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TABLE I-PATIENTS’ BASELINE CHARACTERISTICS TABLE II-CONCOMITANT MEDICATION DURING STUDY PERIOD
Days of treatment
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 atenolol group. By day 7 of treatment the mean activities had
absence of an event at baseline (days 0 and 1) and on treatment (days fallen to 829 IU/1 (59-5970 IU/1) with placebo and 541 IU/1
2-5). This estimate of baseline was very crude since the first 24 h (43-2275 IU/1) with atenolol.
tape-recordings included varying proportions of events before and The CKMB concentration over the week (area under the
after first treatment. The proportion of patients experiencing
supraventricular arrhythmias after the baseline days was calculated curve) was 80% lower in the atenolol group than the placebo
for each group. The treatments were compared by Fisher’s exact group (not significant owing to high variability).
test. McNemar’s test compared the proportion of patients in whom Pathologically high levels of CKMB (more than 3% of total
ST segment and T wave changes developed after treatment (from creatine kinase concentration) were found in both groups at
those who changed within each group) between the groups. 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)
Results
in the atenolol group (p < 005; 3 patients with baseline
Baseline data on the 114 patients are shown in table I. The assessments only were excluded from this analysis). These
mean treated heart rate and blood pressure in patients proportions were essentially the same when patients who
receiving placebo were 91-4 beats/min, 139/80 mm Hg and died were excluded from the analysis. CKMB levels above
those in patients receiving atenolol 76-5 beats/min, 129/76 6% of total creatine kinase, compatible with acute
mm Hg. Table II lists the concomitant medication received myocardial infarction, were detected in 16.7% (5/30) of
by patients. patients receiving placebo but in no patient receiving
Plasma noradrenaline levels in many patients were much atenolol (p 0-053).
=
higher than the normal upper limit of 5 nmol/1 (fig 1). 62% Among the 60 patients in whom arterial CKMB
of patients had an abnormally high plasma noradrenaline measurements were done, 5 in each group had chest injuries.
level at some time during the week of observation. There In the placebo group, but not in the atenolol group there was
was no obvious treatment effect on circulating noradrenaline a significant (p==0’01) positive correlation (r=0-46)
levels. between plasma CKMB and noradrenaline levels. Fig 3
Total creatine kinase activity was raised well beyond the shows the close association between plasma CKMB and
normal hospital laboratory limit of 175 IU/1. At baseline, the noradrenaline concentration in placebo patients with
mean total activity (range) was 1364 IU/1 (75-3240 IU/1) in CKMB levels greater than and less than 3 % of total creatine
the placebo group and 1554 IU/1 (100-5940 IU/1) in the 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
Fig 3-Relation between plasma CKMB and noradrenaline levels in the trial: 1 had second/third-degree heart block; in 2 the
patients who received placebo. systolic blood pressure fell below 90 mm Hg; and 2 patients
588
TABLE III-NUMBERS OF PATIENTS WITH RHYTHM DISTURBANCES whole more sensitively. Samples from the antecubital vein
AND ST-SEGMENT AND T-WAVE CHANGES
,
Reduction in mortality was not a prime end-point of this arterial noradrenaline concentration and cardiac damage, as
trial, which aimed to reduce cardiac morbidity. Long-term manifest indirectly by raised arterial CKMB levels and
(1-year) follow-up is not yet complete (total deaths and directly at necropsy by focal subendocardial necrotic lesions.
This positive relation is abolished by early administration of
in-hospital deaths will be fully reported elsewhere). In brief,
there was no significant drug effect on in-hospital mortality, the beta1-selective beta-blocker atenolol. Beta1-selective
which was directly related to the severity of the head injury. blockade did not affect arterial noradrenaline levels but did
6 hearts were available for detailed post-mortem significantly inhibit the rise in arterial CKMB, abolished the
examination. Focal necrotic lesions were not detected in any focal myocardial necrotic lesions, and appeared to reduce the
of the 4 hearts from atenolol-treated patients (aged 51, 33, likelihood of supraventricular tachycardia and ST-segment
and T-wave changes.
