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Cardiovascular Research 45 (2000) 197–199
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Historical note
Sleep revisited
Peter Sleight
Professor Emeritus of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9 DU, UK
Keywords: Autonomic nervous system; Baroreflex; Blood pressure; Hemodynamics; Hypertension
1. Introduction
How many authors re-read their 30-year-old papers? For
me this was an emotional experience, since two of the
co-authors are dead – John Honour in 1997, and David
Bristow two years ago unexpectedly early – within a year
of his first symptoms of cancer. Both faced ill health with
unusual courage. I am sad that they are not here to share
this reminiscence, both made major contributions to the
study.
John Honour worked for Sir Thomas Lewis and then Sir
George Pickering in Oxford, in whose laboratories this
work was done. John had a wonderful way with apparatus,
particularly Frank Stott’s Portable manometer / recorder for
intra-arterial blood pressure which never seemed to work
properly unless one of them was around. He had a huge
experience of clinical research which was invaluable in
this technically demanding project.
David and Kay Bristow became lifelong friends. We first
met in San Francisco in 1961 when we were both fellows
in Julius Comroe’s Cardiovascular Research Institute. He
spent two sabbaticals in Oxford (1968 and 1988).
He was deservedly the first author on this paper in
Cardiovascular Research, since he contributed to the
methodology, and also did most of the laborious calculations involved in determining baroreflex sensitivity and
cardiac output during the various stages of sleep, including
rapid eye movement (REM) or dreaming sleep. He was
jokingly known as the human computer. Electronic computers now do these calculations in milliseconds, on line.
In the late 1960’s we (usually David) had to measure the
blood pressure and pulse intervals beat by beat from the
paper records produced by Mrs. Grass’s 12-channel pen
recorder, during the rises in pressure produced by the
intravenous injections of phenylephrine boluses. Individual
systolic pressures during the rise in pressure were linearly
regressed against their following pulse intervals. The
measurement, plus the calculation of linear regression
(hand winding a Monroe mechanical calculating machine)
would take an expert around 30 minutes per phenyleprine
injection. Since each night’s study would involve around
30 such injections David Bristow’s right arm became very
well trained by the calculator!
When I myself went on sabbatical to Paul Korner’s
department at the Royal Prince Alfred’s Hallstrom Institute
in Sydney in 1972–3 I returned to Oxford to find myself in
the newly founded British Heart Foundation Field Marshall
Alexander Chair of Cardiovascular Medicine in Oxford,
instead of my previous NHS consultant post (Field Marshal Alexander was the first President of the BHF). I also
found that an old NHS patient had left me her house in her
will! In Sydney I had been comparing the firing rates of
single carotid baroreceptor fibres in normal versus renal
hypertensive dogs, but had also had time to take the first
year course in computing science in Sydney. Therefore,
(mindful of the difficulty in being both a clinical cardiologist and a Monroe calculator winder) I bought what was
then the first electronic computer in the Oxford Hospitals.
This was the size of a large refrigerator but was less
powerful than today’s laptop. My then young technician –
Tim Johnston – rapidly designed and built a superb
interface to digitise all the data. This produced the results
on line (rather than 2 days later) and made the studies so
much more exciting. Jim is now the departmental administrator for my successor Prof. Hugh Watkins, but fortunately
is still able to help me (and others) with our struggles with
the laptop and the Internet, and e-mail attachments!
The other surviving author is Tom Pickering, Sir
George’s son, now Professor of Medicine at Cornell
Medical Centre, New York. He was a delight to work with.
We studied each patient on 3 successive nights. They were
(for those days) intensively monitored – 6 channels of
EEG, eye movement, respiration, ECG, and blood pressure. I was mainly involved on the third night measuring
intra-arterial pressure and cardiac output, returning to my
own bed about 5 a.m. for 2 or 3 hours sleep before the next
day’s clinical work. One can see why more intelligent
investigators choose to study the cat which sleeps during
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198
Cardiovascular and respiratory changes in hypertensives
the day. Here I should pay tribute to my long-suffering
wife who learned to cope with a sleep deprived spouse for
around 6–8 years.
The sleep studies had begun in 1964, when I had been
recruited by George Pickering to come from St. George’s
in London, where I was senior registrar to Aubrey Leatham, and newly returned to the UK from San Francisco. In
San Francisco I had intended to study coronary shock on
drugs, measuring the haemodynamics using the first electromagnetic flowmeters round the aorta and pulmonary
arteries. However, the flowmeter group (Abe Gut, David
Wilcken and Andre Charlier) were still finishing their
studies on the control of left and right ventricular stroke
volume during respiratory and afterload changes. It was
clear that I would not get my programme started, so I
began to work on my own investigating the origin of the
Bezold–Jansch depressor reflex. This work went well and
Dr. Comroe (Uncle Julius) asked me to stay another year. I
wished to record from the afferents of these left ventricular
receptors, so Uncle Julius paid for me to do this with John
Widdicombe in Oxford, in the last 4 months of my second
year at the C.V.R.I. I got bitten by the beauty of nerve fibre
recording (and went through an early mid-life crisis
wondering whether to be a physiologist or a cardiologist).
In 1964 George Pickering had asked me to come to
Oxford on a 3-year MRC senior fellowship and honorary
consultant cardiologist, and quickly asked to to supervise a
young Canadian Rhodes Scholar, Harley Smyth, who was
studying the blood pressure changes during sleep. We
developed the angiotensin baroreflex test because the
previously used tilt test woke the patients [1]!
