- Email: [email protected]
Coronary Flow: The Holy Grail of Echocardiography?
Coronary Flow: The Holy Grail of Echocardiography? Paolo Voci, MD*, and Francesco Pizzuto, MD One of the principal tasks of a physician is to estimate the patient’s reserves. Prognosis is an estimate of the rate at which this reserve may disappear, and therapy is designed to increase this reserve and to prevent or eliminate stresses that might compromise it. —C. Honig
Coronary flow reserve (CFR), the ratio between hyperemic and basal blood flow, describes the functional reserve of a coronary artery conduit (i.e., how much flow it can provide at maximal vasodilation or exertion). Imaging of coronary flow by echocardiography became a reality more than a decade ago and prompted a series of publications on CFR addressing several aspects of coronary artery disease: (1) the detection of coronary artery stenosis1– 6 (2) follow-up after percutaneous coronary intervention7–11 (3) the detection of coronary recanalization and reflow in acute myocardial infarction,12,13 (4) the measurement of changes in the coronary microcirculation,14 –19 and (5) the study of coronary vasomotion.20,21 Doppler ultrasound can be used to quantitate CFR if the vasodilating agent used meets 3 conditions: (1) it should produce maximal dilation of the microcirculation, (2) it should not dilate the epicardial vessel interrogated by the ultrasonic beam (either as a direct chemical effect or as an indirect effect of ischemia or flow-mediated vasodilation), and (3) it should not significantly change systemic hemodynamics, namely, blood pressure and heart rate. Global coronary resistance is the sum of the resistance of the epicardial conductance vessel and that of the microcirculation. Therefore, coronary stenosis and the microcirculation may affect CFR. The resistance of stenosis is generally stable, whereas that of the microcirculation can be reduced during stress and with vasodilators. Two theories were thus generated to explain changes in CFR: one supporting the prominent role of stenosis and the other supporting the idea that the microcirculation is the main limiting factor. Stenosis In his seminal experimental work, Lance Gould established that CFR of 2 discriminates significant (ⱖ70%) from nonsignificant (⬍70%) coronary stenoses.22,23 A series of clinical studies using single photon-emission computed tomography24,25 as well as intracoronary26 and transthoracic coronary4 –9,27 Doppler ultrasound have consistently confirmed that a flow-limiting stenosis introduces a strong
Section of Cardiology, Department of Internal Medicine, University of Rome “Tor Vergata,” Rome, Italy. Manuscript received December 22, 2010; revised manuscript received and accepted December 30, 2010. *Corresponding author: Tel: 39-06-20900382; fax: 39-06-20900382. E-mail address: [email protected] (P. Voci). 0002-9149/11/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2010.12.044
proximal resistance that is rapidly normalized after the mechanical relief of the stenosis by coronary stenting.7 According to these findings, a cut-off value of 2 was widely adopted as the “magic number” demonstrating impairment of coronary flow significant enough to treat invasively by mechanical removal of the stenosis. Very elegantly, Fukui et al28 in this issue of The American Journal of Cardiology have confirmed that preoperative CFR was ⬍2 in left anterior descending coronary arteries (LADs) with significant stenoses and that there was a trend for CFR to be more blunted in long LAD lesions compared to short lesions. Interestingly, coronary artery bypass grafting normalized CFR regardless of the preoperative presentation of the stenosis.28 The investigators correctly measured CFR in the LAD, not in the graft, to prevent the bias of flow competition blunting CFR of the graft.29 Coronary Doppler ultrasound is very effective to follow patients with coronary stents, in whom symptoms and other stress tests may be misleading. In fact, a reduction of CFR ⬍2 after stenting identifies ⱖ70% LAD restenosis8,9 with great sensitivity and specificity, whereas CFR between 2 and 2.5 reflects nonsignificant (intermediate) restenosis that should be conservatively monitored, indicating the safety of deferring treatment when CFR is ⬎2.30 Microcirculation Microcirculation disturbances have been described in a number of conditions, including coronary stenting,31 remote coronary artery disease, gender hormone changes,14 cigarette smoking,15 hypertension,32 left ventricular hypertrophy,33 