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- Wiley Online Library
Journal of Thrombosis and Haemostasis, 9 (Suppl. 1): 118–129 DOI: 10.1111/j.1538-7836.2011.04312.x INVITED REVIEW Discovery of the cardiovascular system: from Galen to William Harvey W. C. AIRD The Center for Vascular Biology Research, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA To cite this article: Aird WC. Discovery of the cardiovascular system: from Galen to William Harvey. J Thromb Haemost 2011; 9 (Suppl.1): 118–129. Summary. The goal of this review is to examine the events that led to discovery of blood circulation. The Ancient Greeks, including Hippocrates and Galen viewed the cardiovascular system as comprising two distinct networks of arteries and veins. Galen claimed that the liver produced blood that was then distributed to the body in a centrifugal manner, whereas air or pneuma was absorbed from the lung into the pulmonary veins and carried by arteries to the various tissues of the body. Arteries also contained blood, which passed from the venous side via invisible pores in the interventricular septum and peripheral anastomoses. This was an open-ended system in which blood and air simply dissipated at the ends of veins and arteries according to the needs of the local tissue. Blood was not seen to circulate but rather to slowly ebb and flow. This view would hold sway for 15 centuries until 1628 when William Harvey published his momentous 72-page book, On the Motion of the Heart and Blood in Animals. Harvey employed experiment and deductive logic to show that arteries and veins are functionally, if not structurally, connected in the lung and the peripheral tissues, and that blood circulates. The mechanical force of the heart replaced GalenÕs elusive attractive powers. Ultimately, Galenism would collapse under the weight of HarveyÕs evidence, and a new paradigm of blood circulation would prevail. Keywords: biology, cardiology, history, vascular. Correspondence: William C. Aird, 330 Brookline Avenue, Boston MA 02215, USA. Tel.: +1 617 667 1031; fax: +1 617 667 1035. E-mail: [email protected] 1 An argument is said to be deductive ÔIf it draws a conclusion from certain premises on the grounds that to deny the conclusion would be to contradict the premisesÕ. 2 Bloodletting would persist as a common therapy for many medical conditions into the early 19th century. Harvey himself was a great bleeder. In fact, he thought his circulation explained why bloodletting worked. If blood is going around the body in a circle, then removing blood may reduce blood pressure and remove the blood of toxins. Introduction Imagine opening the chest cavity of an animal such as a mouse and – without any prior knowledge of the circulation – trying to make sense of the movement of the heart and blood. For those readers who have had occasion to observe the beating heart during open-heart surgery, or the rapid motion of the heart in the living animal, they will appreciate it rises and falls in the chest as it beats. How does this alternating motion correlate with contraction (systole) and dilatation (diastole) of the heart? Is diastole a passive state or an active dilatation? It will also be noted that the arteries pulsate. How does the pulsation relate to the cardiac cycle? Knowing that the arteries contain blood, in what direction is the blood flowing? Cutting open the artery gives little clue about directional flow. Is the system open-ended or closed? This is a difficult question to answer given that the connections between the arteries and veins cannot be seen with the naked eye. The Ancient Greeks had no prior knowledge about the structure and function of the cardiovascular system. Even worse, by the 1600s investigators were working with incorrect prior information. One cannot see the circulation of blood. Thus, its discovery – a turning point in the annals of biomedical history – depended on inference through clever experimental approaches, as pioneered by William Harvey. Why is the discovery of the circulation considered to be so important? Prior to Harvey, the physiology of the body was essentially a question of the refinement of ingested food. Food was transformed in the liver into blood and distributed in veins throughout the body where it was assimilated to restore the tissues gradually lost. In addition to blood, veins also contained other humors, including yellow and black bile. Part of the venous blood was diverted to the heart where it was mixed with air in the left ventricle to form arterial blood imbued with vital spirits. The latter was distributed to tissues of the body through the arteries, providing heat, life and motion. (Some of the arterial blood was sent to the brain for further refinement into psychic spirits). The humors, spirits and heat ebbed and flowed around the body, according to the needs of the tissues. Disease was attributed to an imbalance of humors or a shift in the patterns of flow within the body. Treatment was directed at 2011 International Society on Thrombosis and Haemostasis Discovery of the cardiovascular system 119 restoring the balance or controlling the movement of fluids. Bloodletting (venesection) was a common remedy, as was the use of ligatures (tourniquets) to redirect or divert the flow of blood from one part of the body to another. The system made sense. It was internally cohesive. However, fifteen centuries later, HarveyÕs finding that blood circulates implied that blood was not constantly being consumed in the periphery and replenished by ingested nutrients, but rather that blood was conserved. From a therapeutic standpoint, the rationale for bloodletting – a mainstay of treatment for virtually every disease –was cast into doubt. In short, the new theory of blood circulation changed the intellectual system and worldview of physiology, disease and therapy. As modern-day clinician-scientists, why should we care about the history of the circulation? For one, the historical account reminds us that investigators from different eras should be judged in the context of their own times. It is difficult to put ourselves into the position of those who did not have our answers. However, Galen was a brilliant researcher and thinker, no less driven by a search for the truth than was William Harvey. The Ancient Greeks did their best to generate sound conceptual systems based on data available to them. They did not know that their system was flawed. We can only hope that our current models of the vascular system will be judged fairly and sympathetically by future generations who look back at the errors of our ways. Second, progress in science does not occur in a vacuum, but rather builds on a foundation of scholarship. As Harvey pointed out: Ôthere is no science which does not spring from pre-existing knowledgeÕ. Science did not begin with the molecular revolution, the germ theory or the cell theory. Rather, science began when the Ancient Greeks began searching for non-divine natural causes. Galen inherited and built on the work of the Ancients, Harvey overhauled Galenic doctrine, and we continue to build incrementally on HarveyÕs model. Third, the fact that science fell dead for centuries after GalenÕs death teaches us that scientific reasoning is fragile and can be suppressed under certain political, theological and cultural conditions. Progress in science continues to be hampered by such barriers, as evidenced by the recent debate over human stem cell research. Fourth, the narrative provides insights into the evolution of epistemological thinking, or ways we go about acquiring knowledge and truth about the natural world. One reason to study history is to understand why people thought the way they did, what assumptions did they make and why did they make them? This should remind us to do the same about ourselves. Finally, the story teaches us the importance of questioning existing dogmas when the evidence calls for it. Harvey, while respectful of and deferential to his predecessors, was not afraid to carve his own path. HarveyÕs warnings about the power of authority and dogma are equally pertinent today as they were in his time. Before galen Since the golden age of Greece (around 400 BC), it was appreciated that all animals, including humans, must be 2011 International Society on Thrombosis and Haemostasis nourished, and that the nourishment