PATHOPHYSIOLOGY AND NATURAL HISTORY

Clandestine ischemia in patients with vasospastic anginaIsabel Coma-Canellaa, Diego Martınez-Caroa, Juan Cosın-Salesa,´ ´Elena Fernandez-Jarnea, Maria Jose Garcıa Vellosob and Marta Gimenezb´ ´Background Coronary vasospasms generally occur atrest, but can also be triggered by physical exercise.Anginal pain and ST-segment elevation may be seenduring exercise-stress tests. ST-segment depression,due to nonocclusive vasospasms, has also been foundto occur. When the result of a test is positive,scintigraphy usually reveals perfusion defects. True silent

(or clandestine ischemia normal result of exercise test)with perfusion defects in these patients is very

uncommon.

Objective To stress the need for suspecting occurrenceof coronary vasospasms in order to perform a properdiagnosis.

Methods Eight patients with angina were selected forthis study. They had negative results of exercise testswith perfusion defects detected by thallium-201tomography, normal coronary arteries and vasospasms.Maximal exercise-stress tests with thallium-201tomography were performed. Sizes of perfusion defectswere quantified by examining polar maps. Coronaryangiography and then an intracoronary ergonovinetest were performed for each patient.

Results Significant defects were seen in territory of theright coronary artery, the left anterior descending artery,or both. Lung:heart ratio was normal in every case. Thecoronary arteries were normal and vasospasms wereelicited with ergonovine in all the patients.Correspondence between the location of perfusiondefects and angiographic spasms was generallyobserved. After treatment with calcium antagonists andnitrates all of them improved and defects detected bythallium tomography were no longer found when testswere repeated.

Conclusions Some patients with vasospastic anginamay have normal results of exercise-stress tests andreversible perfusion defects detectable by scintigraphy.This finding must lead one to perform coronaryangiography without administration of nitroglycerinebeforehand and an ergonovine test if the coronaryarteries are normal. Coron Artery Dis 11:383–390Q 2000 Lippincott Williams & Wilkins.

Coronary Artery Disease 2000, 11:383 – 390

Keywords: vasospastic angina, variant angina, exercise-stress test,thallium scintigraphy, clandestine ischemia

Departments of aCardiology and bNuclear Medicine, Clınica Universitaria,´Facultad de Medicina, Universidad de Navarra, Pamplona, Spain.

Correspondence and requests for reprints to I. Coma-Canella,Departamento de Cardiologıa, Clınica Universitaria de Navarra, Apto 4209,´ ´Pamplona, Spain.Fax: +34 948 296500; e-mail: icoma@unav.es

Received 08 July 1999 Revised 25 October 1999Accepted 09 November 1999

IntroductionAnginal pain due to vasospasms occurs typically at rest,mainly during night-time or in the early morning. It canalso be triggered by various stimuli such as ergonovinew x w x w x w x1,2 , exercise 3]5 , cold 6 , hyperventilation 7 ,

w x w xacetylcholine 1 , and aminophylline 8 . Administrationof ergonovine is the most sensitive test for provoking

w xvasospasms 2,9 . The prevalence of angina with ST-Ž .segment shifts elevation or depression among patients

with vasospastic angina during an exercise stress-test isw xabout 50% 10]12 . Exertional ST-segment depression

w xcan be indicative of partial coronary occlusion 7 . Exer-cise-stress testing with perfusion scintigraphy of patientswith vasospastic angina has previously been reportedw x13]23 . The usual presentation is exercise-inducedangina with ST-segment changes and hypoperfusionwith redistribution at rest. After a careful bibliographicsearch we have only found two reports of patients withvasospastic angina who had negative results ofexercise-stress tests and positive results of perfusion

w x w xscans 24,25 . One of them 24 is a case report and thew xother 25 is not focused on these patients. No explana-

tions about this discrepancy are given. We present thedata regarding eight patients with vasospastic anginaand true silent myocardial ischemia or clandestine is-

w xchemia 26 .

