- Email: [email protected]
Use of adenosine echocardiography for diagnosis of coronary artery disease
Use of adenosine echocardiography for diagnosis of coronary artery disease Two-dimensional echocardiography combined with exercise is sensitive and specific in the detectton of coronary artery disease (CAD) by demonstrating transient abnormalities in Wall motion. Frequently, however, patients cannot achieve maximal exercise because of various factors. Pharmacologic stress testing with intravenous adenosine was evaluated as a means of detecting CAD In a noninvasive manner. Patients with suspected CAD underwent echocardiographlc imaging and simultaneous thallium 201 single-photon emission computed tomography during the intravenous administration of 140 pg/kg/min of adenosine. An increase in heart rate, decrease in blood pressure, and increase in double product were observed during adenoslne administration. Initial observations revealed that wall motion abnormalities were induced by adenosine in areas of perfusion defects. The adenosine infusion was well tolerated, and symptoms disappeared within 1 to 2 minutes after termination of the infusion. Therefore preliminary observations suggest that adenosine echocardiography appears to be useful in the assessment of CAD. (AM HEART J 1991;122:285.)
William
A. Zoghbi, MD Houston,
Texas
The usefulness of two-dimensional echocardiography in providing accurate information about regional and global left ventricular function has now been well established. In patients with coronary artery disease (CAD), resting wall motion abnormalities are usually seen in the presence of an ischemic episode or previous myocardial infarction. However, in most patients with CAD, the detection of transient ischemic episodes, manifested by the development of regional wall motion abnormality, requires imaging under conditions that provoke a mismatch between myocardial oxygen supply and demand. Exercise echocardiography has been shown to be sensitive and specific in the detection of CAD.l, 2 When exercise stress testing is used for the detection of ischemia, it is essential that patients achieve an adequate level of exercise. Frequently, however, exercise tolerance may be limited by peripheral vascular disease, chronic obstructive pulmonary disease, or musculoskeletal abnormalities (Fig. 1). Furthermore, several patients undergoing exercise testing are already receiving P-blockers and calcium channel blockers that interfere with the induction of ischemic episodes during exercise. Alternative methods to exercise have thus From the Section of Cardiology Baylor College of Medicine, and The Echocardiography Laboratory, The Methodist Hospital. Reprint requests: William A. Zoghbi. MD, The Methodist Hospital, Section of Cardiology, 6535 Fannin, MS F-905. Houston, TX 7’7030. 4/O/28947
been proposed for the noninvasive assessment of CAD. Of these, the use of pharmacologic stress testing has been the most promising. During the past year, 4722 patients were referred to the Methodist Hospital, Baylor College of Medicine for the noninvasive evaluation of CAD (Fig. 2). Of these, 798 underwent pharmacologic stress testing because the referring physician already suspected that these patients would not be able to withstand maximal exercise. Of the remaining 3924 patients who underwent treadmill exercise testing, 824 did not achieve 85% of their target heart rate and therefore had a nondiagnostic stress test. These patients do not include those in whom significant ST segment depression occurred before reaching the 85% level. Only 120 of the 824 patients were receiving @-blockers. These results suggest that in our institution nearly 34% of patients referred for evaluation of CAD were candidates for pharmacologic stress testing. This percentage is probably representative of tertiary referral hospitals and will undoubtedly vary depending on the patient population studied. PHARMACOLOGIC VASODILATORS
STRESS
TESTING
WITH CORONARY
Several pharmacologic stress agents have been used with imaging modalities, including sympathomimetic agents such as dobutamine and coronary vasodilators such as dipyridamole and more recently adenosine. Previous studies have demonstrated the 285
266
Zoghbi
American
July 1991 Heart Jovrnal
Peripheral vascular disease Pulmonary disease Cerebrovascular disease Musculoskeletal abnormalities Poor condition or motivation Limiting symptoms (fatigue, chest pain) Medications: &blockers, Ca-channel blockers Fig.
1.
Factors limiting exercise.
Nondiagmstc 824 TreadEx \
PhST Candidates I
1m
20
\ I
40
I
60
I
80
I
100
Percent Powlation 2. Distribution of patients (N = 4722) undergoing treadmill exercise and pharmacologicstresstesting for evaluation of CAD at Baylor Collegeof Medicine, 1989to 1990.The nondiagnostictread ex study wasof patients undergoing treadmill test who did not achieve 85% maximal target heart rate and had no significant ST segmentdepressionduring exercise.Ex, exercise; tread, treadmill; PhST, pharmacologic stresstest. Fig.
clinical usefulness of dipyridamole
thallium scintig-
a negative inotropic effect on the myocardium.s The
raphy in the assessment of CAD.3W5 The primary mechanism of dipyridamole-induced coronary vasodilation appears to be indirectly through increased endogenous levels of adenosine.6-8 Dipyridamole inhibits cellular reuptake of adenosine and its metabolism by adenosine deaminase, thus increasing the concentration of interstitial adenosine. In chronically instrumented dogs, adenosine was not found to have
short half-life of adenosine (
Volume
122
Number
I, Part
A4denosinv el‘hoc,nrtflI,~‘rclph?
