795
why
one serum
sample (no. 8) from
a
Discussion
Tissue-culture methods had several
advantages over previous technique for identifying a c.F. serum effect on glucose metabolism. Cells are readily obtained and experimental conditions easily reproduced. Morethe fact that established cell lines have far lower respiratory-rates and presumably increased glycolysislO is helpful for determining serum effects on glucose metabolism. The present studies show that this system is. easier to use than the previous technique and is almost as accurate in distinguishing c.F. homozygotes from heterozygotes. Furthermore, in the present system twenty times as many samples can be assayed under the same conditions at any time. Also, the volume of blood required for one assay is one third of that required for the previous system. These features will aid the characterisation and purification of the factor. We cannot say whether the decrease in CO2 production is due to a reduction in glucose uptake by the cells or a reduction in intracellular glucose oxidation. However, c.F. sera only affected active sodium transport in the in vitro rat jejunum when glucose was present in the incubation medium. When galactose, 3-0-methylglucose, pyruvate, or L-alanine was substituted for glucose a C.F. serum effect was not demonstrated.12 Glucose, galactose, and 3-0-methylglucose seem to share the same carrier across the brush border of rat jejunum whereas L-alanine utilises another carrier." Thus the c.F. serum effect in these experiments could not be attributed to an effect of c.F. factor on transport carriers for either sodium-dependent sugars or aminoacids. The circulating molecules characteristic of c.F. genotypes are small-molecular-weight polypeptides13 and heat-labile proteins with a cationic charge. 14 The factor which reduced carbon-dioxide production from glucose in the present study is precipitated with 50-70% saturated ammonium sulphate and is non-dialysable. over,
We thank Dr Harry Shwachman and Dr William D. Terry for their support. Requests for reprints should be addressed to H. A., National Institutes of Health, Bldg. 10 Rm. 9H 222 Bethesda, M.D. 20014, U.S.A.
REFERENCES 1. Balfe, J. W., Cole, C., Welt, L. G. Science, 1968, 162, 689. 2. Mangos, J. A., McSherry, N. R. Pediat. Res. 1968, 2, 378. 3. Spock, A., Hieck, H. M. C., Cress, H., Logan, W. S. ibid. 1967, 1, 173. 4. Lapey, A., Gardner, J. D. ibid. 1971, 5, 446. 5. Feig, S. A., Segel, G. B., Kern, K. A. ibid. 1974, 8, 594. 6 Fitzpatrick, D. F., Landon, E. J., James, J. Nature New Biol. 1972, 235, 172. 7. Duffy, M. J., Comer, D., Schwarz, V. ibid. 1973, 246, 151. 8. Araki, H., Field, M., Shwachman, H. Pediat. Res. 1975, 9, 932. 9. Yasumura, T., Kawakita, Y. Nippon Rinsho, 1963, 21, 1201. 10. Warshaw, J. B., Rosenthal, M. D. J. Cell Biol. 1972, 52, 283. 11. Goldner, A. M., Schultz, S. G., Curran, P. F. J. gen. Physiol. 1969, 53, 362. 12. Araki, H., Field, M., Shuachman, H. 17th International Cystic Fibrosis Congress, Paris, May, 1976; Abstracts of medical sessions, p. 28. 13. Bowman, B. H., Lankford, B. J., Fuller, G. M. Biochem. Biophys. Res. Com-
mun. 1975, 14, 253. Danes, B. S., Litwin, S. D., Hutteroth,
MICHAEL W. MILLAR-CRAIG
Cardiology Department, Northwick Park Hospital, Watford Road, Harrow, Middlesex HA1 3UJ Continuous intra-arterial blood-pressure and electrocardiogram recordings were obtained in twenty hypertensive and five normotensive ambulant patients. Blood-pressure was highest midmorning and then fell progressively throughout the remainder of the day. Blood-pressure was lowest at 3 A.M. and began to rise again during the early hours of the morning before waking. These findings may have important consequences with regard to the therapeutic management of hypertension. Introduction AN understanding of blood-pressure variation should be fundamental to any therapeutic regimen in which the primary aim is to reduce blood-pressure. Raised bloodpressure increases the risk of both morbidity and mortality due to cardiovascular complications.1-3 The risk of some of these complications, in particular that of stroke, is reduced by the therapeutic lowering of blood-pressure.4-6 In view of these findings, there is a strong case for chronic treatment in any individual who is found on routine screening to have raised blood-pressure. Since the end of the last century7,8 it has been known that blood-pressure falls during sleep. In most instances further data on cyclical changes has been gathered from repeated indirect blood-pressure measurements made either by the patient himself or by nursing staff.9-13 Indirect measurement of blood-pressure is open to considerable error.14 Moreover this error may be increased by the use of automatic blood-pressure measuring devices. 15 The equipment used is cumbersome and interferes with normal activity. In some cases observations have been made in patients who have been restricted to their bed or an adjacent chair. Data obtained in such a way, although valuable in the hospital setting, have little relevance to the blood-pressure changes in the patient exposed to normal environmental stress, both at home and at work. Some studies11,12,16,17 have suggested that blood-pressure is highest in the morning shortly after waking and then progressively falls throughout the day. However, in others9,10,13,18 blood-pressure progressively increased throughout the day. Blood-pressure always fell during
sleep. We have continuously recorded intra-arterial bloodpressure in ambulant outpatients most of whom went to work during the day. 19 Patients and Methods were obtained from twenty untreated patients hypertension who had been referred to the Harrow Hypertensive Clinic. Eighteen patients were male; the average age was 54 years (range 34-72). Mean sphygmoman-
Recordings
with essential
ometer T.
