- Email: [email protected]
Measurements of Coronary Flow Reserve in Clinically Problematic Coronary Stenoses
EVALUATION AND MANAGEMENT
indicate microvascular disease or the presence of an occult lesion in the reference artery. The safety of deferring coronary angioplasty or revascularization of angiographicallyintermediate lesions with normal translesional hemodynamics has been documented by Kern et al. (37). The DEBATE trial showed that normalization of CFR to .2.5 in combination with a reduction of the angiographic diameter stenosis to ,35% after angioplasty is associated with a low event rate. Investigating 225 patients, the investigators found that patients with both a CFR .2.5 and residual diameter stenosis of ,35% had a low incidence of symptoms at 6 months (23 vs. 47%, P 5 0.005), a low need for reintervention (16 vs 34%, P 5 0.02) and a low restenosis rate (16 vs 41%, P 5 0.002). Recently, a new method for evaluating the significance of coronary artery lesions with angiographic indeterminate severity has been introduced (39). Measurement of myocardial fractional flow reserve (FFR) is based on pressure flow analysis during maximal flow. FFR is the fraction of the normal maximal myocardial blood flow that can be achieved through the stenotic nourishing artery. The index is calculated from the ratio of the mean pressure in the coronary artery distal to the lesion to the aortic blood pressure during maximal vasodilatation, and is not dependent on changes in systemic blood pressure or heart rate. The FFR is dependent on the collateral blood flow. The normal value of FFR is 1.0. An index value of ,0.75 is abnormal and indicates that the stenosis is hemodynamically significant. The reported sensitivity of FFR for detecting myocardial ischemia is 88%, with a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 88%. Thus, Doppler flow wires are quite useful in assessing the hemodynamic significance of coronary artery lesions with angiographic narrowing of indeterminate significance and in assessing pathology of the microcirculation in patients with normal or near normal coronary arteries by angiography. In conclusion, at present, angiography is the primary method of assessment of coronary artery disease. However, the recent developments and improvements in IVUS imaging and Doppler flow wire technology have markedly added to the diagnostic accuracy and assessment of the significance of coronary arterial lesions. Moreover, recent trials suggest that both of these methods used during coronary intervention can facilitate improvement in the acute as well as long-term outcome.
PERSPECTIVE
Measurements of Coronary Flow Reserve in Clinically Problematic Coronary Stenoses Francis J. Klocke, MD and Jeffrey Greenberg, MD, Feinberg Cardiovascular Research Institute, Northwestern University Medical School, Chicago, Illinois The difficulties in inferring the functional significance of a coronary stenosis of intermediate severity solely from an arteriogram are well recognized (1,2). This perspective attempts to summarize strengths and limitations of invasive measurements of coronary flow reserve in addressing this relatively common clinical problem. Although non-invasive measurements of flow reserve now provide useful information about coronary pathophysiology, they have not yet been used widely for decisions about the management of an individual stenosis. Background The coronary circulation is notable for its large amount of vasodilatory reserve at the microcirculatory level. Several relevant features are illustrated in Figure 1. Coronary flow is plotted against coronary artery pressure. Point A represents resting flow and pressure in a normal coronary artery; aortic and coronary artery pressures are identical and the resting value of flow is designated as 1.0. The solid line depicts the relationship between flow and pressure when coronary resistance vessels are dilated maximally with a pharmacologic agent such as adenosine (or dipyridamole). In a normal individual, coronary flow typically increases at least 3.5-fold (2) in response to adenosine (moving from A3 B in Figure 1). When a stenosis develops and produces an abnormal resistance in an epicardial artery, distal resistance vessels dilate to maintain flow at the level appropriate to myocardial oxygen demand. Pressure beyond the stenosis is reduced, producing a gradient between aortic pressure (point A) and pressure just beyond the stenosis (point C). Because distal microcirculatory vasodilation has compensated for the stenosis, resting flow is unchanged. However, because a portion of vasodilatory reserve has been used to maintain resting flow, adenosine now produces a smaller increment in coronary flow (C3 D). Thus, there is an inverse relationship between degree of stenosis and coronary flow during maximum vasodilation. For reasons to be discussed subsequently, we should also note that the increase in flow produced by vasodilation increases the pressure difference across the stenosis (A3 D during vasodilation vs A3 C under resting conditions).
