pyruvate. The patients of functional class III with heart disease (table 3) had the highest sixty minute levels, and the duration of the cardiac symptoms and the number of cardiac failures of each patient tended to be expressed by the greater ten and sixty minute changes. This is an encouragement to further investigation, as there is need for precise measurement of the functional capacity of a patient with cardiovascular disease in terms of the actual chemical processes that the body utilizes to perform work. Pulse recovery time following exercise did not seem to correlate with the changes in blood pyruvate except for the hypertensive patients whose ten minute changes and pulse recovery times were of the same magnitude. The group of patients with heart disease was the only one that showed a similar trend in the ten and the sixty minute changes in blood pyruvate for each subject; a high ten minute increase in this group seemed to correspond to a high sixty minute increase. All the hypertensive patients led sedentary lives except 1 truck driver and 1 maintenance man. The former daily lifted heavy objects, while the latter walked about 16 miles (26 kilometers) daily in his work. It is of interest that even though these men were in some form of training, their changes in blood pyruvate were in no way similar to those of the more rigidly trained subjects. The truck driver who daily did some heavy work had a ten minute rise of -j- 64 per cent and a sixty minute change of + 32 per cent, the latter value being the highest in the group. No explanation for this is available. Comparisons of Group Means (figure).—The ten minute values of the trained group contrasted with those of the other groups, and the initial "high normal" levels of some of the trained subjects indicate a change in the mechanism of carbo¬ hydrate utilization of trained persons as opposed to that of subjects in the other groups, whose hearts only are working overtime. This observation suggests a clue to the complex chemical changes involved in "training" and "compensation." These ten minute changes could also conceivably be used as a practical criterion of physical fitness. 9. Dunn, H. L.: (April) 1929. Application of Statistical Methods in Physiology, Physiol. Rev. 9:275 Downloaded From: http://archinte.jamanetwork.com/ by a University of Pittsburgh User on 06/20/2015 made possible by what is known about the work that the heart of a hypertensive person probably of the heart, does more work in twenty-four hours than does the heart of a trained man doing his usual exercise. From this we might expect the hypertensive person to be in some form of training. But the changes in blood pyruvate of the two are notably different. It would appear that the use of body muscles is necessary to achieve the state of training. Thus the old thought that patients with heart disease should exercise up to their respective limits may not have been too far fetched. The mean sixty minute change in blood pyruvate of the trained subjects was 15.1 per cent of the resting levels, that of the untrained subjects —5.7 per cent, that of the hypertensive subjects 0 and that of the subjects with cardiac disease -f- 16.8 per cent. The order of progression from negative to positive sixty minute changes is more or less in keeping with the cardiac function of each group. These sixty minute changes also suggest a possible index of cardiovascular fitness, and further, this test could presumably be used to follow the course of a patient By doing some calculations it can be shown — /o /\/CLAS5 ^.UNTRAINED ' / % GROUP 10 MINUTES I UNTRAINED *63 6 CLASS H-»III TRAINED -»46 0 CLASS * 53 3 3 6 - % GROUP CLASS « 60 MINUTES +16 8 CLASS I UNTRAINED t TRAINED -15 1 0 3 5 7 - Mean changes in blood pyruvate after moderate exercise. with heart disease. This is further supported by the previously mentioned fact that patients of functional class III with heart disease with the poorest cardiac function (with 1 exception) had the highest positive sixty minute changes. This also fits in with a recent paper in which 110 reported high blood levels of pyruvate occurring in patients with heart failure. Comparisons of Lactate.—The literature of changes in blood level of lactic acid following exercise indicates that lactate both in trained and in untrained subjects increases only after strenuous exercise and not after moderate exercise.11 In this study blood pyruvate increased after only light to moderate exercise as much as 131 per cent. Thus, blood pyruvate is available for study as a chemical indicator of physiologic changes related to exercise in untrained subjects on whom severe exercise would be a hardship and in patients who are not capable of undertaking the severe exercise that determination of blood lactate requires. 10. Yanof, Z. A.: Blood Pyruvic Acid in Heart Disease, Arch. Int. Med. 69:1005 (June) 1942. 11. Dill, D. B.: The Economy of Muscular Exercise, Physiol. Rev. 16:263 (April) 1936. Downloaded From: http://archinte.jamanetwork.com/ by a University of Pittsburgh User on 06/20/2015 sixty minute percentage changes were comparable to the stability of blood lactate apparently not after moderate exercise. However, there are no reported changes in lactate that are comparable to the individual negative sixty minute changes in blood pyruvate of the trained group. Blood levels of lactate during rest apparently do not increase with training and so are not comparable to the 4 elevated levels of pyruvate dur¬ ing rest encountered in this study. In the trained subjects the significant and mean thus ten and are The increase of pyruvate in the blood after both moderate and severe 12 exer¬ cise, and the failure of lactate to increase in the blood except after exhausting exercise indicate that pyruvate is an important and obligatory intermediate (if not the principal) metabolite in the chemical mechanism of any muscular contrac¬ tion, with lactate coming into play as a secondary auxiliary system when the anoxic conditions of heavy exercise are present. This fits in with the present day concept of the central place that pyruvic acid occupies in the carbohydrate metabolism of tissue, and is further inferential support of the foregoing observations on the greater sensitivity of pyruvate level in exercise physiology. Analysis of blood pyruvate is also more accurately and more easily accom¬ plished than analysis of lactate. CONCLUSIONS Ten minutes after moderate exercise a group of trained subjects had no sig¬ nificant change in blood level of pyruvate, while untrained subjects and patients with heart disease and with hypertension had in contrast marked rises of pyruvate in the blood. The sixty minute changes of the group of patients with heart disease were significantly high and were proportional to functional capacity. Blood pyruvate measurably increases after moderate exercise in untrained sub¬ jects and in patients with cardiovascular disease, while lactate does not, and so estimations of pyruvate can be utilized in the study of cardiovascular fitness of untrained subjects and patients who are not capable of undertaking the strenuous exercise that measurement of blood lactate requires. Dr. Emmet B. Bay offered guidance and criticism. 950 East Fifty-Ninth Street. Johnson and H. T. Edwards (Lactate and Pyruvate in Blood and Urine After Biol. Chem. 118:427 [April] 1937) and T. E. Friedemann and C. J. Barborka Exercise, J. (The Significance of the Ratio of Lactic to Pyruvic Acid in the Blood After Exercise, ibid. 141:993 [Dec.] 1941) have reported increases in blood pyruvate as accompanying increases in blood lactate in trained subjects after severe exercise. 12. P. E. Downloaded From: http://archinte.jamanetwork.com/ by a University of Pittsburgh User on 06/20/2015
