Keywords
Aerobic exerciseMuscle perfusionMetabolic control of muscle blood flowATP as the “missing vasodilator”Functional sympatholysisErythrocyte ATP and purinergic receptorsSkeletal muscle pump hypothesisAthletic heartHeart as organ of restraintExercisePericardiumIn contrast to the hitherto reviewed studies mainly performed on anesthetized, open-chest animals or on isolated heart preparations, the physiological events that occur in exercising animals or humans provide a unique insight into the function of the cardiovascular system at the limits of its capacity. Under such conditions, the role of central and peripheral circulations becomes more clearly defined and affords us with, yet, strongest evidence for the primal role of the peripheral circulation. It is not surprising that, given the lack of a unifying paradigm on the hemodynamic response to exercise, this field is fraught with many inconsistencies which, in the face of new studies, are becoming increasingly more difficult to reconcile. The argument pivots on the before mentioned degree of contribution of central, versus peripheral factors in the overall control of the circulatory response to exercise (for reviews, see [1–4]).
17.1 The Role of Peripheral Circulation
Blood flow distribution at rest and during maximal exercise in patients with mitral stenosis (MS), in normal individuals (NA), and in highly trained athletes (ATH). Note that at rest and during exercise, blood flow to skin and viscera is similar in all three groups, whereas muscle perfusion varies greatly. (Reproduced from ref. [5], used with permission of the American Physiological Society)
The relationship between exercise intensity and oxygen uptake is similar in individuals with different levels of physical conditioning, but their maximal uptake varies widely. (Reproduced from ref. [7], used with permission of John Wiley and Sons)
17.1.1 Metabolic Control of Muscle Blood Flow
At rest, skeletal muscles exhibit very low perfusion rates. For example, an individual weighing 75 kg has about 30 kg of muscles containing 750 mL of blood (14% of total blood volume, TBV). In comparison, the liver, a highly vascular organ weighing 1.5 kg, contains 500–600 mL (10% of TBV) [8]. Historically, pronounced basal tone of the skeletal muscle vessels was thought to have been maintained by local and systemic vasoconstrictors. Gaskel, the first to describe an increased blood flow with the onset of muscular activity in the 1870s, ascribed it to neurogenic origin [9]. Well over half a century later, Lofving and Mellander demonstrated that the resistance to flow in an acutely denervated cat muscle was decreased by 80–85% with an arterial injection of ATP, or acetylcholine, but did not substantially change to infusion of epinephrine, norepinephrine, serotonin, angiotensin, and vasopressin [10]. In the 1960s Forrester and Lind isolated a substance from human blood which caused an increase in luminescence of the firefly lantern and enhanced the heartbeat in frogs. The active agent was identified as adenosine triphosphate (ATP) and its plasma levels were increased after exercise [11]. Over the years the much-sought for evidence over control of muscle blood flow regulation has shifted to the interaction between the locally formed vasoactive substances and their local as well as systemic sympathetic modulation. In the 1980s, the pivotal role of the vascular endothelium—and its response to sheer stress as well as the production of endothelium derived factor (NO) and prostaglandins—was recognized (for review, see [4]). Since the already known vasodilators, such as acetylcholine, adenosine agonists and antagonists, and NO synthase inhibitors failed to exhibit significant muscle blood flow regulation, the search was on for “a missing vasodilator” [4].
It is currently understood that in resting muscle the vasomotor tone is determined by an inherent myogenic activity of the resistance vessels, modulated by a relatively high myogenic resting tone [12]. During exercise, on the other hand, the primary determinant of the skeletal muscle blood flow, and hence of perfusion, is the increased metabolic rate of the muscle which plays a central role in exercise hyperemia [12, 13].
