Cardiovascular Disease
From the middle of the twentieth century, there was a marked decline in rheumatic heart disease in the UK and other developed countries, and a marked increase in coronary heart disease. Coronary heart disease is due to narrowing of the coronary arteries (atherosclerosis) which supply blood to the heart, followed by blockage of an artery by clot (thrombosis) which causes heart attacks (myocardial infarction). Atherosclerosis and thrombosis also occurred with increasing frequency in the arteries supplying the brain (causing stroke) and the legs (peripheral arterial disease). Cardiovascular disease (comprising coronary heart disease, stroke and peripheral arterial disease) became the commonest cause of death and disability in the UK and other developed countries worldwide.
Stroke and Peripheral Vascular Disease are reviewed in separate sections of this history.
Scotland, especially Glasgow and the West of Scotland, has in the past had one of the highest risks of cardiovascular disease in the world. Hence it was appropriate that the University of Glasgow has been a leader in cardiovascular research over the last 200 years.
Atherosclerosis, Thrombosis, Heart Attacks, Heart Failure and Risk Factors
Atherosclerosis and thrombosis
In 1815, Allan Burns (1781-1813), a Glaswegian and Lecturer in Anatomy at the University, published one of the first books on cardiology in the English language. His hypothesis was that chest pain on exercise (angina pectoris) and leg pain on exercise (intermittent claudication) had a common cause: insufficient blood flow to muscles (ischemia) on exercise. In 1836, Andrew Buchanan, Lecturer in the Department of Medicine, Glasgow Royal Infirmary, described in the London Medical Gazette the presence in body fluids of fibrinogen, the precursor of fibrin, which is the main building block of blood clots and thrombosis. In 1863, Joseph Lister, Regius Professor of Surgery at the Royal Infirmary, reported in the Proceedings of the Royal Society of London that blood clotting could be greatly accelerated by contact with body tissues.
In 1893, John Lindsay Steven, pathologist at Glasgow Royal Infirmary, greatly extended the scant world literature by publishing in the Journal of Pathology and Bacteriology a series of 21 post-mortem examinations showing fibrinoid necrosis of the heart, which was myocardial infarction. He identified male sex and low social class as possible risk factors in this series.
In 1946 it was announced that the Medical Research Council would finance a Clinical Chemotherapy Unit. The building, completed in the 1950s, was at the Western Infirmary between the Tennent Institute and the Physiotherapy Department. The Unit operated under the supervision of Sir John McNee, Regius Professor of Practice of Medicine (see Medicine, Western Infirmary). The director of the Unit was James Reid. After Reid’s death in 1961, Brian Bronte-Stewart (1923-1965) was appointed as director of the unit and the subject of research became the clinical, pathological and epidemiological aspects of atheroma. Bronte-Stewart died in 1965 at the comparatively young age of 42, and is commemorated by the Bronte-Stewart Memorial Lectureship, endowed by private subscription in 1967.
In 1965, William Fulton, Senior Lecturer in the Department of Materia Medica and Therapeutics at Stobhill Hospital published in his book The Coronary Arteries his detailed studies of post-mortem arteriography and microanatomy, which clearly suggested that coronary thrombosis was the cause, and not the result, of myocardial infarction. He later collaborated with David Sumner, biochemist in that Department, to provide proof of causality by injecting, with radio-labelled fibrinogen, patients admitted to the coronary care unit with acute myocardial infarction. They demonstrated at post-mortem examination in those who died that the thrombus was radio-negative: hence its formation had preceded hospital admission and played a causal role in myocardial infarction.
Stuart Douglas (Professor in the Department of Medicine), Royal Infirmary 1964-70, established the West of Scotland Haemophilia and Thrombosis centre in Glasgow Royal Infirmary in 1957. He published a textbook on oral anticoagulants (such as warfarin) and conducted clinical trials of anticoagulants in patients with acute myocardial infarction, and later, trials of antiplatelet drugs (aspirin, dipyridamole). His colleague George McNicol (Department of Medicine, Royal Infirmary) researched in fibrinolysis, and pioneered thrombolysis in peripheral arteries.