21, and 44 years; the fourth patient had substantial coronary
It is highly likely that beta1-blockade per se, and not a
atherosclerosis). In contrast, necrotic lesions were identified
in both of the hearts from 2 placebo-treated patients (aged 16 lowering of blood pressure (reducing afterload on heart),
was responsible for the cardioprotective effect. We have two
and 49 years; the older patient had substantial coronary
reasons for this conclusion. First, in one of our previous
atherosclerosis).
stress studies, involving patients with subarachnoid
Discussion
haemorrhage, prevention of cardiac necrosis by beta-
blockade was demonstrated despite the similarity of blood
The two groups were well matched for sex .distribution, pressure in the placebo and treated groups." Secondly,
mean age, mean time to trial entry, and mean blood pressure myocardial infarct size was -not affected by the non-beta-
before treatment. The mean pretreatment heart rate was blocker nifedipine, despite a significant fall in blood
lower in the atenolol group; since mean baseline plasma pressure.28
noradrenaline levels were similar in the two groups, the The broader implications of this study may be important.
lower heart rate might reflect the greater number of severe Trauma patients, other than those with head injury, who are
cases (with accompanying raised intracranial pressure haemodynamically stable but who show signs of a
leading to a slowing of the heart rate) in the atenolol group. pronounced hyperadrenergic state may benefit from beta1-
High urinary catecholamine levels,’>14 raised plasma selective blockade by reduced cardiac morbidity. The
CKMB activity14,15 and myocardial necrotic lesionsll,14 inhibition of the rise in plasma CKMB and prevention of
have previously been described in stressful disorders in cardiac necrosis by atenolol may be akin to its benefit in
man; such necrotic lesions are associated with excessive significantly limiting infarct size in acute myocardial
intracellular free calcium,18 possibly arising from increased infarction 29 Indeed the inhibition of catecholamine-
activity of slow calcium channels. 19 Head injury is induced cardiac necrosis may be the most important factor
undoubtedly a highly stressful disorder; the plasma in limiting the size of a myocardial infarction. Potential
noradrenaline levels in many patients in our study were cardiac transplant donors perhaps should be treated with
similar to those observed in patients with acute myocardial beta1-blockade to ensure that the recipient does not inherit a
infarction who had not suffered cardiac arrest.2o In our pilot necrosed myocardium. The high plasma catecholamine
study14 we showed that patients with severe head injury levels in moderate to severe heart failure might predispose to
were under great stress, indicated by very high urinary cardiac necrosis and sudden death;inhibition of such an
catecholamine levels. We elected to measure discrete plasma effect might partly explain why beta-blockers benefit some
catecholamines rather than 24 h urinary catecholamines in patients with congestive carcliomyopathy.3n32 Stress may
this study so that we could correlate contemporary plasma accelerate the atheromatous process33 and it has been
noradrenaline and CKMB concentrations. Arterial, rather claimed that aggressive, type-A behaviour increases the
than venous, noradrenaline levels were measured, since they likelihood of cardiac events including death;34beta-blockade
probably estimate sympathetic activity in the body as a may be helpful in such circumstances. Finally, most patients
589
with ischaemic heart disease who die suddenly while LONG LATENCY PRECEDES OVERT
undergoing ambulatory monitoring show ventricular SEROCONVERSION IN SEXUALLY
tachycardia/fibrillation which is usually preceded by an TRANSMITTED HUMAN-
increase in the sinus rate (A. Bayes de Luna, personal IMMUNODEFICIENCY-VIRUS INFECTION
communication) and the hearts of many such subjects show
focal necrotic lesions identical to those we found here.35 ANNAMARI RANKI1,2 SIRKKA-LIISA VALLE2,3
Beta-blockade should modify the prodomal speeding of the MINERVA KROHN1,4 JAAKKO ANTONEN4
heart rate, and prevention of catecholamine-induced JEAN-PIERRE ALLAIN5 MICHAEL LEUTHER5
necrotic lesions might stabilise an excitable left ventricle. GENOVEFFA FRANCHINI1 KAI KROHN1,4
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 Laboratory of Tumor Cell Biology, National Cancer Institute,
statistical expertise.
National Institutes of Health, Bethesda, Maryland, USA;1
Correspondence should be addressed to J. M. C., Department of Department of Dermatology, Helsinki University Central Hospital,
Cardiology, Wythenshawe Hospital, Clay Lane, Wythenshawe, Manchester Helsinki, Finland,2 Aurora Municipal Hospital, Helsinki;3 Institute
M23 9LT. of Biomedical Sciences, University of Tampere, Tampere, Finland;4
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