The Publication of The British Society for Cardiovascular Research Vol

The Publication of The British Society for Cardiovascular Research Vol. 12 No. 2

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Registered Charity Number: J 011141

The Bulletin

The Publication of The British Society for Cardiovascular Research Editors Dr. James Mockridge and Dr. Harold Raat Department of Cardiology The Rayne Institute, St. Thomas' Hospital London SE17EH Tel.:0171-9289292ext.l818 Fax.:0171-9605659 E-mail: j [email protected] E-mail: [email protected]

Dr. Adrian Brady Department of Medical Cardiology Royal Infirmary 16 Alexandra Parade GlasgowG312ER TeL:0141-2114727 Fax.:0141-2111171 Dr. Michael Marber Department of Cardiology The Rayne Institute, St. Thomas' Hospital London SE17EH Tel.:0171-9228191 Fax.:0171-9605659 E-mail: [email protected]

Chairman Prof Gianni Angelini Bristol Heart Institute Bristol Royal Infirmary Bristol BS28HW Tel.:0117-9283145 Fax.: Oil 7-9283871

Dr. Barbara McDermott Department of Therapeutics and Pharmacology The Queen's University of Belfast Whitla Medical Builiding 97 Lisbum Road BelfastBT97BL Tel.: 01232-272242/335770 Fax.:01232-*38346 E-mail: [email protected]

Secretary Dr. Gary F.Baxter The Hatter Institute for Cardiovascular Studies University College Hospital Grafton Way London WC1E6DB Tel.:0171-3809888/9881 Fax.:0171-3885095 E-mail: [email protected]

Dr. Kathryn O. Ryder P.O. Box 6779, Dundee DDI IWN. Tel.:01382-223189 Fax.:01382-221571

Treasurer Dr. Michael J. Curtis Pharmacology Group Kings College London Rayne Institute, St. Thomas' Hospital London SE17EH Tel.:0171-9289292 ext. 2230 Fax.:0171-9280658 E-mail: [email protected] Committee Dr. PaulJ.R. Barton Imperial College School of Medicine National Heart and Lung Institute Dovehouse Street London SW3 6LY Tel.:01713518184 Fax.:0171-3763442 E-mail: [email protected]

Dr. M.-Saadeh Suleiman Bristol Heart Institute University of Bristol Bristol Royal Infirmary Marlborough Street Bristol BS2 8HW TeL:0117-9283519 Fax.:0117-9283581 E-mail: m. s. suleiman@bri stol.ac.uk Dr. Ian Zachary Department of Medicine and Wolfson Institute for Biomedical Research University College London 5 University Street London WC1E6JJ Tel.: 0171-2096620 Fax.: 0171-2096612 E-mail: [email protected]

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Contents Editorial Review Article: Getting to the heart ofthe matter: how can we study the modem historyofcardiovascularresearchandpracticebyDrT.Tansey Secretary's Column Review Article: Cationic amino acid transporters: characteristics, function and role in nitric oxide biosynthesis by Dr A.Baydoun Cardiovascular related meetings BSCR Bulletin BookReview: Renin-Angiotensin British Heart Foundation Grants Cardiovascular Related Wellcome Trust Grants BSCR Autumn Meeting: Myocardial Responses to Sub-Lethallschaemia: preconditioning, stunning and hibemation

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Editorial

Welcome to the Spring issue of The Bulletin. Sorry for a slightly slimmer issue than you're used to but unfortunately one of the contributors failed to meet the deadline and therefore could not be included. Hopefully, the next issue will make up for it! Nevertheless, we do have two review articles; one from Dr Tillie Tansey from the Welcome Institute for the History of Medicine writing about the key figures in the early history of heart transpantation and the other from Dr Anwar Baydoun describing cationic transporters and their role in nitric oxide biosynthesis. This issue's book review is an overseas contribution from Prof Jos Smits from University of Maastricht. Thanks to all our contributors. As we mentioned last time, we are keen to maintain the 'flavour' of the Bulletin by highlighting different topics in cardiovascular research rather than solely providing information about grants and forthcoming meetings. However, in order to achieve this we need your contributions. In particular, we are in need of people to write 'Laboratory Profiles' and 'Careers in Cardiovascular Research' articles.