1
287
Baseline
Baseline
Percent Shortening
Fraction
3. Echocardiographic quantification of regional wall motion at baselineand after administration of intravenous dipyridamole in dogswith severecircumflex coronary artery stenosis.(Modified from Cheirif et al. Reprinted with permissionof The American Collegeof Cardiology. J Am Co11Cardiol 1989;14:155565.) Fig.
Stepwise increase, every minute, in adenosine infusion rate: 50,75,100,140 pglkglmin 140 pglkglmin dose maintained for 4 min Electrocardiographic monitoring
and blood pressure
Endpoints - ~2 mm ST segment depression - intolerable symptoms - High-grade or Third-degree AV block - Systolic blood pressure < 85 mmHg
Fig.
4.
Adenosine stressprotocol. AV, Atrioventricular.
between territories supplied by normal coronary ar-
teries versus those by stenotic arteries. Although ischemia may not necessarily be implied, wall motion abnormalities, angina, and ECG ST depression have been found to develop in patients with severe CAD after the administration of an intravenous or a high
Recently dipyridamole echocardiography was shown to be useful in detecting the extent of CAD after uncomplicated myocardial infarction and in assessing prognosis in patients with CAD. i5, Ifi In studies in which simultaneous thallium and echocardiographic imaging were oral dose of dipyridamole.‘“-”
288
Zoghbi
American
July 1991 Heart Journal
Fig. 5. Echocardiographic still frames (upper panel) and simultaneousSPECT thallium imaging (lower panel) during adenosineinfusion in a patient with a previous apical myocardial infarction and proximal right coronary artery stenosis.The echocardiographicframesin the quad screenare shownat end diastole (left) and end systole (right). The dots in the four quadrants represent the respective end-diastolic contour. During adenosineinfusion, significant hypokinesis occurs in the inferior wall as opposedto baseline (arrows). Apical and distal anterior wall akinesisis also seen.The correspondingthallium 201 tomograms depict anterior, inferior, and apical defects. Redistribution at 4 hours occurs in the anterior and inferior defects, but the apical defect persists.
performed, wall motion abnormalities were frequently demonstrated in areas of thallium perfusion defects.17* l8 The underlying mechanism of ischemia induced by coronary arteriolar vasodilators has been assessed
experimentally. 1g-24In the presence of single-artery coronary stenosis, coronary arteriolar dilation results in an increase in the pressure gradient across the stenosis and a decrease in distal coronary perfusion pressure with a consequent decrease in the endocar-
Volume Number
122 1. Part
Adenosine
1
echocardiography
289
Percent of Pofxila
Facial flushing Headache Dyspnea Chest pain Throat/neck tightness Light-headedness Metallic taste No symptoms
tion
37 23 21 21 12 2 2 21
6. Symptoms experienced among - 62 _ patients in the adenosinetitration study of echocardiography and SPECT. Fig.
dial to epicardial flow ratio. The magnitude of these changes is dependent, among other factors, on the severity of the stenosis and the dose of coronary vasodilator used.lg During severe coronary stenosis, an actual decrease in endocardial flow is observed. In models of multivessel disease with collaterals, a decrease in perfusion pressure at the origin of collateral vessels causes a decrease in collateral flow, thereby producing ischemia. 1g-21In a recent study from our institution performed in open chest dogs with critical circumflex stenosis, the use of intravenous dipyridamole produced similar alterations in perfusion.24 In this study with dipyridamole, echocardiographic methods quantifying regional function (Fig. 3) showed a significant decrease in the shortening fraction in the region perfused by the stenosed artery, with a slight increase in function in the control region. ADENOSINE ECHOCARDIOGRAPHY AND SINGLE-PHOTON EMISSION COMPUTED TOMOGRAPHY THALLIUM IMAGING
Because the coronary vasodilator effects of dipyridamole are achieved predominantly through adenosine, we have been interested in the use of intravenous adenosine combined with echocardiographic imaging for the assessment of CAD. Adenosine is a very attractive pharmacologic agent because of its short half-life of less than 10 seconds. Wilson et a1.25 have recently demonstrated that at an intravenous infusion rate of 140 pgglkglmin of adenosine, maximal coronary dilation occurs in most patients. To assess the feasibility and safety of intravenous adenosine combined with echocardiography and to determine whether wall motion abnormalities occur
in areas of perfusion abnormalities, we are currently conducting a study of simultaneous echocardiography and single-photon emission computed tomography (SPECT) thallium 201 imaging during adenosine infusion.i2 The protocol is shown in Fig. 4. Echocardiographic imaging is started at baseline and continued throughout the infusion and for 2 minutes after the infusion. After 1 minute of the 140 pg dose, 201T1 is injected, and SPECT thallium images are obtained immediately after the infusion. Redistribution images are obtained 4 hours later. The initial population presented here consists of 62 patients; the total population planned for the study is 100 patients. There were 44 male and 18 female patients with a mean age of 62 years. Thirty-six patients had a previous myocardial infarction. Forty-nine patients were receiving heart medication including nitrates, calcium channel blockers, and P-blockers. Standard two-dimensional echocardiographic imaging was performed in multiple views from the parasternal and apical windows. The images were later digitized in a quad-screen format by an independent observer who selected the images that were to be compared. The position on the quad screen of the baseline and images during maximal adenosine infusion was randomized for nonbiased interpretation. All studies were interpreted by another independent observer blinded to all data. An ischemic response during adenosine administration was defined by echocardiography as the development or worsening of a wall motion abnormality compared with baseline and by thallium as a perfusion defect that fills in totally or partially during redistribution. Scar was defined by echocardiography as a fixed wall motion abnormality and by
290
Zoghbi
American
Baseline
Adenosine
P Value
HR (beatdmin)
74 + 15
872 16
0.0001
SBP (mmHg)
132 + 28
121 5 29
0.0001
DBP (mmHg)
76 f 12
69 zk14
0.0001
HR x SBP x lo5 9.8 f 2.8 (beatdmin x mmHg)
10f
3
July 1991 Heart Journat
0.03
Fig. 7. Hemodynamic changesduring adenosineinfusion in the study of echocardiography and SPECT.
