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THE LANCET

Results of Treatment of HypertensionIT has been apparent for more than a decade that

the treatment of severe hypertension improves thepatient’s prognosis. The chances of death from strokeand renal failure are reduced but the incidence ofmyocardial infarction is apparently uninfluenced; -,indeed, in some series, myocardial infarction hasaccounted for a much greater proportion of deaths intreated patients than in untreated patients.2 This

apparent increase in the importance of myocardialinfarction is explained, at least in part, by a reducedlikelihood of death from other causes. Thus, theimpression has arisen that adequate treatment ofhypertension has little or no effect upon the risksfrom coronary heart-disease.

Further evidence on this point has now been pro-vided by BRECKENRIDGE and his colleagues,3 whohave reviewed the course of 1294 hypertensivepatients who began treatment between 1952 and 1967.The patients were divided into two groups: those whobegan treatment between 1952 and 1959, when themain agents were ganglion-blocking drugs; and thosewho began treatment after 1960, when diuretics andeffective adrenergic-blocking agents were available.The patients were classified both by the severity ofretinopathy and by the level of diastolic blood-pressurebefore treatment. Whatever the system of classifi-cation, patients starting treatment in the later yearssurvived longer than those starting treatment earlier.The difference in five-year survival was small, but itwas consistent between groups. Patients presentingwith grade-4 retinopathy, or malignant hypertension,had a five-year survival-rate of 25% in the first

period and 34% in the second, most of the deathsbeing due to pre-existing renal failure. Patients with

grade-3 retinopathy did very much better, with five-year survivals of 70% and 71% in the two periods.For patients without retinal haemorrhages or exudates,five-year survivals were 85% and 87% respectively.In all groups, women fared better than men. Exceptin patients whose initial diastolic pressure exceeded140 mm. Hg, many of whom had impaired renalfunction when first seen, prognosis was unrelated topretreatment level of arterial pressure. This situationis quite unlike that in untreated hypertensive patients,where the prognosis is closely related to the level of1. Leishman, A. W. D. Lancet, 1963, i, 1284.2. Bauer, G. E. Med. J. Aust. 1966, i, 698.3. Breckenridge, A., Dollery, C. T., Parry, E. H. O. Q. Jl Med. 1970,

39, 411.

arterial pressure,4-6 suggesting, indirectly, thatsurvival may be related to the efficiency of arterialpressure control.

Several other interesting points emerged. Renalfailure was the single major cause of death, but over80% of patients dying of this cause had a raisedblood-urea level when they were first seen. Deathsfrom renal failure and cerebrovascular accidents took

place most commonly within the first three years ofstarting treatment. This suggests either that thosedestined to die of these causes do so early, leaving apopulation of patients at lower risk, or, more likely,that the reduction of arterial pressure influences thecourse of vascular disease due to hypertension.By contrast, deaths due to myocardial infarction

were evenly spread throughout the follow-up period,and after the fourth year of treatment myocardialinfarction was the commonest cause of death. This

observation, like those in other treated series, is hardto interpret. It cannot be taken to indicate thattreatment has no effect upon the incidence of myo-cardial infarction, because no satisfactory control

group can be obtained. If patients have a decreasedrisk of dying from strokes or renal failure, they musthave an increased risk of dying, at some time, fromsomething else. The difference in distribution ofcerebrovascular and cardiac deaths is particularlystriking, and suggests that the nature of the vascularlesion in these two territories is different, or that it isaffected differently by treatment. There is someevidence to support the former view; two-thirdsof the patients who died of cerebrovascular disease,and whose brains were examined post mortem, hadcerebral or subarachnoid hoemorrhage. It is quitelikely that treatment of hypertension decreases therisk of haemorrhage much more than the risk ofthrombosis. It is possible that earlier treatment ofyoung patients with mild hypertension could decreasethe risk of myocardial infarction, but to test this isextremely difficult. Those at risk must be identified,and treated or observed over a very long period, whileasymptomatic. It is not easy to maintain the patient’scooperation in this situation, and this is one of themain reasons for the uncertainty about the value oftreatment of patients, of any age, with mild hyper-tension.

Further light has been shed on this problem by theVeterans Administration Cooperative Study Groupon antihypertensive agents.7 This group had pre-viously found a significant reduction in the incidenceof cardiovascular episodes in a controlled trial of

hypotensive agents in men with diastolic blood-

pressures between 115 and 129 mm. Hg.8 The

study has been continued on 380 men, whose diastolic4. Bechgaard, P. Acta med. scand. 1946, suppl. 172, p. 3.5. Leishman, A. W. D. Br. med. J. 1959, i, 1361.6. Sokolow, M., Perloff, D. Circulation, 1961, 23, 697.7. Veterans Administration Cooperative Study Group on Anti-

hypertensive Agents. J. Am. med. Ass. 1970, 213, 1143.8. ibid. 1967, 202, 1028.

218

blood-pressures, measured in hospital, lay between90 and 114 mm. Hg. After initial assessment the

patients were randomly allocated to treatment andcontrol groups: 186 received active treatment with

hydrochlorothiazide, reserpine, and hydrallazine, andthe remainder received placebo tablets. Over a

five-year period, there were 19 deaths due to cardio-vascular disease in the control group, and 8 in thetreated group. In each group there were 2 deathsdue to unrelated conditions. Non-fatal cardiovascularevents were roughly twice as common in the controlas in the treated group, but, as in previous series,the incidence of myocardial infarction was very simi-lar, with 13 events in the control group and 11 in thepatients under treatment.