MethodsPatientsAmong 61 consecutive patients with angina subjectedto symptom-limitedrmaximal exercise tests with thal-

Ž .lium tomography and coronary angiography, 24 39%had negative results of exercise tests with reversibleperfusion defects detected in the thallium-201 tomogra-

Ž .phy study clandestine ischemia . Eight of these patientsŽ .five men, mean age 54"12 years were selectedbecause they had normal coronary arteries andergonovine-induced vasospasms during coronary angiog-raphy.

Analytical dataHemograms were obtained, levels of total cholesterol,high-density lipoprotein and low-density lipoprotein-cholesterol, triglycerides, hepatic enzymes, alkalinephosphatase, creatinine, and uric acid were determinedand urine analysis was performed for each patient.Hypercholesterolemia was diagnosed when the total-

0954-6928 Q 2000 Lippincott Williams & Wilkins

Coronary Artery Disease 2000, Vol 11 No 5384

cholesterol:high-density-lipoprotein-cholesterol ratiowas G5. Hypertriglyceridemia was diagnosed whenlevel of triglycerides was higher than the upper limit ofnormal laboratory range.

Exercise-stress testsImmediately before starting the test a 12-lead electro-cardiogram was recorded; blood pressure and heart ratewere also measured. The test was performed in six

Žcases with an electrically braked bicycle ergometer Sie-.mens Elema, Solna, Sweden , starting without any load

during the first minute. Then, a load of 15 or 20 WŽ .depending on previous training was added everyminute. In two cases a treadmill was used instead of abicycle ergometer. In all cases the test was stopped 1min after the maximal heart rate for each age had beenreached or if there were limiting symptoms. The bloodpressure was measured at baseline, every 3 min there-after, and during the maximal exercise. A three-leadelectrocardiogram was continuously monitored on a

Ž .screen, and a complete 12-lead electrocardiogram wasrecorded every minute during the exercise. Both visualand computer-assisted measurements of ST-segmentchanges 0.06 s after the J point were performed. Theresult was considered positive for ischemia if there wasa horizontal ST segment or a downward shift of )1mm from baseline, measured 0.06 s after the J point,that persisted for three consecutive beats in more thanone lead.

Thallium-201 imagingAll patients underwent stress]rest thallium-201 tomog-raphy after the exercise test. We administered 111 MBqthallium-201 by intravenous injection during the peakexercise and the exercise was continued for one additio-nal minute. Thallium-201 images were acquired within10 min. Redistribution imaging was performed 3]4 hafter the initial stress imaging. Images were obtained on

Ž .a wide-field-of-view rotating gamma camera Siemensequipped with a parallel-hole, all-purpose collimator.

Ž .Briefly, 32 images with a 64=64 matrix were acquiredvia a step-and-shoot method over a 1808 semicircularorbit with a 68 increment for 40 s each. Corrections forflooding, position of center of rotation, and decay wereapplied during reconstruction. Filtered backprojection

Ž .with a Butterworth filter order 5, cutoff 0.5rcm wasused. No correction for attenuation was applied. Tomo-graphic images were analyzed visually by two expertnuclear physicians and the extent of defects was com-puted from the polar map. Both visual and quantitativeanalyses were considered in each case.

Quantification of perfusion defectsThe polar map of coronary territories was obtained from

the thallium-201 single-photon-emission computedw xtomography, according to Cedars Sinai method 27 .

The apex was considered a territory of the left anteriordescending artery. According to the results of our

w xlaboratory 28 , a defect was considered positive forischemia when its extension in the polar map wasG22% for the left anterior descending artery, G26%

Ž .for the right coronary artery RCA , and G14% for theleft circumflex artery.

Analysis of pulmonary thallium uptakeFor all eight subjects, the unprocessed projection imageacquired as part of the post-exercise tomographic pro-jection set that corresponded to the anterior positionŽ .number 9 of 32 was identified. This projection imagewas selected because the ability to distinguish myocar-

Ž .dial and pulmonary regions of interest ROI spatiallywas greatest with this view and for comparison withanterior planar images in previously published studies.Separate ROI were defined for those areas of the leftlung and myocardium that demonstrated the greatestactivities. The lung:heart ratio was the meancountsrpixel for the lung divided by that for the my-

w xocardial ROI 29 . Values below 0.50 were considerednormal.