must somehow be distributed from the intestines to all parts of the body. During this process humors are formed. Hippocrates and his contemporaries were the first to offer sophisticated reasoning in medicine, rejecting a role for divine causation. They maintained that health is associated with a balance of the humors, disease with an imbalance. Thus, disruption of the nutritive process plays a key pathogenic role in disease. Aristotle (384 BC) believed that the heart is the center of the physiological mechanism, the seat of the soul and the source of all blood vessels. Praxagoras (340 BC) was the first to differentiate between arteries and veins. He theorized that arteries begin in the heart and carry pneuma, while veins originate in the liver and carry blood. Herophilus (3rd century BC) recognized that arteries have thicker coats than veins (noting the exception in the lung). Erasistratus (3rd century BC) considered the heart to be the source of both veins and arteries. He believed that arteries normally contain air alone (Fig. 1). He observed that when punctured, an artery bleeds. To explain this paradox, he suggested that blood moves from veins to arteries through invisible anastomoses when the arteries are emptied of air. In summary, Galen inherited a flawed knowledge base from the Ancient Greeks on which to build. Galen Galen the man Galen was born in 129 AD in Pergamum, Asia Minor (presently Bergama, western Turkey) during the height of the Roman Empire. He began his medical studies at the age of 16. His education spanned many years and geographical locations, including Alexandria in Egypt. In 157 AD, at age 28, Galen returned to Pergamum where he was appointed to the post of surgeon to the gladiators. In this role, Galen received on-thejob training as doctor, surgeon, trainer, and nutritionist. In 162 AD, Galen traveled to Rome, where he quickly established a reputation as a leading medical authority. He was ultimately appointed as Physician to the Emperor. Galen carried out the bulk of his experimental work in the form of public demonstrations. He wrote a vast number of works in subjects ranging from medicine, through logic, philosophy, and literary criticism. It is believed that Galen lived well into his 80s, dying between 207 and 216 AD. GalenÕs sources and methodology Galen inherited from the Ancients an intelligible working system of physiology and medicine. He set Hippocratic medicine within a broader anatomical-physiological framework, codifying, systematizing and building on existing knowledge [1,2]. Galen carried out many of his own experiments. He was not allowed access to human bodies (but he did see inside humans in surgery and by chance). Thus, his studies were largely confined to dead or living animals. In addition to experimental evidence, Galen relied heavily on teleological 120 W. C. Aird Fig. 1. Schematic of the cardiovascular system over time. (A) According to Erasistratus, arteries and veins are separate. Veins contain blood (blue color), while arteries contain air (white color). Food is taken up in the intestines by the portal veins, delivered to the liver (black color), transformed into blood and then transported to the vena cava by way of the hepatic vein. From the vena cava, venous blood is delivered to all parts of the body. Some of the blood is diverted to the right ventricle (blue colored chamber in the heart), from where it enters the pulmonary artery to nourish the lungs. Air is taken up in the lungs by the pulmonary veins, transferred to the left ventricle and distributed to the tissues via the arteries. Fuliginous vapors (waste) are excreted by retrograde flow through the mitral valve and pulmonary vein. (B) Galen demonstrated that arteries normally contain blood (red color), not air. Arterial blood is derived from the passage of venous blood through invisible pores in the interventricular septum (shown as interrupted septal wall). (C) Colombo described the pulmonary circuit, in which venous blood in the right ventricle passes through the lungs into the left ventricle and arteries. However, Colombo maintained the Ancient Greek view that blood flow in veins is centrifugal (away from the liver and towards all tissues), with only a small amount entering the right heart. Thus, ColomboÕs system is a hybrid between closed (pulmonary) and open (systemic). (D) Harvey discovered that blood circulates not only in the lung, but also around the whole body. An important clue was the presence of valves in the veins (two of them are shown in white). The liver is no longer the source of veins. Rather, the system is driven by the mechanics of the heart (now shown in black). Transfer of blood from arteries to veins in the lung and periphery may occur through direct connections or anastomoses (as shown) or through porosities in the flesh (the latter mechanism being favored by Harvey). arguments (Nature does nothing in vain) to explain the structure and function of the human body. Galen repeatedly stressed the unity of reason and experience. Some 400 years earlier, Aristotle had introduced formal logic as a means of generating scientific knowledge. In keeping with AristotleÕs teachings, Galen employed deductive logic to arrive at many of his conclusions .1 An example is his demonstration that arteries contain blood, but not air: 1 If arteries contain blood, then they are not filled with pneuma from the heart. 2 But arteries do contain blood. 3 Therefore, arteries are not filled with pneuma from the heart. However, as noted by the Galenic historian, Vivian Nutton, Ô[GalenÕs] conclusions are almost always correctly derived from his premises: it is the premises themselves that are disputableÕ [3]. For example, consider the following demonstration: 1 If the heart is hotter than other organs, then it is the source of innate heat. 2 But the heart is hotter than other organs. 3 Therefore, the heart is the source of innate heat. Here, Galen bases the second premise on what he considered to be clearly evident to the senses, namely that the heart is hotter than other parts of the body. This erroneous premise would go unchallenged for centuries until the invention of the thermometer. GalenÕs view on Nature Galen accepted the ancient doctrine that the four elements (earth, wind, fire, and water) embody the four primary irreducible qualities (the hot, cold, dry and wet). These corresponded to the four essential humors of the body (blood, black bile, yellow bile, and phlegm) [1,4,5]. The humors, in turn, took their origin from the elements found in food. Indeed, GalenÕs physiology started with nutrition. As we will see, food was ultimately transformed into blood, and blood in turn was somehow transmutated into the flesh of tissues. But the human body was more than a series of hungry organs. It had warmth and vitality, it moved voluntarily, it had thoughts. Thus, 2011 International Society on Thrombosis and Haemostasis Discovery of the cardiovascular system 121 overlaid on the nutritive or natural spirits (the blood) was a vital spirit. While the natural spirit had its origin in food and drink, the vital spirit was derived from atmospheric air. Natural spirits were carried by veins, vital spirits by arteries. At the center was the heart, which mediated exchange between blood in the veins and air in the arteries. Like a burning cauldron, the heart also provided the body with innate heat. The heart was a smelterÕs furnace and factory, not a pump. This industrial model of the heart reflected existing technology in Roman society. The analogy of the heart to a force pump was only really made possible when such devices became commonplace in the 16th century. The body parts and their actions resulted from different combinations of the four elements, qualities, and humors. Galen proposed a theory of natural faculties, according to which every part of the body has the power to attract, retain, and concoct or alter its nutritive humors as well as to expel its excrements. At any point in time, the flow of material (e.g., nutriment, pneuma or waste) between body parts seems to follow a gradient of attractive and expulsive powers. Galen agreed with Hippocrates and Aristotle that the heat of the body is innate and inexorably linked to life and the soul. Innate heat is required for alterative processes and is thus indispensable for digestion, nutrition, and