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Use of the epinephrine test in diagnosis of coronary artery disease
Use of the EpinephrineTest in Diagnosis of Coronary Art~~ Disease NICOLA FERRARA, MD, DA!10 LEOSCO, MD, GIANCARLO LONGOBARDI, MD, f’ASQUALE ABETE, MD, MARCO PAPA, MD, CARLO VIGQR!TO, MD, and FRANC0 RENGO, MD
Two-dimensional echocardiographic (2-D echo) and electrocardiographic (ECG) monitoring was performed in 53 patients with angina1 chest pain during infusion of physiologic doses of epinephrine. Technically adequate 2-D echo studies were recorded in 45 patients. Df these 45 patients, 35 had significant coronary artery disease. Twenty-two patients showed ECG changes during the test (ECG sensitivity 63% ), 13 of whom also showed wall motion abnormalities (2-D echo sensitivity 46.5% ). Corn: bined ECG and 2-D echo criteria of a positive test
yielded a sensitivity of 74%. None of the 10 patients without coronary artery disease had electricat or mechanical abnormalities during the test (specificity 100 % ). Thus, the eplnephrine test durfng simultaneous 2-D echo and ECG monitoring is a valid alternative to echocardlographic exercise stress testing. Furthermore, the adequate images obtained during the infusion allow better investigation of relation between wall motion abnormalfties and ECG changes during myocardial ischemia. ‘(Am J Cardiol 1966;56:256-260)
T i wo-dimensional echocardiography (2?D echo) during or immediately after the exercise stress testing is useful for detecting coronary artery disease (CAD).1-6 However, some patients cannot perform the exercise load needed [e.g., those with musculoskeletal, neurologic or obstructive lung disease]. Furthermore, goodquality echocardiograms suitable for analysis are difficult to record whiie the patient is actively moving and the lungs are overinflated during exercise.3 Schechter et al7 reported that the infusion of physiologic doses of epinephrine is a useful stress test in patients with CAD, reporting high values of electrocardiographic (ECG) sensitivity and specificity. In this investigation, we evaluated the effects of physiologic doses of epinephrine on mechanical function of the left ventricle
in patients with typical and atypical chest pain suspected to be caused by myocardial ischemia, and established the relation between ~311 motion abnormalities detected by 2-D echo and. ,ECG changes during epinephrine-induced myocardial ischemia.
Methods We prospectively studied 53 patients (43 men, 10 women, mean age 51 f 8 years) referred for angiographic evaluation of chest pain suspected to be caused by myocardial ischemia. Patients with valvular heart disease, congestive heart failure or severe ventricular arrhythmias were excluded from the study. Calcium antagonist and nitrate therapy had been discontinued for at least 48 hours and P-blocking drug therapy for at least 14 days before the test. Patients avoided coffee and tea for at least 3 hours before the test. Nineteen patients had a clinical history of myocardial infarction. A solution with epinephrine concentration of 4 pg/ml was infused intravenously at dose rates of 0.03, 0.06, 0.12, 0.18, 0.24 and 0.30 rg/kg/min by means of a calibrated infusion pump. The duration of infusion for each dose level was 5 minutes. ECG monitoring in the 12 standard leads was performed throughout the test and~ECG traces were recorded before infusion, at the first; third and fifth minute of each infusion step, at the
From the Istituto di Medicina Interna, Cardiologia e Chirurgia Cardiovascolare, I Cattedra di Medicina Interna, II Facolta di Medicina e Chirurgia, Napoli, and the Fondazione Clinica de1 Lavoro, Centro Medico di Riabilitazione, Campoli M.T., Benevento. Italy. This study was supported in part by Grant 8402483.56 from the CNR, Italy. Manuscript received January 3, 1986; revised manuscript received March 19, 1986, accepted March 20, 1986. Address for reprints: Nicola Ferrara, MD, I Cattedra di Medicina Interna, II Facolta di Medicina e Chirurgia, Via S. Pansini 5, 80131 Napoli, Italy: 256
August
1, 1986
THE AMERICAN
JOURNAL
OF CARDIOLOGY
Volume
257
58
T P’O. 001 loo_ Pulse
beotdmin
60 80!
-
180
P
p
140
FIGURE 1. Hemodynamic changes induced by epinephrine infusion. At peak of the test a significative increase in heart rate, systolic blood pressure (BP) and double product (D.P.) is observed. Diastolic BP decreases in comparison to basal values.
