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2006冠脉血流指数的生理学基础重要的

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2006冠脉血流指数的生理学基础重要的 Physiological Basis of Clinically Used Coronary Hemodynamic Indices Jos A.E. Spaan, PhD; Jan J. Piek, MD; Julien I.E. Hoffman, MD; Maria Siebes, PhD Abstract—In deriving clinically used hemodynamic indices such as fractional flow reserve and coronary flow velocit...
2006冠脉血流指数的生理学基础重要的
Physiological Basis of Clinically Used Coronary Hemodynamic Indices Jos A.E. Spaan, PhD; Jan J. Piek, MD; Julien I.E. Hoffman, MD; Maria Siebes, PhD Abstract—In deriving clinically used hemodynamic indices such as fractional flow reserve and coronary flow velocity reserve, simplified models of the coronary circulation are used. In particular, myocardial resistance is assumed to be independent of factors such as heart contraction and driving pressure. These simplifying assumptions are not always justified. In this review we focus on distensibility of resistance vessels, the shape of coronary pressure-flow lines, and the influence of collateral flow on these lines. We show that (1) the coronary system is intrinsically nonlinear because resistance vessels at maximal vasodilation change diameter with pressure and cardiac function; (2) the assumption of collateral flow is not needed to explain the difference between pressure-derived and flow-derived fractional flow reserve; and (3) collateral flow plays a role only at low distal pressures. We conclude that traditional hemodynamic indices are valuable for clinical decision making but that clinical studies of coronary physiology will benefit greatly from combined measurements of coronary flow or velocity and pressure. (Circulation. 2006;113:446-455.) Key Words: blood flow velocity � blood pressure � collateral circulation � coronary disease � hemodynamics Coronary physiology has a rich history, founded onnumerous animal and theoretical models, and significant milestones were reached as new measuring techniques were developed. Recent progress has been made by applying techniques to measure intracoronary flow, flow velocity, and pressure to aid in clinical decision making, thereby advancing our understanding of human coronary physiology beyond what could be extrapolated from animal studies. One unre- solved issue that has arisen from these studies, however, concerns conflicting interpretations of coronary microvascu- lar resistance, a quantity with crucial relevance for clinical decision making.1–4 There are 2 conflicting interpretations of coronary pressure-flow lines during hyperemia: (1) coronary pressure- flow relations are straight and, in the absence of collateral flow, intercept the pressure axis at venous pressure (Pv); or (2) coronary pressure-flow relations are straight at physiolog- ical pressures and, when linearly extrapolated, intercept the pressure axis at a value well above venous pressure (extrap- olated zero flow pressure [PzfE]); at lower pressures, how- ever, they curve toward the pressure axis, intercepting it at a lower pressure (actual zero flow pressure [Pzf]) that is still higher than Pv. The purpose of this article is to review the physiological literature with respect to coronary pressure-flow relations as relevant to myocardial microvascular resistance. This key issue relates to important assumptions underlying the fre- quently used model of myocardial fractional flow reserve (FFRmyo). We conclude with a synopsis of physiological studies demonstrating the curved nature of pressure-flow relations and how this shape relates to the pressure depen- dence of minimal coronary microvascular resistance. This focused review of coronary physiology is intended to help the clinical reader to translate the physiological analysis of microvascular resistance from bench to bedside and to encourage the use and further development of hemodynamic indices in the clinical setting. Coronary Flow Reserve The concept of coronary flow reserve (CFR) was developed to describe the flow increase available to the heart in response to an increase in oxygen demand.5 Because the perfused tissue mass cannot always be measured, CFR was expressed as the ratio between maximal hyperemic flow and resting flow, with the hyperemic condition implicitly assumed as a standard value.6,7 A pressure drop across a stenosis causes compensatory vasodilation at rest, thereby diminishing the ability of the coronary circulation to adapt to an increase in oxygen demand. In other words, a stenosis reduces CFR. Investigators also recognized that flow per gram of tissue varied throughout the cardiac muscle and that subendocardial perfusion in particular was impeded by forces related to cardiac contraction.8–11 Consequently, CFR varies regionally within the myocardium and is first exhausted in the suben- docardium, especially at higher heart rates.12 Reduced sub- endocardial CFR is a good paradigm to explain why ischemia and infarction start predominantly in this vulnerable region.7 We expect that the concept of subendocardial CFR will From the Departments