Left ventricular and coronary angiographyAngiography was performed for each patient within aweek of the exercise-stress test. No medication apartfrom sublingual administration of nitroglycerine wasgiven in the meanwhile. Left ventricular angiographywas performed with every patient in the right anterioroblique position, and the ejection fraction was calcu-lated in a semi-automatic way. Selective coronaryangiography was performed in the usual projections.

Ergonovine testsErgonovine was injected into each coronary artery inprogressively increasing doses of 1, 5, 10, and 30mgrmin. A three-lead electrocardiogram was continu-ously monitored and a 12-lead electrocardiogram wasrecorded at the time of anginal pain. Coronary angiogra-

Žphy was performed 1 min after the last dose in leftanterior oblique 308 cranio-caudal orientation for theRCA and in right anterior oblique 308 cranio-caudal

.orientation for the left coronary artery . In cases ofsevere symptomatic spasm the test was stopped, coro-nary angiography was done and nitroglycerine was

Ž .administered intracoronarily starting with 0.5 mg . TheŽtest was performed first in the RCA and later if this

.was tolerated well in the left coronary artery. At theend of the test, nitroglycerine was injected intracoronar-

Žily into both coronary arteries except in cases of pre-.mature stoppage of the test and then coronary angiog-

Vasopastic angina Coma-Canella et al. 385

raphy was performed anew in the same projections asthose used previously. According to the criteria es-

w xtablished by Maseri 6 , the result of an ergonovine testwas considered positive in the cases in which transientST-segment and T-wave changes coincided with symp-toms and a reduction of peak d Prd t and an increase inend-diastolic pressure; complete or subtotal occlusion ofone or more segments of coronary artery occurred, withor without detectable stenotic plaque; and segmentalreduction by 50% or more of the diameter of an angio-graphically normal segment of coronary artery occurred.A positive result could be caused by segmental single-vessel spasms, multivessel spasms or diffuse epicardialcoronary spasms.

ResultsClinical dataIn Table 1 we summarize the principal data and theelectrocardiograms of the eight patients. All of themhad angina mainly at rest.

Exercise-stress tests with thallium-201 tomographyIn all cases the results of exercise-stress tests werenormal: neither angina nor ST-segment shifts were pre-sent. However, in every case at least a perfusion defectwas observed. In Table 2 we summarize the data of theexercise-stress tests and the extents of defects detectedby thallium scintigraphy in each coronary territory dur-ing stress and at rest, according to examination of thepolar map. Visually, all the cases were assessed as beingstress-perfusion defects with total or partial redistribu-tion at rest. In case 1, due to a previous myocardialinfarction, reinjection of 37 MBq thallium was per-formed after the rest images had been obtained and avisually smaller inferior defect remained 24 h later. Forcases 3 and 4, who had not previously suffered infarc-tion, no reinjection was done and the persistent visualdefect was interpreted as severe ischemia.

Ventricular and coronary angiographyGlobal left ventricular function was normal for everypatient. Posterior akinesia was present in patient 1. Allthe patients had normal coronary arteries or minimal

Ž .irregularities -50% stenosis .

Relationship between visual defects and ergonovine-induced changesAll the patients had angina and ST-segment elevationwith ergonovine. In Table 3 we show the remainingdata. In general the location of the perfusion defectcorresponded to the location of the coronary spasms.Ergonovine tests were not performed on the left coro-nary arteries of patients 1 and 5 because they hadsevere symptomatic spasms in the RCA. In patient 1ergonovine elicited total occlusion of the proximal RCAand ventricular fibrillation. After an electric shock of300 J, sinus rhythm was restored and the patient recov-ered consciousness without any sequela. A spasm of theleft circumflex artery was elicited only in patient 8.Because the circumflex was a dominant artery, thedefect in this patient corresponded to the inferior areasubtended by the posterior descending artery.

