KeywordsCirculation modelsLeft ventricular modelGuyton’s venous return modelCardiac outputWeber’s circulation modelPeripheral resistanceElastic recoilMean circulatory pressureOhm’s lawHeart failure therapyAortic balloon pump
Models are used to simplify a group of observable events into readily understandable concepts. Over the years, numerous models of circulation have been developed in an effort to elucidate fundamental hemodynamic principles. They attest to ingenuity on the part of investigators but also point to the complexity of the subject at hand. Because the heart is the organ which is thought to provide the total hydraulic energy to the blood, the idea of the heart as a pressure-generating pump is implicit in most commonly used models. Just how much of a role the heart plays in blood propulsion and the relative contribution of the peripheral circulation in the regulation of cardiac output continue, however, to be the subjects of the ongoing debate [1–5]. Because of the multitude of factors which contribute to the regulation of cardiac output, the subject will be approached from the two commonly used perspectives: that of the heart and of the peripheral circulation .
14.1 Left Ventricular View of the Circulation
I do not believe that the heart is the fashioner of the blood, neither do I imagine that the blood has powers, properties, motion, or heat as the gift of the heart…for I hold that the part of the pulse which is designated the diastole depends on another cause, different from the systole, and must always and everywhere precede any systole. I hold that the innate heat is the first cause of dilatation and that the primary dilatation is in the blood itself…. 
It appears that, for Harvey, the cause of motion is different, for blood entering or leaving the heart. The atria distend (i.e., atrial diastole), under the impetus of the blood’s “innate heat,” whereas the ventricles are “impellers” of the blood that is already in motion … “much like a ball player can strike the ball more forcibly and further if he takes on the rebound” .
Harvey, an avid Aristotelian, evidently sought a wider explanation for his newly discovered circulatory phenomena in the Aristotelian concept of circular motion as the archetype of all movement .1 According to Pagel, application of analogies between macrocosm and microcosm already had a long tradition as is evident from a statement by Harvey’s contemporary Giordano Bruno in 1590 that “in us blood continually and rapidly moves in a circle” . A similar idea is expressed by Harvey in the following passage: “Which motion (of the blood) we may be allowed to call circular, in the same way as Aristotle says the air and the rain emulate the circular motion of the superior bodies (planets),” or from the statement, “The heart, consequently, is the beginning of life; the sun of the microcosm, even as the sun in his turn might well be designated the heart of the world” .
Harvey’s discovery of circulation was based upon two key phenomena, namely that venous blood flows in the direction of the heart (as confirmed by direct observation of blood flow in animals and from the structure and directionality of venous valves) and the fact that far greater volume of blood flows through the heart than can be supplied from absorption of nutrients.2 In support of the latter, Harvey resorted to a thought experiment. He made an estimate of cardiac throughput (by multiplying an estimated ventricular volume by the number of beats per unit time) and had an intuitive insight that the blood must move in circles. Notwithstanding the fact that Harvey’s arguments went against the grain of long-established theories (see Sect. 15.3), the sheer number of observed phenomena, meticulously documented and supported by a quantitative estimate, were innately consistent and in due course confirmed the proposed theory.
It is ironic that Rene Descartes (1596–1650), Harvey’s contemporary, was one of the first natural philosophers to embrace Harvey’s revolutionary circulation theory and widely promoted it, although in altered form, through his writings . Unlike Harvey, known for his meticulous observations and inductive method of investigation, by which sense perceptible phenomena are analyzed in light of primal (Aristotelian) principles, Descartes employs a method of a priori (deductive) reasoning, where scientific truths are derived from what is known “clearly and distinctly” to the intellect.3 Descartes’ physiological and cosmological doctrines are first presented as “hypotheses” which serve as “models” of the universe and of the organism in the modern sense. The blood, for Descartes, is no longer a “vital fluid” but only a mixture of materials and a collection of special food particles which serve as fuel for the fire maintained by the heart. The concept of “vital heat” is reduced to a continuous process of combustion—a mere physical-chemical event. Mechanical analogies, if any, implied by Harvey for the explanation of circulatory phenomena become explicit and central in Descartes’ writings . The ultimate aim of Descartes’ natural philosophy was to identify material causes and define mechanical laws that are applicable with equal measure to an organism as well as to a mechanism. In this sense, “The mechanical no longer represents an element within vital organization; through the paradigm of the automaton, it embraces the organism itself” (emphasis by T. Fuchs) .
