- Email: [email protected]
Focus for the new millennium: diffuse coronary artery disease and physiologic measurements of severity
THE PAST AND THE PRESENT: PROLOGUES TO THE FUTURE direct visualization) and optical (reflected light). The extent of involvement of the atherosclerotic wall can be inferred from the coronary lumenogram, and the surface characteristics can be identified by angioscopy and precisely quantitated by IVUS. The distribution and extent of disease of the coronary circulation can thus be identified. Naturally, each technique has its advantages and limitations.
THE NEW CENTURY SERIES K. Lance Gould, MD, Guest Editor
BRIEF REVIEW
Focus for the New Millennium: Diffuse Coronary Artery Disease and Physiologic Measurements of Severity
Coronary angiography and physiologic assessment Coronary angiography fails to detect diffuse mild coronary artery atherosclerosis until late in the patient’s presentation. Current quantitative coronary arteriographic measures of the percent diameter narrowing of the coronary artery lumen do not account for true normal coronary arterial size in determining the severity of segmental or diffuse coronary artery disease because only the lumen of the reference segment is available for comparison. The true size of an artery is often obscured because of Glavovian remodeling. Recently, a theoretic model and practical method using quantitative coronary arteriography for analyzing the structure and function of the coronary epicardial tree in the setting of both segmental and diffuse coronary artery disease has been developed (1). In patients with coronary artery disease, the coronary artery lumen area is, on average, one third to one half smaller than the normal arterial area for the same arterial branch length and left ventricular regional mass. Using the relationship between coronary artery lumen area, summed branch length and distal regional mass, the expected normal anatomic structure of the human coronary artery can be estimated by these physical principles. In the future, anatomic observations of branch length and myocardial mass, coupled to measurements of intracoronary flow reserve and the pressure drop along the course of each coronary artery, can be used to generate a quantitative flow reserve map of the entire coronary tree. This integrated anatomic and functional analysis would fully characterize the clinical impact of both focal and diffuse coronary artery disease and its potential response to interventions.
Morton J. Kern, MD, Department of Internal Medicine, Division of Cardiology, Saint Louis University Health Sciences Center, St. Louis, Missouri iffuse atherosclerotic involvement of human coronary arteries is a major factor contributing to significant morbidity and mortality in the industrialized world. Beginning as yellow streaks on the intimal service, atherosclerosis continues to accumulate, resulting in endothelial dysfunction, impaired nitric oxide synthesis and release and endothelial denudation upon which platelets deposit and release factors stimulating smooth muscle proliferation. Focal plaques grow with episodic erosion, promoting thrombosis and stimulating additional plaque enlargement and often resulting in thrombotic occlusion and acute ischemic syndromes. Early detection and appreciation of the physiologic significance of diffuse coronary artery disease has increasingly important therapeutic implications. Diagnostic techniques for detection and subsequent evaluation after therapy can be divided into two important and complementary categories: anatomic and physiologic. The methods used to acquire data about the coronary arteries for each category can be applied in two ways: noninvasive (indirect) and invasive (direct). The anatomic and physiologic techniques presently used and those that might be used in the near future for diagnosing both focal and diffuse coronary artery disease are discussed (Table 1).
D
Invasive physiologic assessment for coronary artery disease Coronary artery stenoses can be characterized by their resistance to flow and quantitatively assessed by direct pressure (P) and flow velocity (Q) measurements across each stenosis. The curvilinear pressure-flow relationship demonstrates a proportionately increasing pressure loss as a squared function of increasing flow and varies according to the lesion morphology (entrance/exit angles, length, eccentricity and luminal topography). Because net flow is the result of a complex system, extrapolation from quantitative anatomic variables alone to gauge the functional stenotic response has not been reliable. Several practical approaches to applying coronary physi-
Anatomic Methods To detect the anatomic impact of diffuse atherosclerosis, coronary angiography, ultrafast computed tomography (CT) or electron-beam CT, magnetic resonance angiography, intravascular ultrasound (IVUS) and angioscopy have been used. Potentially, new modalities involving thermography and optical coherence tomography may be clinically applicable in the near future. To identify anatomic pathology, imaging modalities use the transmission of electrons to produce x-rays (angiography and fast CT), magnetic resonance imaging (MRI), intravascular ultrasound (IVUS), angioscopy (visible light for
ACC CURRENT JOURNAL REVIEW March/April 2000 © 2000 by the American College of Cardiology Published by Elsevier Science Inc.