of Cardiology (J.J.P.) and Medical Physics (J.A.E.S., M.S.), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; and Department of Pediatrics and Cardiovascular Research Institute, University of California, San Francisco (J.I.E.H.). Correspondence to Jos A.E. Spaan, PhD, Department of Medical Physics, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. E-mail j.a.spaan@amc.uva.nl © 2006 American Heart Association, Inc. Circulation is available at http://www.circulationaha.org DOI: 10.1161/CIRCULATIONAHA.105.587196 446 Basic Science for Clinicians become used in clinical diagnosis once new technological modalities mature.13 Coronary flow velocity reserve (CFVR) measured by Doppler ultrasound was introduced as a surrogate for CFR and was first measured during open heart surgery by applying Doppler suction probes to epicardial arteries for stenosis evaluation. This pioneering work of Marcus and colleagues14 is the clinical precursor of the present-day guidewire-based measuring techniques. Marcus et al demonstrated that CFVR could also be reduced in normal coronary arteries of hearts with hypertrophy resulting from valvar stenosis. The devel- opment of intracoronary catheters and Doppler velocity sensor– equipped guidewires allowed the application of CFVR during catheterization procedures.15,16 A threshold value of CFVR indicative of reversible ischemia varies between 1.7 and 2.17 An important problem in applying CFVR and CFR is their dependence on the level of control resistance, which in turn is affected by oxygen demand or impaired autoregulatory ca- pacity.18 However, as discussed below, hyperemic microvas- cular resistance also depends on hemodynamic conditions. Model for Hyperemic Perfusion Assuming Linear Pressure-Flow Relations Pressure sensor–equipped guidewires were introduced, al- lowing measurement of pressure beyond a stenosis. It was assumed that the ratio between distal pressure (Pd) and aortic pressure (Pa) during maximal hyperemia can be translated to represent an estimate of relative (fractional) maximal flow. Because good pressure measurements are easier to obtain and the dependence on baseline conditions was eliminated, this ratio became favored to quantify the significance of a coronary stenosis. In particular, Pijls et al19 pioneered this field and established pressure-derived indices of stenosis severity in clinical practice. FFRmyo was defined as the ratio of maximal myocardial blood flow distal to a stenotic artery to the theoretical maximal flow in the absence of the stenosis. The principles are illustrated by the model in Figure 1, with parallel normal and stenotic circuits that in this model are assumed to perfuse the same amount of tissue and may or may not be connected by collateral vessels proximal to the capillary bed. Even with collaterals, no collateral vessel flow will occur without a stenosis because no pressure difference is present across the collateral vessels, but collateral flow will occur with a stenosis because the distal pressure in the recipient vessel is lower than Pa in the donor vessel; the difference between the two is the driving pressure for collateral flow. Pressure-based FFRmyo is obtained as (Pd�Pv)/(Pa�Pv), where Pa is proximal coronary arterial (�aortic) pressure, Pd is distal coronary pressure, and Pv is coronary venous pressure. A value for FFRmyo �0.75 indicates that dilatation of the coronary stenosis is likely to relieve ischemia. The physiological derivation for FFRmyo is as follows: (1) FFRmyo� QQN where QN is myocardial flow without stenosis and Q is the myocardial flow when the artery is stenotic and represents the sum of flow through the stenotic vessel (QS) and collateral flow (QC). (2) QN� Pa � Pv RminN and Q�Pd � PvRminS , where RminN and RminS are the minimal resistances for the distal microcirculation without and with a stenosis in the supplying artery, respectively. (3) Therefore, Q QN � Pd � Pv RminN Pa � Pv RminS � Pd � Pv Pa � Pv � RminN RminS so that FFRmyo�(Pd�Pv)/(Pa�Pv) is true only if RminN�RminS. If this were true, then minimal microvascular resistance would be independent of pressure because the respective perfusion pressures Pa and Pd are different. If RminS were higher than RminN, then FFRmyo based on pressure measurements would underestimate the myocardial flow ratio Q/QN. To test this assumption, Pijls et al19 compared (Pd�Pv)/ (Pa�Pv) with the coronary flow ratio QS/QN. Without collat- eral flow, the expected relation passes through the origin, as indicated by the dashed line in Figure 2. Their results showed that with increasing stenosis severity the coronary flow ratio progressively underestimated the pressure-based index. They assumed that this was because collateral flow was missed by measuring coronary flow proximal to the collateral connec- tion. However, the magnitude of collateral flow was not verified by direct measurement. Moreover, in a PET study in humans, actual myocardial flow per gram of tissue was measured distal to a stenotic and reference vessel, and the myocardial flow ratio was plotted