The heart of the matter: cardiovascular medicine & science
Cardiac function and the peripheral circulation have engaged scientists and clinicians at King’s and its partner hospitals for more than a century. The ground-breaking work of pioneering cardiologists Ernest Starling and Lord Brock continues to influence thinking on aspects of cardiovascular research and treatment.
Coronary heart disease is currently the single biggest cause of death in the UK and understanding its causes, finding ways to limit its damage and developing new methods to treat it continue to be important aims for cardiovascular research at King’s College London.
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Cardiac physiology and endocrinology
Late in the nineteenth century, Ernest Starling (1866-1927) worked at Guy’s Hospital where his interests in the mammalian heart and circulation developed. Starling made fundamental observations about the control of lymph and the peripheral circulation, showing that lymph resulted from intracapillary pressure and permeability of the capillary wall and was controlled by blood pressure and osmosis. In 1902, just after his departure from Guy’s to take up the chair of Physiology at University College London (UCL), he marked the advent of endocrinology by discovering secretin. It was the first description of a chemical substance produced in one part of the body that could circulate in the blood and produce a specific response elsewhere in the body. It was Starling who first coined the term ‘hormone’ for such substances.
Starling is best known to clinicians and physiologists for his ‘law of the heart’ – ‘the energy of contraction is a function of the length of the muscle fibres’– a physiological concept that through clinical application still influences management of patients with congestive heart failure. The series of experiments that led to Starling’s law were carried out at UCL between 1912 and 1920, but it was much later that the basic physiological concepts he advanced were applied to clinical features of congestive heart failure. During this time he also carried out innovative studies on the electromotive force of the mammalian heart and with William Bayliss described the first successful attempts to record electrocardiograms in mammals.
Ernest Starling observed in cardiac muscle that the force of contraction increased as the muscle was stretched in response to increased filling of the heart’s chambers. It is essential that heart muscle responds in this way to stretching, otherwise circulation of blood would fail. This became known as ‘Starling’s law’ and is fundamental to the understanding of the heart’s function.
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Understanding blood flow
Starling’s interests were broad and his work influenced many leading cardiologists of the time and continues to do so to this day. One of those influenced by Starling was Henry Barcroft (1904-1988). While at Cambridge Barcroft had developed a simple mechanical instrument called a stromuhr, for measuring the quantity of blood that flows per unit time through a blood vessel. When he moved to Starling’s department at UCL he used the instrument and elegant surgical techniques developed by Starling to study the paradoxical increase in cardiac output after occlusion of the descending aorta. His painstaking work showed that the effect was a mechanical consequence of the redistribution of blood in the circulation and not due to an undiscovered circulatory reflex as had been previously supposed.
A few years later, during his time as Chair of Physiology at Queen’s College Belfast, Barcroft became interested in the human peripheral circulation. He would stand for hours, together with research colleagues, in bins filled with water at core body temperature to test the effect of mechanical contraction of blood vessels on local blood flow. His experiments showed that sustained muscle contraction at 20-30 per cent maximal strength almost completely arrested blood flow in the calf of the subject, whereas rhythmic contractions, such as whilst walking, increased blood flow.
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Nervous control of circulation
Barcroft’s most significant contribution to physiology was his observation that blood vessels in human skeletal muscle are innervated with sympathetic vasoconstrictor nerves. He showed that when ulnar and median nerves are blocked near the elbow, blood flow in the forearm is increased. He concluded that release of vasoconstrictor tone with deep nerve block was deep to skin and presumably in skeletal muscle. He went on to show that the vasodilatation seen in limbs in response to body heating is not controlled by the same vasoconstrictor fibres to muscles, but by release of vasoconstrictor tone in skin vessels only.
During World War II Barcroft collaborated with John McMichael and E P Sharpey-Schafer on the physiological effects of haemorrhage. Following the war, Barcroft was appointed Professor of Physiology at St Thomas’ where he continued his studies of peripheral circulation with a particular interest in the vascular changes that take place after sympathectomy.
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Blood flow and body temperature control
Another physiologist working at the same time as Starling and Barcroft was Ronald Thomson Grant (1892-1989). He was interested in how blood flow is altered in skin under different circumstances. Working at UCL, Grant published his first influential paper in 1924 which explained that the vascular changes that take place in skin following different types of injury result from a single mechanism that is similar to injecting histamine into the skin. In 1930 Grant published a paper that provided the first in vivo evidence of arteriovenous anastomoses – small blood vessels that interconnect an artery and a vein. Using an albino rabbit model he demonstrated the importance of these small vessels in regulating body heat and their sensitivity to sympathetic nerve stimulation.
In 1934 Grant became Director of the newly established MRC Clinical Research Unit at Guy’s Hospital Medical School where he continued to work until the outbreak of World War II, when he was commissioned to work on trauma and shock.
He returned to the Guy’s Unit in 1945 and continued his research until 1957. During this period he showed that there are variations in vascular responses in different parts of the human limb. A major difference is that, although body warming produces large increases in blood flow and skin temperature in hands and feet, it causes only a slight rise of forearm and leg blood flow. This is largely due to distribution of arteriovenous anastomoses, which are plentiful at the extremities but virtually absent in forearm and leg.
Grant also thought it interesting that blood vessels acquire a heightened reactivity to constrictor stimuli after denervation. He provided evidence for the presence of a sympathetic cholinergic nerve mechanism in the central artery of the rabbit’s ear. His work suggested that after nerve section acetylcholine release diminishes and this is, at least in part responsible for the heightened reactivity of the denervated vessel.
Russell (later Lord) Brock (centre right, wearing glasses) with the cardiac surgery team, 1952. Brock was one of the foremost exponents and innovators of open heart surgery, developing in particular operations for diseased heart valves.
