- Email: [email protected]
HÆMODYNAMIC EFFECTS OF PHYSICAL TRAINING IN CORONARY PATIENTS
8
Where
measured, immunoglobin levels (or serum-electrophoretic determination of serum-globulins) were normal for age; in one child (case 2) for whom specific antibodies were assayed, antiviral antibody was adequate for age and immunisation history. The disproportionate immunological defect in these children-absence of delayed hypersensitivity with a relatively intact immunoglobulin-synthesising abilityseems to be due to failure of development of thymic and peripheral lymphoid tissue. Clinically, this is manifested by extreme susceptibility to Candida albicans and Pseudomonas infections, with early death. From the one instance of progressive vaccinia (case 1) in the only child vaccinated, and from previous reports of similar complications in thymic alymphoplasia, it appears that susceptibility to vaccinia-virus infection is also enhanced. Other instances of similar lymphocyte-immunoglobulin dissociation have been observed. Nezelof et al. (1964) described a 14-month-old boy with persistent C. albicans
-
infection, recurrent diarrhoea, fever, weight-loss, respiratory infections, and skin rash. The finding of persistent lymphopenia, normal levels of y-globulin, an epithelioid thymus, and generalised lymphoid-tissue depletion in this child with a clinical history of extreme susceptibility to infection suggested a new immunological disease. DiGeorge (1965) described congenital absence of the thymus and parathyroid glands in a child, which resulted in a clinical picture similar to those already discussed. Serum-y-globulins were normal. Delayed hypersensitivity was defective, but there was no decrease in circulating small lymphocytes. Fireman et al. (1966) reported a patient with clinical and microscopic features similar to those reported here; but immunoglobulin (Ig)M was normal, although IgA and IgG were deficient. The separate origins and functions of tissues which produce immunoglobulins on the one hand and delayed
hypersensitivity on the other have been demonstrated in chickens (Peterson et al. 1965). We now have evidence for dissociation of immunological capabilities in man. It is yet clear, however, whether this dissociation is comparable with the independent formation of different immunological systems in the chicken, as suggested by Peterson et al. (1965), or is indicative of an even greater
not
complexity
in
immunological development. Summary
Two pairs of sibs showed thymic dysplasia (similar to that seen in Swiss-type agammaglobulinaemia), lymphopenia, and normal immunoglobulins. Three of the children died before the age of 2 years after illnesses characterised by recurrent Pseudomonas and monilia infections. Pathological findings included severe thymic alymphoplasia, lymphoid depletion, and normal plasmacells. The fourth child, still alive, has had repeated infections; he has impaired delayed hypersensitivity, severe lymphopenia, and normal immunoglobulins. The findings in these children indicate that delayed hypersensitivity in man is not related to circulating-antibody-
synthesising capacity. Diphtheria antitoxin and salmonella titres were done by Dr. Elliot Ellis at the University of Florida. This investigation was supported in part by American Cancer Society grant T-138-F and U.S. Public Health Service grants AI 04152 and AI 01632. Requests for reprints should be sent to V.A.F. at the Department of Pediatrics, University of Colorado Medical Center, 4200 East Ninth Avenue, Denver, Colorado 80220, U.S.A.
References at foot of next column
HÆMODYNAMIC EFFECTS OF PHYSICAL TRAINING IN CORONARY PATIENTS E. VARNAUSKAS M.D., Ph.D. Stockholm ASSOCIATE PROFESSOR OF MEDICINE
P. HOUK
H. BERGMAN M.D. Uppsala
M.D. Oklahoma
P.
BJÖRNTORP
M.D. Ph.D.
Gothenburg
SENIOR RESEARCH-WORKER
Service, Sahlgrenska Sjukhuset, University of Gothenburg, Gothenburg, Sweden
From the First Medical
EXPERIMENTAL results indicating that exercise promotes the development of the collateral circulation (Eckerstein 1957) and increases the vascularisation of muscle tissue, including the heart muscle (Petren et al. 1936), seems to have led to the use of physical training in patients with coronary disease (Hellerstein et al. 1963, Naughton and Balke 1964, Holloszy et al. 1964, Sloman et al. 1965, Barry et al. 1966). The beneficial effect of exercise on experimental atherosclerosis in rabbits (Kobernick et al. 1957) suggests that physical training may also influence other factors than circulation in atherosclerotic coronary disease. The effect of training in coronary patients has been evaluated by functional classification, electrocardiography (E.C.G.), vital capacity, various exercise tests, and other indirect methods. An improvement in terms of one or several of these tests has been reported by all workers but no direct measurements of blood-flow and related quantities together with intra-arterial pressure recording have been made. Thus there is no evidence that physical training improves impaired myocardial function in coronary patients (Malmcrona et al. 1963, Foster and Reeves 1964, Malmborg 1965). Most of the limited and to some extent controversial data on the haemodynamic effects of physical training in healthy people (Collett and Liljestrand 1924, Freedman et al. 1955, Frick et al. 1963, Cobb and Johnson 1963) do not supply much information about the mechanisms of circulatory adjustment to the increased physical activity. The exception is an investigation by Andrew et al. (1966) who measured the effect of athletic training on cardiac output during exercise in young people. It cannot be excluded that circulatory mechanisms other than effects of the heart can be to a large extent responsible for the feeling of improvement and for the increased working-capacity attained by coronary patients after a period of physical training. We have evaluated the haemodynamic and metabolic changes at rest and during exercise after 4-6 weeks of physical training in patients with coronary disease (Bergman et al. 1966).
Bruton, O. C. (1952) Pediatrics, Springfield, 9, 722. DiGeorge, A. M. (1965) J. Pediatrics, 67, 907. Fireman, P., Johnson, H. A., Gitlin, D. (1966) Pediatrics, Springfield, 37, 485.
Gitlin, D., Craig, J. M. (1963) ibid. 32, 517. Glanzmann, E., Rinkiker, P. (1950) Annls pœdiat. 175, 1. Good, R. A., Bridges, R. A., Zak, S. J., Pappenheimer, A. M. (1959) Mechanisms of Hypersensitivity; p. 467. Boston. Hathaway, W. E., Githens, J. J., Blackburn, W. R., Fulginiti, V., Kempe, C. H. (1965) New. Engl. J. Med. 273, 953. Hitzig, W. H., Willi, H. (1961) Schweiz. med. Wschr. 52, 1625. Janeway, C. A., Apt, L., Gitlin, D. (1953) Trans. Ass. Am. Physns, 66, 200. Nezelof, C., Jammet, M. L., Lortholary, P., Labrune, B., Lamy, M. (1964) Archs fr. Pediat. 21, 897. Peterson, R. D. A., Cooper, M. D., Good, R. A. (1965) Am. J. Med. 38, 579.
