- Email: [email protected]
Comparison of electrocardiography and thallium-201 myocardial scintigraphy for the detection of ergonovine-induced coronary artery spasm: Angiographic correlation
Comparison of electrocardiography and thallium-201 myocardial scintigraphy for the detection of ergonovine-induced coronary artery spasm: Angiographic correlation This study was performed to determine the sensitivity of thallium imaging vs ECG monitoring for detecting coronary artery spasm noninvasively followlng intravenous ergonovlno administration as compared to simuftaneous coronary angiography. Thirty-two patients with insignificant coronary artery disease and chest pain underwent 12-lead ECG monitoring, thaltium imaging, and coronary irterlography tottowing the adminlstration of 0.05, 0.1, 0.2, and 0.3 mg of ergonovine given 5 minutes apart or until chest pain occurred. One minute following the last dose of ergonovine, 2.5 mCi of thallium-201 was injected intravenously, and a final ECG was recorded and repeat coronary arteriography performed. Within 10 minutes following the injection of thallium, imaging was performed in the 4O-degree and 7Wegree left anterior oblique and anterior projections. The ECG, thallium study, and coronary arteriogram were read blindly and results were compared. The ECG, anglogram, and thallium study were read as positive if the following occurred, respectively: 11 mm ST segment elevation, depression,. or T wave reversal; greater than SO% vessel narrowing,; and reversible perfusion defect. Five patients were excluded from analysis because of either catheter-induced spasm, suboptimal thallium studies, or protocol violations. Of the 27 patients included for analysis, six had chest paln, five had a positive angiogram, five had a positive thallium study, and one had a positive ECG. The sensitivity of thallium vs ECG monltoring was 80% VI 25%, and the accuracy was 92% vs 80%. We conclude that thallium imaging greatly increases the noninvasive detection of ergonovine-induced coronary spasm as compared with the ECG with no loss of accuracy. (AM HEART J 1987;113:663.)
Jeffrey G. Shanes, M.D., Dan Pavel, M.D., Michael Blend, Ph.D., D.O., Enrique Olea, M.D., Ronald Krone, M.D., Kathy Lacny, Michael Marmulstein, Robert Malik, M.D., Carol Meyer, M.D., and George T. Kondos, M.D. Chicago, Ill., and St. Louis, MO.
Patients with chest pain and normal or insignificantly diseased coronary arteries may have coronary artery spasm as the etiology for symptoms.l~ 2 In such patients administration of ergonovine during ECG monitoring has been demonstrated to be a safe, noninvasive method for diagnosing coronary artery spasm.3s4 Recently, we reported our results with simultaneous thallium imaging and ECG monitoring during ergonovine administration in patients with
M.D.,
chest pain and recent coronary arteriography demonstrating insignificant coronary artery disease.5 In that group of 100 patients thallium imaging proved more sensitive than ECG monitoring for detecting coronary spasm. The purpose of this study was to validate our previous findings by comparing ECG monitoring and thallium imaging to simultaneously performed coronary arteriography during administration of ergonovine. METHODS
From the Department of Medicine, Cardiology Section, and the Department of Radiology, Nuclear Medicine Section, University of Illinois School of Medicine, and the Department of Medicine, Cardiology Section, Washington University. Supported in part by a National Institutes of Health Biomedical Research Grant. Received for publication April 14, 1986; accepted July 2, 1986. Reprint requests: Jeffrey G. Shanes, M.D., Cardiology Section, University of Illinois Hoepital, PO Box 6998, Chicago, IL 60680.
All patients undergoing coronary arteriography because of symptoms of chest pain were recruited for study. Calcium channel blockers were discontinued at least 24 hours prior to study and long-acting nitrates, at least 4 hours prior to study. Routine right and left heart catheterization, left ventricular angiograpby, and coronary arteriography were performed. Video imagee of the coronary arteriograms were reviewed and if no &e&graphic lumi663
March
664
Shanes
et al.
Table
I. Patient response
American
Agel Patient
No.
9
Baseline CA
yr
Sex
Control
57 53 53 47 30 55 34
F F F F M M M
72
M
N N N N P P Mild disease proximal LAD N
51
F
N
EGG
Site of ST shift
NSSTT N NST NST QII,III,aVF N Q waves VI-V, RBBB LAFB NST V,-V,
Thallium defect
Chest pain
Heart
1997 Journal
Postergonovine CA
Inferior N N Inferior AS
Present Present Present Present Present Present None
MDN MDN RCA 50% -75% MDN LAD 50% -75% RCA 50% -75% LAD 50%-75%
NC
AS
None
LAD 50% -75%
NC
Inferior
None
MDN
NC NC T V, NC NC NC NC
N N
Abbreviations: AS = anteroseptak CA = coronary erteriography; LAD = left anterior descending coronary artery; MDN = mild diffuse narrowing (insignificant); N = normal, NC = no change; NST = nonspecific T wave changes; NSSTT = nonspecific ST and T wave changes; P = mild plaquing; RCA = right coronary artery.
Table
II. Patients excluded
Patient No.
Agel
10
46
F
11
55
FP
12
42
F
13
49
14
39
(~4
Baseline CA
Sex
Proximal RCA catheter spasm 75%-100%
Control
ECG
Site of ST shift
Thallium defect
Chest pain
Postergonovine CA
Reason for exclusion
T I,III,AVF v,-v,
NC
Inferior
None
Normal
Catheter-induced spasm
N
NC
Suboptimal
Mild
MDN
Mild proximal RCA catheter spasm
N
NC
Normal
None
F
N
N
NC
Suboptimal
Present
F
N
Nonspecific T wave abnormality
ST II,III,AVF
AS
Present
Severe proximal RCA catheterinduced spasm Severe proximal RCA catheterinduced spasm Total RCA
S&optimal thallium Catheter-induced spasm
S&optimal thallium and catheter-induced spasm Intracoronary nitroglycerin administered before thallium
Abbreviations: AS = anteroseptal; CA = coronary arteriography; MDN = mild diffuse narrowing (insignificant); N = normal, NC = no change; P = mild plaquing; RCA = right coronary artery.
nal narrowing greater than 50% was seen, ergonovine
intervals following each bolus injection
tasting wasperformed. Patients with significcmt coronary narrowing were not given ergonovine and will not be discussedfurther. Er~onov&~e tcNthtg. Following the demonstration of insignificant coronary artery disease,a portable gamma camera and 12-lead ECG machine were moved into the catheterization laboratory. A la-bad ECG was then
blood pressureand la-lead ECG were recorded. Ergonovine administration wasterminated before the 0.3 mg dose if a classicECG responseoccurred (greater than 2 mm ST segment elevation) or if the patient developed typical symptoms of chest pain. Foilowing the final dose of ergonovine, 2.6 mCi of thallium-201 was injected intrave-
of ergonovine,
obtained. Then, at 4-minute intervals, b&s injections of ergonovine maleate were administered intravenously in
nously. Repaat~ coronary arteriography was rapidly performed and within 10 minutes, data acquisition on the gamma camera was begun. Forty-degree left anterior
this sequence:0.05, 0.1, 0.2, and 0.3 mg. This dosing and sequencehas been previously deacribad.“6 At 3-tiinute
oblique, anterior, and 70-degree left anterior oblique imagesin the catihebrkation laboratory were obtaiied.