BASAL
PEAK
0. P. x 102 1
100
1ao-
p
60
12 BASAL
PEAK
p
I--
--. 1
r BASAL
first, third and fifth minute after termination of infusion and every 5 minutes until return to baseline. Arterial blood pressure was measured at the same time in the arm opposite to the infusion with a cuff sphygmomanometer. Parenteral propranolol (10 mg intravenously] was available to reverse significant adverse effects. The test was terminated before the maximal dose was administered if the patient had significant ventricular arrhythmias, ischemic ST changes or severe chest pain. The ECG criterion for a positive response was horizontal or downsloping ST-segment depression of 0.1 mV or more at the J point lasting longer than 80 ms. Real-time 2-D echo evaluation was performed with the patient in the 30“ to 60’ left lateral decubitus position before, during and after epinephrine infusion using a wide-angle (105’) mechanical sector scanner (Elscint Dynex/c). Images were recorded in the standard parasternal and apical transducer position. Particular attention was given to apical 4- and 2-chamber views and the parasternal short-axis plane. For the purpose of analysis, the left ventricle was separated into 5 segments (anterior, septal, lateral, posteroinferior and apicaQ4 The motion patterns of the individual segments were described as normal, hypokinetic, akinetic, dyskinetic and hyperkinetic. The images were displayed in real time at a rate of 20 frames/s and were recorded by means of l/&nch VHS tape (National Panasonic NV 8200) cassette recorder. The initial echocardiographic examination was performed to record baseline images, explore the cardiac windows and establish the transducer position from which optimal images could be recorded. The transducer position and 2-D echo planes established during the baseline examination facilitated rapid and optimal studies. Echocardiograms at basal condition and during the test were graded independently by 2 observers; in the event of disagreement, a third observer reviewed the case and the majority judgment was binding. Technically adequate 2-D echo studies suitable for analysis
PEAK
were recorded in 45 of 53 patients (85%) and only data from these 45 patients were analyzed. Seventeen of the 45 patients examined presented a clinical history of myocardial infarction. Of the 45 studies analyzed, the interpretation of the test was unanimous in 43 (95%). Cardiac catheterization was performed in all patients using the Sones or Judkins technique.8pg Significant CAD was defined as a decrease of 75% in luminal diameter of at least 1 of the major coronary arteries. The angiographic data were analyzed in the standard fashion by 2 observers who had no knowledge of the results of the test. Statistical analysis: The values of hemodynamic parameters were expressed as the mean f standard deviation. The differences between values obtained at basal condition and at the maximal epinephrine dose were analyzed by the paired t test. The differences between 2-D echo, electrocardiography and 2-D echo plus ECG sensitivity in patients with 3-, 2- and l-vessel disease were analyzed by Fisher’s exact testLo A p value <0.05 was considered significant.
Results Angiographic data: Thirty-five of 45 patients studied showed significant coronary stenoses at cardiac catheterization. Nine patients had l-vessel, 17 had 2vessel and 9 had 3-vessel disease. Hemodynamic changes during epinephrine infusion: With increasing infusion rate, heart rate increased from 75 f 11 to 94 f 15 beats/min (p
255
EPINEPHRINE-INDUCED
TABLE
MYOCARDIAL
I
ISCHEMIA
Epinephrine
Test:
Echocardiographic
and Electrocardiographic
Findings
No. of Patients 2DE +/ECG Presence Absence Total
of CAD of CAD
2DE sensitivity 2DE specificity
(%) = 48.5 (%) = 100
0
4 0 4
2DE O/ECG
+
9 0 9 ECG sensitivity ECG specificity
(%) = 63 (%) = 100
2DE +IECG
+
13 0 13 2DE plus 2DE plus
CAD = coronary artery disease: 2DE + = presence of myocardial asynergy; asynergy; ECG -I- = ST-segment depression; ECG 0 = ST segment normal.