H. J. exp.
CHARLES N. BISHOP
E. B. RAFTERY
Summary
our
14.
CIRCADIAN VARIATION OF BLOOD-PRESSURE
healthy oriental
adult reduced CO2 production, since this disease is rare in orientals. Except for one serum sample from c.F. patients, all other sera from c.F. homozygotes and heterozygotes significantly reduced 14C02 production. Fractions 1 and 3 of the serum samples has no effect on glucose oxidation.
Med.
1973, 137, 1538.
in
clinic diastolic pressure was greater than 110 mm Hg to 110 mm Hg in ten and less than 100 mm Hg in
six, 100
796 4. In each case the mean ambulatory intra-arterial blood-pressure for the period 12 P.M. to 6 P.M. was greater than 150/95
mm Hg. Recordings were made in an additional five patients in whom hypertension had been suspected. In each case the mean clinic diastolic blood-pressure was less than 100 mm Hg, and the mean ambulatory intra-arterial blood-pressure was less than 145/90 mm Hg. These patients were all male and the average age was 29 years (range 19-43). Although this group cannot be regarded as a truly normal population, they were found to be normotensive under the study conditions and were used as a control group for the hypertensive patients. We used a perfused transducer unit developed at Northwick Park.2O Left-brachial-artery cannulation was carried out percutaneously under local anaesthetic. The blood-pressure signal together with the electrocardiogram (E.C.G.) was recorded on magnetic tape by means of a miniature tape recorder (’Medilog’ recorder, Oxford Instruments Ltd). The recordings were carried out for 48 consecutive hours on an outpatient basis. Twenty-two of the patients were able to return to their normal work during the day. The cannula produced little discomfort and only restricted bathing. Informed consent was obtained from each patient, and the project as a whole was approved by the hospital ethical committee. Data was analysed by means of a hybrid computer system.21 The blood-pressure signal and pulse-interval time were analysed in hourly units to obtain mean values for systolic bloodpressure, diastolic blood-pressure, and pulse-interval time for each hour of the 24-hour cycle. Values for heart-rate were obtained by direct conversion from the pulse-interval time.
Fig. 1-Hourly mean systolic and diastolic blood-pressures throughout 24 h in 20 untreated hypertensive patients.
Fig. 2-Hourly mean heart-rates throughout treated hypertensive patients.
24 h in 20
un-
The data obtained axis.
was
assembled
graphically
on a
24-hour
Results
Blood-pressure and Heart-rate in Hypertensive Patients In the twenty hypertensive patients (fig. 1) blood-pressure was highest in the morning and then progressively fell throughout the day (fig. 1). Blood-pressure was lowest at 3 A.M. during sleep, and then began to increase again. By 6 A.M. blood-pressure was increasing rapidly and this rate of increase was accentuated after the patients woke at approximately 7 A.M. Maximum bloodpressure occurred at 10 A.M. This rise in blood-pressure, which began before waking was found in all patients, and was not associated with physical activity as recorded on the patient diaries. Heart-rate (fig. 2) in the same patients was at a maximum at midday and then fell progessively. During sleep, heart-rate was maintained at a low level and did not begin to increase until waking (7 A.M.). It then increased abruptly during the first 2 h after wak-
ing. Blood-pressure and
Heart-rate in Normotensive Patients In the five normotensive patients blood-pressure was highest in the morning (fig. 3). There was no peak of pressure occurring at 10 A.M., as was seen in the hypertensive subjects. Blood-pressure fell in the late afternoon
Fig. 3-Hourly
mean
systolic and diastolic blood-pressures
throughout 24 h in 5 normotensive patients.