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Russell Claude Brock (1903-1980), who graduated from Guy’s Hospital Medical School in 1928, was one of heart surgery’s pioneers. Indeed, his interest in heart surgery came at time when most established medical opinion believed that heart surgery should not be contemplated. Brock held consultant appointments at Guy’s and Brompton Hospitals from 1936 to 1968 during which time his achievements gave him a widespread reputation.
During World War II Brock was thoracic surgeon and regional adviser in thoracic surgery to the Emergency Medical Service in the Guy’s region. Following the war, thoracic surgery techniques and particularly open heartsurgery developed rapidly.
Brock played a major part in pioneering the surgical relief of mitral stenosis and other valvular lesions of the heart. He introduced the technique to correct pulmonary artery stenosis and right ventricular outflow tract obstruction in the beating heart. Brock’s clinical experience demonstrated that even a severely underdeveloped pulmonary outflow tract could be restored to full growth by a successful direct operation.
Guy’s and blue babies
Guy’s surgeon Donald Ross performed the first total correction of Fallot’s tetralogy (or so called ‘blue baby syndrome’) on a patient under one year of age in 1961. The baby was the youngest reported survivor of total correction of Fallot’s by open heart surgery. Now 45, he is also the longest survivor in the world. Ross went on to work at the National Heart Hospital where he performed the UK’s first heart transplant in 1968. The very first ‘blue baby’ operation at Guy’s was in 1947 by world-famous American heart surgeon Alfred Blalock (front centre; visited Guy’s in 1947 and saved the lives of eight British children with the ‘blue baby’ heart condition.) of Johns Hopkins Medical School. Blalock was visiting the medical school as part of a newly established exchange programme between Johns Hopkins and Guy’s Medical School. This exchange programme continues to this day.
Most open heart operations are conducted on a paralyzed heart – cardioplegia – and on coronary bypass. Cardioplegia obviously needs to be safe and reversible. One of the most notable achievements in cardiac surgery was the development of efficient cardioplegic solutions by the biochemist David Hearse at St Thomas’ in the 1970s and 1980s. Operating on the main blood vessels of the body – vascular surgery – was another major advance in treating disease of conditions due to partial or complete obstruction of arteries or, less commonly, veins. Sir Norman Browse (b 1931), Professor of Surgery at St Thomas’, and President of the Royal College of Surgeons from 1992-1995, contributed to this field by popularizing carotid endarterectomy to relieve or prevent cerebral ischaemia.
Abnormal rhythms of the heart – cardiac arrhythmias – are a common cause of illness and death, and although more common in the elderly can also affect children and young adults. The now routine use of cardiac pacemakers currently used for 25,000 patients per annum has transformed the prognosis for many of these patients. Edgar Sowton (1930-1994) was an unusual medical student, gaining simultaneous degrees in physics and medicine at Cambridge. He turned this basic knowledge to good effect in his internationally recognized achievement on the development of cardiac pacemakers and the study of cardiac arrhythmias. He started this work at the Institute of Cardiology, London, and continued it on his appointment to Guy’s.
Stimulating the heart
Edgar Sowton’s career at the Karolinska in Stockholm, the National Heart Hospital in London and then at Guy’s, was devoted to the new clinical science of electrical stimulation of the heart. In the 1960s he became one of the world’s pioneers in the development of pacemakers. He was also one of the first people in the UK to perform coronary angioplasty. The biannual King’s Edgar Sowton Memorial Lecture was established in his memory after his death in 1994.
Biopsy of the heart posed a very difficult problem because of its relative inaccessibility and the risk of bleeding until the development by Peter Richardson at King’s College Hospital of endomyocardial biopsy in the 1970s. This technique is now used world-wide, with the instrument still termed the ‘King’s bioptome’.
Paediatric cardiology has been a strength at Guy’s since its inception. Under the guidance of Michael Tynan (b 1934) the Guy’s team grew an international reputation for its management of congenital heart disease. Surgical and invasive imaging techniques for correcting congenital abnormalities as well as innovations in diagnostic ultrasound all had an important impact on the specialty. These techniques were also developed for se in utero, contributing to the rise of the new discipline of fetal cardiology.
Current research follows in the traditions of the pioneering cardiac and vascular physiology dating back to the days of Starling as well as applied work on the diagnosis and treatment of coronary artery disease and heart failure.
A cardiac pacemaker in place. Pacemakers have transformed the lives of thousands of patients with cardiac arrhythmis.
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Interest in cardiac muscle physiology has been strong at King’s for several decades, notably within the MRC Muscle Group (see page 23) which has focused on fundamental mechanisms of muscle contraction using state-of-the-art biophysical techniques. Recent work has shown that the cellular basis of Starling’s law actually lies at the level of the myofilaments, and that regulation of cardiac muscle is modulated by factors such as endothelial cellderived nitric oxide, and novel protein kinases.
A fundamentally new view of cardiac muscle function has arisen from the discovery that proteins within the muscle sarcomeres are not only important as structural components and in contraction but also serve major cell signalling functions that impact on cardiac growth and development of disease. For example, a giant protein known as titin which spans the entire sarcomere contains domains that are capable of sensing mechanical forces applied to the muscle and then initiating signalling cascades that modulate muscle protein synthesis and atrophy or hypertrophy. This pathway is implicated in certain cardio- myopathies and may provide a new therapeutic target.
Beta blockers for heart disease
Sir James Black (b 1924), Emeritus Professor of Analytical Pharmacology at King’s, received the Nobel Prize for Physiology or Medicine in 1988 for the development of beta-blockers, used for the treatment of coronary heart disease, high blood pressure and heart failure and anti-ulcer histamine receptor blocking drugs, including the best-selling Tagamet. Sir James is credited with introducing analytical pharmacology as a new way of thinking to the process of drug development.
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