In Figures 1]3 we show data corresponding to patient3. In Figure 1 we represent stress and rest scintigraphicimages. A large infero-septal perfusion defect with par-tial redistribution at rest can be observed. A smallinferior defect persists in the resting images, probablydue to severe ischemia, although the possibility of somedegree of diaphragmatic attenuation can not be ex-cluded. In Figure 2 we show ST-segment elevation ininferior leads during injection of ergonovine into theRCA. In Figure 3 we show diffuse narrowing of theentire RCA with a focal spasm.

Clinical evolutionAfter diagnosis of coronary vasospasms, treatment withcalcium antagonists and nitrates was started in every

Table 1 Clinical and electrocardiographic data

PreviousAge myocardial Electrocardiographic

( )Patient Sex years Risk factors infarction Angina during Syncope results

1 Male 60 Smoking, hypercholesterolemia Non-Q Rest and walking No R)S in V22 Male 66 Hypercholesterolemia None Rest and walking Yes Normal3 Male 70 Previous smoking None Rest and meals Yes Minor RBBB4 Female 51 Smoking None Rest and meals No Normal5 Male 49 Previous smoking, None Rest No Normal

hypercholesterolemia, hypertension6 Female 54 Previous smoking, hypertension None Rest No Normal7 Female 34 None None Rest No Normal8 Male 46 Smoking, hypercholesterolemia None Rest No Normal

RBBB, right-bundle-branch block.

Coronary Artery Disease 2000, Vol 11 No 5386

( )Table 2 Data about exercise-stress test and extension of defects % in the polar map of thallium-201 tomography in the variouscoronary territories

Territory( )Patient Duration Reason for Percentage Heart rate Power W Metabolic( )of stopping of maximal beats/min = equivalents LADA RCA LCA Lung:heart

( )exercise heart rate SBP mmHg ratio( )min

Stress Rest Stress Rest Stress Rest

1 12.53 Exhaustion 85 28560 125 6 5.1 11 46.4 8.9 3.0 3.0 0.352 10.23 Exhaustion 81 20035 150 6 7.6 3.2 71.2 0 0 0 0.243 9.39 End of 100 30000 135 6 13.6 15.0 67.8 8.0 0 0 0.27

protocol4 7.38 Exhaustion 90 25840 105 8 35.8 9.2 35 18.8 0 0 0.215 8.55 Exhaustion 93 30210 140 7 21.9 2.3 61.2 0 0 0 0.266 11 Exhaustion 97 32400 150 7 26.3 2.1 0 0 0 0 0.337 12 Exhaustion 98 31280 Treadmill 12 66.0 8.49 14.1 0 10.7 0 0.328 11 Exhaustion 85 25725 Treadmill 11 29.1 8.45 42.8 0 0 0 0.35

SBP, systolic blood pressure; LADA, left anterior descending artery; RCA, right coronary artery; LCA, left circumflex artery.

case. Follow-up ranges between 6 and 20 months.Throughout this time all the patients have improvedand five of them became asymptomatic after startingtreatment. Patient 2 was readmitted because of chestpain; a higher dose of verapamil plus nifedipine wereadministered until he became asymptomatic. Patients 4and 8 also needed higher doses of calcium antagonistsin order to improve their clinical conditions. Stress]restthallium scintigraphy during medication was repeatedfor six patients and clear improvements were observedin all cases.

DiscussionTrue silent ischemia or clandestine ischemia has previ-ously been described as a normal result of exercise-stresstest with reversible perfusion defects detected simulta-

w xneously by myocardial perfusion scintigraphy 26 . Theexplanation is that perfusion images are more sensitivethan are electrocardiographic changes and angina for thedetection of coronary artery disease. In fact, the routine

Žperformance of exercise tests with imaging two-dimen-.sional echocardiography or perfusion imaging is be-

coming more and more common in many centers. Themost recent report about clandestine ischemia dealswith the prognosis of patients with coronary lesions who

w xpresent this pattern 30 .

The unusual finding reported herein regarding the eightpatients with clandestine ischemia is the absence ofcoronary stenosis and the occurrence of ergonovine-induced spasms. This means that clandestine ischemiacan occur in patients with and without coronary lesions.In our series of 61 patients, eight of 24 patients withclandestine ischemia had coronary spasms in normalarteries. However, there is some bias in the selection ofpatients sent for coronary angiography: for patient 6angiography was done because it was suspected that shehad vasospasms even though the perfusion defect wasmild. Other patients with mild perfusion defects werenot sent for coronary angiography. The 16 remainingpatients with clandestine ischemia had significant le-

Ž .sions and typical angina mainly during exercise .

