Saturday 12 September 1987

REDUCTION OF STRESS/ degeneration.4 Similar "catecholamine-induced" necrotic

CATECHOLAMINE-INDUCED CARDIAC
NECROSIS BY BETA1-SELECTIVE BLOCKADE
JOHN M. CRUICKSHANK1,2 GLENN NEIL-DWYER3
JEAN P. DEGAUTE4 YVONNE HAYES2
TIMO KUURNE5
JUHA KYTTA6
JEAN L. VINCENT4 MALCOLM E. CARRUTHERS7
SHANTA PATEL5
Wythenshawe Hospital, Manchester;1 ICI plc, Pharmaceuticals
Division, Cheshire;2 Brook General Hospital, London;3 Erasme
University Hospital, Brussels, Belgium;4 Tampere University
Central Hospital, Finland;5 Töölö Hospital, Helsinki, Finland;6 and
Maudsley Hospital, London7
Summary 114 haemodynamically stable patients with
head injury were randomised,
acute
double-blind, to either placebo or atenolol given
intravenously (10 mg every 6 h) for 3 days then orally (100
mg daily) for a further 4 days. Both groups were equally
stressed as shown by raised arterial noradrenaline levels. In
patients receiving placebo, but not in those receiving
atenolol, there was a significant (p < 0.01) positive
correlation between arterial noradrenaline and levels of the
myocardial isoenzyme of creatine kinase (CKMB). 30% of
the placebo group compared with 7.4% of the atenolol
group (p < 0.05) showed CKMB levels greater than 3% of
total creatine kinase (compatible with myocardial damage).
CKMB levels greater than 6% of total creatine kinase
(compatible with acute myocardial infarction) were present
in 16.7% of patients receiving placebo but in no patients
receiving atenolol (p = 0.053). Atenolol appeared to reduce
significantly the likelihood of supraventricular tachycardia
and ST-segment and T-wave changes and prevented
cardiac necrosis seen at necropsy.
Introduction
lesions have been identified in the hearts of patients with
phaeochromocytoma.5,6 Stressful disorders such as
subarachnoid haemorrhageare also associated with ECG
changes, often accompanied by rises in the plasma level of
the cardiac-specific creatine kinase isoenzyme CKMB8 and
focal myocardial necrotic lesions9-11. These changes can be
inhibited by non-selective beta-blockade. 11,12 Cardiac
morbidity, high plasma CKMB levels, and myocardial
necrosis have also been reported as sequelae of acute head
injuries.13-15 This study was therefore designed to assess a
possible association between increased sympathetic activity
and cardiac morbidity in acute head injuries and the effect of
beta1-selective blockade on cardiac morbidity.
Patients and Methods
114 patients with a primary diagnosis of acute head injury with or
without other extracranial injury were admitted to the intensive-
care or neurosurgical units in four centres (Erasme University
Hospital, Brook General Hospital, Tampere University Central
Hospital, and T&ouml;&ouml;l&ouml; Hospital). Ethical committee approval was
obtained for the study protocol in each of the centres. The nature of
the investigations was explained to the patient’s next-of-kin
whenever possible, and their consent to proceed was obtained
before the patient was entered into the study.
Recruitment took place over 2 years, during which the routine
management practices in each of the four centres remained constant
and largely unaffected by the study protocol. Concurrent treatment
with antibiotics, sedatives, osmotic agents, anticonvulsants,
steroids, and analgesics continued as indicated. The only treatment
specifically excluded during the acute treatment phase was
concurrent use of beta-blocker.
All head-injury patients were considered for entry to the study
provided they were aged 11-70 years and were haemodynamically
stable. Haemodynamic stability was judged by the responsible
physicians, but in general it was defined as a systolic blood pressure
above 100 mm Hg. In addition, all patients had to have clear
airways. Patients were excluded if beta-blockade was
contraindicated (ie, history of asthma or heart failure, or evidence of

IN both animal models and

man catecholamine
administration results in bizarre electrocardiographic
(ECG) changesl-3 accompanied by focal subendocardial
second-degree or third-degree heart block). Patients were
withdrawn from treatment if the systolic pressure fell below 90 mm
Hg or intracranial pressure rose above 50 mm Hg; also if
bronchoconstriction, heart failure, second-degree or third-degree
8559 &copy;
586
TABLE I-PATIENTS’ BASELINE CHARACTERISTICS
*Ranges: placebo 16-67 yr; atenolol 11-70 yr.
tBefore first dose of treatment.
heart block, or a persistent bradycardia of less than 40 beats/min
developed.
