In 1794, John Hunter stated that “blood goes where it is needed” (291). How the blood “knows” where it needs to go, i.e. the vascular mechanisms that enable coronary blood flow to respond to increased O2 requirements of the heart, particularly during exercise, has been the subject of intense research efforts for more than a century (291). These efforts have resulted in major advances in our comprehension of coronary blood flow regulation over the past 50 years, which have been highlighted in several earlier reviews (30, 82, 83, 86, 116, 128, 156, 208, 210, 323, 368). The aim of this chapter is to provide a comprehensive update of the acute and chronic adaptations that regulate coronary blood flow in response to dynamic exercise under physiological conditions in the healthy heart.
THE CORONARY CIRCULATION IN ACUTE EXERCISE
Myocardial O2 Demand
Oxygen consumption by the heart is principally utilized for contraction, with basal metabolism comprising only 10-20% of total O2 consumption (35, 358). The O2 required for contraction is related to heart rate (37, 179, 332), ventricular wall tension (134), muscle shortening (48, 134), and contractility (21, 103, 134, 248). Precise determination of the relative contributions of these individual variables in vivo has been difficult, as pharmacological or electrical modulation of one of these variables often results in alterations of one or more of the other variables. Nevertheless, it is estimated that the exercise-induced increases in O2 consumption can be explained for 50-70% by heart rate, for 15-25% by contractility, and for 15-25% by stroke work (82, 208).
Myocardial O2 Supply
Increases in myocardial O2 demand during exercise are principally met by increasing coronary flow. In several species, including dog (187, 333), sheep (246), and horse (110, 274), O2 supply is enhanced by a prominent increase in hemoglobin concentration (by up to 30-50%), whereas in in humans (290, 292) and swine (93, 150, 209) hemoglobin increases much less. Although myocardial O2 extraction increases slightly further during exercise (226, 233, 241, 253, 337, 338), this increase is limited by the high resting levels of myocardial O2 extraction (60-80% during resting conditions). von Restorff et al. (337) demonstrated that heavy treadmill exercise in dogs produced an increase in myocardial O2 consumption from 0.09± 0.01 at rest to 0.57±0.05 ml/min per g during near maximal exercise that was met by by a 434% increase in coronary flow, an increase in arterial O2 content from 20±1 to 23±1 ml/dl, and a modest increase in O2 extraction from 79±2% to 93±1% (Fig 1). Thus, the principal mechanism for increasing myocardial O2 supply is by increasing coronary flow and, as a result, coronary blood flow is strongly correlated with myocardial O2 consumption. The increase in myocardial blood flow results from a combination of coronary vasodilation, resulting in a decrease of coronary vascular resistance during heavy exercise to 20-30% of resting levels, and a 20-40% elevation of mean aortic blood pressure (17, 168, 187, 226, 253, 274, 285, 337, 338).
Coronary Blood Flow. Left ventricular myocardial blood flow in resting large animals in the awake state and in normal humans is in the range of 0.5 to 1.5 ml/min per g of myocardium (82, 128, 208). Dynamic exercise increases coronary flow in proportion to heart rate, with peak values achieved during maximal exercise typically 3-5 times the resting level (227, 274, 295-297, 329, 338, 349). The strong correlation between coronary flow and heart rate is the result of heart rate being a multiplier for the other determinants of O2 demand (stroke work, contractility), which are computed per beat. Regression analysis of heart rate against left ventricular myocardial blood flow data demonstrates very similar relations between canine, porcine, equine and human data during dynamic exercise (Fig 2).
Oxygen carrying capacity of arterial blood. In the horse, dog, and sheep and to a lesser extent in pigs and humans, O2 supply to the myocardium is facilitated by – increases in hemoglobin concentration during exercise. The hemoconcentration in animals that demonstrate a large increase in hemoglobin during exercise is due to α-adroceptor mediated splenic contraction, ejecting erythrocyte-rich blood into the circulation (82, 206). Augmentation of the arterial O2 content is an important physiological response to exercise in these animals as, for example, splenectomized ponies required higher myocardial blood flows at similar work loads (227). Furthermore, whereas normal ponies had residual coronary vasodilator reserve in response to adenosine infusion even during maximal exercise, vasodilator reserve in the left ventricular subendocardium was exhausted in splenectomized animals during heavy exercise (227). Similarly, preventing the increase in hemoglobin in swine or dogs required a greater increase in coronary blood flow at each level of myocardial O2 consumption (93, 298), indicating that the increase in hemoglobin is also important in these species, although less than in horses. Humans, which lack a muscular splenic capsule, exhibit only a modest increase in hemoglobin during exercise, that is principally mediated by increased capillary filtration of water due to the increased intracapillary pressures resulting from arteriolar dilation (82, 206).
