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Physiol Rev 86: 1263–1308, 2006; doi:10.1152/physrev.00029.2005. Cross-Talk Between Cardiac Muscle and Coronary Vasculature NICO WESTERHOF, CHRISTA BOER, REGIS R. LAMBERTS, AND PIETER SIPKEMA Laboratory for Physiology and Department of Anesthesiology, Institute for Cardiovascular Research Vrije Universiteit, VU University Medical Center, Amsterdam, The Netherlands 1264 1265 1265 1265 1268 1268 1268 1272 1273 1278 1286 1286 1288 1288 1288 1293 1293 1293 1294 1294 1294 1295 1296 1297 Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017 I. Introduction II. The Cardiac Muscle and the Coronary Vasculature A. Functional arrangement of the cardiac muscle and the coronary circulation B. Coronary pressure-flow relationships C. Summary III. The Cardiac Muscle Affects the Coronary Vasculature A. Cardiac muscle and coronary flow in diastole B. Cardiac contraction and coronary flow in systole C. Models explaining the diastolic-systolic changes of the vasculature D. Applications and limitations of the models E. Cardiac contraction augments coronary flow F. Effects of cardiac muscle on the coronary vasculature: summary IV. The Coronary Vasculature Affects the Cardiac Muscle A. Coronary flow and cardiac muscle in diastole B. Coronary flow and cardiac muscle in systole C. Effects of coronary vasculature on cardiac muscle: summary V. Role of the Extracellular Matrix in Cross-Talk A. Theoretical suggestions B. Experimental findings C. Summary VI. Conclusions A. Cardiac muscle affects the coronary vasculature B. Coronary vasculature affects the cardiac muscle C. Extracellular matrix Westerhof, Nico, Christa Boer, Regis R. Lamberts, and Pieter Sipkema. Cross-Talk Between Cardiac Muscle and Coronary Vasculature. Physiol Rev 86: 1263–1308, 2006; doi:10.1152/physrev.00029.2005.—The cardiac muscle and the coronary vasculature are in close proximity to each other, and a two-way interaction, called cross-talk, exists. Here we focus on the mechanical aspects of cross-talk including the role of the extracellular matrix. Cardiac muscle affects the coronary vasculature. In diastole, the effect of the cardiac muscle on the coronary vasculature depends on the (changes in) muscle length but appears to be small. In systole, coronary artery inflow is impeded, or even reversed, and venous outflow is augmented. These systolic effects are explained by two mechanisms. The waterfall model and the intramyocardial pump model are based on an intramyocardial pressure, assumed to be proportional to ventricular pressure. They explain the global effects of contraction on coronary flow and the effects of contraction in the layers of the heart wall. The varying elastance model, the muscle shortening and thickening model, and the vascular deformation model are based on direct contact between muscles and vessels. They predict global effects as well as differences on flow in layers and flow heterogeneity due to contraction. The relative contributions of these two mechanisms depend on the wall layer (epi- or endocardial) and type of contraction (isovolumic or shortening). Intramyocardial pressure results from (local) muscle contraction and to what extent the interstitial cavity contracts isovolumically. This explains why small arterioles and venules do not collapse in systole. Coronary vasculature affects the cardiac muscle. In diastole, at physiological ventricular volumes, an increase in coronary perfusion pressure increases ventricular stiffness, but the effect is small. In systole, there are two mechanisms by which coronary perfusion affects cardiac contractility. Increased perfusion pressure increases microvascular volume, thereby opening stretch-activated ion channels, resulting in an increased intracellular Ca2⫹ transient, which is followed by an increase in Ca2⫹ sensitivity and higher muscle contractility (Gregg effect). Thickening of the shortening cardiac muscle takes place at the expense of the vascular volume, which causes www.prv.org 0031-9333/06 $18.00 Copyright © 2006 the American Physiological Society 1263 1264 WESTERHOF ET AL. build-up of intracellular pressure. The intracellular pressure counteracts the tension generated by the contractile apparatus, leading to lower net force. Therefore, cardiac muscle contraction is augmented when vascular emptying is facilitated. During autoregulation, the microvasculature is protected against volume changes, and the Gregg effect is negligible. However, the effect is present in the right ventricle, as well as in pathological conditions with ineffective autoregulation. The beneficial effect of vascular emptying may be reduced in the presence of a stenosis. Thus cardiac contraction affects vascular diameters thereby reducing coronary inflow and enhancing venous outflow. Emptying of the vasculature, however, enhances muscle contraction. The extracellular matrix exerts its effect mainly on cardiac properties rather than on the cross-talk between cardiac muscle and coronary circulation. I. INTRODUCTION FIG. 1. Mechanisms of cross-talk in the heart, excluding the contribution of neurohumoral regulation. Physiol Rev • VOL 86 • OCTOBER 2006 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017 Coronary perfusion is essential for cardiac function and is regulated in a number of ways. These can be divided into extrinsic, such as the humoral-nervous regulation, and intrinsic, i.e., autoregulation. Autoregulation is the intrinsic tendency of the vasculature to maintain constant blood flow despite changes in perfusion pressure (190) and does not include the effects of extrinsic nerves or hormones (124). The matching of coronary blood flow to cardiac metabolism determines the plateau of the autoregulation and has recently been reviewed by Tune et al. (408). Autoregulation is not restricted to cardiac muscle as it also acts in other organs such as kidney and brain. However, for the vasculature embedded in cardiac and skeletal muscle another component plays a role, namely, the mechanical interaction of the contracting muscle and the vasculature. This interaction results in decreased coronary arterial inflow and increased coronary venous outflow as the cardiac muscle contracts. Inversely, the coronary vasculature itself and the vascular flow and pressure have an effect on cardiac muscle and its contraction. The role of the vascular and the endocardial endothelium in this effect and their related signaling pathways have recently been reviewed (55). Neurohumoral control of the coronary vasculature, the effects of limitations in oxygen supply, and pathology (such as long-term adaptive effects of vessel and cardiac muscle interaction) are not discussed in this review. Earlier reviews of coronary hemodynamics have provided substantial information about the coronary circulation (124, 151, 175, 226, 233, 235, 376, 377, 448, 458). However, limited attention has been given to the mutual interaction (cross-talk) of the cardiac muscle and the coronary vasculature. Modern measurement techniques, presently allowing for the noninvasive determination of human cardiac perfusion and cardiac muscle contraction (35, 176, 182, 269), now make it possible to study crosstalk in the clinical setting. These novel techniques together with a better knowledge of cross-talk will help to improve the understanding of pathological changes, adaptations, and the effects of therapeutic interventions (3, 105, 135, 136, 180, 222, 258, 300, 319, 328, 455). The multiple mutual interactions between the coronary vasculature and the cardiac muscle can be divided into mechanical (including the role of the extracellular matrix) and mediator-based mechanisms (Fig. 1). This review concentrates on the acute mechanical factors that contribute to the two-way interactions between cardiac muscle and vasculature, which we will call mechanical cross-talk. On the one hand, the contracting cardiac muscle generates force and ventricular pressure, shortens and thickens, and increases in stiffness. These changes affect the coronary vasculature and coronary flow. On the other hand, increased vascular filling increases the vascular diameters that affect the neighboring cardiac muscle cells. Furthermore, when the smooth muscle tone changes it affects the mechanical properties of the vascular wall. Both vascular effects influence cardiac muscle contraction. We start with an introduction on the functional arrangement of vasculature and cardiac muscle and then discuss the effect of the cardiac muscle on the coronary vasculature. Subsequently, we review the effect of the coronary vasculature on cardiac muscle. These interactions depend on the mechanical characteristics of the vasculature (e.g., as affected by vasomotor tone), the cardiac muscle (e.g., cardiac muscle contractility), and the extracellular matrix. The published models are introduced and their description of mechanical cross-talk is CROSS-TALK BETWEEN CARDIAC MUSCLE AND CORONARY VASCULATURE discussed in relation to the existing experimental data. The role of the extracellular matrix on cardiac function has been studied (28, 276, 403) and recently reviewed (189). However, the role of the extracellular matrix in mechanical cross-talk is largely unknown, but is discussed as well. Most examples in this review pertain to the left ventricle; the right ventricle is mentioned, when pertinent. II. THE CARDIAC MUSCLE AND THE CORONARY VASCULATURE The coronary circulation is a system of branching vessels that can be divided into the epicardial arteries and veins and the intramyocardial vessels. The mechanical cross-talk between cardiac muscle and vessels mainly takes place at the level of the intramyocardial vessels. The intramyocardial vessels can be further divided into the transmural vessels and the microcirculation. Information about the anatomy of the coronary vasculature and its integration in the muscular network can be found in a number of publications (46, 150, 217, 331, 360, 376, 401, 404, 409a). The detailed structure of coronary arteries, the capillary network, and the venular system and their relation to function has been described by Kassab and coworkers (213–219, 409a). Currently, Spaan et al. (381) are developing a new method where the coronary microcirculatory morphology in situ can be visualized, including the relationship with the cardiac muscle. Pressure measurements in differently sized arteries and arterioles have indicated that under normal conditions, 45–50% of total coronary vascular resistance resides in vessels larger than 100 m (279). Details about the coronary arterial microcirculation and its regulation can be found elsewhere (71, 75). The important role of the coronary microcirculation in coronary disease has been reviewed by Cecchi et al. (65). The number of resistance vessels in the subendocardium is somewhat higher than in the subepicardium (402). As a result of this anatomical difference, the flow in diastole is ⬃10% higher in subendocardial than in subepicardial layers. The greater impeding effect of cardiac muscle contraction on arterial flow in subendocardial compared with subepicardial layers is thus, partly, compensated for by the difference in the number of resistance vessels. Differences in mean flow in the layers are generally small under physiological conditions, but may exist (137). A homogeneous distribution of flow, cardiac metabolism, and muscle function as proposed earlier (414) is probably too simple a view. Local coronary perfusion Physiol Rev • VOL differs, and this heterogeneity increases towards the microcirculation (22, 23, 29, 31, 170, 236, 239, 349, 410, 409a), but this is not related to certain fixed regions (30, 209). Heterogeneity in flow between control and moderate dilation differs little (99) but is different during maximal vasodilation (23). This heterogeneity depends on perfusion pressure (127) and on the perfusate (285); therefore, it is only partially dependent on the anatomy. Heterogeneity of flow is present in ischemia in the patient (344). Oxygen consumption, glucose uptake, glycolytic enzyme activity, and oxygen delivery are related and also heterogeneously distributed (6, 158, 179, 252, 372). In addition to flow heterogeneity, flow regulation (193), metabolic control of flow (98), vasomotion (400), microvascular coronary ␣-adrenergic vasoconstriction (77), and responses to drugs (78, 236, 265) are all heterogeneously distributed. Heterogeneity is greatest at the submillimeter scale (30), but it has not been established if, on this scale, cardiac muscle contraction is also heterogeneously distributed in the heart wall (33). Magnetic resonance imaging (MRI) and positron emission tomography (PET), and even ultrasound, can provide insight into heterogeneity of flow, muscle function, local oxygen consumption, etc. (165, 344). There is also variation in flow with time called “twinkling” (29, 228), resulting from vasomotion. It may therefore be expected that heterogeneity also exists in mechanical cross-talk. B. Coronary Pressure-Flow Relationships Coronary pressure-flow relationships are strongly determined by autoregulation. Furthermore, flow reserve depends on autoregulation, and the supply-to-demand ratio assumes that flow is related to muscle metabolism and is negligible in systole. All three characterizations depend on vasomotor tone and cardiac contractility and thus on the mechanical properties of the vasculature and the cardiac muscle. We show below that the mechanical properties of the vasculature and cardiac muscle affect mechanical cross-talk. 1. Autoregulation Autoregulation (Fig. 2) is the capacity of an organ to regulate its own blood flow when perfusion pressure is challenged (293, 338). Cardiac muscle plays an important role in coronary autoregulation: blood flow adjusts to muscle metabolism, and in the physiological range flow is rather independent of perfusion pressure. The level of the plateau of the autoregulation curve is related to the metabolic state of the heart (293, 306). There are several local autoregulatory control mechanisms that match blood flow to activity of the tissue. By changes in the diameter of mainly the arterioles, where vascular resistance resides (74, 306, 338, 446), flow can be adjusted within a typical 86 • OCTOBER 2006 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017 A. Functional Arrangement of the Cardiac Muscle and the Coronary Circulation 1265 1266 WESTERHOF ET AL. cle can affect smooth muscle tone. A single responsible mediator cannot be distinguished. Metabolites such as adenosine and carbon dioxide play a role, while pH and ions, oxygen, and K⫹-ATP channels also appear to be involved, depending on the conditions (38, 39, 56, 91–93, 112, 116, 124, 181, 225, 294). Metabolic autoregulation is an aspect of cross-talk. However, the mechanical aspect is indirect, since a change in vasomotor tone affects vascular mechanics and thus mechanical cross-talk. 4. Endothelium-based control response time of a few seconds (365, 416). Changes in the diameter of the microvessels in part result from the smooth muscle properties per se, myogenic control, and in part result from factors released from the cardiac muscle, metabolic control, and the endothelium-based control. 2. Myogenic control The vascular transmural blood pressure leads to stress in the circumferential direction of the vessel wall and is called “hoop stress.” This pressure-induced vascular control forms the basis of the myogenic response and results in a change in vessel diameter to maintain a constant hoop stress, as shown in the coronary arterioles of the pig and the human (191, 192, 255, 256, 298). After an increase in the intraluminal pressure (Fig. 3), the diameter initially follows passively, and subsequently active smooth muscle contraction causes the diameter to decrease, leading to normalization of the wall stress. In response to decreased pressure, the opposite effect takes place. The myogenic response resides in the smooth muscle itself, since it is present in vessels without endothelium (254). The effect of myogenic regulation on the resistance distribution of the coronary system has been modeled (86). The myogenic autoregulation is based on hoop stress determining vascular tone and is not the result of mechanical cross-talk. However, vasomotor tone does affect cross-talk. 3. Metabolic control Where the vasculature is in close contact with the cardiac muscle, mediators released from the cardiac musPhysiol Rev • VOL FIG. 3. The myogenic response. An increase in pressure increases vessel diameter and wall stress, causing smooth muscle contraction that reduces the diameter to a size smaller than at the lower, starting, pressure and restores wall stress. 86 • OCTOBER 2006 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017 FIG. 2. Autoregulation maintains flow during constant metabolism and adapts flow to altered metabolism. Over the autoregulation range, i.e., the plateau of the autoregulation curve, flow is rather constant for a range of perfusion pressures. The level of the plateau is related to the metabolic state of the heart. The dashed line indicates maximal pharmacological vasodilation. The dotted line shows the maximal physiological dilation, which is smaller than can be reached pharmacologically. The flow reserve is given by the ratio (B ⫹ A)/A (76, 113). Shear stress is caused by friction between the flow of blood and the vascular wall, and it acts in the axial (longitudinal) direction on the endothelial cells. The main mediator released from the endothelium affecting the smooth muscle cells is NO. This flow-induced control of vascular tone adjusts the diameters such that the shear stress is maintained constant, e.g., increased flow causes an increase in vessel diameter (240 –242, 253, 257). A relationship exists between myogenic and endotheliumbased control (255). It was recently shown that an endothelium-derived hyperpolarizing factor also plays a role in vivo (453). In addition, there is metabolic communication between cardiac muscle and endothelial cells (56). Chilian et al. (74) concluded that a significant part of the arterial tree, with vessels larger than the smallest arterioles, also contributes to total coronary vascular resistance, implying a role of endothelium-based regulation in coronary vascular tone and resistance. The vascular bed acts as a functional syncytium through electrical coupling of vascular cells (100, 335, 357), and changes in coronary resistance take place through “coordinated” action. An elegant concept integrating myogenic, metabolic, and flow-dependent regulation was published by Jones et al. (192), and this was modeled by Cornelissen et al. (85). We conclude that endothelium-based control, by affecting smooth muscle tone and vascular mechanics, plays a role in mechanical cross-talk. All three autoregulatory mechanisms, which to a certain extent are redundant, act together, and the interaction is complex. However, an order of action can be distinguished. If perfusion pressure changes, the endothe- 1267 CROSS-TALK BETWEEN CARDIAC MUSCLE AND CORONARY VASCULATURE lium-mediated regulation and the myogenic response will be activated first, and then, if cardiac muscle contractility and metabolism increase, the metabolic regulation will follow. With a change in cardiac metabolism, the metabolic regulation will be initiated first. The myogenic response will then follow, and the increased flow will result in flow-mediated dilation through increased shear stress. 5. Autoregulation gain Autoregulation gain (G) is a measure of the strength of autoregulation and can be calculated as (see Fig. 4) with ⌬Q/⌬P being the slope of the regulated mean pressure-mean flow relationship and Q/P the slope of the line connecting the point of determination and the origin of the graph, as a (theoretical) measure of the resistance. It can be seen that for perfect autoregulation, the gain equals one and for no autoregulation, assuming the pressure-flow relationship would go through the origin, the gain equals zero. Autoregulation gain can be plotted as a function of pressure to obtain the range of regulation and its dependence on perfusion pressure. The assumption that the not-regulated pressure-flow relationship (dashed line of Fig. 4) goes through the origin has been challenged (see sect. IIIA1). 