Uniform stress level “Stress titration” More time for imaging (LV, RV) and Doppler
omparable sensitivity for CAD? omparable prognostic information? Fig. 8. Pharmacologic stressversus exerciseechocardiography. LV, Left ventricle; RV, right ventricle.
thallium as a fixed perfusion defect. An example of an
ischemic response is shown in Fig. 5. Preliminary comparison of results shows a concordance between adenosine echocardiography and SPECT thallium imaging separating normal from abnormal adenosine studies in 49 of 62 patients or 79%. Analysis of disagreements revealed that in cases of an abnormal thallium result with a normal adenosine echocardiographic study (N = 3), one patient had CAD. In the 10 patients with an abnormal adenosine echocardiography but a normal SPECT thallium study, 7 had CAD. Almost all of these abnormalities were in the area of the inferior base
where inherent difficulties in interpreting perfusion in this segment with SPECT thallium imaging may be encountered. Preliminary
observations revealed
that an ischemic response was detected in 32 % of the population by adenosine echocardiography, in 43 % by SPECT thallium imaging, and increased to 52% when either test was positive. From these preliminary observations, it appears that the combination of adenosine echocardiography and SPECT thallium imaging may improve the sensitivity for the detection of CAD. At this stage of the study, 43 patients underwent cardiac catheterization. The sensitivity for CAD as shown by ischemia or scar by either modal-
Volume Number
122 1, Part
Adenosine
1
ity was 89% for adenosine echocardiography, 83 % for adenosine thallium imaging, and 91% when either test was abnormal, specificity exceeded 85% for all modalities. All patients enrolled thus far tolerated the adenosine infusion well. During the infusion of adenosine, although transient symptoms were experienced by most patients, these resolved within 1 to 2 minutes after the termination of the infusion (Fig. 6). In this initial phase of the study, two patients developed transient, self-limiting, Wenckebach second-degree atrioventricular block. No patient developed thirddegree atrioventricular block. The hemodynamic changes (Fig. 7) included an increase in heart rate, decrease in systolic and diastolic blood pressures, and a slight but significant increase in heart rate/blood pressure product. The sensitivity of adenosine echocardiography and thallium scintigraphy in the general population is probably lower than that reported here because of the prevalence of previous myocardial infarction in the population studied. In a recent study of adenosine echocardiography involving 73 patients who underwent cardiac catheterization, the sensitivity of adenosine echocardiography for CAD was 85 % in the total population and 60% in patients with a normal baseline ECG.26 Further studies are under way in larger populations to evaluate the accuracy of pharmacologic stress testing with adenosine in the assessment of CAD. Thus from these preliminary observations, the intravenous infusion of adenosine in patients with CAD can induce transient wall motion abnormalities in areas of perfusion defects, compatible with an ischemic response. Although the primary mechanism for ischemia is probably a coronary steal phenomenon, the observed alterations in blood pressure and heart rate may further enhance the development of myocardial ischemia. Potential advantages of this modality compared with exercise echocardiography (Fig. 8) include less hyperventilation and cardiac motion with better image quality during stress, allowing quantification of regional function. With pharmacologic stress testing, more time is available for imaging and Doppler evaluation of ventricular filling and ejection dynamics. A more uniform level of stress is achieved in the population tested. The short half-life of adenosine is particularly advantageous in that the duration of induced ischemia is brief after the termination of the infusion. From these initial observations, adenosine echocardiography appears to be safe and well tolerated, and it provides a promising alternative stress modality for the evaluation of CAD.
echocardiography
29
1
REFERENCES
1. Limacher MC, Quinones MA, Poliner LR, Nelson JG, Winters WL, Waggoner AD. Detection of coronary artery disease with exercise two-dimensional echocardiography. Description of a clinically applicable method and comparison with radionuelide ventriculography. Circulation 1983;67:1211-8. 2. Ryan T, Vasey CG, Presti CF, O’Donnell JA, Feigengaum H, Armstrong WF. Exercise echocardiography: detection of coronary artery disease in patients with normal left ventricular wall motion at rest. J Am Co11 Cardicll 1988;11:9939.