These studies were continued in the 1970s by their successors Colin Prentice and Charles Forbes; and from 1978 by Gordon Lowe (Professor of Vascular Medicine, 1993-2009). They included studies of clopidogrel and new anticoagulants. He also researched the role of thrombotic factors (such as fibrinogen) in several epidemiological studies of cardiovascular disease; and performed studies on the prevention and treatment of venous thromboembolism. Professor Isobel Walker in the Department of Haematology at the Royal Infirmary performed studies on genetic thrombophilias and venous thromboembolism (see Medicine – Royal Infirmary and Haematology).
Heart attacks
Thomas Semple (1915-2008), Consultant Cardiologist in the Victoria Infirmary, was the first to present and publish results of successful cardiac resuscitation after heart attacks. He established the first coronary care unit in Glasgow. Such units were subsequently established at the Royal Infirmary, Western Infirmary, Stobhill Hospital and the Southern General Hospital.
Coronary thrombolysis in patients with acute myocardial infarction in Glasgow was pioneered by Stewart Hillis (Senior Lecturer in Materia Medica and Therapeutics) in the coronary care unit at Stobhill Hospital (see Materia Medica). He was later Professor of Cardiovascular and Exercise Medicine (1997). As the Scotland football team doctor, he persuaded the Rangers and Celtic football teams to jointly encourage their supporters to exercise for cardiovascular prevention.
In the twenty-first century, thrombolysis in acute myocardial infarction was largely superseded in Greater Glasgow and Clyde Health Board by acute coronary interventions, performed 24/7 by consultant interventional cardiologists, centred at the new Golden Jubilee Hospital, Clydebank.
Colin Berry (Professor of Cardiology and Imaging, 2007) currently researches the pathophysiology, diagnosis and treatment of coronary heart disease. This is funded by awards from the UK Engineering and Physical Sciences Research Council and the British Heart Foundation. For heart attack research, his group studies the causes, consequences and outcomes of heart muscle injury, using novel medical technologies such as measurement of blood pressure and resistance inside blood vessels, and heart imaging with MRI. Current and future studies aim to identify new treatments. His group is also developing patient-specific computed models from heart scans to better predict clinical outcome. Small blood vessel disease research aims to assess its causes, consequences, and treatment.
Heart Failure
Dr J Fitzgerald Peel, a physician at the Victoria Infirmary, documented the very poor prognosis of patients with heart failure after myocardial infarction, namely 43% mortality, compared with 9.5% for those without heart failure. He published his findings in the British Heart Journal in 1962.
Increased survival after myocardial infarction, and an ageing population, have resulted in increased prevalence of heart failure.
Henry J Dargie was a consultant cardiologist at Glasgow Western Infirmary (1980-2005), Professor of Cardiology (1994-1999), and Director of the National Advanced Heart Failure Service (2005-2010). He established a research centre at the Western Infirmary, where research interests were mainly in heart failure, left ventricular hypertrophy and dysfunction, and ventricular dysrhythmias. He studied the epidemiology of left ventricular dysfunction, heart failure and circulating markers (such as brain natriuretic peptide, BNP) as an MRC and BHF programme grant holder for 10 years.
He also performed clinical trials.
- CIBIS II was the first large trial to demonstrate increased survival in heart failure with a beta blocker, bisoprolol.
- CAPRICORN (performed jointly with Professor Ian Ford of the Robertson Centre for Biostatistics) was the first large trial showing improved survival with beta blockers in patients with heart failure after myocardial infarction.
- IONA was the first large trial to demonstrate improved outcomes with nicorandil in patients with angina.
Many research fellows distinguished themselves as independent heart failure researchers, including
- Professor John Cleland (Former Director of Roberston Centre for Biostatistics, University of Glasgow)
- John McMurray (Professor of Cardiology, University of Glasgow)
- Teresa McDonagh (Professor of Cardiology, Kings College Hospital, London)
- Simon Ray (Professor of Cardiology, Manchester University).