Volume113 Number 3
Thallium us ECG detection
Following completion of the study, arterial and venous sheaths were removed and the patients returned to their rooms. Four hours after the initial study, redistribution images were obtained. Patient safety. Before ergonovine was administered, a 500 cc solution of nitroglycerin was prepared and made available for intravenous or intracoronary use. If severe coronary artery spaamoccurred that, in the opinion of the cardiologist performing the procedure, made withholding nitroglycerin therapy until after thallium imaging unsafe, sublingual, intravenous, or intracoronary nitroglycerin was immediately administered as clinically indicated. This occurred in one patient and those data were analyzed separately. Informed consentwasobtained prior to catheterization in each case,and the protocol was approved by the institutional review board at the University of Illinois. Data analysis. Thallium images were read by three observers (DP, EO, and MB) without knowledge of the ECG or angiographic results. The final interpretation in each study was agreed upon by consensus.A study was considered positive for coronary spasm if an area of hypoperfusion was noted during the initial study with reperfusion occurring on the follow-up scan. The location of the defect was noted in each case. The coronary angiogramswere interpreted by two observers(GTK and JGS) without knowledge of the thallium or ECG results, with no differences occurring in interpretation. An angiogram was read as positive for spasmif greater than 50% narrowing occurred in a coronary segmentascomparedto the same segment prior to ergonovine administration, whether focal or diffuse. The ECGs were alsointerpreted blindly, without knowledgeof the thallium or angiographic results (MM) and were read as positive if an equal to or greater than lmm ST segmentelevation, depression,or T wave reversal occurred. The sensitivity and accuracy of thallium imaging and ECG monitoring were determined by comparing the results obtained for each technique to the coronary arteriogram obtained immediately following ergonovine administration. The sensitivity of thallium imaging and ECG monitoring wasdetermined for eachtest asthe number of positive tests (thallium or ECG) divided by the total number of angiographic studiespositive for spasm.The specificity of thallium imagingand ECG monitoring wasdetermined for each test asthe total number of negative tests (thallium or ECG) divided by the total number of angiographicstudies negative for spasm.The predictive accuracy of thallium imaging and ECG monitoring was determined for each test by adding the number of patients with positive tests (ECG or thallium) and angiogramspositive for spasmplus the number of patients with negative tests (ECG or thallium) and angiogramsnegative for spasmdivided by the total number of patients. RESULTS
Thirty-two
patients
were found to have insignifi-
cant coronary artery disease and were given ergono-
+
of
coronary spasm 665
m7%7mphy -
+ Total
thallium
+ ECG
-----------.
Fig. 1. Resultsof thallium imaging and ECG monitoring vs coronary angiography.
vine according to our protocol. Five patients were excluded from analysis because of either catheterinduced spasm, suboptimal thallium imaging, or protocol violation. These patients will be discussed separately. Of the 27 patients who had adequate thallium studies and fulfilled the study protocol, five patients developed angiographic spasm, five had a positive thallium study, one had a positive ECG response, and six developed chest pain. The clinical, angiographic, and ergonovine test data of these patients are given in Table I. The results of thallium imaging and ECG monitoring vs coronary angiography are illustrated in Fig, 1. Based on these results the calculated sensitivity of thallium imaging vs ECG monitoring was 89% vs 25% and accuracy was 92 % vs 85 % . Five patients were excluded from analysis and data on these patients are summarized in Table II. Patient No. 10 had persistent catheter-induced spasm of the right coronary artery prior to adminis-
tration of ergonovine.This correlated with a thallium defect in the inferior wall that reperfused on delayed imaging. No ECG changes or chest pain occurred in this patient. Patient No. 12 developed severe catheter-induced spasm of the right coronary artery following administration of ergonovine but developed neither chest pain nor ECG changes, and
666
Shanes et al.
Amwkan
March 1987 Heart Journal
Fig. 2. Left anterior oblique projection of right coronary artery. A, Prior to ergonovine administration, vesselappearsnormal. B, After intravenous administration of 0.65 mg ergonovine, total occlusionof vessel occurred.
the thallium study was normal. Patient No. 13 also was excluded because of intense catheter-induced spasm of the right coronary artery following administration of ergonovine. However, thallium imaging in this patient who developed chest pain was suboptimal for interpretation, as was the study of patient No. 11, who also had mild chest pain but no ECG changes or angiographic spasm. Follow-up gastrointestinal studies in this patient demonstrated esophageal spasm. Patient No. 14 was excluded because of a break in the protocol. In this patient, following administration of the last dose of ergonovine, total occlusion of the right coronary artery developed (Fii. 2) in association with severe chest pain and ST segment elevation in leads II, III, and aVr which, in the opinion of the cardiologist performing the procedure, warranted the immediate administration of intracoronary nitroglycerin. Thus, intracoronary nitroglycerin was administered prior to thallium imaging. Thallium imaging in this patient showed relative hypoperfusion of the septum with redistribution on follow-up images (Fig. 3). Adverse reactions aRd eomptio&ions. No complications occurred in any patient. The most &equent adverse reaction was nausea sometimes acoompanied by vomiting. tgustrative case. Patient No. 6, a 55-year-old white man, underwent cardiac catheterixation and coronary angiography for symptoms of chest pain, both
exertional and at rest, for 8 years. Treadmill testing, which was limited by shortness of breath, was inconclusive for coronary disease because of the low work load achieved. Positive risk factors, including cigarette smoking, hypertension, and a strong family history, were present. Coronary angiography revealed only mild difIuse plaquing of the entire coronary tree and therefore ergonovine was given. Following the 6nal dose of ergonovine the patient developed typical chest pain but no ECG changes occurred (Fig. 4). However, coronary angiography revealed significant spasm in the proximal right coronary artery, about 70% (Fig. 5). Thallium imaging performed during this study demonstrated a defect in the lower septum, apex, and inferior-lateral walls with redistribution on delayed imaging (Fig. 6). Quantitative computer processing confirmed these findings. DISCUSWON
Coronary artery spasm may produce symptoms of ischemia in patients with normal or minimally diseased coronary vessels.Ergonovine has been used to provoke coronary spasm for purposes of diagnosis in such patients.1~2Several studies have demonstrated the safety of performing ergonovine provocation outside the catheterization laboratory when done in a coronary care unit or similar setting. Most such studies have used ECG monitoring alone to detect
Volum* Number
113 3
Thallium us ECG detection of coronary spasm 667
Fig. 3. Initial postergonovineand delayed thallium-201 scan in 40-degreeleft anterior oblique view. In the early study there is relative underperfusion of the septum (arrow) with redistribution in the delayed image.