hypertrophic cardiomyopathy,34 non-insulin-dependent diabetes,35 and aging.36 Yet much disagreement still exists regarding how to define and measure this dysfunction and what ultimately is its clinical impact. However, consistent anatomic observations supporting a definite role of microvascular dysfunction are still lacking. The reduction of CFR in different hormonal states14 and passive smoking15 was too mild to explain cyclic chest pain and positive stress test results in fertile women with normal epicardial coronary arteries. Similarly, studies using positron emission tomography showed no difference in CFR between smokers and nonsmokers.37 In light of these findings, it appears that, for most patients, microcirculatory dysfunction, if present, does not significantly affect the value of CFR needed to detect significant coronary stenosis. A diffuse and profound reduction in CFR was described using positron emission tomography in remote, angiographically normal coronary arteries in clinically stable patients with myocardial infarction.38 In some cases, CFR was even close to 1, indicating a complete inability to increase flow at stress, typical of coronary subocclusion. However, it is very hard to imagine a patient with anterior infarction and almost no flow reserve in the remote coronary arteries who is not close to or in overt cardiogenic shock. www.ajconline.org
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The belief that focal coronary artery disease generates a diffuse alteration of coronary flow in a generalized, yet unexplained manner38 can be easily challenged by everyday clinical practice showing that (1) CFR in an angiographically normal coronary artery is never affected by any remote stenosis, previous acute myocardial infarction, or stenting,39 and (2) serial measurements along a coronary artery21 show that CFR is impaired only distal, but not proximal, to the stenosis, confirming that even within the diseased vessel, the disorder is not transmitted to neighboring segments. Elective coronary artery stenting was thought to produce persistent but still unexplained microvascular dysfunction lasting for days or weeks.31,40 Conversely, transthoracic coronary Doppler ultrasound allowed us7 and others8 to show that CFR actually normalizes within the first day after the procedure.7 Finally, we have found an average CFR of 2.8 even in patients who should have had profound microvascular disturbances,41 such as those with dilated or hypertrophic cardiomyopathy, including those in functional class IV, and orthopnea. Corroborating this finding is an intracoronary Doppler ultrasound study depicting an average CFR of 2.8 in patients with dilated cardiomyopathy.42 We may conclude that the issue of microcirculation and CFR has been overemphasized and that, at least in terms of coronary Doppler ultrasound, its biasing effect on the detection of coronary stenosis is at least minimal, which is a great advantage for a technique to be used as a quantitative diagnostic tool. Are All Agents the Same? The agent, the administration modality, and the individual response to the administered drug are crucial to obtain maximal microcirculatory vasodilation and may explain the different results obtained by groups supporting either stenosis or the microcirculation. Most published research on microvascular dysfunction has been conducted using dipyridamole31–37 either at low (0.56 mg/kg) or high (0.84 mg/kg) dose. Dipyridamole is not the ideal drug for CFR, because (1) at low dose, it produces only submaximal vasodilation19; (2) at high dose, it may produce myocardial ischemia, which in turn elicits vasodilation of the epicardial vessel; (3) it may significantly increase heart rate, which increases oxygen consumption and may affect the quality of Doppler ultrasound at hyperemia, because of enhanced wall motion noise; (4) it works indirectly by inhibiting the cellular reuptake of adenosine, a process that may vary from patient to patient, precluding standardization of the final concentration of adenosine (why use a “precursor” if the final active agent is available?); (5) it requires aminophylline as an antidote; and (6) it is not repeatable. For these reasons, it may be possible that many cases studied with dipyridamole (particularly at low dose) have been misinterpreted as cases of microvascular dysfunction. In contrast, adenosine produces an almost instantaneous, maximal, and brisk vasodilation of the microcirculation, with minimal hemodynamic changes, and is repeatable.