Fig. 4-Hourly mean heart-rates throughout tensive patients.
24 h in 5
normo-
797
and evening and reached its nadir during sleep, at 3 A.M. Blood-pressure then began to increase again at 5 A.M. before waking. The timing of this increase and the rate of increase was very similar to that seen in the hypertensive patients. Heart-rate (fig. 4) was highest at 1 P.M. and then fell progressively to reach a low point at 4 A.M. In the normotensive patients heart-rate began to increase at 6 A.M. before waking. Discussion
The 24-hour blood-pressure traces obtained from the hypertensive and normotensive patients were very similar. In both groups pressure fell progressively during the day and rose in the early hours of the morning, before waking. It could be argued that the rise in blood-pressure in the morning was the result of apprehension (especially on the first morning when the cannula was inserted). However, patients were familiar with the laboratory and equipment and we let them rest and checked their blood-pressure to make sure that it had stabilised before they left hospital. However, the strongest argument against the morning pressures being due to apprehension is the fact that the following morning the pressures rose to exactly the same point. By this time the patients had had a line in for 24 h and were familiar with the routine. In both groups heart-rate was at a maximum at midday and then fell progressively to reach a nadir during sleep. However, in the hypertensive group the heart-rate remained low until waking, whereas in the normotensives it seemed to increase before waking. The number of normotensive patients is small, however, the findings accord with those of Clarke et al.,22 who obtained hourly mean heart-rates from the continuous E.c.G. of 86 normal ambulant subjects. Stroke is the most common serious complication of hypertension, and the Framingham study23 has shown that hypertension is the most common and most powerful risk factor in the setiology of stroke. It is often difficult to determine whether cerebral thrombosis or haemorrhage is the cause of a stroke, but evidence suggests24 that while cerebral haemorrhage used to be the commonest cause, since 1953 thrombosis has become a more common cause of stroke. This change may be due to earlier diagnosis and treatment of hypertension.25 In general, blood-pressure is higher in patients dying of cerebral haemorrhage than those dying of cerebral throm-
bosis.26
.
Agnoli27 demonstrated that non-embolic strokes occur most commonly in the 8 hours between 6 A.M. and 2 P.M. Surprisingly he found this trend to be more pronounced in hypotensive and normotensive patients than in hypertensive patients. In a study of 848 stroke patients, Marshall28 demonstrated that cerebral thrombosis
occurs
commonly between midnight and 6 A.M. In women cerebral haemorrhage occurred most commonly between 6 A.M. and midday, but in men the distribution was more
most
uniform. Hypertension is also a risk factor in the development of ischaemic heart-disease.3°29 Both Myers and Dewar30 and Tunstall Pedoe et al. 31 have demonstrated that the peak incidence of myocardial infarction is at about 10 A.M. We believe that in many cases both cerebral haemorrhage and myocardial infarction may be precipitated by rapidly increasing arterial blood-pressure. Cerebral
may be due to rupture of Charcot-Bouchard aneurysms. In myocardial infarction, coronary occlusion may be associated with rupture and fragmentation of a coronary-artery plaque, which has been shown to be a common initiator of coronary thrombosis.32 It seems that from 6 A.M. until 9 A.M., when the arterial blood-pressure is increasing rapidly, active hypotensive therapy is crucial. Hypotensive therapy in hypertensive patients should perhaps be designed to give more satisfactory blood-pressure control during that part of the day. The controlling mechanism for this circadian bloodpressure rhythm is unknown, but it is likely to be neurohormonal. Both cerebral and urinary catecholamines are reduced during sleep but seem to reach a peak in the afternoon.33.34 The circadian pattern of adrenal corticosteroids established by Migeon35 is in many ways similar to the blood-pressure pattern that we have found, but in general concentrations of these hormones are lowest at midnight. Unfortunately there is no detailed data on circulating plasma-hormones in patients outside hospital in their own environment. The rise in blood-pressure in the early morning is probably part of the arousal reaction, and we are undertaking further studies to define its mechanism and the effects (if any) of antihypertensive
haemorrhage
drug therapy. Requests for reprints should
be addressed
to
E.B.R.