Fig. 4. Twelve-lead ECG obtained prior to ergonovine administration (baseline) and after the final dose of ergonovine was administered during chest pain (post-ergonouine). No significant ST segmentchanges are seen.
March
666
Shanes et al.
American
Heart
1987 Journal
Fig. 6. Right anterior oblique projection of right coronary artery. A, Prior to ergonovine administration, vesselappearsnormal. B, Repeat coronary arteriography after ergonovine administration, during chest pain, reveals moderate diffuse narrowing with significant focal stenosisof proximal vessel(arrow).
Fig. 6. Initial postergonovineand delayed thallium-201 scansin IO-degreeleft anterior oblique view. In the early study there is relative underperfusion of the lower septum, apex, and inferior-lateral walls (arrows) with redistribution in the delayed image.Marked lung uptake, which clearson the delayed image, is also noted (curved arrows).
spasm?* Recently, however, severalstudieshave causeconsiderable confusionfrom a diagnostic demonstrated that the ECG response during coro-
nary spasm may be variable. ST segment depression, T wave inversion, or even no ECG changes at all may occur during documented coronary ~pasm.~*~ Therefore, the ECG may lack sensitivity. Furthermore, ergonovine may produce chest pain as a manifestation of provoked esophageal spasm.8 Thus, the development of chest pain following administration of ergonovine, without associated ECG changes, a rather frequent occurrence in some studies, may
standpoint. We previously reported that the addition of simultaneous thallium imaging to ECG monitoring during ergonovine administration, increased the sensitivity of the test for detecting coronary spasm.6 Of 160 patients given ergonovine, 14 demonstrated evidence of coronary spasm, as documented by thallium-201 imaging, while only 50% of these patients developed significant ECG changes. A comparison of ECG monitoring and thallium imaging
Volume Number
113 3
Thallium
us ECG detection
of coronary
spasm
669
was also reported by DiCarlo et al9 in a group of 26 patients. Although a general concordance between ECG and thallium imaging was noted in that study, three patients with positive thallium studies had a negative ECG response, two of whom had a favorable response to chronic therapy with antispasm medications. The development of a thallium perfusion defect following administration of ergonovine may not necessarily indicate coronary spasm. Since ergonovine typically increases the blood pressure, new perfusion defects might develop in areas of noncritical stenosis as a result of ischemia induced by increasing myocardial oxygen demands rather than by spasm. Second, some reports have suggested that within the same patient, coronary spasm may involve several vessels either simultaneously or at various times.13 Therefore, the purpose of our study was to determine whether reversible thallium perfusion defects that occur following administration of ergonovine truly represent angiographically demonstrable coronary spasm, particularly in cases where the ECG is unchanged. We, therefore, administered ergonovine during simultaneous ECG monitoring and thallium-201 imaging according to our noninvasive protocol as we had previously described.5 However, instead of doing so in a noninvasive setting, it was performed in the catheterization laboratory. Thus, we were able to correlate the results of thallium imaging and ECG monitoring with simultaneously performed angiography and validate our previous results that thallium imaging enhances the sensitivity of ergonovine administration over ECG monitoring alone. Our data indicate that, in fact, thallium perfusion defects occur during episodes of coronary spasm, as previously described, and that the site of the perfusion defect correlates with the involved vessel. Moreover, thallium imaging proved to be more sensitive for detecting coronary spasm than ECG monitoring alone, with an overall sensitivity rate of 80% vs 25% for the ECG. Since the number of patients in our study was small, it should be emphasized that the sensitivity and accuracy of thallium imaging over ECG monitoring alone, as we have calculated it, should not be considered exact until data from larger studies are obtained. Nevertheless, this smaller study that we
um imaging in the catheterization laboratory during administration of ergonovine when coronary angiography is performed. However, the clinical practice in many centers is that patients with chest pain found to have normal coronary arteries during angiography are not given ergonovine in the catheterization laboratory. Rather, several days later, they are given ergonovine in a noninvasive setting while the ECG alone is monitored. This is particularly true in busy laboratories where administration of ergonovine is not practical because of the time-consuming nature of the test. It is in this setting that we believe our results indicate that thallium imaging, in addition to ECG monitoring, is required to improve the diagnostic sensitivity and accuracy of the test. Of the patients included for analysis, only one had false positive results of thallium study (No. 9). This patient had no chest pain and careful review of the data showed no ECG changes and no significant narrowing of the coronary vessels. Reanalysis of the defect confirmed its presence. However, the defect was quite small and localized to the inferoposterior region of heart and was seen only in the anterior view but not the 40-degree or 70-degree left anterior oblique view. Since positioning of the patient on the catheterization examination table is somewhat limited and the defect was seen only in one view, we believe this defect probably represents a technical artifact. It is interesting to note the high incidence of catheter-induced spasm that occurred in this group of patients. Of five patients excluded from analysis, three had catheter-induced spasm: two prior to ergonovine administration and one following ergonovine administration. It would be intriguing to hypothesize that patients with coronary spasm might perhaps be more likely to develop catheterinduced spasm, but none of these patients had an abnormal response to ergonovine, thus ruling out this connection in these patients. It is likely, however, that ergonovine administration potentiated the development of catheter-induced spasm, since it developed in one patient only after administration of ergonovine (No. 13) and appeared to potentiate the degree of catheter-induced spasm in another (No. 12). This effect can probably be attributed to the nonspecific vasoconstricting properties of ergo-
have performed with angiographiccorrelation con-
novine on smooth muscles.Onecould speculatethat
firms our previous data in a larger group of 100 patients (without simultaneously performed angiography) that thallium imaging is more sensitive than ECG monitoring alone for detecting coronary spasm. We do not believe it necessary to perform thalli-
such an effect could lead to false positive ergonovine studies when they are performed during coronary arteriography. It may appear difficult to reconcile our data with results of previous studies which have reported a high sensitivity for detecting coronary artery spasm
March
670
Shanes et al.