Evaluating More Arteries Despite the prominent role of the LAD in the prognosis of coronary artery disease, the evaluation of other coronary arteries is also important. Because most infarctions occur either in the LAD or in the posterior descending coronary artery (PD) distribution territory,43 we have also concentrated on PD flow.5 On the basis of our experience, it is feasible to measure CFR in the PD in about 50% of patients, regardless of whether its origin is from the right or circumflex coronary artery.5 The lower success rate of imaging the PD compared to the LAD is due to 4 main factors: (1) the PD runs deep into the chest, whereas the LAD is more superficial; (2) the PD runs close to the right ventricular inflow tract and to the mid cardiac vein, which generate strong and disturbing flow signals5; (3) adenosine-induced hyperventilation interferes more with PD than with LAD imaging; and (4) a dedicated transducer has been designed only for the LAD. Imaging of the PD can be improved by several methods: (1) the use of ultrasound contrast agents; (2) the use of specific A2A adenosine receptor agonists, which produce less or no hyperventilation44; (3) the design of specific probes and software; and (4) reduction of the heart rate to minimize wall motion artifacts on Doppler sampling. The Achilles Heel Unfortunately, the early stages of coronary atherosclerosis, characterized by angiographically nonsignificant but potentially unstable plaques, cannot be detected by measuring CFR. Also, there are no data on left main coronary artery disease. An important development in ultrasound is the improvement of direct imaging of the LAD to detect focal acceleration of flow at rest, as a sign of preclinical atherosclerosis. We take the opportunity of this editorial to make another appeal to industry, clinicians, and researchers to invest in this field and not to abandon a treasure like coronary Doppler ultrasound, a “green,” cheap, and sustainable technique which is not inferior to computed tomography to detect significant LAD disease.45 The fact that few clinicians use coronary Doppler ultrasound is not a good argument against its validity: when Johann Christian Doppler46 opened the way to diagnostic ultrasound with his report “On the Colored Light of the Double Stars and Certain Other Stars of the Heavens,” only 6 individuals were in attendance. 1. Voci P, Testa G, Plaustro G. Imaging of the distal left anterior descending coronary artery by transthoracic color-Doppler echocardiography. Am J Cardiol 1998;81(suppl):74G–78G. 2. Hozumi T, Yoshida K, Ogata Y, Akasaka T, Asami Y, Takagi T, Morioka S. Noninvasive assessment of significant left anterior descending coronary artery stenosis by coronary flow velocity reserve with transthoracic color Doppler echocardiography. Circulation 1998; 97:1557–1562. 3. Caiati C, Montaldo C, Zedda N, Bina A, Iliceto S. New noninvasive method for coronary flow reserve assessment. Contrast-enhanced transthoracic second harmonic echo Doppler. Circulation 1999;99: 771–778. 4. Okayama H, Sumimoto T, Hiasa G, Nishimura K, Morioka N, Yamamoto K, Kawada H. Assessment of intermediate stenosis in the left anterior descending coronary artery with contrast-enhanced trans-
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thoracic color-Doppler echocardiography. Coron Artery Dis 2003;14:247–254. Voci P, Pizzuto F, Mariano E, Puddu PE, Chiavari P, Romeo F. Measurement of coronary flow reserve in the anterior and posterior descending coronary arteries by transthoracic Doppler Ultrasound. Am J Cardiol 2002;90:988 –991. Voci P, Pizzuto F. Coronary flow: how far can we go with echocardiography? J Am Coll Cardiol 2001;38:1885–1887. Pizzuto F, Voci P, Mariano E, Puddu PE, Sardella G, Nigri A. Assessment of flow velocity reserve by transthoracic Doppler and venous adenosine infusion, before and after left anterior descending coronary stenting. J Am Coll Cardiol 2001;38:155–162. Ruscazio M, Montisci R, Colonna P, Caiati C, Chen L, Lai G, Cadeddu M, Pirisi R, Iliceto