Gould KL, Westcott RJ, Albro PC, Hamilton GW. Noninvasive assessment of coronary stenoses by myocardial imaging during pharmacologic vasodilation. II. Clinical methodology and feasibility. Am J Cardiol 1978;41:279-87. 4. Borges-Neto S, Mahmarian JJ, Jain A, Roberth R, Verani MS, Quantitative thallium-201 single photon emission computed tomography after oral dipyridamole for assessing the presence, anatomic location and severity of cororarg artery disease. J Am Co11 Cardiol 1988;11:962-9. 5. Boucher CA, Brewster DC, Darling RC, Okada RD, Strauss HW, Pohost GM. Determination of cardiac risk by dipyridamole-thallium imaging before peripheral vascular surgery. N Engl J Med 1985;312:389-94. 6. Knabb RM, Gidday JM, Ely SW, Rubio R, Berne RM. Effects of dipyridamole on myocardial adenosine anti active hyperemia. Am J Physiol 1984;247:H804-10. 7. Klabunde RE. Dipyridamole inhibition of adenosine metabolism in human blood. Eur J Pharmacol 1983;93:21-6. 8. Conradson TBG, Dixon CMS, Clarke B. Barnes PJ. Cardiovascular effects of infused adenosine in man: potentiation by dipyridamole. Acta Physiol Stand 1987;129:387-91. 9. Freeman GL, Colston JT, Hultman J. Influence of adenosine on left ventricular performance in conscious dogs. Am J Physiol 1990;258:H424-30. 10. Moser GH, Schrader J, Deussen A. Turnover of adenosine in plasma of human and dog blood. Am J Physi,)l 1989;256(Cell Physiol 25):C799-806. 11. Verani MS, Mahmarian JJ, Hixson JB, Boyce TM, Staudacher RA. Diagnosis of coronary artery disease by controlled coronary vasodilation with adenosine and thallium-201 scintigraphy in patients unable to exercise. Circulation 1990;82: 3.
80-i.
12. Trakhtenbroit AD, Cheirif J, Kleiman NS, et al. Intravenous adenosine echocardiography, a new pharmacologic stress test: preliminary results and comparison with simultaneous thallium scintigraphy. J Am Co11 Cardiol 1990;15:234A. 13. Picano E, Latanzi F, Masini M, Distante A, L’Abbate A. High dose dipyridamole echocardiography test in etfort angina pettoris. J Am Co11 Cardiol 1986:8:848-54. 14. Picano E, Pirelli S, Marzilli I& et al. Usefulness of high-dose dipyridamole echocardiography t,est in cororlary angioplasty. Circulation 1989:80:807-15. 15. Picano E, Severi s, Michelassi C, et al. Prognostic importance of dipyridamole-echocardiography test in coronary artery disease. Circulation _ - 1989;80:450-7. 16. Bolognese L, Sarasso G, Aralda D, Bongo AS, Rossi L, Rossi P. High dose dipyridamole echocardiography early after uncomplicated acute myocardial infarction: correlation with exercise testing and coronary angiography. .I ,4m Co11Cardiol 1989;14:357-63. 17. Jain A, Suarez J. Mahmarian JJ, Zoghbi WA, Quinones MA. Verani MS. Functional significance of myocardial perfusion defect induced by dipyridamole using thallium-201 single photon emission computed tomography and two-dimensional echocardiography. Am J Cardiol 1990;66:802-6. 18. Labovitz AJ, Person AC, Chaitman BR. Doppler and 2. dimensional echocardiographic assessment of left ventricular function before and after intravenous dipyridamole stress testing for detection of coronary artery disease. Am J Cardiol 1988;62:1180-5. 19. Gross GJ, Warltier DC. Coronary steal in f(%urmodels of sin-
July 1991 292
20. 21. 22. 23.
Zoghbi gle or multiple vessel obstruction in dogs. Am J Cardiol 1981; 48:84-91. Becker LC. Conditions for vasodilator-induced coronary steal in experimental myocardial ischemia. Circulation 1978;57: 1103-10. Patterson RE, Kirk ES. Coronary steal mechanisms in dogs with one-vessel occlusion and other arteries normal. Circulation 1983;67:1009-15. Meerdink DJ, Okada RD, Leppo JA. The effect of dipyridamole on transmural blood flow gradients. Chest 1989;96: 400-5. Londos C, Cooper DMF, Wolff J. Subclasses of adenosine receptors. Proc Nat1 Acad Sci U S A 1980;77:2551-4.