In addition to the common findings regarding theseeight patients, there are some individual data that merita comment. Patient 1 suffered an acute myocardialinfarction secondary to coronary spasms. Although oc-currence of vasospasms has been found to be a cause of

w xmyocardial infarction 31 , it is an uncommon cause ofinfarction in the absence of stenotic coronary lesions. Inaddition, two patients had previously had repetitivesyncopal episodes during angina, probably due to severe

w xdisturbances of rhythm 32 .

Table 3 Relationships between visual location of defects by thallium scintigraphy and sites of coronary vasospasms

Patient Perfusion defects Coronary spasms

1 Inferior and septal Total occlusion of the proximal RCA, ventricular fibrillation( ) ( )2 Infero-apical Diffuse narrowing 95% of the entire RCA and focal spasm 60% in the LCA

( )3 Infero-septal Focal subtotal occlusion with distal diffuse narrowing 90% of the RCA( ) ( )4 Septal Diffuse narrowing 90% of the LADA and focal spasm 95% in the RCA

5 Inferior Total occlusion of the RCA( ) ( )6 Anterior Diffuse narrowing 90% of the LADA and focal spasm 90% in the RCA

( ) ( )7 Antero-septal Diffuse narrowing of the RCA 80% and of the LADA 95%( ) ( )8 Infero-septal Diffuse narrowing 85% of the LADA and focal spasm 95% in a dominant LCA

RCA, right coronary artery; LADA, left anterior descending artery; LCA, left circumflex artery.

Vasopastic angina Coma-Canella et al. 387

( ) ( )From top to bottom: short-axis, vertical and horizontal long-axis views during stress S and 4 h later at rest R . There is an infero-septal perfusiondefect during stress, which is partially reversible at rest.

Exercise causes an increase in coronary blood flow,leading to flow-dependent dilatation of coronary arteriesin normal subjects, but it can induce coronary constric-

tion in patients with coronary spastic angina, partly dueto a deficiency in bioactivity of endothelial nitric oxidew x33 . The spasms produce anginal pain and ST-segment

A 12-lead electrocardiogram recorded during an ergonovine test of the right coronary artery reveals remarkable ST-segment elevation in inferiorleads and ST-segment depression in V –V . The patient complained of angina at this moment.1 4

Coronary Artery Disease 2000, Vol 11 No 5388

( )a Diffuse narrowing and a focal occlusive spasm in the right coronary( ) ( )artery after intracoronary administration of ergonovine E . b The

( )same artery after administration of nitroglycerine N .

shifts. Although the typical ST-segment shift is eleva-tion, the artery need not be totally occluded by thespasm, in which case an ST-segment depressionw x10]12,34,35 can occur. The prevalence of a positiveresult of exercise-stress testing among patients withvasospastic angina is variable, and depends on theprevalence of presentation with spontaneous angina andthe time between the last episode and the exercise test.

Vasospastic angina occurs typically at rest, but somepatients have angina both at rest and during exercise.Even patients with angina solely at rest may havepositive results in exercise-stress testing. Authors ofprevious reports on exercise-stress testing with perfu-sion imaging of patients with vasospastic angina de-

Žscribed the typical findings i.e. angina, ST-segment.elevation, and a reversible myocardial perfusion defect

w x7,36]39 . In the absence of a previous infarction, ST-segment elevation during exercise is indicative of tran-

w xsmural ischemia and locates the site of ischemia 40 .The ST-segment elevation can be due to vasospasms ina normal coronary artery or a stenotic artery. In anycase, coronary angiography is mandatory and the infor-mation given by perfusion with thallium does not changethe decision about whether to perform angiography.