versus FFR.20 In this setting, collateral flow was included in the measurements, but a similar underestimation was reported. Such underestimation would also follow if microvascular resistance increased as distal perfusion pressure fell. It is therefore important to Figure 1. Model of the coronary circulation. Top and bottom circuits represent equivalent myocardial mass. Without stenosis in the bottom, RminS�RminN, QC�0, QS�QN, and Pd�Pa. QS indicates hyperemic flow with stenosis; QN, hyperemic flow without stenosis; and Qc, collateral flow. Spaan et al Coronary Physiological Indices 447 explore alternative explanations for the deviation between the dashed and solid lines in Figure 2. Distensibility of Resistance Vessels as Rationale for Pressure Dependence of Coronary Resistance At maximal vasodilation, the state at which FFRmyo is defined, diameters of all vessels depend on distending pressure and more at lower than higher pressure. This fundamental prop- erty has been demonstrated in many studies on isolated and in situ vessels without tone. When normalized to the diameter at a pressure of 100 mm Hg, the pressure-diameter relations of blood vessels are independent of size. A compilation of such in vitro data is shown in Figure 3.21 The diameter change induced by a 10-mm Hg pressure change amounts to 1% at a mean pressure of 80 mm Hg, 4% at 40 mm Hg, and 10% at 20 mm Hg. These numbers seem small, but because pressure drop in tubes is inversely related to the fourth power of the diameter (Poiseuille’s law), these diameter changes corre- spond to 4%, 16%, and 40% resistance variations for 10- mm Hg pressure variations at the different mean pressures. The change in vessel diameter corresponding to a pressure increase from 50 to 100 mm Hg, as may occur when a stenosis is dilated by balloon angioplasty, is �8%, corre- sponding to a resistance change of 32%. Direct observations of resistance vessels at the subepicardium and subendocar- dium demonstrate a similar response to pressure changes of in situ vessels with diameter in the order of 100 �m.22 During hyperemia and at an arterial pressure of 100 mm Hg, �25% of total coronary resistance is in venules and veins �200 �m.23 These vessels are rather distensible, and their resis- tance to flow will increase when Pd decreases as a result of flow limitation through a stenosis. When the effect of pressure changes on the diameter of dilated arterioles and other vessels constituting the microcirculation is considered, minimal microvascular resistance should decrease substan- tially in patients when a stenosis is dilated. In vivo studies have demonstrated this fundamental rela- tion between vascular diameters, volume, and resistance by investigating relationships between intramural vascular vol- ume and resistance and the effect of arterial pressure on these relationships.24 Recent results from studies using ultrasound contrast showed a decrease of microvascular volume during hyperemia of�50% when arterial pressure was lowered from 80 to 40 mm Hg.25 This corresponds with earlier studies in which intramural blood volume was measured in different ways.26 Moreover, pressure dependence of coronary resis- tance was clearly demonstrated by experiments in which coronary flow increased when the arterial-venous pressure difference was kept constant by increasing both pressures by the same amount, which is only possible when resistance decreases with pressure.27 These findings are important be- cause they imply that a stenosis not only adds resistance to flow in the epicardial arteries but additionally impedes myocardial perfusion by increasing microvascular resistance via the passive elastic behavior of the microvascular walls at vasodilation. Coronary Pressure-Flow Relations and Microvascular Resistance To translate results obtained in isolated vessels to an intact circulation, we make use of coronary pressure-flow relations at maximal vasodilation that are usually presented with pressure (independent variable) on the horizontal axis and flow (dependent variable) on the vertical axis. Many physi- ological studies show that these pressure-flow lines, even in the absence of collateral vessels, are straight at physiological pressures but follow a convex curve toward the pressure axis at lower pressures, and the zero flow intercept on the pressure axis Pzf is higher than Pv (solid line in Figure 4). When the Figure 2. Typical measurement of the relation between FFR, QS/QN, and the pressure ratio (Pd�Pv)/(Pa�Pv). Circles repre- sent control; triangles, increased Pa (phenylephrine); squares, decreased Pa (nitroprusside). QS indicates hyperemic flow with stenosis; QN, hyperemic flow without stenosis. Adapted from Pijls et al19 (Figure 6, panel 5). The axes of the original figure have been reversed to facilitate comparison with other figures in this article. Figure 3. Passive pressure-diameter relations of isolated resis- tance arteries. Diameters at 100 mm Hg varied between 0.065 and 0.260 mm. For details, see Cornelissen et al.21 448 Circulation January 24, 2006 straight