6. Flow reserve Flow reserve at any given pressure is the difference between regulated and not-regulated flow. As such, it is influenced by changes in metabolism (which change the autoregulatory plateau) as well as by a stenosis, which changes the maximal flow. The functional behavior of a coronary artery stenosis is difficult to estimate from images (angiography, MRI, and even multislice computed tomography). Therefore, interventions combined with measurements of pressure or pressure gradient and/or flow have been proposed to quantify the functional sever- 7. Coronary flow reserve Flow reserve is the ratio of maximal flow obtained by coronary vasodilation and the resting or reference flow [see Fig. 2, ratio (A⫹B)/A] (97, 145–148, 234, 236, 271). This ratio is reduced when a stenosis is present. The microcirculatory resistance and the maximal dilatory capacity of the microcirculation, together with the severity of the stenosis, determine the resting flow and the maximal flow. Thus the coronary flow reserve (CFR) depends not only on the severity of the stenosis but also on the state of the microcirculation. A short coronary occlusion may be used to obtain vasodilation. However, this physiological dilation may be less than when vasodilation is obtained pharmacologically (113, 137, 259). With a larger flow than in physiological dilation, a larger estimate of CFR is obtained (see Fig. 2). Since the myogenic response takes place in 15 or more seconds (365), and the metabolic control starts even later, this sets the minimally required duration of the occlusion (83). A value of CFR ⬎2 is used as cut-off value; a CFR ⬍2 implies a functional stenosis. In the beating heart, mean flow and mean maximal flow are affected by cardiac muscle contraction. When the CFR is determined in diastole only (280), the confounding effect of cardiac contraction is not included in the results. However, vascular emptying and compliance (capacitance) may then play a role, but their effects can be corrected (24). Bishop and Samady (45) recently reviewed the subject of CFR. Hoffman (171, 172) discussed the limitations of and the difficulties with CFR. The main limitations are that the function of the microcirculation is not accounted for, e.g., maximal dilation is often not achieved (113, 149). Furthermore, the CFR only gives global information, whereas flow is heterogeneously distributed (22). We conclude that the CFR depends on the microcirculation, which is affected by cardiac muscle contraction and thus depends on mechanical cross-talk. 8. Fractional flow reserve Another functional estimate of the severity of a stenosis is the fractional flow reserve (FFR) (320). The FFR is the ratio of the maximal flow (Qmax,s) in the bed perfused by the stenosed artery and the maximal flow in a normal, unstenosed area (Qmax,n). Therefore FIG. 4. The definition of autoregulation gain is as follows: G ⫽ 1 ⫺ slopeA/slopeU ⫽ 1 ⫺ (⌬Q/⌬P)/(Q/P) ⫽ 1 ⫺ (⌬Q/Q)/(⌬P/P). Gain depends on the working point. Physiol Rev • VOL FFR ⫽ Qmax,s/Qmax,n ⫽ 关共Pd ⫺ Pv兲/Rst兴/关共Pprox 86 • OCTOBER 2006 • ⫺ Pv兲/Rn兴 ⬵ Pd/Pprox www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017 G ⫽ 1 ⫺ 共⌬Q/⌬P兲/共Q/P兲 ⫽ 1 ⫺ 共⌬Q/Q兲/共⌬P/P兲 ity of a stenosis (145–148, 281, 310). Since this characterization requires pressure and/or flow measurements, including the pressure distal of the stenosis, simpler characterizations such as coronary flow reserve and fractional flow reserve have been introduced. 1268 WESTERHOF ET AL. stress or systolic pressure and heart rate (337, 345, 386). When expressed per heart beat, the area under the systolic part of ventricular or aortic pressure can be used as an estimate of oxygen demand. In this way, we can apply the so-called supply-to-demand ratio (173), which is directly related to the ratio of the areas under diastolic and systolic pressure. The supply-to-demand ratio depends on the duration of diastole with respect to the heart period, i.e., the diastolic time fraction. This time fraction has recently received attention (82, 123, 129, 295, 412). The supply-todemand ratio also depends on the ratio of systolic and diastolic pressure, which decreases with age (448) and exercise (114), and can give information about (pharmacological) interventions (207, 208). The supply-to-demand ratio is determined by crosstalk because tissue perfusion in systole depends on cardiac muscle contraction. C. Summary Autoregulation of flow is an integrated and coordinated control by an apparently redundant system based on three interacting mechanisms: myogenic control, metabolic control, and endothelium-based control. The gain of autoregulation can be quantified. Autoregulation modulates the mechanics of the vasculature and thus affects mechanical cross-talk. The supply of oxygen mainly depends on diastolic flow, and thus on the diastolic time fraction. However, even a small flow in systole, e.g., at high heart rates, can contribute to perfusion and is affected by cardiac contraction. Thus the supply-to-demand ratio depends on mechanical cross-talk. Quantification of a stenosis is often based on CFR and FFR. However, CFR depends on the microcirculation as well, and thus on the effect of cardiac muscle contraction. The FFR assumes that the bed distal of the stenosis and the normal representative bed are similarly influenced by cardiac muscle contraction. Therefore, both CFR and FFR are affected by cross-talk. 9. Supply-to-demand ratio Oxygen delivery to the cardiac muscle should be in equilibrium with the oxygen use or demand. Supply is related to arterial inflow because coronary oxygen extraction is close to its maximal value. If it is assumed that the effect of cardiac contraction on the subendocardial layers is such that coronary perfusion is negligible in systole, arterial inflow only takes place in diastole. The supply then can be calculated as the area under the perfusion pressure in diastole. When there is no stenosis present, this equals the area under the diastolic aortic pressure. Thus, under these assumptions, diastolic pressure and the duration of diastole are the determinants of oxygen supply. Oxygen demand mainly depends on ventricular wall Physiol Rev • VOL III. THE CARDIAC MUSCLE AFFECTS THE CORONARY VASCULATURE In this section we discuss the global findings on coronary pressure-flow relationships of the coronary vasculature in diastole and in systole. A. Cardiac Muscle and Coronary Flow in Diastole 1. Instantaneous pressure-flow relationship and zero-flow pressure intercept A vascular bed, in our case the coronary system, can be characterized in terms of steady-state and instanta- 86 • OCTOBER 2006 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017 with Pd being the pressure distal of the stenosis and Pprox the proximal or, in practice, aortic pressure during maximal dilation. The Rst and Rn are the resistances of the stenosed and normal distal beds during maximal vasodilation. With the assumption that the microvascular bed of the stenosed area and the normal area have the same minimal resistance, and with the assumption that venous or intercept pressure (Pv) (see below) is small with respect to Pd, it holds that the FFR is close to the ratio Pd/Pprox (275, 320, 361). Keeping these limiting assumptions in mind, the FFR is then an index of lesion severity only, not including the effect of the microcirculation (96, 226). It has been agreed that for values ⬍0.75 (88, 226), the stenosis is functionally significant. For a segmented stenosis, the approach is more complicated. The main advantage of the FFR is that it can be derived from flow measurements only that can be carried out noninvasively using ultrasound Doppler or MRI. The measurement of distal pressure would obviate a flow measurement but may, even using a thin pressure wire, increase apparent stenosis severity. The relationship between flow velocity and the pressure drop over a stenosis is an accurate and direct quantification of the functional properties of the stenosis, but more difficult to obtain because measurement of proximal and distal pressures, together with flow, is required (26, 280, 361). It has not been established whether the maximal flow in muscle areas distal of a stenosis is similar to maximal flow in a normal area. Furthermore, it is not known whether the effect of cardiac contraction on the coronary vasculature is similar in these two areas. When the CFR and FFR are studied in diastole, the microcirculation is studied without the confounding effect of the cardiac contraction (see below) (120, 248), and cross-talk will be minimal. Flow during maximal dilation is, in part, determined by cardiac contraction, and FFR may thus depend on cross-talk. CROSS-TALK BETWEEN CARDIAC MUSCLE AND CORONARY VASCULATURE FIG. 5. The instantaneous relationship between pressure and flow can be obtained from a (long) diastole and characterizes the coronary vasculature without the confounding effect of cardiac muscle contraction and during an assumed constant vasomotor tone. [Adapted from Bellamy (36).] FIG. 6. The autoregulation curve is shown together with instantaneous pressure-flow relationships. The instantaneous relationships define the vasoactive state of the coronary vasculature. At lower perfusion pressure, the slope increases (smaller resistance, Ri), and as a result of vasodilation, the intercept pressure also decreases. [Adapted from Dole and Bishop (107).] Physiol Rev • VOL depend on the vasoactive state of the coronary bed. For increased perfusion pressure, the vasculature constricts as a result of autoregulation, and the resistance and intercept of the instantaneous pressure-flow relation increase, thereby keeping mean flow in the steady-state constant (107, 238). In humans, the zero-flow pressure intercept of the instantaneous pressure-flow relation is ⬃40 mmHg in control and ⬃15 mmHg in vasodilation (307). A Pf⫽0 is not only found in the left heart but also in the right heart in diastole (430). These intercept pressures are significantly higher than coronary sinus pressure, left ventricular end-diastolic pressure, and right atrial pressure. The mechanisms causing the zero-flow pressure intercept are still poorly understood. The instantaneous pressure-flow relationships with the zero-flow pressure intercept have been likened to a waterfall mechanism, i.e., increases in venous pressure do not affect flow as long as this pressure is lower than the waterfall pressure (Fig. 7). The intercept pressure depends on vasomotor tone, suggesting that it arises from the smooth muscle in the arteriolar wall. That the intercept is based on vascular properties is also based on the fact that it exists in many beds, including the whole systemic circulation (57). Spaan (375, 376) has suggested that the large compliance found in the microcirculation [⬃0.07 ml · mmHg⫺1 · 100 g tissue⫺1 (375, 376) to ⬃0.38 ml · mmHg⫺1 · 100 g tissue⫺1 (380)], depending on heart rate (91, 92) and vasoactive state (423), may explain the intercept. An intravascular volume of ⬃12 ml/100 g muscle has been reported (196, 411). This large microcirculatory compliance indeed appears to be present, because venous outflow, from blood stored in the microvascular reservoir (compliance), persists after a sudden stop of arterial inflow (80, 201, 347). After arterial inflow is resumed in a stepwise manner, venous outflow is delayed, suggesting an unstressed vascular volume or large compliance, estimated to be ⬃4 ml/100 g muscle (407). Several authors (142, 201) showed, in the in situ dog heart during maximal vasodilation, evidence for the existence of a microvascular unstressed volume, which re- FIG. 7. The principle of a waterfall. Venous pressure does not determine the flow when it is below the waterfall pressure. It is the proximal arterial minus the distal waterfall pressure that determines the flow. When the arterial pressure falls below the waterfall pressure, the flow stops. 86 • OCTOBER 2006 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017 neous pressure-flow relationships (36, 37, 50). The steadystate relationship is the one that is measured after regulation has taken place (see autoregulation curve of Fig. 2). The instantaneous relationship is determined over a short time period (⬃1 s), and the vasculature is assumed to be in a “fixed” vasoactive state (106, 416). The instantaneous relationship between pressure and flow of the coronary circulation can be determined during a long diastole (e.g., obtained through vagal stimulation) so that the coronary vasculature is characterized without the confounding effect of cardiac muscle contraction, i.e., with minimal mechanical cross-talk (Fig. 5). The instantaneous pressureflow relationship, therefore, describes the momentary state of the vascular bed. Figure 6 shows the steady state, or autoregulation curve, together with instantaneous pressure-flow relationships as determined from a range of steady-state pressures (36). The instantaneous relationships in general appear to be straight (36) or curvilinear (237, 238) with a so-called zero-flow pressure intercept, Pf⫽0, i.e., with negligible flow, pressure is still present. The inverse of the slope of the instantaneous pressureflow relationship is the instantaneous resistance (Ri). The instantaneous resistance and the intercept pressure both 1269 1270 WESTERHOF ET AL. Versluis et al. (424) showed, in isolated perfused rat papillary muscle, that the waterfall is located in arterioles larger than 110 m. It has still not been proven beyond doubt that the intercept is a real intercept and not an apparent intercept, i.e., an intercept obtained by extrapolation of the data. Kanatsuka et al. (210) analyzed in detail the momentary value of the diameter of arterioles in the coronary bed while pressure was decreasing. It was found that the diameters of arterial microvessels gradually decline as aortic pressure falls. This suggests that the coronary resistance does not remain constant during a long diastole, even when the bed is maximally dilated (210). The finding that even during maximal vasodilation a zero-flow pressure intercept is present suggests that a venous waterfall may exist. A distal, venous, waterfall was indeed shown to exist in the epicardial coronary veins (409), and also in the skeletal muscle veins (51). Such a separate venous waterfall can be seen and studied by cannulation of the venous system (409). Increased coronary sinus pressure was shown to decrease flow, but this was less than the decrease in perfusion pressure (arterial minus venous pressure), suggesting a waterfall mechanism (303). A large coronary venous compliance may also explain this waterfall. The instantaneous pressure-flow relationship should be considered with caution. It has been shown that the relationship may not be linear (238). The relationships may include a contribution of arterial compliance, because the flow that fills the arterial compliance depends on the rate of change of perfusion. Thus, when the pressure and flow change occur too rapidly, errors result. These errors and suggestions for correction have been reported (24, 61, 237, 282, 283). Instantaneous pressure-flow relationships are determined over such a short period of time that they describe the bed in a particular state at the working point. It may therefore be suggested that the ratio of the slopes of the autoregulation curve and the slope of the instantaneous pressure-flow relationship, the regulatory index, are a better measure of gain of autoregulation than the formula given in the section on autoregulation gain (416). 2. Summary FIG. 8. A possible explanation for the apparent intercept. The “plateau” of the pressure-area relationship relates to the apparent intercept. An increase in vasomotor tone increases the plateau of the pressure-area relationship together with the apparent zero-flow pressure intercept. [Adapted from Sipkema and Westerhof (364).] Physiol Rev • VOL The instantaneous pressure-flow relationships are determined in diastole and so rapidly that vasomotor tone may be assumed constant. The relationships describe the coronary vasculature in “fixed state” of the vasculature and without the confounding effects of the cardiac muscle and are therefore not affected by mechanical cross-talk. The slope and intercept of the relationships both depend on smooth muscle tone. The intercept is most likely the result of a large microvascular compliance. 86 • OCTOBER 2006 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017 sults in delayed venous outflow after sudden resumption of stopped arterial inflow. The filling of the intramyocardial compartment above its unstressed volume affects the diastolic pressure-flow relationships (142), but not their intercept, indicating that arterial inflow depends on the compliance in the microcirculation. In cardiac arrest, the blood stored in the microcirculation is discharged to the venous side keeping venules open while arterioles decrease in size (167). Sipkema and Westerhof (364) showed that the apparent intercept of the pressure-flow relationship of a thinwalled latex microtube (Fig. 8) depends on the plateau of its pressure-cross-sectional area relationship, which, in turn, depends on vasomotor tone. Both explanations as given by Spaan and Sipkema support the hypothesis that (microvascular) compliance plays a major role in the explanation of the zero-flow pressure intercept (364, 375, 376). An additional suggestion that the intercept is related to vessel wall properties is that when the coronary perfusion fluid is changed from blood to a crystalloid medium, an intercept pressure remains (342, 415). However, others have shown that the perfusion medium does affect the intercept, suggesting that the rheological properties of blood may play a role as well (205, 352). It has also been suggested that surface tension between blood and vessel wall (358, 359) and the glycocalyx (84, 325, 425) might contribute to the intercept pressure. The zero-flow pressure intercept is related to intramyocardial pressure, but the relation is complex (348). If the heart is subjected to both luminal and external pressures, using an airtight chamber, the zero-flow pressure of the diastolic pressure-flow relationship is affected but the slope of the relationship is not (24). This suggests that intramyocardial pressure can contribute to the pressure-flow relationship. However, the effect is small since in diastole left ventricular and intramyocardial pressures are lower than the intercept pressure (297). CROSS-TALK BETWEEN CARDIAC MUSCLE AND CORONARY VASCULATURE 3. Effect of ventricular volume changes on coronary flow in diastole pressure of 70 mmHg, shows changes in microvascular resistance, calculated on the basis of a model, of about a factor of 2 (87, 380). However, this study applied stretch starting from short lengths, namely, “slack length.” Model calculations predict that when muscle length increases from ⬃70 to 90% of Lmax, corresponding to a ventricular lumen volume increase by a factor of 2, diastolic flow is decreased by ⬃30% (426). When the pressure-area relationship of an isolated vessel and the pressure-area relationship of the muscle cavity in which the vessel fits are added, the pressure-area relationship of the vessel embedded in muscle is obtained (159, 427). It was shown that increased diastolic chamber stiffness does affect coronary vascular compliance (435). In diastole, the cardiac muscle contributes little to the pressure-area relationship of an embedded arteriole, while the pressure-area relationship of an embedded vein is almost entirely determined by the surrounding muscle (Fig. 10). Because the small arteries and the arterioles, but not the venules, mainly determine coronary resistance, the diastolic cardiac muscle influences coronary resistance only marginally. The chosen condition of maximal vasodilation reduces the effect of the smooth muscle (see Fig. 6, where smooth muscle tone affects both slope, i.e., resistance, and intercept) on the pressure-flow relationships. Thus, from these studies with maximal vasodilation and in diastolic arrest, it may be assumed that a venous waterfall, which is reported to exist in epicardial veins, plays a role (117, 409, 434, 436). In the dilated heart in diastole, with increased cardiac muscle stiffness and higher diastolic ventricular pressure, the cardiac muscle has a larger effect on the embedded arteries and arterioles. Thus, in the dilated heart, and with most flow taking place in diastole, vasodilatory capacity of the coronary circulation is reduced and flow reserve is decreased (59). 