It is possible that exercise elicited coronary spasms inour patients with partial occlusion of vessels, less severethan that induced by ergonovine. This degree of occlu-sion might be insufficient to induce electrocardio-graphic changes or angina, but sufficient to induce aperfusion defect detectable by thallium scintigraphy. Aless probable explanation is that there was an increasein peripheral coronary vascular resistance, which hasbeen found to be associated with vasospastic anginaw x41 . In these cases multiple perfusion defects with

w xelevated lung:heart indexes were observed 41 , but thiswas not the case for our patients. The absence ofabnormalities in lung:heart ratio for our patients is notsurprising, for some of the perfusion abnormalities couldbe secondary to attenuation of the thallium images bysoft tissue. If the perfusion study had not been done,the result would have been considered negative. Al-though there is no definitive proof for the occurrence ofa nonocclusive spasm during the exercise test, we canfind no better explanation for the data obtained withour patients.

The decision to perform coronary angiography is notusually taken for patients with atypical chest painŽ .mainly at rest and negative results of exercise-stresstesting. For this reason these patients will not beproperly diagnosed. In fact, patient 1 had not previouslybeen sent for coronary angiography because his predis-charge exercise test had given a normal result afteracute myocardial infarction and patient 2 had neitherbeen administered antianginal treatment nor been sentfor angiography because an exercise-stress test had givena negative result 2 years earlier.

Even in cases of angiography being performed, if occur-rence of vasospasms is not suspected and ergonovinetesting is not performed, these patients are diagnosed ashaving atypical chest pain with normal coronary arteries,and the results of the scintigraphic test are consideredfalse positives. Undiagnosed coronary vasospasms maybe among the reasons for the low specificity of perfu-sion images, whereas coronary angiography is con-sidered the optimal method to use.

In conclusion, vasospastic angina can be diagnosed onlyif it is suspected and provoked. It is probably morecommon than is usually thought. Some patients with

Vasopastic angina Coma-Canella et al. 389

normal coronary arteries and vasospastic angina maypresent clandestine ischemia. Although this can alsooccur in patients with coronary lesions, the associationof atypical angina and this finding must lead one toperform coronary angiography without previous admin-istration of nitroglycerine and an ergonovine test if thecoronary arteries are normal.

References

1 Sueda S, Ochi N, Kawada H, Uraoka T. Usefulness of intracoronaryinjection of acetylcholine and ergonovine in patients with variant angina.J Cardiol 1998; 31:145 – 150.

2 Waters DD, Crean PA, Roy D, Theroux P. Problems related to thedetection of myocardial ischemia caused by coronary vasospasm. Can

( )J Cardiol 1986; 2 suppl A :173A – 179A.

3 Brunelli C, Lazzari M, Simonetti I, L’Abbate A, Maseri A. Variablethreshold of exertional angina: a clue to a vasospastic component. EurHeart J 1981; 2:155 – 161.

4 Specchia G, De Servi S, Falcone C, Bramucci E, Angoli L, Mussini A,et al. Coronary arterial spasm as a cause of exercise-inducedST-segment elevation in patients with variant angina. Circulation 1979;59:948 – 954.

5 De Servi S, Falcone C, Gavazzi A, Mussini A, Bramucci E, Curti MT, etal. The exercise test in variant angina: results in 114 patients. Circulation1981; 64:684 – 688.

6 Maseri A. Ischemic heart disease . New York: Churchill Livingstone;1995. pp. 559–588.

7 Sueda S, Mineoi K, Kondou T, Yano K, Ochi T, Ochi N, et al. Usefulnessof thallium-201 myocardial scintigraphy during hyperventilation andaccelerated exercise test in patients with vasospastic angina and nearlynormal coronary artery. J Cardiol 1998; 31:207 – 213.

8 Baldini U, Dini FL, Marchetti M, Micheli G, Magini G.Dipyridamole-echocardiography test in the diagnosis of vasomotorangina. G Ital Cardiol 1997; 27:1169 – 1173.

9 Waters DD, Szlachcic J, Bonan R, Miller DD, Dauwe F, Theroux P.Comparative sensitivity of exercise, cold pressor and ergonovine testingin provoking attacks of variant angina in patients with active disease.Circulation 1983; 67:310 – 315.