To better understand metabolic control during muscular activity, let us take a brief look at the functional organization of the vascular supply in the muscle. The basic element of blood flow control is the microvascular unit (MVU) consisting of 20–30 adjacent muscle fibers occupying the volume of some 0.1 mm3 [14]. Such a unit is perfused by a terminal arteriole which branches into 10–20 capillaries, each measuring about 500–1000 μm, arranged in the direction of muscle fibers. Significantly, there are no precapillary sphincters that would permit independent control of flow through the MVU. Rather, the key control point in the regulation of blood flow is a parent conduit or a terminal arteriole feed vessel, giving rise to a group of terminal arterioles which finally branch into the above mentioned capillary network [15]. Such an arrangement indicates a relatively loose control of perfusion during contractions of individual motor units, i.e., of the group of muscle fibers innervated by a single motor neuron. The motor units (in which all muscle fibers belong to the same type, i.e., fast fatigable, fast fatigue-resistant and slow) are distributed randomly in the body of the muscle and typically measure several centimeters in length. Thus, neither the MVU nor the organization of the motor unit is conducive to a selective control of muscle perfusion either at rest or during activity. On the contrary, such an arrangement of vascular and neuromuscular elements suggests a “feed forward” control of perfusion by which many MVU’s are perfused in advance of recruitment of motor units. It has been argued that prior perfusion of the microvascular beds would minimize the delay in oxygen delivery upon recruitment of additional motor units (see [16] for review).
Aerobic exercise is accompanied by a general increase in sympathetic activity—a response known as the “exercise pressor reflex,” directed to active as well as to resting muscles [17, 18]. In inactive muscles, the “pressor reflex” causes vasoconstriction, whereas in active muscles, the effect of increased sympathetic activity has no measurable effect, and vasodilatation is maintained despite of high levels of circulating catecholamines. The overriding of sympathetic vasoconstriction by the metabolic demands of the muscle, known as “functional sympatholysis,” is believed to play a pivotal role in the distribution of cardiac output between the maximally dilated vessels in working muscles and other organ systems [6, 12]. A review by Joyner and Halliwill suggests that, at least in humans, neurally mediated vasodilation in active muscle does not play a significant role [19]. This is fortuitous, given the fact that the muscle mass comprises some 30–60% of total body weight, vasodilation of muscular loops would cause a profound drop in peripheral resistance leading to cardiovascular collapse even during a moderate degree of muscular activity (see below). Thus, sympathetic modulation can direct the blood flow to where it is needed—the contracting muscles.
As mentioned, blood flow to the muscle is correlated linearly with oxygen consumption; however, the arteriolar tone is modified by a plethora of modulating signals including heat stress, flow and transmural pressure (wall shear stress), sympathetic activity (cateholamines), vasoactive hormones, by substances derived from the vascular endothelium, and by several locally and systemically produced vasoactive metabolites. It appears that the multiplicity of factors affecting the microvascular control of blood flow would assure an ample, or at least an adequate, supply of oxygen to the tissues in need. It turns out, however, that the total flow in and out of the tissues does not reflect the actual events at the capillary level.
Since the multifaceted story of muscle blood flow control continues to emerge, our discussion is limited to more recent developments in this prolific area of research. While it had been well recognized that vascular endothelium controls the responsiveness of the arteriolar smooth muscle in response to blood and tissue oxygen levels, the exact location which would directly affect the capillary perfusion and match it with the metabolic demands of the tissues remained a riddle until Ellsworth and coworkers demonstrated that the red blood cells (RBCs) are the actual link between the tissue oxygen demand and its supply at the level of the capillaries [20]. Of interest, the existence of local control in matching perfusion and blood oxygenation in the lung, known as the hypoxic pulmonary vasoconstriction, had been known since the 1940s (see Chap. 19), whereas such directed distribution of blood flow in the peripheral tissues was recognized only in the mid-1990s. The question then arose as to which specific pathway or component of the RBC would be responsible for matching supply of oxygen to the working muscle?