American
Heart
1987 Journal
with ECG monitoring alone. We believe this discrepancy can be explained by the different populations of patients tested. For example, Waters et al.’ found the ECGs to be positive in all 17 of their patients (with known coronary artery spasm) who were given ergonovine. However, these 17 patients were all documented to have had recurrent spontaneous chest pain and ST segment elevation prior to testing. Thus, these patients represent a select group, with a more active form of coronary artery spasm. In such a group the ECG would be expected to be more sensitive. Schroeder et al.” also reported a high sensitivity for ECG monitoring to detect coronary artery spasm in a group of patients undergoing ergonovine testing during simultaneous angiography and ECG monitoring. However, in this group ECG changes occurred only in the patients who developed total or near-total focal spasm in response to ergonovine administration. Most of the patients in this group also had previously been documented to have spontaneous ST segment elevation in association with chest pain. Thus, this group too probably represented patients with a more active disease state. In fact, in that study it was noted that three patients who had milder degrees of spasm, 50% to 70 % , did not develop ECG changes and did not have chest pain. Our group is more representative of the type of patient usually referred for ergonovine testing. In clinical practice, patients with normal coronary arteries and documented spontaneous chest pain and ST segment elevation would usually not be subjected to ergonovine testing because the diagnosis would be obvious. Our patients, however, had recurrent chest pain and normal coronary vessels, but ST segment shifts could not be documented and thus were submitted for ergonovine testing. Thus, this group of patients would appear to have a less active form of Prinzmetal’s angina, and it appears from our data that in such patients the ECG lacks sensitivity. We believe that our group is more representative of patients typically given ergonovine in clinical practice. The analysis of patient No. 8, excluded from our
monitoring and thallium-201 imaging without simultaneously performing coronary arteriography. In three patients, thallium studies demonstrated increased uptake in the area of myocardium thought to be involved with spasm based on the ECG. The authors postulated that the increased uptake of thallium seen probably represented a hyperemic response. Thus, this too may explain the findings of relative underperfusion of the septum relative to the inferior-lateral wall in our patient. However, quantitative processing in our patient demonstrated true underperfusion of the septum and normal rather than increased perfusion of the lateral wall. Perhaps other unrecognized causes for septal hypoperfusion may have been operative in our patient, including small vessel spasm in the septal distribution or unrecognized spasm of the left anterior descending artery. Postergonovine angiography of the left coronary system was not performed in this patient. Finally, this study, although not designed to, highlights some of the potential advantages of noninvasive thallium and ECG monitoring during ergonovine administration vs coronary arteriography for detecting coronary spasm. In the catheterization laboratory the procedure proved lengthy, adding an average of 23.8 rt 3.8 minutes to the total procedure. In high-volume catheterization laboratories this may make administration of ergonovine impractical. Also, coronary artery catheter-induced spasm occurred rather frequently. In two patients it developed following ergonovine administration, possibly potentiated by ergonovine’s nonspecific smooth muscle constricting effects.16 Since catheter-induced spasm may occur even in distal coronary segments,” the significance of the angiogram in such cases following ergonovine administration might lead to diagnostic errors. Clinical implications. Some patients may have coronary artery spasm as the etiology for symptoms of chest pain. Therefore, ergonovine has been used as a provocative test in order to diagnose or exclude coronary spasm as a cause for symptoms in patients with insignificant coronary disease. Our data indi-
results because of a protocol violation, warrants
cate that, when performed as a noninvasive proce-
further scrutiny. Following the final dose of ergonovine, chest pain, inferior ST segment elevation, and total occlusion of the proximal right coronary artery occurred. This patient received intracoronary nitroglycerin before thallium imaging was obtained. Thallium imaging demonstrated relative hypoperfusion of the septum with normal distribution on follow-up studies. This case is of particular interest in view of a recent report by Kronenberg et a.l,ls who administered intravenous ergonovine during ECG
dure, ECG monitoring alone is not sensitive enough to exclude coronary spasm in patients given ergonovine. The addition of simultaneously performed thallium imaging appears essential. By doing so, the sensitivity of the test is signifmantly increased with no loss in accuracy. We thank Jonas Juska, Bhupendra Patel, and Ken Markwell for their excellent technical support, Frances Jefferson and Carol Davis for their expert preparation of this manuscript, and Dr. Bruce Brundage for his critical review.
Volume
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Number
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Thallium usECG detection of coronary spasm 671
REFERENCES
1. Ma&pin RN. Relation of coronary arterial spasm to sites of organic stenosis. Am J Cardiol 1980;46:143. 2. Oliva P, Potts D, Plum R. Coronary arterial spasm in Prinzmetal angina: documentation by coronary arteriography. N Engl J Med 19X$288:745. 3. Ginsburg R, Lamb IH, Bristow MR, Schroeder JS, Harrison DC. Application and safety of outpatient ergonovine testing in accurately detecting coronary spasm in patients with possible variant angina. AM H&ART J 1981;102:698. 4. Waters DD, Theroux P, Szlachic J, Dauwe F, Crittin J, Bonan R, Misgala HF. Ergonovine testing in a coronary care unit. Am J Cardiol 1980,46:922. 5. Shanes JG, Krone RJ, Shah B, Fischer K, Eisenkramer G, Humphrey J. Non-invasive ergonovine maleate provocative testing for coronary artery spasm: the need for routine thallium-201 imaging. Cathet Cadiovasc Diagn 1983;9:271. 6. Whittle JL, Feldman RL, Pepine CJ, Curry RC, Conti CR. Variability of electrocardiographic responses to repeated ergonovine provocation in variant angina patients with coronary artery spasm. AM HEART J 1982,103:161. Rovai D, Distante A, Moscarelli E, Morales MA, Picano E, Palombo C. L’Abbata A. Transient mvocardial ischemia with minimal electrocardiographic changes: an echocardiographic study in patients with Prinxmetal’s angina. AM HEART J 1985;109:78. Gravino FN, Perloff JK, Yeatman LA, Ippolitti AF. Coronary arterial spasm versus esophageal spasm: response to ergonovine. Am J Med 1981;70:1293. DiCarlo LA Jr, Botvinick EH, Canhasi BS, Schwartz AS,
10.
11. 12. 13. 14.
Chatterjee K. Value of non-invasive assessment of patients with atypic chest pain and suspected coronary spasm using ergonovine t’infusion and thallium-201 scintigraphy. Am J Cardiol 1984;54:744. Maseri A, Parodi 0, Severi S, Pesola A. Transient transmural reduction of myocardial blood flow demonstrated by thallium-201 scintigraphy as a cause of recurrent angina. Circulation 1976;54:280. McLaughlin PR, Doherty PW, Martin RP, Gorris ML, Harrison DC. Myocardial imaging in patients with reproducible variant angina. Am J Cardiol-1977;39:126. Gerson MC. Noble RJ. Wann LS. Faris JV. Morris SN. Non-invasive documentation of Prinsmetal’s angina. Am J Cardiol 1979;43:329. Dunn RF, Kelly DT, Sadick N, Uren R. Multivessel coronary artery spasm. Circulation 1979; 60~451. Schroeder JS, Bolen JL, Quint RA, Clark DA, Hayden WG, Higgins CB, Wexler L. Provocation of coronary spasm with ergonovine maleate: new test with results in 57 patients undergoing coronary arteriography. Am J Cardiol 1977; AOzAR7. __.__
.