American
Heart Journal
24. Cheirif J, Zoghbi WA, Bolli R, O’Neill PG, Hoyt BD, Quinones MA. Assessment of regional myocardial perfusion by contrast echocardiography. II. Detection of changes in transmural and subendocardial perfusion during dipyridamole-induced hyperemia in a model of critical coronary stenosis. J Am Co11 Cardiol 1989;14:1555-65. 25. Wilson RF, Wyche K, Christensen BV, Zimmer S, Laxson DD. Effects of adenosine on human coronary arterial circulation. Circulation 1990;82:1595-606. 26. Trakhtenbroit AD, Cheirif J, Kleiman NS, Verani MS, Zoghbi WA. Adenosine echocardiography in the diagnosis of coronary artery disease: comparison with coronary angiography [Abstract}. Circulation 1990;82(suppl III):III-193.
William
A. Zoghbi, MD Houston,
Texas
The usefulness of two-dimensional echocardiography in providing accurate information about regional and global left ventricular function has now been well established. In patients with coronary artery disease (CAD), resting wall motion abnormalities are usually seen in the presence of an ischemic episode or previous myocardial infarction. However, in most patients with CAD, the detection of transient ischemic episodes, manifested by the development of regional wall motion abnormality, requires imaging under conditions that provoke a mismatch between myocardial oxygen supply and demand. Exercise echocardiography has been shown to be sensitive and specific in the detection of CAD.l, 2 When exercise stress testing is used for the detection of ischemia, it is essential that patients achieve an adequate level of exercise. Frequently, however, exercise tolerance may be limited by peripheral vascular disease, chronic obstructive pulmonary disease, or musculoskeletal abnormalities (Fig. 1). Furthermore, several patients undergoing exercise testing are already receiving P-blockers and calcium channel blockers that interfere with the induction of ischemic episodes during exercise. Alternative methods to exercise have thus From the Section of Cardiology Baylor College of Medicine, and The Echocardiography Laboratory, The Methodist Hospital. Reprint requests: William A. Zoghbi. MD, The Methodist Hospital, Section of Cardiology, 6535 Fannin, MS F-905. Houston, TX 7’7030. 4/O/28947
been proposed for the noninvasive assessment of CAD. Of these, the use of pharmacologic stress testing has been the most promising. During the past year, 4722 patients were referred to the Methodist Hospital, Baylor College of Medicine for the noninvasive evaluation of CAD (Fig. 2). Of these, 798 underwent pharmacologic stress testing because the referring physician already suspected that these patients would not be able to withstand maximal exercise. Of the remaining 3924 patients who underwent treadmill exercise testing, 824 did not achieve 85% of their target heart rate and therefore had a nondiagnostic stress test. These patients do not include those in whom significant ST segment depression occurred before reaching the 85% level. Only 120 of the 824 patients were receiving @-blockers. These results suggest that in our institution nearly 34% of patients referred for evaluation of CAD were candidates for pharmacologic stress testing. This percentage is probably representative of tertiary referral hospitals and will undoubtedly vary depending on the patient population studied. PHARMACOLOGIC VASODILATORS
STRESS
TESTING
WITH CORONARY
Several pharmacologic stress agents have been used with imaging modalities, including sympathomimetic agents such as dobutamine and coronary vasodilators such as dipyridamole and more recently adenosine. Previous studies have demonstrated the 285
266
Zoghbi
American
July 1991 Heart Jovrnal
Peripheral vascular disease Pulmonary disease Cerebrovascular disease Musculoskeletal abnormalities Poor condition or motivation Limiting symptoms (fatigue, chest pain) Medications: &blockers, Ca-channel blockers Fig.
1.
Factors limiting exercise.
Nondiagmstc 824 TreadEx \
PhST Candidates I
1m
20
\ I
40
I
60
I
80
I
100
Percent Powlation 2. Distribution of patients (N = 4722) undergoing treadmill exercise and pharmacologicstresstesting for evaluation of CAD at Baylor Collegeof Medicine, 1989to 1990.The nondiagnostictread ex study wasof patients undergoing treadmill test who did not achieve 85% maximal target heart rate and had no significant ST segmentdepressionduring exercise.Ex, exercise; tread, treadmill; PhST, pharmacologic stresstest. Fig.
clinical usefulness of dipyridamole
thallium scintig-
a negative inotropic effect on the myocardium.s The
raphy in the assessment of CAD.3W5 The primary mechanism of dipyridamole-induced coronary vasodilation appears to be indirectly through increased endogenous levels of adenosine.6-8 Dipyridamole inhibits cellular reuptake of adenosine and its metabolism by adenosine deaminase, thus increasing the concentration of interstitial adenosine. In chronically instrumented dogs, adenosine was not found to have
short half-life of adenosine (
Volume
122
Number
I, Part
A4denosinv el‘hoc,nrtflI,~‘rclph?
1
287
Baseline
Baseline
Percent Shortening
Fraction
3. Echocardiographic quantification of regional wall motion at baselineand after administration of intravenous dipyridamole in dogswith severecircumflex coronary artery stenosis.(Modified from Cheirif et al. Reprinted with permissionof The American Collegeof Cardiology. J Am Co11Cardiol 1989;14:155565.) Fig.