John McMurray is Professor of Medical Cardiology (1995) and Deputy Director of the School of Cardiovascular and Medical Sciences. His research interests are in heart failure, coronary heart disease, atrial fibrillation and cardiovascular complications of diabetes and chronic kidney disease, with a focus on clinical trials and epidemiology. He has been principal investigator, member of executive committee, or member of steering committee in many large trials of heart failure, other cardiovascular diseases, renal disease or diabetes. In 2013, he was identified as one of the 400 most influential biomedical researchers in the world.
Risk factors and their control
Epidemiology – the study of disease in populations – traditionally studied infections and nutrition. However, as these major causes of death were replaced from the 1950s by cardiovascular disease, epidemiologists turned their studies to its causes and prevention.
Large prospective studies of samples of the general population, such as the Framingham Study in the United States, identified by the 1960s the major risk factors for coronary heart disease, stroke and peripheral arterial disease. Some were non-modifiable (age, male sex, family history) but others were modifiable (smoking, blood pressure, blood lipids, and subsequently obesity and diabetes mellitus.)
The major prospective epidemiological studies in the West of Scotland were the MIDSPAN studies of middle-aged men and women, initiated in 1964 by Victor Hawthorne (1921-2014), Senior Lecturer in the Department of Epidemiology and Preventive Medicine (1966-1978). Originally performed in employment settings, from 1972-1976 these studies were undertaken in the general populations of Paisley and Renfrew. After Hawthorne moved to the University of Michigan, the study was continued by Graham Watt (Professor of General Practice, 1994-2016) and included the offspring of the participants. This study confirmed the classical risk factors in Scotland, and added new ones including reduced lung function (measured by breathing tests) and social deprivation.
The other prospective study in the West of Scotland was the North Glasgow component of the World Health Organisation’s MONICA Study (Monitoring of Cardiovascular Disease) which was combined with the Scottish Heart Health Study across Scotland, both led by Professor Hugh Tunstall-Pedoe in Dundee. Graham Watt and Caroline Morrison (Public Health) contributed to the Glasgow studies. The twenty year follow up of participants led to production of the ASSIGN risk score , recommended for cardiovascular risk prediction in Scotland by the Scottish Intercollegiate Guidelines Network.
Since smoking was established in the 1960s as a major cause of cardiovascular, cancer and other diseases, public health education and government measures (e.g. advertising bans) have reduced the number of active smokers. Scottish Government legislation against passive smoking in public places led to a further drop in coronary heart disease, documented by Jill Pell (Professor of Epidemiology and now Public Health.
Studies on the role of blood lipids (cholesterol) in cardiovascular disease were initiated by Professor Veitch Lawrie in the Department of Medical Cardiology, Royal Infirmary. Professors Stuart Cobbe and Peter Macfarlane in that department, together with Professors James Shepherd and Chris Packard in Pathological Biochemistry, and Professor Ian Ford of the Robertson Centre for Biostatistics, led the West of Scotland Coronary Prevention Study, which showed that pravastatin reduced the risk of coronary heart disease in men (see Cardiology and Pathological Biochemistry). Shepherd, Packard, Macfarlane and Ford, together with Professor David Stott (see Geriatric Medicine) subsequently led the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) Study, which showed that pravastatin also reduced the risk of coronary heart disease and stroke in older men and women.
Despite population reductions in smoking, blood pressure and cholesterol levels, a marked increase in weight and obesity in Scotland and other countries contributes to cardiovascular disease, diabetes and cancer.
Mike Lean (Professor of Human Nutrition, 1992-date) has researched extensively in human nutrition, obesity and diabetes; including measurement of waist circumference as a measure of cardiovascular risk (see ). Naveed Sattar (Professor of Metabolic Medicine, 2005-date) has also researched in obesity and diabetes, as well as new cardiovascular risk factors (inflammatory markers and vitamins) (see Pathological Biochemistry).