13
1062-1458/00/$20.00 PII S1062-1458(00)00041-6
THE PAST AND THE PRESENT: PROLOGUES TO THE FUTURE
to the ischemic potential of a stenosis. His team developed formulas for a pressure-derived estimate of the percentage of normal expected coronary blood flow called the FFR. The FFR is the fraction of maximal coronary blood flow that would go through the stenotic vessel as a percentage of blood flow through the same artery in the theoretic absence of the stenosis. The FFR reflects myocardial perfusion (both antegrade and collateral) rather than merely transstenotic pressure loss (i.e., a stenosis gradient) and is thus differentiated from coronary flow. FFR is calculated at peak vasodilator response, thus assuming coronary resistance is minimal across both the epicardial and microvascular beds. FFR, the ratio of the absolute distal coronary and aortic pressures measured during maximal hyperemia, is therefore independent of driving pressure, heart rate, systemic blood pressure or status of the microcirculation. Calculation of an FFR value of less than 0.75 in patients with stable angina is strongly related to provocable myocardial ischemia using multiple stress testing methods (4). Microcirculatory flow impairment, nonetheless, remains the major concern in accurately assessing a stenosis using absolute CVR, relative CVR or FFR. In patients in whom the target vessel supplies an area of myocardial infarction with or without left ventricular dysfunction, neither absolute CVR nor rCVR can confidently identify the lesion-specific nature of flow impairment because the rCVR relies on the assumption that the microvascular circulatory response is uniformly distributed among the myocardial beds. When the CVR is severely blunted (e.g., severe hypertrophy, hypertension), the discriminating difference between the target and reference regions will also be reduced. rCVR might not be sensitive enough to reflect the impact of a stenosis in such a low-flow setting. In addition, in patients with three-vessel coronary disease, there may be no suitable reference vessel prohibiting use of rCVR. A lesion in this situation is best assessed by a pressure-derived estimate of coronary flow, the FFR. Figure 1 presents an example of physiologic measurements of stenosis severity in a patient with diffuse and focal coronary artery disease. Diffuse coronary artery disease may theoretically adversely affect the FFR because an attenuated increase in flow during maximal vasodilatation could minimize the maximal FFR value. Because the hyperemic decline in epicardial coronary pressure (i.e., FFR) reflects the extent to which the epicardial resistance reduces myocardial perfusion, it can be argued that in this setting, a normal FFR indicates that the conduit resistance is not a major contributing factor to perfusion impairment and that enlargement of any conduit obstruction would not restore normal perfusion. FFR and Doppler velocimetry are complementary, describing the physiology of both the epicardial stenosis and microvascular disease (if present) and the potential contribution to inducible myocardial ischemia. It should be recognized that the normal
Table 1. METHODS TO ASSESS CORONARY ARTERY DISEASE Anatomic
Physiologic
MRA*
PET MRA-velocity
Fast CT Thermography* Indirect
Direct
Ischemia testing (pharmacologic exercise) Electrocardiography Echocardiography Radionuclide Angiography IVUS Angioscopy Optical Coherence Tomography*
Coronary flow velocity Coronary pressure IVUS-based flow* Thermography*
*Future applications. CT, computed tomography; IVUS, intravascular ultrasound; MRA, magnetic resonance angiography; PET, positron emission tomography.
ologic measurements in the cardiac catheterization laboratory using sensor-tipped guidewires have been refined and validated (2). These approaches include measurement of poststenotic absolute coronary velocity reserve (CVR), relative CVR (rCVR) and pressure-derived fractional flow reserve (FFR). Ambiguity regarding the specific nature of an abnormal CVR due to an impaired microvascular response or diffuse coronary artery disease rather than a focal stenosis has been reduced or eliminated with rCVR and FFR. The quantification of microvascular flow impairment can thus be separately determined with CVR measurements. Absolute CVR is the capacity of the coronary artery and supplied vascular bed to achieve maximal flow in response to hyperemic stimulation under existing hemodynamic conditions. Although CVR has been advocated as the measure of flow limitation attributable to a stenotic narrowing, CVR is the result of two major interacting components (epicardial and microvascular flow). An abnormal value is therefore not specific for stenosis alone. Assuming that global myocardial reserve (i.e., the microcirculation) is uniformly distributed, the use of a reference vessel reserve and the computation of an rCVR (rCVR ⫽ the ratio of the target vessel CVR to the reference vessel CVR) can be postulated to specifically reflect the effect of a stenosis on coronary flow independent of loading conditions, hemodynamics or microcirculation. rCVR, like FFR (vide infra), is theoretically independent from and not affected by the microvascular circulation or other physiologic variables that can reduce absolute CVR (e.g., diffuse coronary artery disease, hypertrophy, diabetes and tachycardia) in the absence of an epicardial stenosis. Pressure-derived fractional flow reserve: Bringing the past to the future. Pijls et al. (3,4) eloquently demonstrated that the absolute distal coronary pressure during maximal hyperemia, but not the resting pressure gradient, is related
ACC CURRENT JOURNAL REVIEW March/April 2000
14
THE PAST AND THE PRESENT: PROLOGUES TO THE FUTURE
Figure 1. (A) A 72-year-old woman with diabetes and hypertension had chest pain, shortness of breath and exertional dizziness and reversible inferior wall myocardial ischemia on stress cardiolyte and 2-3mm ST depression inferolaterally while on calcium antagonist, aspirin and angiotensin-converting enzyme inhibitor therapies. Coronary angiography demonstrates a long, diffuse right coronary artery stenosis with a CVR (top right) of 1.3. Quantitative coronary angiography of the right coronary artery indicates the stenosis is 71% (bottom left); CVR in the left anterior descending reference vessel (bottom right) is 1.8, relative CVR ⫽ 1.3/1.8 ⫽ 0.72. (B) After angioplasty was performed (top left), the percent diameter stenosis was ⬍ 35%, but the CVR was 1.1 (relative CVR ⫽ 0.61) (top right). A stent was placed with ⬍ 10% diameter narrowing (bottom left). The CVR was improved (1.5) but not normalized (relative CVR 4.5/1.8 ⫽ 0.83). (C) FFR of the myocardium was also measured. Before angioplasty, the FFR was ⬍ 0.4. After angioplasty, the FFR was 0.74 and improved to 0.96 after stenting.
threshold of FFR (less than 0.75) for ischemia was derived from a selected stable patient population with single-vessel coronary disease and normal left ventricular function. The data are limited for patients with microvascular disease, acute or remote myocardial infarction and unstable angina. Caution should be applied in extending the current physiologic criteria to such patients. FFR may still assist in characterizing the impact of diffuse
coronary artery disease. As described in Figure 2, the typical atherosclerotic coronary artery with diffuse disease has a serial cascade of asymmetric stenotic branching units contributing to pressure loss and flow diversion along the vessel’s length. As such, there is no single value of coronary flow reserve or pressure (FFR) that uniquely characterizes the pathophysiologic behavior of the artery in this situation. A change in any stenotic segment will alter the pressure flow
ACC CURRENT JOURNAL REVIEW March/April 2000
15
THE PAST AND THE PRESENT: PROLOGUES TO THE FUTURE
Figure 2. A schematic of mixed segmental and diffuse narrowings and associated pressure drops along the length of the artery at maximum flow. (A) Predominant, more severe single segmental stenoses with less diffuse narrowing, suitable for angioplasty or bypass surgery. (B) Predominantly diffuse disease or multiple stenoses with less segmental narrowing, not appropriate for angioplasty or bypass surgery. Reprinted with permission from Gould KL. Coronary artery stenosis and reversing atherosclerosis, 2nd ed. London: Arnold Publishing, 1999. characteristics of the entire artery distal to that point. Mechanical therapy for such physiology would likely be ineffective in restoring normal coronary perfusion.