S. Detection of coronary restenosis after coronary angioplasty by contrast-enhanced transthoracic echocardiographic Doppler assessment of coronary flow velocity reserve. J Am Coll Cardiol 2002;40:896 –903. Pizzuto F, Voci P, Mariano E, Puddu PE, Chiavari PA, Romeo F. Noninvasive coronary flow reserve assessed by transthoracic coronary Doppler ultrasound in patients with left anterior descending coronary artery stents. Am J Cardiol 2003;91:522–526. Lethen H, Tries HP, Brechtken J, Kersting S, Lambertz H. Comparison of transthoracic Doppler echocardiography to intracoronary Doppler guidewire measurements for assessment of coronary flow reserve in the left anterior descending artery for detection of restenosis after coronary angioplasty. Am J Cardiol 2003;91:412– 417. Hozumi T, Yoshida K, Akasaka T, Asami Y, Kanzaki Y, Ueda Y, Yamamuro A, Takagi T, Yoshikawa J. Value of acceleration flow and the prestenotic to stenotic coronary flow velocity ratio by transthoracic color Doppler echocardiography in noninvasive diagnosis of restenosis after percutaneous transluminal coronary angioplasty. J Am Coll Cardiol 2000;35:164 –168. Voci P, Mariano E, Pizzuto F. Puddu PE, Romeo F. Coronary recanalization in anterior myocardial infarction: the open perforator hypothesis. J Am Coll Cardiol 2002;40:1205–1213. Hozumi T, Kanzaki Y, Ueda Y, Yamamuro A, Takagi T, Akasaka T, Homma S, Yoshida K, Yoshikawa J. Coronary flow velocity analysis during short-term follow-up after coronary reperfusion: use of transthoracic Doppler echocardiography to predict regional wall motion recovery in patients with acute myocardial infarction. Heart 2003;89: 1163–1168. Hirata K, Shimada K, Watanabe H, Muro T, Yoshiyama M, Takeuchi K, Hozumi T, Yoshikawa J. Modulation of coronary flow velocity reserve by sex, menstrual cycle and hormone replacement therapy. J Am Coll Cardiol 2001;38:1879 –1884. Otsuka R, Watanabe H, Hirata K, Tokai K, Muro T, Yoshiyama M, Takeuchi K, Yoshikawa J. Acute effects of passive smoking on the coronary circulation in healthy young adults. JAMA 2001;286:436 – 441. Asami Y, Yoshida K, Hozumi T, Akasaka T, Takagi T, Kaji S, Kawamoto T, Ogata Y, Yagi T, Morioka S, Yoshikawa J. Assessment of coronary flow reserve in patients with hypertrophic cardiomyopathy using transthoracic color-Doppler echocardiography. J Cardiol 1998; 32:247–252. Bartel T, Yang Y, Müller S, Wenzel RR, Baumgart D, Philipp T, Erbel R. Noninvasive assessment of microvascular function in arterial hypertension by transthoracic Doppler harmonic echocardiography. J Am Coll Cardiol 2002;39:2012–2018. Galderisi M, Cicala S, Caso P, De Simone L, D’Errico A, Petrocelli A. Coronary flow reserve and myocardial diastolic dysfunction in arterial hypertension. Am J Cardiol 2002;90:860 – 864. Kozàkovà M, Palombo C, Pratali L, Pittella G, Galetta F, L’Abbate A. Mechanisms of coronary flow reserve impairment in human hypertension. An integrated approach by transthoracic and transesophageal echocardiography. Hypertension 1997;29:551–559. Voci P, Testa G, Plaustro G, Caretta Q. Coronary Doppler intensity changes during handgrip: a new method to detect coronary vasomotor tone in coronary artery disease. J Am Coll Cardiol 1999;34:428 – 434. Voci P, Pizzuto F, Romeo F. Coronary flow: a new asset for the echo lab? Eur Heart J 2004;25:1867–1879. Gould KL, Lipscomb K. Effects of coronary stenoses on coronary flow reserve and resistance. Am J Cardiol 1974;34:48 –55. Gould KL, Lipscomb K, Hamilton GW. Physiologic basis for assessing severe coronary stenosis: instantaneous flow response and regional