15. Kronenberg MW, Robertson RM, Born ML, Steckley RA, Robertson D. Friesineer GC. Thallium-201 untake in variant angina: probable d;monstration of myo&dial reactive hyperemia in man. Circulation 1982;66:1332. 16. Cinriano PR. Guthaner DF. Orlick AE. Ricci DR. Wexler L. Silverman JF. The effects of ergonovine maleate on coronary arterial size. Circulation 19735982. 17. Lafia P, Dincer B. Coronary artery catheter induced spasm. Cathet Cardiovasc Diagn 1982;8:607.
Jeffrey G. Shanes, M.D., Dan Pavel, M.D., Michael Blend, Ph.D., D.O., Enrique Olea, M.D., Ronald Krone, M.D., Kathy Lacny, Michael Marmulstein, Robert Malik, M.D., Carol Meyer, M.D., and George T. Kondos, M.D. Chicago, Ill., and St. Louis, MO.
Patients with chest pain and normal or insignificantly diseased coronary arteries may have coronary artery spasm as the etiology for symptoms.l~ 2 In such patients administration of ergonovine during ECG monitoring has been demonstrated to be a safe, noninvasive method for diagnosing coronary artery spasm.3s4 Recently, we reported our results with simultaneous thallium imaging and ECG monitoring during ergonovine administration in patients with
M.D.,
chest pain and recent coronary arteriography demonstrating insignificant coronary artery disease.5 In that group of 100 patients thallium imaging proved more sensitive than ECG monitoring for detecting coronary spasm. The purpose of this study was to validate our previous findings by comparing ECG monitoring and thallium imaging to simultaneously performed coronary arteriography during administration of ergonovine. METHODS
From the Department of Medicine, Cardiology Section, and the Department of Radiology, Nuclear Medicine Section, University of Illinois School of Medicine, and the Department of Medicine, Cardiology Section, Washington University. Supported in part by a National Institutes of Health Biomedical Research Grant. Received for publication April 14, 1986; accepted July 2, 1986. Reprint requests: Jeffrey G. Shanes, M.D., Cardiology Section, University of Illinois Hoepital, PO Box 6998, Chicago, IL 60680.
All patients undergoing coronary arteriography because of symptoms of chest pain were recruited for study. Calcium channel blockers were discontinued at least 24 hours prior to study and long-acting nitrates, at least 4 hours prior to study. Routine right and left heart catheterization, left ventricular angiograpby, and coronary arteriography were performed. Video imagee of the coronary arteriograms were reviewed and if no &e&graphic lumi663
March
664
Shanes
et al.
Table
I. Patient response
American
Agel Patient
No.
9
Baseline CA
yr
Sex
Control
57 53 53 47 30 55 34
F F F F M M M
72
M
N N N N P P Mild disease proximal LAD N
51
F
N
EGG
Site of ST shift
NSSTT N NST NST QII,III,aVF N Q waves VI-V, RBBB LAFB NST V,-V,
Thallium defect
Chest pain
Heart
1997 Journal
Postergonovine CA
Inferior N N Inferior AS
Present Present Present Present Present Present None
MDN MDN RCA 50% -75% MDN LAD 50% -75% RCA 50% -75% LAD 50%-75%
NC
AS
None
LAD 50% -75%
NC
Inferior
None
MDN
NC NC T V, NC NC NC NC
N N
Abbreviations: AS = anteroseptak CA = coronary erteriography; LAD = left anterior descending coronary artery; MDN = mild diffuse narrowing (insignificant); N = normal, NC = no change; NST = nonspecific T wave changes; NSSTT = nonspecific ST and T wave changes; P = mild plaquing; RCA = right coronary artery.
Table
II. Patients excluded
Patient No.
Agel
10
46
F
11
55
FP
12
42
F
13
49
14
39
(~4
Baseline CA
Sex
Proximal RCA catheter spasm 75%-100%
Control
ECG
Site of ST shift
Thallium defect
Chest pain
Postergonovine CA
Reason for exclusion
T I,III,AVF v,-v,
NC
Inferior
None
Normal
Catheter-induced spasm
N
NC
Suboptimal
Mild
MDN
Mild proximal RCA catheter spasm
N
NC
Normal
None
F
N
N
NC
Suboptimal
Present
F
N
Nonspecific T wave abnormality
ST II,III,AVF
AS
Present
Severe proximal RCA catheterinduced spasm Severe proximal RCA catheterinduced spasm Total RCA
S&optimal thallium Catheter-induced spasm
S&optimal thallium and catheter-induced spasm Intracoronary nitroglycerin administered before thallium
Abbreviations: AS = anteroseptal; CA = coronary arteriography; MDN = mild diffuse narrowing (insignificant); N = normal, NC = no change; P = mild plaquing; RCA = right coronary artery.
nal narrowing greater than 50% was seen, ergonovine
intervals following each bolus injection
tasting wasperformed. Patients with significcmt coronary narrowing were not given ergonovine and will not be discussedfurther. Er~onov&~e tcNthtg. Following the demonstration of insignificant coronary artery disease,a portable gamma camera and 12-lead ECG machine were moved into the catheterization laboratory. A la-bad ECG was then
blood pressureand la-lead ECG were recorded. Ergonovine administration wasterminated before the 0.3 mg dose if a classicECG responseoccurred (greater than 2 mm ST segment elevation) or if the patient developed typical symptoms of chest pain. Foilowing the final dose of ergonovine, 2.6 mCi of thallium-201 was injected intrave-
of ergonovine,
obtained. Then, at 4-minute intervals, b&s injections of ergonovine maleate were administered intravenously in
nously. Repaat~ coronary arteriography was rapidly performed and within 10 minutes, data acquisition on the gamma camera was begun. Forty-degree left anterior
this sequence:0.05, 0.1, 0.2, and 0.3 mg. This dosing and sequencehas been previously deacribad.“6 At 3-tiinute
oblique, anterior, and 70-degree left anterior oblique imagesin the catihebrkation laboratory were obtaiied.