9 Patients and Methods
Barker and Summerson (1941) and plasma volume was measured with 131I-tagged albumin in 3 patients. The exercise was done on a bicycle ergometer (Holmgren and Mattsson 1954), work load being adjusted individually to the patient’s submaximal physical capacity which was assessed clinically and from a work test with E.C.G. recording. The work load varied between 150 and 500 k.p.m. per minute.
Patients 8 males
aged
43-55 and 1 female
(no. 9) aged 59
were
selected for investigation (table i). The selection depended
on
ability, domestic and economic, to participate in the training programme. All patients were active in their professions and almost all were engaged in some additional physical activities such as housework, long-distance walking, or
their
Training
gardening. The diagnosis of coronary disease was established on clinical and laboratory grounds. Coronary angiography was planned in all patients, and we intended to repeat the investigation after a year of training. Coronary angiography was not done in 2 patients because of the atherosclerotic changes in the femoral arteries and in 1 patient because of generally negative attitude towards the investigation. The findings in the other 5 patients
The same bicycle ergometer, permitting graded exercise with continuous E.c.G. monitoring, was used for training. The duration of each training-session was 30 minutes. A basal work load was chosen for each person and this was increased by 50% for every 1-3 minutes at intervals of 5 minutes. The training started with the same work load as during the haemodynamic investigation. The exercise level was increased gradually during the training-period. The general condition of the patient was were graded and are presented in table I. the determining factor for the speed and the limit of the No patient was in cardiac failure or was given digitalis. The increase in work load. cardiac size, on X-ray, did not exceed 470 c.cm. per sq. m. Patients came to the laboratory every day during the first body-surface area. All of them had a history of angina pectoris week and every other day (Sundays excluded), during the on exertion. Only 4 patients (nos. 5, 7, 8, and 9) were taking weeks. This time schedule was accomplished by all following glyceryl trinitrate occasionally. with the exception of a few occasions when the patients The patients were in hospital for 7-10 days for clinical and patients did not appear because of intercurrent minor illness or technical laboratory investigations including coronary angiography reasons. All patients were in a well-trained condition at least (Varnauskas et al. 1962, Paulin 1964). for 1 week before the second haemodynamic investigation. Hcemodynamic Measurements The cycling was usually done under the supervision of a Tests were done 3-5 days before the beginning of the doctor with the assistance of a nurse. All modern resuscitation training and were repeated 4-6 weeks after it, using exactly the equipment was always at hand, but it was never needed. same methods and procedure. 5 patients had chest pain on exercise at least once during the The patients were investigated in the morning before breakmonth of training, but it was not regarded as a complication since one of the purposes of the investigation was the evaluation of fast. The brachial artery and subclavian vein were catheterised and the patient was allowed to rest for 30 minutes. At the end the effect of training on symptoms. Cycling was discontinued, of this period heart-rate, blood-pressure, oxygen consumption, however, for a period of time needed for the pain to disappear and cardiac output were measured and blood-samples for or at least for 1 minute and then resumed again on a somewhat blood-gas analysis were taken. The patient then started to lower exercise level. 1 patient had slight supraventricular tachycardia during the exercise and the same measurements were repeated after 5 and 25 minutes of exercise, and also during the recovery period. cycling on the first day of training, but he did not have any The E.c.G. was monitored continuously. The brachialsymptoms from his tachycardia and the cycling could be comartery pressure was measured by connecting the intra-arterial pleted. The training proceeded uneventfully during later weeks. catheter to the electromanometer set, consisting of a variableThe programme of training was interrupted for a week in inductance pressure transducer feeding an amplifier (Elema). another patient because of tendovaginitis crepitans in one of Blood-pressure and one E.c.G. lead were recorded photo- the heel tendons. The work load tolerated by the patients could be increased graphically. Expired air for analysis was collected in a Douglas bag. Oxygen and carbon dioxide were measured in a considerably towards the end of the training-period. This does Scholander apparatus, and the oxygen consumption and not necessarily represent the real increase in working-capacity, carbon-dioxide production were calculated. Arterial bloodbecause the initial work load might have been too low in some were for the carbon and of the patients. oxygen, dioxide, analysed samples value of oxygen capacity in aBeckman B ’ spectrophotometer. The heart-rate increased gradually during each cycling and The cardiac output was determined by the dye dilution reached highest values at the end of the cycling. The highest (Hamilton et al. 1931) using bromsulphthalein as the indicator heart-rate reached after the training, was well in excess of the (Wassen 1956). The arteriovenous oxygen difference was highest value obtained before the training. The increase of the heart-rate corresponded to the progressively increasing work calculated from oxygen consumption and cardiac output, by the Fick formula. Blood-lactate was measured by the method of load during this period. ’
TABLE I-ANTHROPOMETRIC AND CLINICAL DETAILS BEFORE AND AFTER TRAINING
Figures in parentheses show values after A = Stenosis without delayed filling.
a
month’s
training.
B= c=
Stenosis with Occlusion.
delayed filling,
:-.; = Normal.
P = Pathological.
10 TABLE II-THE RESULTS OF THE HIRMODYNAMIC STUDIES
The patients were instructed to live their normal life during the training-period. Medical treatment was not changed. Results
’
The working-capacity, assessed clinically, increased in all patients. The patients noted that a strikingly heavier degree of exertion was necessary to provoke chest pain and/or breathlessness after the training than before. They might have increased their daily physical activities apart from training, but this is difficult to assess. The mean differences between hxmodynamic values before and after training are shown in table n. The haemodynamic data were not accepted from the pretraining investigation in patient 8 because he had a vasovagal reaction with bradycardia and blood-pressure fall towards the end of exercise, and thus was not in a steady state. His results were excluded from the statistical calculations. An error in the time setting of the rotating blood-sample collector for cardiac output measurement, made it necessary to omit the cardiac output values and related measurements from the post-training run in patient 6. Leakage in the collecting system of expired air, caused the exclusion of ventilation and oxygen consumption values during the fifth minute of exercise in the
difference
only about 2 beats per minute and thus biologically important. were only small changes in the ventilation was
may not be
There between the two occasions of measurement but the differences were inconclusive. There were no consistent changes in the oxygen uptake (fig. 1). This relatively good conformity of ventilation and oxygen consumption between the two investigations, suggests that the patients were in a relatively basal state
in patient 7. The results of the female patient were not included in the statistical calculations. The values of the heart-rate showed a small decrease after training in the majority of the patients. This decrease The was significant only for the recovery periods.
post-training investigation
Fig. 2-Effect of training
The 45° line represents
on
For
consumption in male patients. values before and after training.
oxygen
equal
key
see
fig.