Erythrocytes as oxygen sensors and modulators of vascular tone. Physical deformation of erythrocytes (RBCs) and their entry into the region with increased metabolic demands results in drop in hemoglobin oxygen saturation (SO2) and prompts release of ATP. Free ATP reacts with endothelial purinergic receptors (PR) causing production of vasodilators, including nitric oxide (NO) and products of arachidonic acid metabolism. Vasodilation spreads along the vessel walls in the direction opposite to the flow of blood (upstream) to encompass proximal feed arterioles, resulting in increased perfusion of the microvascular beds. (Adapted from ref. [23], used with permission of P&T)
Just how do the torus-shaped RBCs, devoid of a nucleus, accomplish this complex task? In addition to being filled with hemoglobin, the RBCs contain μ-molar amounts of ATP which is readily released under a variety of stimuli such as hypoxia, increased CO2, decreased pH or upon mechanical deformation to which RBCs are subject when traversing the narrow capillaries [24]. Studies have shown that the amount of ATP release is related to conformational change in hemoglobin indicating that a drop in oxygen content is directly responsible for the release of ATP [25]. For ATP to increase local perfusion, and thus delivery of oxygen, it must exert its action at the arteriolar level upstream from the actual site of trigger. The phenomenon of conducted vasodilation first demonstrated in vivo on a hamster cheek pouch by Ellsworth [20], and since confirmed by others, is affected by ATP binding to the capillary endothelial purinergic receptors (P2y) and triggering vasodilatory response beyond the site of its initiation. (The distribution of ATP-selective P2y2 receptor in human skeletal muscle microvascular endothelium is higher than any of the nine known types of purinergic receptors [26]). ATP, a purine-based molecule, in turn stimulates the release of nitric oxide (NO) and products of arachidonic acid metabolism (prostaglandins) which diffuse to the adjacent vascular smooth muscle and cause vasodilation. Of note, ATP is also released from the endothelial cells in response to shear stress and hypoxia [27].
In addition to playing a key role in the mediating of vasodilation of the arterioles, the circulating ATP can oppose the vasoconstrictor effect of exercise-induced release of catecholamines which, left unchecked, would lead to profound vasoconstriction. It has been proposed that ATP binding to endothelial P2 receptors causes conducted hyperpolarization of endothelial cells along the vessel wall and of the neighboring vascular smooth muscle and thus opposes sympathetic vasoconstriction (functional sympatholysis) [24]. Beyond producing ATP and vasodilatory substances (NO, prostaglandins), the endothelial cells therefore provide an effective conduit for the spread of ionic currents along the vessel walls and into the surrounding vascular smooth muscle cells. The endothelial cell signaling model leading to relaxation of the vascular smooth muscle by activation of potassium (hyperpolarizing) channels has been worked out to a considerable detail [28]. Thus, by causing direct vasodilation and by limiting the degree of sympathetic vasoconstriction, the ATP plays a dual role in assuring adequate blood flow and oxygen supply during aerobic exercise.
The groundbreaking concept that the RBCs serve not only as passive transporters of oxygen but play an active role in its procurement (in the lungs), as well as regulate its supply in the tissues, is an essential clue to resolving the debate over the control and integration of the local and systemic oxygen signaling. Controlled release of ATP, the universal energy currency molecule, by the mobile erythrocyte thus provides the optimal common denominator for the regulation of skeletal muscle blood flow and oxygen delivery. For a further perspective on the role of the RBCs in various pathophysiological states, see Chap. 21.
