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Cardiovascular Endocrinology:
doi: 10.1097/XCE.0000000000000021
Cardiovascular Biomarkers in Animal Models - A Bridge to Human Disease Edited by Jens Peter Goetze and Lisbeth Hoier Olsen: Editorials

Ernest Henry Starling: the history of cardiovascular endocrinology and the continuous need for developing animal models

Henriksen, Jens H.

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Department of Clinical Physiology and Nuclear Medicine, Center for Functional and Diagnostic Imaging and Research, Faculty of Medicine and Health Sciences, Hvidovre Hospital, University of Copenhagen, Denmark

Correspondence to Jens H. Henriksen, MD, DMSc, Department of Clinical Physiology and Nuclear Medicine, 239, Center for Functional and Diagnostic Imaging and Research, Faculty of Medicine and Health Sciences, Hvidovre Hospital, University of Copenhagen, DK-2650 Hvidovre, Denmark Tel: +45 3862 2203; fax: +45 3862 3750; e-mail: jens.h.henriksen@hvh.regionh.dk

Received October 08, 2013

Accepted January 07, 2014

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Introduction

The English physiologist, Ernest Henry Starling (1866–1927) (Fig. 1) in 1896, provided a quantitative explanation of the transcapillary transport of fluid. Six years later, he discovered the first hormone and introduced the concept of hormones in 1905, and at the time of the First World War, he formulated the fundamental law on the mechanical effect of the mammalian heart 1–3. The transcapillary fluid transport, the hormone concept and the law of the heart all bear witness to a remarkable individual with an ability to interpret experimental data comprehensively and critically. All physicians today are trained in this fundamental physiological knowledge as a matter of course, but Starling’s numerous publications from 1890 to 1928 contributed considerably towards the transition of circulatory physiology from a qualitative discipline to a quantitative science. The present paper deals with Starling’s achievements in cardiovascular physiology and endocrinology.

Fig. 1
Fig. 1
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Early scientific works

E.H. Starling, C.J. Martin, G.N. Stewart and W.M. Bayliss were members of a group of physiologists working under Professor E.A. Schäfer at University College London (UCL). The topic was the innervation and contraction of the mammalian heart 4–6. Bayliss and Starling determined the propagation of electrical activation and mechanical contractions. Their electrical recordings showed a delay of about 0.15 s at the atrioventricular junction 4. Starling then investigated the effect of the vagal and sympathetic nerves on the auricles, the atrioventricular junction and the ventricles 5. He and Bayliss found that the vagal nerves suppress/delay at all three locations and the sympathetic nerves have the opposite effect in the mammalian heart. In addition, they developed a method for simultaneous registration of pressure variations in the aorta and the left ventricle 6. This equipment used continuous photographic recordings of volume changes in a small air-filled capillary tube connected with both the aorta and the left ventricle. The changes in volume in the capillary space provided an almost undamped recording of the variations in the aortic and ventricular pressure.

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The transcapillary filtration theory

The German physiologist, Carl F.W. Ludwig, had proposed a filtration hypothesis which could explain certain aspects of fluid transport across capillaries. Rudolf Heidenhain, however, argued that this transport had to occur by ‘vital’ forces 7. In 1893, Starling believed that the transport of peptone into the lymph must be ascribed to the active secretion of endothelial cells in the capillary wall. Numerous discussions with Bayliss brought clarification and subsequently experimental advancements. The essential point now is that Starling and Bayliss presented qualified estimates of changes in the hydrostatic pressure of the capillaries on the basis of changes in arterial and venous pressures in different vascular beds 8,9. All results indicated that mechanisms of a simple physicochemical nature alone were able to explain the transport of fluid and solutes across the capillary membrane, including the formation of lymph. Moreover, Starling had realized that the colloid osmotic pressure of the plasma proteins plays an essential role in transcapillary fluid dynamics 9.

Starling’s elegant concept of transcapillary fluid dynamics was not given a favourable reception and still less acceptance 10. The filtration theory was described in his own texts and in a chapter in Schäfer’s ‘Textbook of Physiology’ in 1898 11, but it was not a general entry in contemporary textbooks on physiology 10. It was not until Eugene Landis had come up with his experimental results in 1926 that August Krogh (Nobel Prize 1920) showed interest in Starling’s transcapillary transport mechanisms 1–3,12–16.