These results provide good evidence of a beneficialeffect of treatment in men with mild hypertension,but the findings are not necessarily generally applic-able. The patients were all men, selected on thebasis of inpatient blood-pressure recordings, andthere was rigorous control of tablet taking andattendance; the investigators deserve all credit for adrop-out rate of only 15% of patients in five years.It is well known that many patients with a moderateincrease in casual arterial pressure show a strikingblood-pressure fall within a few days of admission tohospital, and such patients were excluded from thistrial. It is not practical to admit all patients withmild hypertension to hospital, and decisions oftenhave to be made on the basis of outpatient blood-pressure measurements. There is a clear need forfurther examination of this problem in women aswell as in men.

E.B. Virus, Burkitt Lymphoma, andNasopharyngeal Carcinoma

ALTHOUGH the relation between Epstein-Barr(E.B.) virus, Burkitt lymphoma, and nasopharyngealcarcinoma is still uncertain, several advances havebeen achieved. The first indications that E.B. virus

might be associated with these two seemingly dis-parate forms of malignant disease came from sero-logical evidence that patients with Burkitt lymphomaand anaplastic nasopharyngeal carcinoma both

developed high-titre antibodies against E.B. virus 1;precipitins were also demonstrated with soluble

antigens prepared from cultured Burkitt cells.2,3 3

Much work has now been done on E.B.-virus-associated antigens and antibodies in these two

conditions, and a complicated situation is emerging.Four separate antigenic complexes have been

1. Henle, G., Henle, W., Diehl, V. Proc. natn. Acad. Sci. U.S.A.1968, 59, 94.

2. Old, L. J., Boyse, E. A., Oettgen, H. F., de Harven, E., Geering, G.,Williamson, B., Clifford, P. ibid. 1966, 56, 1699.

3. Old, L. J., Boyse, E. A., Geering, G., Oettgen, H. F. Cancer Res.1968, 28, 1288.

defined in cultured tumour cells, and four corre-sponding antibodies have been demonstrated in

patients’ sera. The four antigenic complexes areE.B.-virus capsid antigen, the E.B.-virus-associatedmembrane antigen, the

" early " E.B.-virus antigen,and the soluble antigen which evokes precipitins:the first two of these are the best documented. -l

The intracellular capsid antigen appears duringvirus maturation and is demonstrated by indirectimmunofluorescence on fixed target cells õ; togetherwith the corresponding antibody, it forms the con-ventional system used for titrating E.B.-virus anti-bodies. The membrane antigen, 6 revealed byimmunofluorescence on living target cells, is thoughtto represent viral envelope components.7 Thoughseparate from capsid antigens, membrane antigensare closely related to them 8-11: they are not depen-dent on the presence of demonstrable intracellularviral antigen, but they seem to be determined bythe E.B.-virus genome, since they are absent fromcell lines which lack the virus. The original techniqueof measuring antibodies against membrane antigenshas been replaced by the more reliable " blocking "test,10 in which the potency of a test serum is deter-mined by its ability to block the activity of a standardreference serum-the IgG fraction of a known posi-tive serum, labelled with a fluorescent dye. The

early E.B.-virus antigen is a new discovery,12 andits full implications are not yet clear. Like the

capsid antigen, it is found in the cytoplasm of theinfected cells. The corresponding antibodies havebeen found in many (but not all) patients withBurkitt lymphoma and nasopharyngeal carcinoma,where they may reflect " extensive, current or veryrecent E.B.-virus-associated disease processes ".12The various E.B.-virus-associated antigenic systemshave been mainly defined in lines of Burkitt tumourcells. Nasopharyngeal carcinoma is more difficultto establish in vitro,13-15 but capsid and membraneantigens have been demonstrated in cultured

lymphoblastic cells from nasopharyngeal carcinomasindistinguishable from those found in culturedBurkitt cells.14

4. Gunvén, P., Klein, G., Henle, G., Henle, W., Clifford, P. Nature,1970, 228, 1053.

5. Henle, G., Henle, W. Cancer Res. 1967, 27, 2442.6. Klein, G., Clifford, P., Klein, E., Stiernswärd, J. Proc. natn. Acad.

Sci. U.S.A. 1966, 55, 1628.7. Keller, J. M., Spear, P. G., Roizman, B. ibid. 1970, 65, 865.8. Klein, G., Pearson, G., Nadkarni, J. S., Nadkarni, J. J., Klein, E.,

Henle, G., Henle, W., Clifford, P. J. exp. Med. 1968, 128,1011.

9. Klein, G., Pearson, G., Henle, W., Diehl, V., Niederman, J. C.ibid. p. 1021.

10. Klein, G., Pearson, G., Henle, G., Henle, W., Goldstein, G.,Clifford, P. ibid. 1969, 129, 697.

11. Pearson, G., Klein, G., Henle, G., Henle, W., Clifford, P. ibid.p. 707.

12. Henle, W., Henle, G., Zajac, B. A., Pearson, G., Waubke, R.,Scriba, M. Science, 1970, 169, 188.

13. De Thé, G., Ambrosioni, J. C., Ho, H. C., Kwan, H. C. Nature,1969, 221, 770.

14. De Schryver, A., Klein, G., de Thé, G. Clin. exp. Immunol. 1970,7, 161.

15. De Thé, G., Ho, H. C., Kwan, H. C., Desgranges, C., Favre, M. C.Int. J. Cancer, 1970, 6, 189.