epinephrine infusion). Thirteen of these 22 patients had a clinical history of myocardial infarction. Two-dimensional echocardiographic and electrocardiographic changes during epinephrine infusion (Table I and Fig. 2 and 3): Table II lists 2-D echo and ECG changes in relation to the number of coronary vessels involved. In 12 patients we observed an increased degree of asynergy and in 5 patients new wall motion abnormalities were seen in segments that were considered normal at basal condition. Four patients with angiographic evidence of CAD had severe chest pain during the test; 3 of these patients had combined 2-D echo and ECG abnormalities and 1 patient had only ischemic ST changes. The onset of ventricular arrhythmias was observed in 3 patients (6.6%). Of 35 patients with angiographic * evidence of CAD, only 2 (5.7%) had life-threatening ventricular arrhythmias during the test (ventricular tachycardia in 1 and ventricular bigeminy in 1). Only 1 of these 2 patients had myocardial asynergy during the test before the appearance of arrhythmias. One patient
2DE O/ECG
0
Total
9 10 19 ECG sensitivity ECG specificity
35 IO 45 (%) = 74 (% ) = 100
2DE 0 = absence
of myocardial
without CAD had ventricular bigeminy. All arrhythmias promptly disappeared on terminating the infusion, without need of pharmacologic intervention. The test was terminated in 3 patients because of onset of ventricular arrhythmias and in 22 patients because of ST-segment depression. No patient had to stop the test because of the appearance of isolated chest pain without ischemic ST changes. Furthermore, we did not have to administer intravenous propranolol to reverse significant adverse effects. Site of mechanical and electrical abnormalities developing during epinephrine infusion: Wall motion abnormalities were posteroinferior and lateral in 7 patients, anterior and septal in 4, posteroinferior in 2, lateral in. 2, septal in 1 and apical in 1 patient. STsegment depression was observed in the anterolateral leads of all patients with a positive ECG test response. Reproducibility of the test: Twenty of 45 patients in our study group repeated the test at least 48 hours after the first examination. The second test was graded by observers who had no knowledge of the first test. In 19 patients the epinephrine test was reproducible. Only 1
FIGURE 2. Apical 4-chamber view at end-diastole (ED) and end-systole (ES). In the basal condition, contractility of septal, lateral and apical segments results are normal and there is no evidence of electrocardiographic abnormalities. During epinephrine infusion, a clear dyskinesla of the apical tract of the interventricular septum occurs; in this patient the electrocardiogram remains unchanged.
August
TABLE II Epinephrine Test: Coronary Vessels Involved
Echocardiographic
1, 1986
THE AMERICAN
and Electrocardiographic
JOURNAL
OF CARDIOLOGY
Findings
and Number
Volume
58
259
of
No. of Patients 2DE +/ECG 3VD 2VD 1 VD Total
0
2DE OlECG
1 1 2 4
2 DE sensitivity (%) ECG sensitivity (%) 2DE plus ECG sensitivity
+
2DE + IECG
2 6 1 9
(%)
2DE 0 /EGG 0
5 7 1 13
1 3 5 9
3VD
2VD
IVD
67 78 89
47 76 82
33 22” 44
* p <0.05 vs 3 VD and 2 VD. 2DE i- = presence of myocardial asynergy; 2DE 0 = absence depression: ECG 0 = ST segment normal; VD = vessel disease.
patient had an anomalous increase of diastolic pressure compared with the first study, while ECG and mechanical findings remained unchanged.
Discussion Schechter et al7 suggested that epinephrine infusion in physiologic doses could be a useful tool for detecting CAD, and demonstrated the safety of this test in patients with coronary narrowings. They showed that this test may be considered an acceptable alternative to exercise stress testing for identifying patients with CAD. In this investigation, we demonstrated that 2-D echo study during epinephrine infusion is a complement to ECG monitoring, offering useful information about the site of ischemia and the relations between mechanical dysfunction and electrical changes.
FIGURE 3. Apical 4-chamber view at end-diastole (ED) and end-systole (ES). In the basal condition and during epinephrine infusion, myocardial contractility appears to be normal; clear STsegment depression occurs during the test.
