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Cardiovascular Research 45 (2000) 197–199 www.elsevier.com / locate / cardiores www.elsevier.nl / locate / cardiores 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 0008-6363 / 00 / $ – see front matter 2000 Elsevier Science B.V. All rights reserved. PII: S0008-6363( 99 )00328-4 198 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.