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Thallium us ECG detection
Following completion of the study, arterial and venous sheaths were removed and the patients returned to their rooms. Four hours after the initial study, redistribution images were obtained. Patient safety. Before ergonovine was administered, a 500 cc solution of nitroglycerin was prepared and made available for intravenous or intracoronary use. If severe coronary artery spaamoccurred that, in the opinion of the cardiologist performing the procedure, made withholding nitroglycerin therapy until after thallium imaging unsafe, sublingual, intravenous, or intracoronary nitroglycerin was immediately administered as clinically indicated. This occurred in one patient and those data were analyzed separately. Informed consentwasobtained prior to catheterization in each case,and the protocol was approved by the institutional review board at the University of Illinois. Data analysis. Thallium images were read by three observers (DP, EO, and MB) without knowledge of the ECG or angiographic results. The final interpretation in each study was agreed upon by consensus.A study was considered positive for coronary spasm if an area of hypoperfusion was noted during the initial study with reperfusion occurring on the follow-up scan. The location of the defect was noted in each case. The coronary angiogramswere interpreted by two observers(GTK and JGS) without knowledge of the thallium or ECG results, with no differences occurring in interpretation. An angiogram was read as positive for spasmif greater than 50% narrowing occurred in a coronary segmentascomparedto the same segment prior to ergonovine administration, whether focal or diffuse. The ECGs were alsointerpreted blindly, without knowledgeof the thallium or angiographic results (MM) and were read as positive if an equal to or greater than lmm ST segmentelevation, depression,or T wave reversal occurred. The sensitivity and accuracy of thallium imaging and ECG monitoring were determined by comparing the results obtained for each technique to the coronary arteriogram obtained immediately following ergonovine administration. The sensitivity of thallium imaging and ECG monitoring wasdetermined for eachtest asthe number of positive tests (thallium or ECG) divided by the total number of angiographic studiespositive for spasm.The specificity of thallium imagingand ECG monitoring wasdetermined for each test asthe total number of negative tests (thallium or ECG) divided by the total number of angiographicstudies negative for spasm.The predictive accuracy of thallium imaging and ECG monitoring was determined for each test by adding the number of patients with positive tests (ECG or thallium) and angiogramspositive for spasmplus the number of patients with negative tests (ECG or thallium) and angiogramsnegative for spasmdivided by the total number of patients. RESULTS
Thirty-two
patients
were found to have insignifi-
cant coronary artery disease and were given ergono-
+
of
coronary spasm 665
m7%7mphy -
+ Total
thallium
+ ECG
-----------.
Fig. 1. Resultsof thallium imaging and ECG monitoring vs coronary angiography.
vine according to our protocol. Five patients were excluded from analysis because of either catheterinduced spasm, suboptimal thallium imaging, or protocol violation. These patients will be discussed separately. Of the 27 patients who had adequate thallium studies and fulfilled the study protocol, five patients developed angiographic spasm, five had a positive thallium study, one had a positive ECG response, and six developed chest pain. The clinical, angiographic, and ergonovine test data of these patients are given in Table I. The results of thallium imaging and ECG monitoring vs coronary angiography are illustrated in Fig, 1. Based on these results the calculated sensitivity of thallium imaging vs ECG monitoring was 89% vs 25% and accuracy was 92 % vs 85 % . Five patients were excluded from analysis and data on these patients are summarized in Table II. Patient No. 10 had persistent catheter-induced spasm of the right coronary artery prior to adminis-
tration of ergonovine.This correlated with a thallium defect in the inferior wall that reperfused on delayed imaging. No ECG changes or chest pain occurred in this patient. Patient No. 12 developed severe catheter-induced spasm of the right coronary artery following administration of ergonovine but developed neither chest pain nor ECG changes, and
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Fig. 2. Left anterior oblique projection of right coronary artery. A, Prior to ergonovine administration, vesselappearsnormal. B, After intravenous administration of 0.65 mg ergonovine, total occlusionof vessel occurred.
the thallium study was normal. Patient No. 13 also was excluded because of intense catheter-induced spasm of the right coronary artery following administration of ergonovine. However, thallium imaging in this patient who developed chest pain was suboptimal for interpretation, as was the study of patient No. 11, who also had mild chest pain but no ECG changes or angiographic spasm. Follow-up gastrointestinal studies in this patient demonstrated esophageal spasm. Patient No. 14 was excluded because of a break in the protocol. In this patient, following administration of the last dose of ergonovine, total occlusion of the right coronary artery developed (Fii. 2) in association with severe chest pain and ST segment elevation in leads II, III, and aVr which, in the opinion of the cardiologist performing the procedure, warranted the immediate administration of intracoronary nitroglycerin. Thus, intracoronary nitroglycerin was administered prior to thallium imaging. Thallium imaging in this patient showed relative hypoperfusion of the septum with redistribution on follow-up images (Fig. 3). Adverse reactions aRd eomptio&ions. No complications occurred in any patient. The most &equent adverse reaction was nausea sometimes acoompanied by vomiting. tgustrative case. Patient No. 6, a 55-year-old white man, underwent cardiac catheterixation and coronary angiography for symptoms of chest pain, both
exertional and at rest, for 8 years. Treadmill testing, which was limited by shortness of breath, was inconclusive for coronary disease because of the low work load achieved. Positive risk factors, including cigarette smoking, hypertension, and a strong family history, were present. Coronary angiography revealed only mild difIuse plaquing of the entire coronary tree and therefore ergonovine was given. Following the 6nal dose of ergonovine the patient developed typical chest pain but no ECG changes occurred (Fig. 4). However, coronary angiography revealed significant spasm in the proximal right coronary artery, about 70% (Fig. 5). Thallium imaging performed during this study demonstrated a defect in the lower septum, apex, and inferior-lateral walls with redistribution on delayed imaging (Fig. 6). Quantitative computer processing confirmed these findings. DISCUSWON
Coronary artery spasm may produce symptoms of ischemia in patients with normal or minimally diseased coronary vessels.Ergonovine has been used to provoke coronary spasm for purposes of diagnosis in such patients.1~2Several studies have demonstrated the safety of performing ergonovine provocation outside the catheterization laboratory when done in a coronary care unit or similar setting. Most such studies have used ECG monitoring alone to detect
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Thallium us ECG detection of coronary spasm 667
Fig. 3. Initial postergonovineand delayed thallium-201 scan in 40-degreeleft anterior oblique view. In the early study there is relative underperfusion of the septum (arrow) with redistribution in the delayed image.
Fig. 4. Twelve-lead ECG obtained prior to ergonovine administration (baseline) and after the final dose of ergonovine was administered during chest pain (post-ergonouine). No significant ST segmentchanges are seen.