Stepwise increase, every minute, in adenosine infusion rate: 50,75,100,140 pglkglmin 140 pglkglmin dose maintained for 4 min Electrocardiographic monitoring
and blood pressure
Endpoints - ~2 mm ST segment depression - intolerable symptoms - High-grade or Third-degree AV block - Systolic blood pressure < 85 mmHg
Fig.
4.
Adenosine stressprotocol. AV, Atrioventricular.
between territories supplied by normal coronary ar-
teries versus those by stenotic arteries. Although ischemia may not necessarily be implied, wall motion abnormalities, angina, and ECG ST depression have been found to develop in patients with severe CAD after the administration of an intravenous or a high
Recently dipyridamole echocardiography was shown to be useful in detecting the extent of CAD after uncomplicated myocardial infarction and in assessing prognosis in patients with CAD. i5, Ifi In studies in which simultaneous thallium and echocardiographic imaging were oral dose of dipyridamole.‘“-”
288
Zoghbi
American
July 1991 Heart Journal
Fig. 5. Echocardiographic still frames (upper panel) and simultaneousSPECT thallium imaging (lower panel) during adenosineinfusion in a patient with a previous apical myocardial infarction and proximal right coronary artery stenosis.The echocardiographicframesin the quad screenare shownat end diastole (left) and end systole (right). The dots in the four quadrants represent the respective end-diastolic contour. During adenosineinfusion, significant hypokinesis occurs in the inferior wall as opposedto baseline (arrows). Apical and distal anterior wall akinesisis also seen.The correspondingthallium 201 tomograms depict anterior, inferior, and apical defects. Redistribution at 4 hours occurs in the anterior and inferior defects, but the apical defect persists.
performed, wall motion abnormalities were frequently demonstrated in areas of thallium perfusion defects.17* l8 The underlying mechanism of ischemia induced by coronary arteriolar vasodilators has been assessed
experimentally. 1g-24In the presence of single-artery coronary stenosis, coronary arteriolar dilation results in an increase in the pressure gradient across the stenosis and a decrease in distal coronary perfusion pressure with a consequent decrease in the endocar-
Volume Number
122 1. Part
Adenosine
1
echocardiography
289
Percent of Pofxila
Facial flushing Headache Dyspnea Chest pain Throat/neck tightness Light-headedness Metallic taste No symptoms
tion
37 23 21 21 12 2 2 21
6. Symptoms experienced among - 62 _ patients in the adenosinetitration study of echocardiography and SPECT. Fig.
dial to epicardial flow ratio. The magnitude of these changes is dependent, among other factors, on the severity of the stenosis and the dose of coronary vasodilator used.lg During severe coronary stenosis, an actual decrease in endocardial flow is observed. In models of multivessel disease with collaterals, a decrease in perfusion pressure at the origin of collateral vessels causes a decrease in collateral flow, thereby producing ischemia. 1g-21In a recent study from our institution performed in open chest dogs with critical circumflex stenosis, the use of intravenous dipyridamole produced similar alterations in perfusion.24 In this study with dipyridamole, echocardiographic methods quantifying regional function (Fig. 3) showed a significant decrease in the shortening fraction in the region perfused by the stenosed artery, with a slight increase in function in the control region. ADENOSINE ECHOCARDIOGRAPHY AND SINGLE-PHOTON EMISSION COMPUTED TOMOGRAPHY THALLIUM IMAGING
Because the coronary vasodilator effects of dipyridamole are achieved predominantly through adenosine, we have been interested in the use of intravenous adenosine combined with echocardiographic imaging for the assessment of CAD. Adenosine is a very attractive pharmacologic agent because of its short half-life of less than 10 seconds. Wilson et a1.25 have recently demonstrated that at an intravenous infusion rate of 140 pgglkglmin of adenosine, maximal coronary dilation occurs in most patients. To assess the feasibility and safety of intravenous adenosine combined with echocardiography and to determine whether wall motion abnormalities occur
in areas of perfusion abnormalities, we are currently conducting a study of simultaneous echocardiography and single-photon emission computed tomography (SPECT) thallium 201 imaging during adenosine infusion.i2 The protocol is shown in Fig. 4. Echocardiographic imaging is started at baseline and continued throughout the infusion and for 2 minutes after the infusion. After 1 minute of the 140 pg dose, 201T1 is injected, and SPECT thallium images are obtained immediately after the infusion. Redistribution images are obtained 4 hours later. The initial population presented here consists of 62 patients; the total population planned for the study is 100 patients. There were 44 male and 18 female patients with a mean age of 62 years. Thirty-six patients had a previous myocardial infarction. Forty-nine patients were receiving heart medication including nitrates, calcium channel blockers, and P-blockers. Standard two-dimensional echocardiographic imaging was performed in multiple views from the parasternal and apical windows. The images were later digitized in a quad-screen format by an independent observer who selected the images that were to be compared. The position on the quad screen of the baseline and images during maximal adenosine infusion was randomized for nonbiased interpretation. All studies were interpreted by another independent observer blinded to all data. An ischemic response during adenosine administration was defined by echocardiography as the development or worsening of a wall motion abnormality compared with baseline and by thallium as a perfusion defect that fills in totally or partially during redistribution. Scar was defined by echocardiography as a fixed wall motion abnormality and by
290
Zoghbi
American
Baseline
Adenosine
P Value
HR (beatdmin)
74 + 15
872 16
0.0001
SBP (mmHg)
132 + 28
121 5 29
0.0001
DBP (mmHg)
76 f 12
69 zk14
0.0001
HR x SBP x lo5 9.8 f 2.8 (beatdmin x mmHg)
10f
3
July 1991 Heart Journat
0.03
Fig. 7. Hemodynamic changesduring adenosineinfusion in the study of echocardiography and SPECT.