Myocardial O2 Extraction. In many species, the increased O2 demand during exercise is met in part by an increased myocardial O2 extraction (82, 208), with widening of the arterio-venous O2 difference and a decrease in coronary venous O2 content (Fig 2). Thus, in dogs (9, 338) and horses (226), myocardial O2 extraction increases progressively with higher exercise intensity. In humans, O2 extraction also increases during heavy exercise (154, 158, 168, 188), but lower exercise loads (<70% of maximum heart rate) do not result in increased myocardial O2 extraction or decreased coronary venous O2 levels [6,23,94–97]. In contrast, O2 extraction in swine remains essentially unchanged during exercise, even during exercise at 80–90% of maximal heart rate (27, 84, 92-95, 235, 237, 238). This increase in O2 extraction during intense exercise in dogs and horses is not the result of exhaustion of coronary vasodilator reserve, since a further increase in CBF can be elicited with pharmacological (20, 47, 227, 273, 297, 349) or ischaemic (338, 349) vasodilator stimuli. The presence of significant vasodilator reserve in the normal heart even during heavy exercise is supported by the absence of metabolic evidence of ischaemia, as several studies demo
nstrated continued lactate consumption even during heavy exercise (158, 168, 176, 241).
Determinants of Coronary Blood Flow
Effective perfusion pressure. The perfusion pressure of the coronary bed equals the drop in pressure across the coronary bed, with the entrance pressure being aortic pressure. However, since extravascular forces are exerted by the surrounding myocardium on the intramural coronary vasculature, the effective back pressure that impedes coronary blood flow cannot simply be equated to right atrial pressure. The interaction between the extravascular compressive forces and intravascular distending pressure can be described by a “vascular waterfall” model and is particularly important during the systolic phase (77, 159) but, to a lesser extent, also during the diastolic phase (25, 327, 336, 340). Thus, during systole myocardial contraction results in high levels of intramyocardial pressure that compress the intramural coronary vessels, thereby impeding coronary arterial inflow (Fig 3) (153, 184, 187, 297, 346). In addition, blood from intramural vessels is retrogradely pumped into the epicardial coronary arteries as the contracting myocardium compresses the coronary microvessels during each systole (167, 181, 346). This retrograde flow is enhanced during exercise by a forward expansion wave in the aorta late in systole (27). During diastole intraventricular pressures transmitted into the left ventricular wall exert a small compressive force on the intramural vasculature (5, 98, 105, 167), creating waterfalls at the level of the arterioles and the venules, and possibly the epicardial veins (327, 336, 346). For an in-depth review of the interaction of the coronary vasculature and the myocardium see Westerhof et al. (346).
The mechanical effects of cardiac contraction on coronary flow are best understood by examining the coronary pressure-flow relation, which is obtained by measuring coronary flow over a wide range of coronary artery pressures. During maximum coronary vasodilation, the pressure-flow relationship is determined by the maximum vascular conductance, represented by the slope of the relationship, and the x-intercept or pressure at which flow ceases (zero flow pressure; Pzf). Changes in Pzf are determined principally by changes of the extravascular compressive forces (3, 190, 300, 361). Using this approach, Duncker et al. (96) studied the effect of exercise on coronary blood flow in dogs, using arterial infusion of adenosine to produce maximum coronary vasodilation. When the coronary resistance vessels were maximally dilated with adenosine, exercise to increase heart rate from 118 beats/min at rest to 213 beats/min during exercise caused blood flow in the maximally vasodilated coronary circulation to decrease from 5.66±0.41 ml/min per gram of myocardium during resting conditions to 4.62±0.43 ml/min/gram during exercise despite a significant increase in aortic pressure. The decrease of coronary blood flow resulted from an increase of Pzf from 13±1 mmHg at rest to 23±2 mmHg during exercise, as well as a decrease in the slope of the pressure-flow relation from 12.3±0.9 to 10.9±0.9 (ml.min-1. g-1)/mmHg during exercise (Fig 4). Several factors may account for the exercise-induced alterations in the pressure-flow relation. Thus, the increases in heart rate reduce maximum coronary blood flow rates by increasing the total time spent in systole (8), while the increased contractility enhances systolic compression of the intramural coronary vessels (195, 230, 311, 321). However, the increased contractility will simultaneously augment myocardial relaxation which acts to increase the diastolic perfusion time (88, 283, 366). Finally, an increase in left ventricular filling pressures decrease maximum coronary blood flow (5, 98, 105). Analysis of the individual contributions of each of these variables to the changes in the coronary pressure-flow relation produced by exercise, demonstrated that left ventricular diastolic pressure and heart rate contributed to the increases in the Pzf, while the increase in contractility did not exert a significant effect (96), most likely because the impeding effect of the increased contraction force was compensated by enhanced relaxation that acted to increase diastolic perfusion time.