Therefore, if any of you would like to suggest a colleague's lab or their own or someone who has made a significant contribution to cardiovascular research, here or abroad, it would be great to hearfromyou. See the opposite page for our contact details. As we mentioned in our Editorial in the last issue, we have been giving some thought to adding a new feature aimed primarily at PhD students who have just finished, or are about tofinish,their studies. The aim of this feature is to give an opportunity for students to write a short summary (1 -2 pages ofA4) describing not only the work done, but also to share their experiences during their studentship. In addition, it would also be a way to 'advertise' their skills and research interests throughout the cardiovascular research arena. If you're a PhD student and would be interested in writing such an article please get in contact with us and we will give you fiirther details. We look forward to hearing from you.

Cover artwork copyright Anthony Wright, 1997 Cover design copyright Sidn Rees and Anthony Wright, 1997 3

James Mockridge & Harold Raat

Getting to the heart of the matter: how can we study the modern history of cardiovascular research and practice? Dr Tillie M Tansey Twentieth Century Medicine Group, Wellcome Institute for the History of Medicine, 183 Euston Road, London NWl 2BE

Many scientists moan, with some justification, about the proliferation of published material in their disciplines, and the impossibility of 'keeping up with the literature'. George Lundberg, until recently the editor of JAMA, has estimated that 2 million biomedical articles appear each year. He suggested two strategies for the reader keen to keep abreast of all this literature: one was that the active researcher should read two articles per day throughout the year - unfortunately by the end of the year that still left 60-centuries worth of reading to be done. An alternative, Lundberg proposed, somewhat tongue-in-cheek, was that the busy scientist should read 6000 articles every day! By judiciously reading/scanning the core joumals oftheir disciplines, taking a regular look at an indexing/ abstracting source such as Current Contents or Medline, and by attending meetings and talking with colleagues, the busy researcher has the possibility of keeping up with the main developments in his field. But what hope has the poor historian of modem medicine, who not only has to make sense ofthis mass of published data, but is also expected to scour archives for additional unpublished accounts and illuminating details? And paradoxically these records might not be enough. In this era of telephone, fax and e-mail communication, and when national and international meetings are occurring all over the globe, all the time, what survives ofthese interactions? How can historians attempt to understand, reconstmct, and convey to others, the stories of the recent past and their significance? Should contemporary researchers acknowledge that a part of their current intellectual responsibility is to present and future historians? The extensive published record of modem medicine and medical science raises particular problems for historians: it is often presented in a piecemeal but formal fashion, sometimes seemingly designed to conceal rather than reveal the processes by which scientific medicine is conducted. The distinguished

immunologist and Nobel Laureate Sir Peter Medawar once suggested, in a famous article entitled, 'Is the scientific paper a fi^ud', that therigid,formal structure of scientific papers meant that much literature 'misrepresents the processes of thought that accompanied or gave rise to the work that is described ...', allowing for little individual expression or amplification. Tuming to unpublished archives for elucidation, as historians do, can introduce additional difficulties: in the United Kingdom public records, which includes hospital records and those of Govemment fiinded bodies such as the MRC, are subject to a restriction that keeps papers hidden for at least thirty years; in the case of clinical and other records the period of closure is 100 years. Equally, specialist archives can present problems: the survival ofpersonal papers can be erratic, many are lost during the lifetime of an individual, as space constraints or relocation demand the jettisoning of material without proper regard for its significance. Probably even more papers are wrongly discarded as worthless and uninteresting by their owners, or by relatives acting immediately after a bereavement. Thus historians of contemporary medicine are increasingly tuming, or returning, to the traditional technique of oral history to supplement, or extend, existing records, and to create new resources. Recognising that many of the principal sources of contemporary medical history are still walking around, often on increasingly elderly andfragilelegs, historians are attempting to hear, and record, the accounts of the historical actors themselves. Aparticularly specialised form oforal history is the Witness Seminar, and to date, the Wellcome Tmst's History of Twentieth Century Medicine Group has arranged almost twenty such meetings in medicine and the biomedical sciences. A Witness Seminar as a workshop where several people associated with a specific set of circumstances, or a discovery, are invited to meet together to discuss, debate, and even disagree about the events to which 4