Professor Gordon D O Lowe
Blood Pressure and the Medical Research Council Blood Pressure Unit
Blood pressure is a major risk factor for coronary heart disease, stroke and heart failure. The history of its research in Glasgow is considered in this section. In 1964, Anthony F Lever and J Ian S Robertson, then working at St. Mary's Hospital, London, published their account of the world's first reliable and sensitive method for the assay, in blood, of the enzyme renin, secreted by the kidney. Concurrently, Robert Fraser, a steroid biochemist also at St. Mary's Hospital, developed the first assay technique for circulating aldosterone, a sodium-retaining adrenocortical steroid.
In 1967 these three, together with Jehoiada J Brown, were invited by the Medical Research Council to set up the Blood Pressure Unit at the Western Infirmary, Glasgow. Soon added to the team was the peptide biochemist J J Morton. The facilities comprised laboratories, an animal house, and dedicated clinical wards, E3 and E4. During the Unit's lifetime, improved laboratories, a diet kitchen, a library, and offices were added, but the establishment remained small compared with similar contemporary institutes. It soon earned a distinguished international reputation and had an influence wholly disproportionate to its size.
Decisive early developments were reliable assays for the octapeptide angiotensin II, the active product of renin, and of its inactive decapeptide precursor angiotensin I. Amongst the many actions of angiotensin II are stimulation of aldosterone secretion and elevation of blood pressure. Critical also were assay methods for corticosteroids additional to aldosterone which are relevant to renal and cardiac function and disorders. Always emphasized was the need for strict quantitative measurements of these substances, sampled under carefully controlled circumstances (most especially concerning dietary intake) and assessment of the relation of those measurements to the relevant dose-response curves. Essential though such an approach is, few other departments worldwide possessed, at that time, the expertise or dedication to pursue it adequately.
Several reasons can be adduced for the success of the Blood Pressure Unit.
- Foremost was the availability of a comprehensive array of meticulously calibrated measurement techniques for the evaluation of physiological and pathophysiological control of blood pressure and of cardiac and renal function. These methods were continuously updated and re-evaluated. Not only were they deployed in both fundamental and clinical research, but they also facilitated the provision of a major national and international diagnostic service, notably for renovascular hypertension and aldosterone-secreting adrenocortical adenoma.
- A second major influence was close collaboration with other university and hospital departments. Instances are measurements of total body electrolyte content, especially of sodium and potassium, with Keith Boddy at the Scottish Universities Research and Reactor Centre, East Kilbride; animal experiments with Kenneth Hosie of the University of Glasgow School of Veterinary Medicine, Garscube; population studies with Professor Graham Watt of the University of Glasgow Department of General Practice; and investigations of the pathogenesis and treatment of cardiac failure with Henry Dargie and John Cleland at the Western Infirmary. The pharmacological treatment of hypertension, and especially of essential hypertension, including most particularly the use of drugs acting against various components of the renin-angiotensin system, was undertaken together with physicians across Glasgow in the Glasgow Blood Pressure Clinic.
- Third, the work of the Unit was continually exposed to scrutiny through frequent invited lectures and by an enormous body of published articles.
- Fourth, and arguably the most influential, from its inception to its end the Unit attracted a continuous stream of very high quality research fellows both from within the UK and from many overseas countries. They contributed enormously to the Unit's research and clinical programmes, as well as enhancing its reputation when they returned home. One who remained was the gifted Anna Dominiczak, who went on to become Professor of Medicine and Vice Principal of the University of Glasgow (see below).
In 1980, Brown, Lever and Robertson jointly received the Robert Tigerstedt Award made by the International Society of Hypertension. In 1987, Robertson left the Unit and took up work at the Janssen Research Foundation, Beerse, Belgium, concurrently becoming Visiting Professor of Medicine at the Prince of Wales Hospital, Chinese University of Hong Kong.
The Unit reached its natural end with the retirement of the director Anthony Lever in 1994, an occasion marked by a Festschrift dedicated to Brown, Lever and Robertson, (Journal of Human Hypertension 1995; 9:371-521).