REFERENCES The authors submitted an extensive and important list of references. Because of space limitations, the list is being kept in the Editorial Office and is available upon request to that office. Please telephone: (317) 630-6447 or fax (317) 274-4469. Address correspondence and reprint requests to Robert J. Siegel, MD, Division of Cardiology, Room 5335, 8700 Beverly Boulevard, Los Angeles, CA 90048.
ACC CURRENT JOURNAL REVIEW March/April 1998 © 1998 by the American College of Cardiology Published by Elsevier Science Inc.
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1062-1458/98/$19.00 PII S1062-1458(98)00004-X
EVALUATION AND MANAGEMENT
A 28% average reduction in flow reserve has been reported in essential hypertension with normal coronary arteries (4), and a 59% average reduction in aortic stenosis with normal coronary arteries requiring valve replacement (5). [2] In any given individual, the relationship between coronary flow and pressure during maximum vasodilation also varies dynamically. Alterations in flow reserve produced by changes in heart rate and ventricular preload have been documented clinically as well as experimentally, leading to suggestions that measurements be performed during atrial pacing at a standard heart rate, e.g., 100 bpm (6). Figure 2A demonstrates that the position of the flow-pressure line during maximum vasodilation is indeed influenced by heart rate. Although it is less well appreciated, the flow-pressure line during pharmacologic dilation is also subject to dynamic vasoconstrictor influences. Figure 2B illustrates a change in the relationship produced by intracoronary infusion of phenylephrine, an a1 agonist. a1 receptor stimulation has been shown to limit coronary flow responses in the presence of a coronary stenosis during exercise (7). Endothelial dysfunction (8) and extracardiac vasoconstrictor influences (9) may also adversely affect the balance between vasodilatory and vasoconstrictor influences in stressful situations. [3] Because traditional values of flow reserve are calculated as the ratio of vasodilated flow to resting flow just prior to vasodilation, they are also affected by variations in resting flow caused by variations in resting myocardial oxygen demand. In the case of tachycardia, the rate-induced increase in pre-vasodilation flow contributes importantly to observed reductions in flow reserve (6). [4] Because clinical measurements of coronary flow reserve provide an average value for the entire ventricular wall, they may underestimate reductions in reserve in the inner layers of the ventricular wall. Figure 2C illustrates differences in coronary flow during maximum vasodilation in the outer and inner halves of the ventricular wall and in the posterior papillary muscle of a chronically instrumented dog during two degrees of partial circumflex artery occlusion. The more limited flow reserve in subendocardial tissue and the posterior papillary muscle is concordant with the earliest appearance of ischemia in these areas. While these complexities always need to be considered in individual cases, experience during the past decade has documented a useful role for traditional measurements of flow reserve in selected situations. White (2), who has played a leading role in coronary applications of Doppler technology, suggests that these include: (a) the functional evaluation of intermediate grade stenoses; (b) assessment of the need for lesion-specific interventional therapy; (c) evaluation of the severity of lesions in saphenous vein bypass grafts and at graft-native vessel anastomotic sites; and (d) assessment of the coronary microcirculation (2). The iden-
Figure 1. Relationship between coronary flow and coronary artery pressure during maximum pharmacologic vasodilation. See text for details. Traditional Measurements of Flow Reserve Coronary flow reserve has traditionally been defined as the ratio of flow during maximum vasodilation to that observed under resting conditions (flow at point B/flow at point A, and flow at point D/flow at point C, in Figure 1). The ability to measure flow reserve with Doppler velocity catheters has provided a greatly improved understanding of pathophysiology in coronary artery disease. However, as discussed in a previous review (3), the interpretation of a flow reserve measurement in an individual patient involves several complexities: [1] The relationship between flow and pressure during maximum vasodilation can vary substantially from individual to individual, i.e., the solid line in Figure 1 can vary in both slope and position along the pressure axis (the horizontal axis). Because ventricular hypertrophy occurs commonly in clinically evident coronary artery disease, its effects are of particular interest. The attribution of a diminished value of flow reserve to a stenosis presumes that downstream microcirculatory vessels are able to vasodilate normally. However, because the degree of microcirculatory proliferation is disproportionately small in relation to the increase in ventricular mass in a hypertrophied ventricle, maximum flow in each unit of ventricular tissue is reduced, i.e., the slope of the flow-pressure line during maximum vasodilation is reduced.