2.
cardiac output.
the first examination and that they performed similar amount of work on both occasions. The cardiac output was lower after the training than before, in all phases of the investigation (fig. 2). Differences were significant only for the two sets of measurements during exercise; the increase from rest to exercise was nearly the same on both occasions. The arteriovenous oxygen difference increased with the decreasing cardiac output, but was significant only during the fifth minute of exercise (fig. 3). Significantly lower values of stroke volume were found during the twenty-fifth minute of exercise and during the recovery period. These differences were quite small and seem to have resulted from the more pronounced decrease of cardiac output rather than from the heart-rate. The blood-pressure was generally slightly but not significantly lower after training.
during
a
Fig. l-Effect of training
on
11
Fig. 3-Effect of training
on
arteriovenous oxygen difference in
males.
For
key
see
fig.
2.
The result of the simultaneous blood-flow and bloodpressure decrease was reflected in the lower values of the effective left-ventricular work during the two phases of exercise. The haemoglobin values were slightly and consistently higher after the training than before, in all phases of the haemodynamic investigations. Since resting-values for plasma volume in the 3 patients where it was determined were unchanged, the increase of hxmoglobin suggests a real increase of the total haemoglobin and total bloodvolume. The haemoglobin capacity of the blood increased in all patients, except one. The mean increase was not significant. Respiratory quotients were somewhat lower after the training than before, except in 1 patient. The differences were not significant. Blood-lactate was lower, especially in the exercise period (fig. 4). The fasting-values of serum-cholesterol and serumtriglycerides which were elevated in the majority of the patients, disclosed variable and inconclusive changes after training. There was no substantial weight loss during the period of study. The heart size, determined by X-ray, remained unchanged. The haemodynamic changes noted after training were of the same direction and similar in magnitude in the female patient. Discussion
of measurements were obtained from Complete a few only patients; and some of the statistically insets
Fig. 4-Effect of training For
key
see
on
fig.
blood-lactate. 2.
significant changes after physical training might be significant if the investigations were repeated on a larger number of patients. Are these changes due to increased physical activity of the patient or can they be explained by lesser degree of anxiety during the second investigation ? The decrease of cardiac output was the most outstanding haemodynamic effect of physical training (fig. 2). This lesser degree of anxiety during the second investigation could be suspected as a responsible factor for the decrease of cardiac output. But then one would also expect a significant decrease of ventilation and oxygen consumption, but this did not happen. The blood-lactate after training diminished. This strongly suggests that the decrease of blood-flow was a physiologically significant result of the physical training and does not indicate that psychological relaxation and increased self-confidence had any significant effect on the hxmodynamic results. This suggestion is further supported by the observation that similar investigations repeated within 1 week in this laboratory, disclosed no significant differences in blood-flow, heart-rate or bloodpressure (Schroder 1964). It is also improbable that the decrease in cardiac output was due to less work being done by the patient during the post-training investigation. The basic mechanism of the cardiac output decrease be a more effective redistribution of blood-flow from the different organ systems and non-exercising muscles to the capillary bed of the exercising muscles. I The increase of the arteriovenous oxygen difference (fig. 3) which was due to the lowering of the oxygen content in the mixed venous blood is evidence for this hypothesis. Concentration of oxygen in mixed venous blood is here determined by the ratio of its rate of exchange with the tissue to the blood-flow through the tissue of different organs. The well-known effect of exercise in decreasing renal and splanchnic blood-flow may be enhanced by the physical training. The lower blood-supply to these, and possibly other systems, would result in a decrease of venous oxygen content if the rate of oxygen exchange with the tissue remains unchanged or increases. Blood-flow redistribution may also take place within the working muscle. The availability of oxygen to a tissue depends not only on the composition of the blood and its rate of flow through the tissue but also on the distribution of the flow-i.e. on the number and distribution of open capillaries. The blood-flow through the compartments of relatively rapid circulation and of low rate of oxygen exchange, may be cut down by some mechanism after a period of physical training, thus decreasing the of venous blood with higher oxygen content. admixture This, together with increased vascularisation, would then result in the enlargement of the effective area for oxygen diffusion in the exercising muscles. An improvement of oxygen supply to the working muscle cell would be expected. Indirect evidence that this really happened is found in the blood-lactate which decreased significantly after the training (fig. 4). The improvement of aerobic metabolism is also suggested by a slight decrease in respiratory quotient, even though this decrease was not significant in our series. The more effective blood-flow redistribution was probably promoted by an increased ability of the vessels to constrict in some regions and to dilate in the capillary bed of the exercising muscles. There was also another important factor contributing to the mechanism responsible for the lowering of the total blood-flow after the seems to
A3
12
training: the hxmoglobin and oxygen capacity of the blood increased, as compared with the pre-training values, even though plasma volume remained unchanged in the 3 patients in whom it was measured. Haemoglobin is known to increase in healthy people (Astrand 1956) and in patients with neurocirculatory disturbances (Holmgren et al. 1959). The blood-pressure decreased in most instances but the decrease was not significant. The lowering of the cardiac output, together with unchanged or increased blood-volume, may have contributed to this decrease in blood-pressure. The pressure drop, together with the decreased blood-flow, resulted in a significant lowering of the left-ventricular work. This suggests a decreased energy demand on the left ventricle, even if the effective left-ventricular work is poorly related to the total energy consumption of the left ventricle. There was no doubt about the improvement of the symptoms in all these patients. They tolerated a higher degree of exertion before the appearance of chest pain or dyspnoea and the consumption of glyceryl trinitrate was reduced in patients who were using this medication. It is, however, difficult to demonstrate conclusively that this subjective improvement was a direct result of the hsemodynamic changes, observed after 1 month of training. The psychological rehabilitation and the increased selfconfidence which probably accompanied the physical training may have played an important role in raising the pain threshold. On the other hand, an increased selfconfidence would also encourage a higher degree of daily physical activity apart from the cycling, and this confirms the haemodynamic effects of the training conducted by us. The hxmodynamic effect of training which could possibly be responsible for an increased working capacity with respect to symptoms is probably the significantly lowered left-ventricular work. To this could be added the possibility that training may accelerate a development of collateral intercoronary circulation and thus improve the blood-supply to the ischaemic parts of the myocardium, as demonstrated in animal experiments (Eckerstein 1957). Repetition of the coronary angiography and coronary blood-flow measurements which are included in the present study may give more direct evidence to evaluate the validity of this speculation. The biological significance of the inconclusive serum cholesterol and triglyceride changes is difficult to assess. It is interesting to note that similar findings were observed in animals with cholesterol-induced atherosclerosis (Kobernick et al. 1957). Exercise did not influence the serum-level of cholesterol, phospholipids, cholesterol esters, and total cholesterol/phospholipid ratios. But the deposit of the atheromatous plaques in the aorta was significantly smaller in the exercise group of animals than in the sedentary group.