17.1.2 Skeletal Muscle Pump Hypothesis
Quantitative changes in blood flow in the forearm muscles during sustained contractions were first measured by occlusion pletysmography in the 1930s by Grant who noted a small increase in the volume of the limb during contraction and a larger one during muscular relaxation, when the blood rapidly filled the veins [29]. In the subsequent decade several reports were published on the circulatory changes during muscular activity which led to the muscle pump hypothesis in the 1940s (for review see [9, 30]). The next phase of research on skeletal muscle blood flow focused on the rapidity of its onset. Rushmer, for example, performed a series of studies on dogs with chronically implanted Doppler transmitters across the left ventricle and demonstrated that the increase in CO occurs within a single heartbeat of the onset of exercise [31]. Similarly, Guyton et al. showed a sudden, threefold increase in CO in anesthetized dogs with spinal cord transection in which hind leg muscles and sciatic nerves were stimulated with cyclical current, simulating muscle activity. Since the increase in CO occurred in the absence of nervous (and cardiac) stimulation, it was ascribed to a combination of metabolically induced muscle vasodilation and to translocation of blood into the central compartment, with resulting increase in MCP. Without significant augmentation from the periphery, argued Guyton, the heart itself cannot increase CO more than a few percent [32]. On the basis of rapid re-filling of lower leg veins during exercise observed by venographic imaging, Almen and Nylander proposed that the contracting muscle works similarly to a “bellows pump” [33] in which changes in muscle length, in turn, affect length and diameter of the veins [34].
Over the years, several revisions and refinements were added to the muscle pump concept, and in their review Rowell et al. specify three requirements for its effective operation: intact venous valves, maintenance of low blood volume within muscle veins and increase in “driving pressure” [8]. Similarly, Delp and Laughlin characterized activity of the muscle pump as “contraction-induced, rhythmic propulsion of blood from skeletal muscle vasculature which facilitates venous return to the heart and perfusion of skeletal muscle.” It is implicit in this characterization that muscular action adds hydraulic energy to the circulating blood and that any degree of increased blood flow due to metabolic increase in vascular conductance and blood flow is not due to the action of the pump [12].
Because of the dramatic increase in CO with concomitant shifts of the blood volume into the working musculature, Rowell et al. suggested that the muscle pump can be viewed as the second heart at the venous return part of the circuit, having the capacity to generate blood flow rivaling that of the left ventricle [8]. On the basis of extensive analysis of the central and peripheral factors which limit the circulatory response to exercise, Rowland likewise contends that, in addition to a central cardiac pump which supplies the muscles, a second or peripheral pump, responsible for systemic venous return is indispensable for the following reasons: i) to assure adequate cardiac diastolic filling, due to gravitational sequestration of blood at the onset of upright exercise, ii) because of large outputs, e.g., in the order of 1000 mL per second at maximal exercise, the output of the peripheral pump must be equal to the central (cardiac) pump, since “the heart cannot expel the blood it does not receive,” and finally, iii) maximal response to exercise is determined by the peripheral pump, which “drives the system,” unlike the central pump, which “sustains it” [1]. This view is further echoed by Sheriff in whose analysis a large, as yet unexplained, discrepancy existing between the levels of blood flows achieved by maximal chemical vasodilation and through voluntary exercise cannot be explained [34].
Despite the above listed, seemingly well-grounded imperative for the muscle pump hypothesis, some researchers have argued that the evidence for its existence is at best circumstantial [35], sparking a lively debate on the topic [34, 36, 37]. As noted by Laughlin and Schrage, one of the major difficulties with the theory lies in the fact that there is no satisfactory method to directly measure variability of venous pressure within the contracting muscle itself [38]. In addition, animal models in which direct or indirect electrical stimulation of the muscles has been applied—to show the effect of muscular contraction on muscle hyperemia—have proven just the opposite, namely that the volume of blood expelled from the muscle during contraction is small in comparison to blood displaced by the arterial inflow [35]. More significantly, the changes of blood flow through the muscle in response to exercise are far greater than those accounted for by measuring local arterial and venous pressures [39]. The validity of the mechanistic pressure-suction model of muscle-activated blood flow has been further questioned on grounds of the virtually instantaneous, contraction-linked surge in muscle blood flow with the onset of exercise [40, 41], followed by metabolically induced hyperemia [42, 43]. This view is supported by findings which suggest that, in the absence of vasodilation, muscle contractions per se do not elicit an increase in blood flow [44]. In their review on blood flow dynamics in the working muscle Tschakovsky and coworkers proposed an exponential model of exercise-induced muscle hyperemia with an early perfusion peak within 5–7 s (phase I), followed by the second increase reaching a plateau in 15–25 s (phase II) and a gradual transition during sustained, heavy exercise into the third phase, with maximal blood flows [45].