4. Summary FIG. 9. Coronary pressure-flow relationships measured in the isolated maximally vasodilated heart in diastolic arrest are only slightly affected by left ventricular volume. The two filling pressures relate to a volume increase of about two times. [Adapted from Sipkema et al. (362).] Physiol Rev • VOL The data in the literature regarding the contribution of the diastolic cardiac muscle on the coronary vasculature are not consistent. Some publications report a small effect on resistance vessels, while others show a substantial effect. The differences may, in part, result from differences in initial cardiac muscle length and amount of stretch. However, it appears that if there is an effect it is stronger on the intercept than on the slope of the pressure-flow relationships. A model accounting for vessels embedded in cardiac muscle predicts little effect on arterioles but a strong effect on venules. The pericardium, and therefore the venous waterfall, may also account for part of the differences reported. However, reconsideration of the models and more experiments under well-defined 86 • OCTOBER 2006 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017 Several groups have reported diastolic pressure-flow relationships during maximal vasodilation. Figure 9 shows a representative example of coronary pressureflow relationships in the isolated maximally vasodilated rabbit heart in diastolic arrest for two filling pressures, corresponding to a ventricular volume change of about a factor of 2 (362). The effect is only slightly dependent on the muscle layer, i.e., subendocardial or subepicardial (264). In the open-chest dog, an increase in left ventricular volume from 20 to 50 ml (diastolic left ventricular pressure from ⬃5 to ⬃20 mmHg) did not significantly affect diastolic coronary arterial inflow (132, 134). However, when volume was increased to 60 ml (diastolic left ventricular pressure of ⬃28 mmHg), flow decreased by ⬃16%. In other studies using the isolated dog heart (436) or the in situ dog heart (119), the pressure-flow relationships in diastole show a change in the intercept but little change in slope with ventricular volume changes. After pericardiectomy, the effect of ventricular filling on the relationships is decreased possibly explaining the differences between the in situ (117, 119) and isolated heart (362). Aldea et al. (5) studied the effects of changes in ventricular lumen pressure and extraventricular pressure on coronary flow in diastolic arrest. They found an almost parallel shift to higher intercept pressures of the coronary pressure-flow relationships, when either lumen pressure or external pressure was increased. However, they also found an increase in venous pressure. Studies on the isolated perfused papillary muscle show that muscle length has little effect on coronary flow in diastole (9). Monoaxial and biaxial stretching of the isolated perfused and maximally dilated interventricular septum of the dog was reported to result in an increase in intercept pressure and resistance (333). Biaxial stretching of this preparation from slack to ⬃20%, at a perfusion 1271 1272 WESTERHOF ET AL. 1. Arterial inflow and venous outflow conditions are necessary. In the dilated heart, maximal flow and therefore CFR is limited. B. Cardiac Contraction and Coronary Flow in Systole The coronary arterial inflow is impeded and venous outflow is augmented during cardiac muscle contraction. In contraction the total vascular volume is decreased, which means that the resistance of the vasculature is increased. The cardiac muscle is also stiffer so that compliance of the embedded vasculature is decreased, also resulting in a decrease in vascular volume. The vascular volume decrease causes blood to be pumped out. This results in the arterial inflow impediment and venous outflow augmentation. Here we discuss these phenomena as an introduction to the models reported in the literature. Physiol Rev • VOL FIG. 11. Systolic coronary flow impediment. Coronary flow decreases in systole and may even reverse. [Adapted from Gregg and Green (153).] 86 • OCTOBER 2006 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017 FIG. 10. Top: schematic presentation of an isolated vessel (left) and a vessel embedded in muscle (right). Middle: diastolic pressure-area relationships of an isolated arteriole (left) and an isolated venule (right) and of the muscle cavity in which they are embedded (thin lines). Bottom: pressure-area relationships of the vessels surrounded by muscle. The dashed lines are the pressure-area relationships of the vessel alone, given for comparison with the middle panels. [Adapted from Vis et al. (427).] Anrep and co-workers (12, 13) and Gregg and coworkers (153–156) have already shown that coronary arterial inflow is impeded and venous outflow is augmented during cardiac contraction. When the coronary bed is vasodilated and cardiac muscle contractility is high, arterial inflow may even reverse in early systole (see Fig. 11). This so-called systolic arterial flow impediment has been confirmed by many research groups in isolated heart studies (48, 175, 245–249) and in the in situ heart (5, 73, 111, 115, 128, 152, 154, 175, 197, 200, 267, 412), and it has been observed in humans as well (26, 128, 198, 278, 286). It is also observed in the circumflex coronary artery in control and in increased cardiac contractility (200) and has been seen in septal coronary artery stenosis (141, 204, 227). Coronary mean pressure-mean flow relationships measured in the heart in situ during maximal vasodilation show that mean flow decreases with exercise as a result of the decreased duration of diastole. This finding emphasizes that the major contribution to mean flow is during diastole and that systolic flow is small (115). Increased venous outflow in systole is found in the great cardiac vein, and the magnitude is greater with increased contractility [202; see for discussion also the publications by Olson and Bugni (314), Hoffman and Spaan (175), and Spaan et al. (378)]. With vasodilation the vascular diameters and vascular volumes increase. This implies a smaller resistance and larger amount of blood stored in the vasculature. Thus, in vasodilation, both mean flow and the difference between diastolic and systolic flow are increased (49). Many researchers assumed that the cardiac muscle contraction generates a ventricular lumen pressure that is communicated to the interstitium, thereby causing an intramyocardial pressure (20, 111). The increased intramyocardial pressure subsequently causes a decrease in the transmural vascular pressure and thus a decrease in vascular diameter. The decrease in vascular diameters in systole causes a decrease in vascular volume, and this volume is “pumped” to venous and arterial sides of the coronary circulation. The diameter decrease also causes an increase in coronary resistance. However, there is not CROSS-TALK BETWEEN CARDIAC MUSCLE AND CORONARY VASCULATURE The impulse response has subsequently been used to derive input impedance [for details about the calculation, see Sipkema et al. (366)]. The input impedance of the coronary bed in systole and diastole is shown in the right panels of Figure 12B. It may be seen that only the 0-Hz term and low frequencies of the input impedance are affected by cardiac contraction, while the higher harmonics of the input impedance are not affected by cardiac contraction. This result is confirmed by the work of Cornelissen et al. (87) and Spaan et al. (380) who showed, by analyzing their experimental data using a lumped model of the coronary circulation, that cardiac muscle contraction exerts its main effects on the proximal part of the microcirculation (their resistance 1). 3. Summary 2. Coronary arterial input impedance The decrease in coronary arterial inflow in systole is based on changes in the coronary vascular system. The changes in the arterial part of the circulation can be studied by the derivation of arterial input impedance, which is a comprehensive description of the entire coronary arterial system. While peripheral resistance mainly characterizes the peripheral vasculature, the input impedance gives a description including both the proximal part of the vasculature, the arterial conduit vessels, and the periphery (448). Input impedance cannot be determined in the standard way by applying Fourier analysis on the pressure and flow signals, because during a heart beat the contracting cardiac muscle affects the system, i.e., we are studying a time-varying system (448). Therefore, the socalled impulse response method has been applied in systole and diastole (266, 366, 417). It was shown that the response is rather short in duration so that it can be determined in systole and diastole separately. In the left panels of Figure 12A, the impulse responses are shown, superimposed on the pressure waveform. By subtracting the waveform without impulse response from the one containing the impulse response, the response alone is calculated. As a result of cardiac contraction, flow in large arteries is impeded in systole and flow in large veins is augmented in systole. The magnitude of coronary arterial flow impediment depends on perfusion pressure and cardiac muscle contractility. Venous outflow depends on cardiac contractility and venous pressure. Two mechanisms exist to explain the findings. First, cardiac contraction causes, via the generation of ventricular pressure, an intramyocardial pressure. This decreases vascular transmural pressure and vascular diameter and volume and increases resistance. Second, cardiac contraction results in changes in the muscle properties such as stiffness, and the muscle length and thickness vary over the cardiac cycle. These phenomena directly affect the vasculature. The cardiac muscle contraction results in vascular volume and resistance changes, which mainly take place in the microcirculation. C. Models Explaining the Diastolic-Systolic Changes of the Vasculature The contracting cardiac muscle exerts an impeding effect on arterial inflow and augments venous outflow. FIG. 12. A: the impulse response of the coronary bed. A short impulse (a few milliseconds) of flow results in a pressure response as a function of time (top panel). This pressure is superimposed on the pressure resulting from cardiac contraction (dotted line). When this latter pressure is subtracted, the pure impulse response is obtained (bottom panel). B: the coronary arterial input impedance derived from the impulse response. The differences between diastole and systole are only present in the mean term, implying that the effect of cardiac contraction is mainly present in the periphery. [Adapted from Van Huis et al. (417).] Physiol Rev • VOL 86 • OCTOBER 2006 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017 only an effect of intramyocardial pressure on the vasculature but also a direct contribution of the cardiac muscle on the vasculature. The cardiac muscle becomes stiffer in systole; it may shorten and thicken leading to a decrease in vascular diameters and volume. Shortening of the cardiac muscle cells will also deform the vasculature (change branching angles at bifurcations and increase vascular tortuosity). The two mechanisms, the indirect effect through ventricular pressure and the direct effects of the cardiac muscle, both play a role depending on the conditions. For example, the contribution of ventricular pressure depends on the elastance of the ventricular wall, i.e., in systole, when the ventricular muscle is stiff, the effect of ventricular pressure is shielded off by muscle stiffness (243). The concepts and models are discussed below. 1273 1274 WESTERHOF ET AL. isovolumic), and the layer in the heart wall (subepicardial, subendocardial). 1. The waterfall model The first well-described and accepted model to explain coronary arterial inflow impediment in systole is based on the “vascular” waterfall (111) (Fig. 7). As mentioned above, the vasculature alone exhibits a zero-flow pressure intercept, which is a vascular waterfall dependent on smooth muscle tone but independent of the surrounding (cardiac) muscle. In this section we discuss the waterfall that results from cardiac muscle contraction. We therefore prefer the term waterfall model instead of the term vascular waterfall model as is most often used in the literature. Farhi et al. (122) elegantly showed that in ventricular fibrillation a cardiac muscle- and smooth muscle-based waterfall exists and that vasodilation could lower the waterfall pressure. The main aspect of the waterfall model is that the flow is not determined by the arterial minus venous pressure and vascular resistance, but by arterial minus waterfall pressure and vascular resistance (51, 122). This means that calculations of resistance, by dividing the arteriovenous pressure difference by flow (or since venous pressure is much lower than arterial pressure, simply arterial pressure divided by flow) are not correct (see sect. IIB5). The waterfall model as proposed by Downey and Kirk (111) states that ventricular pressure generates a so-called intramyocardial or interstitial pressure Pim, which acts on the outer surface of the blood vessels (Fig. 13A, left). This intramyocardial pressure is transmitted to the vascular lumen and forms the basis of the waterfall pressure. The intramyocardial pressure is assumed to be equal to ventricular pressure Plv at the subendocardium, and negligible at the subepicardium (111): Pim ⫽ k⫻Plv, with k ⫽ 1 at the subendocardium and k ⫽ 0 at the subepicardium. The intramyocardial pressure is largest in FIG. 13. The waterfall model. A: the intramyocardial pressure or interstitial pressure, here presented as external pressure to the vessel, causes a (partial) collapse, and this distal intravascular pressure is close to the external or intramyocardial pressure. Intramyocardial pressure is assumed to result from ventricular lumen pressure and equals that pressure in the subendocardial layers of the heart wall, and is decreasing to negligible values at the subepicardial side of the wall. The electrical representation of the model (A, right) contains a one-way valve, given by the diode, to prevent flow from interstitium to vessel lumen. The electrical model therefore does not allow for an increase in venous outflow during an increase in Pim due to cardiac contraction. B: predicted pressure-(in)flow relationships. Part, Pim, and kPlv are arterial, intramyocardial, and ventricular pressure, respectively. Pv is venous pressure, and the zero-flow intercept pressure is Pd ⫽ Pim. R is vascular resistance. [Adapted from Downey and Kirk (111).] Physiol Rev • VOL 86 • OCTOBER 2006 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017 The coronary arterial input impedance data show that this effect of contraction on coronary flow mainly results from changes in the vasculature. The effect of cardiac muscle contraction on the coronary vasculature is based on two mechanisms. The cardiac muscle contraction increases ventricular lumen pressure, which results in an increase in interstitial or intramyocardial pressure. This pressure is proportional to ventricular pressure and decreases the vascular transmural pressure, and thereby vessel diameter. This concept forms the basis of the waterfall model (111), and the intramyocardial pump model (19, 379). Experiments have shown that pressure, applied in the lumen of the ventricle and externally by means of a pressure chamber (5) or through the pericardium (395), has an effect on coronary pressure-flow relationships. The contraction of the cardiac muscle causes a decrease in vascular diameters and deformation of the blood vessels by a direct effect. This concept is formulated by the varying elastance model. An increase in stiffness of the cardiac muscle (vessel environment) decreases vessel lumen similar to what happens in the ventricular lumen during contraction (245, 387, 447); in the muscle shortening and thickening model, the shortening and related thickening of the muscle fibers during contraction cause a decrease in vessel diameters (426, 450); and in the vascular deformation model, deformation of the vasculature, vessel shortening, changes in bifurcation angles, and changes in tortuosity result from muscle contraction (169). Contractility has an effect on coronary pressure-flow relationships independent of ventricular lumen pressure (247, 420). It turns out that neither of these concepts, alone, completely describes what happens to the coronary vasculature during cardiac muscle contraction. Also the contribution of their effects depends on the contractile state of the heart, the mode of cardiac contraction (isobaric, CROSS-TALK BETWEEN CARDIAC MUSCLE AND CORONARY VASCULATURE FIG. 14. The intramyocardial pump model. This model improves the waterfall model. The intramyocardial pump model mimics the decrease in arterial inflow and increased venous outflow in systole and allows for reversal of arterial inflow. The capacitor in the electrical analog implies that during maintained contraction, “heart arrested in systole,” flow is not different from arrest in diastole. Symbols are as in Figure 13. [Adapted from Spaan et al. (378).] in systole is accounted for (Fig. 14). However, the compliance in the model prevents changes in mean flow between the heart arrested in diastole and systole. The electrical representation of the model contains a capacitor, implying this same limitation in static conditions. The model has been extended to include the changes in flow in the steady state of contraction, by making the resistances dependent on intramyocardial pressure (53, 376). Several lumped and distributed models have been based on the intramyocardial pump concept (19, 20, 42, 58, 66, 369 – 371, 461, 462). The modified intramyocardial pump model (53, 175, 376) does include changes in vascular volume and resistance but does not include vascular compliance changes. 3. The varying elastance model The assumption that left ventricular pressure is an accurate predictor of coronary arterial flow impediment was challenged by the experiments in the isolated bloodperfused cat heart as shown in Figure 15 (249). Similar results were observed in the in situ dog heart (420). When contractility of the heart is maintained constant while the ventricular load is changed in such a way that the ventricle contracts isovolumically (i.e., nonejecting contraction) or isobarically (i.e., contractions without pressure generation in the ventricular lumen), coronary arterial inflow is similarly affected. Thus, while ventricular pressure is changed, but aortic and coronary sinus pressures are kept constant, the effect of cardiac muscle contraction on coronary flow is similar. This led to the hypothesis that it is the variation in stiffness of the cardiac muscle during the cardiac cycle that is the cause of the flow impediment (245–247). The increasing stiffness of the muscle in systole affects the vascular volume and the lumen of the ventricle similarly, as exemplified in Figure 16. The formulation is based on the varying elastance concept as introduced by Suga et al. (387). The varying properties of the cardiac 2. The intramyocardial pump model Spaan et al. (376, 378, 379) introduced the intramyocardial pump model, originally suggested by Arts and Reneman (19, 20), which is based on the pumping action of the cardiac muscle in analogy to the ventricular pump. The intramyocardial pump model improved the waterfall model such that reversal of arterial inflow in systole (Fig. 11) can be explained and the increase in venous outflow Physiol Rev • VOL FIG. 15. Coronary flow during isovolumic beats (left, no ejection) and isobaric contractions (right, no pressure development) is similarly impeded in systole. [Adapted from Krams et al. (247).] 