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distribution during coronary hyperemia as measures of coronary flow reserve. Am J Cardiol 1974;33:87–94. Heller LI, Cates C, Popma J, Deckelbaum LI, Joye JD, Dahlberg ST, Villegas BJ, Arnold A, Kipperman R, Grinstead WC, Balcom S, Ma Y, Cleman M, Steingart RM, Leppo JA. Intracoronary Doppler assessment of moderate coronary artery disease: comparison with 201Tl imaging and coronary angiography. Circulation 1997;96:484 – 490. Vogel RA. Assessing stenosis significance by coronary arteriography: are the best variables good enough? J Am Coll Cardiol 1988;12:692– 693. Serruys PW, di Mario C, Piek J, Schroeder E, Vrints C, Probst P, de Bruyne B, Hanet C, Fleck E, Haude M, Verna E, Voudris V, Geschwind H, Emanuelsson H, Mühlberger V, Danzi G, Peels HO, Ford AJ Jr, Boersma E. Prognostic value of intracoronary flow velocity and diameter stenosis in assessing the short- and long-term outcomes of coronary balloon angioplasty: the DEBATE study (Doppler Endpoints Balloon Angioplasty Trial Europe). Circulation 1997;96:3369 –3377. Matsumura Y, Hozumi T, Watanabe H, Fujimoto K, Sugioka K, Takemoto Y, Shimada K, Muro T, Yoshiyama M, Takeuchi K, Yoshikawa J. Cut-off value of coronary flow velocity reserve by transthoracic Doppler echocardiography for diagnosis of significant left anterior descending artery stenosis in patients with coronary risk factors. Am J Cardiol 2003;92:1389 –1393. Fukui T, Watanabe H, Aikawa M, Tsunoda Y, Tabata M, Takanashi S. Assessment of coronary flow velocity reserve by transthoracic Doppler echocardiography before and after coronary artery bypass grafting. Am J Cardiol 2011 (in press). Pizzuto F, Voci P, Mariano E, Puddu PE, Aprile A, Romeo F. Evaluation of flow in the left anterior descending coronary artery but not in the left internal mammary graft predicts significant stenosis of the arterial conduit. J Am Coll Cardiol 2005;45:424 – 432. Ferrari M, Schnell B, Werner GS, Figulla HR. Safety of deferring angioplasty in patients with normal coronary flow velocity reserve. J Am Coll Cardiol 1999;33:82– 87. van Liebergen RAM, Piek JJ, Koch KT, de Winter RJ, Lie KI. Immediate and long term effect of balloon angioplasty or stent implantation on the absolute and relative coronary blood flow velocity reserve. Circulation 1998;98:2133–2140. Galderisi M, Caso P, Cicala S, De Simone L, Barbieri M, Vitale G, de Divitiis O, Paolisso G. Positive association between circulating free insulin-like growth factor-1 levels and coronary flow reserve in arterial systemic hypertension. Am J Hypertens 2002;15:766 –772. Galderisi M, de Simone G, Cicala S, De Simone L, D’Errico A, Caso P. Coronary flow reserve in hypertensive patients with appropriate or inappropriate left ventricular mass. J Hypertens 2003;21:1– 6. Cortigiani L, Rigo F, Gherardi S, Galderisi M, Sicari R, Picano E. Prognostic implications of coronary flow reserve on left anterior descending coronary artery in hypertrophic cardiomyopathy. Am J Cardiol 2008;102:1718 –1732. Yokoyama L, Monomura S, Ohtake T, Yonekura K, Nishikawa J, Sasaki Y, Omata M. Reduced myocardial flow reserve in non-insulin dependent diabetes mellitus. J Am Coll Cardiol 1997;30:1472–1477. Czernin J, Müller P, Chan S, Brunken RC, Porenta G, Krivokapich J, Chen K, Chan A, Phelps ME, Schelbert HR. Influence of age and hemodynamics on myocardial blood flow and flow reserve. Circulation 1993;88:62– 69. Campisi R, Czernin J, Schoeder H, Sayre JW, Marengo FD, Phelps ME, Schelbert HR. Effect of long-term smoking on myocardial blood flow, coronary vasomotion, and vasodilator capacity. Circulation 1998;98:119 –125. Uren NG, Crake T, Lefroy DC, de Silva R, Davies GJ, Maseri A. Reduced coronary vasodilator function in infarcted and normal myocardium after myocardial infarction. N Engl J Med 1994;331:222–227. Pizzuto F, Voci P, Mariano E, Puddu PE, Spedicato P, Romeo F. Coronary flow reserve of the angiographically normal left anterior descending coronary artery in patients with remote coronary artery disease. Am J Cardiol 2004;94:577–582. Kern MJ, Puri S, Bach RG, Donohue TJ, Dupouy P, Caracciolo EA, Craig WR, Aguirre F, Aptecar E, Wolford TL, Mechem CJ, DuboisRamdle JL. Abnormal coronary flow velocity reserve after coronary artery stenting in patients: role of relative coronary flow reserve to assess potential mechanisms. Circulation 1999;100:2491–2498. Voci P, Pizzuto F, Romeo F. The ghost of microcirculation. Eur Heart J 2005;26:849 – 850.