Nevertheless, research continued within the University of Department of Medicine and Therapeutics run by the Regius Professor, John Reid (see Materia Medica, and Medicine Western Infirmary). In addition to undertaking blood pressure research, he set up an acute stroke unit at the Western Infirmary. There were two externally funded Blood Pressure Groups: the MRC Blood Pressure Group headed by Professor John Connell, and the British Heart foundation (BHF) Blood Pressure Group led by Professor Anna Dominiczak. These two groups became the core of the BHF Glasgow Cardiovascular Research Centre in 2000. The MRC programme grants continued to Professors Connell and Fraser until 2009, when Professor Connell was appointed Dean of Medicine at the University of Dundee.
Dr J Ian S Robertson
The work of the Unit and of its successor Groups can be accessed via the following publications: -
1) Brown JJ et al. Angiotensin II, Aldosterone, and Arterial Pressure: A Quantitative Approach. Hypertension 1979;1:159-179. This is the published account of the invited Corcoran Memorial Lecture delivered by Dr Robertson to the American Heart Association at Cleveland, Ohio, USA in 1978. It sets out in detail the assay techniques the Unit had developed, the principles for their application, and examples of their deployment in a wide range of clinical and experimental circumstances. The authors are listed alphabetically, including Drs Lever, Fraser, Morton, Brown and six further collaborators.
2) Robertson JIS, Nicholls MG (editors). The Renin-Angiotensin System, Gower/Mosby, London/New York 1993. Professor Nicholls is a New Zealand physician who worked in the Unit for several years. This massive two-volume book has sections on biochemistry, physiology, pathophysiology and therapeutics. It surveys, and sets in scientific and medical context, the Unit’s output over the previous 25 years, together with accounts of cognate studies carried out concurrently globally. It expounds in detail on the renin-angiotensin system, its wide pervasion into numerous aspects of physiology and pathophysiology, and on the importance of agents designed to interrupt the system and hence its actions.
3) Connell JMC et al. A Lifetime in Aldosterone Excess: Long term Consequences of Altered Regulation of Aldosterone Production for Cardiovascular Function. Endocrine Reviews 2008; 29: 133-154. This surveys the later work done by Professor Fraser and his colleagues of the Blood Pressure Group, and relates such studies to those of the earlier Blood Pressure Unit. It centres on the genes encoding adrenocortical enzymes, in particular aldosterone synthase and 11beta-hydroxylase, linking inheritance of specific versions of these genes with aldosterone synthesis and blood pressure. A pressor mechanism involving small but sustained elevation of ACTH is elaborated.
4) Jeffs B, Clark JS, Anderson NH, Gratton J, Brosnan MJ, Gauguier D, Reid JL, Macrae IM, Dominiczak AF. Sensitivity to cerebral ischaemic insult in a rat model of stroke is determined by a single genetic locus. Nature Genetics 1997;16:364-367.
Anna Dominiczak, British Heart Foundation Chair of Cardiovascular Medicine (1997-2010); Regius Professor of Medicine 2009-date and the first ever woman to hold any Regius Chair at the University researches in blood pressure and cardiovascular genomics. She played a leading role in establishing the BHF Glasgow Cardiovascular Research Centre and the School of Cardiovascular and Medical Sciences, considered in the next section.
The British Heart Foundation Glasgow Cardiovascular Research Centre (GCRC) and The Institute of Cardiovascular & Metabolic Health
With growing interest in cardiovascular research by many non-clinical and clinical scientists in several departments in the University of Glasgow, it was becoming increasingly evident by 2000 that there was a need to bring this critical mass together. In 1999/2000, the British Heart Foundation (BHF) announced a UK-wide competition for infrastructure funding.
The Glasgow team led by Professor Dame Anna Dominiczak had seven senior Principal Investigators (Dominiczak, Connell, McMurray, Cobbe, Smith, Baker, MacLean) and won £5.2 million towards the new BHF Glasgow Cardiovascular Research Centre (BHF GCRC). It operated as a virtual centre between August 2002 and December 2004, based in the Division of Cardiovascular & Medical Sciences which was located in the Gardiner Institute, Western Infirmary.