Summary
hxmodynamic and metabolic effects investigate of physical training, 8 male and 1 female middle-aged patients with coronary disease were examined during rest and while exercising before and after a month of training on a bicycle ergometer. All patients improved clinically the
To
increased exercise tolerance with respect to angina pectoris (and dyspnoea). Hxmodynamically there was an adjustment of the circulation towards a hypokinetic state and a reduction of the work of the left ventricle. Furthermore, the increase in blood-lactate resulting from exercise was significantly less after training. The hxmoglobin was significantly increased.
and showed
an
This work was supported by a grant from the Swedish National Association against heart and chest disease. Requests for reprints should be addressed to Dr. E. Varnauskas, Sahlgrenska Sjukuset, University of Gothenburg, Gothenburg, Sweden. REFERENCES
Andrew, G. M., Guzman, C. A., Becklake, M. R. (1966) J. appl. Physiol. 21, 603.
Åstrand,
P.-O. (1956) Physiol. Rev. 36, 307. Barker, S. D., Summerson, W. H. (1941) S biol. Chem. 138, 535. Barry, A. J., Daly, J. W., Pruett, E. D. R., Jteinmetz, J. R., Birkhead, N. C., Rodahl, K. (1966) Am. J. Cardiol. 17, 1. Bergman, H., Bjorntorp, P., Houk, P., Varnauskas, E., Westerlund, A. (1966) Svenska Läkartidn. 63, 407. Cobb, L. A., Johnson, W. P. (1963) J. clin. Invest. 42, 800. Collett, M. E., Liljestrand, G. (1924) Skand. Arch. Physiol. 45, 29. Eckerstein, R. W. (1957) Circulation Res. 5, 230. Foster, G. L., Reeves, T. J. (1964) J. clin. Invest. 43, 1758. Freedman, M. E., Snider, G. L., Brostoff, P., Kimelblot, S., Katz, L. N. (1955) J. appl. Physiol. 8, 37. Frick, M. H., Konttinen, A., Sarajas, H. S. S. (1963) Am. J. Cardiol. 12, 142. Hamilton, W. F., Moore, J. W., Kinsman, J. M., Spurling, R. G. (1931) Am. J. Physiol. 99, 534. Hellerstein, H. K., Hirsch, E. Z., Cumler, W., Allen, L., Polster, S., Zucker, N. (1963) in Coronary Heart Disease (edited by W. Likoff and J. H. Moyer); p. 448. London and New York. Holloszy, J. O., Skinner, J. S., Barry, A. J., Cureton, T. K. (1964) Am. J. Cardiol. 14, 761. Holmgren, A., Jonsson, B., Levander, M., Linderholm, H., Mossfeldt, F., Sjostrand, T., Strörn, G. (1959) Acta med. scand. 165, 89. Mattsson, K. H. (1954) Scand. J. clin. Lab. Invest. 6, 137. Kobernick, S. D., Niwayama, G., Zuchlewski, A. C. (1957) Proc. Soc. exp. Biol. Med. 96, 623. Malmborg, R. O. (1965) Acta med. scand. 177, suppl. 426. Malmcrona, R., Cramer, G., Varnauskas, E. (1963) ibid. 174, 557. Naughton, J., Balke, B. (1964) Am. J. med. Sci. 247, 286. Paulin, S. (1964) Acta radiol. suppl. 233. Petrén, T., Sjöstrand, T., Sylven, B. (1936) Arbeitsphysiol. 9, 376. Schröder, G. (1964) Scand. J. clin. Lab. Invest. 16, 559. Sloman, G., Pitt, A., Hirsch, E. Z., Donaldson, A. (1965) Med. J. Aust. 1,4. Varnauskas, E., Paulin, S., Forsberg, S. Å. (1962) Int. Congr. Radiol. Wassén, A. (1956) Scand. J. clin. Invest. 8, 189. -
BACTERIOLOGY AND BILE-SALT METABOLISM IN PATIENTS WITH INTESTINAL MALABSORPTION
JEJUNAL
SOAD
TABAQCHALI
M.B. St. And. RESEARCH FELLOW
C. C. BOOTH And., F.R.C.P.
M.D. St.
PHYSICIAN AND LECTURER
POSTGRADUATE MEDICAL SCHOOL OF
LONDON,
LONDON
W.12
BILE salts, which are needed for normal fat absorption, present in the jejunal lumen in conjugated forms. When these conjugated bile salts are exposed to the activity of colonic bacteria they are hydrolysed to form free bile acids, mainly cholic acid and chenodeoxycholic acid. Cholic acid is further broken down into deoxycholic acid and other metabolites (Bergstrom et al. 1960). Of these, deoxycholic acid has been shown to be toxic to the small intestinal mucosa in vitro (Dawson and Isselbacher 1960). The upper small intestine ordinarily is sterile in the fasting state (Cregan et al. 1953, Tabaqchali et al. 1966). In patients with steatorrhoea caused by the stagnant-loop syndrome, however, there is usually a luxuriant growth of colonic bacteria in the small bowel. In these patients the steatorrhoea has been suggested to be due to a toxic effect of free bile acids formed by bacterial activity in the lumen of the small gut (Dawson and Isselbacher 1960). It has further been shown that deoxycholic acid may inhibit the uptake and esterification of fatty acids by the intestinal mucosa in vitro (Dawson and Isselbacher 1960, Donaldson are
1965).