the generation of humors. The innate heat derives from the heart (especially the left ventricle) and the arteries. Galen rejected AristotleÕs brain as a cooling device, claiming instead that it is the lungs that refrigerate the heart. In addition to his vitalism, Galen accepted certain mechanistic explanations. For example, he agreed with some of his predecessors that nature abhors a vacuum and that there is a tendency for a vacuum to become refilled. For Galen, this is a mechanical law that explains how active dilatation of body cavities (such as the heart and arteries) creates traction and draws neighboring matter into itself. In contrast to the powerful vital attractive power of all body parts that operates at small distances, the mechanical vacuum effect can exert traction even across large distances. GalenÕs view on the cardiovascular system Veins contain blood According to Galen, the liver is the source of all veins and the principle instrument of sanguification [4–7] (Fig. 1). In the stomach, food is concocted into chyle, which is then delivered to the small intestine and absorbed into veins. The chyle is carried in the portal vein to the liver, where nutriment becomes actual blood, which is charged with natural spirits. Blood is purified in the liver and then enters the hepatic vein through invisible connections between branches of the portal and hepatic veins. The blood moves from the hepatic vein to the inferior vena cava, which through its branches supplies all the parts of the body above and below the liver. In other words, blood moves centrifugally from the center (the liver) to the periphery. This is an open-ended system designed to provide one-time distribution of food. Each part of the body attracts and retains 2011 International Society on Thrombosis and Haemostasis only enough blood for its immediate requirements. Blood that is assimilated into tissue is ultimately lost though invisible emanation. The parts receive fresh supplies from the liver as needed. As such, movement of blood was subsumed under the theory of nutrition according to which each body attracts, retains, and assimilates food, and expels its superfluities. A portion of blood nourishes the lung via the right ventricle A small amount of blood entering the vena cava is diverted to the right auricle, which is considered an outgrowth of the caval system. From the right auricle blood enters the right ventricle. Dilatation of the right ventricle draws in blood from the vena cava. The right ventricle further elaborates and attenuates the blood, rendering it fine and thin. Some of this refined blood enters the pulmonary artery. Blood in the pulmonary artery nourishes the lung. A small portion of the blood (the thinner part) in the pulmonary artery is squeezed through invisible anastomoses into the pulmonary veins, from which it too is absorbed by the lungs, providing them with vital spirits. Finally, some blood in the right ventricle passes into the left ventricle through invisible pores in the interventricular septum. The heart intrinsically pulsates Galen recognized that both ventricles pulsate even when their nerves are severed or the heart is removed from the thorax. Thus, the power of pulsation has its origin in the heart itself. The heart dilates during diastole and contracts during systole. Diastole is an active process during which the heart snatches up or sucks in the inflowing blood like a smithÕs bellow or sponge. The filling of the heart in diastole causes the heart to twist and the apex to rise and strike the chest wall. Systole serves to expel residues from the left ventricle into the pulmonary vein. Respiration cools the innate heat and yields vital spirits The outer air is concocted in the lung to form pneuma. Pneuma is then transmitted by the pulmonary veins into the left ventricle where it cools the innate heat and where it meets the venous blood received through the septum. Together, these conditions result in further concoction into vital spirits, which are then distributed to tissues in arteries. Noxious vapors, generated as a byproduct of the innate heat are expelled into the pulmonary vein during systole and ultimately expired through the airways. Retrograde movement in the pulmonary vein is made possible because the mitral valve has only two outgrowths (valves), which cannot be accurately closed. Thus, the pulmonary veins serve as ventilating ducts, inhaling cool air into the left ventricle, and exhaling heated air and smokey vapors. Stated another way, the left ventricle ventilates itself by inhaling and exhaling through the pulmonary veins. The lungs also serve to aid the flow of blood by their rise and fall, as well as to provide physical protection to the heart. Arteries contain air and blood Erasistratus had argued that arteries normally contain air or pneuma alone. Galen proved experimentally that all arteries in the body contain a portion of 122 W. C. Aird blood. This was demonstrated by ligating an artery in two places, slicing open the intervening segment, and finding blood, but no air. If arteries contain blood, how does it get there from the veins? Galen suggested that blood permeates from pulmonary arteries to pulmonary veins through invisible channels. However, the resulting blood in the pulmonary veins does not reach the left ventricle, but rather is used by the lungs as nourishment. In other words, there is no pulmonary circuit. Instead, blood in the left ventricle (and hence the systemic arteries) is derived directly from the right ventricle, through invisible pores in the interventricular septum. Arteries vs. veins Galen noticed that certain properties differed between arteries and veins. For example, veins are located in both superficial and deep locations, whereas arteries are always deep. Arteries pulsate, veins do not. The tunic of arteries is denser than that of veins. The blood in arteries and veins is qualitatively different. Compared with veins, the blood contained in arteries is hotter, thinner and more spirituous. The arterial pulse is an intrinsic property of the blood vessel The arterial pulse is an inherent property of the blood vessel. It is a vital power that springs from the heart and is transmitted through the coats of the arteries. GalenÕs claim was based on a famous experiment (later criticized by Harvey) in which he placed a hollowed reed into a severed artery. When he tightened a ligature around the vessel wall over the hollow tube, he noted that the distal arterial segment stopped pulsating. The whole body breathes in and out Arteries are not expanded because they are filled. Rather, they are filled because they are expanded. When expanded, the arteries draw in from all sides. When contracted, they squeeze out on all sides. Exchange occurs through pores or vents in the coats of the arteries or through mouths that open into the gut of outer skin. GalenÕs model amounts to a type of skin breathing, where arteries on the surface of the body draw in airy substance that surrounds us (during diastole), and eliminate smoky, vaporous residue derived from the burning up of the juices (during systole) throughout the whole animal. The intake of air into dilated arteries serves to cool the natural heat, whereas the expulsion of smoky, vaporous residue serves to purge the innate heat. In short, the arterial pulse and respiration serve the same ends. All is in all None of the parts of the body is absolutely pure. Everything shares in everything else. Thus, while arteries are primarily instruments of the pneuma, they have their share of thin, pure spirituous blood. Veins are primarily instruments of the blood or other nutriment, but contain a little mistlike air. All over the body, arteries and veins communicate with one another by common openings and exchange of blood and pneuma occurs through certain invisible and extremely narrow passages or inosculations. Through these junctions, the arteries draw from the veins, when they expand, and squeeze into them when contracting. Thus, the movement of blood and air is neither directional nor rapid. Rather, the contents of blood vessels move slowly, hither and thither. Medical implications of GalenÕs theory Many internal and external factors were thought to interfere with nutrition and blood flow, and thus produce disease. In external hemorrhages, blood is attracted