+
of myocardial
asynergy;
Total 9 17 9 35
ECG i- = ST-segment
Sensitivity and specificity: In our study, ECG and 2-D echo sensitivity were 63% and 48.5‘70, respectively. These data are different from those reported by Shechter et a1,7 who found an ECG sensitivity of 87%. The larger study population and the relatively low prevalence of 3-vessel disease in patients examined in our investigation may justify the different values of sensitivity. Most important, combined 2-D echo and ECG criteria of a positive test yielded a sensitivity of 74%. The high specificity reported by Shechter (100%) is confirmed in our study by the absence of ECG and 2-D echo false-positive results. Subgrouping the patients according to severity of CAD, we observed a higher 2-D echo and ECG sensitivity of the test in patients with 3- and Z-vessel disease than in patients with l-vessel disease. However, this
260
EPINEPHRINE-INDUCED
MYOCARDIAL
ISCHEMIA
‘difference achieved statistical significance only for ECG sensitivity in patients with 3- and X-vessel disease vs those with l-vessel disease. Mechanisms of epinephrine-induced ischemia: Epinephrine infusion produces an increase in myocardial oxygen consumption through changes in heart rate, systolic blood pressure and ventricular inotropism. Furthermore, the decrease in diastolic time and in diastolic blood pressure are 2 other possible factors provoking myocardial ischemia. These combined mechanisms explain induction of ischemia at a lower rate-pressure product compared with exercise testing. Relation between electrocardiographic and 2-dimensional echocardiographic findings: Many experimentaP-I3 and clinical studie+l6 indicate that during acute myocardial ischemia left ventricular mechanical abnormalities can precede the appearance of ischemic ECG changes or represent the only expression of myocardial ischemia. During episodes of Prinzmetal’s angina, Distante et a114J5showed the presence of echocardiographic signs of ischemia in the absence of both ST-segment changes and angina1 pain. Sugishita et all6 demonstrated that regional myocardial dysfunction during exercise echocardiography in patients with angina pectoris is an earlier indicator of ischemia than ST-segment changes. Furthermore, these observations are confirmed by 2-D echo studies performed during the dipyridamole test in patients with CAD.17 In our study, 13 of 35 patients with CAD showed both ECG and 2-D echo signs of ischemia, 4 had wall motion abnormalities only and 9 had ECG changes without 2-D echo signs of ischemia. Although it is known that mechanical abnormalities during myocardial ischemia may or may not be combined with ischemic ST changes and angina1 pain, the significance of isolated ECG alterations without evidence of mechanical dysfunction observed during epinephrine infusion is unclear. Our investigation does not address this issue. We suggest some hypotheses: (1) ST-segment depression may not always represent a specific marker of ischemia as suggested by the presence of false-positive ECG findings during exercise stress test. (2) Hyperkinesia induced by /3-adrenergic stimulation could mask small areas of ischemic asynergies responsible for ECG changes. (3) The qualitative analysis of 2-D echocardiograms may not in all cases allow recognition of the presence of regional myocardial asynergy. Site of ischemia: Our results show that ECG leads showing ST-segment depression do not reflect the true site of ischemia in patients with combined ECG and mechanical abnormalities induced by epinephrine. This observation is in agreement with studies reported
by other investigators17-lg using different tools for unmasking latent myocardial ischemia. Safety of the test: Our results suggest that epinephrine infusion at physiologic doses is safe. In fact, the onset of ventricular arrhythmias was observed in only 3 of 45 patients studied (6.6%). Furthermore, these arrhythmias promptly disappeared on terminating the infusion, without need of pharmacologic intervention. Acknowledgment: We are grateful to Mary Spears for reviewing this manuscript for English language.
References 1. Crawford MH, Amon KW, Vance WS. Exercise Z-dimensional echocardiography. Quantitation of left ventricular performance in patients with severe angina pectoris. Am / Cardiol 1983;51:1-6. 2. Mason S]. Weiss JL, Weisfeldt M, Garrison jB, Fortuin NJ. Exercise echocardiography: detection of wall motion abnormalities during ischemia. Circulation
1979;59:50-59.
3. Maurer G, Nanda NC. Two dimensional echocardiographic evaluation of exercise-induced left and right ventricular asynergy: c&r&ation with thalliurn scanning. Am J Cardiol 1981;48:720-727. 4. Morganroth 1. Chen CC, David D, Sawin HS. Naito M, Parrotto C, Meixell L. Exercise cross-sectional echocardiographic diagnosis of coronary artery disease. Am r Cardiol 1981;47:20-26. 5. Robertson WS. Feigenbaum H, Armstrong WF, Dillon JC, O’Donnel 1, McHenry PW. Exercise echocardiography: a clinically practical addition in the evaluation of coronary artery disease. [ACC 1983;2:1085-1091. 6. Wann LS, Faris JV, Childress RH. Dillon ]C, Weyman AE, Feigenbaum H. Exercise cross sectional echocardiography in ischemic heart disease. Circulation
1979:60:1300-1308.