10 Bertrand ME, Lablanche JM, Tilmant PY, Thieuleux FA. Coronary arteryspasm. A propos of 165 cases. Arch Mal Cœur Vaiss 1983;76:712 – 721.

11 Castello R, Alegrıa E, Merino A, Hidalgo R, Aparici M, Martınez-Caro D.´ ´ ´The value of the exercise stress test in patients with coronary

[ ]vasospasm in Spanish . Rev Esp Cardiol 1989; 42:240 – 245.

12 Kaski JC, Crea F, Meran D, Rodriguez L, Araujo L, Chierchia S, et al.Local coronary supersensitivity to diverse vasoconstrictive stimuli inpatients with variant angina. Circulation 1986; 74:1255 – 1265.

13 Campeau RJ, Spellman JG, Tenaglia AN. Spontaneous coronary artery[ ]spasm documented in a young woman case report . Clin Nucl Med

1996; 21:452 – 455.

14 Conte FJ, Tilkemeier P. Successful treatment of vasospastic angina andsymptomatic polymorphic ventricular tachycardia with calciumantagonists and nitrates based on a diagnosis made with exercise 201Tl imaging. J Nucl Cardiol 1996; 3:550 – 551.

15 Kruithoff WA, Schraml FV, Silverman DE. Tl-201 scintigraphy inmultivessel exercise-induced variant angina. Clin Nucl Med 1996;21:675 – 678.

16 Waters DD, Szlachcic J, Bourassa MG, Scholl JM, Theroux P. Exercisetesting in patients with variant angina: results, correlation with clinicaland angiographic features and prognostic significance. Circulation1982; 65:265 – 274.

17 Fuller CM, Raizner AE, Chahine RA, Nahormek P, Ishimori T, Verani M,et al. Exercise-induced coronary arterial spasm: angiographicdemonstration, documentation of ischemia by myocardial scintigraphyand results of pharmacologic intervention. Am J Cardiol 1980; 46:500–506.

18 Aoki M, Koyanagi S, Sakai K, Irie T, Takeshita A, Nakamura M, et al.Exercise-induced silent myocardial ischemia in patients with vasospasticangina. Am Heart J 1990; 119:551 – 556.

19 Kugiyama K, Yasue H, Okumura K, Goto K, Minoda K, Miyagi H, et al.Supression of exercise-induced angina by magnesium sulfate in patientswith variant angina. J Am Coll Cardiol 1998; 12:1177 – 1183.

20 Kugiyama K, Yasue H, Okumura K, Minoda K, Takaoka K, MatsuyamaK, et al. Simultaneous multivessel coronary artery spasm demonstratedby quantitative analysis of thallium-201 single photon emissioncomputed tomography. Am J Cardiol 1987; 60:1009 – 1014.

21 Kugiyama K, Yasue H, Horio Y, Morikami Y, Fujii H, Koga Y, et al.Effects of propranolol and nifedipine on exercise-induced attack inpatients variant angina: assessment by exercise thallium-201 myocardialscintigraphy with quantitative rotational tomography. Circulation 1986;74:374 – 380.

22 Minoda K, Yasue H, Kugiyama K, Okumura K, Motomura K, ShimomuraO, et al. Comparison of the distribution of myocardial blood flowbetween exercise-induced and hyperventilation-induced attacks ofcoronary spasm: a study with thallium-201 myocardial scintigraphy. AmHeart J 1994; 127:1474 – 1480.

23 Motomura K, Kugiyama K, Yasue H, Minoda K, Okumura K, Inobe Y, etal. Influence of exercise-induced coronary artery spasm on thallium-201initial distribution and washout kinetics in patients with variant andclassic angina pectoris. Am J Cardiol 1994; 73:661 – 665.

24 Murthy DR, Kallal JE, Ahlberg AW, Heller GV. Use of exercise myocardialperfusion imaging to guide and assess the effectiveness of medicaltherapy in coronary artery vasospasm. J Nucl Cardiol 1998;5:234 – 235.

25 Aoki M, Koyanagi S, Sakai K, Irie T, Takeshita A, Nakamura M, et al.Exercise-induced silent myocardial ischemia in patients with vasospasticangina. Am Heart J 1990; 119:551 – 556.