The BHF funding was followed by a joint University and BHF fundraising effort and the £25 million BHF GCRC was opened by HRH Princess Anne in April 2006. This initiative brought together researchers of international standing working in disparate and outdated buildings across Glasgow into one state of the art building on the Gilmorehill campus of the University. It has an MRI suite; a joint NHS/University clinical research facility; state of the art laboratories (electrophysiology, cardiac, vascular, genomics, phenotyping and blood pressure); and a biological services facility with operating theatres.
The BHF GCRC, linked to the Glasgow Biomedical Research Centre and Wolfson Medical School forms the University of Glasgow’s “triangle of excellence”, which aims to ensure the strategic competitiveness of the University as an International Centre of Excellence.
Headed initially (2002-2010) by the Director Professor Dame Anna Dominiczak, it brought together five research groups led by internationally recognised principal investigators who were programme grant holders and had the potential and flexibility to include other emerging research groups.
These included the
- BHF Blood Pressure Group (Professor Dame Anna Dominiczak)
- BHF Cardiac Group (Professor Stuart Cobbe)
- MRC Blood Pressure Group (Professor John Connell)
- Electrophysiology and Heart Failure group (Professor Godfrey Smith)
- Heart Failure & Clinical Trials group (Professor John McMurray)
Restructuring of the University of Glasgow in 2010 saw the formation of a) the College of Medical, Veterinary and Life Sciences (MVLS) and b) the School of Cardiovascular & Metabolic Health.
In 2011, Professor Rhian Touyz, Canada Research Chair in Hypertension at the University of Ottawa, was recruited and appointed as the new Director of the School of Cardiovascular & Metabolic Health. During the period 2011-16, the main research themes of cardiac, vascular, metabolic & diabetes as well as the emerging areas such as omics, renal and stroke made significant advances.
In April 2014, Professor Touyz was awarded a £3M research grant to establish the BHF Centre of Research Excellence in Vascular Science and Medicine in ICAMS.
In 2015 the Western Infirmary closed and all clinical services moved to the new Queen Elizabeth University Hospital (QEUH). New purpose built Clinical Research Facilities were opened at the Royal Infirmary and the QEUH, providing opportunities for high quality clinical studies for ICAMS researchers.
In November 2016, there was a major refinement of research direction in ICAMS.
ICAMS has now over 400 members of staff, of which there are 80 principal investigators annually focusing on research in three primary areas: Cardiac, Vascular and Metabolic pathophysiology. Research is conducted in an integrated and translational manner addressing clinical conditions and diseases such as heart failure, ischaemic heart disease, arrhythmias, hypertension, atherosclerosis, diabetes, pulmonary hypertension, stroke and chronic kidney disease.
To better reflect the multidisciplinary research, which focuses on clinical conditions, there has been a streamlining of strategy, which builds on the areas of scientific excellence (see figure).
Summary of research excellence
Glasgow scientists have contributed to advancing knowledge in the field of cardiovascular science and medicine with over 4500 publications in the fields of cardiovascular disease, blood pressure, hypercholesterolaemia, diabetes, heart failure and stroke over the past 10 years. Of these, 198 papers were published in top journals (Nature, Science, New England Journal of Medicine and the Lancet).
The total value of research awards since 2000 has reached £158 million.
In the Research Excellence Framework, 2014, cardiovascular research was returned in the Unit of Assessment 1 ranking 6th in the UK. There were 10 impact case studies selected from all areas of cardiovascular medicine, which contributed to the outstanding assessment of our impact. Indeed, cardiovascular medicine was the biggest source of impact cases across the entire University.
It is through the leadership in clinical trials that impact for both the local population and patients globally can be understood. Some landmark studies have been instrumental in changing the practice of medicine and many are fundamental to international guidelines on the diagnosis, prevention and treatment of cardiovascular disease.
Professor Anna F. Dominiczak and Professor Rhian M Touyz
Unless otherwise noted, images provided by authors