86 • OCTOBER 2006 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017 subendocardial layers, and thus the effect of contraction is strongest there. This model explains that with decreased perfusion pressure, as distal to a stenosis, ischemia is mostly subendocardial. The electrical representation of this model is given in Figure 13A, right. The diode in the electrical analog was introduced to prevent blood being pumped from the interstitium into the vascular system. However, the anatomical equivalent of the diode is missing, and it does not allow for negative arterial inflow in systole. Another limitation of the (electrical representation of the) model is that venous outflow does not increase in systole. The waterfall model assumes that the resistance is not affected by cardiac contraction and that the waterfall is located distally from the resistance. The model predicts coronary flow reduction in systolic cardiac arrest. This flow is only close to systolic flow in the beating heart, when also ventricular pressure has a systolic value. When in systolic arrest ventricular pressure is low, flow is not impeded, in contrast to what has been observed experimentally (362). The intramyocardial pressure effect is supported by the finding that the zero-flow pressure intercept of the coronary pressure-flow relationships is increased when lumen pressure and external pressure are increased together in the heart arrested in diastole (5). However, the zero-flow pressure intercept is little affected by an increase in pericardial pressure (260), apparently contradicting the waterfall model. The waterfall model does not account for changes in vascular resistance and volume. 1275 1276 WESTERHOF ET AL. muscle during contraction cause an increase in the slope [the elastance, E(t)] of the pressure-volume relationships of the ventricular, interstitial, and vascular compartments. When cardiac contractility is increased, the magnitude of the E(t) curve also increases, and the vascular volume decreases. The greater decrease in vascular volume causes a larger decrease in coronary arterial inflow (247) and a greater increase in venous outflow in systole. More exactly formulated, the rate of change of vascular volume determines the sum of the decrease in arterial flow and the increase of venous outflow. Baan et al. (25) and Van Winkle et al. (420) confirmed the major effect of ventricular elastance on flow impediment in the dog heart in situ. The varying elastance model implies that all arteries, capillaries, and veins are subject to the variations in cardiac muscle stiffness during contraction. Thus the suggestion implied in the waterfall model and intramyocardial pump model that cardiac contraction has its effect on the microcirculation only is not assumed in the varying elastance model. This model also abandons the idea that the effect of contraction acts via ventricular lumen pressure. The model explains that there are differences in pressure-flow relationships between diastole and systole not only in the beating heart but also in the arrested heart, in isolated perfused papillary muscle (9, 263), and in skeletal muscle. Calculations based on the varying elastance hypothesis have been carried out by Vis and co-workers (426 – 429). When an artery is embedded in muscle, the pressurePhysiol Rev • VOL volume relationship depends on the vascular wall properties and on the (varying) elastic properties of the surrounding myocardium. This means that both the elastic properties of the vessel wall and of the cardiac muscle in which the vessel is embedded contribute to the pressure-diameter relationship (Fig. 17). While for an artery in diastole its wall properties mainly determine resistance and compliance, in systole the role of the cardiac muscle properties is considerable. For a venule, the pressurediameter relationship is almost entirely determined by the surrounding muscle, both in diastole and in systole. Thus, in systole, with increased stiffness of the cardiac muscle, the muscle contributes to the pressure-diameter relationship of the vein as well as the artery. When changes in diameter due to cardiac contraction are calculated, the cross-sectional area of the arteriole decreases by ⬃50% (at a distending pressure of ⬃40 mmHg) and that of the venule by ⬃40% (at a distending pressure of ⬃7 mmHg), both at their working pressure level (Fig. 17). Thus venules are not being compressed (collapsed) completely as would be expected when intramyocardial pressure is close to ventricular pressure in the subendocardial layers. These calculations are based on vessels embedded in isolated cardiac tissue where, in contrast to the wall in the intact heart, ventricular pressure is not present. The varying elastance model accounts for vascular volume, resistance, and compliance changes. The model holds for shortening and muscle-isometric contractions, 86 • OCTOBER 2006 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017 FIG. 16. The varying elastance model. The ventricular lumen and vascular volume are both subject to the time-varying properties of the cardiac muscle. In the top two panels, the ventricular pressure-volume trajectories, dashed arrows, are shown during an isovolumic contraction (left) and an isobaric contraction (right). In the bottom two panels, the corresponding pressure-volume trajectories of the vascular volume (dashed arrows) are shown. These vascular trajectories are the same when contractility is maintained, because the perfusion pressure and venous pressure (loading conditions of the vasculature) are the same. When the load on the heart is changed, the effect on the vasculature remains the same. CROSS-TALK BETWEEN CARDIAC MUSCLE AND CORONARY VASCULATURE although the latter conditions, in practice, are nonexistent. 4. The muscle shortening and thickening model Muscle shortening also affects the vasculature since during contraction muscle cell volume is constant and muscle shortening implies an increase in muscle diameter. The increase in muscle diameter partly takes place at the expense of the vessels, thereby decreasing their diameters as shown in Figure 18 (450). This effect is not present in muscle-cell isometric contractions, because when the muscle length does not change, the diameter does not change either. The effects of changes in muscle length on the coronary vasculature in diastole have been discussed above (sect. IIIA3). Quantitative information on the effect of muscle thickening and shortening during contraction on coronary flow is lacking. ies is small (459). However, Pries et al. (324) showed that the geometry of blood vessels of the microcirculation is a determinant of resistance. It has been calculated that the capillaries, that are tethered to the cardiac muscle, also change in length during contraction (125). Mainly because deformation is not easily quantifiable and surrounding muscle structure is very complex (66, 274, 277), quantitative information is lacking. Tortuosity can be indexed by the ratio of shortest distance and total length of a vessel, but changes in tortuosity resulting from cardiac contraction have not been quantified either. Tortuosity also changes with cardiac remodeling (186). Coronary arteries bend during cardiac contraction (326) and bifurcations will change in shape (318), causing changes in velocity distribution and in resistance. McCulloch et al. (290) have reported on the complex relationship between circumferential, longitudinal, radial fiber strains, and cross-fiber strains with local blood flow. They have shown that the relationship between flow and systolic strain depends on segment orientation. In the low pressure left atrium, the velocities in the small arteries and veins are related to ventricular contraction (203), arguing in favor of the vascular deformation model. Deformation of the transmurally penetrating vessels is particularly complex (168, 169). This is in part due to the effect of shearing forces, and at present, no good model exists. Figure 19 shows the importance of the transmural vessels in the beating heart (72). The perfusion pressure, when expressed as arterial minus venous pressure, is at the subendocardium only about half of that at the subepicardium (70). This means that a decrease in perfusion pressure, such as distal of a stenosis, affects the subendocardial perfusion more than subepicardial perfusion (296). This pressure drop over the transmural vessels may be an alternative or a complementary explanation for the fact that subendocardial layers are more prone to ischemia than subepicardial layers 5. The vascular deformation model The effect of contraction on the deformation of the vasculature (changes in shape of the vascular cross-sections, branching angles, and vessel tortuosity) has received little attention. The effect in large coronary arterPhysiol Rev • VOL FIG. 18. The muscle shortening and thickening model. During muscle contraction and shortening, the muscles increase in diameter at the expense of the coronary vasculature. Purely muscle-isometric contractions would not affect the coronary flow. 86 • OCTOBER 2006 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017 FIG. 17. Blood vessels are embedded in muscle. When the cardiac muscle contracts, and becomes stiffer, the surroundings play a larger role. These model calculations show that an isolated arteriole has a pressure-area relationship given by the thick solid line (top, left), while the cavity in the cardiac muscle has a pressure-area relationship in diastole, thin line and systole, dashed line. When the arteriole is embedded in the muscle (bottom, left), the thick line gives the diastolic relationship, and the dotted line gives the systolic relationship. For a constant intravascular pressure of 40 mmHg, the diameter of the arteriole changes by ⬃50% between diastole and systole. The pressure-area relationships of the venule and surrounding muscle are given in the two right panels. The pressure-diameter relationship of the venule embedded in the muscle is almost entirely determined by the surrounding muscle, both in diastole and systole. For a constant intravascular pressure of 7 mmHg, the venular area will change by ⬃40%. [Adapted from Vis et al. (427).] 1277 1278 WESTERHOF ET AL. FIG. 19. When perfusion pressure is defined as the arteriolar-venular pressure gradient, it is about half as high in the subendocardial layers than in the subepicardial layers, thereby showing the importance of the transmural vasculature. [Adapted from Chilian and DeFily (72).] 6. Summary Two basic mechanisms have been proposed to explain the effect of cardiac muscle contraction on the vasculature. The first mechanism is that cardiac contraction through the generation of ventricular lumen pressure causes an intramyocardial pressure, and intramyocardial pressure affects vascular transmural pressure. Thus, without ventricular pressure generation, the coronary vasculature is not affected by cardiac muscle contraction (isobaric ventricular contraction and contraction in isolated papillary muscle). The waterfall model and the intramyocardial pump model are both based on this concept. The second mechanism explains the effect of contraction by means of a direct effect of the cardiac muscle on the vasculature, and the ventricular lumen pressure does not play a role. The varying elastance model, the muscle shortening and thickening model, and the vascular deformation model are aspects of this mechanism. These models can explain local effects of contraction and heterogeneity. Both mechanisms play a role, depending on the layer in the wall and mode of contraction, and can explain why subendocardial perfusion is most prone to perfusion limitation in systole. D. Applications and Limitations of the Models 1. Arterial inflow and venous outflow In systole, arterial inflow is impeded and venous outflow augmented. Coronary flow impediment results from changes in vessel diameter after contraction of the cardiac muscle. In the small vessels, the diameter variaPhysiol Rev • VOL 86 • OCTOBER 2006 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017 (169). Myocardial ischemia and reperfusion results in a transmural gradient of dysfunction in radial and crossfiber segments, but not in fiber segments (288). Hoffman (169) has presented a review of transmural vessels that are subject to deformation. tion results in a resistance change (Poiseuille’s law, Ref. 448) and in the larger vessels the diameter change mainly gives a volume change. Thus the magnitude of the arterial inflow impediment depends on the rate of change of vascular volume, the resistance, and the perfusion pressure. If resistance is high, mean flow is small, and the rate of change of the vascular volume is large (such as during high cardiac contractility), the volume change produces reversal of arterial inflow (backflow). Similarly, the rate of change of the vascular volume and the venous pressure determine the increase in venous outflow. The lower venous pressure causes most of the volume to move to the venous side of the coronary circulation. The waterfall model (111) is based on an intramyocardial pressure Pim that is transmitted to the interstitium and, subsequently, to the intramyocardial blood vessels generating a “back pressure” (Fig. 13A). The intramyocardial pressure is assumed to be proportional to ventricular lumen pressure Plv and decreasing from subendocardium to subepicardium. The increase in back pressure in systole explains arterial inflow impediment. Thus the relationships between pressure and arterial inflow show a change in intercept, but no change in slope (resistance) during cardiac contraction (Fig. 13B). Vascular volume and vascular resistance changes are not made explicit in this model. Therefore, the increase in venous outflow and the reversal of arterial inflow in systole are not represented in the model. When intramyocardial pressure is higher than arterial pressure, the model implicitly assumes that flow is not reversing but is negligible. This is made clear in the electrical representation of the model (Fig. 13A, right), which contains a diode. The diode does not have a direct hydraulic equivalent but was introduced to prevent volume from moving from the extravascular to the intravascular compartments when intramyocardial pressure is higher than coronary arterial pressure. The intramyocardial pump model (Fig. 14) (378) maintained the idea that intramyocardial pressure is proportional to ventricular lumen pressure, but made a conceptual step forward by allowing for arterial flow impediment, inflow reversal, and venous outflow increase in systole. The vascular compliance is modeled, but constant, and vascular volume changes are modeled by the changes in intramyocardial pressure (Pim). In the original publication (378) resistance is not changed during contraction. In a subsequent approach (53) the arterial and venous resistance were made to change as well. Since the waterfall model and the intramyocardial pump model require ventricular pressure as an essential intermediate step to explain coronary flow impediment, they do not predict flow impediment during isobaric ventricular contractions (Fig. 15) and in isolated perfused papillary muscle (9, 263). The varying elastance model (Figs. 16 and 17) predicts vascular volume changes and thus changes in coro- CROSS-TALK BETWEEN CARDIAC MUSCLE AND CORONARY VASCULATURE 2. Static versus dynamic systole The separation of pressure-flow relationships into diastolic and systolic relationships is difficult to perform. This difficulty is mainly caused by the fact that not only pressure and flow are time dependent but that the vasculature varies in time as well. Several investigators have, in different ways, attempted to separate the coronary pressure-flow relationships into their systolic and diastolic subparts. For instance, the relation between mean flow and pressure and the pressure-flow relationship in diastolic arrest can be subtracted to estimate the systolic pressure-flow relationship (22, 128, 184). On the one hand, errors may occur because the filling and emptying of the vascular compartment is not easy to account for in this subtraction approach, but on the other hand, Bouma et al. (48) showed that the coronary flow impediment in systole is mainly the result of resistance changes, rather than arterial compliance changes. Aldea et al. (5) have reported pressure-flow relationships in systolic arrest in the in situ heart. Sipkema et al. (362) reported pressure-flow relationships in the isolated rabbit heart arrested in diastole and in systole (Fig. 20). The data show that pressureflow relationships are different between diastole and systole in the beating heart and in cardiac arrest. Similar results have been reported on the interventricular septum Physiol Rev • VOL FIG. 20. An example of pressure-flow relationships in systole and diastole in the beating heart and the same heart arrested in systole and in diastole. [Adapted from Sipkema et al. (362).] (273). Lamberts et al. (264) showed that pressure-flow relationships in the subendocardial and subepicardial layers of the isolated rat heart also differ between diastolic and systolic arrest. The waterfall model (Fig. 13) predicts differences between the coronary pressure-flow relationships in the beating heart as well as in static systole and diastole as obtained by cardiac arrest. However, the differences in systolic and diastolic flow in the arrested heart are predicted to take place only if ventricular pressure is high in the systolic arrest. The intramyocardial pump model, in its original form (Fig. 14), does not predict differences in the pressure-flow relationships in the diastolically and systolically arrested heart (378). However, Spaan and coworkers (243, 376, 380) have improved the intramyocardial pump model to include changes in resistance with cardiac contraction so that static contraction effects are predicted. The varying elastance model applies to both the beating condition and to arrest. In the beating condition, both the changes in resistance and in vascular volume play a role, while in arrest only the larger resistance in systole is contributing. Therefore, the differences between systolic and diastolic flow are present in both the beating and arrested heart, but smaller in cardiac arrest. The muscle shortening and thickening model and the vascular deformation model both predict that the coronary flow in the heart arrested in systole is smaller than in diastole, but quantification is missing. In summary, pressure-flow relationships in the heart arrested in systole and arrested in diastole show that flow impediment is present and not only found in the beating condition. This difference in inflow implies that resistance is higher because vascular volume is smaller. All models can account for this except the original version of the intramyocardial pump model. In the waterfall model, it is 86 • OCTOBER 2006 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017 nary resistance. The varying elastance model also explains the changes in vascular compliance, because the vessel wall and the cardiac muscle in which the vasculature is embedded determine in situ vascular compliance. The muscle thickening and shortening model (Fig. 18) predicts changes in vascular volume and thus also in resistance during cardiac contraction. This model explains arterial inflow impediment and venous flow augmentation. The vascular deformation model is predicted to mainly change resistance, and therefore, backflow and venous outflow augmentation are not included in the model. Neither of these two models has been worked out quantitatively. It was shown that cardiac contraction also forms an important defense against the formation of interstitial edema (8, 419). In summary, under physiological conditions, all models contribute to the explanation of coronary arterial inflow impediment. The effect of cardiac contraction based on the intermediate role of ventricular pressure cannot explain the flow impediment in isobaric beats (Fig. 15) and isolated perfused cardiac muscle. The varying elastance model and the muscle shortening and thickening model, and the vascular deformation model, through their direct effect on the vasculature, can explain impediment in isobaric contractions and isolated muscle. The venous outflow augmentation in systole is not included in the waterfall model. 