Where
measured, immunoglobin levels (or serum-electrophoretic determination of serum-globulins) were normal for age; in one child (case 2) for whom specific antibodies were assayed, antiviral antibody was adequate for age and immunisation history. The disproportionate immunological defect in these children-absence of delayed hypersensitivity with a relatively intact immunoglobulin-synthesising abilityseems to be due to failure of development of thymic and peripheral lymphoid tissue. Clinically, this is manifested by extreme susceptibility to Candida albicans and Pseudomonas infections, with early death. From the one instance of progressive vaccinia (case 1) in the only child vaccinated, and from previous reports of similar complications in thymic alymphoplasia, it appears that susceptibility to vaccinia-virus infection is also enhanced. Other instances of similar lymphocyte-immunoglobulin dissociation have been observed. Nezelof et al. (1964) described a 14-month-old boy with persistent C. albicans
-
infection, recurrent diarrhoea, fever, weight-loss, respiratory infections, and skin rash. The finding of persistent lymphopenia, normal levels of y-globulin, an epithelioid thymus, and generalised lymphoid-tissue depletion in this child with a clinical history of extreme susceptibility to infection suggested a new immunological disease. DiGeorge (1965) described congenital absence of the thymus and parathyroid glands in a child, which resulted in a clinical picture similar to those already discussed. Serum-y-globulins were normal. Delayed hypersensitivity was defective, but there was no decrease in circulating small lymphocytes. Fireman et al. (1966) reported a patient with clinical and microscopic features similar to those reported here; but immunoglobulin (Ig)M was normal, although IgA and IgG were deficient. The separate origins and functions of tissues which produce immunoglobulins on the one hand and delayed
hypersensitivity on the other have been demonstrated in chickens (Peterson et al. 1965). We now have evidence for dissociation of immunological capabilities in man. It is yet clear, however, whether this dissociation is comparable with the independent formation of different immunological systems in the chicken, as suggested by Peterson et al. (1965), or is indicative of an even greater
not
complexity
in
immunological development. Summary
Two pairs of sibs showed thymic dysplasia (similar to that seen in Swiss-type agammaglobulinaemia), lymphopenia, and normal immunoglobulins. Three of the children died before the age of 2 years after illnesses characterised by recurrent Pseudomonas and monilia infections. Pathological findings included severe thymic alymphoplasia, lymphoid depletion, and normal plasmacells. The fourth child, still alive, has had repeated infections; he has impaired delayed hypersensitivity, severe lymphopenia, and normal immunoglobulins. The findings in these children indicate that delayed hypersensitivity in man is not related to circulating-antibody-
synthesising capacity. Diphtheria antitoxin and salmonella titres were done by Dr. Elliot Ellis at the University of Florida. This investigation was supported in part by American Cancer Society grant T-138-F and U.S. Public Health Service grants AI 04152 and AI 01632. Requests for reprints should be sent to V.A.F. at the Department of Pediatrics, University of Colorado Medical Center, 4200 East Ninth Avenue, Denver, Colorado 80220, U.S.A.
References at foot of next column
HÆMODYNAMIC EFFECTS OF PHYSICAL TRAINING IN CORONARY PATIENTS E. VARNAUSKAS M.D., Ph.D. Stockholm ASSOCIATE PROFESSOR OF MEDICINE
P. HOUK
H. BERGMAN M.D. Uppsala
M.D. Oklahoma
P.
BJÖRNTORP
M.D. Ph.D.
Gothenburg
SENIOR RESEARCH-WORKER
Service, Sahlgrenska Sjukhuset, University of Gothenburg, Gothenburg, Sweden
From the First Medical
EXPERIMENTAL results indicating that exercise promotes the development of the collateral circulation (Eckerstein 1957) and increases the vascularisation of muscle tissue, including the heart muscle (Petren et al. 1936), seems to have led to the use of physical training in patients with coronary disease (Hellerstein et al. 1963, Naughton and Balke 1964, Holloszy et al. 1964, Sloman et al. 1965, Barry et al. 1966). The beneficial effect of exercise on experimental atherosclerosis in rabbits (Kobernick et al. 1957) suggests that physical training may also influence other factors than circulation in atherosclerotic coronary disease. The effect of training in coronary patients has been evaluated by functional classification, electrocardiography (E.C.G.), vital capacity, various exercise tests, and other indirect methods. An improvement in terms of one or several of these tests has been reported by all workers but no direct measurements of blood-flow and related quantities together with intra-arterial pressure recording have been made. Thus there is no evidence that physical training improves impaired myocardial function in coronary patients (Malmcrona et al. 1963, Foster and Reeves 1964, Malmborg 1965). Most of the limited and to some extent controversial data on the haemodynamic effects of physical training in healthy people (Collett and Liljestrand 1924, Freedman et al. 1955, Frick et al. 1963, Cobb and Johnson 1963) do not supply much information about the mechanisms of circulatory adjustment to the increased physical activity. The exception is an investigation by Andrew et al. (1966) who measured the effect of athletic training on cardiac output during exercise in young people. It cannot be excluded that circulatory mechanisms other than effects of the heart can be to a large extent responsible for the feeling of improvement and for the increased working-capacity attained by coronary patients after a period of physical training. We have evaluated the haemodynamic and metabolic changes at rest and during exercise after 4-6 weeks of physical training in patients with coronary disease (Bergman et al. 1966).
Bruton, O. C. (1952) Pediatrics, Springfield, 9, 722. DiGeorge, A. M. (1965) J. Pediatrics, 67, 907. Fireman, P., Johnson, H. A., Gitlin, D. (1966) Pediatrics, Springfield, 37, 485.
Gitlin, D., Craig, J. M. (1963) ibid. 32, 517. Glanzmann, E., Rinkiker, P. (1950) Annls pœdiat. 175, 1. Good, R. A., Bridges, R. A., Zak, S. J., Pappenheimer, A. M. (1959) Mechanisms of Hypersensitivity; p. 467. Boston. Hathaway, W. E., Githens, J. J., Blackburn, W. R., Fulginiti, V., Kempe, C. H. (1965) New. Engl. J. Med. 273, 953. Hitzig, W. H., Willi, H. (1961) Schweiz. med. Wschr. 52, 1625. Janeway, C. A., Apt, L., Gitlin, D. (1953) Trans. Ass. Am. Physns, 66, 200. Nezelof, C., Jammet, M. L., Lortholary, P., Labrune, B., Lamy, M. (1964) Archs fr. Pediat. 21, 897. Peterson, R. D. A., Cooper, M. D., Good, R. A. (1965) Am. J. Med. 38, 579.