Thus, the heart (and, by extension, the entire body) could no longer be the source of any emotion that could be considered uniquely human, since the bodily mechanics of emotions were obviously quite similar in humans and in animals. 
By all accounts, Harvey, too, “despised” the mechanistic philosophy that had facilitated the success of his circulation theory and confronted Descartian and Baconian philosophers head-on by writing his most comprehensive work well over two decades after “De Motu Cordis” (1628). “On Generation of Living Creatures” (1651) contains a summary of Harvey’s life-long research efforts, “a sort of apotheosis on the blood” . In spite of his enormous efforts, Harvey and his adherents were not a match to the advent of the new mechanical-intellectual tide that swept across Europe after the 1640s, which rejected vitalist and Aristotelian principles and sought to interpret the living phenomena through mechanical associations that necessarily follow from the laws of nature.6
Giovanni Borelli (1608–1679), recognized as the father of modern biomechanics, emphasized hydraulic properties of the circulation and proposed that the heart acts like a piston ejecting blood into flexible tubes, the arteries. In a treatise “On the Movement of Animals” (1680), Borelli compared the work of the heart to the skeletal muscle and calculated that the motive force exerted by the heart is equal to supporting an excess of 3000 lb . Others applied an array of mechanical contraptions to explain the circulation, for example, Johannes Bohn (1697) who stated: “What a hydraulic pump or piston achieves, the heart brings about in the living machine and the circulatory movement of all liquids. Just like the former does with water, so the latter gives the blood its first impulse by driving it forward. When the heart and pump stop, the fluids of both also stand still” (cited in ).
The first quantitative estimations of arterial pressure were performed by Stephen Hales (1677–1761) by means of inserting glass tubes into the arteries of several species of animals. In a series of papers published in 1733 by the Royal Society as Statical Essays: containing Haemastatics, Hales described the measurement of pressure on the carotid artery of a mare, estimated ventricular volume from wax casts of hearts, and deduced aortic flow velocity in a dog . Needless to say, such interventions almost invariably ended with demise of the experimental animal, and no other method was available for the estimation of arterial pressure for clinicians except by surgical exposure of the artery. Hale’s ability to conceive the blood as a “pressurized liquid” that could be defined in terms of hydraulics is dependent to a large extent on the prior work of Pascal.
Almost a century later (1828), J. Poiseuille (1797–1869) applied the use of mercury manometer for the measurement of the arterial pressure by connecting a manometer tubing to an arterial cannula filled with an anticoagulant. The insight by Karl Vierordt (1855) that arterial pressure can be measured indirectly by registering the amount of force needed to occlude the artery was a breakthrough. Vierordt’s sphygmomanometer was an ingenious device working on the principle of a scale, with cups and levers attached to a kymograph. The pressure in the radial artery was determined by the amount of weights needed for its occlusion. Several improvements on the method followed which eventually led to S. Riva-Rocci’s invention of a pneumatic cuff applied round the girth of the arm (1896) . Ease of application, accuracy, and harmlessness to the patient ensured widespread popularity and use of the technique. The unintended consequence of the invention was that clinicians increasingly lost appreciation for the nuances of the arterial pulse, which in addition to pressure yielded a number of other qualities about the state of the cardiovascular system (cf. Sect. 22.1) While hailed by some, an editorial in the British Medical Journal at the time held the view that the use of sphygnomanometer “pauperizes our senses and weakens clinical acuity” .