1279 1280 WESTERHOF ET AL. the increase in back pressure rather than resistance increase that explains the impediment. The waterfall model and the intramyocardial pump model require that in systolic arrest, ventricular pressure is high for flow to be smaller. In some reports, the difference in pressure-flow relationships between static and dynamic systole is small, suggesting that the role of vascular compliance is limited. However, arterial inflow reversal must result from the rate of change of vascular volume, implicating vascular compliance. 3. Coronary arterial input impedance Physiol Rev • VOL 4. Effect of contraction in layers of the heart wall In the normal physiological condition, mean flow in subendocardial and subepicardial layers differs little (176, 237, 249). However, during perfusion in systole only, flow is smaller in subendocardial layers than in subepicardial layers (110). The contributions of contractility and aortic pressure (afterload) were shown to depend on the layer in the heart wall, and dobutamine decreased systolic subendocardial flow less than subepicardial systolic flow (184). However, systolic flow was not measured but calculated from the difference in flow between beating and systolic arrest. In general, subendocardial flow is more affected by cardiac muscle contractility than subepicardial layers. The waterfall and the intramyocardial pump model explain, by assuming that Pim ⫽ k⫻Plv, with k ⫽ 1 at the subendocardium and k ⫽ 0 at the subepicardium, that the effect of contraction is most important in the subendocardial layers. Aldea et al. (5) studied the effects of luminal and external pressure on coronary overall flow and flow in different layers and showed the importance of pressure in the wall. The varying elastance model, under the assumption that no differences in cardiac muscle properties exist between subendocardial and subepicardial layers, cannot explain the different effects of cardiac muscle contraction in these layers. Although detailed information on cardiac muscle properties, length, and shortening in different layers has not been reported, these differences may exist. For instance, a recent study by Neagoe et al. (308) reports 86 • OCTOBER 2006 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017 The changes in coronary arterial input impedance with cardiac contraction are shown in Figure 12. Other studies report similar results (60, 194, 195, 445). The general finding is that the impedance, and parameters derived from models such as the windkessel model (282, 444, 445, 448), are little affected by contraction except for the resistance, which is mainly located in the microcirculation. The small effect at low frequencies, where compliance dominates the input impedance (448), suggests that most compliance is located in the epicardial arteries, and variation with contraction is small. Spaan et al. (380) derived, in the isolated perfused interventricular septum in diastole, the coronary arterial input impedance (in terms of its inverse, i.e., admittance) by using sine waves of pressure and flow. They showed, on the basis of a two-compartment model, that input impedance depends on perfusion pressure and that volume dependence of the resistances of the model is required to obtain reasonable estimates of intramyocardial compliance (⬃0.3 ml · mmHg⫺1 · 100 g tissue⫺1). The waterfall model (111) and the original version of the intramyocardial pump model (378), where resistances were assumed to be constant, do not correctly predict the changes in input impedance, i.e., the change in resistance. The later version of the intramyocardial pump model (376), where resistance does change, is in agreement with the impedance change. The varying elastance model is supported by the fact that resistance changes are due to changes in muscle stiffness. The results obtained by wave intensity analysis also support the varying elastance model (174, 389, 390). The muscle shortening and thickening model and the vascular deformation model also predict changes in resistance. Surprisingly, little attention has been paid to the analysis of flow waveforms in the coronary circulation. In the systemic and pulmonary circulation, numerous studies exist that extract important information from the pressure and flow waveforms themselves, as well as by means of impedance calculation and wave reflection (315, 448). This type of sophisticated analysis has not yet been developed for the coronary circulation. Sun et al. (389, 390) used wave-intensity analysis to obtain information on the effects of cardiac contraction on the coronary system. These authors were able to separate the effects of contraction in proximal (aortic) and distal (microcirculatory) (389) and show that coronary systolic flow impediment depends on contractility (390). Thus wave intensity analysis provides important information (174), but its use is still limited. Recently, several clinical groups indicated the importance of the information contained in the flow waveform, especially its pulsatility, i.e., the difference between maximal diastolic flow and minimal systolic flow, by showing that in bundle branch block peak flow and acceleration of flow differ from the normal pattern (367, 368). Also, the effect of thrombolysis in infarction (454), aortic stenosis (224), hypertrophic cardiomyopathy (4), and aortic stenosis (456) on the arterial inflow pattern has been reported. In summary, the varying elastance model, the muscle shortening and thickening model, and the vascular deformation model explain input impedance better than the waterfall model and the intramyocardial pump model. Data on input impedance in diastolically and systolically arrested hearts are not yet available. Waveform analysis is virtually lacking in coronary research but could provide important information. CROSS-TALK BETWEEN CARDIAC MUSCLE AND CORONARY VASCULATURE Myocardial bridging (7), where an epicardial coronary artery runs intramurally through the myocardium, results in compression of the artery in systole and decreased perfusion pressure in systole. Subepicardial intramyocardial pressure is negligible according to the waterfall model and intramyocardial pump model and therefore do not suggest a role of cardiac contraction in bridging. The varying elastance model, the muscle shortening and thickening model, and the vascular deformation model can explain the effect of contraction on bridging. In summary, the waterfall model and intramyocardial pump model explain the smaller flow in systole in subendocardial layers compared with that in subepicardial layers. This explains the finding that infarcts are most often found at the subendocardium. The varying elastance model, the muscle thickening and shortening model, and the vascular deformation model can explain layer-dependent effects on flow if muscle properties, lengths, or shortening differ between layers, and when the effect of contraction on transmural vessels, lowering the subendocardial perfusion gradient, are taken into account. Quantitative comparison between the effects of intramyocardial pressure, differences in muscle properties in different layers, and the effect on transmural vessels require more measurements and modeling. 5. Cardiac contraction and the coronary microcirculation FIG. 21. Model calculations on the effect of cardiac contraction on vessel area (top) and resistance (bottom) in subendocardial and subepicardial layers of the heart. E is the effect of elastance, P the effect of ventricular pressure, and is the effect of muscle shortening. Isovolumic and isobaric contractions are indicated by iv and ib, respectively. It can be seen that the contributions of ventricular pressure, elastance changes, and muscle shortening depend on the type of contraction and layer in the heart wall. [Adapted from Vis et al. (426).] Physiol Rev • VOL A) FLOW AND VELOCITY IN THE MICROCIRCULATION. Blood flow and blood flow velocity in the coronary microcirculation during contraction have been reported (21, 79, 81, 199, 206, 230, 231, 406). In subepicardial arterioles and venules (15–30 m in diameter) and in capillaries, flow velocity during the isometric contraction phase of the left ventricle decreases strongly and even reverses (Fig. 22). Then, already during the remaining part of systole, flow increases and subsequently decreases slowly in diastole due to the decreasing perfusion, or aortic, pressure (Fig. 22A). These data on microvascular velocity in the subepicardium (Fig. 22A) hardly show the reversal of arteriolar inflow and no augmentation of venular outflow in systole. Actually, the velocities, in arteriole and venule, are rather similar in magnitude and wave shape (21). Differences between subendocardial and subepicardial arterial blood flow velocities are shown in Figure 22, B and C, and these patterns show some similarities. In the wall of the left atrium in systole, flow is impeded in the small arteries and increased in the veins (203). These findings suggest that the effect of the contracting muscle is located distal of the small venules, or that in the microcirculation heterogeneity (see below) is large and that the decreased arterial inflow and increased venous outflow are only seen in the large vessels as a summated effect (79). 86 • OCTOBER 2006 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017 layer-dependent differences in the expression patterns of titin isoforms at least implying differences in diastolic function of muscles in these layers. The muscle shortening and thickening model and the vascular deformation model can explain differences in the layers, because shortening of the cardiac muscle fibers, and thus vascular deformation, are most prominent in the subendocardium. The three models also predict deformation of the transmural vessels in systole, which results in a decrease in perfusion pressure of the subendocardial layers (Fig. 19). A quantitative comparison between the effect of intramyocardial pressure and the effect of an increased pressure gradient over the transmural vessels on subendocardial flow is not available. Model calculations show (Fig. 21) that when the varying elastance, intramyocardial pressure, and muscle shortening are taken into account, their contributions depend on the myocardial layer (426). It may also be seen from these calculations that for isovolumic contractions where muscle shortening is small, pressure and muscle stiffness play the major role, whereas for isobaric contractions, shortening is an important contributor to flow impediment. This is a strong argument favoring a role for both mechanisms (via ventricular pressure and direct effects) depending on the layers and condition of contraction. 1281 1282 µ WESTERHOF ET AL. µ Physiol Rev • VOL behave the same way. Diameter or volume changes of coronary resistance vessels in control and vasodilation can be measured in the intact heart using high-speed NMR (165), and this could potentially open the way to study the microvasculature during the cardiac cycle in the in vivo heart. That complete collapse of vessels is not taking place argues against an intramyocardial pressure in the subendocardium that is close to ventricular pressure. This is especially the case for thin-walled venules where a much larger pressure outside than inside the vessel would result in complete collapse. The waterfall model and intramyocardial pump model predict that with an intramyocardial pressure close to ventricular lumen pressure, both arteriole and venule would be compressed in systole. That a complete vascular collapse does not occur is an argument in favor of the varying elastance model, the muscle shortening and thickening model, and the vascular deformation model (see also sect. IIID6). This can be understood as follows: local effects of contraction produce a local interstitial pressure, but the magnitude of this pressure depends also on how easily interstitial fluid can move out and how blood from the vessels can be pumped out. If the local volume is constant (“isovolumic”), the intramyocardial pressure will be high. When blood is pumped out, interstitial pressure will be much lower. Veins are a lowpressure system and thin walled, and the displacement of the blood can be large so that intramyocardial pressure in the vicinity of the veins is small and they will not be compressed more than the arterioles. Calculations by Vis et al. (427) show that indeed diameter changes in arte- 86 • OCTOBER 2006 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017 µ The waterfall model and the intramyocardial pump model are made to explain the global effects of contraction on arterial inflow (and venous outflow) only. The varying elastance model, the muscle shortening and thickening model, and the vascular deformation model predict, depending on the local behavior of the cardiac muscle, what happens (250). However, their applicability to the microcirculation has not been tested. B) DIAMETERS IN THE MICROCIRCULATION. Neither subendocardial arterioles nor subendocardial venules are completely compressed (collapsed) in systole (305, 422, 452, 166). In fact, both the diameter of the small subendocardial artery and vein change in the order of 11 and 30%, respectively, around their mean during the cardiac cycle (Fig. 22, B–D). Hiramatsu et al. (166) reported similar results on diameter changes in venules and arterioles. The diameter changes in arteriole and venule (Fig. 22B) while blood is pumped out against a high pressure in the arteriole, and a low pressure in the venule is roughly similar in pattern as well. This suggests that intravascular pressure does not increase much in the venule, thereby protecting the venular diameter from large changes. The diameter of the subepicardial arteriole changes little during contraction, while the diameter of the subendocardial arteriole decreases by ⬃30% (Fig. 22, C and D). It has been reported that capillary volume and thus capillary diameter vary little between diastole and systole in arrested, i.e., static, conditions (405). Whether or not this is also the case in the beating heart remains unclear. Nevertheless, because subendocardial diameters of arterioles and venules both vary over the cardiac cycle in a similar manner (Fig. 22B) (440), it is reasonable to assume that the capillaries also FIG. 22. A: red blood cell velocity in subepicardial arterioles (12.8 ⫾ 4.1 m), capillaries and venules (16.5 ⫾ 6.5 m). The arteriolar velocity graph is repeated for comparison. [Adapted from Ashikawa et al. (21).] B: the diameter changes in a subendocardial arteriole and venule. Both the venule and arteriole do not collapse under the external pressure. [Adapted from Yada et al. (452).] C and D: diameter changes and flow velocity in subepicardial (left) and subendocardial (right) arterioles. The R signifies the R-wave in the ECG. [Adapted from Toyota et al. (406).] CROSS-TALK BETWEEN CARDIAC MUSCLE AND CORONARY VASCULATURE Physiol Rev • VOL principle, able to account for heterogeneity of perfusion, but needs to be developed in further detail. D) VENULES PROTECT ARTERIOLES FROM COLLAPSE. If an arteriole is accompanied by, or is in close proximity to, venules, the venules will decrease in size during contraction, thereby “unloading” the interstitium, giving a lower intramyocardial pressure, and protecting the arteriole. It has been calculated that the thin-walled vein with lower intraluminal pressure varies ⬃30% in diameter and the change in arteriolar diameter is only ⬃10% (Fig. 23). Thus the resistance arteries are protected from changes by the variations in venular diameter (428). This theoretical prediction is partly supported by experimental data. Subendocardial arterioles and venules both decrease by ⬃10% in diameter is systole (166), which is roughly in line with the prediction of Vis et al. (426). Yada and co-workers (451, 452) reported that the change in subendocardial diameters depends on vasomotor tone, which changes the vascular mechanical properties. Hiramatsu et al. (166) showed that in systole, an intramyocardial arteriole, when accompanied by a venule, decreased in diameter, while the venular diameter was not affected. So apparently, direct coupling between arterioles and venules is not sufficiently described by the model of Vis et al. (426). Note that the accompaniment of arterioles and venules is species dependent (217–219). In summary, At the microcirculatory level, flows are not clearly showing arteriolar systolic flow impediment and venular flow augmentation, while these phenomena are obvious in flows measured in large epicardial arteries FIG. 23. When an arteriole is accompanied by two venules, the effect of cardiac contraction is mainly on the venules. The venules, with low pressure and thin wall, are easily emptied and change in diameter while the arteriole is “protected.” [Adapted from Vis et al. (428).] 