We had previously noted that after angiotensin injections
and the initial reflex bradycardia there was a later tachycardia. We now know that this is likely to be due to several
factors, including a brainstem action of AII which increases sympathetic tone, decreases vagal tone, and decreases the gain of the baroreflex.
David Bristow suggested that we used a pure a-agonist
phenylephrine instead, since it did not have these central
effects.
2. What did we learn?
We showed that the blood pressure fall (about 10%) was
closely related to sleep, and so the changes were initiated
by the nervous system and not merely due to recumbency
or rest. The baroreflex gain was reduced in patients with
hypertension. We later showed that BRS gain was also
independently reduced by increasing age [2]. BRS gain
tended to increase during slow wave sleep, and as in our
earlier study [1] consistently increased during dreams.
Cardiac output was unchanged by sleep in normals but
tended to fall in hypertensives (due to higher awake
sympathetic tone). Peripheral resistance therefore fell in
most during sleep, probably due to sympathetic withdrawal.
3. What did we miss, what were the limitations?
This study was very labour intensive and full of
frustrations, e.g. when the patient awoke. As a result the
number of subjects was small and not matched. This raises
the question of whether the comparisons between the
normal and hypertensive subjects were valid. Although I
spent many years interested in baroreflexes and the autonomic control of the circulation I completely missed the
importance of these measures as a prognostic index in
patients with heart disease, as developed first by Peter
Schwartz in Milan, and Maria Theresa La Revere in
Montescano / Pavia, who showed in the ATRAMI study [3]
that low BRS was a powerful predictor of future risk after
an index myocardial infarction, independent of, and additional to, the conventional markers such as poor LV
function.
We are still uncertain of the mechanisms underlying this
association, which may be related to reduced reflex
buffering of rises of arterial pressure, together with reduction of ventricular fibrillation threshold when vagal tone is
reduced.
Although unfashionable I believe reduced BRS can play
an important role in the rise in blood pressure seen with
ageing, either from peripheral (carotid and aortic) vessel
wall stiffening by disease, or equally by central nervous
re-setting of the reflex (as seen in mental stress or arousal).
4. Why was this paper successful?
Part of the success was the novel methodology, which
has stood the test of time. For the first time we had a
reproducible method to quantify the gain of the baroreceptor heart rate reflex. The principle of the method –
particularly the regression of pressure against RR interval,
which gives a linear plot – is now applied using noninvasive measures of beat to beat arterial pressure.
The paper also was one of the first to quantify the
haemodynamic changes during sleep, and began the explosive growth of present day sleep laboratories.
5. Postscript
In 1992 / 3 I spent a sabbatical in Pavia, dividing my
time between Luciano Bernardi’s laboratory in the Ospedale San Matteo’s Clinica Medica I, University of Pavia
(Prof. Giorgio Finardi), and the large group in the then
Fondazione Clinica del Lavoro (Prof. Luigi Tavazzi) in the
Montescano medical centre. I went to Pavia to learn more
about heart rate variability, which was then becoming a hot
Key publication: J.D. Bristow et al. / Cardiovascular Research 1969
topic, but which was (and is still) incompletely understood.
With Bernardi I largely studied normals, including ourselves, while in Montescano, with Maria Theresa La
Revere, Andrea Mortara, Roberto Maestri and Gianni
Pinna, we studied patients with heart failure. (Pavia is the
largest cardiac transplant centre in Italy.) This proved to be
very productive and enormously enjoyable particularly
working again in the lab, and getting one’s own hands
dirty, and with the company of young enthusiastic colleagues. It made me re-think my life; and so I retired from
my Oxford Chair two years earlier than I needed. I am glad
to report that this is one of the best things I have ever
done, and I now occasionally find my name towards the
front of a paper [4,5]! This Italian collaboration continues
still, 5 or 6 years later, with bursts of frenetic activity
around twice a year in Italy, and more leisurely analysis
back in Oxford, where I am similarly stimulated by Dr.
Barbara Casadei and her team.
David Bristow was successively Chief of Cardiology
and Chief of Medicine in the Oregon Health Sciences
Center. They wished him to stay on for an unprecedented
third term, but with typical self-discipline he refused. He
will be greatly missed as a true role model to the young. I
199
thank the editor for this opportunity to pay my respects to
David and John.
References
[1] Smyth HS, Sleight P, Pickering GW. Reflex regulation of arterial
pressure during sleep in man. A quantitative method of assessing
baroreflex sensitivity. Circ Res 1969;24:109–121.
[2] Gribbin B, Pickering TG, Sleight P, Pete R. Effect of age and high
blood pressure on baroreflex sensitivity in man. Circ Res
1971;29:424–431.
[3] La Revere MT, Bigger Jr. TT, Marcus FI, Mortara A, Schwartz PJ.
for the ATRAMI (Autonomic Tone and Reflexes After Myocardial
Infarction) Investigators. Baroreflex sensitivity and heart rate variability in prediction of total cardiac mortality after myocardial
infarction. Lancet 1998;351:478–484.
[4] Sleight P, La Revere MT, Mortara A, Pinna G, Maestri R, Leuzzi S,
Bianchini B, Tavazzi L, Bernardi L. Physiology and pathophysiology of heart rate and blood pressure variability in humans: is power
spectral analysis largely an index of baroreflex gain? Clin Sci
1995;88:103–109.
[5] Piepoli M, Sleight P, Leuzzi S, Valle S, Spadacini G, Passino C,
Johnston J, Bernardi L. Origin of respiratory sinus arrhythmia in
conscious humans: An important role for arterial carotid baroreceptors. Circulation 1997;95(7):1813–1821.