REFERENCES
1. Actuarial Society of America and the Association of Life Insurance Medical Directors. Supplement to Blood Pressure Study. New York, 1941. 2. Metropolitan Life Insurance Company. Blood Pressure: Insurance Experience and its Implications. New York, 1961. 3. Kannel, W. B., Dawber, T. R. Br.J. Hosp. Med. 1974, 11, 508. 4. Freis, E. D. J. Am. med. Ass. 1967, 202, 1028. 5. Leishman, A. W. D. Br. med. J. 1959, i, 1361. 6. Smirk, F. H. N.Z. med. J. 1964, 63, 413. 7. Hill, L. Lancet, 1898, i, 282. 8. Howell, W. H. J. exp. Med. 1897, 2, 313. 9. Brooks, H., Carroll, J. H. Archs intern. Med. 1912, 10, 97. 10. Mueller, S. C., Brown, G. E. Ann. int. Med. 1930, 3, 1190. 11. Kain, K. K., Hinman, A. T., Sokolow, M. Circulation, 1964, 30, 882. 12. Zulch, K. J., Hossmann, V. Germ. med. Mon. 1967, 12, 513. 13. Scheving, L. A., Sheving, L. E., Halberg, F. in Chronobiology (edited by L. E. Sheving, F. Halberg, and J. E. Pauly); p. 386. Tokyo, 1974. 14. Raftery, E. B., Ward, A. P. Cardiovasc. Res. 1968, 2, 210. 15. Labarthe, D. R., Hawkins, C. M., Remington, R. D. Am. J. Cardiol. 1973,
32, 546. Schneider, R. A., Costiloe, J. P. Am. Heart J. 1975, 90, 695. Irving, J. B., Kerr, F., Ewing, D. J., Kirby, B. J. Br. Heart J. 1974, 36, 859. Richardson, D. W., Honour, A. J., Fenton, G. W., Stott, F. W., Pickering, G. W. Clin. Sci. 1964, 26, 445. 19. Goldberg, A. D., Raftery, E. B., Green, H. L. Postgrad. med. J. 1976, 52, suppl. 7, p. 104. 20. Millar-Craig, M. W., Raftery, E. B. Proceedings of 2nd International Symposium on Ambulatory Monitoring (in the press). 21. Goldberg, A. M. M.D. thesis, University of Sheffield, 1976. 22. Clarke, J. M., Hamer, J., Shelton, J. R., Taylor, S., Venning, G. R. Lancet, 1976, ii, 508. 23. Kannel, W. B., Dawber, T. R., Sorlie, P., Wolf, P. A. Stroke, 1976, 7, 327. 24. Yates, P. O. Lancet, 1964, i, 65. 25. Gordon, P. C. Can. med. Ass. J. 1966, 95, 1004. 26. Aring, C. D., Merritt, H. H. Archs intern. Med. 1935, 56, 435. 27. Agnoli, A., Manfredi, M., Mossuto, L., Piccinelli, A. Revue neurol. 1975, 131, 597. 28. Marshall, J. Stroke, 1977, 8, 230. 29. Yater, W. M., Traum, A. H., Brown, W. G., Fitzgerald, R. P., Geisler, M. A., Wilcox, B. B. Am. Heart J. 1948, 36, 334. 30. Myers, A., Dewar, H. A. Br. Heart J. 1975, 37, 1133. 31. Tunstall Pedoe, H., Morris, J. N., Bngden, W., McDonald, L. Lancet, 1975, 16. 17. 18.
ii, 833. 32. Davies, M. J., Woolf, N., Robertson, W. B. Br Heart J. 1976, 38, 659. 33. Faucheux, B., Kuchel, O., Cuche, J. L., Messerli, F. H., Buu, N. T., Barbeau, A., Genest, J. Endocrine Res. Commun. 1976, 3, 257. 34. Ziegler, M. G., Lake, C. R., Wood, J. H., Ebert, M. H. Nature, 1976, 264, 656. 35. Migeon, C. J. Tyler, F. H., Mahoney, J. P., Florentin, A. A., Castle, H., Bliss, E. L., Samuels, L. T. J. clin. Endocr. Metab. 1956, 16, 622.