severity of coronary artery disease and have been used to determine the functional significance of localized stenoses (5,6). Standard technique PET scanning and, potentially, MR coronary flow velocity can discriminate between focal localized obstructions to coronary flow compared with a diffuse gradual reduction in flow along a coronary conduit not amenable to mechanical therapy. Dynamic PET imaging has excellent specificity in patients with a low likelihood of coronary artery disease, whereas an abnormal PETdetermined coronary reserve in angiographically normal territories appears to represent early functional abnormalities of vascular reactivity or possible diffuse atherosclerotic involvement. PET techniques may be more sensitive than coronary angiography to identify the early stages of atherosclerotic coronary artery disease. As noted for the hemodynamic
Noninvasive physiologic assessment of focal and diffuse coronary artery disease Both invasive and noninvasive physiologic methods attempt to address the impact of diffuse or focal narrowing of the coronary arteries on myocardial perfusion and the ischemic threshold for myocardial function. Ischemic stress testing, often obtained in patients with diffuse atherosclerotic coronary artery disease who may have concomitant focal accumulations, may not be sufficiently discriminative to differentiate subtle regional abnormalities of coronary blood flow caused by diffuse coronary artery disease. PET scanning. Regional myocardial blood flow measurements using positron emission tomography (PET) reflect the
ACC CURRENT JOURNAL REVIEW March/April 2000
16
THE PAST AND THE PRESENT: PROLOGUES TO THE FUTURE
Figure 3. A schematic of the longitudinal, base to apex, myocardial perfusion abnormality due to diffuse coronary artery narrowing compared with segmental perfusion defects due to localized stenoses. Modified with permission from Gould KL. Coronary artery stenosis and reversing atherosclerosis, 2nd ed. London: Arnold Publishing, 1999.
effects of diffuse coronary artery disease, a gradual decrement of pressure and flow along the course of the vessel is a characteristic finding (Figure 2). An artery with a predominant focal narrowing suitable for coronary angioplasty or bypass surgery will have a localized pressure drop, whereas
diffuse coronary artery disease demonstrates a gradual pressure drop along the course of the vessel. The same physiologic response is also detected with PET imaging as a graded longitudinal perfusion deficit from base to apex elicited during hyperemic stress (Figure 3) (7). Unlike most cur-
ACC CURRENT JOURNAL REVIEW March/April 2000
17
THE PAST AND THE PRESENT: PROLOGUES TO THE FUTURE
IVUS-determined flow One of the potentially new applications of IVUS is the determination of volumetric coronary flow based on the decorrelation of radiofrequency signals. IVUS can identify the direction of blood flow in the plane of ultrasound imaging. As particles move across this plane, radiofrequency echo signals decorrelate at a rate proportional to flow velocity (12). The characterization of the relationship between the correlation of echo signals and the scattered motion across the ultrasound beam provides a local transverse velocity and volumetric flow calculation based on a cross-sectional area. Because motion velocities of the vascular wall tissue are significantly lower than blood, the tissue velocities can be extracted by establishing a threshold level. No contour tracing of the arterial lumen is necessary. Because all velocities in the imaging plane are integrated, an accurate volumetric measurement across the imaging plane can be established. This new method is being validated against classical electromagnetic flow measurements and is presently under clinical evaluation in several laboratories in Europe and North America (13).
rently available noninvasive imaging techniques, PET can resolve subtle perfusion gradients and differentiate focal flow-limiting stenoses associated with substantial regional flow disparity. A graded longitudinal perfusion abnormality is differentiated from a segmental defect in that the typical abrupt reduction in regional myocardial perfusion due to a segmental coronary obstruction is not seen. Subtle longitudinal perfusion gradients have not been widely appreciated, often obscured by severe regional perfusion defects of coexistent focal stenosis. For mild-to-moderate diffuse coronary narrowing without localized flow-limiting stenosis, significant regional perfusion defects are apparent in large numbers of patients and serve to identify diffuse atherosclerosis despite the absence of significant or critical stenoses. The graded perfusion deficit of diffuse coronary artery disease is consistent with direct measurements of coronary flow and pressure in such vessels using intracoronary Doppler or pressure-sensor guidewires. Proximally measured coronary flow reserve is greater than that measured in the distal arterial segments in the absence of critical lesions (8). A longitudinal base to apex perfusion gradient detecting subangiographic atherosclerosis appears to confirm the diffuse, rather than the focal, nature of coronary artery disease in some patients and can support a vigorous antiatherosclerotic risk factor reduction program (9). Future studies of graded perfusion imaging will be important in gauging efficacy of pharmacologic intervention for these patients.