they were common witnesses. The entire proceedings of such a meeting are recorded and transcribed, and then edited for publication, and all or part offifteenhave been, or are about to be, published on behalf of The Wellcome Trust. The early history ofheart transplantation in the UK was one such meeting, co-organised and chaired by Professor Tom Treasure, Professor of Cardiothoracic Surgery at St. George's Hospital Medical School in London. Several early pioneers of heart transplantation in the UK discussed the early events leading to thefirstUK heart transplant, and the sequelae that have shaped modem heart transplant programmes. Participants included surgeons, anaesthetists and cardiologists involved in the early transplants in the UK. The surgeons involved in the veryfirsttransplant, Mr Donald Ross, Sir Keith Ross and Professor Donald Longmore all described events surrounding their involvements in that operation, peribrmed on the 3rd of May 1968 at the National Heart Hospital, London. This followed the world's first ever human heart transplant performed by Christiaan Bamard on Louis Washkansky at the Groote Schuur Hospital, Cape Town, South Afiica, on 3 December 1967. As Donald Ross reminded the audience though,' it was the father figures in this area, Messrs Shumway and Lower of Palo Alto, California, near San Francisco, who had been scientifically working on transplantation of the heart in animals. We were all playing around with it technically, excited about this sewing in of the heart, which is in fact when you come to think about it, is quite a simple plumbing job.' Bamard, like other heart surgeons, went to Stanford University in Palo Alto, saw the technical advances that Norman Shumway and his team were achieving, and decided to perform the operation in a human subject. Ross continued' within a couple of months he did it. He had the courage to do it, but the background knowledge comes from Shumway, there's no doubt about that.' Almost immediately after the pioneering work in South Afiica, there was a rush around the world, as national pride seemingly demanded at least one heart transplant each country could call their own. Dr Renee Fox, a medical sociologist from the University of Pennsylvania, commented that during 1968,105 cardiac transplants were performed around the world, 60 of them over the course of September to November of that year. Another member ofthefirstBritish surgical team, Professor Donald Longmore, recalled a sUghtly earlier period, when, with Sir Thomas Holmes Sellors, later

President of the Royal College of Surgeons, he had applied for a British Heart Foundation grant, for preliminary experiments on heart transplants in dogs, 'and we were told that the roars of laughter could be heard two or three blocks away. In late 1963, we got a grant £6 000, which in those days was a very large sum of money and I rented a laboratory in the Royal Veterinary College for six old pence a year, and we set about what we thought was a very scientific approach and we were also supported by the Wellcome [Trust]'. Amongst visitors to the lab was Christiaan Bamard, and the entire team for the first British transplant, who carried out thefiillexperimental procedure twice. Sir Keith Ross, the third surgical member of the team, also recalled his experiences of thatfirsthuman operation. In the late 1950s he had worked in Shumway's lab, gaining considerable experience in valve surgery, and in September 1967 was appointed a Consultant at the National Heart Hospital. On May 3rd 1968 he had the responsibility of taking out the donor heart, whilst Donald Ross took responsibility for the recipient patient. Sir Keith recalled 'one was aware, very much I think, while this was going on, that this was a historic moment and slightly unreal in the relative calm of the operating theatre at the National Heart Hospital.' That historic moment was almost immediately picked up by the press, and all the witnesses of the first UK heart transplant recalled their naivety towards the media at the time, with little or no consideration given towards public relations following such the event, either by the individuals themselves or the National Heart Hospital. Another general consensus was the lack of bureaucracy and constraints, which allowed the event to take place. No special arrangements were made to fund the operation, and there was no involvement of any ethical committee. With no legal precedent, this later proved to be a problem, and Donald Longmore vividly recalled his appearance at the Coroners Court to justify the removal of the functioning donor heart, and being asked for his definition of death. Similar problems for Shumway's team in Califomia had resulted in the threat of being indicted for murder, and the meeting heard from Professor John Bunker, who had been the anaesthetist for Shumway'sfirstdonor. Bunker recalled 'The local coroner [in Palo Alto] was not pleased that the heart was removed before he could carry out an autopsy. He said, afterwards, 'When I do an autopsy, I don't want anyone fiddling with my bodies.' Shumway was