to the wound. Internally, an abnormal flux of blood to one site of the body may produce swelling and inflammation. Alternatively, there may be larger scale movements of blood, for example from the center to the periphery (outward movement, or expansion) or from the periphery to the center (inward movement, or concentration). Therapies were designed to alter or correct a harmful flux of humors. These included the application of heat, massages, ligatures, or venesection in strategic, specific sites of the body. GalenÕs legacy Galen was faced with a bewildering array of facts. He knew that the heart moved and tapped against the chest wall, that breathing was essential to life, that heat was extinguished in death, that the valves of the heart functioned, that arteries and veins were connected with the heart, and that these two blood vessel types were structurally different and contained blood of different color. Determining the various movements of the living heart must have been extremely challenging. Nonetheless, Galen developed a system of remarkable internal coherence, one that provided an explanation for digestion, the production of blood, the distribution of nourishment around the body, and the generation and conveyance of heat. In short, the functions of the liver, veins and right heart were to deliver the products of a healthy diet to the various parts of the body, while the functions of the lung, left heart and arteries were to deliver fresh air and to cool the body. All of this was consistent with NatureÕs intent. More importantly, the system provided a rational foundation for therapy. GalenÕs most significant contribution was to synthesize existing knowledge, including the Ancient Greek heritage of humoral medicine. However, he also made original observations. He was to the first to convincingly demonstrate that arteries contain blood. His argument that blood must normally pass from veins to arteries via anastomoses in the lung and periphery was novel as was his misguided reference to imaginary holes in the interventricular septum. The question of how blood got from the right ventricle of the heart to the left ventricle would challenge investigators for the next 1500 years. Its answer would provide an important clue about the circulation of blood. The dark ages, middle ages and the Renaissance The fall of the Roman Empire was followed by a long period of time (500–1400 AD) in which the scholarly tradition was closely intertwined with – and controlled by – the Church [8– 11]. There was no interest in acquiring new knowledge through 2011 International Society on Thrombosis and Haemostasis Discovery of the cardiovascular system 123 experimentation. Rather the focus – on the part of philosophers and the clergy – was to preserve and organize Ancient Greek teachings and to reconcile these with theology. GalenÕs teleological leanings fit well with Christian doctrine. His work became scripture and its theological status rendered it immune to reasoned challenge. Any new findings or anomalies were made to fit GalenÕs physiology and anatomy. Compared with the Latin West, the intellectual conditions in Byzantium and the Islamic world were far superior. Arabic authors had access to many more works of the Ancient Greeks than did the West. In the mid-13th century, Ibn al-Nafis of Damascus provided the first description of the pulmonary circulation. He wrote that blood does not permeate the interventricular septum, but rather circulates in the lungs via invisible connections between the pulmonary arteries and veins. In 1547, Ibn al-NafisÕs work was translated into Latin. However, there is no evidence that his ideas were known to Servetus and Colombo who rediscovered the pulmonary circulation in the 1500s. In the 12th century, animal dissection was initiated in Salerno for the first time since Antiquity. Dissection of human bodies appears to have begun in the late 13th century at the University of Bologna. Over the next 2 centuries, the objective of dissections was not to investigate, but rather to study and teach the works of Galen. In the 1400s, the Renaissance in Italy ushered in a new era of learning and discovery. With the emergence of the polymath, art and science began to inform each other in important ways. Leonardo da Vinci (1452–1519), who was interested in the link between form and action of the human body, was the first to make accurate drawings of the heart, including its valves. In a departure from Galen, who claimed that the heart was not a muscle, Leonardo wrote: Ôthe heart is a vessel made of thick muscle, vivified and nourished by artery and vein as are other musclesÕ. Leonardo was the first to identify the atria as heart chambers, and to provide a description of atherosclerotic coronary arteries. These discoveries notwithstanding, Leonardo – like everyone else in his time – was an avowed Galenist. Andreas Vesalius (1514–64), a Flemish professor of anatomy at Padua, carried out his own dissections (unlike Galen, he had access to human corpses) and began to point out errors in GalenÕs work. In particular, he questioned the existence of pores in the interventricular septum. One of VesaliusÕs great contributions was his use of detailed, realistic illustrations of the human body in what amounted to the first modern textbook of anatomy. Michael Serveto (also known as Servetus, 1511–1553), a Spanish philosopher-theologian, published a treatise in which he proposed that blood is driven from the right ventricle to the lungs, where it mingles with inspired air and is ultimately drawn into the left ventricle. There is no evidence that Serveto actually carried out his own experiments. Realdo Colombo (also known as Columbus, 1516–1559), an Italian anatomist and student of Vesalius bred in the Galenic tradition, provided an anatomical account of the pulmonary transit of blood (Fig. 1). He based his theory on 2011 International Society on Thrombosis and Haemostasis three observations. First, he noted that the pulmonary vein is full of blood, which would not be the case if the vessel were constructed solely for conveying air and vapors. Second, he was unable to demonstrate pores in the interventricular septum. Third, he recognized that the heart valves are competent and thus vital blood cannot return to the lungs. Since all organs of the body are in need of vital spirits, how else could the lung receive them except by the aorta and pulmonary circuit (apparently, Colombo did not identify the bronchial arteries, though Leonardo had described them some years earlier)? His observations were reported in a posthumous publication in 1559. Colombo made no reference to the work of Ibn al-Nafis or Servetus, and was probably unaware of their contributions (indeed, Harvey would later allude only to the work of Colombo). It is important to point out that neither Servetus nor Colombo overthrew Galenic doctrine. Both continued to maintain that only a small amount of the venous blood was diverted to the right heart (and hence the left ventricle). Most of the blood remained in the vena cava and was distributed centrifugally to the periphery. The pulmonary circuit simply replaced the septal pores as a means of transferring blood from the right to left ventricles. Girolamo Fabrizio (also known as Fabricius, 1537–1619), professor of anatomy at Padua when Harvey studied there, identified venous valves in 1574 and published a description of them in 1603. As an adherent of Galenism, Fabricius proposed that the valves function to slow the centrifugal flow of blood to the periphery. In other words, they serve to prevent forceful, excessive outward movement of blood due to gravity and peripheral attraction to the lower part of the limbs at the expense of under-nourishing the upper parts. This was only a minor departure from Galen, who believed that the flow of blood was controlled by the attractive power of the parts, which drew blood as needed. In 1571, Andrea Cesalpino (also known as Caesalpinus, 1519–1603), a former student of ColomboÕs and now a professor of medicine at Pisa, confirmed the existence of the pulmonary circuit. In a departure from his predecessors, he posited that the heart, and not the liver, is the main source of nutriment. Cesalpino envisioned that veins carry some (but not all) of the nutriment from the gut and liver to the heart where it receives