86 • OCTOBER 2006 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017 rioles and venules are not considerably different, and measurements show the same (Figs. 17 and 21). The roughly similar effects of contraction on venular and arteriolar diameters could suggest that capillary diameter changes will also be of the same magnitude. Because the arterial compartment (arteries ⬎200 m), the venous compartment (veins ⬎200 m), and the capillary compartment all account for ⬃30 – 40% of the coronary blood volume (218), all compartments contribute similarly to the volume changes and the intramyocardial pump. C) HETEROGENEITY OF FLOW. In the maximally dilated heart in diastole, where the role of both smooth muscle and cardiac muscle contraction is minimal, it can be assumed that perfusion heterogeneity is determined by the vascular anatomy. Models based on fractal branching patterns can give an explanation based on the anatomy (33, 213– 215). However, metabolic flow regulation (158) and local effects of contraction are expected to play a role, and local perfusion is then not determined by the vascular anatomy alone. Nevertheless, fractal flow patterns have been reported in the regulating coronary bed as well (29, 30, 32, 33, 96). The waterfall model (111) and intramyocardial pump model (376, 378) account for layer differences, i.e., more coronary flow impediment in subendocardial layers than in subepicardial layers in systole (111, 137). The varying elastance model (245–249) was originally presented as a lumped model as well. The calculations by Vis et al. (426) can, in principle, account for heterogeneity of coronary flow if there is heterogeneity in muscle behavior. However, this has not been worked out quantitatively, and no experimental data are available. Intramyocardial pressure depends on the local “load” of the interstitium as mentioned above (see also sect. IIID6). This means that with heterogeneity in muscle contraction and in vessel density and size, heterogeneity in impediment can arise. Similarly, local differences in muscle shortening and thus thickening may cause flow heterogeneity. Deformation of the vasculature may also depend on the region. In addition to these effects, it appears that isolated subendocardial and subepicardial arteries respond somewhat differently to transvascular pressure pulsations (374). Comprehensive models are needed to account for heterogeneity, shape changes, and different effects of contraction on layers in the wall (128) and their interaction. Most models are based on the effect of contraction via ventricular pressure only and cannot explain heterogeneity. Models now being developed should include local effects (41, 42, 66, 369 –371, 427– 429) and thus give new insight into local coronary flows, diameters, and intramyocardial pressure (369). The waterfall model and intramyocardial pump model only explain the global effect of contraction on coronary perfusion. The other group of models is, in 1283 1284 WESTERHOF ET AL. 6. Intramyocardial pressure A) MEASUREMENT OF INTRAMYOCARDIAL PRESSURE. Many attempts to measure intramyocardial pressure, starting with those of Gregg (152) and more recently by others (40, 162, 162, 297, 327), were carried out to relate intramyocardial pressure and flow impediment (124, 175, 309, 376, 443). The methods are summarized in Figure 24 and discussed in the legend. The closed method mimics contractions where the interstitial cavity is under “isovolumic” conditions (see below), and the perfusion method mimics what happens to blood flow during contraction, including vascular emptying. The three other methods measure pressure in, presumably, the interstitium, and it is not clear whether the local “cavity” is in an “isovolumic” condition (see below). The micropipette method probably causes the smallest amount of damage, but whether this small cavity can be considered isovolumic is not known and difficult to determine. B) INTRAMYOCARDIAL PRESSURE EXPLAINED. The varying elastance model pertains not only to the ventricular lumen, but to the interstitium as well (Figs. 16 and 24). Furthermore, the pressure in the interstitium depends on the varying stiffness of the cardiac muscle and on the “load” on the cavity where pressure is measured. If the cavity behaves “isovolumic” (compare the isovolumically contracting ventricle), measured pressure will be high. If the FIG. 24. Methods to measure intramyocardial pressure. The open method simply introduces a small, fluid-filled catheter in the muscle, and pressure is measured with an external transducer. In the closed method, a small tube with a closed end is introduced into the ventricular wall. In this way an “isovolumic” intramyocardial pressure is measured. In the perfusion method, a thin tube is threaded through the wall; the tube is perfused with a constant pressure, and the flow impediment is measured. In the solid state method, a catheter-tip manometer, usually with recessed sensor tip, is inserted in the wall and pressure is measured. With the micropipette method, a very small micropipette (⬃7 m) is inserted in the wall, and pressure is obtained using the servo-null technique; with this method damage is presumably minimal. Physiol Rev • VOL 86 • OCTOBER 2006 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017 and veins. The waterfall model and intramyocardial pump model are global models, accounting for differences in the effects of cardiac contraction in different layers, but not for heterogeneity. The varying elastance model, the muscle shortening and thickening model, and the vascular deformation model can explain local differences when heterogeneity in cardiac muscle contraction exists. Further studies are required to quantify the effects of heterogeneity of cardiac muscle contraction on local flow. The changes in diameters of both arterioles and venules are not much different, and venules do not collapse in systole. This is difficult to explain with the high intramyocardial pressure predicted by the waterfall model and intramyocardial pump model. The varying elastance model, the muscle shortening and thickening model, and the vascular deformation model suggest another explanation for intramyocardial pressure (see sect. IIID6) and can explain that diameter changes in arterioles and venules are of the same order. The thin-walled low-pressure venules can protect arterioles in their proximity from strong diameter decreases in systole because the venules “unload” the interstitium, resulting in a lower intramyocardial pressure. Models need to be developed to match the local, heterogeneous effects of cardiac muscle contraction with the global effects of cardiac contraction on coronary flow. CROSS-TALK BETWEEN CARDIAC MUSCLE AND CORONARY VASCULATURE In summary, analogous to what happens in the ventricular cavity, the measured intramyocardial pressure depends not only on cardiac muscle contraction, but also on how the cavity, where it is measured, behaves. If the cavity is behaving “isovolumically,” i.e., no volume displacement, intramyocardial pressure is high. If the vessels (venules and arterioles) and the, local, interstitial space can be emptied, i.e., when the volume can be pumped out (“low load”), the intramyocardial pressure development due to contraction will be small. Thus intramyocardial pressure depends on mechanical cross-talk and is not simply related to ventricular pressure as assumed by the waterfall model and intramyocardial pump model. 7. Flow reserve and supply-to-demand ratio CFR (see above) is the ratio of flows during maximal vasodilation and reference conditions. It depends on the resistance of the stenosis and that of the microcirculation. Cardiac contraction affects the coronary microvasculature in systole, and the magnitude of this effect depends on the cardiac contraction and the mechanical properties of the vasculature, which in turn depends on the vasoactive state. Thus the CFR depends not only on the severity of the stenosis but also on the effect of cardiac contraction on microcirculatory resistance. The effect of contrac- FIG. 25. The varying elastance hypothesis applied to the interstitium. A: the interstitial or intramyocardial pressure is considered as a “lumen” with surrounding cardiac muscle. The muscle properties change, causing an increase in elastance of the cavity in systole. Intramyocardial pressure depends on the elastance increase and the ease with which fluid can leave the interstitial space or with which blood and lymph vessels can empty. B: intramyocardial pressures are shown in diastole and systole in control (isovolumic, “working”) and isobaric (“nonworking”) beats. The increase in intramyocardial pressure in systole is still present in isobaric contractions, supporting the varying elastance hypothesis. [Adapted from Mihailescu and Abel (297).] Physiol Rev • VOL 86 • OCTOBER 2006 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017 sensor causes damage and interstitial fluid leaks out (compare ejecting ventricle), the measured variations in pressure over the cardiac cycle will be low. This may explain the variation in the reports on intramyocardial pressure (443). The measurements of intramyocardial pressure using the servo-null method, thereby causing minimal damage (163, 164, 297), show that intramyocardial pressure increases from the subepicardium to the subendocardium. However, the dependence on ventricular pressure is limited. Even for isobaric beats where ventricular pressure is negligible, intramyocardial pressure is still considerable (Fig. 25). Kresh et al. (251) showed that intramyocardial pressure in the subendocardium may be higher than ventricular pressure. These findings can be considered evidence that intramyocardial pressure is not directly proportional to and always smaller than ventricular lumen pressure. Both the waterfall model and the intramyocardial pump model assume that for isobaric beats, when no ventricular pressure is generated, intramyocardial pressure is negligible as well, and thus flow impediment is not expected. Nevertheless, flow impediment under these conditions is found (see Fig. 15). During both isovolumic and isobaric contractions, the varying elastance, muscle shortening and thickening, and vascular deformation models have an effect on the interstitium, blood vessels, and flow. 1285 1286 WESTERHOF ET AL. E. Cardiac Contraction Augments Coronary Flow It has been shown in the intact heart (332), and in isolated coronary vessels (126, 143, 323, 373, 374), that cyclic vascular or transmural (143) pressures affect smooth muscle tone. This effect may be direct (143) or through endothelial mediators, such as endothelium-derived hyperpolarization factor (126, 323) or nitric oxide (NO) (373, 374). Altman et al. (10) were one of the first to show that NO syntheses inhibition during exercise antagonized coronary vasodilation. Also longitudinal (axial) cyclic stretch affects the cytoskeleton of (renal artery) endothelium, together with vascular reactivity (363). It can therefore be hypothesized that cardiac contraction, through external pressure and deformation of the vascular wall, including the endothelial cells, can also affect smooth muscle tone. Compression of the entire heart, large enough for coronary flow to stop, as surrogate for externally induced changes in vessel diameter due to contraction, is followed by reactive hyperemia as a result of vasodilation. The hyperemic response is qualitatively similar to the well-known short coronary artery occlusion (341), which is also followed, after release, by a reactive hyperemia (Fig. 26). Both the compression- and occlusion-induced hyperemia are eliminated by inhibition of NO synthesis using NG-nitro-L-arginine methyl ester (LPhysiol Rev • VOL FIG. 26. Top: reactive hyperemia obtained by external cardiac compression, mimicking extravascular compression (Ext Pr), and coronary artery occlusion in control (top 2 tracings) and after L-NAME (bottom 2 tracings). The top tracing shows mean coronary flow as a function of time following a coronary occlusion and as a result of external cardiac compression, as indicated by the second tracing. In both interventions, flow is stopped and hyperemia follows. However, the hyperemia following coronary occlusion is smaller than the one caused by compression. Bottom: after NO blockade by L-NAME, the hyperemia has disappeared (bottom 2 tracings). It is therefore concluded that compression of the coronary vasculature by application of an external pressure, and most likely also by cardiac muscle contraction, is affecting vasomotor tone through NO signaling. [Adapted from Sun et al. (388).] NAME) (388). Gattulo et al. (133) also showed that NO is involved in reactive hyperemia. Apparently the diameter changes of the vessels, resulting from pulse pressure (332) or from cardiac contraction and compression, have an effect on the endothelium and vasoreactivity. This indirect dilatory effect of cardiac muscle contraction on the coronary vasculature may in part compensate for the direct compression of the vasculature and the flow impediment. In summary, cardiac contraction, through changes in transmural pressure, results in release of mediators contributing to vasodilation. It is suggested that longitudinal stretch of the vessels also has an effect. F. Effects of Cardiac Muscle on the Coronary Vasculature: Summary Mechanical cross-talk depends on the mechanical properties of the cardiac muscle (contractility) and the mechanical properties of the vasculature (vasomotor tone). In diastole, the effect of the cardiac muscle on the coronary arteries and arterioles is controversial, but probably small. The diastolic cardiac muscle does determine venous compliance. The effects of cardiac filling and papillary muscle length on coronary flow depend on the working muscle length and the amount of stretch, which may, in part, explain the differences. In systole the cardiac muscle has an effect on arteries, arterioles, and veins, and contraction impedes arterial inflow and augments coronary venous outflow. The main effects take place in the smaller intramyocardial vessels. These global findings are not clearly mirrored in the mi- 86 • OCTOBER 2006 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017 tion may be avoided by determining pressure-flow relationships in diastole only (280). The FFR is the ratio of the maximal flow in the bed perfused by the stenosed artery and the maximal flow in a normal, unstenosed area. When muscle contractility differs between these areas, for instance, when cardiac muscle contractility is higher in the normal region than in the region distal of the stenosis, maximal flow in the reference region is underestimated and the FFR is not a good measure of the stenosis severity. The supply-to-demand ratio assumes that the effect of cardiac contraction (on the subendocardial layers) is such that coronary perfusion is negligible in systole. The systolic flow impediment in systole depends on cardiac contractility and ventricular pressure. Therefore, flow in subendocardial layers may not always be negligible in systole, thereby making the supply-to-demand ratio meaningless. In summary, the CFR and the FFR depend on the effect of cardiac muscle contraction on the coronary vasculature. Thus these parameters may not give the correct information about the severity of a stenosis. The supplyto-demand ratio assumes negligible systolic flow in subendocardial layer. However, subendocardial systolic flow depends on cardiac muscle contraction and, when this flow is not negligible, the supply-to-demand ratio is meaningless. CROSS-TALK BETWEEN CARDIAC MUSCLE AND CORONARY VASCULATURE have shown that when regional contraction is abolished and elastance is small, ventricular pressure has an effect on the vasculature or starts to play a more prominent role (108, 243, 317). Pagliaro et al. (317) have shown that for low left ventricular pressures, the major determinant of flow impediment is contractility, while at high left ventricular pressure, the pressure is most important (317). It was also shown that lymph vessels are protected from collapse from high ventricular pressure by the stiff systolic muscle (160, 418). Epicardial lymph pressure during stop flow was shown to depend on ventricular pressure (161). However, experimental quantification is still limited because intramyocardial pressure is difficult to measure and depends on local “load” (443). Moreover, muscle shortening and thickening and vessel deformation at the micro scale are also difficult to quantify. The overall picture of factors contributing to coronary flow impediment is qualitatively summarized in Figure 27. Detailed models of global pressure-flow relationships exist (41, 42, 66, 369 –371, 427– 429) but are, in general, only based on the intramyocardial pressure being proportional to ventricular pressure. Thus the effect of contraction on layers is included and the predictions can be tested against experiments (128, 264). However, comprehensive models including the contribution of (local) muscle contraction are necessary to incorporate the local effects. In this way, heterogeneity, local effects of con- FIG. 27. Comprehensive summary of the effect of cardiac contraction on the coronary vasculature. Cardiac muscle contraction causes, apart from the heart acting as a pump and generating ventricular pressure, a pumping action on the interstitium and vasculature. The two major mechanisms of cardiac muscle contraction on the coronary vasculature are as follows: the contraction of the cardiac muscle cells generates a ventricular pressure, which in turn generates an intramyocardial pressure. Increased intramyocardial pressure causes a decrease in transmural pressure and vascular diameters. The waterfall model and the intramyocardial pump model are based on this effect. The cardiac muscle cells contract and thereby stiffen, shorten, and thicken. Increased cardiac muscle stiffness decreases vascular diameters and volume, giving a pumping action. In addition, interstitial volumes decrease, thereby producing an intramyocardial pressure. Muscle shortening and thickening in ejecting contractions lead to vascular deformation (changes in branching angles, tortuosity) and vascular volume changes. The varying elastance model, the muscle shortening and thickening model, and the vascular deformation model are based on these effects. Both of these major effects play a role. Their contribution depends on the type of contraction and on the layer in the heart wall (subendocardium or subepicardium). In isobaric ventricular contractions and in the isolated papillary muscle, the first mechanism does not contribute. Physiol Rev • VOL 86 • OCTOBER 2006 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017 crocirculation. Two basic mechanisms play a role in coronary flow impediment in systole. First, the muscle-generated tension produces a pressure in the ventricular lumen, and through this pressure an intramyocardial pressure is generated, in such a way that it decreases from subendocardium to subepicardium. In other words the ventricular pressure is a necessary intermediate step in the flow impediment. The waterfall model and intramyocardial pump model are based on this mechanism. Second, muscle contraction per se results in increased stiffness of the muscle and in shortening, and thickening, thereby deforming the vasculature. The varying elastance model, the muscle shortening and thickening model, and vascular deformation model are based on this mechanism and explain a direct effect on the vasculature. Muscle contraction also results in an intramyocardial pressure that depends on the local “load” (443). Data on isolated papillary muscle show flow impediment (9), which can only be explained on the basis of the direct effect of muscle contraction on the vasculature and not through ventricular pressure because there is no lumen present. The summary is given in Figure 27. Calculations by Vis and co-workers (426 – 429) (Fig. 21) show that both mechanisms contribute to flow impediment depending on the way the heart contracts (isovolumically or isobarically) and on the layer in the heart wall (subendocardial or subepicardial). Several publications 1287 1288 WESTERHOF ET AL. traction, shape changes of the vasculature (324, 325), and the interaction of these effects can be accounted for and perhaps translated into the global effects of contraction. IV. THE CORONARY VASCULATURE AFFECTS THE CARDIAC MUSCLE A. Coronary Flow and Cardiac Muscle in Diastole In 1960, Salisbury et al. (343) demonstrated that alterations in coronary perfusion changed diastolic left ventricular distensibility. This phenomenon was attributed to an “erectile effect” of the coronary vasculature. Although some investigators could not reproduce this effect (1, 398), it is generally agreed that an increase in coronary perfusion shifts the diastolic ventricular pressure-volume relationship upward and leftward, leading to increased ventricular stiffness (89, 121, 130, 131, 287, 289, 304, 313, 334, 431, 449). However, there is discussion whether flow is related to shear force or to pressure in the vasculature, or both (212). Interpretation of the mechanism of how perfusion affects diastolic stiffness is complicated in the whole heart due to the complex geometry of heart and vasculature (31, 383), metabolic limitations (431), and lack of accurate measurement of wall stress (177). In isolated perfused papillary muscle, where vessels and muscle fibers predominantly run in parallel and metabolic demand is not limited by perfusion (354), coronary arterial pressure shifts the diastolic stress-strain relationship upward and to the left (Fig. 28) (8). In addition, a crossover point is seen at low stress, and below this crossover point the effect of coronary perfusion on the stress-strain relationship is reversed. When stress-strain relationships of isolated blood vessels in the longitudinal, i.e., axial direction, are studied for different distending or perfusion pressures, a crossover point is also found (441, 442). A twocomponent model, as shown in Figure 29, consisting of vessels and muscle cells in parallel, shows that the effect of perfusion (in terms of coronary vascular filling) on the cardiac muscle can be explained by changes in mechanical behavior of the vasculature in the axial direction rather than by formation of edema or changes in cardiac muscle properties (8). Thus the diastolic pressure-volume relationship of the heart is not only determined by the muscle characteristics and extracellular matrix, but also, Physiol Rev • VOL FIG. 28. Coronary perfusion has a mechanical effect on the diastolic force-length relationship of cardiac muscle. Increased perfusion pressure makes the blood vessels stiffer in their axial direction. Therefore, in the isolated papillary muscle, where vessels and muscle fibers predominantly are parallel, the whole muscle becomes stiffer as well. At very small stretch (strain), close to slack length, a crossover point is found. The crossover point results from vascular properties. [Adapted from Allaart et al. (8).] to a small extent, by coronary perfusion pressure through changes in mechanical cross-talk between vasculature and cardiac muscle. For the intact ventricle, this implies that at low ventricular filling pressures an increase in coronary perfusion pressure augments ventricular filling, whereas at high ventricular filling pressures the vasculature contributes to protection against overstretching of the ventricle. The crossover point is in the low physiological range, since it occurs at ⬃10% above slack length of the cardiac muscle. In the physiological range of muscle lengths and ventricular volumes, an increased perfusion pressure increases the diastolic pressure-volume relationship of the ventricle towards a stiffer behavior (8, 287, 289, 304, 313, 431). In summary, the diastolic pressure-volume relationship of the ventricle is affected by vascular filling through changes in vessel mechanics. In the physiological range of muscle lengths, the increased vascular filling increases diastolic stiffness, but the effect is small. B. Coronary Flow and Cardiac Muscle in Systole In this section we discuss the effect of coronary filling and perfusion on the cardiac muscle. Vascular filling or perfusion exerts an effect on the contracting cardiac muscle by two mechanisms. An increase in the microvascular volume opens stretch-activated channels, and Ca2⫹ influx in the cardiac muscle cells is increased followed by an increase in calcium sensitivity of the contractile apparatus (Gregg effect). Vascular emptying augments cardiac muscle contraction by a direct effect. 