Immediately after haemodynamic stabilisation (mean time 20-2 h
after trauma) patients meeting the entry criteria were randomised in
a double-blind manner to treatment with either atenolol 10 mg
intravenously every 6 h for 3 days, followed by 100 mg by mouth
once a day for 4 days, or matching placebo, comprising 2 ampoules
isotonic placebo intravenously every 6 h for 3 days, followed by 2
tablets by mouth once a day for 4 days. Beta1-selective atenolol was
chosen because in the presence of high adrenaline concentrations
non-selective beta-blockade can induce pronounced hypertension
by the unmasking of uninhibited alpha-constrictor activity. The
intravenous doses were administered as slow (1 mg/min) bolus
injections during which the patient’s heart rate was monitored. The
injection was stopped if the heart rate fell below 40 beats/min and
further injections were withheld until the heart rate had risen above
40 beats/min.
The severity of the head injury was assessed before entry to the
trial by means of the Glasgow coma scale and pupil response. A
head injury was defined as severe if the score on the Glasgow coma
scale was less than 7 or equal to 7 with no pupil response and
moderate to mild if the score was greater than 7 or 7 with pupil
response. Heart rate and blood pressure were recorded before the
first dose of treatment and then every 4 h throughout the duration of
treatment.
Daily 24 h double-channel ECG recordings were made in 104
patients for up to 5 days. All tapes were analysed by standard
predefined criteria for the recording of events. Supraventricular
Fig I-Arterial noradrenaline levels in 69
Shaded area = normal limits; horizontal
TABLE II-CONCOMITANT MEDICATION DURING STUDY PERIOD
tachycardia was described as a run of 3 or more supraventricular
beats with a rate of 150 beats/min or more; accelerated
idioventricular rhythm as a run of 3 or more consecutive ventricular
ectopic beats with a rate of 60-99 beats/min; and ventricular
tachycardia as a run of 3 or more ventricular ectopic beats with a rate
of 100 beats/min or more. The Brook Hospital tapes were analysed
by B. Gill with a Reynolds ’Pathfinder Analyser’; the Belgian and
Finnish tapes were all analysed by Professor S. Degre with an
Avionix 445 system.
In three of the centres an arterial cannula was routinely inserted
into the radial artery of the non-dominant arm as part of the normal
management practice, to monitor the patient’s blood pressure,
arterial blood gases, and pH. In these centres arterial blood samples
were withdrawn from the cannulated arm daily between 0800 and
1000 h. Noradrenaline was measured 16 in 69 patients and creatine
kinase 17 in 60 patients. Arterial analyses in the remaining 45 patients
were not possible. CKMB isoenzyme was determined as previously
described.8
At necropsy, the coronary arteries were examined. Blocks were
taken from the posterior wall, lateral wall, anterior wall,
intraventricular septum, and apex of the left ventricle and examined
by previously described histological methods1O for focal necrosis.
All data from all
patients were analysed in an attempt to reduce
any possible biases. The CKMB data were investigated in two ways.
First, the area under the blood concentration/time curve was
calculated for each patient by the trapezoidal rule and was analysed
by the Wilcoxon rank-sum test. Secondly, the proportions of
patients with raised CKMB levels (ie, more than 3 % of total
creatine kinase, compatible with myocardial damage, and more than
6 % of total creatine kinase, compatible with acute myocardial
infarction) after the baseline days were calculated. The respective
proportions in each treatment group were compared by Fisher’s
exact test. The relation between noradrenaline and CKMB was
investigated by scatter plots. The peak noradrenaline level for each
patient was plotted against the isoenzyme value at the same time.
Spearman’s rank correlation coefficient was calculated and its
significance tested by a t approximation.
patients.
bars = daily means.

Days
Fig 2-Arterial CKMB Concentration as percentage of total creatine kinase in 60 patients.
Non-shaded area = values consistent with myocardial damage.
The ECG results were summarised according to the presence or
absence of an event at baseline (days 0 and 1) and on treatment (days
2-5). This estimate of baseline was very crude since the first 24 h
tape-recordings included varying proportions of events before and
after first treatment. The proportion of patients experiencing
supraventricular arrhythmias after the baseline days was calculated
for each group. The treatments were compared by Fisher’s exact
test. McNemar’s test compared the proportion of patients in whom
ST segment and T wave changes developed after treatment (from
those who changed within each group) between the groups.
Results
Baseline data on the 114 patients are shown in table I. The
mean treated heart rate and blood pressure in patients
receiving placebo were 91-4 beats/min, 139/80 mm Hg and
those in patients receiving atenolol 76-5 beats/min, 129/76
mm Hg. Table II lists the concomitant medication received
by patients.