its final perfection and is then distributed to the body through the arteries. The rest of the venous blood moved centrifugally from the liver to tissues. Caesalpinus envisioned that (only under certain circumstances, such as with the use of a ligature or tourniquet) blood would pass from the arteries to the veins in the periphery. Although he came close to describing the circulation, Caesalpinus still viewed the system as providing one-way delivery of nutriment to the tissues. In 1627, Cesare Cremonini developed a quantitative argument implicating a role for arteries not just as a vehicle for heat and spirit but also as an instrument of nutrition. He pointed out that arterial blood, once generated is diffused in Ôgreat quantityÕ to the entire body. He asked what becomes of it if it is 124 W. C. Aird always generated but not consumed as nutrient. Surely it would grow to infinity, he concluded. In summary, the revival of experimental investigation in the 1500s, while opening the door to progress, did not lead to the downfall of GalenÕs system of physiology. So persuasive was GalenÕs theory that these new findings were simply integrated as small modifications into the ancient scheme. William harvey Harvey the man William Harvey was born in 1578 AD in Kent, England. In 1593, he matriculated as a student at Gonville and Caius College, Cambridge, where he studied classics, rhetoric and philosophy. After receiving his Bachelor of Arts degree in 1597, Harvey studied medicine at Padua in Italy, the greatest medical school of the time. The curriculum at the time revolved around GalenÕs physiology and anatomy and AristotleÕs physiology. In Padua, Harvey studied under Fabricius, and it is likely that he saw a demonstration of the venous valves well before their discovery was published in 1603. It is noteworthy that while Harvey was at Padua, Galileo occupied the chair of mathematics. The extent to which Galileo influenced HarveyÕs approach to experimental research is debated. Harvey returned to England in 1602, and in 1604 was appointed Assistant Physician at St. BartholomewÕs Hospital. In 1615, Harvey was appointed Lumleian Lecturer (a lifetime appointment) at the Royal College of Physicians. In this capacity, Harvey lectured twice a week at the College in anatomy and surgery in 6-year cycles. HarveyÕs lecture notes from 1616, which have been preserved, attest to the early seeds of his theory of the circulation. In 1628, Harvey published his findings in a modest 72-page book written in Latin, entitled Exercitatio Anatomica de Motu Cordis et Sanguinis in Animalibus (which translates as Anatomical Exercises on the Motion of the Heart and Blood in Animals). He published two rebuttals to his critics in 1649. Harvey served as Physician to the King (initially James I, then Charles I). He married but had no children. He died in 1657 at the age of 79. HarveyÕs sources and methodology Harvey realized that observation, while key to the scientific method, must be followed by the formulation of a hypothesis [9,12]. The validity of that hypothesis, in turn, requires repetitive, directed experiments. In this respect, Harvey was a modern thinker. However, he remained partly embedded in the ancient doctrine. He was a great admirer of Aristotle, adopting his teleological ideas, his program in comparative anatomy and some of his views on the natural world, including its vitalistic core. Like Aristotle, Harvey saw the unity of various circular motions in the universe and parallelism between microcosm and macrocosm. Circular movement symbolized perfection, perpetuity and preservative qualities. Indeed, this analogy may have been critical to HarveyÕs reasoning. Harvey inherited AristotleÕs use of observations and deductive logic to acquire new knowledge. Consistent with his hypothetical-deductive approach, Harvey did not use teleology as final proof, but rather as a means to establish testable premises. That being said, he did not shy away from occasional teleological arguments. For example: 1 If Nature does nothing in vain, she would not have added the right ventricle for the sole purpose of nourishing the lungs. 2 But Nature did add a right ventricle. 3 Therefore, Nature added the right ventricle for another purpose. Early in his career, Harvey did not outright discard Galenic doctrine. Indeed, much like his Renaissance predecessors, he initially aimed to advance or push forward the work of the Ancient Greeks. Although Harvey would eventually replace the Galenic system of physiology with a new model, he continued to espouse an essentially vitalistic and qualitative picture of the human body. However, it is important to point out that Harvey was careful to distinguish what he considered fact (e.g., the circulation of blood) from what he considered speculation (e.g., the purpose of the circulation of blood). Finally, Harvey leveraged his rhetorical skills, social standing, and his connection with the Royal College and the Court to promulgate his new theory. HarveyÕs view on Nature Like the Ancient Greeks, Harvey viewed the body as being moved by vital forces and comprising humors. In contrast to Galen, who assigned primary importance to formed organs, Harvey believed in the primacy of the blood. For Harvey, blood was not only nutriment, but also the ultimate repository of heat and spirits. He believed that the spirits in the veins and arteries were not distinct from the blood Ôany more that the flame of a lamp is distinct from the inflammable vapor that is on fireÕ. The blood is imbued with spirit much like wine contains spirit. ÔFor a wine, when it has lost all its spirit, is no longer wine, but a vapid liquor or vinegar, so blood without spirit is not blood, but something elseÕ. Harvey rejected mechanical explanations that were emerging as part of the Scientific Revolution, led by such contemporaries as Galileo, Rene Descartes and Francis Bacon. The scientific revolution rejected the Ancients wholesale, and ushered in an era of mathematics, mechanization and an atomic theory. The world was no longer seen in qualitative terms but rather in mathematical terms. For example, the terms ÔhotÕ or ÔcoldÕ were represented by numbers on a temperature scale. According to the atomic theory, matter could be broken up into discrete entities, which were not cold, hot, dry or wet, but rather possessed quantities of length, breadth, depth and motion. These elements interacted with one another in a mechanical manner. Particles interacted and reacted according to laws of physics, not according to a final cause. As such, the human body came to be seen as complex machine. These uncompromising views contrasted with HarveyÕs vitalistic leanings. 2011 International Society on Thrombosis and Haemostasis Discovery of the cardiovascular system 125 HarveyÕs description of the movement of the heart and arteries Against skin breathing As pointed out earlier, the Ancient Greeks believed that arteries suck in air during diastole and expel fuliginous vapors during systole through the pores of the flesh and skin [10,13–16]. Harvey argued that if arteries are filled in diastole with air, then why when one plunges into a bath of water or oil, does the arterial pulse not become smaller or slower, since the bath will interfere with the uptake of air? Moreover, how do those arteries that lie deep within tissues absorb air during diastole? How does the fetus draw air into its arteries through the abdomen of the motherÕs abdominal wall, and how do deep diving mammals absorb air through the infinite mass of water? How is it that during systole, arteries expel vapors, but not vital spirits? If arteries attract blood from the left ventricle during arterial diastole, how can they at the same time attract air from the body surface? Arterial pulse is due to impulses of the blood from the left ventricle Harvey criticized GalenÕs experiment with the reed, even doubting that the experiment was ever carried out. Indeed, we learn later (in his letters published in 1649) that Harvey repeated the experiment and found the opposite, namely that the artery distal to the ligatured segment containing the tube continues to pulsate. When an artery is cut, blood spurts out and escapes with force, alternately in jets, with the jets corresponding to arterial systole (when the arteries are dilated). The jets occur only from the