why
one serum
sample (no. 8) from
a
Discussion
Tissue-culture methods had several
advantages over previous technique for identifying a c.F. serum effect on glucose metabolism. Cells are readily obtained and experimental conditions easily reproduced. Morethe fact that established cell lines have far lower respiratory-rates and presumably increased glycolysislO is helpful for determining serum effects on glucose metabolism. The present studies show that this system is. easier to use than the previous technique and is almost as accurate in distinguishing c.F. homozygotes from heterozygotes. Furthermore, in the present system twenty times as many samples can be assayed under the same conditions at any time. Also, the volume of blood required for one assay is one third of that required for the previous system. These features will aid the characterisation and purification of the factor. We cannot say whether the decrease in CO2 production is due to a reduction in glucose uptake by the cells or a reduction in intracellular glucose oxidation. However, c.F. sera only affected active sodium transport in the in vitro rat jejunum when glucose was present in the incubation medium. When galactose, 3-0-methylglucose, pyruvate, or L-alanine was substituted for glucose a C.F. serum effect was not demonstrated.12 Glucose, galactose, and 3-0-methylglucose seem to share the same carrier across the brush border of rat jejunum whereas L-alanine utilises another carrier." Thus the c.F. serum effect in these experiments could not be attributed to an effect of c.F. factor on transport carriers for either sodium-dependent sugars or aminoacids. The circulating molecules characteristic of c.F. genotypes are small-molecular-weight polypeptides13 and heat-labile proteins with a cationic charge. 14 The factor which reduced carbon-dioxide production from glucose in the present study is precipitated with 50-70% saturated ammonium sulphate and is non-dialysable. over,
We thank Dr Harry Shwachman and Dr William D. Terry for their support. Requests for reprints should be addressed to H. A., National Institutes of Health, Bldg. 10 Rm. 9H 222 Bethesda, M.D. 20014, U.S.A.
REFERENCES 1. Balfe, J. W., Cole, C., Welt, L. G. Science, 1968, 162, 689. 2. Mangos, J. A., McSherry, N. R. Pediat. Res. 1968, 2, 378. 3. Spock, A., Hieck, H. M. C., Cress, H., Logan, W. S. ibid. 1967, 1, 173. 4. Lapey, A., Gardner, J. D. ibid. 1971, 5, 446. 5. Feig, S. A., Segel, G. B., Kern, K. A. ibid. 1974, 8, 594. 6 Fitzpatrick, D. F., Landon, E. J., James, J. Nature New Biol. 1972, 235, 172. 7. Duffy, M. J., Comer, D., Schwarz, V. ibid. 1973, 246, 151. 8. Araki, H., Field, M., Shwachman, H. Pediat. Res. 1975, 9, 932. 9. Yasumura, T., Kawakita, Y. Nippon Rinsho, 1963, 21, 1201. 10. Warshaw, J. B., Rosenthal, M. D. J. Cell Biol. 1972, 52, 283. 11. Goldner, A. M., Schultz, S. G., Curran, P. F. J. gen. Physiol. 1969, 53, 362. 12. Araki, H., Field, M., Shuachman, H. 17th International Cystic Fibrosis Congress, Paris, May, 1976; Abstracts of medical sessions, p. 28. 13. Bowman, B. H., Lankford, B. J., Fuller, G. M. Biochem. Biophys. Res. Com-
mun. 1975, 14, 253. Danes, B. S., Litwin, S. D., Hutteroth,
MICHAEL W. MILLAR-CRAIG
Cardiology Department, Northwick Park Hospital, Watford Road, Harrow, Middlesex HA1 3UJ Continuous intra-arterial blood-pressure and electrocardiogram recordings were obtained in twenty hypertensive and five normotensive ambulant patients. Blood-pressure was highest midmorning and then fell progressively throughout the remainder of the day. Blood-pressure was lowest at 3 A.M. and began to rise again during the early hours of the morning before waking. These findings may have important consequences with regard to the therapeutic management of hypertension. Introduction AN understanding of blood-pressure variation should be fundamental to any therapeutic regimen in which the primary aim is to reduce blood-pressure. Raised bloodpressure increases the risk of both morbidity and mortality due to cardiovascular complications.1-3 The risk of some of these complications, in particular that of stroke, is reduced by the therapeutic lowering of blood-pressure.4-6 In view of these findings, there is a strong case for chronic treatment in any individual who is found on routine screening to have raised blood-pressure. Since the end of the last century7,8 it has been known that blood-pressure falls during sleep. In most instances further data on cyclical changes has been gathered from repeated indirect blood-pressure measurements made either by the patient himself or by nursing staff.9-13 Indirect measurement of blood-pressure is open to considerable error.14 Moreover this error may be increased by the use of automatic blood-pressure measuring devices. 15 The equipment used is cumbersome and interferes with normal activity. In some cases observations have been made in patients who have been restricted to their bed or an adjacent chair. Data obtained in such a way, although valuable in the hospital setting, have little relevance to the blood-pressure changes in the patient exposed to normal environmental stress, both at home and at work. Some studies11,12,16,17 have suggested that blood-pressure is highest in the morning shortly after waking and then progressively falls throughout the day. However, in others9,10,13,18 blood-pressure progressively increased throughout the day. Blood-pressure always fell during
sleep. We have continuously recorded intra-arterial bloodpressure in ambulant outpatients most of whom went to work during the day. 19 Patients and Methods were obtained from twenty untreated patients hypertension who had been referred to the Harrow Hypertensive Clinic. Eighteen patients were male; the average age was 54 years (range 34-72). Mean sphygmoman-
Recordings
with essential
ometer T.