An increase in extravascular compressive forces during exercise is unlikely to be of physiologic significance in the normal coronary circulation, as coronary vasodilator reserve capacity persists even during heavy exercise (20, 47, 207, 227, 274, 349). However, when the O2 carrying capacity of the blood is reduced by anemia or hypoxia, or when occlusive coronary artery disease reduces perfusion pressure distal to a stenosis, then the elevated extravascular forces produced by exercise can result in a functionally significant impediment of coronary flow rate.
Coronary Vascular Resistance: During exercise the increase in mean arterial pressure only slightly outweighs the increase in effective back pressure opposing coronary flow, so that the net perfusion pressure does not increase more than by 30% (96, 226). Consequently, a 4 to 6-fold increase in coronary flow as occurs during heavy exercise must be met by a large decrease in vascular resistance. Indeed, maximal exercise is accompanied by reductions in computed coronary resistance to 20-40% of basal resting values in humans (158, 168) dogs (337), swine (47) and horses (227, 274). In the maximally vasodilated coronary bed, flow to the various regions of the heart is determined by the length of the vasculature, the cross-sectional area of the vessels as well as the number of parallel vessels that supply a particular region. Intravascular pressure measuremens during basal conditions have demonstrated that up to 90% of resistance to flow resides in the coronary small arteries and arterioles, hence the term coronary resistance vessels (60, 63).
Transmural Distribution of Left Ventricular Myocardial Blood Flow
There are significant transmural differences in the determinants of perfusion within the left ventricular wall. First, the total length of the vessels supplying the subendocardium is longer than those supplying the subepicardium. In addition, cardiac contraction compresses the intramural vasculature during systole, impeding blood flow especially to the subendocardium. To facilitate augmented flow during diastole to compensate for systolic underperfusion, the subendocardium has a 10% higher arteriolar and capillary density (30), so that during maximal pharmacological vasodilation under resting conditions flow to the subendocardium is similar to flow to the subepicardium (85, 286). In addition, there is evidence that the subendocardial resistance vessels are more sensitive to mediators of vasodilation including adenosine (286) and endothelium-dependent dilators (275). These structural and functional adaptations aid in maintaining blood flow to the subendocardial layers.
Systolic compression of intramyocardial vessels: Cardiac contraction impedes coronary blood flow during systole so that under basal resting conditions arterial inflow occurs principally during diastole. Measurements of epicardial coronary artery inflow in dogs (187) and swine (27, 297) demonstrate that at rest only 15-20% of left ventricular flow occurs during systole (Fig 3). However, the high heart rates produced by exercise result in progressive encroachment of systole on the diastolic interval, while absolute blood flow rates during systole increase. Consequently, as much as 40-50% of total coronary artery flow can occur during the systolic phase during heavy exercise (187, 297). The increase in the fraction of coronary blood flow during systole has implications for the transmural distribution of myocardial blood flow, as the compressive effects of myocardial contraction on intramural coronary microvessels is not expressed uniformly across the left ventricular wall (Fig 5). Thus, myocardial compressive force increases from
intrathoracic pressure at the epicardial surface to equal or to exceed intraventricular pressure at the endocardial surface (3, 44). Interaction of this gradient of tissue pressure with the intravascular distending pressure creates an array of vascular waterfalls across the left ventricular wall that particularly impedes subendocardial blood flow during systole (77, 85, 159, 181). Furthermore, as the contracting myocardium compresses the intramural vessels during each systole, blood from coronary microvessels within the innermost myocardial layers is pumped retrogradely into more superficial subepicardial and epicardial coronary arteries. Consequently, subendocardial