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42. Teragaki M, Yanagi S, Toda I, Sakamoto K, Hirota K, Takeuchi K, Yoshikawa J. Coronary flow reserve correlates left ventricular diastolic dysfunction in patients with dilated cardiomyopathy. Catheter Cardiovasc Intervent 2003;58:43–50. 43. Roberts W, Gardin J. Myocardial infarction: a confusion of terms and definitions. Am J Cardiol 1978;42:868 – 872. 44. Udelson JE, Heller GV, Wackers FJ, Chai A, Hinchman D, Coleman PS, Dilsizian V, DiCarli M, Hachamovitch R, Johnson JR, Barrett RJ, Gibbons RJ. Randomized, controlled dose-ranging study of the selective adenosine A2A receptor agonist binodenoson for pharmacological
stress as an adjunct to myocardial perfusion imaging. Circulation 2004;109:457– 464. 45. Pizzuto F, Voci P, Bartolomucci F, Puddu PE, Strippoli G, Broglia L, Rossi P. Usefulness of coronary flow reserve measured by echocardiography to improve the identification of significant left anterior descending coronary artery stenosis assessed by multidetector computed tomography. Am J Cardiol 2009;104:657– 664. 46. Doppler C. Uber das farbige Licht der Dopplersterne und einiger anderer Gestirne des Himmels. Abhandl Konigl Bohm Ges Ser 1843; 2:465– 482.
Coronary flow reserve (CFR), the ratio between hyperemic and basal blood flow, describes the functional reserve of a coronary artery conduit (i.e., how much flow it can provide at maximal vasodilation or exertion). Imaging of coronary flow by echocardiography became a reality more than a decade ago and prompted a series of publications on CFR addressing several aspects of coronary artery disease: (1) the detection of coronary artery stenosis1– 6 (2) follow-up after percutaneous coronary intervention7–11 (3) the detection of coronary recanalization and reflow in acute myocardial infarction,12,13 (4) the measurement of changes in the coronary microcirculation,14 –19 and (5) the study of coronary vasomotion.20,21 Doppler ultrasound can be used to quantitate CFR if the vasodilating agent used meets 3 conditions: (1) it should produce maximal dilation of the microcirculation, (2) it should not dilate the epicardial vessel interrogated by the ultrasonic beam (either as a direct chemical effect or as an indirect effect of ischemia or flow-mediated vasodilation), and (3) it should not significantly change systemic hemodynamics, namely, blood pressure and heart rate. Global coronary resistance is the sum of the resistance of the epicardial conductance vessel and that of the microcirculation. Therefore, coronary stenosis and the microcirculation may affect CFR. The resistance of stenosis is generally stable, whereas that of the microcirculation can be reduced during stress and with vasodilators. Two theories were thus generated to explain changes in CFR: one supporting the prominent role of stenosis and the other supporting the idea that the microcirculation is the main limiting factor. Stenosis In his seminal experimental work, Lance Gould established that CFR of 2 discriminates significant (ⱖ70%) from nonsignificant (⬍70%) coronary stenoses.22,23 A series of clinical studies using single photon-emission computed tomography24,25 as well as intracoronary26 and transthoracic coronary4 –9,27 Doppler ultrasound have consistently confirmed that a flow-limiting stenosis introduces a strong
Section of Cardiology, Department of Internal Medicine, University of Rome “Tor Vergata,” Rome, Italy. Manuscript received December 22, 2010; revised manuscript received and accepted December 30, 2010. *Corresponding author: Tel: 39-06-20900382; fax: 39-06-20900382. E-mail address: [email protected] (P. Voci). 0002-9149/11/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2010.12.044
proximal resistance that is rapidly normalized after the mechanical relief of the stenosis by coronary stenting.7 According to these findings, a cut-off value of 2 was widely adopted as the “magic number” demonstrating impairment of coronary flow significant enough to treat invasively by mechanical removal of the stenosis. Very elegantly, Fukui et al28 in this issue of The American Journal of Cardiology have confirmed that preoperative CFR was ⬍2 in left anterior descending coronary arteries (LADs) with significant stenoses and that there was a trend for CFR to be more blunted in long LAD lesions compared to short lesions. Interestingly, coronary artery bypass grafting normalized CFR regardless of the preoperative presentation of the stenosis.28 The investigators correctly measured CFR in the LAD, not in the graft, to prevent the bias of flow competition blunting CFR of the graft.29 Coronary Doppler ultrasound is very effective to follow patients with coronary stents, in whom symptoms and other stress tests may be misleading. In fact, a reduction of CFR ⬍2 after stenting identifies ⱖ70% LAD restenosis8,9 with great sensitivity and specificity, whereas CFR between 2 and 2.5 reflects