If we take the process of the circulation of the blood with the greatest generality, then we are dealing with the movement of the fluid through the tubes, which in a circular way, turn back onto themselves, and with the course of this movement in a certain amount of time. This task is of a purely mechanical nature; nothing prevents the assumption that the heart’s pump, as a mechanical middle, is adequate to solve this task. The heart is a pump and possesses as such enough force to drive the mass of blood in a circular movement through the entire vascular system. (cited in )
Although the physical conditions under which Poiseuille’s law is applied are implicit in the method by which it was derived experimentally, it was nevertheless applied widely to circulation phenomena and formed the framework for the pressure-propulsion theory .
The idea of resistance is unambiguous when applied to rigid tubes perfused by homogenous fluid flowing in a laminar stream…complexities are introduced when these concepts are extended to the pulmonary (as well as to systemic) circulation: the vascular bed is a non-linear, visco elastic, frequency-dependent system, perfused by a complicated non-Newtonian fluid; moreover, the flow is pulsatile, so that the inertial factors, reflected waves, pulse wave velocity, and interconversions of energy become relevant considerations…as a result of many active and passive influences which may affect the relationship between the pressure gradient and flow, the term “resistance” is bereft of its original physical meaning: instead of representing a fixed attribute of blood vessel, it has assumed physiological meaning as a product of a set of circumstances. 
Since flow (CO) and pressures are readily obtained by invasive (and noninvasive) methods, this formulation (Ohm’s law for fluids) has found a widespread application among investigators and clinicians alike.7 The presence of such relationship is certainly suggested by experiments where the heart has been replaced by an artificial pump, and an increase in pump flow (output) results in increase in arterial pressure and a simultaneous decrease in central venous pressure [30–32] (see also Sect. 16.7). However, the problem arises when a causal relationship existing between voltage and current which are independently verifiable is transposed on to a complex system of conduits comprising the circulation. Such an oversimplification can give an erroneous idea about the state of organ perfusion in various hyperdynamic circulatory states, where low values of resistance are obtained in the face of decreased organ perfusion, leading to multiple organ failure. For example, in a patient with septic shock, a decrease in arterial pressure down to 50% of control, the vascular resistance may increase in a nonreactive bed such as the skin, but might decrease in the brain, heart, and skeletal muscle with overall resistance unchanged. Another example is about three times increase in cardiac output during dynamic exercise in highly trained athletes, in the face of decreased peripheral resistance to one third of its resting value, while maintaining normal or slightly decreased mean arterial pressures . Since the additional energy for blood propulsion during exercise is supposedly provided by contracting muscles (skeletal muscle pump), application of Ohm’s law to define global cardiovascular function is arguable .
It has become apparent over the years that, in fact, a far more complex relationship exists between the heart chamber filling pressures, aortic pressure, and cardiac output as purported by left ventricular (LV) view of the circulation. Numerous studies have failed to demonstrate significant correlation between CVP, pulmonary capillary wedge pressure (PCWP), and CO and call for a better understanding of clinical hemodynamics [35–39]. It is little surprising that treatment modalities  and classification of heart failure  and pulmonary hypertension have undergone through so many revisions .
Since its inception in the 1950s, the concept of PCWP has been subject to considerable debate. Among several criteria adopted at the time for deciding whether it is a dependable measure of left atrial pressure, none was found to be consistently reliable . The problems associated with the clinical application of PCWP in heart failure are well known (see  for review) and have lost significant ground to more dynamic Doppler studies. There is little appreciation among clinicians of the fact that pulmonary venous wedge pressure (PVWP) is, in fact, slightly higher than pulmonary artery wedge pressure (PAWP)  or that the pressure gradient between the mean PA pressure and LA can be as low as 1–2 mmHg , raising the question whether the pressure gradient across the pulmonary circuit is the sole driving force for the blood?