vessels need to be refilled in diastole, analogous to the emptying and recharging of a capacitor (167, 181, 346)). Therefore, epicardial artery inflow during systole is directed toward the subepicardium, while antegrade subendocardial blood flow is confined exclusively to diastole. Furthermore, as the exercise-induced tachycardia leads to a shortening of diastole, a relatively greater part of diastole is required to refill the subendocardial vessels, thereby delaying net forward flow into the subendocardial microvessels. To study the effects of the increased force of cardiac contraction and increased heart rate during exercise, maximum coronary vasodilating of the coronary circulation is required to negate the confounding influence of metabolic vasoregulation of coronary resistance vessel tone, thereby allowing selective study of the impeding effects of myocardial contraction. Using this approach, Duncker et al. (85) observed that exercise caused a redistribution of blood flow toward the subepicardium away from the subendocardium (Fig 4), consistent with the concept of the intramyocardial pump (167). Despite the impeding effects of myocardial contraction on blood flow to the deeper myocardial layers during exercise, it should be noted that in the normal heart with intact coronary tone a modest net transmural gradient of blood flow favoring the subendocardium exists, which reflects the higher systolic tensions and O2 requirements of the innermost layers (343). Maintenance of this normal pattern of transmural perfusion requires augmentation of subendocardial blood flow during diastole in proportion to the degree of systolic underperfusion. This diastolic gradient of blood flow, in turn, depends on a transmural gradient of vascular resistance, with resistance during diastole being lowest in the subendocardium (8).
Subendocardial/subepicardial blood flow ratio: The transmural distribution of myocardial blood flow during exercise has been assessed using the radioactive microsphere technique. In most studies, the left ventricular wall has been divided into three or four layers, with the transmural distribution of perfusion being expressed as the ratio of myocardial blood flow to the innermost layer (subendocardium) divided by flow to the outermost layer (subepicardium) and termed the endo/epi ratio. In chronically instrumented awake dogs and swine endo/epi blood flow ratios at rest have been reported in the range of 1.09-1.49 (9, 11, 16, 17, 20, 46, 47, 75, 85, 91, 92, 144, 196, 207, 254, 268, 296, 297, 338, 349). ENDO/EPI ratios depend somewhat on the size microsphere used. In early studies in which 7-10 μm diameter microspheres were used, endo/epi ratios decreased during exercise, with values near 1.0 during heavy exercise (17, 20, 349). In contrast, when 15 μm diameter microspheres were employed, higher endo/epi ratios have generally been observed with values between 1.10-1.31 during heavy exercise (Fig 6) (9, 11, 196, 257, 258, 268, 296, 297), although several studies in swine reported values near 1.00 (46, 47, 92, 144, 207). The reasons for the discrepancy in the transmural distribution of microspheres during exercise based on size are unclear, but may include arteriovenous shunting of a small fraction of the 7-10 μm spheres from the subendocardial microvessels, as well as preferential streaming of 15 μm spheres into penetrating arteries that deliver blood to the subendocardium (328). Standard-bred horse and ponies show a greater decrease in endo/epi ratio during exercise compared to dogs and swine (Fig 6). Using 15-μm diameter microspheres, Armstrong and associates (4) observed a decrease in endo/epi ratio from 1.24 at rest to 1.05 during heavy treadmill exercise in standard bred horses. Manohar et al. (227, 274) even reported a decrease in endo/epi ratios in ponies from 1.18-1.27 at rest to 0.97-0.99 during exercise. These marked drops in endo/epi may be due, at least in part, to the prominent increase in left ventricular end-diastolic pressure that occurred in horses from 11±2 mmHg at rest to 36±4 mmHg during heavy exercise, contrasting with the modest increases in left atrial pressure or left ventricular end-diastolic pressure from 2-5 mmHg during resting conditions to 5-15 mmHg during heavy exercise in dogs (2, 9, 11, 17, 97, 170, 268) and swine (92, 297, 349).