nonsignificant (intermediate) restenosis that should be conservatively monitored, indicating the safety of deferring treatment when CFR is ⬎2.30 Microcirculation Microcirculation disturbances have been described in a number of conditions, including coronary stenting,31 remote coronary artery disease, gender hormone changes,14 cigarette smoking,15 hypertension,32 left ventricular hypertrophy,33 hypertrophic cardiomyopathy,34 non-insulin-dependent diabetes,35 and aging.36 Yet much disagreement still exists regarding how to define and measure this dysfunction and what ultimately is its clinical impact. However, consistent anatomic observations supporting a definite role of microvascular dysfunction are still lacking. The reduction of CFR in different hormonal states14 and passive smoking15 was too mild to explain cyclic chest pain and positive stress test results in fertile women with normal epicardial coronary arteries. Similarly, studies using positron emission tomography showed no difference in CFR between smokers and nonsmokers.37 In light of these findings, it appears that, for most patients, microcirculatory dysfunction, if present, does not significantly affect the value of CFR needed to detect significant coronary stenosis. A diffuse and profound reduction in CFR was described using positron emission tomography in remote, angiographically normal coronary arteries in clinically stable patients with myocardial infarction.38 In some cases, CFR was even close to 1, indicating a complete inability to increase flow at stress, typical of coronary subocclusion. However, it is very hard to imagine a patient with anterior infarction and almost no flow reserve in the remote coronary arteries who is not close to or in overt cardiogenic shock. www.ajconline.org
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The belief that focal coronary artery disease generates a diffuse alteration of coronary flow in a generalized, yet unexplained manner38 can be easily challenged by everyday clinical practice showing that (1) CFR in an angiographically normal coronary artery is never affected by any remote stenosis, previous acute myocardial infarction, or stenting,39 and (2) serial measurements along a coronary artery21 show that CFR is impaired only distal, but not proximal, to the stenosis, confirming that even within the diseased vessel, the disorder is not transmitted to neighboring segments. Elective coronary artery stenting was thought to produce persistent but still unexplained microvascular dysfunction lasting for days or weeks.31,40 Conversely, transthoracic coronary Doppler ultrasound allowed us7 and others8 to show that CFR actually normalizes within the first day after the procedure.7 Finally, we have found an average CFR of 2.8 even in patients who should have had profound microvascular disturbances,41 such as those with dilated or hypertrophic cardiomyopathy, including those in functional class IV, and orthopnea. Corroborating this finding is an intracoronary Doppler ultrasound study depicting an average CFR of 2.8 in patients with dilated cardiomyopathy.42 We may conclude that the issue of microcirculation and CFR has been overemphasized and that, at least in terms of coronary Doppler ultrasound, its biasing effect on the detection of coronary stenosis is at least minimal, which is a great advantage for a technique to be used as a quantitative diagnostic tool. Are All Agents the Same? The agent, the administration modality, and the individual response to the administered drug are crucial to obtain maximal microcirculatory vasodilation and may explain the different results obtained by groups supporting either stenosis or the microcirculation. Most published research on microvascular dysfunction has been conducted using dipyridamole31–37 either at low (0.56 mg/kg) or high (0.84 mg/kg) dose. Dipyridamole is not the ideal drug for CFR, because (1) at low dose, it produces only submaximal vasodilation19; (2) at high dose, it may produce myocardial ischemia, which in turn elicits vasodilation of the epicardial vessel; (3) it may significantly increase heart rate, which increases oxygen consumption and may affect the quality of Doppler ultrasound at hyperemia, because of enhanced wall motion noise; (4) it works indirectly by inhibiting the cellular reuptake of adenosine, a process that may vary from patient to patient, precluding standardization of the final concentration of adenosine (why use a “precursor” if the final active agent is available?); (5) it requires aminophylline as an antidote; and (6) it is not repeatable. For these reasons, it may be possible that many cases studied with dipyridamole (particularly at low dose) have been misinterpreted as cases of microvascular dysfunction. In contrast, adenosine produces an almost instantaneous, maximal, and brisk vasodilation of the microcirculation, with minimal hemodynamic changes, and is repeatable.