The future for plaque physiology: Thermography and optical coherence tomography Activation of macrophages in the acute ischemic syndrome promotes plaque rupture, thrombosis and vasoconstriction. Ex vivo studies have demonstrated that thermal heterogeneity in human carotid atherosclerotic plaques can identify those most likely to rupture (14). In human atherosclerotic coronary arteries, a 3F thermography catheter (15) demonstrated thermal heterogeneity over a spatial resolution of 0.5 mm in coronary arteries in 20% of patients with stable angina, 40% of patients with unstable angina and 67% of patients with acute myocardial infarction. No thermal heterogeneity was evident in control subjects. In patients with diffuse atherosclerosis, thermography may be expected to identify those regions likely to undergo activation in the near term and be used to support early intervention or verify the stabilization of such regions after mechanical or pharmacologic therapy. Optimal coherence tomography (OCT) represents a new imaging modality for microvascular structure at a level of resolution not previously achieved with IVUS (16). OCT is a unique catheter-based technique utilizing back-reflected infrared light to obtain in situ micron scale tomographic imaging. OCT images, even in heavily calcified tissue, can differentiate between lipid-based and water-based plaque constituents. OCT axial resolution permits evaluation of small structural details, such as the thickness of intimal caps, the presence of fissures among diffuse regions of atherosclerosis and the extent of lipid pool collections within plaques. Because OCT does not require direct contact with the vessel wall, it can be performed with a catheter integrated with
The future: Magnetic resonance and IVUS imaging of coronary blood flow Noninvasive measurements of absolute coronary blood flow and CVR can be obtained with phase-contrast MRI (10). A high correlation (r ⬎ 0.89) between MRI and invasive measurements of arterial flow and CVR was observed (10). Cine velocity and coded phase-contrast MRI can noninvasively measure absolute coronary arterial flow in the left anterior descending artery in humans and, by using pharmacologically-induced hyperemia, can reliably distinguish between individuals with normal and abnormal coronary flow. In this way, MRI may also have significant advantages in evaluating patients after acute myocardial infarction. Furber et al. (11) measured infarct-related coronary artery blood flow using phase-contrast MRI in patients after reperfusion for acute myocardial infarction and found a good correlation between phase-contrast MRI and intracoronary Doppler average peak velocities. MRI velocity measurements have a similar spectrum of flow heterogeneity as reported for direct Doppler examination. The potential to quantify coronary flow velocity and thereby evaluate the quality of flow restoration after acute myocardial infarction and reperfusion therapy directed at the microcirculation may have substantial therapeutic applications.
ACC CURRENT JOURNAL REVIEW March/April 2000
18
THE PAST AND THE PRESENT: PROLOGUES TO THE FUTURE
relatively inexpensive optical fibers. The high contrast and high resolution between tissues and its ability to penetrate calcium makes OCT an attractive new diagnostic imaging technique with specific application to atherosclerotic plaque physiology.
6. Demer LL, Gould KL, Goldstein RA, Kirkeeide RL. Diagnosis of coronary artery disease by positron emission tomography: comparison to quantitative coronary arteriography in 193 patients. Circulation 1989;79:825–35. 7. Gould KL, Martucci JP, Goldberg DI, et al. Short-term cholesterol lowering decreases in size and severity of perfusion abnormalities by positron emission tomography after dipyridamole in patients with coronary artery disease. Circulation 1994;89:1530 – 8.
Conclusion Diffuse coronary artery disease is a ubiquitous companion of angiographically-defined focal atherosclerosis. Although mechanical interventions can provide palliative revascularization, the future resides in pharmacologic or vascular genetic therapies to stabilize, retard and reverse the insidious process of plaque growth and activation. Diagnostic abilities to quantify the anatomic and physiologic features of the diffusely diseased coronary artery will promote effective therapies, reduce unnecessary and ineffective attempts to restore normal coronary blood flow mechanically and potentially improve long-term outcomes in patients with coronary artery disease.
8. Donohue TJ, Miller DD, Bach RG, et al. Correlation of poststenotic hyperemic coronary flow velocity and pressure with abnormal stress myocardial perfusion imaging in coronary artery disease. Am J Cardiol 1996; 77:948 –54. 9. Gould K, Omish D, Scherwitz L, et al. Changes in myocardial perfusion abnormalities by positron emission tomography after long-term, intense risk factor modification. JAMA 1995;274:894 –901. 10. Hundley WG, Lange RA, Clarke GD, et al. Assessment of coronary arterial flow and flow reserve in humans with magnetic resonance imaging. Circulation 1996;93:1502– 8. 11. Furber AP, Lethimonnier F, Le Jeune J, et al. Noninvasive assessment of the infarct-related coronary artery blood flow velocity using phase-contrast magnetic resonance imaging after coronary angioplasty. Am J Cardiol 1999;84:24 –30. 12. Li W, van der Steen AFW, Lancee CT. Temporal correlation of bloodscattering signals in vivo from radiofrequency intravascular ultrasound. Ultrasound Med Biol 1996;22:583–90.
REFERENCES 1. Seiler C, Kirkeeide RL, Gould KL. Basic structure-function of the epicardial coronary vascular tree—the basis of quantitative coronary arteriography for diffuse coronary artery disease. Circulation 1992;85:1987–2003. 2. Kern MJ, De Bruyne B, Pijls NHJ. From research to clinical practice: Current role of intracoronary physiologically based decision making in the cardiac catheterization laboratory. J Am Coll Cardiol 1997;30:613–20. 3. Pijls NH, Van Gelder B, Van der Voort P, et al. Fractional flow reserve: A useful index to evaluate the influence of an epicardial coronary stenosis on myocardial blood flow. Circulation 1995;92:3183–93. 4. Pijls NH, De Bruyne B, Peels K, et al. Measurement of fractional flow reserve to assess the functional severity of coronary-artery stenoses. N Engl J Med 1996;334:1703– 8. 5. Muzik O, Duvernoy C, Beanlands RSB, et al. Assessment of diagnostic performance of quantitative flow measurements in normal subjects and patients with angiographically documented coronary artery disease by means of nitrogen-13 ammonia and positron emission tomography. J Am Coll Cardiol 1998;31:534 – 40.
13. Carlier S, Li W. In vivo validation of a new intracoronary volumetric blood flow measurement method with intravascular ultrasound [abstract]. Circulation (in press, 1999). 14. Casscells W, Hathorn B, David M, et al. Thermal detection of cellular infiltrates in living atherosclerotic plaques: possible implications for plaque rupture and thrombosis. Lancet 1996;347:1447–9. 15. Stefanadis C, Diamantopoulos L, Vlachopoulos C, Tsiamis E, Dernellis J, Toutouzas K, Stefanadi E, Toutouzas P. Thermal heterogeneity within human atherosclerotic coronary arteries detected in vivo: A new method of detection by application of a special thermography catheter. Circulation 1999;99:1965–71. 16. Tearney GJ, Brezinski ME, Boppart SA, et al. Catheter-based optical imaging of a human coronary artery. Circulation 1996;94:3013. Address correspondence and reprint requests to Morton J. Kern, MD, Director, J.G. Mudd Cardiac Catheterization Laboratory, Saint Louis University Health Sciences Center, 3635 Vista Avenue at Grand Boulevard, St. Louis, MO 63110.