Plasma noradrenaline levels in many patients were much
higher than the normal upper limit of 5 nmol/1 (fig 1). 62%
of patients had an abnormally high plasma noradrenaline
level at some time during the week of observation. There
was no obvious treatment effect on circulating noradrenaline
levels.
Total creatine kinase activity was raised well beyond the
normal hospital laboratory limit of 175 IU/1. At baseline, the
mean total activity (range) was 1364 IU/1 (75-3240 IU/1) in
the placebo group and 1554 IU/1 (100-5940 IU/1) in the
Fig 3-Relation between plasma CKMB and noradrenaline levels in
patients who received placebo.
587
of treatment
atenolol group. By day 7 of treatment the mean activities had
fallen to 829 IU/1 (59-5970 IU/1) with placebo and 541 IU/1
(43-2275 IU/1) with atenolol.
The CKMB concentration over the week (area under the
curve) was 80% lower in the atenolol group than the placebo
group (not significant owing to high variability).
Pathologically high levels of CKMB (more than 3% of total
creatine kinase concentration) were found in both groups at
baseline (fig 2). The proportion of treated patients whose
maximum CKMB level was more than 3% of total creatine
kinase was 30% (9/30) in the placebo group and 7-4% (2/27)
in the atenolol group (p < 005; 3 patients with baseline
assessments only were excluded from this analysis). These
proportions were essentially the same when patients who
died were excluded from the analysis. CKMB levels above
6% of total creatine kinase, compatible with acute
myocardial infarction, were detected in 16.7% (5/30) of
patients receiving placebo but in no patient receiving
atenolol (p 0-053).
=
Among the 60 patients in whom arterial CKMB
measurements were done, 5 in each group had chest injuries.
In the placebo group, but not in the atenolol group there was
a significant (p==0’01) positive correlation (r=0-46)
between plasma CKMB and noradrenaline levels. Fig 3
shows the close association between plasma CKMB and
noradrenaline concentration in placebo patients with
CKMB levels greater than and less than 3 % of total creatine
kinase.
The incidence of supraventricular and ventricular
arrhythmias is shown in table ill. The only significant
difference between the groups was the smaller number of
patients with supraventricular tachycardia on treatment in
the atenolol group (p < 00001). Sinus bradycardia occurred
during treatment in 2 placebo-treated patients and in 1
atenolol-treated patient. Sinus block or arrest which
reverted spontaneously occurred in 3 placebo-treated and 4
atenolol-treated patients. Third-degree atrioventricular
block occurred in 1 atenolol-treated patient.
The effect of treatment on ST-segment and T-wave
changes is also shown in table III. Such changes were
significantly (p < 005) less likely to develop in patients who
received atenolol.
5 of the 58 placebo-treated patients were withdrawn from
the trial: 1 had second/third-degree heart block; in 2 the
systolic blood pressure fell below 90 mm Hg; and 2 patients
588
TABLE III-NUMBERS OF PATIENTS WITH RHYTHM DISTURBANCES
AND ST-SEGMENT AND T-WAVE CHANGES
,
Differences between placebo and atenolol groups on treatment not significant
except: *p< 0-0001; tp 0-057; tp 0-062.
= =
were transferred another ward. 9 of the 56 atenolol-
to
treated patients were withdrawn: 1 had wheezing, ileus
developed in 1, 1 had raised intracranial pressure, in 5 the
systolic blood pressure fell below 90 mm Hg; and 1 patient
was transferred to another ward.
Reduction in mortality was not a prime end-point of this
trial, which aimed to reduce cardiac morbidity. Long-term
(1-year) follow-up is not yet complete (total deaths and
in-hospital deaths will be fully reported elsewhere). In brief,
there was no significant drug effect on in-hospital mortality,
which was directly related to the severity of the head injury.
6 hearts were available for detailed post-mortem
examination. Focal necrotic lesions were not detected in any
of the 4 hearts from atenolol-treated patients (aged 51, 33,
21, and 44 years; the fourth patient had substantial coronary
atherosclerosis). In contrast, necrotic lesions were identified
in both of the hearts from 2 placebo-treated patients (aged 16
and 49 years; the older patient had substantial coronary
atherosclerosis).
Discussion
The two groups were well matched for sex .distribution,
mean age, mean time to trial entry, and mean blood pressure
before treatment. The mean pretreatment heart rate was
lower in the atenolol group; since mean baseline plasma
noradrenaline levels were similar in the two groups, the
lower heart rate might reflect the greater number of severe
cases (with accompanying raised intracranial pressure
leading to a slowing of the heart rate) in the atenolol group.