Starling’s filtration theory has inspired numerous subsequent investigators. The comprehensive studies of Pappenheimer and Soto-Riviera from the late 1940s deserve special mention 14. Recent years have witnessed considerable debate as to whether the simple version of the transcapillary filtration principle given in numerous textbooks on physiology is correct 1,12,15–17. Most likely it is not. Under the steady state, there is no downstream net capillary absorption. Michel and Levick have described these challenges 15–17. However, this does not change the general applicability of Starling’s filtration principle, as Starling did not anticipate a steady state, rather the opposite.

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The discovery of the first hormone and the introduction of the hormone concept

Charles J. Martin was present when Starling and Bayliss, in the afternoon of Wednesday, 16 January 1902, discovered secretin 18: ‘In an anaesthetized dog, … a few cubic centimetres of acid were introduced into the denervated loop of jejunum. To our surprise a similarly marked secretion was produced. I remember Starling saying: ‘Then it must be a chemical reflex’. Rapidly cutting off a further piece of jejunum he rubbed its mucus membrane with sand in weak HCl, filtered, and injected into the jugular vein of the animal. After a few moment the pancreas responded by a much greater secretion than had occurred before. It was a great afternoon’.

The name secretin was used for the new peptide substance transported by the blood in a preliminary report to The Royal Society 7 days later 19. No fewer than 18 scientific papers on the newly discovered secretin were published in 1902 1,3,20. After consulting various experts (among them the physician, W.B. Hardy and the classical scholar, W.T. Vesey, at Cambridge), Starling and Bayliss gave this new regulatory principle the name ‘hormone’ in 1905. Greek hormao (δρμω′υ), a substance transported by the blood that starts, urges on, initiates, irritates and stimulates. Starling introduced the hormone concept in a series of lectures beginning on 20 June 1905. Other examples of ‘chemical messengers’ named in Starling and Bayliss’ papers are adrenaline, antidiuretic factor from the posterior pituitary lobe and carbon dioxide.

The concept of hormone regulation shook the very foundations of the theory that organ functions are regulated solely by the nervous system. Ivan Pavlov (Nobel Prize 1904) and the Russian school of physiologists at first refused to accept Bayliss and Starling’s results 21,22, and Pavlov’s experiments could not be reproduced in London. This enigma was not solved until 1912, when one of Pavlov’s pupils, G.V. Anrep, came to London. When the premedication with morphine was stopped, the experimental results were the same in London and St Petersburg. The difference could be put down to an atropine effect. Anrep repeated Bayliss and Starling’s experiments in London and was then fully aware of the reason why these experiments could not be reproduced in St Petersburg: there, the acid extract had been over-neutralized and had become alkaline, thereby destroying the secretin. Agreement was thus reached as to the results of these complicated experiments. Confronted with the final proofs that the experiments were valid, Pavlov said: ‘Of course they are right. It is clear that we did not take out an exclusive patent for the discovery of truth’ 22.

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Circulatory investigations: the heart–lung preparation and the law of the heart

Starling resumed investigations into circulatory and cardiac functions along with several young scientists in 1909. His primary intention was to separate the effects of asphyxia into those caused by reduced oxygen and those caused by increased carbon dioxide 23–25. While working on these topics together with Kaya, Bolton, Jerusalem and later Knowlton, Markwalder and Patterson, he developed a heart–lung preparation (Fig. 2). The systemic circulation was substituted by an artificial connection from the aorta to the right atrium, which enabled regulation of the haemodynamic resistance and determination of the flow. The system allowed blood sampling for analysis and addition of bioactive components to the circulation. With this set-up, questions on the physiology of the heart, coronary perfusion and the composition of the blood could be investigated. The frequency of the isolated heart was found to depend on the temperature of the blood. The coronary circulation was found to possess a remarkable ability to extract oxygen from the blood. A further finding was that the coronary perfusion was highly dependent on the level of the arterial blood pressure.

Fig. 2
Fig. 2
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Starling was not the first to conduct experiments on an isolated heart. The American physiologist Henry N. Martin 26 developed a heart–lung preparation in Baltimore in 1880–1881. Martin’s pupils, William H. Howell and Frank Donaldson 27, were the first to describe a relation between venous filling and the mechanical function of the heart in 1881–1884. In 1895, Otto Frank investigated the relation between the filling pressure and maximum intraventricular pressure developed during contraction in the frog heart 28.