ACC CURRENT JOURNAL REVIEW March/April 2000
19
THE NEW CENTURY SERIES K. Lance Gould, MD, Guest Editor
BRIEF REVIEW
Focus for the New Millennium: Diffuse Coronary Artery Disease and Physiologic Measurements of Severity
Coronary angiography and physiologic assessment Coronary angiography fails to detect diffuse mild coronary artery atherosclerosis until late in the patient’s presentation. Current quantitative coronary arteriographic measures of the percent diameter narrowing of the coronary artery lumen do not account for true normal coronary arterial size in determining the severity of segmental or diffuse coronary artery disease because only the lumen of the reference segment is available for comparison. The true size of an artery is often obscured because of Glavovian remodeling. Recently, a theoretic model and practical method using quantitative coronary arteriography for analyzing the structure and function of the coronary epicardial tree in the setting of both segmental and diffuse coronary artery disease has been developed (1). In patients with coronary artery disease, the coronary artery lumen area is, on average, one third to one half smaller than the normal arterial area for the same arterial branch length and left ventricular regional mass. Using the relationship between coronary artery lumen area, summed branch length and distal regional mass, the expected normal anatomic structure of the human coronary artery can be estimated by these physical principles. In the future, anatomic observations of branch length and myocardial mass, coupled to measurements of intracoronary flow reserve and the pressure drop along the course of each coronary artery, can be used to generate a quantitative flow reserve map of the entire coronary tree. This integrated anatomic and functional analysis would fully characterize the clinical impact of both focal and diffuse coronary artery disease and its potential response to interventions.
Morton J. Kern, MD, Department of Internal Medicine, Division of Cardiology, Saint Louis University Health Sciences Center, St. Louis, Missouri iffuse atherosclerotic involvement of human coronary arteries is a major factor contributing to significant morbidity and mortality in the industrialized world. Beginning as yellow streaks on the intimal service, atherosclerosis continues to accumulate, resulting in endothelial dysfunction, impaired nitric oxide synthesis and release and endothelial denudation upon which platelets deposit and release factors stimulating smooth muscle proliferation. Focal plaques grow with episodic erosion, promoting thrombosis and stimulating additional plaque enlargement and often resulting in thrombotic occlusion and acute ischemic syndromes. Early detection and appreciation of the physiologic significance of diffuse coronary artery disease has increasingly important therapeutic implications. Diagnostic techniques for detection and subsequent evaluation after therapy can be divided into two important and complementary categories: anatomic and physiologic. The methods used to acquire data about the coronary arteries for each category can be applied in two ways: noninvasive (indirect) and invasive (direct). The anatomic and physiologic techniques presently used and those that might be used in the near future for diagnosing both focal and diffuse coronary artery disease are discussed (Table 1).
D
Invasive physiologic assessment for coronary artery disease Coronary artery stenoses can be characterized by their resistance to flow and quantitatively assessed by direct pressure (P) and flow velocity (Q) measurements across each stenosis. The curvilinear pressure-flow relationship demonstrates a proportionately increasing pressure loss as a squared function of increasing flow and varies according to the lesion morphology (entrance/exit angles, length, eccentricity and luminal topography). Because net flow is the result of a complex system, extrapolation from quantitative anatomic variables alone to gauge the functional stenotic response has not been reliable. Several practical approaches to applying coronary physi-
Anatomic Methods To detect the anatomic impact of diffuse atherosclerosis, coronary angiography, ultrafast computed tomography (CT) or electron-beam CT, magnetic resonance angiography, intravascular ultrasound (IVUS) and angioscopy have been used. Potentially, new modalities involving thermography and optical coherence tomography may be clinically applicable in the near future. To identify anatomic pathology, imaging modalities use the transmission of electrons to produce x-rays (angiography and fast CT), magnetic resonance imaging (MRI), intravascular ultrasound (IVUS), angioscopy (visible light for
ACC CURRENT JOURNAL REVIEW March/April 2000 © 2000 by the American College of Cardiology Published by Elsevier Science Inc.
13
1062-1458/00/$20.00 PII S1062-1458(00)00041-6
THE PAST AND THE PRESENT: PROLOGUES TO THE FUTURE
to the ischemic potential of a stenosis. His team developed formulas for a pressure-derived estimate of the percentage of normal expected coronary blood flow called the FFR. The FFR is the fraction of maximal coronary blood flow that would go through the stenotic vessel as a percentage of blood flow through the same artery in the theoretic absence of the stenosis. The FFR reflects myocardial perfusion (both antegrade and collateral) rather than merely transstenotic pressure loss (i.e., a stenosis gradient) and is thus differentiated from coronary flow. FFR is calculated at peak vasodilator response, thus assuming coronary resistance is minimal across both the epicardial and microvascular beds. FFR, the ratio of the absolute distal coronary and aortic pressures measured during maximal hyperemia, is therefore independent of driving pressure, heart rate, systemic blood pressure or status of the microcirculation. Calculation of an FFR value of less than 0.75 in patients with stable angina is strongly related to provocable myocardial ischemia using multiple stress testing methods (4). Microcirculatory flow impairment, nonetheless, remains the major concern in accurately assessing a stenosis using absolute CVR, relative CVR or FFR. In patients in whom the target vessel supplies an area of myocardial infarction with or without left ventricular dysfunction, neither absolute CVR nor rCVR can confidently identify the lesion-specific nature of flow impairment because the rCVR relies on the assumption that the microvascular circulatory response is uniformly distributed among the myocardial beds. When the CVR is severely blunted (e.g., severe hypertrophy, hypertension), the discriminating difference between the target and reference regions will also be reduced. rCVR might not be sensitive enough to reflect the impact of a stenosis in such a low-flow setting. In addition, in patients with three-vessel coronary disease, there may be no suitable reference vessel prohibiting use of rCVR. A lesion in this situation is best assessed by a pressure-derived estimate of coronary flow, the FFR. Figure 1 presents an example of physiologic measurements of stenosis severity in a patient with diffuse and focal coronary artery disease. Diffuse coronary artery disease may theoretically adversely affect the FFR because an attenuated increase in flow during maximal vasodilatation could minimize the maximal FFR value. Because the hyperemic decline in epicardial coronary pressure (i.e., FFR) reflects the extent to which the epicardial resistance reduces myocardial perfusion, it can be argued that in this setting, a normal FFR indicates that the conduit resistance is not a major contributing factor to perfusion impairment and that enlargement of any conduit obstruction would not restore normal perfusion. FFR and Doppler velocimetry are complementary, describing the physiology of both the epicardial stenosis and microvascular disease (if present) and the potential contribution to inducible myocardial ischemia. It should be recognized that the normal
Table 1. METHODS TO ASSESS CORONARY ARTERY DISEASE Anatomic
Physiologic
MRA*
PET MRA-velocity
Fast CT Thermography* Indirect
Direct
Ischemia testing (pharmacologic exercise) Electrocardiography Echocardiography Radionuclide Angiography IVUS Angioscopy Optical Coherence Tomography*
Coronary flow velocity Coronary pressure IVUS-based flow* Thermography*
*Future applications. CT, computed tomography; IVUS, intravascular ultrasound; MRA, magnetic resonance angiography; PET, positron emission tomography.
