In Conversation With ... Professor Keith Fox
In the second in Professor Jeremy Pearson's 'In Conversation With...' series, our Associate Medical Director talks to Professor Keith Fox, former BHF Professor of Cardiology, about his life and career across several continents, from his gap year in 1960s Malawi, to 4 years in St.Louis, MO, to returning to his Alma Mater, Edinburgh.
Professor Fox was the BHF Duke of Edinburgh Chair of Cardiology between 1989 and 2014 at the University of Edinburgh, and he retains the title of Professor of Cardiology there.
'Although Keith has relinquished many of his commitments and no longer directs a research team, he keeps in contact with his colleagues and still has plenty of external professional responsibilities as a member or leader of committees overseeing international clinical trials.
Keith was born in Zimbabwe. After education there and in Malawi, where he excelled academically, he spent a gap year at the Queen Elizabeth Hospital in Malawi before taking up his place at medical school in Edinburgh in 1970. There was no tradition of medicine in the family: his father was a bank manager. Keith has many hair-raising tales of that gap year, from working in the diagnostic labs where he mouth-pipetted blood samples from patients who were suffering from “thin” – later understood to be HIV – to assisting the surgeon with a trauma victim suffering from severe head wounds from attack by a leopard. Hardly standard training, this must have meant Keith arrived in Edinburgh with the most unusual clinical experience of any new medical student in several years.
During medical training he initially had no fixed idea of which specialty to pursue. However, encouraged by an outstanding clinical cardiologist, Dr Bobby Marquis, and by a burgeoning realisation of how little was understood about the early phases of myocardial infarction, Keith became highly enthusiastic about tackling the challenges, with the potential to substantially improve diagnosis and treatment. He told me his career-long research in the field has been driven by wanting to understand the triggers for and impact of coronary thrombosis.
Presciently Keith decided that the best way to get ahead in academic cardiology was to gain research experience in the US and in 1981, with the help of Professor Michael Oliver, then the BHF Duke of Edinburgh chairholder, he gained a fellowship for 2 years to work in the one of the world’s premier Cardiology departments at Washington University in St. Louis, headed by Burton Sobel. Here, with Steven Bergmann, Keith carried out pioneering experimental research taking advantage of the early expertise in PET scanning established in the department to show for the first time that intravenous administration of tissue plasminogen activator (tPA), in contrast to streptokinase, could efficiently and rapidly lyse a coronary thrombus. The tPA for the experiments was prepared in Désiré Collen’s lab in Belgium and Keith recounted how it took three attempts to get a batch to St. Louis without customs hold-ups and without allowing the tPA to thaw out and inactivate. Persistence was rewarded: the work was published in Science and is the first of several highly cited papers from his time at Washington University, which he describes as “hard work but inspiring”. Shortly afterwards the team, in collaboration with Leuven, published the first clinical study on the use of tPA, in the New England Journal of Medicine.
Keith’s stay in St. Louis extended to 4 years and by then he had a permanent residence visa, but it was time to make the choice whether to remain or return to the UK. Andrew Henderson, then BHF Professor of Cardiology in Cardiff and another who had BTA (“Been To America”) for a research stint, attracted Keith back to a senior lectureship. I think it is fair to say that despite Andrew’s huge endeavours academic clinical cardiology in Cardiff could not match the inspiration Keith had found at Washington University. Within a couple of years Keith, hardly lacking in ambition, was looking for opportunities for a chair in cardiology elsewhere in the UK. The first to come up was in Edinburgh in 1989, where Michael Oliver was retiring, and Keith was the successful candidate. Thus he returned to his alma mater and began the next phase of his career, which combined increasing academic leadership in Edinburgh with a long (and still evolving) series of highly influential international clinical studies. Interestingly, one of his first communications from the BHF after his appointment was from the Head of Research Funds (Valerie Mason) congratulating him but pointing out that his predecessor had left a deficit on the BHF Chair account that would need to be cleared before Keith could access new funds!
While in Cardiff Keith was a member of the steering committee for the first of the multicentre RITA (Randomised Intervention Treatment of Angina) trials. This compared the outcomes of angioplasty versus bypass surgery and reported in 1993 after 2.5 years’ follow-up. Carried out before the adoption of stenting after angioplasty, at the time the trial was an important advance towards improved long-term event-free survival and better relief of angina. It led immediately to RITA 2 (where Keith was a member of the executive committee), comparing angioplasty versus conservative medical treatment in patients unsuitable for bypass surgery. First reported in 1997 and with a long-term follow-up published in 2003, RITA 2 convincingly demonstrated that PTCA led to better symptomatic improvement without increased risk of death or MI. RITA 3, with Keith now the lead investigator, extended these results to confirm that prompt routine angiography of angina patients followed by revascularization where needed led to a lower risk of death or MI over 5 years than did medical treatment where angiography was only carried out if symptoms worsened. All three trials were supported by the BHF and RITA 3 has changed guidelines internationally.