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EVALUATION AND MANAGEMENT
tification of a “culprit” lesion prior to intervention, and the avoidance of intervention in lesions that are of concern arteriographically but prove not to be flow-limiting, are especially attractive. Newer Approaches In recent years approaches for assessing flow reserve which involve measurements only during vasodilation have been suggested. These avoid confounding effects of the level of resting flow in the traditional calculation. Perhaps the most promising such approach is the “pressure-derived fractional flow reserve” (10 –12). This technique capitalizes on the availability of narrow (0.0140) fluid-filled pressure-monitoring guide wires which can be inserted through stenotic lesions. These devices allow post-stenotic pressure in the coronary artery to be measured accurately, i.e., without interfering effects of catheters which compromise lumen size (thereby increasing the intraarterial pressure drop). The crucial measurement is the pressure difference between the aorta and the guide wire tip during pharmacologic vasodilation, i.e., the trans-stenotic pressure gradient during maximum vasodilation (the distance between points A and D on the pressure axis in Figure 1). “Fractional flow reserve” is expressed as the quotient of mean post-stenotic pressure to mean aortic pressure, e.g., an aortic pressure of 100 mm Hg and a post-stenotic pressure of 75 mm Hg would yield a fractional flow reserve of 0.75. Fractional flow reserve measurements have been reported to be more reproducible than simultaneous measurements of traditional flow reserve (coefficient of variation 4.0 vs 14.9%) (12). This finding is thought to reflect greater difficulty in obtaining appropriate Doppler velocity recordings than post-stenotic pressure measurements. It seems consistent with the need for care in obtaining optimal signals emphasized by those with most experience with Doppler catheters and wires (2). It may also relate to the relatively steep slope of velocity-pressure (or flow-pressure) relationships during maximum vasodilation. The ability to quantify the pressure gradient across a stenosis should facilitate the consideration of individual coronary lesions in a manner having several similarities to approaches for evaluating valvar aortic stenosis. On the basis of initial clinical experience, Pijls et al. (11) have suggested that a trans-stenotic gradient .25% of mean aortic pressure (i.e., a fractional flow reserve value ,0.75) is a suitable value for identifying clinically significant lesions in patients with normal left ventricular size and function and without left ventricular hypertrophy or previous myocardial infarction. Although the fractional flow reserve measurement avoids problems related to variable levels of flow (and post-stenotic pressure) prior to vasodilation, it is subject to limitations arising from variations in the flow-pressure relationship during maximum vasodilation in the same manner as tradi-
Figure 2. Measurements of flow and post-stenotic coronary artery pressure in a dog chronically instrumented with a circumflex artery flowmeter, variable circumflex artery occluder and post-occluder pressuremeasurement catheter: (A) The flow-pressure relationship shifts to the right as heart rate (H.R.) is increased (atrial pacing). Maximum flow is ;15% less at any given pressure when heart rate is increased from 95 to 140, and ;30% less at a heart rate of 180. (B) The flowpressure also shifts to the right in response to intracoronary infusion of phenylephrine, an a1 adrenergic agonist. (Heart rate constant at 100.) (C) Vasodilated flow varies within the ventricular wall. The solid line is the flow-pressure relation for the full-thickness wall, obtained as in panels A and B. The dashed lines have been derived from simultaneous measurements employing fluorescent microspheres at two degrees of circumflex constriction. The full-thickness ventricular wall was divided into inner and outer halves for microsphere analysis. The dashed lines indicate the average differences in the flow-pressure relation for the inner and outer halves, and for the posterior papillary muscle (which was analyzed separately). Vasodilated flow decreases progressively across the ventricular wall, reaching a nadir in the papillary muscle. (Heart rate again constant at 100.)