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Participants in the Wellcome Trust's Witness Seminar on Early UK Heart Transplants

Figure 1 Professor Tom Treasure

Figure 2 Mr Donald Ross

Figure 3 Professor Donald Longmore

Figure 4 Sir Terence English

All photographs courtesy of the Wellcome Trust Medical Photographic Library

therapeutic innovations, which proceed along a pathway of exhilaration, criticism, review, and finally partial or complete acceptance. The final section of the seminar contained contributionsfromSir Terence English who commented on the later work of Norman Shumway, who continued to operate and persisted during the seventies in researching and using anti-rejectionfreatments,such as ATG. Shumway also assessed the impact of cyclosporin,firstused clinically by Sir Roy Calne in 1978 in kidney transplantations, and it was used in Stanford for heart transplantation in 1980 when Mr John Wallwork first had experience of it. Cyclosporin was introduced into Sir Terence's transplant programme at Papworth Hospital in March 1982. Sir Terence also discussed in particular the formal establishment ofa heart transplant programme in Britain.

not deterred by the possibility that he might be indicted for murder, nor was I. So we went ahead, willy nilly, and fortunately the district attorney for the State of Califomia took a much more realistic view of the matter'. These events highlighted the need for a legal definition ofclinical death, and which culminated in our present criteria of brain stem death. It was generally agreed that the poor success of the early heart transplants in Britain was due to a lack of experience and in particular the lack of ability to treat or even recognise immunological rejection. The "medicine by committee approach" which evolved could not work in the midst of disputes between surgeons, physicians and other hospital personnel. The unacceptably poor results led to a voluntary clinical moratorium and Dr Renee Fox discussed the moratorium in the light ofthe history of a wide range of 6

The Department of Health and Social Security established a Transplant Advisory Panel advised the Chief Medical Officer on criteria to be met by any centre before a cardiac transplant programme could be approved. Sir Terence descibed how, after working with Shumway at Stanft)rd and later with Professor Roy Calne at Addenbrookes Hospital in Cambridge, he set about establishing a specialist heart transplant centre at Papworth. The encouraging results in Cambridge and also at Sir Magdi Yacoub's unit at Harefield enabled both centres to receive supra regional funding with additional centres being established at the end ofthe eighties and early nineties. The seminar lasted for over ft^ur hours and provided a fascinating insight into many historical events which have shaped the field of heart transplantation as described by the principal sources of this contemporary medical history. It will be published in September 1999, and suggests one mechanism whereby medical scientists and practitioners of today can assist the medical historian of tomorrow.

Secretary's Column

Submission Of Abstracts To The Bulletin

WHERE ARE THEY NOW? Dr AAhmed, previously of the University of Dundee Dr P Brooksby, address unknown Dr R A J Challiss, address unknown; Dr S Herbsthofer, previously ofVienna; Mr C Marston, address unknown; Dr A L Rothaul, previously of British Biotech; Dr D D Sandeman, address unknown; Dr AG Violaris, address unknown; Dr D R Wheeldon, previously of Papworth Hospital; Dr E Winslow, address unknown.