The first two of the four papers on the law of the heart were published by Knowlton and Starling in 1912 29 and Markwalder and Starling in 1914 30. These papers confirmed Starling’s earlier conclusion from 1897, namely, that within wide limits, the cardiac output is independent of the arterial blood pressure (outflow resistance) and that the cardiac output is proportional to the venous flow. The third paper on the law of the heart by Patterson and Starling in 1914 31 contains the first schematic drawing of what we today call Starling curves: the relation between cardiac performance (output) and end-diastolic pressure. It was further shown that if the end-diastolic pressure is increased beyond a certain limit, cardiac performance falls.

The fourth paper on the law of the heart, also published in 1914 32, had Piper in addition to Patterson as co-author. Hans Piper was German, and this work was probably a joint venture between Starling’s laboratory in London and Max Rubner’s laboratory in Berlin just before the outbreak of the First World War 1. The term law of the heart appears for the first time in this paper (J Physiol 1914; 48: 472), and is explained as follows: ‘The mechanical energy set free on passage from the resting to the contracted state depends on the area of chemically active surfaces, i.e., on the lengths of the muscle fibres’, and the law of the heart is valid for ‘… the whole behaviour of the isolated mammalian heart’. The concept of the law of the heart is elaborated in more detail in relation to the end-diastolic pressure and the initial length of the heart fibre. The law of the heart was subsequently presented in the famous Linacre lecture at St John’s College, Cambridge, in 1915, but was not printed until 1918 33.

To explain the adjustment of cardiac output to increased arterial pressure, Starling uses the following picture: ‘It is as if we had a motor vehicle, which automatically opened the throttle so soon as the road began to go uphill’ 34. Like the fibres of striated skeletal muscles, the fibres of the heart muscle can contract more forcefully if they are stretched before contraction. This important observation of the influence of preload on stroke volume and the ability of the heart ventricle, independent of external factors, to adjust the output of one ventricle to that of the other, Starling explained in a later lecture on the function of the heart (1923) in the following manner: ‘The heart has thus the power of automatically increasing the energy evolved at each contraction in proportion to the mechanical demands made upon it, behaving in this way almost like a sentient, intelligent creature’ 35.

The background of Starling’s interest in contractions of the heart muscle was a paper on the contraction of skeletal muscles by Magnus Blix from 1892 36. Starling sent Charles Lovatt Evans to work with A.V. Hill (Nobel Prize 1922) at Cambridge. Hill’s laboratory had very sensitive calorimetric equipment for the determination of heat development under various conditions and patterns of contractions of muscles. Evans and Hill published a paper in 1914 37 that confirmed the validity of the so-called viscoelastic theory and also apparently the theoretical basis for the descending leg on the ‘Starling-curve’. Wallace O. Fenn 38 subsequently showed that the premises for the viscoelastic theory in skeletal muscle did not apply. Fenn acknowledged both Hill and Starling in the publication. Hill later took full responsibility for the erroneous viscoelastic theory, but hints between the lines that Starling ‘seduced’ him 39. In view of the general validity of the relation between the length of a muscle fibre and its mechanical energy, the above considerations may seem to be theoretical or technical details. Nonetheless, they have given rise to decades-long discussions about the presence or absence of a descending leg in the contraction curve of the normal heart ventricle and how the contraction curves should be presented.

In the following years, Starling (Fig. 3) further developed and generalized the law of the heart. He applied it as a basis to explain the circulatory changes that take place from rest to physical exercise. Starling described the events in the following way: first, increased venous return to the heart, owing to muscular activity; second, increased stroke volume induced by increased filling of heart ventricles; third, increased heart rate by cessation of vagal tone; and finally, enhanced mechanical effects of elevated circulating adrenaline, leading to a more complete emptying of the ventricles.