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EVALUATION AND MANAGEMENT
fully. Findings in ongoing and future multicenter trials will be helpful in clarifying these issues. Current Use of Flow Reserve Measurements Invasive measurements of flow reserve seem particularly well suited to the assessment of problematic stenoses being considered for interventional therapy. The experience of the Iowa and Minnesota groups (13) confirms that stenoses which appear severe arteriographically often are not flowlimiting, and indicates that anginal status related to such lesions can improve even though angioplasty is deferred. Because of the potential limitations discussed above, however, false-positive and false-negative results are possible. For example: ●
Satisfactory recordings of coronary velocity are not always obtained, even in experienced hands. ● Values of flow reserve can be reduced independently of the effect of a stenosis by tachycardia, increased preload, vasodilator-induced hypotension, ventricular hypertrophy, previous myocardial infarction and inadvertent use of an inadequate stimulus for maximum vasodilation. ● Conversely, ischemia in the distribution of a “culprit” lesion might be associated with a normal value of fullthickness flow reserve if the ischemic area is confined to the inner ventricular layers and/or papillary muscle. ● A “false negative” result might also occur in an individual whose ischemic episodes result from transient vasoconstriction in a stenotic lesion and/or the vascular bed which it supplies. ● The relation of a reduction in flow reserve identified pharmacologically to myocardial ischemia requires clinical correlation. While a reduction in flow reserve indicates an increased susceptibility to myocardial ischemia, it does not establish that an imbalance between myocardial O2 demand and supply necessarily occurs. If active, asymptomatic individuals with latent coronary disease were somehow identified and underwent measurements of coronary flow reserve, reductions in pharmacologically recruitable reserve would no doubt be identified before myocardial ischemia was demonstrable. Conversely, a normal value of flow reserve in a patient with convincingly documented ischemia in another setting could reflect a dynamic limitation in flow reserve not apparent at the time of measurement.
Figure 3. Effect of a rightward shift in the flow-pressure relationship on the calculation of fractional flow reserve. The shift reduces the transstenotic pressure gradient during vasodilation [A3 E vs A3 D] as well as the traditional value for flow reserve. The calculated value of fractional flow reserve (pressure at point E/pressure at point A) is greater, i.e., less abnormal, than originally (pressure at point D/ pressure at point A).
tional flow reserve measurements. Any shift in this relationship affects the measured value of post-stenotic pressure as well as the corresponding value of flow. Figure 3 illustrates a shift to the right of the relationship, as might occur with tachycardia or transient downstream vasoconstriction. The calculated value of fractional flow reserve increases because the trans-stenotic pressure gradient is less at the reduced level of vasodilated flow, i.e., the reduction in maximum attainable flow is associated with a less abnormal value of fractional flow reserve. Situations in which the flow-pressure relationship is shifted statically, e.g., ventricular hypertrophy, have not yet been examined systematically. As with traditional measurements of flow reserve, substantial clinical experience will be required to place measurements of fractional flow reserve in proper context for routine patient care. The measurement of post-stenotic coronary pressure may prove more widely applicable than a Doppler velocity measurement. The independence of effects of resting flow also seems advantageous. Nevertheless, potentially confounding factors will need to be evaluated care-
Because positive and negative predictive accuracies of flow reserve measurements are available only in selected patient subsets, the practical importance of confounding factors in the broad spectrum of coronary disease (or the lack thereof) requires continued study. Thus, seasoned clinical judgment remains an essential component of decision making involving flow reserve measurements in individual cases.
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EVALUATION AND MANAGEMENT
9. Lalouschek W, Muller C, Gamper G, Weissel M, Turetschek K. Myocardial ischemia with normal coronary arteries associated with thoracic myelitis (Letter). New Engl J Med 1997;337:1920.
REFERENCES 1. Klocke FJ. Cognition in the era of technology: “Seeing the shades of gray.” J Am Coll Cardiol 1990;16:763–9. 2. White CW. Clinical applications of Doppler coronary flow reserve measurements. Am J Cardiol 1993;71:10D–16D. 3. Klocke FJ. Measurements of coronary flow reserve: Defining pathophysiology versus making decisions about patient care. Circulation 1987;76: 1183–9. 4. Strauer BE. Ventricular function and coronary hemodynamics in hypertensive heart disease. Am J Cardiol 1979;44:999 –1006. 5. Marcus ML, Doty DB, Hiratzka LF, Wright CB, Eastham CL. Decreased coronary reserve. A mechanism of angina pectoris in patients with aortic stenosis and normal coronary arteries. New Engl J Med 1982;307:1362– 6. 6. McGinn AL, White CW, Wilson RF. Interstudy variability of coronary flow reserve: Influence of heart rate, arterial pressure and ventricular preload. Circulation 1990;81:1319 –30. 7. Laxson DD, Dai X-Z, Homans DC, Bache RJ. The role of a1- and a2-adrenergic receptors in mediation of coronary vasoconstriction in hypoperfused ischemic myocardium during exercise. Circulation Res 1989; 65:1688 –97. 8. Duncker DJ, Bache RJ. Inhibition of nitric oxide production aggravates myocardial hypoperfusion during exercise in the presence of a coronary artery stenosis. Circulation Res 1994;74:629 – 40.