7. Schechter E, Wilson MF, Kong YS. Physiologic responses to epinephrine infusion: the basis for a new stress test for coronary artery disease. Am Heart 1 19t?3;105:554-560. 8. Sones FM Jr, Shirey EK. Cinecoronary arteriography. Mod Concepts Cardiovasc Dis 1962;31:735-741. 9. judkins MP. Selective coronary arteriography. Radiology 1967;89:815-818. 10. Snedecor GW, Cochran WG. Statistical Methods. 6th ed. Ames, IA: Iowa State University Press, 1980:221. 11. Battler A, Froelicher VF. Gallagher KP, Kemper WS, Ross J Jr. Dissociation between regional myocardial dysfunction and ECG changes during ischemia in the conscious dog. Circulation 1980;62:735-744. 12. Pandian NG, Kerber RE. Two-dimensional echocardiography in experimental coronary occlusion. Part I. CircuIation 1982;66:597-602. 13. Pandian NG, Kieso RA. Kerber RE. Two-dimensional echocardiography in experimental coronary stenosis. Part II. Circulation 1982;66:603-611. 14. Distante A, Rovai D, Picano E, Moscarelli E, Palombo C, Morales MA, Michelassi C, L’Abbate A. Transient changes in left ventricular mechanics during attacks of Prinzmetal angina: an M-mode echocardiographic study. Am Heart [ 1984;107:465-470. 15. Distante A, Rovai D, Picano E, Moscarelli E, Morales MA, Palombo C, L’Abbate A. Transient changes in left ventricular mechanics during attacks of Primmetal aneina: a two-dimensional echocardiomaohic studv. Am Heart I " 1984;108:440-426.
16. Sugishita Y, Koscki S, Matsude M, Tamura T, Yamaguchi I, Ito I. Dissociation between regional myocardial dysfunction and ECG changes during myocardial ischemk induced by exercise in patients with angina pectoris. Am Heart 1 1983;106:1-8. 17. Picano E, Distante A, Masini M, Morales MA, Lattanzi F. L’Abbate A. Dipyridamole-echocardiography test in effort angina pectoris. Am r Cardiol 1985;56:452-456.
18. Kaolan MA, Morris GN, Aconow WS, Parker DP, Ellestad MH. Inability of the >ubmaximaI treadmill stress test to predict the location of corona& disease. Circulation 1973;47:250-256. 19. Fow RM, Makki A, Iskandrian AS. Relation between electrocardiographic and scintigraphic location of myocardial ischemia during exercise in one vessel coronary artery disease. Am 1 Cardiol 1984;53:1529-1531.
Two-dimensional echocardiographic (2-D echo) and electrocardiographic (ECG) monitoring was performed in 53 patients with angina1 chest pain during infusion of physiologic doses of epinephrine. Technically adequate 2-D echo studies were recorded in 45 patients. Df these 45 patients, 35 had significant coronary artery disease. Twenty-two patients showed ECG changes during the test (ECG sensitivity 63% ), 13 of whom also showed wall motion abnormalities (2-D echo sensitivity 46.5% ). Corn: bined ECG and 2-D echo criteria of a positive test
yielded a sensitivity of 74%. None of the 10 patients without coronary artery disease had electricat or mechanical abnormalities during the test (specificity 100 % ). Thus, the eplnephrine test durfng simultaneous 2-D echo and ECG monitoring is a valid alternative to echocardlographic exercise stress testing. Furthermore, the adequate images obtained during the infusion allow better investigation of relation between wall motion abnormalfties and ECG changes during myocardial ischemia. ‘(Am J Cardiol 1966;56:256-260)
T i wo-dimensional echocardiography (2?D echo) during or immediately after the exercise stress testing is useful for detecting coronary artery disease (CAD).1-6 However, some patients cannot perform the exercise load needed [e.g., those with musculoskeletal, neurologic or obstructive lung disease]. Furthermore, goodquality echocardiograms suitable for analysis are difficult to record whiie the patient is actively moving and the lungs are overinflated during exercise.3 Schechter et al7 reported that the infusion of physiologic doses of epinephrine is a useful stress test in patients with CAD, reporting high values of electrocardiographic (ECG) sensitivity and specificity. In this investigation, we evaluated the effects of physiologic doses of epinephrine on mechanical function of the left ventricle
in patients with typical and atypical chest pain suspected to be caused by myocardial ischemia, and established the relation between ~311 motion abnormalities detected by 2-D echo and. ,ECG changes during epinephrine-induced myocardial ischemia.