High urinary catecholamine levels,’>14 raised plasma
CKMB activity14,15 and myocardial necrotic lesionsll,14
have previously been described in stressful disorders in
man; such necrotic lesions are associated with excessive
intracellular free calcium,18 possibly arising from increased
activity of slow calcium channels. 19 Head injury is
undoubtedly a highly stressful disorder; the plasma
noradrenaline levels in many patients in our study were
similar to those observed in patients with acute myocardial
infarction who had not suffered cardiac arrest.2o In our pilot
study14 we showed that patients with severe head injury
were under great stress, indicated by very high urinary
catecholamine levels. We elected to measure discrete plasma
catecholamines rather than 24 h urinary catecholamines in
this study so that we could correlate contemporary plasma
noradrenaline and CKMB concentrations. Arterial, rather
than venous, noradrenaline levels were measured, since they
probably estimate sympathetic activity in the body as a
whole more sensitively. Samples from the antecubital vein
are greatly influenced by local sympathetic forearm
activity. 2122
CKMB isoenzyme is specific to the myocardium,
forming about 22% of the total myocardial creatine kinase
activity. 23 Plasma CKMB levels in acute myocardial
infarction relate to the extent of myocardial damage
measured at necropsy24.25 and have prognostic significance.26
CKMB activity is undetectable in plasma in normal resting
subjects by our methods; others have reported similar
negative fmdings.27 A CKMB level exceeding 3% of a total
elevated creatine kinase level in this laboratory is indicative
of myocardial damage in resting hospital inpatients. In this
study CKMB levels were persistently raised in significantly
more placebo-treated than atenolol-treated patients. The
difference was not due to direct trauma, since chest injury
was not common and was equally distributed between the
groups. Nor was it due to skeletal-muscle trauma; in a
separate study in 10 patients undergoing major orthopaedic
surgery, CKMB levels did not exceed 2% of total creatine
kinase. 14
This study is the first, to our knowledge, on stress in man
to demonstrate a significant positive correlation between
arterial noradrenaline concentration and cardiac damage, as
manifest indirectly by raised arterial CKMB levels and
directly at necropsy by focal subendocardial necrotic lesions.
This positive relation is abolished by early administration of
the beta1-selective beta-blocker atenolol. Beta1-selective
blockade did not affect arterial noradrenaline levels but did
significantly inhibit the rise in arterial CKMB, abolished the
focal myocardial necrotic lesions, and appeared to reduce the
likelihood of supraventricular tachycardia and ST-segment
and T-wave changes.
It is highly likely that beta1-blockade per se, and not a
lowering of blood pressure (reducing afterload on heart),
was responsible for the cardioprotective effect. We have two
reasons for this conclusion. First, in one of our previous
stress studies, involving patients with subarachnoid
haemorrhage, prevention of cardiac necrosis by beta-
blockade was demonstrated despite the similarity of blood
pressure in the placebo and treated groups." Secondly,
myocardial infarct size was -not affected by the non-beta-
blocker nifedipine, despite a significant fall in blood
pressure.28
The broader implications of this study may be important.
Trauma patients, other than those with head injury, who are
haemodynamically stable but who show signs of a
pronounced hyperadrenergic state may benefit from beta1-
selective blockade by reduced cardiac morbidity. The
inhibition of the rise in plasma CKMB and prevention of
cardiac necrosis by atenolol may be akin to its benefit in
significantly limiting infarct size in acute myocardial
infarction 29 Indeed the inhibition of catecholamine-
induced cardiac necrosis may be the most important factor
in limiting the size of a myocardial infarction. Potential
cardiac transplant donors perhaps should be treated with
beta1-blockade to ensure that the recipient does not inherit a
necrosed myocardium. The high plasma catecholamine
levels in moderate to severe heart failure might predispose to
cardiac necrosis and sudden death;inhibition of such an
effect might partly explain why beta-blockers benefit some
patients with congestive carcliomyopathy.3n32 Stress may
accelerate the atheromatous process33 and it has been
claimed that aggressive, type-A behaviour increases the
likelihood of cardiac events including death;34beta-blockade
may be helpful in such circumstances. Finally, most patients

with ischaemic heart disease who die suddenly while
undergoing ambulatory monitoring show ventricular
tachycardia/fibrillation which is usually preceded by an
increase in the sinus rate (A. Bayes de Luna, personal
communication) and the hearts of many such subjects show
focal necrotic lesions identical to those we found here.35
Beta-blockade should modify the prodomal speeding of the
heart rate, and prevention of catecholamine-induced
necrotic lesions might stabilise an excitable left ventricle.