In parallel Keith was increasing his research leadership and influence in two other related areas. The first was involvement in a series of multinational trials to understand the optimal antiplatelet and anticoagulant regimes for patients either with acute coronary symptoms or undergoing revascularization. The earliest of these (Keith’s most highly cited paper, from a trial co-chaired with Professor Salim Yusuf in McMaster University in Canada) showed in 2001 that addition of clopidogrel to aspirin reduced cardiovascular events in patients with acute coronary syndromes but at the expense of increased major bleeding. Several trials followed, involving anti-platelet agents or new anti-thrombotics like hirudin and fondaparinux. In 2017 Keith (again with Salim Yusuf), designed a trial to test the impact of combining a low dose of a novel anticoagulant with or without an anti-platelet in patients with vascular disease. The COMPASS trial reduced rates of death, cardiovascular death and stroke and showed net clinical benefit despite an increase in bleeding. His current research studies involve novel anti-thrombotics with the goal of reducing thrombotic events among patients with elevated bleeding risk.
The second area was the development of the Global Registry of Acute Coronary Events (GRACE). Beginning in 2002 Keith gathered a team of investigators from 14 countries to collect detailed information on how variation in treatment of patients with acute coronary syndromes affected outcome. Originally envisaging a relatively short-term snapshot, the registry has expanded to cover over 100,000 patients in over 30 countries and has seen validation and international adoption of the GRACE risk score – combining clinical variables including biomarkers and ECG information – as a guide to the management of these patients. The scoring system has been modified to keep pace with newer biomarkers and revised definitions of myocardial infarction and shows no sign of becoming outdated. This work has led to an ongoing cluster randomised trial to prospectively test the impact of applying the GRACE score.
In parallel with his research successes Keith had been working hard to grow and strengthen his department in Edinburgh. With a steady influx of carefully chosen bright young people the breadth and depth of cardiovascular research in Edinburgh expanded rapidly. One early recruit who made his way up the ranks from a Junior Fellowship was David Newby, who became a BHF Professor in 2009 and is now the current BHF Duke of Edinburgh Professor of Cardiology. From the start David has had an interest in new radiotracers to expand the use and value of PET scanning, particularly for detection of active inflammation or calcification in blood vessels, which I suspect must have been fostered by Keith’s experience in Missouri. In conversation Keith was keen to credit the help and collegiality of colleagues across the School of Medicine, who shared his vision, with his ability to raise the profile of his department, but it’s equally clear it would not have happened without his leadership. A significant landmark was the opening of the new purpose-built Queen’s Medical Research Institute in 2005 – by the Duke of Edinburgh as Chancellor of the University – alongside the new Royal Infirmary in south Edinburgh, thus co-locating world class research teams and clinical research facilities in cardiology and inflammation. His Royal Highness was a regular visitor and supporter of the medical school, though Keith confided that at the end of a long and tiring day with multiple tours of the new institute on its official opening to show off its wonderful facilities and state of the art equipment Prince Philip’s interest and courtesy did lapse, with an abrupt end to the visit that included one of the off the cuff remarks for which he was renowned.
Keith also became a leading figure in several national and international professional organisations, in each case leaving his mark as a moderniser. These included the British Cardiovascular Society, where he was President from 2009-2012; and the European Society of Cardiology where his stint as chair of the annual conference Programme Committee from 2012-14 marked the transition to a modern and meritocratic meeting programme, with competitive slots for presentation in response to submitted and independently marked abstracts, enhancing the meeting’s attractiveness to younger delegates and cementing its place as the premier cardiology congress in the world. In his “spare time” (his words, though I don’t believe he had any) he became involved in Action on Smoking and Health and is now President of ASH Scotland, a position that he has used to great benefit as a major influencer leading the Scottish government to be the first of the UK’s four nations, in 2006, to ban smoking in public places with immediate and substantial benefits on cardiovascular (as well as lung) health.
Keith is a keen walker and cyclist, no doubt contributing significantly to his svelte figure. As a medical student he took part in two successive years in a group walk from London to Edinburgh, fundraising for charities including the BHF. He has also raised money for the BHF in the London to Brighton bike ride and two years ago he led a group of cyclists on an ambitious (some would say foolhardy) 500 mile bike ride in Malawi, raising funds for local hospitals including the Queen Elizabeth Hospital where his medical career had started. Keith’s passion for the outdoors and his independent spirit are epitomized in an episode from a tour he made in Myanmar a few years ago, with his wife Aileen and other CLOTS (“cardiologists living outside their salaries”) and their partners. Although it became obvious that the tour guides were also chaperones to prevent straying, on one morning Keith announced that he and Aileen were going birdwatching. Despite the guides’ protestations he was not deterred and they returned that evening with an impressive set of photos of exotic birds. A guide then noticed that the background view beautifully showed off a top-secret military establishment. Nick Boon [Cardiologist and former BHF Trustee and Committee Chairman], who told me this story, did not reveal how Keith and Aileen escaped incarceration.
Looking back on some of the highlights of his research career Keith was characteristically thoughtful and generous. While being proud of the global influence of his clinical research (leading to an h Index that most of us will never reach) he ascribes his successes to “luck”, obviously an oversimplification, and the support of colleagues. Even if there has been an element of luck it has been Keith’s talent to seek it out and capitalize on it profitably. When asked what he thought the future holds for his field of medicine he was quick to comment that his research is only one aspect of the vastly increasing capacity for detailed individual phenotyping (including genetic information) and that he was confident that these developments would enable a future step change in targeted and personalised treatments for angina and heart attack patients.
Finally, when I asked him how the BHF Chair had helped his career, he said that being part of the family of BHF Chairholders had been uniquely valuable, as conversations with these colleagues from different specialties had given him unexpected insights into possibilities for enhancing his own research programme and opportunities for new collaborations.'