10. Pijls NHJ, Van Gelder B, Van der Voort P, Peels K, Bracke FALE, Bonnier HJRM, El Gamal MIH. Fractional flow reserve. A useful index to evaluate the influence of an epicardial coronary stenosis on myocardial blood flow. Circulation 1995;92:3183–93. 11. Pijls NHJ, de Bruyne B, Peels K, Van der Voort PH, Bonnier HJRM, Bartunek J, Koolen JJ. Measurement of fractional flow reserve to assess the functional severity of coronary-artery stenoses. New Engl J Med 1996;334: 1703– 8. 12. de Bruyne B, Bartunek J, Sys SU, Pijls NHJ, Heyndrickx GR, Wijns W. Simultaneous coronary pressure and flow measurements in humans. Feasibility, reproducibility, and hemodynamic dependence of coronary flow velocity reserve, hyperemic flow versus pressure slope index, and fractional flow reserve. Circulation 1996;94:1842–9. 13. Lesser JL, Wilson RF, White CW. Physiologic assessment of coronary stenoses of intermediate severity can facilitate patient selection for coronary angioplasty. J Coronary Artery Dis 1990;1:697–705. Address correspondence and reprint requests to Francis J. Klocke, MD, Feinberg Cardiovascular Research Institute, Tarry 12-703 (T233), Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL 60611-3008.
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indicate microvascular disease or the presence of an occult lesion in the reference artery. The safety of deferring coronary angioplasty or revascularization of angiographicallyintermediate lesions with normal translesional hemodynamics has been documented by Kern et al. (37). The DEBATE trial showed that normalization of CFR to .2.5 in combination with a reduction of the angiographic diameter stenosis to ,35% after angioplasty is associated with a low event rate. Investigating 225 patients, the investigators found that patients with both a CFR .2.5 and residual diameter stenosis of ,35% had a low incidence of symptoms at 6 months (23 vs. 47%, P 5 0.005), a low need for reintervention (16 vs 34%, P 5 0.02) and a low restenosis rate (16 vs 41%, P 5 0.002). Recently, a new method for evaluating the significance of coronary artery lesions with angiographic indeterminate severity has been introduced (39). Measurement of myocardial fractional flow reserve (FFR) is based on pressure flow analysis during maximal flow. FFR is the fraction of the normal maximal myocardial blood flow that can be achieved through the stenotic nourishing artery. The index is calculated from the ratio of the mean pressure in the coronary artery distal to the lesion to the aortic blood pressure during maximal vasodilatation, and is not dependent on changes in systemic blood pressure or heart rate. The FFR is dependent on the collateral blood flow. The normal value of FFR is 1.0. An index value of ,0.75 is abnormal and indicates that the stenosis is hemodynamically significant. The reported sensitivity of FFR for detecting myocardial ischemia is 88%, with a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 88%. Thus, Doppler flow wires are quite useful in assessing the hemodynamic significance of coronary artery lesions with angiographic narrowing of indeterminate significance and in assessing pathology of the microcirculation in patients with normal or near normal coronary arteries by angiography. In conclusion, at present, angiography is the primary method of assessment of coronary artery disease. However, the recent developments and improvements in IVUS imaging and Doppler flow wire technology have markedly added to the diagnostic accuracy and assessment of the significance of coronary arterial lesions. Moreover, recent trials suggest that both of these methods used during coronary intervention can facilitate improvement in the acute as well as long-term outcome.