orifice closest to the heart. If arterial dilatation serves to suck in air, as Galen would have it, the severed artery should not Ôthrow blood to such a distanceÕ. Just because the arterial wall is thick does not mean that the pulsatile property proceeds along them from the heart. In fact, we observe a normal pulsation in arterial aneurysms, where the coat is attenuated. (In a communication that was published in 1649, Harvey tells us about the case of a patient of his who had evidence of a calcified aorta at autopsy yet who had demonstrated a pulse in the legs and feet during life). Contraction of the ventricles occurs at the same time as the arteries are distended. When the heart stops beating, the arteries lose pulsation. Blood spurts from a severed artery at the same time that the heart contracts. Thus, in contrast to what the Ancients believed, contraction (systole) of the heart occurs simultaneously with dilatation (systole) of the arteries. ÔThe arteries, therefore, are distended, because they are filled like sacs or bladders, and are not filled because they expand like bellowsÕ. The arterial pulse can be compared to Ôblowing into a glove and producing simultaneous increase in volume of all its fingersÕ. Harvey attributed arterial diastole to an inherent property of the vessel wall (which we know today to involve elastic recoil). ÔThus the arteries are dilated by the heart, but subside of themselvesÕ. Clinical evidence for this conclusion was provided by the observation that patients with compression or infarction of the artery results in reduced pulsation distally. 2011 International Society on Thrombosis and Haemostasis Arteries and veins contain the same blood The Ancient Greeks believed in a dual system of veins and arteries. Galen proposed that veins contain blood, whereas arteries contain blood imbued with vital spirits. Harvey believed that both arteries and veins contain the same blood. Indeed, arterial and venous blood, when removed from the body and allowed to sit in a basin, demonstrate the same color, similar consistency in the coagulated state, and the same height (volume) when cooled. Harvey wrongly attributed the redder color of freshly removed arterial blood to the fact that the thick arterial coats render the outlets smaller and that these smaller orifices act like a sieve, allowing escape of the lighter, thinner part of blood. He even claimed that in obese patients, subcutaneous fat compresses the veins so that phlebotomy yields thinner, more florid blood, not unlike that of an artery. Although arteries and veins contain the same blood, Harvey acknowledged that arterial blood is more spirituous and Ôpossessed of higher vital forceÕ. The blood and spirits do not flow in the arteries separately but as one body. Against the right ventricle serving merely to supply nourishment to the lungs In the Galenic system, the right ventricle serves a Ôprivate functionÕ, namely to provide the lung with nourishment (blood). In contrast, the left ventricle is designed for the egress of vital spirits and regress of fuliginous vapors. However, both ventricles are structurally similar and display comparable action, motion and pulse. How, Harvey asked, can we explain the dichotomy in function of identically structured right and left ventricles? Moreover, the pulmonary artery and vein are roughly the same size, and so it seems unlikely that the former serves a private function (providing nourishment to the lung) and the latter a public function (providing pneuma to the left ventricle). If only a portion of blood from the vena cava reaches the right ventricle (the rest proceeding to the superior vena cava), then why is the pulmonary artery so large, in fact of greater capacity than both iliac veins? Why was ÔNature reduced to the necessity of adding another ventricle for the sole purpose of nourishing the lungsÕ? Why does the lung require so much nourishment and why does the nutriment for this organ (but not others such as the brain and eyes) require additional concoction in the right ventricle? Against the left ventricle serving for egress and regress of spirits Harvey called into question GalenÕs claim that the left ventricle draws in air and expels vapors through the same blood vessel (the pulmonary vein). If the mitral valve allows retrograde flow of such vapors, how can it prevent the escape of air? If the pulmonary artery has the single purpose of delivering blood to the lungs, why should we presume that the pulmonary vein (which is almost as large and has the coats of a vein) has multiple functions (e.g., air passing from the lungs into the left ventricle and vapors passing from the left ventricle into the lungs)? Why would Nature construct a single vessel for opposing flow of air and vapors? If the pulmonary vein serves as a conduit for air and vapors, why when it is cut does one only see blood? If the pulmonary 126 W. C. Aird artery was designed for conveyance of air, then why is it structured as a blood vessel, and not like the annular bronchi? Against the transit of blood from the vena cava to aorta through holes in the interventricular septum Galen held that vital spirits require both air and blood and that blood entered the left ventricle via hidden porosities in the interventricular system. Like Vesalius and Colombo, Harvey could not demonstrate these septal pores. He went a step further and claimed that they simply did not exist. He pointed out that the septum is denser and more compact than most parts of the body. Moreover, given that the right and left ventricles contract and dilate simultaneously, how can one ventricle extract substances from the other? Why should these foramina permit exchange of blood from right to left sides, but not of air from left to right? Why do we need to invoke invisible channels when the pulmonary vein and the lax, soft, spongy substance of the lung offer an open route? There are examples in nature whereby blood is transferred from veins to arteries through visible open passages. For example, in fish, the heart consists of a single atrium and ventricle through which blood readily passes from the venous trunk to aorta. In the mammalian fetus, blood is transferred from the venous to arterial side through visible, conspicuous patent channels, namely the foramen ovale and the ductus arteriosus. When these close postnatally, why would Nature replace them with invisible pores in the septum? Why not accomplish the same though the substance of the lungs? Finally, if blood permeates the septum, why then is the septum supplied by coronary vessels? In favor of pulmonary transit of blood from vena cava to aorta In addition to the points outlined above, Harvey argued that if the whole of nutritive juices pass through the liver, then surely the whole of blood can pass though the lungs. After all, the liver is dense, while the substance of the lung is loose and spongy. Moreover, in contrast to the liver, which has no impelling power, the lung receives blood under force from the right ventricle. Finally, the pulmonary valves prevent blood from returning to the heart from the pulmonary artery. Harvey concludes that Ôblood is continually permeating from the right to left ventricle, from the vena cava into the aorta, through the porosities of the lungsÕ. (Marcello Malpighi would later use light microscopy to identify these porosities as capillaries). Nature added the right ventricle not to nourish the lungs, but to propel blood through the lungs into the cavity of the left ventricle. The intrinsic motion of the heart is systole, not diastole The heart is erected and rises upwards and strikes the chest wall when contracted. When grasped in the hand, the heart becomes harder during contraction, creating a tension that is similar to contracting skeletal muscle. A contracted heart becomes paler in color. When the ventricle is pierced, blood is forcefully projected outwards when the heart is contracted. Thus, Harvey states: Ôone action of the heart is the transmission of the blood and its distribution, by means of the arteries, to the very extremities of the bodyÕ. In addition to this action, Harvey speculates that there may be other functions, including adding heat, spirit or perfection to the blood, but decides not to address these questions. Quantity of blood is too great to be explained by open system of blood vessels