Fig. 3
Fig. 3
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However, a stumbling block to the general applicability of the law of the heart was the fact that the heart volume decreased during physical exercise. Starling realized that the experimental results attained with the isolated heart–lung preparation must have limited validity in the intact organism 40. As suggested above, and as illustrated in his scientific work already before the turn of the century, the autonomic nervous system, especially the sympathetic nervous system, is an important modifying factor. This also applies in heart failure. Starling expressed it in 1921 as follows: ‘I cannot pretend to have explained all the phenomena of uncompensated heart disease. I have shown that a consideration of the isolated heart–lung enables us to understand how heart failure … must lead to a delimitation of output, but it is hardly conceivable that the failing heart … does not itself invoke the interaction of the central nervous system … either to increase the response of the heart muscle … or plausibly to save the muscle at the expense of other organs … when the heart is in danger of failing through excessive fatigue’ 40.

Starling continued experimentation with this preparation and investigated the regulation of the blood pressure and control of the circulation by cross-perfusion of dogs. An important observation was that an increase in aortic pressure dilates the blood vessels in the systemic circulation, provided that the depressor nerves are intact. Changes in blood pressure in the arterial supply to the brain induce changes in the opposite direction in the arterial blood pressure in the rest of the body. These fundamental principles of vasomotor regulation had earlier been suspected, but not until then determined quantitatively.

Starling’s law of the heart has inspired numerous investigations. The very comprehensive studies of Sarnoff 41and Suga and Sagava 42 deserve special mention. Over the last 35 years, Starling’s contribution to the mechanical effects of heart muscle contraction has been assessed differently 12,41–47: from unoriginal and erroneous 45, to a detailed analysis of substantial experimental results 2,44,46, to a most visionary contribution of growing importance even today 43,44. Chapman’s balanced description deserves attention 2.

H. Barcroft recounts in 1976 that, as a young student, he had met Starling and seen a film on the heart–lung preparation 48. The light was too poor in Starling’s laboratory at UCL to make a film, but he had been told that the proper light sources for filming were available at the Sorbonne. There, it turned out that the light was still too weak. However, Starling was determined to carry through the filming of the heart–lung preparation. He cut the organs free, went outside into the yard and fixed the preparation and its attachments to a fence. Here, the light was good enough, but the fence was only a few metres from a public thoroughfare. Barcroft recalled the amazement on the faces of the French passers-by when they realized that it was a beating heart that hung on the fence. Starling was satisfied with the film which was made in 1925.

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Animal experiments

In 1899, Starling became Jodrell Professor of Physiology at UCL and began to modernize the experimental facilities here. In 1901, August Krogh was in London and wrote home to his wife Dr Marie Krogh in Copenhagen: ‘I have visited a professor in physiology, E.H. Starling, whose laboratory I saw and where I attended a very interesting vivisection (‘vivisection’ is a term denoting the earlier practice of performing section on living, not anaesthetized, animals for the purpose of study. The opponents of animal experiments, and sometimes also the professionals, in this period used the term, even though almost all animal experiments were carried out on anaesthetized animals, which were later killed. British physiologists had been put in a straitjacket by the antivivisection legislation of 1876 and the antivivisectionist movement worked hard to get the legislation further tightened.) …’ 1. Starling conducted animal experiments for almost 40 years, often on dogs. His defence of animal experimentation aroused the hostility of animal protection leagues, and the antivivisectionists were very troublesome. Starling’s battle against antivivisectionists was long and fierce. The leader of the antivivisectionists, the Hon. Stephen W. C. Coleridge, reported Bayliss and Starling for having operated on a dog without anaesthesia. After an investigation, this accusation was judged unfounded. Bayliss, however, felt that his name had been dishonoured and he sued Stephen Coleridge. At the trial on November 1903, the animal experiment was presented. A photograph of the reconstruction shows the experimental set-up (Fig. 4). Bayliss won the lawsuit and received a compensation of £2000. This large sum was subsequently donated to a research fund at UCL and thus, at least in part, used for further animal experiments 1,2. A ‘Royal Commission on Vivisection’ was set up in 1906 to modernize and tighten the old legislation of 1876. A group of scientists formed a committee with Starling in the chair. Starling’s strategy was to stress the historical aspects and the necessity of using animals for medical, cardiovascular and hormonal research, and he underlined the importance of protecting the animals from pain. Starling’s committee was later continued as a ‘Research Defence Society’. Stephen Coleridge attempted for many years to influence Starling’s views, but without any success. Throughout his career, Starling stressed the importance of animal experimentation.