26 Williams KA, Taillon LA, Carter JE. Asymptomatic and electically silentmyocardial ischemia during upright leg cycle ergometry and treadmill

( )exercise clandestine myocardial ischemia . Am J Cardiol 1993;72:1114 – 1120.

27 Garcıa EV, Van Train K, Maddahi J, Pringent F, Friedman J, Areeda J, et´al. Quantification of rotational thallium-201 myocardial tomography. JNucl Med 1985; 26:17 – 26.

28 Arbizu J, Martı JM, Garcıa-Bolao I, Garcıa MJ, Iglesias I, Alegrıa E, et al.´ ´ ´ ´Quantification of myocardial tomography with thallium in coronary

[ ]disease. Evaluation of the Cedars-Sinai technique in Spanish . RevEsp Cardiol 1994; 47:368 – 374.

29 Kahn IK, Carry MM, McGhie I, Pippin JJ, Akers MS, Corbett JR, et al.Quantification of postexercise lung thallium-201 uptake during singlephoton emission computed tomography. J Nucl Med 1989;30:288 – 294.

30 Candell-Riera J, Santana-Boado C, Bermejo B, Castell-Conesa J,Aguade-Bruix S, Canela T, et al. Prognosis of ‘clandestine’ myocardial´ischemia, silent myocardial ischemia, and angina pectoris in medicallytreated patients. Am J Cardiol 1998; 82:1333 – 1338.

31 Nakamura M, Takeshita A, Nose Y. Clinical characteristics associatedwith myocardial infarction, arrhythmias, and sudden death in patientswith vasospastic angina. Circulation 1987; 75:1110 – 1116.

32 Miller DD, Waters DD, Szlachcic J, Theroux P. Clinical characteristicsassociated with sudden death in patients with variant angina. Circulation1982; 66:588 – 592.

33 Kugiyama K, Ohgushi M, Motoyama T, Sugiyama S, Ogawa H,Yoshimura M, et al. Nitric oxide-mediated flow-dependent dilation isimpaired in coronary arteries in patients with coronary spastic angina. JAm Coll Cardiol 1997; 30:920 – 926.

34 Sacknoff DM, Wilentz JR, Schiffer MB, Bush M, Coplan NL.Exercise-induced ST segment depression: relationship to nonocclusivecoronary artery spasm. Am Heart J 1993; 125:242 – 244.

35 Schulman P, Ferree JW, Del-Mastro PR. Clinical and angiographicfindings in a patient with vasospasm that occurred within an anomalouscoronary artery. Cathet Cardiovasc Diagn 1984; 10:363 – 368.

36 Hill JA, Conti CR, Feldman RL, Pepine CJ. Coronary artery spasm andits relationship to exercise in patients without severe coronaryobstructive disease. Clin Cardiol 1988; 11:489 – 494.

37 Gallik DM, Bucay M, Mahmarian JJ, Verani MS. Thallium-201tomography in the management of exercise-induced coronary spasm.Am Heart J 1992; 124:1078 – 1081.

38 Caralis DG, Kern MJ, Dotson S, Castello R. Intermittent coronaryspasm during graded exercise. Clin Cardiol 1992; 15:383 – 386.

39 Matsumura K, Nakase E, Haiyama T, Hasegawa A, Saito T. Evaluationof coronary hemodynamics and exercise 201Tl-myocardial scintigraphyin patients with vasospastic angina. Kaku Igaku 1992; 29:615 – 623.

Coronary Artery Disease 2000, Vol 11 No 5390

40 Candell-Riera J, Castell J, Rius A, Buxeda M, Moragas G, Palet J, et al.ST-segment elevation during the exercise-test and perfusion

[ ]scintigraphy in patients without infarction in Spanish . Rev Esp Cardiol1995; 48:600 – 605.

41 Matsumura K, Nakase E, Haiyama T, Hasegawa A, Saito T. Evaluationof coronary hemodynamics and exercise 201 Tl-myocardial scintigraphyin patients with vasospastic angina. Kaku Igaku 1992; 29:615 – 623.