ologic measurements in the cardiac catheterization laboratory using sensor-tipped guidewires have been refined and validated (2). These approaches include measurement of poststenotic absolute coronary velocity reserve (CVR), relative CVR (rCVR) and pressure-derived fractional flow reserve (FFR). Ambiguity regarding the specific nature of an abnormal CVR due to an impaired microvascular response or diffuse coronary artery disease rather than a focal stenosis has been reduced or eliminated with rCVR and FFR. The quantification of microvascular flow impairment can thus be separately determined with CVR measurements. Absolute CVR is the capacity of the coronary artery and supplied vascular bed to achieve maximal flow in response to hyperemic stimulation under existing hemodynamic conditions. Although CVR has been advocated as the measure of flow limitation attributable to a stenotic narrowing, CVR is the result of two major interacting components (epicardial and microvascular flow). An abnormal value is therefore not specific for stenosis alone. Assuming that global myocardial reserve (i.e., the microcirculation) is uniformly distributed, the use of a reference vessel reserve and the computation of an rCVR (rCVR ⫽ the ratio of the target vessel CVR to the reference vessel CVR) can be postulated to specifically reflect the effect of a stenosis on coronary flow independent of loading conditions, hemodynamics or microcirculation. rCVR, like FFR (vide infra), is theoretically independent from and not affected by the microvascular circulation or other physiologic variables that can reduce absolute CVR (e.g., diffuse coronary artery disease, hypertrophy, diabetes and tachycardia) in the absence of an epicardial stenosis. Pressure-derived fractional flow reserve: Bringing the past to the future. Pijls et al. (3,4) eloquently demonstrated that the absolute distal coronary pressure during maximal hyperemia, but not the resting pressure gradient, is related
ACC CURRENT JOURNAL REVIEW March/April 2000
14
THE PAST AND THE PRESENT: PROLOGUES TO THE FUTURE
Figure 1. (A) A 72-year-old woman with diabetes and hypertension had chest pain, shortness of breath and exertional dizziness and reversible inferior wall myocardial ischemia on stress cardiolyte and 2-3mm ST depression inferolaterally while on calcium antagonist, aspirin and angiotensin-converting enzyme inhibitor therapies. Coronary angiography demonstrates a long, diffuse right coronary artery stenosis with a CVR (top right) of 1.3. Quantitative coronary angiography of the right coronary artery indicates the stenosis is 71% (bottom left); CVR in the left anterior descending reference vessel (bottom right) is 1.8, relative CVR ⫽ 1.3/1.8 ⫽ 0.72. (B) After angioplasty was performed (top left), the percent diameter stenosis was ⬍ 35%, but the CVR was 1.1 (relative CVR ⫽ 0.61) (top right). A stent was placed with ⬍ 10% diameter narrowing (bottom left). The CVR was improved (1.5) but not normalized (relative CVR 4.5/1.8 ⫽ 0.83). (C) FFR of the myocardium was also measured. Before angioplasty, the FFR was ⬍ 0.4. After angioplasty, the FFR was 0.74 and improved to 0.96 after stenting.
threshold of FFR (less than 0.75) for ischemia was derived from a selected stable patient population with single-vessel coronary disease and normal left ventricular function. The data are limited for patients with microvascular disease, acute or remote myocardial infarction and unstable angina. Caution should be applied in extending the current physiologic criteria to such patients. FFR may still assist in characterizing the impact of diffuse
coronary artery disease. As described in Figure 2, the typical atherosclerotic coronary artery with diffuse disease has a serial cascade of asymmetric stenotic branching units contributing to pressure loss and flow diversion along the vessel’s length. As such, there is no single value of coronary flow reserve or pressure (FFR) that uniquely characterizes the pathophysiologic behavior of the artery in this situation. A change in any stenotic segment will alter the pressure flow
ACC CURRENT JOURNAL REVIEW March/April 2000
15
THE PAST AND THE PRESENT: PROLOGUES TO THE FUTURE
Figure 2. A schematic of mixed segmental and diffuse narrowings and associated pressure drops along the length of the artery at maximum flow. (A) Predominant, more severe single segmental stenoses with less diffuse narrowing, suitable for angioplasty or bypass surgery. (B) Predominantly diffuse disease or multiple stenoses with less segmental narrowing, not appropriate for angioplasty or bypass surgery. Reprinted with permission from Gould KL. Coronary artery stenosis and reversing atherosclerosis, 2nd ed. London: Arnold Publishing, 1999. characteristics of the entire artery distal to that point. Mechanical therapy for such physiology would likely be ineffective in restoring normal coronary perfusion.