Lower extremity and systemic hemodynamics during incremental exercise and graded femoral artery infusion of ATP. Open circles depict systemic hemodynamics and filled circles represent leg hemodynamics. Data points are mean ± SEM for 9 subjects. ∗ different from exercise, p < 0.05. (Reproduced from ref. [46], used with permission of John Wiley and Sons)
During incremental arterial infusion of ATP, there was an increase in CO which closely matched the increase caused by the active leg exercise, whereas the vascular conductance, stroke volumes, and MAPs were significantly higher during ATP infusion than with the active exercise. In contrast, no changes in CO, leg blood flow, or MAP occurred during venous infusion of ATP, suggesting that increases in CO during exercise or ATP infusion are brought about by increased blood flow through the muscle. Of further interest is the fact that ATP infusion did not affect metabolism of the tested leg as indicated by unchanged leg VO2, glucose uptake and lactate release and femoral venous temperature, suggesting that an activation component, which triggers the metabolic changes in the muscle is not activated by intralumenal ATP. The authors concluded that the skeletal muscle pump is not obligatory for sustaining CO or maintaining muscle blood flow during one-legged exercise in humans. Moreover, the contribution of the muscle pump and of mechanically induced vasodilation is small in comparison with the effects of limb muscle vasodilation [46]. High vascular conductance with ATP infusion confirmed previous reports in which ATP infusion increased vascular conductance during maximal exercise by a further 17% [47] and overrides sympathetic vasoconstrictor activity in human skeletal muscle [48]. It appears that matching of metabolic demands of the contracting myocytes is brought about between locally formed vasoactive substances (ATP, ADP, AMP and adenosine) [18, 49] and increased perfusion caused by intralumenal ATP released by the circulating erythrocytes [50–52]. A growing body of data suggests that ATP is the key modulator of local and systemic hemodynamics during exercise. Its brief half-life (less than 1 s), and immediate availability from the circulating red blood cells make it a likely candidate to be “the missing vasodilator” [3, 53].
17.2 The Heart in Exercise
The heart represents less than 5% of body weight and during basal conditions receives around 60–70 mL of blood per 100 g of tissue. The high capillary density (exceeding that of the striated muscle by a factor of 8) facilitates diffusion and extraction of oxygen, which reaches the range of 60–80% of the available arterial oxygen content even at rest. The heart can therefore meet increasing energetic demands of exercise only by increasing coronary perfusion which, at peak exertion, parallels that of the skeletal muscle. Due to considerable interspecies variation, detailed pathways of the “metabolic” increase in (human) coronary blood flow in response to exercise have not been elucidated. For example, studies in dogs suggest that “metabolic dilation of canine coronary resistance vessels is regulated via a myriad of vasodilator systems that act in concert to match coronary blood flow to myocardial oxygen demand so that when one system fails, back-up systems ensure an adequate oxygen supply to the myocardium” [54]. Since there are no valves in cardiac veins, the existence of a muscle pump in the myocardium has not been proposed as a mechanism which maintains its perfusion [4].
The remarkable ability of the heart to increase its performance by four to six times in the course of incremental exercise is attributed to increased contractility (Emax) due to beta-adrenergic stimulation and an enhanced ventricular diastolic compliance which improves diastolic filling in the order of 60% [55]. Untrained subjects typically demonstrate an initial rise in SV averaging 28% (range 13–46%), reaching a plateau which remains unchanged to the point of exhaustion (see [56] for review), in contrast to highly trained endurance athletes in whom SV may continue to rise progressively to the point of maximal exercise [57]. The increased diastolic chamber compliance is, therefore, the single most important mechanism for increasing SV, noted particularly in endurance athletes, in whom, surprisingly, the contractility is no greater than in non-athletes [58].