H. J. exp.
CHARLES N. BISHOP
E. B. RAFTERY
Summary
our
14.
CIRCADIAN VARIATION OF BLOOD-PRESSURE
healthy oriental
adult reduced CO2 production, since this disease is rare in orientals. Except for one serum sample from c.F. patients, all other sera from c.F. homozygotes and heterozygotes significantly reduced 14C02 production. Fractions 1 and 3 of the serum samples has no effect on glucose oxidation.
Med.
1973, 137, 1538.
in
clinic diastolic pressure was greater than 110 mm Hg to 110 mm Hg in ten and less than 100 mm Hg in
six, 100
796 4. In each case the mean ambulatory intra-arterial blood-pressure for the period 12 P.M. to 6 P.M. was greater than 150/95
mm Hg. Recordings were made in an additional five patients in whom hypertension had been suspected. In each case the mean clinic diastolic blood-pressure was less than 100 mm Hg, and the mean ambulatory intra-arterial blood-pressure was less than 145/90 mm Hg. These patients were all male and the average age was 29 years (range 19-43). Although this group cannot be regarded as a truly normal population, they were found to be normotensive under the study conditions and were used as a control group for the hypertensive patients. We used a perfused transducer unit developed at Northwick Park.2O Left-brachial-artery cannulation was carried out percutaneously under local anaesthetic. The blood-pressure signal together with the electrocardiogram (E.C.G.) was recorded on magnetic tape by means of a miniature tape recorder (’Medilog’ recorder, Oxford Instruments Ltd). The recordings were carried out for 48 consecutive hours on an outpatient basis. Twenty-two of the patients were able to return to their normal work during the day. The cannula produced little discomfort and only restricted bathing. Informed consent was obtained from each patient, and the project as a whole was approved by the hospital ethical committee. Data was analysed by means of a hybrid computer system.21 The blood-pressure signal and pulse-interval time were analysed in hourly units to obtain mean values for systolic bloodpressure, diastolic blood-pressure, and pulse-interval time for each hour of the 24-hour cycle. Values for heart-rate were obtained by direct conversion from the pulse-interval time.
Fig. 1-Hourly mean systolic and diastolic blood-pressures throughout 24 h in 20 untreated hypertensive patients.
Fig. 2-Hourly mean heart-rates throughout treated hypertensive patients.
24 h in 20
un-
The data obtained axis.
was
assembled
graphically
on a
24-hour
Results
Blood-pressure and Heart-rate in Hypertensive Patients In the twenty hypertensive patients (fig. 1) blood-pressure was highest in the morning and then progressively fell throughout the day (fig. 1). Blood-pressure was lowest at 3 A.M. during sleep, and then began to increase again. By 6 A.M. blood-pressure was increasing rapidly and this rate of increase was accentuated after the patients woke at approximately 7 A.M. Maximum bloodpressure occurred at 10 A.M. This rise in blood-pressure, which began before waking was found in all patients, and was not associated with physical activity as recorded on the patient diaries. Heart-rate (fig. 2) in the same patients was at a maximum at midday and then fell progessively. During sleep, heart-rate was maintained at a low level and did not begin to increase until waking (7 A.M.). It then increased abruptly during the first 2 h after wak-
ing. Blood-pressure and
Heart-rate in Normotensive Patients In the five normotensive patients blood-pressure was highest in the morning (fig. 3). There was no peak of pressure occurring at 10 A.M., as was seen in the hypertensive subjects. Blood-pressure fell in the late afternoon
Fig. 3-Hourly
mean
systolic and diastolic blood-pressures
throughout 24 h in 5 normotensive patients.