14.1.1 Heart Failure Therapy
The trends in pharmacologic therapy of acute heart failure syndromes are an eloquent example of a shift from treatment modalities in the 1960s and 1970s, which primarily support the pressure propulsion concept of heart’s action, such as the use of potent sympathomimetic amines (epinephrine, isoproterenol, and dopamine) [49, 50], to a ubiquitous use of vasodilators. In fact, the use of inotropes (dobutamine and milrinone) is currently reserved for the treatment of a minority of patients with severe systolic dysfunction who do not tolerate vasodilators due to hypotension . For example, data from ADHERE (Acute Decompensated Heart Failure national Registry)  trial showed that of 150,000 patients with acute heart failure, the systolic blood pressure was lower than 90 mmHg in fewer than 3% of patients, suggesting harmful effect. Of note, mortality in those treated with inotropes was higher (19%), in comparison with the group not receiving the inotropes (14%) . Accordingly, the clinical practice guidelines of the Heart Failure Society of America (HFSA), the American College of Cardiology Foundation/American Heart Association (ACCF/AHA), as well as the European Society of Cardiology (ESA) recommend the use of vasodilators and deemphasize the use of inotropes in the management of acute heart failure syndromes . From the range of available inotropes, dobutamine and milrinone are chosen for their significant vasodilatory effect. Of further interest is the fact that, in addition to standard treatment (diuretics and ACE inhibitors), the use of β-blockers is universally recommended in all patients with stable, mild, moderate, and severe heart failure with ischemic or nonischemic cardiomyopathies and reduced LV ejection fraction . Surely, such pharmacotherapy is counterintuitive, if the heart is supposed to be a pressure propulsion pump! According to this model, the β-blockers would further weaken the failing heart (pump), and the vasodilators decrease the pressure head needed by the pump in order to drive the blood around the circuit more effectively.
Ever since the introduction into clinical practice by Kantrowitz and colleagues in 1968, the intra-aortic balloon pumps (IABP) have been widely used in patients with myocardial infarction complicated by cardiogenic shock with the goal of improving coronary perfusion by afterload reduction, with concomitant increase in CO and perfusion to vital organs . The purported hemodynamic effect of IABPs was evidently based on the “heart as a pump model,” and over the years, the insertion of IABPs has become a standard of care (class I recommendation), in spite of several outcome studies showing their limited effectiveness . It is hardly surprising that recently published results of IABP-SHOCK II trial found no difference in 30-day mortality or hemodynamic improvement in patients in cardiogenic shock and early revascularization procedure, with or without the IABP . In the editorial accompanying this landmark study, O’Connor and Rogers question continued use of the IAPB and call for “development of novel and innovative strategies to treat this condition.” They further note that “The results of IABP-SHOCK II trial parallel those from many recent outcome trials that have challenged our understanding of the management of acute and chronic heart failure, including those regarding the use of pulmonary artery catheters and the role of revascularization in ischemic cardiomyopathy.” . On the basis of collective evidence, the joint American College of Cardiology, the American Heart Association, and the European Society of Cardiology downgraded recommendations and level of evidence for the use of IAPB in the treatment of cardiogenic shock from class Ib (should be used) to class IIb (may/can be used) . Finally, Su et al. in a 2015 meta-analysis of 17 studies examined the effectiveness of IABPs in the total of 3266 patients with acute myocardial infarction, with or without cardiogenic shock. Again, no significant difference in short- and/or long-term mortality was shown between patients receiving IABP support and controls. The presence or absence of cardiogenic shock did not influence the results .
Chronic heart failure is a global health problem affecting 30–50 million patients worldwide . In the Unites States alone, 5.1 million people are affected by chronic heart failure, with an additional 825,000 cases of newly diagnosed cases each year amounting to 1 million hospital admissions at an estimated cost of $30 billion . In spite of significant advances in the treatment of acute coronary syndromes in the past 30 years, the 5-year overall mortality of chronic heart failure patients of around 50% remains unacceptably high . Surprisingly, the development of new drugs for chronic heart failure has diminished to a fraction in comparison to that in the 1990s. According to Packer, the investment in large clinical trials has declined because the promising results of phase II clinical trials are rarely confirmed by definitive large-scale trials. This dire situation has arisen, in part, due to the fact that the “primary mechanisms of the disorder are poorly understood” .