Uniform stress level “Stress titration” More time for imaging (LV, RV) and Doppler
omparable sensitivity for CAD? omparable prognostic information? Fig. 8. Pharmacologic stressversus exerciseechocardiography. LV, Left ventricle; RV, right ventricle.
thallium as a fixed perfusion defect. An example of an
ischemic response is shown in Fig. 5. Preliminary comparison of results shows a concordance between adenosine echocardiography and SPECT thallium imaging separating normal from abnormal adenosine studies in 49 of 62 patients or 79%. Analysis of disagreements revealed that in cases of an abnormal thallium result with a normal adenosine echocardiographic study (N = 3), one patient had CAD. In the 10 patients with an abnormal adenosine echocardiography but a normal SPECT thallium study, 7 had CAD. Almost all of these abnormalities were in the area of the inferior base
where inherent difficulties in interpreting perfusion in this segment with SPECT thallium imaging may be encountered. Preliminary
observations revealed
that an ischemic response was detected in 32 % of the population by adenosine echocardiography, in 43 % by SPECT thallium imaging, and increased to 52% when either test was positive. From these preliminary observations, it appears that the combination of adenosine echocardiography and SPECT thallium imaging may improve the sensitivity for the detection of CAD. At this stage of the study, 43 patients underwent cardiac catheterization. The sensitivity for CAD as shown by ischemia or scar by either modal-
Volume Number
122 1, Part
Adenosine
1
ity was 89% for adenosine echocardiography, 83 % for adenosine thallium imaging, and 91% when either test was abnormal, specificity exceeded 85% for all modalities. All patients enrolled thus far tolerated the adenosine infusion well. During the infusion of adenosine, although transient symptoms were experienced by most patients, these resolved within 1 to 2 minutes after the termination of the infusion (Fig. 6). In this initial phase of the study, two patients developed transient, self-limiting, Wenckebach second-degree atrioventricular block. No patient developed thirddegree atrioventricular block. The hemodynamic changes (Fig. 7) included an increase in heart rate, decrease in systolic and diastolic blood pressures, and a slight but significant increase in heart rate/blood pressure product. The sensitivity of adenosine echocardiography and thallium scintigraphy in the general population is probably lower than that reported here because of the prevalence of previous myocardial infarction in the population studied. In a recent study of adenosine echocardiography involving 73 patients who underwent cardiac catheterization, the sensitivity of adenosine echocardiography for CAD was 85 % in the total population and 60% in patients with a normal baseline ECG.26 Further studies are under way in larger populations to evaluate the accuracy of pharmacologic stress testing with adenosine in the assessment of CAD. Thus from these preliminary observations, the intravenous infusion of adenosine in patients with CAD can induce transient wall motion abnormalities in areas of perfusion defects, compatible with an ischemic response. Although the primary mechanism for ischemia is probably a coronary steal phenomenon, the observed alterations in blood pressure and heart rate may further enhance the development of myocardial ischemia. Potential advantages of this modality compared with exercise echocardiography (Fig. 8) include less hyperventilation and cardiac motion with better image quality during stress, allowing quantification of regional function. With pharmacologic stress testing, more time is available for imaging and Doppler evaluation of ventricular filling and ejection dynamics. A more uniform level of stress is achieved in the population tested. The short half-life of adenosine is particularly advantageous in that the duration of induced ischemia is brief after the termination of the infusion. From these initial observations, adenosine echocardiography appears to be safe and well tolerated, and it provides a promising alternative stress modality for the evaluation of CAD.
echocardiography
29
1
REFERENCES
1. Limacher MC, Quinones MA, Poliner LR, Nelson JG, Winters WL, Waggoner AD. Detection of coronary artery disease with exercise two-dimensional echocardiography. Description of a clinically applicable method and comparison with radionuelide ventriculography. Circulation 1983;67:1211-8. 2. Ryan T, Vasey CG, Presti CF, O’Donnell JA, Feigengaum H, Armstrong WF. Exercise echocardiography: detection of coronary artery disease in patients with normal left ventricular wall motion at rest. J Am Co11 Cardicll 1988;11:9939.