Methods We prospectively studied 53 patients (43 men, 10 women, mean age 51 f 8 years) referred for angiographic evaluation of chest pain suspected to be caused by myocardial ischemia. Patients with valvular heart disease, congestive heart failure or severe ventricular arrhythmias were excluded from the study. Calcium antagonist and nitrate therapy had been discontinued for at least 48 hours and P-blocking drug therapy for at least 14 days before the test. Patients avoided coffee and tea for at least 3 hours before the test. Nineteen patients had a clinical history of myocardial infarction. A solution with epinephrine concentration of 4 pg/ml was infused intravenously at dose rates of 0.03, 0.06, 0.12, 0.18, 0.24 and 0.30 rg/kg/min by means of a calibrated infusion pump. The duration of infusion for each dose level was 5 minutes. ECG monitoring in the 12 standard leads was performed throughout the test and~ECG traces were recorded before infusion, at the first; third and fifth minute of each infusion step, at the
From the Istituto di Medicina Interna, Cardiologia e Chirurgia Cardiovascolare, I Cattedra di Medicina Interna, II Facolta di Medicina e Chirurgia, Napoli, and the Fondazione Clinica de1 Lavoro, Centro Medico di Riabilitazione, Campoli M.T., Benevento. Italy. This study was supported in part by Grant 8402483.56 from the CNR, Italy. Manuscript received January 3, 1986; revised manuscript received March 19, 1986, accepted March 20, 1986. Address for reprints: Nicola Ferrara, MD, I Cattedra di Medicina Interna, II Facolta di Medicina e Chirurgia, Via S. Pansini 5, 80131 Napoli, Italy: 256
August
1, 1986
THE AMERICAN
JOURNAL
OF CARDIOLOGY
Volume
257
58
T P’O. 001 loo_ Pulse
beotdmin
60 80!
-
180
P
p
140
FIGURE 1. Hemodynamic changes induced by epinephrine infusion. At peak of the test a significative increase in heart rate, systolic blood pressure (BP) and double product (D.P.) is observed. Diastolic BP decreases in comparison to basal values.
BASAL
PEAK
0. P. x 102 1
100
1ao-
p
60
12 BASAL
PEAK
p
I--
--. 1
r BASAL
first, third and fifth minute after termination of infusion and every 5 minutes until return to baseline. Arterial blood pressure was measured at the same time in the arm opposite to the infusion with a cuff sphygmomanometer. Parenteral propranolol (10 mg intravenously] was available to reverse significant adverse effects. The test was terminated before the maximal dose was administered if the patient had significant ventricular arrhythmias, ischemic ST changes or severe chest pain. The ECG criterion for a positive response was horizontal or downsloping ST-segment depression of 0.1 mV or more at the J point lasting longer than 80 ms. Real-time 2-D echo evaluation was performed with the patient in the 30“ to 60’ left lateral decubitus position before, during and after epinephrine infusion using a wide-angle (105’) mechanical sector scanner (Elscint Dynex/c). Images were recorded in the standard parasternal and apical transducer position. Particular attention was given to apical 4- and 2-chamber views and the parasternal short-axis plane. For the purpose of analysis, the left ventricle was separated into 5 segments (anterior, septal, lateral, posteroinferior and apicaQ4 The motion patterns of the individual segments were described as normal, hypokinetic, akinetic, dyskinetic and hyperkinetic. The images were displayed in real time at a rate of 20 frames/s and were recorded by means of l/&nch VHS tape (National Panasonic NV 8200) cassette recorder. The initial echocardiographic examination was performed to record baseline images, explore the cardiac windows and establish the transducer position from which optimal images could be recorded. The transducer position and 2-D echo planes established during the baseline examination facilitated rapid and optimal studies. Echocardiograms at basal condition and during the test were graded independently by 2 observers; in the event of disagreement, a third observer reviewed the case and the majority judgment was binding. Technically adequate 2-D echo studies suitable for analysis
PEAK
were recorded in 45 of 53 patients (85%) and only data from these 45 patients were analyzed. Seventeen of the 45 patients examined presented a clinical history of myocardial infarction. Of the 45 studies analyzed, the interpretation of the test was unanimous in 43 (95%). Cardiac catheterization was performed in all patients using the Sones or Judkins technique.8pg Significant CAD was defined as a decrease of 75% in luminal diameter of at least 1 of the major coronary arteries. The angiographic data were analyzed in the standard fashion by 2 observers who had no knowledge of the results of the test. Statistical analysis: The values of hemodynamic parameters were expressed as the mean f standard deviation. The differences between values obtained at basal condition and at the maximal epinephrine dose were analyzed by the paired t test. The differences between 2-D echo, electrocardiography and 2-D echo plus ECG sensitivity in patients with 3-, 2- and l-vessel disease were analyzed by Fisher’s exact testLo A p value <0.05 was considered significant.