9 Patients and Methods
Barker and Summerson (1941) and plasma volume was measured with 131I-tagged albumin in 3 patients. The exercise was done on a bicycle ergometer (Holmgren and Mattsson 1954), work load being adjusted individually to the patient’s submaximal physical capacity which was assessed clinically and from a work test with E.C.G. recording. The work load varied between 150 and 500 k.p.m. per minute.
Patients 8 males
aged
43-55 and 1 female
(no. 9) aged 59
were
selected for investigation (table i). The selection depended
on
ability, domestic and economic, to participate in the training programme. All patients were active in their professions and almost all were engaged in some additional physical activities such as housework, long-distance walking, or
their
Training
gardening. The diagnosis of coronary disease was established on clinical and laboratory grounds. Coronary angiography was planned in all patients, and we intended to repeat the investigation after a year of training. Coronary angiography was not done in 2 patients because of the atherosclerotic changes in the femoral arteries and in 1 patient because of generally negative attitude towards the investigation. The findings in the other 5 patients
The same bicycle ergometer, permitting graded exercise with continuous E.c.G. monitoring, was used for training. The duration of each training-session was 30 minutes. A basal work load was chosen for each person and this was increased by 50% for every 1-3 minutes at intervals of 5 minutes. The training started with the same work load as during the haemodynamic investigation. The exercise level was increased gradually during the training-period. The general condition of the patient was were graded and are presented in table I. the determining factor for the speed and the limit of the No patient was in cardiac failure or was given digitalis. The increase in work load. cardiac size, on X-ray, did not exceed 470 c.cm. per sq. m. Patients came to the laboratory every day during the first body-surface area. All of them had a history of angina pectoris week and every other day (Sundays excluded), during the on exertion. Only 4 patients (nos. 5, 7, 8, and 9) were taking weeks. This time schedule was accomplished by all following glyceryl trinitrate occasionally. with the exception of a few occasions when the patients The patients were in hospital for 7-10 days for clinical and patients did not appear because of intercurrent minor illness or technical laboratory investigations including coronary angiography reasons. All patients were in a well-trained condition at least (Varnauskas et al. 1962, Paulin 1964). for 1 week before the second haemodynamic investigation. Hcemodynamic Measurements The cycling was usually done under the supervision of a Tests were done 3-5 days before the beginning of the doctor with the assistance of a nurse. All modern resuscitation training and were repeated 4-6 weeks after it, using exactly the equipment was always at hand, but it was never needed. same methods and procedure. 5 patients had chest pain on exercise at least once during the The patients were investigated in the morning before breakmonth of training, but it was not regarded as a complication since one of the purposes of the investigation was the evaluation of fast. The brachial artery and subclavian vein were catheterised and the patient was allowed to rest for 30 minutes. At the end the effect of training on symptoms. Cycling was discontinued, of this period heart-rate, blood-pressure, oxygen consumption, however, for a period of time needed for the pain to disappear and cardiac output were measured and blood-samples for or at least for 1 minute and then resumed again on a somewhat blood-gas analysis were taken. The patient then started to lower exercise level. 1 patient had slight supraventricular tachycardia during the exercise and the same measurements were repeated after 5 and 25 minutes of exercise, and also during the recovery period. cycling on the first day of training, but he did not have any The E.c.G. was monitored continuously. The brachialsymptoms from his tachycardia and the cycling could be comartery pressure was measured by connecting the intra-arterial pleted. The training proceeded uneventfully during later weeks. catheter to the electromanometer set, consisting of a variableThe programme of training was interrupted for a week in inductance pressure transducer feeding an amplifier (Elema). another patient because of tendovaginitis crepitans in one of Blood-pressure and one E.c.G. lead were recorded photo- the heel tendons. The work load tolerated by the patients could be increased graphically. Expired air for analysis was collected in a Douglas bag. Oxygen and carbon dioxide were measured in a considerably towards the end of the training-period. This does Scholander apparatus, and the oxygen consumption and not necessarily represent the real increase in working-capacity, carbon-dioxide production were calculated. Arterial bloodbecause the initial work load might have been too low in some were for the carbon and of the patients. oxygen, dioxide, analysed samples value of oxygen capacity in aBeckman B ’ spectrophotometer. The heart-rate increased gradually during each cycling and The cardiac output was determined by the dye dilution reached highest values at the end of the cycling. The highest (Hamilton et al. 1931) using bromsulphthalein as the indicator heart-rate reached after the training, was well in excess of the (Wassen 1956). The arteriovenous oxygen difference was highest value obtained before the training. The increase of the heart-rate corresponded to the progressively increasing work calculated from oxygen consumption and cardiac output, by the Fick formula. Blood-lactate was measured by the method of load during this period. ’
TABLE I-ANTHROPOMETRIC AND CLINICAL DETAILS BEFORE AND AFTER TRAINING
Figures in parentheses show values after A = Stenosis without delayed filling.
a
month’s
training.
B= c=
Stenosis with Occlusion.
delayed filling,
:-.; = Normal.
P = Pathological.
10 TABLE II-THE RESULTS OF THE HIRMODYNAMIC STUDIES
The patients were instructed to live their normal life during the training-period. Medical treatment was not changed. Results
’
The working-capacity, assessed clinically, increased in all patients. The patients noted that a strikingly heavier degree of exertion was necessary to provoke chest pain and/or breathlessness after the training than before. They might have increased their daily physical activities apart from training, but this is difficult to assess. The mean differences between hxmodynamic values before and after training are shown in table n. The haemodynamic data were not accepted from the pretraining investigation in patient 8 because he had a vasovagal reaction with bradycardia and blood-pressure fall towards the end of exercise, and thus was not in a steady state. His results were excluded from the statistical calculations. An error in the time setting of the rotating blood-sample collector for cardiac output measurement, made it necessary to omit the cardiac output values and related measurements from the post-training run in patient 6. Leakage in the collecting system of expired air, caused the exclusion of ventilation and oxygen consumption values during the fifth minute of exercise in the
difference
only about 2 beats per minute and thus biologically important. were only small changes in the ventilation was
may not be
There between the two occasions of measurement but the differences were inconclusive. There were no consistent changes in the oxygen uptake (fig. 1). This relatively good conformity of ventilation and oxygen consumption between the two investigations, suggests that the patients were in a relatively basal state
in patient 7. The results of the female patient were not included in the statistical calculations. The values of the heart-rate showed a small decrease after training in the majority of the patients. This decrease The was significant only for the recovery periods.
post-training investigation
Fig. 2-Effect of training
The 45° line represents
on
For
consumption in male patients. values before and after training.
oxygen
equal
key
see
fig.