We thank Prof S. Degre and Barbara Gill for analysing the ECG data; Dr
B. Doshi for post-mortem examinations on hearts; and Mrs Lesley France for
statistical expertise.
Correspondence should be addressed to J. M. C., Department of
Cardiology, Wythenshawe Hospital, Clay Lane, Wythenshawe, Manchester
M23 9LT.
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589
LONG LATENCY PRECEDES OVERT
SEROCONVERSION IN SEXUALLY
TRANSMITTED HUMAN-
IMMUNODEFICIENCY-VIRUS INFECTION
ANNAMARI RANKI1,2 SIRKKA-LIISA VALLE2,3
MINERVA KROHN1,4 JAAKKO ANTONEN4
JEAN-PIERRE ALLAIN5 MICHAEL LEUTHER5
GENOVEFFA FRANCHINI1 KAI KROHN1,4
Laboratory of Tumor Cell Biology, National Cancer Institute,
National Institutes of Health, Bethesda, Maryland, USA;1
Department of Dermatology, Helsinki University Central Hospital,
Helsinki, Finland,2 Aurora Municipal Hospital, Helsinki;3 Institute
of Biomedical Sciences, University of Tampere, Tampere, Finland;4
and Abbott Laboratories, North Chicago, Illinois, USA5
Summary Signs of latent HIV infection were sought
in stored serum samples collected before
overt seroconversion, confirmed by enzyme-linked
immunosorbent assay (ELISA), from 9 subjects with
human-immunodeficiency-virus (HIV) infection, in serum
from 25 seronegative sexual partners of HIV-seropositive
men and from 23 other seronegative, homosexually active
men. Free HIV antigen and/or low-titre antibodies to
recombinant structural (core, env) or non-structural (3’orf,
sor, tat) proteins were seen 6-14 months before
seroconversion in all 9 subjects who seroconverted.
Antibodies against core proteins detected by western blot
were usually the first sign of latent HIV infection. 5 of the 25
ELISA-negative exposed partners have shown HIV
antigenaemia and antibodies against core proteins for 16-34
months. By in-situ hybridisation, HIV-specific RNA was
detected in peripheral-blood non-lymphoid mononuclear
cells in some of the latently infected partners. All subjects
with latent HIV infection had normal numbers of T4
lymphocytes but half of them lost their in-vitro proliferative
T-cell response to a recall antigen (purified protein
derivative of tuberculin). Early HIV infection, characterised
by a low-level and restricted antibody response towards
HIV core and regulatory proteins, seems mainly to affect
antigen-presenting cells.
Introduction
THE diagnosis of human-immunodeficiency-virus (HIV)
infection is currently based on the demonstration of
antibodies to the viral proteins by commercial enzyme-
linked immunosorbent assay (ELISA) methods, confirmed
by immunoblotting assay. In some cases seroconversion
follows a primary syndrome characterised by pharyngitis,
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by early intravenous beta blockade in suspected acute myocardial infarction.
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converting enzyme inhibitors in improving survival. Am 3’ Med 1986; 81 (supI4C):
32-35.
31. Anderson JL, Lutz JR, Gilbert EM, et al. A randomised trial of low dose beta blockade
therapy for idiopathic dilated cardiomyopathy. 4tK.y Cardiol 1985; 55: 471-75.
32. Englemeier RS, O’Connell JB, Walsh R, Rad N, Scanlon PJ, Gunnar RM.
Improvement in symptoms and exercise tolerance by metoprolol in patients with
dilated cardiomyopathy: a double-blind, randomized, placebo controlled trial.
Circulation 1985; 72:536-6.
33. Kaplan JR, Manuck SB, Clarkson TB, Adams MR. Effects of propranolol HCL on
behaviourally-mduced atherosclerosis in monkeys. 9th Asian-Pacific Congress of
Cardiology. Feb 11-15, 1987: Auckland, New Zealand: 151 (abstr).
34. Friedman M, Thoresen CE, Gill JJ, et al. Alteration of type A behaviour and its effect
on cardiac recurrences in post myocardial infarction patients: summary results of
the recurrent coronary prevention project. Am Heart J 1986; 112: 653-65.
35. Davies MJ, Thomas AC, Knapman PA, Hangarmer JR. Intramyocardial platelet
aggregation in patients with unstable angina suffering sudden ischaemic cardiac
death. Circulation 1986; 73:418-27.