severity of coronary artery disease and have been used to determine the functional significance of localized stenoses (5,6). Standard technique PET scanning and, potentially, MR coronary flow velocity can discriminate between focal localized obstructions to coronary flow compared with a diffuse gradual reduction in flow along a coronary conduit not amenable to mechanical therapy. Dynamic PET imaging has excellent specificity in patients with a low likelihood of coronary artery disease, whereas an abnormal PETdetermined coronary reserve in angiographically normal territories appears to represent early functional abnormalities of vascular reactivity or possible diffuse atherosclerotic involvement. PET techniques may be more sensitive than coronary angiography to identify the early stages of atherosclerotic coronary artery disease. As noted for the hemodynamic
Noninvasive physiologic assessment of focal and diffuse coronary artery disease Both invasive and noninvasive physiologic methods attempt to address the impact of diffuse or focal narrowing of the coronary arteries on myocardial perfusion and the ischemic threshold for myocardial function. Ischemic stress testing, often obtained in patients with diffuse atherosclerotic coronary artery disease who may have concomitant focal accumulations, may not be sufficiently discriminative to differentiate subtle regional abnormalities of coronary blood flow caused by diffuse coronary artery disease. PET scanning. Regional myocardial blood flow measurements using positron emission tomography (PET) reflect the
ACC CURRENT JOURNAL REVIEW March/April 2000
16
THE PAST AND THE PRESENT: PROLOGUES TO THE FUTURE
Figure 3. A schematic of the longitudinal, base to apex, myocardial perfusion abnormality due to diffuse coronary artery narrowing compared with segmental perfusion defects due to localized stenoses. Modified with permission from Gould KL. Coronary artery stenosis and reversing atherosclerosis, 2nd ed. London: Arnold Publishing, 1999.
effects of diffuse coronary artery disease, a gradual decrement of pressure and flow along the course of the vessel is a characteristic finding (Figure 2). An artery with a predominant focal narrowing suitable for coronary angioplasty or bypass surgery will have a localized pressure drop, whereas
diffuse coronary artery disease demonstrates a gradual pressure drop along the course of the vessel. The same physiologic response is also detected with PET imaging as a graded longitudinal perfusion deficit from base to apex elicited during hyperemic stress (Figure 3) (7). Unlike most cur-
ACC CURRENT JOURNAL REVIEW March/April 2000
17
THE PAST AND THE PRESENT: PROLOGUES TO THE FUTURE
IVUS-determined flow One of the potentially new applications of IVUS is the determination of volumetric coronary flow based on the decorrelation of radiofrequency signals. IVUS can identify the direction of blood flow in the plane of ultrasound imaging. As particles move across this plane, radiofrequency echo signals decorrelate at a rate proportional to flow velocity (12). The characterization of the relationship between the correlation of echo signals and the scattered motion across the ultrasound beam provides a local transverse velocity and volumetric flow calculation based on a cross-sectional area. Because motion velocities of the vascular wall tissue are significantly lower than blood, the tissue velocities can be extracted by establishing a threshold level. No contour tracing of the arterial lumen is necessary. Because all velocities in the imaging plane are integrated, an accurate volumetric measurement across the imaging plane can be established. This new method is being validated against classical electromagnetic flow measurements and is presently under clinical evaluation in several laboratories in Europe and North America (13).
rently available noninvasive imaging techniques, PET can resolve subtle perfusion gradients and differentiate focal flow-limiting stenoses associated with substantial regional flow disparity. A graded longitudinal perfusion abnormality is differentiated from a segmental defect in that the typical abrupt reduction in regional myocardial perfusion due to a segmental coronary obstruction is not seen. Subtle longitudinal perfusion gradients have not been widely appreciated, often obscured by severe regional perfusion defects of coexistent focal stenosis. For mild-to-moderate diffuse coronary narrowing without localized flow-limiting stenosis, significant regional perfusion defects are apparent in large numbers of patients and serve to identify diffuse atherosclerosis despite the absence of significant or critical stenoses. The graded perfusion deficit of diffuse coronary artery disease is consistent with direct measurements of coronary flow and pressure in such vessels using intracoronary Doppler or pressure-sensor guidewires. Proximally measured coronary flow reserve is greater than that measured in the distal arterial segments in the absence of critical lesions (8). A longitudinal base to apex perfusion gradient detecting subangiographic atherosclerosis appears to confirm the diffuse, rather than the focal, nature of coronary artery disease in some patients and can support a vigorous antiatherosclerotic risk factor reduction program (9). Future studies of graded perfusion imaging will be important in gauging efficacy of pharmacologic intervention for these patients.
The future for plaque physiology: Thermography and optical coherence tomography Activation of macrophages in the acute ischemic syndrome promotes plaque rupture, thrombosis and vasoconstriction. Ex vivo studies have demonstrated that thermal heterogeneity in human carotid atherosclerotic plaques can identify those most likely to rupture (14). In human atherosclerotic coronary arteries, a 3F thermography catheter (15) demonstrated thermal heterogeneity over a spatial resolution of 0.5 mm in coronary arteries in 20% of patients with stable angina, 40% of patients with unstable angina and 67% of patients with acute myocardial infarction. No thermal heterogeneity was evident in control subjects. In patients with diffuse atherosclerosis, thermography may be expected to identify those regions likely to undergo activation in the near term and be used to support early intervention or verify the stabilization of such regions after mechanical or pharmacologic therapy. Optimal coherence tomography (OCT) represents a new imaging modality for microvascular structure at a level of resolution not previously achieved with IVUS (16). OCT is a unique catheter-based technique utilizing back-reflected infrared light to obtain in situ micron scale tomographic imaging. OCT images, even in heavily calcified tissue, can differentiate between lipid-based and water-based plaque constituents. OCT axial resolution permits evaluation of small structural details, such as the thickness of intimal caps, the presence of fissures among diffuse regions of atherosclerosis and the extent of lipid pool collections within plaques. Because OCT does not require direct contact with the vessel wall, it can be performed with a catheter integrated with
The future: Magnetic resonance and IVUS imaging of coronary blood flow Noninvasive measurements of absolute coronary blood flow and CVR can be obtained with phase-contrast MRI (10). A high correlation (r ⬎ 0.89) between MRI and invasive measurements of arterial flow and CVR was observed (10). Cine velocity and coded phase-contrast MRI can noninvasively measure absolute coronary arterial flow in the left anterior descending artery in humans and, by using pharmacologically-induced hyperemia, can reliably distinguish between individuals with normal and abnormal coronary flow. In this way, MRI may also have significant advantages in evaluating patients after acute myocardial infarction. Furber et al. (11) measured infarct-related coronary artery blood flow using phase-contrast MRI in patients after reperfusion for acute myocardial infarction and found a good correlation between phase-contrast MRI and intracoronary Doppler average peak velocities. MRI velocity measurements have a similar spectrum of flow heterogeneity as reported for direct Doppler examination. The potential to quantify coronary flow velocity and thereby evaluate the quality of flow restoration after acute myocardial infarction and reperfusion therapy directed at the microcirculation may have substantial therapeutic applications.