Apical displacement of the A-V (valve) plane during diastole represents 60% of the total SV at rest [59] and increases significantly even after short-term endurance training [60]. There is a reciprocal relationship between the heart rate and SV, i.e., as the HR doubles, the SV halves, which limits CO. This effect is ameliorated by adrenergically controlled force–frequency relation (FFR), an intrinsic mechanism of the myocardium by which the strength of contraction is markedly enhanced, allowing the maintenance of SV in the face of decreased diastolic filling times [61]. There is a linear relationship between HR and intensity of exercise up to maximum rates which can increase up to two and a half times in untrained and up to five times in trained athletes [62]. Thus, an immediate response to exercise is marked by a 30–40% increase in SV; however, the value differs with position in which the exercise is performed, i.e., supine, sitting, or upright. Stroke volumes reach similar values, regardless of position, after exercise stabilization and remain the same to exhaustion [2]. Similarly, LV end-diastolic dimensions remain stable, or possibly decline with exercise intensity [2]. The lack of incremental change in SV and ventricular size in progressive exercise is remarkable, considering the large increase in venous return. Linden proposed that changes in HR constitute the basic mechanism for controlling the heart volume and size [62]. As the heart rate increases during maximum exercise, the diastolic filling time progressively shortens to the point of becoming shorter than the systolic ejection time, indicating a remarkable rate of diastolic filling [56]. Theoretical and experimental studies by Lauboeck moreover demonstrate a progressive shortening of isovolumic contraction period at increased heart rates, until it disappears entirely at the rate of about 140 beats/min. Conditions thus prevail during strenuous exertion where the blood begins to flow through the aortic valve even before the closure of the mitral valve, suggesting a continuous flow of blood through the heart [63, 64].
It is imperative that the size of the heart is kept small, because in accordance with Laplace’s law, at constant wall thickness, the heart with greater diameter would have to work at increased wall tension [1]. This would constitute an energetic disadvantage and pose a danger of right ventricular overdistension [65]. It is apparent that the pericardium also plays a crucial role in controlling the size of the heart during periods of large volume throughputs. Studies in pigs have shown that removal of pericardium results in 33% increase in EDV and a 29% increase CO within 2–3 weeks of treadmill exercise [66]. Increase in SV and EDV was also demonstrated in untrained, pericardiectomized dogs [67]. Exercise-induced endurance training leads to “physiological” LV hypertrophy, i.e., athletic heart, characterized by increased LV cavity dimension and mass, and preserved contractility [68–71], which distinguishes it from hypertrophic cardiomyopathy, responsible for up to a third of sudden deaths in young athletes [72].
Helical orientation of myocardial fibers, as discussed in Chap. 13, adds significantly to the heart’s ability to “hold up” against the increasing momentum of the moving blood in aerobic exercise. During systolic contraction, the ventricular chamber undergoes a counterclockwise torsion of the apex relative to its base, followed by untwisting (clockwise rotation) of the apex during the isovolumic relaxation and early diastole [73]. Tischler and Niggel reported an increase in systolic twist (apical minus basal rotation) by 8.4 ± 2.8° (86%) during a short bout (60 s) of maximal treadmill exercise in young adults [74] and Notomi et al., measured an increase in systolic twist from 11.4 ± 4° at rest to 24 ± 8° during submaximal supine bicycle exercise [75]. Compared to age-matched, non-trained individuals, professional soccer players have a reduced angle of left ventricular twist and torsion velocities at rest [76], suggesting that larger hearts, with more inertia, interrupt the flow of blood more efficiently. It is of interest that patients with hypertrophic cardiomyopathy show an increased LV twist at rest when compared with normal subjects, however, with apical and basal rotation in the same direction (rather than in the opposite, as is the norm). These differences are enhanced during exercise, where patients fail to respond with an increase in LV twist from baseline and have a significant delay in untwisting [75], thus predisposing them to a potential catastrophic reduction in forward flow.