At the time of writing, the BSCR can look forward to three main meetings (two this year and another in Autumn 2000), a workshop in April and a joint session at the British Cardiac Society in May. I would stress the importance of early planning for such events. It is not too early to submit proposals for meetings, workshops or British Cardiac Society symposia in 2000 and beyond. As I mentioned in my last letter, the Committee will be pleased to consider all suggestions. Further details ofthe support available for meetings and workshops are available from me and I would urge all members to at least consider areas of interest that should be covered by future meetings. Even if you are not prepared to organise a meeting yourself, contact me and give me the name of someone who might be cajoled into doing it. Since the last Bulletin mailing, it is clear that there are several subscribing members of the Society whose addresses are unknown to us. 1 think it unlikely that these people are "of no fixed abode" but rather that having moved on to pastures new, they have failed to notify us of their new addresses. I attach a list of Dr Tansey is Historian of Modern Medical members for whom we do not have a current address History/Convenor of the Twentieth Century and would ask readers who know of the whereabouts Medicine Group, Wellcome Institutefor the History of these members to contact me so that I can update of Medicine our records accordingly. If the Bulletin you are holding now has been redirected to you from a previous or incorrect address, I would ask you to drop me a line with your correct address.

Abstracts presented at BSCR meetings, such as the recent Signal Transduction and Growth Control in the Cardiovascular System at University College London, can be published in The Bulletin. It is a good forum to present preliminary data, for students to develop presentation skills and for more senior authors to give us a snapshot of work they will present elsewhere. Please send your abstract on disk saved as a PC-compatible file, preferably as a Word document, accompanied by a hard copy. Please Gary Baxter ensure disks are free of viruses as infected disks cannot be read. Send to the Editors or to the meeting organisers marked for our attention. 7

Cationic amino acid transporters: characteristics, function and role in nitric oxide biosynthesis Dr Anwar R Baydoun

Biosciences Department, University of Hertfordshire, Hatfield, Herts, ALIO 9BA The discovery in 1987 that endotheliumderived relaxing factor is nitric oxide (NO) [ 1 ] was followed a year later with reports that the cationic amino acid L-arginine is the physiological precursor for nitric oxide [2]. It has since been established that the terminal guanidinium nitrogen of L-arginine is metabolised via a series of oxidation reactions resulting in NO production, with citmUine being formed as a co-product. These novelfindingsstimulated new interest in amino acid transport with several groups, including ours, focusing in understanding the characteristics, fiinction and regulation of L-arginine transports. Considerable attention is also being given to identifying the role of L-arginine transporters in NO synthesis, with a view to exploiting these systems as potential targets for novel pharmacological and/or molecular interventions. In this review I will give an overview of the physiological and molecular characteristics,fianctionand regulation of L-arginine transporters. I will also discuss data that point to a critical role for L-arginine transport in the regulation of NO synthesis. I will start however by giving a summary of the pathways associated with NO biosynthesis. This will only be dealt with in brief since other articles, published in recent issues ofthis Bulletin, have already discussed this topic in more detail.

pathways [reviewed in 4 and 5]. Both the endothelial and neuronal NOS are constitutively expressed, dependent upon Ca^^ and calmodulin for activation, and produce picomolar amounts of NO over short periods of time following agonist stimulation. Under normal physiological conditions, NO produced via the constitutive endothelial L-arginine-nitric oxide pathway appears to be a key physiological regulator ofvascular tone, maintaining the vasculature in a constant state of vasodilatation [6,7]. In contrast, synthesis of NO via the inducible pathway involves induction of a Ca^^/calmodulininsensitive NO synthase (iNOS) previously identified in macrophages and now known to be induced in a wide variety of cell types including the endothelium, vascular smooth muscle cells and cardiac myocytes. Expression of this enzyme is time-dependent and involves de novo protein synthesis, which can be inhibited by the protein synthesis inhibitor cycloheximide and also by the glucocorticoid dexamethasone [see 3-5]. Once induced the activity of the enzyme is sustained over prolonged periods and generates quantitatively more NO compared to its constitutive isoforms. Source of substrate for NO synthesis The source of L-arginine for NO synthesis appears to depend on the physiological state and biosynthetic pathway being activated. L-arginine on it own has no significant effect on blood pressure in vivo [6,7], on coronary perfusion pressure in vitro [8,9], or on the tension developed by isolated aortic rings [10], suggesting that basal NO synthesis is not limited by subsfrate availability. This is perhaps predictable since L-arginine is present in high concentrations in endothelial cells (-0.8 mM) [11]. The K„ of eNOS for L-arginine is