ACC CURRENT JOURNAL REVIEW March/April 2000
18
THE PAST AND THE PRESENT: PROLOGUES TO THE FUTURE
relatively inexpensive optical fibers. The high contrast and high resolution between tissues and its ability to penetrate calcium makes OCT an attractive new diagnostic imaging technique with specific application to atherosclerotic plaque physiology.
6. Demer LL, Gould KL, Goldstein RA, Kirkeeide RL. Diagnosis of coronary artery disease by positron emission tomography: comparison to quantitative coronary arteriography in 193 patients. Circulation 1989;79:825–35. 7. Gould KL, Martucci JP, Goldberg DI, et al. Short-term cholesterol lowering decreases in size and severity of perfusion abnormalities by positron emission tomography after dipyridamole in patients with coronary artery disease. Circulation 1994;89:1530 – 8.
Conclusion Diffuse coronary artery disease is a ubiquitous companion of angiographically-defined focal atherosclerosis. Although mechanical interventions can provide palliative revascularization, the future resides in pharmacologic or vascular genetic therapies to stabilize, retard and reverse the insidious process of plaque growth and activation. Diagnostic abilities to quantify the anatomic and physiologic features of the diffusely diseased coronary artery will promote effective therapies, reduce unnecessary and ineffective attempts to restore normal coronary blood flow mechanically and potentially improve long-term outcomes in patients with coronary artery disease.
8. Donohue TJ, Miller DD, Bach RG, et al. Correlation of poststenotic hyperemic coronary flow velocity and pressure with abnormal stress myocardial perfusion imaging in coronary artery disease. Am J Cardiol 1996; 77:948 –54. 9. Gould K, Omish D, Scherwitz L, et al. Changes in myocardial perfusion abnormalities by positron emission tomography after long-term, intense risk factor modification. JAMA 1995;274:894 –901. 10. Hundley WG, Lange RA, Clarke GD, et al. Assessment of coronary arterial flow and flow reserve in humans with magnetic resonance imaging. Circulation 1996;93:1502– 8. 11. Furber AP, Lethimonnier F, Le Jeune J, et al. Noninvasive assessment of the infarct-related coronary artery blood flow velocity using phase-contrast magnetic resonance imaging after coronary angioplasty. Am J Cardiol 1999;84:24 –30. 12. Li W, van der Steen AFW, Lancee CT. Temporal correlation of bloodscattering signals in vivo from radiofrequency intravascular ultrasound. Ultrasound Med Biol 1996;22:583–90.
REFERENCES 1. Seiler C, Kirkeeide RL, Gould KL. Basic structure-function of the epicardial coronary vascular tree—the basis of quantitative coronary arteriography for diffuse coronary artery disease. Circulation 1992;85:1987–2003. 2. Kern MJ, De Bruyne B, Pijls NHJ. From research to clinical practice: Current role of intracoronary physiologically based decision making in the cardiac catheterization laboratory. J Am Coll Cardiol 1997;30:613–20. 3. Pijls NH, Van Gelder B, Van der Voort P, et al. Fractional flow reserve: A useful index to evaluate the influence of an epicardial coronary stenosis on myocardial blood flow. Circulation 1995;92:3183–93. 4. Pijls NH, De Bruyne B, Peels K, et al. Measurement of fractional flow reserve to assess the functional severity of coronary-artery stenoses. N Engl J Med 1996;334:1703– 8. 5. Muzik O, Duvernoy C, Beanlands RSB, et al. Assessment of diagnostic performance of quantitative flow measurements in normal subjects and patients with angiographically documented coronary artery disease by means of nitrogen-13 ammonia and positron emission tomography. J Am Coll Cardiol 1998;31:534 – 40.
13. Carlier S, Li W. In vivo validation of a new intracoronary volumetric blood flow measurement method with intravascular ultrasound [abstract]. Circulation (in press, 1999). 14. Casscells W, Hathorn B, David M, et al. Thermal detection of cellular infiltrates in living atherosclerotic plaques: possible implications for plaque rupture and thrombosis. Lancet 1996;347:1447–9. 15. Stefanadis C, Diamantopoulos L, Vlachopoulos C, Tsiamis E, Dernellis J, Toutouzas K, Stefanadi E, Toutouzas P. Thermal heterogeneity within human atherosclerotic coronary arteries detected in vivo: A new method of detection by application of a special thermography catheter. Circulation 1999;99:1965–71. 16. Tearney GJ, Brezinski ME, Boppart SA, et al. Catheter-based optical imaging of a human coronary artery. Circulation 1996;94:3013. Address correspondence and reprint requests to Morton J. Kern, MD, Director, J.G. Mudd Cardiac Catheterization Laboratory, Saint Louis University Health Sciences Center, 3635 Vista Avenue at Grand Boulevard, St. Louis, MO 63110.
ACC CURRENT JOURNAL REVIEW March/April 2000
19