17.3 Changes in Pulmonary Circulation
It is given that any increase in systemic flow during progressive exercise is paralleled by a matching increase in pulmonary blood flows. Unlike in the systemic circuit where, due to blood redistribution, the muscles are super-perfused at the “expense” of other organ systems (which receive less blood than during basal conditions, Fig. 17.1), the pulmonary vessels respond to increased functional flows by recruitment of the capillary beds. In the adult lung, flow can be increased threefold before any change in the pulmonary artery pressure can be detected. Once “fully recruited,” further increase in flows results in linear increase in pulmonary artery and venous pressures [77] and activation of intrapulmonary arteriovenous pathways [78]. Large increase in flow results in distension and recruitment of the pulmonary microcirculation [79] and a twofold decrease in mean capillary transit time [80] reflected in linear increase in PAm (mean pulmonary artery pressure), from an average of 14 to 25 mmHg at maximal exercise [81]. In spite of highly compliant vasculature, systolic PA pressures up to 60 mmHg and higher have been reported in trained athletes [82–84]. The excess flow is further indicated by additional arteriovenous shunting, as seen in progressive rise in A-aDO2 (alveolar-arterial oxygen difference) [85]. Increase in exercise intensity results in increased rate of oxygen uptake by the lung which is similar in trained and untrained subjects; however, the maximal rates are significantly greater in trained athletes [38] (Fig. 17.2). Some deterioration in pulmonary gas exchange (in the range of 10–15%) due to shunting reaches peak values immediately after the onset of exercise and remains stable to exhaustion [86].
The factors which lead to such marked increase in PA pressures during exercise are not fully understood and cannot be accounted for in the context of the pressure propulsion theory, considering the fact that pulmonary vascular resistance (PVR) does not rise in exercise and may even decline [87, 88]. It is not clear whether increase in pressure is the result of increased pulmonary flow, a change on PVR or the combination of both, leaving the clinicians to question the significance of PA pressures as such [84]. The situation is further compounded by data which indicate that left atrial (LA) pressure can exceed 20 mmHg and pulmonary capillary wedge pressures (PCWP) can reach up to 36 mmHg or higher during strenuous exercise; these values significantly exceed the Starling equilibrium at the alveolo-capillary membrane and the threshold for generation of pulmonary edema [89]. It is well known that progressive exercise and increased pulmonary flows are linearly related to the degree of tricuspid valve regurgitant flows, which have become a standard noninvasive screening method for assessment of PA pressures at rest and during exercise in normal subjects and in those with suspected pulmonary hypertension. One would expect that increasing diastolic incompetence of the tricuspid valve during strenuous exercise would work against the pumping action of the RV at the time when it is most critical. Or, is it possible that the thin-walled RV is overdistended by the large increase in venous return, generated by the opened muscular loops?
17.4 “The Sleeping Giant”
The blood flow to exercising muscles increases up to 100-fold above the basal values, or 2.5 L kg−1 min−1 in the quadriceps muscle [90, 91] and can reach up to 3–4 L kg−1 min−1 in trained athletes [92]. Concern has been raised that this level of perfusion could overwhelm the “pumping capacity” of the heart, with concomitant drop in CO and blood pressure, if similar level of hyperemia would be achieved in most muscle groups during the whole body exercise [3, 90]. Calbet et al. demonstrated that during submaximal exercise in well-trained athletes, i.e., cross-country skiers, the legs receive 60% and the arms 35% of CO (CO values ranged around 27 L min−1). When compared to baseline conditions, the mean systolic and diastolic arterial pressures were lower by 14, 11, and 34% respectively. To maximally perfuse all limbs, the calculated CO should have been 33–34 L min−1, or some 4 L more than the measured values. In case of maximal exercise, the calculated CO of 37–40 L min−1 would be needed to perfuse arms and legs, without compromising systemic blood pressure and perfusion of other vascular beds. In view of these remarkable discrepancies, the authors (rightfully) concluded that “The combined conductance of arms and legs exceeded the pumping capacity of the heart…implying that muscular vasodilatory response during maximal exercise must be restrained to maintain perfusion pressure” [93], the problem being that the mechanism of this “restraint” has yet to be identified.