Gould KL, Westcott RJ, Albro PC, Hamilton GW. Noninvasive assessment of coronary stenoses by myocardial imaging during pharmacologic vasodilation. II. Clinical methodology and feasibility. Am J Cardiol 1978;41:279-87. 4. Borges-Neto S, Mahmarian JJ, Jain A, Roberth R, Verani MS, Quantitative thallium-201 single photon emission computed tomography after oral dipyridamole for assessing the presence, anatomic location and severity of cororarg artery disease. J Am Co11 Cardiol 1988;11:962-9. 5. Boucher CA, Brewster DC, Darling RC, Okada RD, Strauss HW, Pohost GM. Determination of cardiac risk by dipyridamole-thallium imaging before peripheral vascular surgery. N Engl J Med 1985;312:389-94. 6. Knabb RM, Gidday JM, Ely SW, Rubio R, Berne RM. Effects of dipyridamole on myocardial adenosine anti active hyperemia. Am J Physiol 1984;247:H804-10. 7. Klabunde RE. Dipyridamole inhibition of adenosine metabolism in human blood. Eur J Pharmacol 1983;93:21-6. 8. Conradson TBG, Dixon CMS, Clarke B. Barnes PJ. Cardiovascular effects of infused adenosine in man: potentiation by dipyridamole. Acta Physiol Stand 1987;129:387-91. 9. Freeman GL, Colston JT, Hultman J. Influence of adenosine on left ventricular performance in conscious dogs. Am J Physiol 1990;258:H424-30. 10. Moser GH, Schrader J, Deussen A. Turnover of adenosine in plasma of human and dog blood. Am J Physi,)l 1989;256(Cell Physiol 25):C799-806. 11. Verani MS, Mahmarian JJ, Hixson JB, Boyce TM, Staudacher RA. Diagnosis of coronary artery disease by controlled coronary vasodilation with adenosine and thallium-201 scintigraphy in patients unable to exercise. Circulation 1990;82: 3.
80-i.
12. Trakhtenbroit AD, Cheirif J, Kleiman NS, et al. Intravenous adenosine echocardiography, a new pharmacologic stress test: preliminary results and comparison with simultaneous thallium scintigraphy. J Am Co11 Cardiol 1990;15:234A. 13. Picano E, Latanzi F, Masini M, Distante A, L’Abbate A. High dose dipyridamole echocardiography test in etfort angina pettoris. J Am Co11 Cardiol 1986:8:848-54. 14. Picano E, Pirelli S, Marzilli I& et al. Usefulness of high-dose dipyridamole echocardiography t,est in cororlary angioplasty. Circulation 1989:80:807-15. 15. Picano E, Severi s, Michelassi C, et al. Prognostic importance of dipyridamole-echocardiography test in coronary artery disease. Circulation _ - 1989;80:450-7. 16. Bolognese L, Sarasso G, Aralda D, Bongo AS, Rossi L, Rossi P. High dose dipyridamole echocardiography early after uncomplicated acute myocardial infarction: correlation with exercise testing and coronary angiography. .I ,4m Co11Cardiol 1989;14:357-63. 17. Jain A, Suarez J. Mahmarian JJ, Zoghbi WA, Quinones MA. Verani MS. Functional significance of myocardial perfusion defect induced by dipyridamole using thallium-201 single photon emission computed tomography and two-dimensional echocardiography. Am J Cardiol 1990;66:802-6. 18. Labovitz AJ, Person AC, Chaitman BR. Doppler and 2. dimensional echocardiographic assessment of left ventricular function before and after intravenous dipyridamole stress testing for detection of coronary artery disease. Am J Cardiol 1988;62:1180-5. 19. Gross GJ, Warltier DC. Coronary steal in f(%urmodels of sin-
July 1991 292
20. 21. 22. 23.
Zoghbi gle or multiple vessel obstruction in dogs. Am J Cardiol 1981; 48:84-91. Becker LC. Conditions for vasodilator-induced coronary steal in experimental myocardial ischemia. Circulation 1978;57: 1103-10. Patterson RE, Kirk ES. Coronary steal mechanisms in dogs with one-vessel occlusion and other arteries normal. Circulation 1983;67:1009-15. Meerdink DJ, Okada RD, Leppo JA. The effect of dipyridamole on transmural blood flow gradients. Chest 1989;96: 400-5. Londos C, Cooper DMF, Wolff J. Subclasses of adenosine receptors. Proc Nat1 Acad Sci U S A 1980;77:2551-4.
American
Heart Journal
24. Cheirif J, Zoghbi WA, Bolli R, O’Neill PG, Hoyt BD, Quinones MA. Assessment of regional myocardial perfusion by contrast echocardiography. II. Detection of changes in transmural and subendocardial perfusion during dipyridamole-induced hyperemia in a model of critical coronary stenosis. J Am Co11 Cardiol 1989;14:1555-65. 25. Wilson RF, Wyche K, Christensen BV, Zimmer S, Laxson DD. Effects of adenosine on human coronary arterial circulation. Circulation 1990;82:1595-606. 26. Trakhtenbroit AD, Cheirif J, Kleiman NS, Verani MS, Zoghbi WA. Adenosine echocardiography in the diagnosis of coronary artery disease: comparison with coronary angiography [Abstract}. Circulation 1990;82(suppl III):III-193.