A major obstacle that Harvey faced as he collected his data was that any findings could be interpreted as an artifact of the system, as an unusual or pathologic pattern of blood flow. Any outside influence on the system could alter the rate and/or direction of normal blood flow. He needed quantitative proof in the intact organism. Harvey asked himself: Ôwhat might be the quantity of blood which was transmittedÕ by the heart? He carried out what amounted to a thought experiment. He had found that the left ventricle contained up to 2 ounces of blood. He then assumed different ejection fractions (1/4, 1/5, 1/6 or 1/8) and multiplied the resulting stroke volume by the heart rate (which he estimated as only 33 per min). In this way, he arrived at a cardiac output that exceeded the total volume of blood in the whole body (between 3.9 and 31 kg per 30 min, values that vastly underestimate the true cardiac output, but nonetheless exceed the total volume of blood in the body). Importantly, more blood passes through the heart than can be supplied by the food consumed or that can be contained in veins at the same moment. Moreover, the quantity of blood must be far greater than that required for nutrition (a process by which blood is assimilated, becomes coherent and transforms into the substance of the tissue). In an open-ended system of arteries, this large quantity of blood would cause the arteries to rupture. Thus, Ôit is matter of necessity that the blood perform a circuit, that it return to whence it set outÕ. Stated another way, blood must continually return to the heart to provide for the quantitative requirements of the heartbeat. To prove this point, Harvey tied or used his fingers to constrict the veins entering the heart of fish or a snake and noted that the space between the constriction and the heart, as well as the heart itself became empty and pale (Fig. 2). On the other hand, compression of the aorta caused the heart to become distended and blue-purple in color. These changes were reversed with loosening of the constriction. Blood enters a limb by arteries and returns from it by veins Harvey employed two types of ligatures (tourniquets) on the arm (Fig. 3). The first was a tight ligature that compresses both the arteries and veins, resulting in loss of pulsation beyond the ligature. The tight ligature was used clinically to stem the flow of blood during amputations, for the castration of animals and for the ablation of tumors. The other was a ligature of medium tightness, which compresses the veins but not the arteries. The arterial pulse can still be palpated distally. This type of ligature was used clinically in bloodletting. The Ancient Greeks believed that with the medium-tight ligature, more blood was attracted to the distal arm via the veins (a similar argument was made for heat, pain and a vacuum drawing blood). Hippocrates wrote: Ôligatures set the 2011 International Society on Thrombosis and Haemostasis Discovery of the cardiovascular system 127 Fig. 2. Proof that arteries receive blood from veins by transmission through the heart. (A) Tying the veins below the 2-chambered heart of a fish, Harvey recognized that the space between the ligature and the heart quickly becomes empty, thus indicating that blood returns to the heart. (B) Harvey described seizing the vena cava of a live snake (laid open) between the finger and thumb. He found that the part that intervenes between the fingers and the heart almost immediately becomes empty, while the heart becomes smaller and paler in color. The size and color of the heart return to normal when the impediment to flow is removed. On the contrary, if the aorta is compressed, the heart becomes inordinately distended and assumes a deep purple or even livid color. These changes are reversed when the obstacle is removed. Harvey concluded: ÔHere then we have evidence of two kinds of death: extinction from deficiency, and suffocation from excessÕ. (C) Harvey claimed that if the aorta of a dog or a sheep be tied at the base of the heart, and the carotid or any other artery be opened, the artery will be empty and the veins Ôreplete with bloodÕ. This is consistent with the notion that Ôarteries receive blood from the veins in no other way than by transmission through the heartÕ. blood in motionÕ. In the case of the tight ligature, Harvey noted that not only is the distal pulse lost, but also the artery proximal to the tourniquet rises higher with each systole, throbs more violently and seems fuller. When the ligature is loosened so that it is of medium tightness, the pulse can now be felt. The hand and arm become deeply colored and distended, engorged with blood. The subject reports a sensation of warmth. In contrast, the veins above the ligature are not swollen. Based on his observations with ligatures, Harvey concluded that blood enters the arm by the arteries and leaves by the veins. Blood must pass from arteries into veins through anastomoses or porosities of the flesh. According to Harvey, blood is forced upwards through the veins by virtue of muscle action in the extremities. 2011 International Society on Thrombosis and Haemostasis Venous valves promote centripetal flow of blood from the lesser to the greater veins Fabricius discovered that veins contain valves. The valves of veins are directed upwards or towards the trunks of veins. Fabricius believed that the valves serve to hinder gravity-dependent outward flow of blood. Harvey commented that even veins that are not subjected to gravity effects in the upright, erect position contain valves. Moreover, if blood flows centrifugally, why would its passage from larger to smaller veins not be sufficient to retard flow? Harvey was unable to pass a probe through a large vein into a smaller vein, whereas he readily passed a probe in the opposite (outer to inner) direction. Harvey then used a series of ligature experiments to prove that the venous valves prevent retrograde centrifugal flow of blood in the veins. 128 W. C. Aird Fig. 3. Schematic of HarveyÕs experiments with ligatures. Harvey employed tight ligatures (top) to compress the arteries and veins leading to the hand or medium-tight ligatures (bottom) to compress the veins only. The tight ligature results in reduced arterial blood flow to the extremity (denoted by dotted red line), loss of pulse at the wrist and a cold hand. The arteries proximal to the ligature become distended (denoted by thickened red line). The medium-tight ligature results in unimpaired arterial flow of blood to the extremity, but impaired venous drainage. Thus the arterial pulse at the wrist is intact, while the distal veins are distended (denoted by the thickened blue line). The hand becomes swollen and deeply colored. V, vein; A, artery. Blood is transferred from veins to arteries by way of porosities in the tissue Harvey stated his belief that blood moves from the right to left ventricle via minute inosculations of vessels or hidden porosities in the lung. Similarly, in the extremities, Harvey considered that the blood passes from arteries to veins either through arterial-venous anastomoses or by the porosities of the flesh that are permeable to blood. Harvey would later write: ÔI have never succeeded in tracing any connection between arteries and veins by a direct anastomoses of their orificesÕ. Rather, the blood is ÔurgedÕ from the porosities into the small veins by virtue of the impulse of the blood. Thus, contrary to popular belief, Harvey did not favor the existence of a direct connection (i.e., capillaries) between veins and arteries. HarveyÕs legacy Today, HarveyÕs theory of blood circulation is widely recognized as the foundation for modern medicine [17,18]. However, at the time, his discovery was met with skepticism. The theory was controversial because it ran counter to the existing dogmas of the time. Anticipating the opposition to his revolutionary theory, Harvey wrote in his book: Ô… not only do I fear danger to myself from the malice of a few, but I dread lest I have all men as enemiesÕ. Many of HarveyÕs detractors were invested in ancient doctrine. What was the purpose of the circulation when the whole process would lead to re-cooking of the blood and its conversion to bile? In fever, wouldnÕt the circulation repeatedly deliver putrid material to the whole body? Where were the arterial-venous