We are clearly faced with a paradox here in the sense that even in moderate degree of exercise blood flow to the muscle can easily exceed what the heart could supply as a propulsion pump. Hence, the theory that the CO is the limiting step in the capacity of the cardiovascular system to deliver oxygen to the muscles [94]. This is the situation in the best-case scenario in a dynamic exercise, when the (hypothetical) muscle pump is doing at least as much work as the heart. Is the heart performing a double role of impelling, i.e., accelerating and “restraining” the blood at the same time? As mentioned before, a profound decrease in peripheral resistance as seen in exercise can cause a drop in MAP, jeopardizing perfusion of the brain and heart, and ultimately, of the working muscles. It is of interest that exercise-related syncope, due to hypotension and cerebral hypo-perfusion, shares many similarities with advanced degrees of vasodilatory shock. The latter is associated with decreased myocardial contractility (in spite of increased cardiac outputs) and exhibits resistance to vasopressors [95] (cf. Sect. 21.3).
A further problem concerns the above-mentioned immediate, substantial increase in blood flow after release of the first muscle contraction, i.e., faster than could be accounted for by the “metabolic vasodilation” [42, 43]. A related question concerns the inertia of some 5 L of blood which must be moved within a matter of seconds up to remarkable flow velocities, invoking an image of a row of cars, which all drive off at the same time, rather than being pushed from behind resulting in a pileup. The exercising muscle has aptly been referred to as “the sleeping giant, whose blood flow must be under tonic vasoconstrictor constraint if hypotension is to be averted” [4]. In a recent review on the subject, Calbet and Joyner submitted that “Despite the effort made by several generations of physiologists over the past 150 years, many questions remain on the regulatory mechanisms that elicit and maintain skeletal muscle hyperemia and how cardiac output and muscle hyperemia are coupled during heavy exercise in humans” [3]. The existing problems of exercise hyperemia have been summarized by Tschakovsky and Sheriff [43] and were subject of a thought-provoking editorial [96].
It is proposed that the conflicting observation can be resolved only when the blood is not assumed to be an inert fluid “pumped” around the circuit by the heart, but a “self-moving” agent with flow directly coupled to the metabolic needs of the working muscles. The existence of a so-called muscle pump serves the same purpose as the heart, namely to “restrain” the massive increase in venous return, with venous valves protecting against the backflow and peripheral congestion. Performance of the heart during exercise is perhaps the best example of the fact that the heart sets itself against the flow of blood and impedes, rather than propels it. Enhanced systolic torsion (counterclockwise rotation of the apex relative to the base) [56, 75, 97], increased myocardial mass and enlarged ventricular cavities are physiological adaptations to increased flow. In keeping with the greatly increased venous return, the mean arterial pressure is kept low to accommodate for increased oxygen requirements by the working muscles and, yet, is adequate to sustain perfusion of vital organs. Only when seen as an organ of restraint, can the heart place itself effectively against the “runaway train” of oncoming blood to maintain only moderately increased MAP even during maximal exercise. It does this by increasing its diastolic compliance (which markedly improves diastolic filling) and increased contractility, which increases maximal systolic contraction and, thus, ejection fraction. Both mechanisms allow the heart to maintain normal (or near normal) dimensions and protect it from overdistension in the face of greatly increased blood flow (“cardiac throughput”).