PERSPECTIVE
Measurements of Coronary Flow Reserve in Clinically Problematic Coronary Stenoses Francis J. Klocke, MD and Jeffrey Greenberg, MD, Feinberg Cardiovascular Research Institute, Northwestern University Medical School, Chicago, Illinois The difficulties in inferring the functional significance of a coronary stenosis of intermediate severity solely from an arteriogram are well recognized (1,2). This perspective attempts to summarize strengths and limitations of invasive measurements of coronary flow reserve in addressing this relatively common clinical problem. Although non-invasive measurements of flow reserve now provide useful information about coronary pathophysiology, they have not yet been used widely for decisions about the management of an individual stenosis. Background The coronary circulation is notable for its large amount of vasodilatory reserve at the microcirculatory level. Several relevant features are illustrated in Figure 1. Coronary flow is plotted against coronary artery pressure. Point A represents resting flow and pressure in a normal coronary artery; aortic and coronary artery pressures are identical and the resting value of flow is designated as 1.0. The solid line depicts the relationship between flow and pressure when coronary resistance vessels are dilated maximally with a pharmacologic agent such as adenosine (or dipyridamole). In a normal individual, coronary flow typically increases at least 3.5-fold (2) in response to adenosine (moving from A3 B in Figure 1). When a stenosis develops and produces an abnormal resistance in an epicardial artery, distal resistance vessels dilate to maintain flow at the level appropriate to myocardial oxygen demand. Pressure beyond the stenosis is reduced, producing a gradient between aortic pressure (point A) and pressure just beyond the stenosis (point C). Because distal microcirculatory vasodilation has compensated for the stenosis, resting flow is unchanged. However, because a portion of vasodilatory reserve has been used to maintain resting flow, adenosine now produces a smaller increment in coronary flow (C3 D). Thus, there is an inverse relationship between degree of stenosis and coronary flow during maximum vasodilation. For reasons to be discussed subsequently, we should also note that the increase in flow produced by vasodilation increases the pressure difference across the stenosis (A3 D during vasodilation vs A3 C under resting conditions).
REFERENCES The authors submitted an extensive and important list of references. Because of space limitations, the list is being kept in the Editorial Office and is available upon request to that office. Please telephone: (317) 630-6447 or fax (317) 274-4469. Address correspondence and reprint requests to Robert J. Siegel, MD, Division of Cardiology, Room 5335, 8700 Beverly Boulevard, Los Angeles, CA 90048.
ACC CURRENT JOURNAL REVIEW March/April 1998 © 1998 by the American College of Cardiology Published by Elsevier Science Inc.
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1062-1458/98/$19.00 PII S1062-1458(98)00004-X
EVALUATION AND MANAGEMENT
A 28% average reduction in flow reserve has been reported in essential hypertension with normal coronary arteries (4), and a 59% average reduction in aortic stenosis with normal coronary arteries requiring valve replacement (5). [2] In any given individual, the relationship between coronary flow and pressure during maximum vasodilation also varies dynamically. Alterations in flow reserve produced by changes in heart rate and ventricular preload have been documented clinically as well as experimentally, leading to suggestions that measurements be performed during atrial pacing at a standard heart rate, e.g., 100 bpm (6). Figure 2A demonstrates that the position of the flow-pressure line during maximum vasodilation is indeed influenced by heart rate. Although it is less well appreciated, the flow-pressure line during pharmacologic dilation is also subject to dynamic vasoconstrictor influences. Figure 2B illustrates a change in the relationship produced by intracoronary infusion of phenylephrine, an a1 agonist. a1 receptor stimulation has been shown to limit coronary flow responses in the presence of a coronary stenosis during exercise (7). Endothelial dysfunction (8) and extracardiac vasoconstrictor influences (9) may also adversely affect the balance between vasodilatory and vasoconstrictor influences in stressful situations. [3] Because traditional values of flow reserve are calculated as the ratio of vasodilated flow to resting flow just prior to vasodilation, they are also affected by variations in resting flow caused by variations in resting myocardial oxygen demand. In the case of tachycardia, the rate-induced increase in pre-vasodilation flow contributes importantly to observed reductions in flow reserve (6). [4] Because clinical measurements of coronary flow reserve provide an average value for the entire ventricular wall, they may underestimate reductions in reserve in the inner layers of the ventricular wall. Figure 2C illustrates differences in coronary flow during maximum vasodilation in the outer and inner halves of the ventricular wall and in the posterior papillary muscle of a chronically instrumented dog during two degrees of partial circumflex artery occlusion. The more limited flow reserve in subendocardial tissue and the posterior papillary muscle is concordant with the earliest appearance of ischemia in these areas. While these complexities always need to be considered in individual cases, experience during the past decade has documented a useful role for traditional measurements of flow reserve in selected situations. White (2), who has played a leading role in coronary applications of Doppler technology, suggests that these include: (a) the functional evaluation of intermediate grade stenoses; (b) assessment of the need for lesion-specific interventional therapy; (c) evaluation of the severity of lesions in saphenous vein bypass grafts and at graft-native vessel anastomotic sites; and (d) assessment of the coronary microcirculation (2). The iden-