In view of the forgoing, several authors have questioned the single-organ concept of heart failure based on the traditional hemodynamic view. Schulze proposed that in view of the complex systemic neurohormonal response activated in chronic heart failure, the validity of the heart-as-a-pump paradigm can no longer be supported . In a recent review of circulation models, Alexander moreover suggested that the current impasse in new therapies of heart failure may have arisen on account of the deeply entrenched pressure propulsion paradigm and submitted that “superseding of the pressure-propulsion model may steer researchers away from pharmacological and device blind alleys and lead them instead to wide avenues of discovery and progress in therapy” . Similar arguments were raised in a recent review of circulation models .
14.2 Regulation of Cardiac Output by the Periphery
The experimental results which we wish to bring forward are largely such as might be predicted by anyone with a knowledge of elementary principles of circulation. Our justification in bringing them forward however is that they have not been so predicted, and it was only after obtaining the results that we asked ourselves why they had not occurred to us before. In fact they seem to form part of a forgotten or disregarded chapter in the physiology of the circulation, although they are of great importance for the question of pressure in the capillaries of the abdominal organs and therefore of the physiological processes of secretion and transudation which take place in these organs. 
We see on the simplified model of the circulation that the pump (the heart) cannot increase the mean pressure exerted on the walls of the system of the tubes by the fluid contained within them. It can in fact only give rise to unequal distribution of the pressure, by diminishing the pressure in the veins by pumping fluid out of them and increasing the pressure in the arteries to a corresponding extent by pumping the fluid into them. The mean pressure of the fluid in this model can only be increased by distending the tubes to a larger extent by the injection of more fluid into them. 
Starling went on to refine the concept of the mean systemic pressure by further experimentation and delivered a series of lectures on heart failure in 1897, where he proposed that, “Somewhere in the circulation there must be a point where the pressure is neither raised nor lowered and where, therefore, the pressure is independent of cardiac activity” . The location of this point would be of great significance in the genesis of heart failure; should it be located in arterioles (upstream of the capillaries), the capillary pressure would rise and the filtration of fluid into interstitium would increase. If, on the other hand, the point was in the veins (downstream of the capillaries), the pressure would fall, as the (left) heart failed. This occurs, reasoned Starling, due to resistance in the vessels which incurs a loss of energy of the flowing blood, as dictated by the law of conservation of energy. In the capillaries with a large total cross section, the flow is very slow, but the pressure is relatively large. In the veins, on the other hand, the flow velocity is greater but occurs at a lower pressure. “It thus follows,” concluded Starling, “that the neutral point in the vascular system, where the mean systemic pressure is neither raised nor lowered by the inauguration of the circulation, lies considerably on the venous side of the capillaries—at any rate, in most parts of the body” . Starling stressed the importance of mean systemic pressure (MSP) and, in turn, of venous circulation on CO by experimenting on a mammalian heart-lung preparation. Together with the “law of the heart,” the concept of MSP became an essential component of the pressure propulsion model of circulation .
The significance of mean circulatory pressure was reexamined by Starr and Rawson who constructed a mechanical model of circulation in order to simulate various forms of heart failure. The model predicted that an increase in MSP (termed “static pressure” in their study) was brought on as a compensatory mechanism in congestive heart failure and not as a result of it . To verify the theory, Starr performed direct measurements of “dead pressure” on “recently deceased patients” suffering with congestive heart failure (CHF) and concluded that “systemic venous congestion of the congestive heart failure is not fully explained as the direct mechanical consequence of weakness of either right or the whole heart.” Clearly, other factors such as the hypothetical “static pressure” play an important role .
14.3 Guyton’s Venous Return Model
The model conceived by Weber and Starling was fully developed by Guyton and his co-workers, who systematically investigated the importance of peripheral circulation in the control of cardiac output. The sheer volume of their work, spanning over several decades, has shaped the basic understanding of cardiovascular physiology for generations of students, researchers, and clinicians.