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Fig. 6. Right anterior oblique projection of right coronary artery. A, Prior to ergonovine administration, vesselappearsnormal. B, Repeat coronary arteriography after ergonovine administration, during chest pain, reveals moderate diffuse narrowing with significant focal stenosisof proximal vessel(arrow).
Fig. 6. Initial postergonovineand delayed thallium-201 scansin IO-degreeleft anterior oblique view. In the early study there is relative underperfusion of the lower septum, apex, and inferior-lateral walls (arrows) with redistribution in the delayed image.Marked lung uptake, which clearson the delayed image, is also noted (curved arrows).
spasm?* Recently, however, severalstudieshave causeconsiderable confusionfrom a diagnostic demonstrated that the ECG response during coro-
nary spasm may be variable. ST segment depression, T wave inversion, or even no ECG changes at all may occur during documented coronary ~pasm.~*~ Therefore, the ECG may lack sensitivity. Furthermore, ergonovine may produce chest pain as a manifestation of provoked esophageal spasm.8 Thus, the development of chest pain following administration of ergonovine, without associated ECG changes, a rather frequent occurrence in some studies, may
standpoint. We previously reported that the addition of simultaneous thallium imaging to ECG monitoring during ergonovine administration, increased the sensitivity of the test for detecting coronary spasm.6 Of 160 patients given ergonovine, 14 demonstrated evidence of coronary spasm, as documented by thallium-201 imaging, while only 50% of these patients developed significant ECG changes. A comparison of ECG monitoring and thallium imaging
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us ECG detection
of coronary
spasm
669
was also reported by DiCarlo et al9 in a group of 26 patients. Although a general concordance between ECG and thallium imaging was noted in that study, three patients with positive thallium studies had a negative ECG response, two of whom had a favorable response to chronic therapy with antispasm medications. The development of a thallium perfusion defect following administration of ergonovine may not necessarily indicate coronary spasm. Since ergonovine typically increases the blood pressure, new perfusion defects might develop in areas of noncritical stenosis as a result of ischemia induced by increasing myocardial oxygen demands rather than by spasm. Second, some reports have suggested that within the same patient, coronary spasm may involve several vessels either simultaneously or at various times.13 Therefore, the purpose of our study was to determine whether reversible thallium perfusion defects that occur following administration of ergonovine truly represent angiographically demonstrable coronary spasm, particularly in cases where the ECG is unchanged. We, therefore, administered ergonovine during simultaneous ECG monitoring and thallium-201 imaging according to our noninvasive protocol as we had previously described.5 However, instead of doing so in a noninvasive setting, it was performed in the catheterization laboratory. Thus, we were able to correlate the results of thallium imaging and ECG monitoring with simultaneously performed angiography and validate our previous results that thallium imaging enhances the sensitivity of ergonovine administration over ECG monitoring alone. Our data indicate that, in fact, thallium perfusion defects occur during episodes of coronary spasm, as previously described, and that the site of the perfusion defect correlates with the involved vessel. Moreover, thallium imaging proved to be more sensitive for detecting coronary spasm than ECG monitoring alone, with an overall sensitivity rate of 80% vs 25% for the ECG. Since the number of patients in our study was small, it should be emphasized that the sensitivity and accuracy of thallium imaging over ECG monitoring alone, as we have calculated it, should not be considered exact until data from larger studies are obtained. Nevertheless, this smaller study that we
um imaging in the catheterization laboratory during administration of ergonovine when coronary angiography is performed. However, the clinical practice in many centers is that patients with chest pain found to have normal coronary arteries during angiography are not given ergonovine in the catheterization laboratory. Rather, several days later, they are given ergonovine in a noninvasive setting while the ECG alone is monitored. This is particularly true in busy laboratories where administration of ergonovine is not practical because of the time-consuming nature of the test. It is in this setting that we believe our results indicate that thallium imaging, in addition to ECG monitoring, is required to improve the diagnostic sensitivity and accuracy of the test. Of the patients included for analysis, only one had false positive results of thallium study (No. 9). This patient had no chest pain and careful review of the data showed no ECG changes and no significant narrowing of the coronary vessels. Reanalysis of the defect confirmed its presence. However, the defect was quite small and localized to the inferoposterior region of heart and was seen only in the anterior view but not the 40-degree or 70-degree left anterior oblique view. Since positioning of the patient on the catheterization examination table is somewhat limited and the defect was seen only in one view, we believe this defect probably represents a technical artifact. It is interesting to note the high incidence of catheter-induced spasm that occurred in this group of patients. Of five patients excluded from analysis, three had catheter-induced spasm: two prior to ergonovine administration and one following ergonovine administration. It would be intriguing to hypothesize that patients with coronary spasm might perhaps be more likely to develop catheterinduced spasm, but none of these patients had an abnormal response to ergonovine, thus ruling out this connection in these patients. It is likely, however, that ergonovine administration potentiated the development of catheter-induced spasm, since it developed in one patient only after administration of ergonovine (No. 13) and appeared to potentiate the degree of catheter-induced spasm in another (No. 12). This effect can probably be attributed to the nonspecific vasoconstricting properties of ergo-
have performed with angiographiccorrelation con-
novine on smooth muscles.Onecould speculatethat
firms our previous data in a larger group of 100 patients (without simultaneously performed angiography) that thallium imaging is more sensitive than ECG monitoring alone for detecting coronary spasm. We do not believe it necessary to perform thalli-
such an effect could lead to false positive ergonovine studies when they are performed during coronary arteriography. It may appear difficult to reconcile our data with results of previous studies which have reported a high sensitivity for detecting coronary artery spasm
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1987 Journal