Figure 1. Relationship between coronary flow and coronary artery pressure during maximum pharmacologic vasodilation. See text for details. Traditional Measurements of Flow Reserve Coronary flow reserve has traditionally been defined as the ratio of flow during maximum vasodilation to that observed under resting conditions (flow at point B/flow at point A, and flow at point D/flow at point C, in Figure 1). The ability to measure flow reserve with Doppler velocity catheters has provided a greatly improved understanding of pathophysiology in coronary artery disease. However, as discussed in a previous review (3), the interpretation of a flow reserve measurement in an individual patient involves several complexities: [1] The relationship between flow and pressure during maximum vasodilation can vary substantially from individual to individual, i.e., the solid line in Figure 1 can vary in both slope and position along the pressure axis (the horizontal axis). Because ventricular hypertrophy occurs commonly in clinically evident coronary artery disease, its effects are of particular interest. The attribution of a diminished value of flow reserve to a stenosis presumes that downstream microcirculatory vessels are able to vasodilate normally. However, because the degree of microcirculatory proliferation is disproportionately small in relation to the increase in ventricular mass in a hypertrophied ventricle, maximum flow in each unit of ventricular tissue is reduced, i.e., the slope of the flow-pressure line during maximum vasodilation is reduced.
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tification of a “culprit” lesion prior to intervention, and the avoidance of intervention in lesions that are of concern arteriographically but prove not to be flow-limiting, are especially attractive. Newer Approaches In recent years approaches for assessing flow reserve which involve measurements only during vasodilation have been suggested. These avoid confounding effects of the level of resting flow in the traditional calculation. Perhaps the most promising such approach is the “pressure-derived fractional flow reserve” (10 –12). This technique capitalizes on the availability of narrow (0.0140) fluid-filled pressure-monitoring guide wires which can be inserted through stenotic lesions. These devices allow post-stenotic pressure in the coronary artery to be measured accurately, i.e., without interfering effects of catheters which compromise lumen size (thereby increasing the intraarterial pressure drop). The crucial measurement is the pressure difference between the aorta and the guide wire tip during pharmacologic vasodilation, i.e., the trans-stenotic pressure gradient during maximum vasodilation (the distance between points A and D on the pressure axis in Figure 1). “Fractional flow reserve” is expressed as the quotient of mean post-stenotic pressure to mean aortic pressure, e.g., an aortic pressure of 100 mm Hg and a post-stenotic pressure of 75 mm Hg would yield a fractional flow reserve of 0.75. Fractional flow reserve measurements have been reported to be more reproducible than simultaneous measurements of traditional flow reserve (coefficient of variation 4.0 vs 14.9%) (12). This finding is thought to reflect greater difficulty in obtaining appropriate Doppler velocity recordings than post-stenotic pressure measurements. It seems consistent with the need for care in obtaining optimal signals emphasized by those with most experience with Doppler catheters and wires (2). It may also relate to the relatively steep slope of velocity-pressure (or flow-pressure) relationships during maximum vasodilation. The ability to quantify the pressure gradient across a stenosis should facilitate the consideration of individual coronary lesions in a manner having several similarities to approaches for evaluating valvar aortic stenosis. On the basis of initial clinical experience, Pijls et al. (11) have suggested that a trans-stenotic gradient .25% of mean aortic pressure (i.e., a fractional flow reserve value ,0.75) is a suitable value for identifying clinically significant lesions in patients with normal left ventricular size and function and without left ventricular hypertrophy or previous myocardial infarction. Although the fractional flow reserve measurement avoids problems related to variable levels of flow (and post-stenotic pressure) prior to vasodilation, it is subject to limitations arising from variations in the flow-pressure relationship during maximum vasodilation in the same manner as tradi-
Figure 2. Measurements of flow and post-stenotic coronary artery pressure in a dog chronically instrumented with a circumflex artery flowmeter, variable circumflex artery occluder and post-occluder pressuremeasurement catheter: (A) The flow-pressure relationship shifts to the right as heart rate (H.R.) is increased (atrial pacing). Maximum flow is ;15% less at any given pressure when heart rate is increased from 95 to 140, and ;30% less at a heart rate of 180. (B) The flowpressure also shifts to the right in response to intracoronary infusion of phenylephrine, an a1 adrenergic agonist. (Heart rate constant at 100.) (C) Vasodilated flow varies within the ventricular wall. The solid line is the flow-pressure relation for the full-thickness wall, obtained as in panels A and B. The dashed lines have been derived from simultaneous measurements employing fluorescent microspheres at two degrees of circumflex constriction. The full-thickness ventricular wall was divided into inner and outer halves for microsphere analysis. The dashed lines indicate the average differences in the flow-pressure relation for the inner and outer halves, and for the posterior papillary muscle (which was analyzed separately). Vasodilated flow decreases progressively across the ventricular wall, reaching a nadir in the papillary muscle. (Heart rate again constant at 100.)