Fig. 4-Hourly mean heart-rates throughout tensive patients.
24 h in 5
normo-
797
and evening and reached its nadir during sleep, at 3 A.M. Blood-pressure then began to increase again at 5 A.M. before waking. The timing of this increase and the rate of increase was very similar to that seen in the hypertensive patients. Heart-rate (fig. 4) was highest at 1 P.M. and then fell progressively to reach a low point at 4 A.M. In the normotensive patients heart-rate began to increase at 6 A.M. before waking. Discussion
The 24-hour blood-pressure traces obtained from the hypertensive and normotensive patients were very similar. In both groups pressure fell progressively during the day and rose in the early hours of the morning, before waking. It could be argued that the rise in blood-pressure in the morning was the result of apprehension (especially on the first morning when the cannula was inserted). However, patients were familiar with the laboratory and equipment and we let them rest and checked their blood-pressure to make sure that it had stabilised before they left hospital. However, the strongest argument against the morning pressures being due to apprehension is the fact that the following morning the pressures rose to exactly the same point. By this time the patients had had a line in for 24 h and were familiar with the routine. In both groups heart-rate was at a maximum at midday and then fell progressively to reach a nadir during sleep. However, in the hypertensive group the heart-rate remained low until waking, whereas in the normotensives it seemed to increase before waking. The number of normotensive patients is small, however, the findings accord with those of Clarke et al.,22 who obtained hourly mean heart-rates from the continuous E.c.G. of 86 normal ambulant subjects. Stroke is the most common serious complication of hypertension, and the Framingham study23 has shown that hypertension is the most common and most powerful risk factor in the setiology of stroke. It is often difficult to determine whether cerebral thrombosis or haemorrhage is the cause of a stroke, but evidence suggests24 that while cerebral haemorrhage used to be the commonest cause, since 1953 thrombosis has become a more common cause of stroke. This change may be due to earlier diagnosis and treatment of hypertension.25 In general, blood-pressure is higher in patients dying of cerebral haemorrhage than those dying of cerebral throm-
bosis.26
.
Agnoli27 demonstrated that non-embolic strokes occur most commonly in the 8 hours between 6 A.M. and 2 P.M. Surprisingly he found this trend to be more pronounced in hypotensive and normotensive patients than in hypertensive patients. In a study of 848 stroke patients, Marshall28 demonstrated that cerebral thrombosis
occurs
commonly between midnight and 6 A.M. In women cerebral haemorrhage occurred most commonly between 6 A.M. and midday, but in men the distribution was more
most
uniform. Hypertension is also a risk factor in the development of ischaemic heart-disease.3°29 Both Myers and Dewar30 and Tunstall Pedoe et al. 31 have demonstrated that the peak incidence of myocardial infarction is at about 10 A.M. We believe that in many cases both cerebral haemorrhage and myocardial infarction may be precipitated by rapidly increasing arterial blood-pressure. Cerebral
may be due to rupture of Charcot-Bouchard aneurysms. In myocardial infarction, coronary occlusion may be associated with rupture and fragmentation of a coronary-artery plaque, which has been shown to be a common initiator of coronary thrombosis.32 It seems that from 6 A.M. until 9 A.M., when the arterial blood-pressure is increasing rapidly, active hypotensive therapy is crucial. Hypotensive therapy in hypertensive patients should perhaps be designed to give more satisfactory blood-pressure control during that part of the day. The controlling mechanism for this circadian bloodpressure rhythm is unknown, but it is likely to be neurohormonal. Both cerebral and urinary catecholamines are reduced during sleep but seem to reach a peak in the afternoon.33.34 The circadian pattern of adrenal corticosteroids established by Migeon35 is in many ways similar to the blood-pressure pattern that we have found, but in general concentrations of these hormones are lowest at midnight. Unfortunately there is no detailed data on circulating plasma-hormones in patients outside hospital in their own environment. The rise in blood-pressure in the early morning is probably part of the arousal reaction, and we are undertaking further studies to define its mechanism and the effects (if any) of antihypertensive
haemorrhage
drug therapy. Requests for reprints should
be addressed
to
E.B.R.
REFERENCES
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