Vasomotor tone on the transmural distribution of myocardial blood flow: Several studies indicate that active coronary vascular tone is important to maintain blood flow to the deeper myocardial layers during exercise. Thus, with dogs and swine performing treadmill exercise, coronary vasodilation with dipyridamole or adenosine caused the endo/epi ratio to drop well below 1.0 (85, 207, 297, 349). These findings could be interpreted to suggest that at the high heart rates produced by exercise, active vascular tone is necessary to maintain a transmural gradient of vascular resistance, which favours perfusion of the subendocardial layers during diastole. In contrast, Barnard et al. (20) reported that the ENDO/EPI ratio during heavy exercise in dogs increased from 1.03 during control conditions to 1.15 after the administration of dipyridamole, while intravenous adenosine was reported to have no effect on the endo/epi ratio during maximal exercise in ponies (227, 274). Furthermore, Breisch et al. (47) reported that during heavy exercise in swine the endo/epi ratio was maintained near unity during vasodilation with adenosine. An explanation for the disparity between the various studies is not readily found, but it does not appear to involve adenosine-induced changes in arterial blood pressure. The dose of adenosine used in these studies is critically important, since submaximal doses of adenosine cause preferential dilation of subendocardial resistance vessels which could oppose the mechanical effects that impair perfusion of the subendocardium (281). Most important, however, is the observation that during severe exercise, adenosine or dipyridamole infusion increased the absolute levels of subendocardial blood flow (20, 47, 85, 207, 227, 274, 297, 349), implying that not only total coronary vasodilator reserve but also subendocardial vasodilator reserve had not been exhausted.
Coronary Blood Flow to the Right Ventricle
In horse and dogs under basal resting conditions right ventricular blood flow expressed per g of myocardium constitutes typically 50-60% of left ventricular myocardial blood flow, while its transmural distribution either slightly favors the subendocardium or is uniform (16, 17, 22, 227, 228, 268). In swine, right ventricular myocardial blood flow under resting conditions amounts 70-90% of left ventricular flow with an end/epi ratio of 1.50 (92, 207, 296). The lower resting flow in the right ventricle is the result of a lower right ventricular myocardial O2 consumption (147, 369), consistent with the markedly lower right ventricular, compared to left ventricular, systolic pressures. Interestingly, the lower levels of O2 consumption are associated with significantly lower levels of O2 extraction (46±3%) by the right ventricle (147, 360).
In response to graded treadmill exercise, right ventricular myocardial blood flow amounts 75-100% of left ventricular flow during the highest levels of exercise, and increases as a direct function of heart rate (16, 17, 22, 92, 207, 227, 228). The transmural distribution of right ventricular m
yocardial blood flow in dogs (16, 17, 268) and swine (207, 296) does not change from rest to heavy treadmill exercise. The relatively greater exercise-induced increase in right ventricular myocardial blood flow during severe exercise (3 to 6-fold) as compared to myocardial blood flow in the left ventricle (2.5-4 fold), most likely reflects the larger increase in right ventricular O2 consumption (147), secondary to the pronounced elevations in pulmonary artery pressure during exercise (92, 370). The relative increase in right ventricular myocardial flow during heavy exercise is largest in ponies (8-10 fold, (227, 228)) as compared to either dogs (5-6 fold, (16, 17)), or swine (3-4 fold, (92, 207). This is consistent with the marked pulmonary hypertension that occurs during exercise in horses, with mean pulmonary pressure increasing from 20-30 mmHg during resting conditions to 65-90 mmHg during maximal treadmill exercise (227, 228), and with the accompanying marked exercise-induced increase in right ventricular work load in this species.
The very high resting values of myocardial O2 extraction (60-80%) in the left ventricle require an increase in myocardial blood flow even at relatively low levels of exercise. In contrast, resting myocardial O2 extraction in the right ventricle is much lower, so that 80-90% of the increment in O2 consumption produced by mild exercise (60% of maximal heart rate) in dogs could be met by an augmentation of myocardial O2 extraction from 46±3% at rest to 68±2% during exercise, with O2 extraction further increasing to 82±1% during exercise at 80% of maximal heart rate (Fig. 7) (147). The different control mechanisms regulating myocardial O2 extraction in the right versus the left ventricle remain incompletely understood. However, the blunted response of right ventricular myocardial blood flow to exercise, together with the marked increase in O2 extraction does not appear to be due to the exhaustion of coronary vasodilator reserve (23, 227). Zong et al. (369) demonstrated that the large increase in O2 extraction during exercise could be in part explained by an exaggerated α-adrenergic vasoconstrictor influence on the right ventricular vasculature. Nevertheless, following α-adrenergic blockade a significant increase in right ventricular O2 extraction still occurred, indicating that other mechanisms must be involved as well. Future studies are required to further unravel the vascular control mechanisms in the right ventricular myocardium and how these influence the myocardial O2 balance in the right ventricle.