2.
cardiac output.
the first examination and that they performed similar amount of work on both occasions. The cardiac output was lower after the training than before, in all phases of the investigation (fig. 2). Differences were significant only for the two sets of measurements during exercise; the increase from rest to exercise was nearly the same on both occasions. The arteriovenous oxygen difference increased with the decreasing cardiac output, but was significant only during the fifth minute of exercise (fig. 3). Significantly lower values of stroke volume were found during the twenty-fifth minute of exercise and during the recovery period. These differences were quite small and seem to have resulted from the more pronounced decrease of cardiac output rather than from the heart-rate. The blood-pressure was generally slightly but not significantly lower after training.
during
a
Fig. l-Effect of training
on
11
Fig. 3-Effect of training
on
arteriovenous oxygen difference in
males.
For
key
see
fig.
2.
The result of the simultaneous blood-flow and bloodpressure decrease was reflected in the lower values of the effective left-ventricular work during the two phases of exercise. The haemoglobin values were slightly and consistently higher after the training than before, in all phases of the haemodynamic investigations. Since resting-values for plasma volume in the 3 patients where it was determined were unchanged, the increase of hxmoglobin suggests a real increase of the total haemoglobin and total bloodvolume. The haemoglobin capacity of the blood increased in all patients, except one. The mean increase was not significant. Respiratory quotients were somewhat lower after the training than before, except in 1 patient. The differences were not significant. Blood-lactate was lower, especially in the exercise period (fig. 4). The fasting-values of serum-cholesterol and serumtriglycerides which were elevated in the majority of the patients, disclosed variable and inconclusive changes after training. There was no substantial weight loss during the period of study. The heart size, determined by X-ray, remained unchanged. The haemodynamic changes noted after training were of the same direction and similar in magnitude in the female patient. Discussion
of measurements were obtained from Complete a few only patients; and some of the statistically insets
Fig. 4-Effect of training For
key
see
on
fig.
blood-lactate. 2.
significant changes after physical training might be significant if the investigations were repeated on a larger number of patients. Are these changes due to increased physical activity of the patient or can they be explained by lesser degree of anxiety during the second investigation ? The decrease of cardiac output was the most outstanding haemodynamic effect of physical training (fig. 2). This lesser degree of anxiety during the second investigation could be suspected as a responsible factor for the decrease of cardiac output. But then one would also expect a significant decrease of ventilation and oxygen consumption, but this did not happen. The blood-lactate after training diminished. This strongly suggests that the decrease of blood-flow was a physiologically significant result of the physical training and does not indicate that psychological relaxation and increased self-confidence had any significant effect on the hxmodynamic results. This suggestion is further supported by the observation that similar investigations repeated within 1 week in this laboratory, disclosed no significant differences in blood-flow, heart-rate or bloodpressure (Schroder 1964). It is also improbable that the decrease in cardiac output was due to less work being done by the patient during the post-training investigation. The basic mechanism of the cardiac output decrease be a more effective redistribution of blood-flow from the different organ systems and non-exercising muscles to the capillary bed of the exercising muscles. I The increase of the arteriovenous oxygen difference (fig. 3) which was due to the lowering of the oxygen content in the mixed venous blood is evidence for this hypothesis. Concentration of oxygen in mixed venous blood is here determined by the ratio of its rate of exchange with the tissue to the blood-flow through the tissue of different organs. The well-known effect of exercise in decreasing renal and splanchnic blood-flow may be enhanced by the physical training. The lower blood-supply to these, and possibly other systems, would result in a decrease of venous oxygen content if the rate of oxygen exchange with the tissue remains unchanged or increases. Blood-flow redistribution may also take place within the working muscle. The availability of oxygen to a tissue depends not only on the composition of the blood and its rate of flow through the tissue but also on the distribution of the flow-i.e. on the number and distribution of open capillaries. The blood-flow through the compartments of relatively rapid circulation and of low rate of oxygen exchange, may be cut down by some mechanism after a period of physical training, thus decreasing the of venous blood with higher oxygen content. admixture This, together with increased vascularisation, would then result in the enlargement of the effective area for oxygen diffusion in the exercising muscles. An improvement of oxygen supply to the working muscle cell would be expected. Indirect evidence that this really happened is found in the blood-lactate which decreased significantly after the training (fig. 4). The improvement of aerobic metabolism is also suggested by a slight decrease in respiratory quotient, even though this decrease was not significant in our series. The more effective blood-flow redistribution was probably promoted by an increased ability of the vessels to constrict in some regions and to dilate in the capillary bed of the exercising muscles. There was also another important factor contributing to the mechanism responsible for the lowering of the total blood-flow after the seems to
A3
12
training: the hxmoglobin and oxygen capacity of the blood increased, as compared with the pre-training values, even though plasma volume remained unchanged in the 3 patients in whom it was measured. Haemoglobin is known to increase in healthy people (Astrand 1956) and in patients with neurocirculatory disturbances (Holmgren et al. 1959). The blood-pressure decreased in most instances but the decrease was not significant. The lowering of the cardiac output, together with unchanged or increased blood-volume, may have contributed to this decrease in blood-pressure. The pressure drop, together with the decreased blood-flow, resulted in a significant lowering of the left-ventricular work. This suggests a decreased energy demand on the left ventricle, even if the effective left-ventricular work is poorly related to the total energy consumption of the left ventricle. There was no doubt about the improvement of the symptoms in all these patients. They tolerated a higher degree of exertion before the appearance of chest pain or dyspnoea and the consumption of glyceryl trinitrate was reduced in patients who were using this medication. It is, however, difficult to demonstrate conclusively that this subjective improvement was a direct result of the hsemodynamic changes, observed after 1 month of training. The psychological rehabilitation and the increased selfconfidence which probably accompanied the physical training may have played an important role in raising the pain threshold. On the other hand, an increased selfconfidence would also encourage a higher degree of daily physical activity apart from the cycling, and this confirms the haemodynamic effects of the training conducted by us. The hxmodynamic effect of training which could possibly be responsible for an increased working capacity with respect to symptoms is probably the significantly lowered left-ventricular work. To this could be added the possibility that training may accelerate a development of collateral intercoronary circulation and thus improve the blood-supply to the ischaemic parts of the myocardium, as demonstrated in animal experiments (Eckerstein 1957). Repetition of the coronary angiography and coronary blood-flow measurements which are included in the present study may give more direct evidence to evaluate the validity of this speculation. The biological significance of the inconclusive serum cholesterol and triglyceride changes is difficult to assess. It is interesting to note that similar findings were observed in animals with cholesterol-induced atherosclerosis (Kobernick et al. 1957). Exercise did not influence the serum-level of cholesterol, phospholipids, cholesterol esters, and total cholesterol/phospholipid ratios. But the deposit of the atheromatous plaques in the aorta was significantly smaller in the exercise group of animals than in the sedentary group.