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EVALUATION AND MANAGEMENT
fully. Findings in ongoing and future multicenter trials will be helpful in clarifying these issues. Current Use of Flow Reserve Measurements Invasive measurements of flow reserve seem particularly well suited to the assessment of problematic stenoses being considered for interventional therapy. The experience of the Iowa and Minnesota groups (13) confirms that stenoses which appear severe arteriographically often are not flowlimiting, and indicates that anginal status related to such lesions can improve even though angioplasty is deferred. Because of the potential limitations discussed above, however, false-positive and false-negative results are possible. For example: ●
Satisfactory recordings of coronary velocity are not always obtained, even in experienced hands. ● Values of flow reserve can be reduced independently of the effect of a stenosis by tachycardia, increased preload, vasodilator-induced hypotension, ventricular hypertrophy, previous myocardial infarction and inadvertent use of an inadequate stimulus for maximum vasodilation. ● Conversely, ischemia in the distribution of a “culprit” lesion might be associated with a normal value of fullthickness flow reserve if the ischemic area is confined to the inner ventricular layers and/or papillary muscle. ● A “false negative” result might also occur in an individual whose ischemic episodes result from transient vasoconstriction in a stenotic lesion and/or the vascular bed which it supplies. ● The relation of a reduction in flow reserve identified pharmacologically to myocardial ischemia requires clinical correlation. While a reduction in flow reserve indicates an increased susceptibility to myocardial ischemia, it does not establish that an imbalance between myocardial O2 demand and supply necessarily occurs. If active, asymptomatic individuals with latent coronary disease were somehow identified and underwent measurements of coronary flow reserve, reductions in pharmacologically recruitable reserve would no doubt be identified before myocardial ischemia was demonstrable. Conversely, a normal value of flow reserve in a patient with convincingly documented ischemia in another setting could reflect a dynamic limitation in flow reserve not apparent at the time of measurement.
Figure 3. Effect of a rightward shift in the flow-pressure relationship on the calculation of fractional flow reserve. The shift reduces the transstenotic pressure gradient during vasodilation [A3 E vs A3 D] as well as the traditional value for flow reserve. The calculated value of fractional flow reserve (pressure at point E/pressure at point A) is greater, i.e., less abnormal, than originally (pressure at point D/ pressure at point A).
tional flow reserve measurements. Any shift in this relationship affects the measured value of post-stenotic pressure as well as the corresponding value of flow. Figure 3 illustrates a shift to the right of the relationship, as might occur with tachycardia or transient downstream vasoconstriction. The calculated value of fractional flow reserve increases because the trans-stenotic pressure gradient is less at the reduced level of vasodilated flow, i.e., the reduction in maximum attainable flow is associated with a less abnormal value of fractional flow reserve. Situations in which the flow-pressure relationship is shifted statically, e.g., ventricular hypertrophy, have not yet been examined systematically. As with traditional measurements of flow reserve, substantial clinical experience will be required to place measurements of fractional flow reserve in proper context for routine patient care. The measurement of post-stenotic coronary pressure may prove more widely applicable than a Doppler velocity measurement. The independence of effects of resting flow also seems advantageous. Nevertheless, potentially confounding factors will need to be evaluated care-
Because positive and negative predictive accuracies of flow reserve measurements are available only in selected patient subsets, the practical importance of confounding factors in the broad spectrum of coronary disease (or the lack thereof) requires continued study. Thus, seasoned clinical judgment remains an essential component of decision making involving flow reserve measurements in individual cases.
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