Fig. 4
Fig. 4
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Lack of a Nobel Prize

Starling had close scientific relations with at least seven Nobel laureates – but he did not himself become a Nobel Prize laureate 49. Starling published his first scientific paper together with F.R. Hopkins (Nobel Prize 1929). I. Pavlov is seen on photographs of the Bayliss–Starling family around the turn of the century. H.H. Dale and O. Loewi (Nobel Prize 1936) were fellows at UCL at the beginning of the century. A.V. Hill’s early works on muscle contraction were a premise to the law of the heart, and Starling got Hill to succeed him as Jodrell Professor at UCL. Starling corresponded with August and Marie Krogh for several years and met them in London and Stockholm 1,49.

Starling was aware of the Nobel Prize right from its beginning, as in 1901, he received an invitation from the Karolinska Institute to suggest candidates 49. He nominated the Editor of the Journal of Physiology J.N. Langley, and on four subsequent occasions, Starling nominated C.S. Sherrington (Nobel Prize 1932). In 1913, Starling and Bayliss were nominated for the Nobel Prize in Physiology or Medicine for their discovery of the first hormone by Professor Emile Lahousse from Ghent and Otto Loewi, now a professor at the University of Graz. The Nobel Committee gave Starling a rather favourable evaluation, but concluded, ‘… it would not hurt to await further developments so as to see what the continuing work reveals’ 49. In 1914, Starling and Bayliss were again nominated for the Nobel Prize, this time by Professor Pol André Bouin from Nancy. Starling was put on the ‘short list’ of last-round candidates, which means that he actually had a fair chance of winning the Prize that year.

Later, Starling was nominated by Boris Babkin, but seemed to have fallen out of favour with the Committee. Prizes withheld during World War I, and the political and personal attitudes of the Nobel awarding bodies relating to the relevance of a recent discovery also contributed. In addition, personal tensions developed between Starling and the chairman of the Medical Nobel Committee, Johan Erik Johansson, Professor of Physiology at the Karolinska Institute 49. Moreover, Starling clearly criticized the judgement of the Nobel Committee in awarding the prize to MacLeod and Banting instead of to Banting and Best.

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Closing remarks

Starling was not a clinical physiologist nor a cardiovascular pathophysiologist in the modern sense, but his interest in the combination of physiology and clinical medicine contributed considerably towards the quantification of organ function in human diseases, both as basic knowledge of pathophysiology and for clinical diagnosis 50. Starling’s scientific achievements have stood the test of time. The circulatory dynamics and ‘the chemical correlation of the body’ set the agenda for medical research for over a hundred years. The term hormone is by now familiar to all, but it is Starling’s term, and before him, the search made little sense. He saw the great potential of circulatory physiology, including the understanding and clinical treatment of congestive heart failure.

In some ways, Starling was an outsider. He was, like many other scientists, for a while caught in an administrative–political web, but was forceful enough to escape. Throughout his life, he stressed fundamental scientific attitudes and ideas with remarkable persistence and power. Starling expressed the following maxim on the choice between life as a ‘poor’ full-time researcher and a wealthy physician: ‘Under present conditions a man, when he obtains a position on a hospital staff … engages his consulting rooms at a high rental in some fashionable quarter. He imagines it is more to his advantage to wait for the crumbs which fall from the great man’s table than to spend his time in adding to our knowledge of medicine. … In the course of years … the man has wasted the productive years of his life, has lost touch with the exact methods of the laboratory, has been left behind by the advances of the collateral biological sciences. He may now become a respected West End consultant; he will never add anything to the science of medicine’.

Not until 1981 did it become clear that the heart itself produces peptide hormones with effects on the circulation, neuroendocrine systems and the kidney. Nevertheless, it is reasonable to declare Starling the first man in cardiovascular endocrinology: he invented the hormonal concept, established experimental evidence of humeral regulation, described the microvascular fluid dynamics, formulated the law of the heart and contributed considerably towards the understanding of congestive heart failure. Although not fully recognized in his lifetime, we know the importance of his pioneering work, mainly on experimental animals, now a hundred years later.

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Acknowledgements

The author would like to thank his secretary Georgina Narvaez, BsC, for her skillful handling of the manuscript.

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Conflicts of interest

There are no conflicts of interest.

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