with ECG monitoring alone. We believe this discrepancy can be explained by the different populations of patients tested. For example, Waters et al.’ found the ECGs to be positive in all 17 of their patients (with known coronary artery spasm) who were given ergonovine. However, these 17 patients were all documented to have had recurrent spontaneous chest pain and ST segment elevation prior to testing. Thus, these patients represent a select group, with a more active form of coronary artery spasm. In such a group the ECG would be expected to be more sensitive. Schroeder et al.” also reported a high sensitivity for ECG monitoring to detect coronary artery spasm in a group of patients undergoing ergonovine testing during simultaneous angiography and ECG monitoring. However, in this group ECG changes occurred only in the patients who developed total or near-total focal spasm in response to ergonovine administration. Most of the patients in this group also had previously been documented to have spontaneous ST segment elevation in association with chest pain. Thus, this group too probably represented patients with a more active disease state. In fact, in that study it was noted that three patients who had milder degrees of spasm, 50% to 70 % , did not develop ECG changes and did not have chest pain. Our group is more representative of the type of patient usually referred for ergonovine testing. In clinical practice, patients with normal coronary arteries and documented spontaneous chest pain and ST segment elevation would usually not be subjected to ergonovine testing because the diagnosis would be obvious. Our patients, however, had recurrent chest pain and normal coronary vessels, but ST segment shifts could not be documented and thus were submitted for ergonovine testing. Thus, this group of patients would appear to have a less active form of Prinzmetal’s angina, and it appears from our data that in such patients the ECG lacks sensitivity. We believe that our group is more representative of patients typically given ergonovine in clinical practice. The analysis of patient No. 8, excluded from our
monitoring and thallium-201 imaging without simultaneously performing coronary arteriography. In three patients, thallium studies demonstrated increased uptake in the area of myocardium thought to be involved with spasm based on the ECG. The authors postulated that the increased uptake of thallium seen probably represented a hyperemic response. Thus, this too may explain the findings of relative underperfusion of the septum relative to the inferior-lateral wall in our patient. However, quantitative processing in our patient demonstrated true underperfusion of the septum and normal rather than increased perfusion of the lateral wall. Perhaps other unrecognized causes for septal hypoperfusion may have been operative in our patient, including small vessel spasm in the septal distribution or unrecognized spasm of the left anterior descending artery. Postergonovine angiography of the left coronary system was not performed in this patient. Finally, this study, although not designed to, highlights some of the potential advantages of noninvasive thallium and ECG monitoring during ergonovine administration vs coronary arteriography for detecting coronary spasm. In the catheterization laboratory the procedure proved lengthy, adding an average of 23.8 rt 3.8 minutes to the total procedure. In high-volume catheterization laboratories this may make administration of ergonovine impractical. Also, coronary artery catheter-induced spasm occurred rather frequently. In two patients it developed following ergonovine administration, possibly potentiated by ergonovine’s nonspecific smooth muscle constricting effects.16 Since catheter-induced spasm may occur even in distal coronary segments,” the significance of the angiogram in such cases following ergonovine administration might lead to diagnostic errors. Clinical implications. Some patients may have coronary artery spasm as the etiology for symptoms of chest pain. Therefore, ergonovine has been used as a provocative test in order to diagnose or exclude coronary spasm as a cause for symptoms in patients with insignificant coronary disease. Our data indi-
results because of a protocol violation, warrants
cate that, when performed as a noninvasive proce-
further scrutiny. Following the final dose of ergonovine, chest pain, inferior ST segment elevation, and total occlusion of the proximal right coronary artery occurred. This patient received intracoronary nitroglycerin before thallium imaging was obtained. Thallium imaging demonstrated relative hypoperfusion of the septum with normal distribution on follow-up studies. This case is of particular interest in view of a recent report by Kronenberg et a.l,ls who administered intravenous ergonovine during ECG
dure, ECG monitoring alone is not sensitive enough to exclude coronary spasm in patients given ergonovine. The addition of simultaneously performed thallium imaging appears essential. By doing so, the sensitivity of the test is signifmantly increased with no loss in accuracy. We thank Jonas Juska, Bhupendra Patel, and Ken Markwell for their excellent technical support, Frances Jefferson and Carol Davis for their expert preparation of this manuscript, and Dr. Bruce Brundage for his critical review.
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Number
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1. Ma&pin RN. Relation of coronary arterial spasm to sites of organic stenosis. Am J Cardiol 1980;46:143. 2. Oliva P, Potts D, Plum R. Coronary arterial spasm in Prinzmetal angina: documentation by coronary arteriography. N Engl J Med 19X$288:745. 3. Ginsburg R, Lamb IH, Bristow MR, Schroeder JS, Harrison DC. Application and safety of outpatient ergonovine testing in accurately detecting coronary spasm in patients with possible variant angina. AM H&ART J 1981;102:698. 4. Waters DD, Theroux P, Szlachic J, Dauwe F, Crittin J, Bonan R, Misgala HF. Ergonovine testing in a coronary care unit. Am J Cardiol 1980,46:922. 5. Shanes JG, Krone RJ, Shah B, Fischer K, Eisenkramer G, Humphrey J. Non-invasive ergonovine maleate provocative testing for coronary artery spasm: the need for routine thallium-201 imaging. Cathet Cadiovasc Diagn 1983;9:271. 6. Whittle JL, Feldman RL, Pepine CJ, Curry RC, Conti CR. Variability of electrocardiographic responses to repeated ergonovine provocation in variant angina patients with coronary artery spasm. AM HEART J 1982,103:161. Rovai D, Distante A, Moscarelli E, Morales MA, Picano E, Palombo C. L’Abbata A. Transient mvocardial ischemia with minimal electrocardiographic changes: an echocardiographic study in patients with Prinxmetal’s angina. AM HEART J 1985;109:78. Gravino FN, Perloff JK, Yeatman LA, Ippolitti AF. Coronary arterial spasm versus esophageal spasm: response to ergonovine. Am J Med 1981;70:1293. DiCarlo LA Jr, Botvinick EH, Canhasi BS, Schwartz AS,
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Chatterjee K. Value of non-invasive assessment of patients with atypic chest pain and suspected coronary spasm using ergonovine t’infusion and thallium-201 scintigraphy. Am J Cardiol 1984;54:744. Maseri A, Parodi 0, Severi S, Pesola A. Transient transmural reduction of myocardial blood flow demonstrated by thallium-201 scintigraphy as a cause of recurrent angina. Circulation 1976;54:280. McLaughlin PR, Doherty PW, Martin RP, Gorris ML, Harrison DC. Myocardial imaging in patients with reproducible variant angina. Am J Cardiol-1977;39:126. Gerson MC. Noble RJ. Wann LS. Faris JV. Morris SN. Non-invasive documentation of Prinsmetal’s angina. Am J Cardiol 1979;43:329. Dunn RF, Kelly DT, Sadick N, Uren R. Multivessel coronary artery spasm. Circulation 1979; 60~451. Schroeder JS, Bolen JL, Quint RA, Clark DA, Hayden WG, Higgins CB, Wexler L. Provocation of coronary spasm with ergonovine maleate: new test with results in 57 patients undergoing coronary arteriography. Am J Cardiol 1977; AOzAR7. __.__
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15. Kronenberg MW, Robertson RM, Born ML, Steckley RA, Robertson D. Friesineer GC. Thallium-201 untake in variant angina: probable d;monstration of myo&dial reactive hyperemia in man. Circulation 1982;66:1332. 16. Cinriano PR. Guthaner DF. Orlick AE. Ricci DR. Wexler L. Silverman JF. The effects of ergonovine maleate on coronary arterial size. Circulation 19735982. 17. Lafia P, Dincer B. Coronary artery catheter induced spasm. Cathet Cardiovasc Diagn 1982;8:607.