86 • OCTOBER 2006 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017 In this section we discuss the influences of the coronary vasculature and its perfusion on the diastolic properties of the heart and on cardiac contraction. The effects of coronary perfusion on cardiac muscle contraction and oxygen consumption, independent of oxygen supply limitations, are discussed, excluding alleviation of limited oxygen supply by increasing perfusion. CROSS-TALK BETWEEN CARDIAC MUSCLE AND CORONARY VASCULATURE 1289 FIG. 29. Model of diastolic cross-talk between vessels and muscle. The forcelength relationship of isolated blood vessels depends on vascular, transmural pressure and “rotates” around a crossover point with increasing transmural pressure (left panel). In the intact perfused cardiac muscle, the force-length relationship depends on the vessel and muscle properties combined, and the diastolic relationship also rotates around a crossover point (right panel). In 1958, Gregg and co-workers (157, 291) described that an increase in coronary perfusion alters cardiac muscle contraction and oxygen consumption, independent of changes in myocardial oxygen supply, the “Gregg effect.” Reperfusion is here not considered as part of the Gregg effect (118). The effect itself and the mechanism on which it is based have been the subject of discussion over the last decades, and it has become evident that the Gregg effect depends on the degree of autoregulation (27, 94, 95, 212). Increased perfusion within the autoregulation range does not show an increase in (regional) mechanical function or oxygen consumption, implying that with good autoregulation the Gregg effect is minimal (212, 299, 355, 356, 385). Several experimental studies have suggested that in stunned myocardium the Gregg phenomenon does not only apply to oxygen consumption but also to contractile function (382). In the right ventricle, where autoregulation is poor under physiological conditions, the Gregg effect is consistently found (27, 109). Because autoregulation resides mainly in the microvasculature, it is likely that the mechanism behind the Gregg effect is related to alterations in microvascular volume (16, 17, 27, 104, 261, 262, 304, 350, 351, 353). It was shown that the effect of perfusion on contraction depends more on the contractile state of the muscle than on the length of the muscle (Fig. 30) (9). From Figure 30 it can be seen that at low contractility (low Ca2⫹ concentration in the external medium) a strong increase in force takes place with perfusion, while at high contractility (high Ca2⫹ concentration) the increase in force with perfusion is small. These findings suggest that intracellular Ca2⫹ plays a role in this phenomenon (229). Figure 30 also shows that at similar muscle length force increases with perfusion, and the changes in the diastolic lengthtension relationship are small with respect to the changes Physiol Rev • VOL in the systolic relationships (compare Figs. 28 and 30). These data indicate that a “garden hose effect,” i.e., a change in muscle length with an increase in perfusion pressure (16, 130, 322), plays a minor role. This has been confirmed by many experimental studies (8, 27, 43, 104, 183, 229, 262, 353) and was well reviewed by Downey et al. (109). Also, shear stress-induced release of inotropic endothelial factors has been suggested (101, 103, 432), but this was not confirmed by experimental findings (261, 262, 329, 330). Finally, the magnitude of the Gregg effect appears to be dependent on the type of metabolic substrate used (316), with a more pronounced effect in the presence of free fatty acids. In the context of the above it can be hypothesized that the Gregg effect is based on microvascular volume changes that affect the cardiac muscle cell, including its FIG. 30. The effect of coronary perfusion on cardiac contraction in the isolated perfused papillary muscle of the rat. For low contractile state, the perfusion strongly augments cardiac force development. For a high contractile state, the effect of perfusion is much smaller, but still present. [Adapted from Schouten et al. (353).] 86 • OCTOBER 2006 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017 1. The Gregg effect 1290 WESTERHOF ET AL. 33). Both the force and the Ca2⫹ alterations are inhibited by blockade of stretch-activated ion channels (SACs) with gadolinium or streptomycin, as indicated by the dashed lines of Figure 33 (261, 262). The sustained increase in force, which is still present after the [Ca2⫹]i has returned to its preintervention level, is also completely inhibited by blockade of the SACs. It therefore results from changes in Ca2⫹ sensitivity (261, 262) or endothelin-1 signaling (321), which are triggered by the initial increase in the intracellular Ca2⫹ transient. The role of NO (Fig. 34) (34, 262), angiotensin type 1 receptor (321), cytochrome P-450 and cyclooxygenase (34), the endothelial glycocalyx (340), FIG. 32. The Gregg effect is based on alterations in microvascular volume that affect the cardiac muscle cell, including its membranous elements. The data are from the isolated perfused papillary muscle of the rat. Left: relationship between developed force, coronary flow, and muscle diameter following a sudden, sustained, increase in perfusion, a perfusion step. Right: the effect of a perfusion impulse. After a perfusion step, the developed force (Fdev) increases gradually, starts to decline after ⬃60 s, and reaches an increased steady state after ⬃125 s. The muscle diameter increases instantly due to vascular filling, followed by a gradual increase due to interstitial filling (muscle length at 100% maximal force: 4.1 mm; cross-sectional area: 0.35 mm2). After a perfusion pulse, the Fdev is transiently increased for ⬃50 s, whereas muscle diameter returns to basal values within ⬃10 s. [Adapted from Lamberts et al. (262).] µ µ membrane (Fig. 31). In the isolated, perfused and not autoregulating papillary muscle, a step increase in coronary perfusion gives a rapid filling of the vasculature, which results in an initial increase in diameter of the whole muscle. This increase is followed by a slower increase in muscle diameter due to edema formation (Fig. 32, left). The increase in vascular filling immediately augments force, and this is followed by a slower increase in force, which subsequently reduces somewhat to reach a constant, but sustained elevated level. A short pulse of coronary perfusion, producing a transient volume change, results in a transient increase in force, lasting ⬃50 s with negligible edema formation (Fig. 32, right). For both sustained (229, 261, 262) and transient (262) perfusion changes, the peak intracellular Ca2⫹ transient is altered concomitantly (as shown for the sustained change in Fig. FIG. 33. A stepwise increase in coronary perfusion pressure increases developed muscle force (top) and induces a change in the intracellular Ca2⫹ transient (bottom). Force increases to a new steadystate level, but the Ca2⫹ transient is only temporarily increased. After a blockade of the stretch-activated channels (using gadolinium, Gd3⫹), a perfusion increase fails to alter force and Ca2⫹ transient. [Adapted from Lamberts et al. (261).] Physiol Rev • VOL 86 • OCTOBER 2006 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017 FIG. 31. Coronary (micro)vascular filling deforms the adjacent muscle, called transverse deformation. CROSS-TALK BETWEEN CARDIAC MUSCLE AND CORONARY VASCULATURE and edema formation itself (211) appears to be minimal in the inotropic response. Apparently, it is the initial change in muscle diameter, due to vascular volume change (Fig. 31) (27, 262), that triggers the short-term (through increased Ca2⫹ entry) as well as the long-term (through increased Ca2⫹ sensitivity) increase in force. Because the Gregg effect is dependent on capillary perfusion (102, 104) and not on the coronary arterial endothelium through released inotropic substances (101, 103, 329, 330), or affected by changes in venous pressure (67, 232, 303, 433), the location of the SACs is either on the capillary endothelium or on the cardiomyocytes or both. A point of discussion has been whether the Gregg effect is related to alterations in coronary pressure or coronary flow. Although several studies have suggested that it is alteration in coronary flow (1, 140, 212, 391), it appears most likely that coronary pressure-induced changes in microvascular volume determine the Gregg effect (27, 109, 262). This conclusion is supported by others (16, 17, 90, 157). Under normal physiological conditions, the Gregg effect is small or not observed because autoregulation prevents the microvascular volume from changing (27, 94, 95, 212). The effect is uncovered during ineffective autoregulation (109), as in the right ventricle or in pathological situations, such as the onset of hibernation or distal of a stenosis. In low coronary perfusion, or when autoregulation is ineffective, the Gregg effect may constitute an immediate mechanism that increases pump function of Physiol Rev • VOL the heart following increased coronary perfusion, while preventing a mismatch between cardiac contractility and oxygen delivery. In this explanation, the increased oxygen consumption with increased perfusion is secondary to the increase in pressure or force, because oxygen consumption is coupled to force development (337, 345, 448). A) SYSTOLIC STIFFNESS. Another suggested explanation of the Gregg effect is based on the concept of systolic ventricular stiffness, defined as the slope of the wall forcesegment length relationship in systole (43, 109, 183, 272) [for details, see Fig. 1 of the publication by Bian and Downey (43)]. Increased coronary perfusion increases internal resistance to muscle shortening, which increases systolic ventricular stiffness. The stiffer left ventricular wall causes an increase in oxygen demand, since more energy must be expended to deform the stiffer ventricular wall during ejection. However, so-defined systolic ventricular stiffness is not a true indicator of cardiac muscle stiffness alone, but also depends on the afterload, i.e., aortic pressure, which in turn is determined by properties of the systemic vasculature. Thus an increase in systolic stiffness is not an accurate measure to describe changes in the cardiac muscle. In summary, the increase in cardiac muscle contractility with increased coronary perfusion is only found when autoregulation is weak or absent, suggesting that the effects are to be found in the microcirculation. Increased vessel filling (“hoop stress”) results in the opening of SACs, giving an increase in intracellular calcium followed by an increase in calcium sensitivity of the contractile apparatus of the cardiac muscle. The reported increase in oxygen consumption with increased perfusion is secondary to the increased contractility. 2. Coronary vascular emptying augments cardiac contraction The cardiac muscle diameter increases when the muscle shortens, because intracellular volume remains constant. The diameter increase is at the expense of the coronary vascular diameters and thus on vascular volume (Fig. 35) (144), which results in a decrease in arterial inflow (flow impediment) and an increase in venous outflow in systole, as discussed above. The alterations in vascular volume have been viewed as merely a consequence of the compressive forces generated by the contraction of the surrounding myocardium. However, because the coronary vasculature is intertwined with the myocardium, emptying of the vasculature could facilitate cardiomyocyte thickening and hence shortening. For instance, when the coronary perfusion medium in perfused rat papillary muscles is made more viscous (by about a factor of 10, with Tyrode viscosity is ⬃1 cP, with dextran 500 kDa ⬃10 cP) and the ease of vascular emptying is decreased, contraction is impeded 86 • OCTOBER 2006 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017 FIG. 34. After a stepwise increase in perfusion, developed muscle force increases. Blockade of the stretch-activated channels by gadolinium (Gd3⫹) abolishes the increase. NOS inhibition by L-NNA and use of an NO donor (sodium nitroprusside, SNP) do not affect the response. [Adapted from Lamberts et al. (262).] 1291 1292 WESTERHOF ET AL. FIG. 35. During muscle contraction and shortening, the muscle cells increase in diameter. The increase in diameter results from an increase in intracellular pressure. The increased intracellular pressure counteracts the force generated by the contractile apparatus. The increase in muscle diameter takes place at the expense of the coronary vasculature. The ease of vascular deformation, and thus vascular emptying, determines the intracellular pressure. Purely fiber-isometric contractions do not affect the coronary vasculature, and force generation is not counteracted. FIG. 36. When the perfusion medium is made more viscous and vascular emptying is decreased, contraction is impeded. In muscle isometric contractions, force development is decreased (top). This effect is stronger in the muscle when it shortens (bottom). Vascular emptying allows muscle thickening during shortening, but when the vasculature cannot empty, the muscle thickening is impeded and an intracellular pressure builds up counteracting the tension generated by the contractile apparatus. The dextran results compare to “low Tyrode” perfusion in terms of flow (Q) and “high Tyrode” perfusion in terms of pressure (P). [Top panel adapted from Willemsen et al. (450).] Physiol Rev • VOL cannot empty, the shortening muscle cannot thicken and builds up an intracellular pressure. This, in turn, counteracts the tension generated by the contractile apparatus resulting in a reduction of the net force. An increase in perfusion pressure increases force development on the one hand, but impedes vascular emptying to the arterial side, leading to a smaller force on the other hand. However, most vascular emptying during contraction is by means of venous outflow, because coronary sinus pressure is low and venular resistance is small. Thus the net result of these two counteracting effects depends on the conditions. When autoregulation is strong, and the Gregg effect is small, increased arterial pressure with (some) reduction in vascular emptying may lower force. When autoregulation is poor and the Gregg effect is strong, vascular emptying to the arterial side is expected to have little effect. It has been reported that the addition of dextran (with a molecular mass of 500 kDa) to the perfusion fluid in isolated perfused guinea pig hearts decreases contractility by ⬃50% (138). Dextran binds to the endothelial luminal surface, and this binding affects the shear-sensing system. For this particular dextran, this effect makes the force decrease due to decreased vascular emptying even larger. However, the 50% decrease can only be explained in part by shear sensing because an endothelium-derived effect on contractility is at maximum 15% (55, 270) or less (262). In polycythemia, blood viscosity is increased, but the increase is from ⬃3 cP at a hematocrit of 40% to ⬃4.5 cP at a hematocrit of 60% (448). Therefore, the effects of polycythemia on muscle contraction through vascular emptying are relatively small. In conclusion, when the intramyocardial pump cannot displace intravascular fluid, muscle contraction is reduced, but the effect of changes in blood viscosity is small. 