Results Angiographic data: Thirty-five of 45 patients studied showed significant coronary stenoses at cardiac catheterization. Nine patients had l-vessel, 17 had 2vessel and 9 had 3-vessel disease. Hemodynamic changes during epinephrine infusion: With increasing infusion rate, heart rate increased from 75 f 11 to 94 f 15 beats/min (p
255
EPINEPHRINE-INDUCED
TABLE
MYOCARDIAL
I
ISCHEMIA
Epinephrine
Test:
Echocardiographic
and Electrocardiographic
Findings
No. of Patients 2DE +/ECG Presence Absence Total
of CAD of CAD
2DE sensitivity 2DE specificity
(%) = 48.5 (%) = 100
0
4 0 4
2DE O/ECG
+
9 0 9 ECG sensitivity ECG specificity
(%) = 63 (%) = 100
2DE +IECG
+
13 0 13 2DE plus 2DE plus
CAD = coronary artery disease: 2DE + = presence of myocardial asynergy; asynergy; ECG -I- = ST-segment depression; ECG 0 = ST segment normal.
epinephrine infusion). Thirteen of these 22 patients had a clinical history of myocardial infarction. Two-dimensional echocardiographic and electrocardiographic changes during epinephrine infusion (Table I and Fig. 2 and 3): Table II lists 2-D echo and ECG changes in relation to the number of coronary vessels involved. In 12 patients we observed an increased degree of asynergy and in 5 patients new wall motion abnormalities were seen in segments that were considered normal at basal condition. Four patients with angiographic evidence of CAD had severe chest pain during the test; 3 of these patients had combined 2-D echo and ECG abnormalities and 1 patient had only ischemic ST changes. The onset of ventricular arrhythmias was observed in 3 patients (6.6%). Of 35 patients with angiographic * evidence of CAD, only 2 (5.7%) had life-threatening ventricular arrhythmias during the test (ventricular tachycardia in 1 and ventricular bigeminy in 1). Only 1 of these 2 patients had myocardial asynergy during the test before the appearance of arrhythmias. One patient
2DE O/ECG
0
Total
9 10 19 ECG sensitivity ECG specificity
35 IO 45 (%) = 74 (% ) = 100
2DE 0 = absence
of myocardial
without CAD had ventricular bigeminy. All arrhythmias promptly disappeared on terminating the infusion, without need of pharmacologic intervention. The test was terminated in 3 patients because of onset of ventricular arrhythmias and in 22 patients because of ST-segment depression. No patient had to stop the test because of the appearance of isolated chest pain without ischemic ST changes. Furthermore, we did not have to administer intravenous propranolol to reverse significant adverse effects. Site of mechanical and electrical abnormalities developing during epinephrine infusion: Wall motion abnormalities were posteroinferior and lateral in 7 patients, anterior and septal in 4, posteroinferior in 2, lateral in. 2, septal in 1 and apical in 1 patient. STsegment depression was observed in the anterolateral leads of all patients with a positive ECG test response. Reproducibility of the test: Twenty of 45 patients in our study group repeated the test at least 48 hours after the first examination. The second test was graded by observers who had no knowledge of the first test. In 19 patients the epinephrine test was reproducible. Only 1
FIGURE 2. Apical 4-chamber view at end-diastole (ED) and end-systole (ES). In the basal condition, contractility of septal, lateral and apical segments results are normal and there is no evidence of electrocardiographic abnormalities. During epinephrine infusion, a clear dyskinesla of the apical tract of the interventricular septum occurs; in this patient the electrocardiogram remains unchanged.
August
TABLE II Epinephrine Test: Coronary Vessels Involved
Echocardiographic
1, 1986
THE AMERICAN
and Electrocardiographic
JOURNAL
OF CARDIOLOGY
Findings
and Number
Volume
58
259
of
No. of Patients 2DE +/ECG 3VD 2VD 1 VD Total
0
2DE OlECG
1 1 2 4
2 DE sensitivity (%) ECG sensitivity (%) 2DE plus ECG sensitivity
+
2DE + IECG
2 6 1 9
(%)
2DE 0 /EGG 0
5 7 1 13
1 3 5 9
3VD
2VD
IVD
67 78 89
47 76 82
33 22” 44
* p <0.05 vs 3 VD and 2 VD. 2DE i- = presence of myocardial asynergy; 2DE 0 = absence depression: ECG 0 = ST segment normal; VD = vessel disease.
patient had an anomalous increase of diastolic pressure compared with the first study, while ECG and mechanical findings remained unchanged.