anastomoses in the tissues that HarveyÕs theory demanded? DidnÕt Harvey vastly overestimate the cardiac output, because blood was boiled in the heart and thus was volumetrically expanded? Perhaps the violent, painful deaths suffered by research animals interfered with natural conditions. Could HarveyÕs findings in animals be rightly extrapolated to humans? What was the divine rationale for the circulation? Beyond the intellectual realm, it would take even longer for HarveyÕs discovery to have a practical impact. Part of the reason was that Harvey was most interested in reporting the facts, without speculating on their therapeutic implications. Some argued that the new theory lacked any clinical relevance. What were they to tell their patients, whose expectations were based on a doctorpatient relationship steeped in ancient doctrine? Like alternative medicine today, humoral medicine had the advantage that it was tailored to the individual patient. Was it reasonable to abandon longstanding successful therapies simply because of a change in the underlying theoretical rationale? The controversy surrounding HarveyÕs model for the circulation of blood would persist until MalpighiÕs discovery of capillaries in 1661. Its impact on clinical practice would not be realized until well after HarveyÕs death.2 Conclusion In todayÕs world it seems unfathomable that there was ever a time when blood was not known to circulate. Yet the circulation of blood eluded investigators until the 1600s. Both Galen and Harvey were brilliant thinkers, far ahead of their time. Both received the best education in their day. Both were clinicianscientists, driven by a search for the truth. They understood the value of anatomical dissection and comparative anatomy. True, 2011 International Society on Thrombosis and Haemostasis Discovery of the cardiovascular system 129 Harvey had access to human corpses, whereas Galen did not. But the discovery of the circulation was in no way contingent upon human dissection. From a technological standpoint, there was little to separate the two. Both had access to dissecting instruments and tourniquets. Neither one had the benefit of a microscope. So what did Harvey possess that Galen lacked? First, he inherited a different knowledge base. Galen took as his starting point the work of the Hippocratic investigators as well as that of Herophilus and Erasistratus. He set out to synthesize and build on established models of physiology and disease. Harvey benefited from key observations (i.e., clues) on the part of his predecessors, including VesaliusÕs insistence that he could not find pores in the interventricular system, FabriciusÕs demonstration of the venous valves, and ColomboÕs ÔdiscoveryÕ of the pulmonary transit. However, rather than integrate these findings into a Galenic framework, Harvey leveraged them to support a new theory of blood circulation. Second, unlike so many of his predecessors, Harvey was prepared to challenge dogma and authority. Although deferential to the Ancient Greeks, he was willing to reject their doctrines. Third, Harvey benefited from an emerging intellectual environment that stressed the importance of experimental reproducibility and quantitation. Harvey was far more interested in proximate, mechanical explanations than he was in teleological causes. Finally, in their use of analogies to represent the cardiovascular system, Galen and Harvey may have been influenced by the technologies of their day. Galen was interested in comparisons with smithÕs bellows. In contrast, Harvey was likely to have been informed by force pumps, which were common in his time. In the final analysis a confluence of circumstances – largely out of their control, and apparent only with the benefit of hindsight – is responsible for Harvey being ÔrightÕ and Galen being ÔwrongÕ. In contrast to HarveyÕs pro-Galenic critics, it is tempting to speculate that had Galen himself read HarveyÕs little book of 72 pages, he would have embraced its conclusions with uncommon fervor and praise. Galen was keen to observe and understand. He recognized differences in the structure of blood vessels in different parts of the body. He saw that arteries and veins contain different kinds of blood. For Galen there was a dynamic complexity in the system whereby the delivery of blood (with its humors and spirits) matched the needs of the underlying tissue. GalenÕs system was ÔaliveÕ and vital. By contrast, HarveyÕs circulation was more mechanical, being centered on a force pump, the heart, which delivered a relatively constant amount of blood around and around the body through a series of conduit vessels. There was a certain monotony and periodicity to his system. Arterial and venous blood was identical and there was little reference to vascular diversity, save for the venous valves. Today, a fuller understanding of the vasculature and its endothelial lining points to something far more complex than HarveyÕs system. Venous and arterial blood is indeed different. Blood does not simply circulate around and around the body, but is dynamically regulated in content and flow. The structure and function of the vasculature differs between different organs. Sometimes the reason to study history is not to learn to avoid 2011 International Society on Thrombosis and Haemostasis past mistakes but in fact to return to past questions. Perhaps GalenÕs complexity gets at something that is really right. Acknowledgements The author wishes to thank Vivian Nutton and Jane Maienschein for critically reviewing the manuscript and for their helpful suggestions. See [19–22] for additional recommended reading. Disclosure of Conflict of Interest The author states that he has no conflict of interest. References 1 Nutton V. Ancient Medicine. London; New York: Routledge, 2004. 2 Hankinson RJ. The Cambridge Companion to Galen. Cambridge, UK; New York: Cambridge University Press, 2008. 3 Nutton V. Portraits of science. Logic, learning, and experimental medicine. Science 2002; 295: 800–1. doi: 10.1126/science.1066244295/ 5556/800 [pii]. 4 Galen, De Lacy P. On the Doctrines of Hippocrates and Plato. Berlin: Akademie-Verlag, 1978. 5 Galen, May MT. Galen on the Usefulness of the Parts of the Body. Peri chreias mori*on [romanized form] De usu partium. Ithaca, NY: Cornell University Press, 1968. 6 Galen, Furley DJ, Wilkie JS. Galen on Respiration and the Arteries. Princeton, NJ: Princeton University Press, 1984. 7 Galenus, Singer CJ. On Anatomical Procedures. London, New York: Published for the Wellcome Historical Medical Museum by Oxford University Press, 1956. 8 Key JD, Keys TE, Callahan JA. Historical development of concept of blood circulation. An anniversary memorial essay to William Harvey. Am J Cardiol 1979; 43: 1026–32. 9 Pagel W. The philosophy of circles-cesalpino-Harvey; a penultimate assessment. J Hist Med Allied Sci 1957; 12: 140–57. 10 Bylebyl JJ. The growth of HarveyÕs De motu cordis. Bull Hist Med 1973; 47: 427–70. 11 Siraisi NG. Medieval and Renaissance medicine: continuity and diversity. J Hist Med Allied Sci 1986; 41: 391–4. 12 Ghiselin MT. William HarveyÕs methodology in De motu cordis from the standpoint of comparative anatomy. Bull Hist Med 1966; 40: 314– 27. 13 Harvey W. On the Motion of the Heart and Blood in Animals. Chicago: H. Regnery Co., 1962. 14 Bylebyl JJ. William Harvey, a conventional medical revolutionary. JAMA 1978; 239: 1295–8. 15 Bylebyl JJ. Nutrition, quantification and circulation. Bull Hist Med 1977; 51: 369–85. 16 Bylebyl JJ. The medical side of HarveyÕs discovery: the normal and the abnormal. Henry E Sigerist Suppl Bull Hist Med 1979; 2: 28–102. 17 Lubitz SA. Early reactions to HarveyÕs circulation theory: the impact on medicine. Mt Sinai J Med 2004; 71: 274–80. 18 French R. Harvey, clinical medicine and the College of Physicians. Clin Med 2002; 2: 584–90. 19 Pagel W. William HarveyÕs Biological Ideas; Selected Aspects and Historical Background. New York, NY: Hafner Pub. Co., 1967. 20 Whitteridge G. William Harvey and the Circulation of the Blood. London, New York: Macdonald; American Elsevier, 1971. 21 French RK. William HarveyÕs Natural Philosophy. Cambridge, UK; New York: Cambridge University Press, 1994. 22 Singer CJ. A Short History of Anatomy from the Greeks to Harvey. New York, NY: Dover Publications, 1957.
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