86 • OCTOBER 2006 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017 and force development is decreased (Fig. 36) (340, 450). No effect is expected in single muscle fibers, or in isolated muscle preparations and ventricular wall sections, where all muscle cells would contract isometrically and where the fibers do not shorten and thus do not thicken. However, during muscle isometric contractions, some of the fibers shorten and thicken at the expense of the vessels. In shortening contractions, all muscle fibers shorten and the effect is larger (Fig. 36, bottom). When muscle fiber thickening is almost completely prevented by filling the vasculature with gelatin, or by placing an external stiff tube around the isolated papillary muscle, the decrease in force is very pronounced (450). Thus vascular emptying allows muscle fiber thickening during shortening. However, when the vasculature CROSS-TALK BETWEEN CARDIAC MUSCLE AND CORONARY VASCULATURE C. Effects of Coronary Vasculature on Cardiac Muscle: Summary We have discussed mechanical cross-talk of the coronary vessels on the cardiac muscle. Coronary perfusion affects the diastolic ventricular properties through changes in the lengthwise stiffness of the coronary vasculature. In the face of a limitation of oxygen supply, an increase in perfusion enhances cardiac muscle contractility via the increased oxygen supply. However, the Gregg phenomenon pertains to the effect of an increased perfusion on myocardial contractility and subsequently on oxygen consumption independent of changes in myocardial oxygen supply. The Gregg effect is only seen when autoregulation is poor so that microvascular volume can change with perfusion. The first step in the mechanism is opening of stretch-sensitive channels, and thereby increasing intracellular [Ca2⫹]i, followed by an increase in Ca2⫹ sensitivity. Physiol Rev • VOL Coronary vascular emptying plays a role in cardiac muscle contraction. When vascular emptying is impeded, cardiac muscle cell thickening is diminished, intracellular pressure builds up, and development of the force generated by the contractile apparatus of the cell is counteracted so that net force is reduced. This mechanism is always in action even during autoregulation. V. ROLE OF THE EXTRACELLULAR MATRIX IN CROSS-TALK Although myocardial pump function is based on contraction of the myocytes, the predominant cell type in the heart is the fibroblast. The major role of the fibroblasts is deposition of the extracellular matrix (ECM). The ECM of the heart consists of an integrated collagen, fibrin, and elastin network, which maintains tissue integrity and intercellular communication (62, 63, 187, 188, 244, 438). The cardiac extracellular collagen matrix comprises 2– 6% of left ventricular dry weight (439). Over the last decades, several studies reported interventions with the collagen structure, using many different techniques, to study the effects of extracellular matrix on contraction in healthy and diseased hearts (28, 44, 64, 68, 221, 250, 263, 276, 284, 311, 384, 396, 403, 460). Excessive collagen deposition or pathological fibrosis has been associated with left ventricular dysfunction, hypertension, myocardial ischemia, and heart failure. Three major changes have been described: 1) a change in collagen content, 2) a conformational change in collagen type (type III decreases, type I increases), and 3) an increase in collagen cross-linking. Most of these studies confirm the notion (62, 276, 437) that the extracellular collagen matrix prevents overstretching of sarcomeres during filling by increasing passive stiffness at higher pressures and serve to maintain the unloaded geometry in the ventricle. Although there are prominent consequences for cardiac function when the collagen matrix structure is altered, knowledge regarding the role of the matrix in mechanical cross-talk is limited. A. Theoretical Suggestions Although one might assume that an accumulation of ECM proteins increases tissue stiffness and adversely affects myocardial muscle shortening and viscoelasticity, it is unknown whether increased collagen content, e.g., during hypertrophy and heart failure, particularly affects coronary flow properties and impediment during cardiac contraction. Several analyses and suggestions have been given about the role of the extracellular matrix in crosstalk. Beyar et al. (40) presented the effect of the interconnecting collagen fibers in a model simulation. Gosse and Clementy (139) suggested that during cardiac hypertro- 86 • OCTOBER 2006 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017 How changes in venous outflow affect cardiac contraction has not been well established. In the blood-perfused dog heart, elevated coronary sinus pressure was shown to increase ventricular wall volume and decrease diastolic ventricular compliance (434). Increased venous outflow pressure was also shown to increase the intramyocardial pressure, thereby increasing the zero-flow pressure intercept of pressure-flow relationships (185). It was also shown that increased coronary sinus pressure has either a negative effect on contraction (67, 178, 434) or little or no effect (232, 303, 433, 457). These differences may, in part, be explained by the role of a waterfall mechanism (339), arising from smooth muscle tone and/or from cardiac muscle contraction, since changes in venous pressure below the waterfall pressure are not expected to have an effect on coronary flow and vascular emptying. It was also shown that the effect of increasing coronary sinus pressure was different in systole and diastole (301, 302, 346), suggesting that not only the smooth muscle tone-related waterfall plays a role, but also the waterfall resulting from cardiac contraction. Increases in coronary venous pressure should always be referenced against the magnitude of the waterfall, and it can only then be studied how coronary flow responds. In summary, muscle contraction, with shortening, results in a build-up of intracellular pressure, which produces muscle thickening. Vascular emptying allows the cardiac muscles to thicken more easily so that intracellular pressure is lower. This lower intracellular pressure counteracts the tension developed by the contractile apparatus to a lesser extent. The result is an increase in muscle tension in systole. Increased arterial pressure has a small or negligible effect on emptying, but an increase in venous pressure can have a negative effect on cardiac contraction by decreasing vascular emptying. 1293 1294 WESTERHOF ET AL. B. Experimental Findings Recently some experimental data have been published. Lamberts et al. (263) investigated the effects of removal of the collagen struts, connecting vasculature and cardiac muscle, using collagenase in the isolated perfused papillary muscle of the rat. They found that removal did not affect coronary flow in diastole and did not alter systolic flow impediment (Fig. 37). Moreover, the systolic change in muscle diameter was not altered, showing that emptying of the coronary vasculature during contraction was also not affected. In spontaneously hyper- tensive rats, the collagen content was reduced using collagenase and an advanced glycation end-product (AGE) cross-link breaker, without any effects on coronary blood flow, coronary flow reserve (see above), or coronary resistance (392). These data indicate that the collagen struts are not important in directly and acutely ameliorating coronary flow impediment as suggested from long-term clinical observations (15, 396, 399, 460). Charan et al. (67) showed in sheep hearts that edema induced by augmented coronary venous pressure did not influence total coronary flow. Lamberts et al. (263) observed edema formation after collagenase treatment but did not observe changes in diastolic flow and flow impediment with the edema. These findings suggest that the direct effect of the matrix on the vasculature and the indirect effects resulting from edema play a minor role, and may counteract each other. Thus, contrary to expectations and theoretical models, the role of the extracellular matrix on systolic flow impediment appears to be small. Perhaps this role is of importance in extreme conditions, such as an enlarged ventricle. Experimental evidence is still too scant to provide a clear image of the role of the extracellular matrix in cross-talk. C. Summary On the basis of the limited information available, it appears that the extracellular matrix exerts its effect mainly on cardiac contraction via diastolic and systolic properties of the heart rather than on cross-talk with the coronary circulation. VI. CONCLUSIONS FIG. 37. The effect of collagen type I removal on diastolic flow and systolic flow impediment in isolated perfused papillary muscle of the rat at a length of 95% Lmax during isometric contractions is not significant. [Adapted from Lamberts et al. (263).] Physiol Rev • VOL This physiological review reports on the mechanical cross-talk between the cardiac muscle and the coronary vasculature in the normal heart and normal isolated myocardium. The major aspects of cross-talk are summarized in Figure 38. A major part of the mechanical cross-talk in the normal heart takes place at the level of the microcirculation. Although many studies have been concerned with the diseases of the larger, epicardial, coronary arteries, it has recently become clear that the intramyocardial coronary vasculature, which is in close contact with the cardiac muscle, is often affected and of great importance for muscle perfusion. Especially in coronary heart disease, but also in hypertrophy and failure, where the muscle cells of the vasculature and their distances are changed, mechanical cross-talk may be different. Coronary arterial inflow and local perfusion can be measured noninvasively, and information on the conduit arteries and the coronary intramyocardial vasculature has 86 • OCTOBER 2006 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017 phy, the increased thickness and stiffness of the ventricular wall might additionally stress the coronary vasculature due to an increase in systolic and, especially, diastolic pressure. The extracellular collagen structure between cardiac muscle cells and the coronary vasculature, in particular the collagen struts, have been proposed to decrease the effect of cardiac contraction on the vasculature by preventing collapse of the capillaries in systole (2, 46), and to increase interstitial pressure in diastole (312). It was also proposed that the collagen fibers affect the transmission of radial forces, which in turn play a role in the generation of intramyocardial pressure (40). Additionally, it has been suggested that myocardial edema, probably as a result of structural alterations of the collagen matrix, decreases vascular lumens and may affect coronary flow as well (462). However, these suggestions have not been confirmed experimentally, either because the critical experiments were not performed or the experiments did not support these suggestions. CROSS-TALK BETWEEN CARDIAC MUSCLE AND CORONARY VASCULATURE been obtained in the patient (see sect. I and Ref. 336). MRI allows for noninvasive measurement of local myocardial strains. However, local fiber stress or tension cannot be measured and can only be derived through model calculations (18, 177). The presently available basic knowledge on cardiac mechanics, coronary morphology, finite element modeling, and computational flow dynamics, together with new measurement techniques, should make it possible to better understand the cross-talk on a more detailed scale and open the way to studying and quantifying its role in the microcirculation. A. Cardiac Muscle Affects the Coronary Vasculature The data in the literature regarding the effect of the diastolic cardiac muscle on the coronary vasculature are not consistent, and probably depend on the reference conditions chosen. The effects in diastole depend on the (changes in) muscle length and appear, in the physiological range of ventricular volumes, to be small. More experiments under well-defined conditions and reconsideration of the models are necessary. Coronary flow is affected by cardiac muscle contraction through two interacting, and simultaneously acting, mechanisms. The models based on these mechanisms are summarized in Figure 27. The first mechanism invokes the intermediary effect of ventricular pressure that generates intramyocardial pressure acting on the vasculature (waterfall model and intramyocardial pump model) and the second mechanism is through a direct effect on the vasculature (varying elastance model, muscle shortening and thickening model, and vascular deformation model). The magnitudes of their contributions depend on the mechanical properties of the cardiac muscle (e.g., contractility) and the mechanical properties of the vasculature (e.g., Physiol Rev • VOL vasomotor tone). The effects therefore depend on the layer in the heart wall (subepicardial or subendocardial) and on the way the heart contracts (isovolumic, isobaric). In the arrested heart in systole, the flow is smaller than when arrested in diastole, and the coronary resistance and intercept pressure are increased. The waterfall model explains this through an increased intercept pressure, while the other models predict an increase in resistance, either by a diameter decrease or by vascular deformation. During rhythmic contractions, the vascular volume changes cause the resistance change, while the rate of change of the vascular volume results in “pumping.” This pump action results in arterial inflow impediment and venous outflow augmentation. Except for the waterfall model, all the models explain these effects. The two mechanisms differ with respect to the prediction of what happens with an increase in contractility. The direct mechanisms predict an increased flow impediment when cardiac contractility increases. The mechanisms acting through ventricular pressure require that ventricular pressure be increased with increased contractility. However, since the load on the heart determines ventricular pressure as well, increased contractility does not always parallel an increased ventricular pressure (Fig. 15), and thus intramyocardial pressure. Although some quantitative analysis has been performed (see Fig. 21), and some modeling of these effects has been carried out (459), the solid experimental quantitative analysis of the two mechanisms and their relative contributions to coronary flow impediment is still lacking. Many detailed models account only for the effect of contraction through ventricular pressure (450, 452, 455). However, models accounting for the direct effects of muscle contraction are still limited (53, 66, 292). Coronary flow reserve depends on the microcirculation, and thus on the effect of cardiac muscle contraction. The fractional flow reserve assumes that the bed distal of the stenosis and the normal bed are similarly influenced by cardiac muscle contraction. With possible differences in cardiac muscle contractility, maximal flow in these beds may differ, and errors in fractional flow reserve may occur. The supply of oxygen mainly depends on diastolic flow, and thus on the diastolic time fraction. However, even a small flow in systole, especially at high heart rates, can contribute to perfusion and is affected by cardiac contraction, making the supply-to-demand ratio dependent on mechanical cross-talk. In the maximally dilated heart in diastole, where the role of both smooth muscle and cardiac muscle contraction is minimal, it can be assumed that perfusion heterogeneity is determined by the vascular anatomy. Especially those models based on fractal branching patterns can give an explanation based on the anatomy (33, 213). However, local perfusion is not only determined by the vascular 86 • OCTOBER 2006 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017 FIG. 38. Summary of the major mechanisms of mechanical cross-talk. 1295 1296 WESTERHOF ET AL. Physiol Rev • VOL In cardiac hypertrophy, the coronary vasculature changes, but it is not entirely clear how. In cardiac hypertrophy obtained through hypertension, a significant decrease in both myocardial arteriolar and capillary density has been reported (52, 268). However, in hypertrophy due to volume overload, the microcirculation was reported to grow proportionally (69), and in renal hypertension capillary density in heart muscle is decreased (11). In hypertrophy where minimal microvascular resistance is increased, flow reserve is decreased (220), but this does not directly affect cardiac function at rest (146). The lower pressure limit of autoregulation is shifted to higher pressures, which suggests that lowering blood pressure is not beneficial, but vasodilation is (146, 328, 397). The pulsations in coronary arterial inflow depend on the wave shape of the perfusion pressure (aortic pressure) and on the pattern and effect of cardiac muscle contraction and the variations in coronary arterial input impedance. Tadaoka and co-workers (393, 394) have shown that in patients with hypertrophy caused by hypertension, but with normal arteriograms, diastolic coronary arterial inflow is impaired. Gibson et al. (135) showed that after myocardial infarction the amplitude of the pulsations in flow, even after correction for the changes in pressure, appears to increase. B. Coronary Vasculature Affects the Cardiac Muscle In this review we only reported on the effects of the coronary vasculature on the cardiac muscle independent of changes in myocardial oxygen supply. The diastolic pressure-volume relationship of the ventricle is affected by vascular filling through changes in vessel mechanics, but the effect is small. Cardiac contraction is augmented by the coronary vasculature through two mechanisms. First, increased vascular filling (“hoop stress”) results in the opening of SACs, giving an increase in intracellular calcium followed by an increase in calcium sensitivity of the contractile apparatus of the cardiac muscle. The reported increase in oxygen consumption with increased perfusion is secondary to the increased contractility. The increased cardiac muscle contractility with increased coronary perfusion, in the absence of oxygen limitation, is only found when autoregulation is weak or absent, suggesting that the effects are to be found in the microcirculation. Second, muscle contraction, with shortening, results in a build-up of intracellular pressure, which gives muscle thickening. Vascular emptying allows the cardiac muscles to thicken more easily so that intracellular pressure is lower. This lower intracellular pressure counteracts the tension developed by the contractile apparatus to a lesser extent. The result is an increase in muscle tension in systole. 86 • OCTOBER 2006 • www.prv.org Downloaded from http://physrev.physiology.org/ by 10.220.33.6 on May 2, 2017 anatomy, but local autoregulation (158) and local effects of contraction are important as well. At the microcirculatory level, flow and red blood cell velocity do not clearly show arteriolar systolic flow impediment and venular flow augmentation (Fig. 22), while these phenomena are obvious in epicardial arteries and veins. These findings emphasize the importance of the direct and local effects of cardiac muscle contraction on flow. Changes in diameter of intramyocardial venules and arterioles are of the same order, and venules do not collapse in systole (Fig. 22). The waterfall model and intramyocardial pump model assume that intramyocardial pressure is proportional to ventricular pressure and thus predict that this pressure is higher than venular pressure in most layers of the wall, and higher than arteriolar pressure in subendocardial layers. Thus these vessels are predicted to collapse in systole, which is not in line with the experimental findings (Fig. 22). The varying elastance model, the muscle shortening and thickening model, and the vascular deformation model exert their effects locally depending on muscle contraction and the local “load.” Analogous to what happens in the ventricular cavity, the measured intramyocardial pressure depends not only on cardiac muscle contraction, but also on how the vessels (venules and arterioles) and the local interstitial space can be emptied. Therefore, heterogeneity in intramyocardial pressure exists, and intramyocardial pressure development close to the coronary veins and venules is small so that they will not collapse. Similarly, the thin-walled low-pressure venules can protect arterioles in their proximity from strong diameter decreases in systole (Fig. 23). Models describing perfusion heterogeneity have been proposed (53, 66, 292, 426 – 429). However, the contributions of local contraction effects and metabolism as part of an explanation for perfusion heterogeneity need to be worked out both experimentally and theoretically. Quantification of the effects is difficult, but is important because infarcts are often of a heterogeneous and of a “patchy” character (47). The coronary microcirculation can be affected exclusively (syndrome X, anginal chest pain, positive exercise test, and angiographically normal coronary arteries) so that even with normal epicardial arteries angina may arise. The angina may be due to the increased microcirculatory resistance and through an increase in the effect of the intramyocardial pump so that flow reversal in systole increases (180). The coronary flow reserve and fractional flow reserve are dependent on the changes that occur in the (normal) intramyocardial vasculature (223) and are decreased with increased resistance. It has been reported that in hypertensive patients without epicardial lesions, coronary flow reserve is decreased before muscle mass is increased (14, 54), showing the importance of the coronary vasculature. CROSS-TALK BETWEEN CARDIAC MUSCLE AND CORONARY VASCULATURE 4. 5. 6. 7. 8. 9. 10. 11. C. Extracellular Matrix 12. The extracellular matrix plays an important role in the diastolic pressure-volume relationship of the ventricle (276), as well as in the generation of muscle tension and ventricular pressure (62). 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