part is linearly extrapolated, it intercepts the pressure axis at a value (PzfE) that is even higher. The shape of the solid curve is consistent with microvas- cular resistance gradually increasing with decreasing Pd.28 This increase in resistance is indicated by the difference in slope of the dashed and dotted lines in Figure 4 that both start at Pd�Pv. The dashed line is defined when Pd�Pa and flow�QN and the inverse of its slope equals RminN. The dotted line connects to the pressure-flow relation at a lower value of Pd as determined by a given stenosis. Hence, the inverse of its slope represents RminS and is higher than RminN. The similarity between Figure 2 and Figure 4 is better appreciated by converting Figure 2 into a pressure-flow plot by assuming constant values for QN, Pa, and Pv. Then the solid line in Figure 2 represents the pressure-flow relation for the given Pa and is similar to the extrapolated solid curve in Figure 4. An important difference is that the line in Figure 2 lacks the curvature found in other studies for lower flow levels. However, it is clear that collateral flow is not the only explanation for the deviation between the pressure and flow ratios depicted in Figure 2. Diastolic Coronary Pressure-Flow Relations Flow and pressure decrease during arrest or a long diastole, and flow near the origin of a major epicardial artery reaches zero when coronary pressure is �40 mm Hg during autoreg- ulation and between 5 and 15 mm Hg during maximal vasodilation, ie, Pzf exceeds Pv. The pressure-flow lines can be remarkably straight, especially at physiological pres- sures.29 An elevated Pzf can be found because of capacitive flow from epicardial and particularly intramyocardial micro- circulation.26,30 This interpretation is strongly supported by the observation that coronary venous outflow continues even when pressure has decayed to Pzf.31 This venous outflow at cessation of inflow has to come from a pool of blood within the microcirculation, which also constitutes the intramyocar- dial compliance.32 Pzf values above Pv could not be due to collateral flow in those experiments because pressure at the source of all epicardial vessels was essentially equal at all times. Pzf and the whole pressure-flow line are shifted to the right (higher pressures) by left ventricular hypertrophy,33 elevated Pv caused by pericardial tamponade, or an increase in right or left ventricular diastolic pressures.34,35 The effect of this shift is to decrease CFR and increase FFR independent of any associated stenosis. A few studies in humans have examined long diastoles induced by intracoronary injections of high doses of adeno- sine or ATP and demonstrated the curvature at low pressure, although zero flow velocity was never reached.36,37 These clinical studies are consistent with the animal studies in that PzfE is high (30 to 40 mm Hg) when coronary autoregulation is present and �20 mm Hg at full vasodilation. The slope of the hyperemic diastolic coronary velocity–aortic pressure curve was proposed as an index for stenosis severity.36 However, interpretation of these diastolic aortic pressure– coronary flow relations is hampered by the superimposed hemodynamic effects of microcirculation and stenosis that can be overcome with modern guidewire technology measuring pressure and velocity distal to a stenosis simultaneously.3,38 Back Pressure and Coronary Microvascular Resistance The calculation of resistance requires knowledge of the pressure distal to the resistance; this is called the back pressure. It is commonly but erroneously assumed that coronary back pressure can be deduced from the arterial pressure-flow relation by measuring the intercept of this relationship with the pressure axis. Resistance must be calculated when blood is flowing, whereas the intercept is obtained at zero flow, when the reduced pressure has altered diameters in the coronary vascular bed sometimes even to the point of collapse. Studies on microvascular diameters in subendocardium and subepicardium have not found such collapse in the presence of flow.39 When the heart is overfilled in diastole, pressure in epicardial veins may be uncoupled from and higher than right atrial pressure and correlate better with left ventricular diastolic pressure.40,41 In the examples discussed in relation to Figures 4 and 5, Pv has been taken as back pressure, assuming normal diastolic left ventricular filling. Effect of Cardiac Contraction on Coronary Pressure-Flow Relations Most studies of pressure-flow relations were done during diastole or cardiac arrest, and it is important to know how cardiac contraction affects these relations. More than 50 years ago, Sabiston and Gregg42 observed an increase in coronary flow at constant pressure when the heart was arrested by Figure 4. Interpretation of measured pressure-flow relations without collateral vessels. Solid curve represents a measured pressure flow relation. Dashed line indicates pressure-flow line when resistance is constant at RminN, and
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