Discussion Schechter et al7 suggested that epinephrine infusion in physiologic doses could be a useful tool for detecting CAD, and demonstrated the safety of this test in patients with coronary narrowings. They showed that this test may be considered an acceptable alternative to exercise stress testing for identifying patients with CAD. In this investigation, we demonstrated that 2-D echo study during epinephrine infusion is a complement to ECG monitoring, offering useful information about the site of ischemia and the relations between mechanical dysfunction and electrical changes.
FIGURE 3. Apical 4-chamber view at end-diastole (ED) and end-systole (ES). In the basal condition and during epinephrine infusion, myocardial contractility appears to be normal; clear STsegment depression occurs during the test.
+
of myocardial
asynergy;
Total 9 17 9 35
ECG i- = ST-segment
Sensitivity and specificity: In our study, ECG and 2-D echo sensitivity were 63% and 48.5‘70, respectively. These data are different from those reported by Shechter et a1,7 who found an ECG sensitivity of 87%. The larger study population and the relatively low prevalence of 3-vessel disease in patients examined in our investigation may justify the different values of sensitivity. Most important, combined 2-D echo and ECG criteria of a positive test yielded a sensitivity of 74%. The high specificity reported by Shechter (100%) is confirmed in our study by the absence of ECG and 2-D echo false-positive results. Subgrouping the patients according to severity of CAD, we observed a higher 2-D echo and ECG sensitivity of the test in patients with 3- and Z-vessel disease than in patients with l-vessel disease. However, this
260
EPINEPHRINE-INDUCED
MYOCARDIAL
ISCHEMIA
‘difference achieved statistical significance only for ECG sensitivity in patients with 3- and X-vessel disease vs those with l-vessel disease. Mechanisms of epinephrine-induced ischemia: Epinephrine infusion produces an increase in myocardial oxygen consumption through changes in heart rate, systolic blood pressure and ventricular inotropism. Furthermore, the decrease in diastolic time and in diastolic blood pressure are 2 other possible factors provoking myocardial ischemia. These combined mechanisms explain induction of ischemia at a lower rate-pressure product compared with exercise testing. Relation between electrocardiographic and 2-dimensional echocardiographic findings: Many experimentaP-I3 and clinical studie+l6 indicate that during acute myocardial ischemia left ventricular mechanical abnormalities can precede the appearance of ischemic ECG changes or represent the only expression of myocardial ischemia. During episodes of Prinzmetal’s angina, Distante et a114J5showed the presence of echocardiographic signs of ischemia in the absence of both ST-segment changes and angina1 pain. Sugishita et all6 demonstrated that regional myocardial dysfunction during exercise echocardiography in patients with angina pectoris is an earlier indicator of ischemia than ST-segment changes. Furthermore, these observations are confirmed by 2-D echo studies performed during the dipyridamole test in patients with CAD.17 In our study, 13 of 35 patients with CAD showed both ECG and 2-D echo signs of ischemia, 4 had wall motion abnormalities only and 9 had ECG changes without 2-D echo signs of ischemia. Although it is known that mechanical abnormalities during myocardial ischemia may or may not be combined with ischemic ST changes and angina1 pain, the significance of isolated ECG alterations without evidence of mechanical dysfunction observed during epinephrine infusion is unclear. Our investigation does not address this issue. We suggest some hypotheses: (1) ST-segment depression may not always represent a specific marker of ischemia as suggested by the presence of false-positive ECG findings during exercise stress test. (2) Hyperkinesia induced by /3-adrenergic stimulation could mask small areas of ischemic asynergies responsible for ECG changes. (3) The qualitative analysis of 2-D echocardiograms may not in all cases allow recognition of the presence of regional myocardial asynergy. Site of ischemia: Our results show that ECG leads showing ST-segment depression do not reflect the true site of ischemia in patients with combined ECG and mechanical abnormalities induced by epinephrine. This observation is in agreement with studies reported
by other investigators17-lg using different tools for unmasking latent myocardial ischemia. Safety of the test: Our results suggest that epinephrine infusion at physiologic doses is safe. In fact, the onset of ventricular arrhythmias was observed in only 3 of 45 patients studied (6.6%). Furthermore, these arrhythmias promptly disappeared on terminating the infusion, without need of pharmacologic intervention. Acknowledgment: We are grateful to Mary Spears for reviewing this manuscript for English language.
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