Evaluating More Arteries Despite the prominent role of the LAD in the prognosis of coronary artery disease, the evaluation of other coronary arteries is also important. Because most infarctions occur either in the LAD or in the posterior descending coronary artery (PD) distribution territory,43 we have also concentrated on PD flow.5 On the basis of our experience, it is feasible to measure CFR in the PD in about 50% of patients, regardless of whether its origin is from the right or circumflex coronary artery.5 The lower success rate of imaging the PD compared to the LAD is due to 4 main factors: (1) the PD runs deep into the chest, whereas the LAD is more superficial; (2) the PD runs close to the right ventricular inflow tract and to the mid cardiac vein, which generate strong and disturbing flow signals5; (3) adenosine-induced hyperventilation interferes more with PD than with LAD imaging; and (4) a dedicated transducer has been designed only for the LAD. Imaging of the PD can be improved by several methods: (1) the use of ultrasound contrast agents; (2) the use of specific A2A adenosine receptor agonists, which produce less or no hyperventilation44; (3) the design of specific probes and software; and (4) reduction of the heart rate to minimize wall motion artifacts on Doppler sampling. The Achilles Heel Unfortunately, the early stages of coronary atherosclerosis, characterized by angiographically nonsignificant but potentially unstable plaques, cannot be detected by measuring CFR. Also, there are no data on left main coronary artery disease. An important development in ultrasound is the improvement of direct imaging of the LAD to detect focal acceleration of flow at rest, as a sign of preclinical atherosclerosis. We take the opportunity of this editorial to make another appeal to industry, clinicians, and researchers to invest in this field and not to abandon a treasure like coronary Doppler ultrasound, a “green,” cheap, and sustainable technique which is not inferior to computed tomography to detect significant LAD disease.45 The fact that few clinicians use coronary Doppler ultrasound is not a good argument against its validity: when Johann Christian Doppler46 opened the way to diagnostic ultrasound with his report “On the Colored Light of the Double Stars and Certain Other Stars of the Heavens,” only 6 individuals were in attendance. 1. Voci P, Testa G, Plaustro G. Imaging of the distal left anterior descending coronary artery by transthoracic color-Doppler echocardiography. Am J Cardiol 1998;81(suppl):74G–78G. 2. Hozumi T, Yoshida K, Ogata Y, Akasaka T, Asami Y, Takagi T, Morioka S. Noninvasive assessment of significant left anterior descending coronary artery stenosis by coronary flow velocity reserve with transthoracic color Doppler echocardiography. Circulation 1998; 97:1557–1562. 3. Caiati C, Montaldo C, Zedda N, Bina A, Iliceto S. New noninvasive method for coronary flow reserve assessment. Contrast-enhanced transthoracic second harmonic echo Doppler. Circulation 1999;99: 771–778. 4. Okayama H, Sumimoto T, Hiasa G, Nishimura K, Morioka N, Yamamoto K, Kawada H. Assessment of intermediate stenosis in the left anterior descending coronary artery with contrast-enhanced trans-
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