Summary
hxmodynamic and metabolic effects investigate of physical training, 8 male and 1 female middle-aged patients with coronary disease were examined during rest and while exercising before and after a month of training on a bicycle ergometer. All patients improved clinically the
To
increased exercise tolerance with respect to angina pectoris (and dyspnoea). Hxmodynamically there was an adjustment of the circulation towards a hypokinetic state and a reduction of the work of the left ventricle. Furthermore, the increase in blood-lactate resulting from exercise was significantly less after training. The hxmoglobin was significantly increased.
and showed
an
This work was supported by a grant from the Swedish National Association against heart and chest disease. Requests for reprints should be addressed to Dr. E. Varnauskas, Sahlgrenska Sjukuset, University of Gothenburg, Gothenburg, Sweden. REFERENCES
Andrew, G. M., Guzman, C. A., Becklake, M. R. (1966) J. appl. Physiol. 21, 603.
Åstrand,
P.-O. (1956) Physiol. Rev. 36, 307. Barker, S. D., Summerson, W. H. (1941) S biol. Chem. 138, 535. Barry, A. J., Daly, J. W., Pruett, E. D. R., Jteinmetz, J. R., Birkhead, N. C., Rodahl, K. (1966) Am. J. Cardiol. 17, 1. Bergman, H., Bjorntorp, P., Houk, P., Varnauskas, E., Westerlund, A. (1966) Svenska Läkartidn. 63, 407. Cobb, L. A., Johnson, W. P. (1963) J. clin. Invest. 42, 800. Collett, M. E., Liljestrand, G. (1924) Skand. Arch. Physiol. 45, 29. Eckerstein, R. W. (1957) Circulation Res. 5, 230. Foster, G. L., Reeves, T. J. (1964) J. clin. Invest. 43, 1758. Freedman, M. E., Snider, G. L., Brostoff, P., Kimelblot, S., Katz, L. N. (1955) J. appl. Physiol. 8, 37. Frick, M. H., Konttinen, A., Sarajas, H. S. S. (1963) Am. J. Cardiol. 12, 142. Hamilton, W. F., Moore, J. W., Kinsman, J. M., Spurling, R. G. (1931) Am. J. Physiol. 99, 534. Hellerstein, H. K., Hirsch, E. Z., Cumler, W., Allen, L., Polster, S., Zucker, N. (1963) in Coronary Heart Disease (edited by W. Likoff and J. H. Moyer); p. 448. London and New York. Holloszy, J. O., Skinner, J. S., Barry, A. J., Cureton, T. K. (1964) Am. J. Cardiol. 14, 761. Holmgren, A., Jonsson, B., Levander, M., Linderholm, H., Mossfeldt, F., Sjostrand, T., Strörn, G. (1959) Acta med. scand. 165, 89. Mattsson, K. H. (1954) Scand. J. clin. Lab. Invest. 6, 137. Kobernick, S. D., Niwayama, G., Zuchlewski, A. C. (1957) Proc. Soc. exp. Biol. Med. 96, 623. Malmborg, R. O. (1965) Acta med. scand. 177, suppl. 426. Malmcrona, R., Cramer, G., Varnauskas, E. (1963) ibid. 174, 557. Naughton, J., Balke, B. (1964) Am. J. med. Sci. 247, 286. Paulin, S. (1964) Acta radiol. suppl. 233. Petrén, T., Sjöstrand, T., Sylven, B. (1936) Arbeitsphysiol. 9, 376. Schröder, G. (1964) Scand. J. clin. Lab. Invest. 16, 559. Sloman, G., Pitt, A., Hirsch, E. Z., Donaldson, A. (1965) Med. J. Aust. 1,4. Varnauskas, E., Paulin, S., Forsberg, S. Å. (1962) Int. Congr. Radiol. Wassén, A. (1956) Scand. J. clin. Invest. 8, 189. -
BACTERIOLOGY AND BILE-SALT METABOLISM IN PATIENTS WITH INTESTINAL MALABSORPTION
JEJUNAL
SOAD
TABAQCHALI
M.B. St. And. RESEARCH FELLOW
C. C. BOOTH And., F.R.C.P.
M.D. St.
PHYSICIAN AND LECTURER
POSTGRADUATE MEDICAL SCHOOL OF
LONDON,
LONDON
W.12
BILE salts, which are needed for normal fat absorption, present in the jejunal lumen in conjugated forms. When these conjugated bile salts are exposed to the activity of colonic bacteria they are hydrolysed to form free bile acids, mainly cholic acid and chenodeoxycholic acid. Cholic acid is further broken down into deoxycholic acid and other metabolites (Bergstrom et al. 1960). Of these, deoxycholic acid has been shown to be toxic to the small intestinal mucosa in vitro (Dawson and Isselbacher 1960). The upper small intestine ordinarily is sterile in the fasting state (Cregan et al. 1953, Tabaqchali et al. 1966). In patients with steatorrhoea caused by the stagnant-loop syndrome, however, there is usually a luxuriant growth of colonic bacteria in the small bowel. In these patients the steatorrhoea has been suggested to be due to a toxic effect of free bile acids formed by bacterial activity in the lumen of the small gut (Dawson and Isselbacher 1960). It has further been shown that deoxycholic acid may inhibit the uptake and esterification of fatty acids by the intestinal mucosa in vitro (Dawson and Isselbacher 1960, Donaldson are
1965).