Provocative testing for coronary arterial spasm: Rationale, risk and clinical illustrations

Provocative Testing for Coronary Arterial Spasm :Rationale, Risk and Clinical Illustrations

CATHERINE NELSON, MDBOGDAN NOWAK, MDHENRY CHILD$, MDLARRY WEINRAUCH, MDSTANLEY FORWAND, MD, FACC

Cambridge, Massachusetts

From the Department of Cardiology, Mount AuburnHospital, Cambridge, Massachusetts . Manuscriptreceived November 23, 1976; revised manuscriptreceived January 24, 1977, accepted January 26,1977 .

Address for reprints : Stanley Forwand, MD,Department of Cardiology, 330 Mt. Auburn Street,Cambridge, Massachusetts 02138 .

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October 1977 The American Journal of CARDIOLOGY Volume 40

Two cases of Prinzmetal's variant angina are presented in which coronaryspasm was documented by electrocardiographic evidence obtained inthe coronary care unit during provocative testing with ergonovine maleateafter the arteriographic demonstration of anatomically normal coronaryarteries. The rationale and risks of provocative testing for spasm in patientswith chest pain and anatomically normal coronary arteries are reviewed .The advantages of performing provocative testing in the coronary careunit after arteriography rather than In the catheterization laboratory duringcoronary arteriography are discussed .

Provocative testing to document myocardial ischemia has a long history .The anoxemia test used inhalation of 10 percent oxygen to elicit elec-trocardiographic changes in patients with "diminished coronary re-serve." 1 More recently, the use of exercise testing in diagnosing classicHeberden's angina has increased, and coronary arteriography has pro-vided the anatomic correlate for the majority of patients with restingor exercise-induced S-T segment abnormalities. In these studies, a groupof patients with clinical angina pectoris and arteriographically docu-mented normal major coronary vessels has been identified . 2,3 The sizeof the subset of patients in this group whose pain is caused by coronaryarterial spasm is unknown .

Recent reports4-8 have described the use of pharmacologic agents toprovoke coronary arterial spasm during coronary arteriography in pa-tients with angina pectoris and normal coronary arteries . This type oftesting has proved useful in identifying coronary spasm as the cause ofchest pain in some patients with Prinzmetal's variant angina . However,diagnosis has been complicated by the fact that coronary spasm occursspontaneously during coronary arteriography in 1 to 3 percent of pa-tients .s-11 The clinical implication of this type of induced spasm remainsunclear, although in most cases the spasm appears to be a local responseto mechanical irritation of the proximal coronary artery by the catheterrather than an indication of a clinically significant abnormality 10 '11

When performed during coronary arteriography, provocative testingpermits visualization of an evoked coronary spasm . However, occasionsarise when such testing, although desirable, cannot be carried out duringarteriography-for example, when drugs such as atropine or nitroglyc-erin that may reverse coronary spasm have been administered routinelybefore it is realized that the coronary arteries are normal, when a cathetercauses damping of coronary arterial pressure and must be withdrawnquickly or when spontaneous spasm occurs .

In the presence of angiographically demonstrated normal coronaryarteries, the appearance of anginal pain and S-T segment changes uponadministration of agents known to produce coronary spasm may beconsidered diagnostic of coronary spasm . Angiographic documentationof the spasm, although dramatic, may be difficult to accomplish becauseof the vasodilating effect of the contrast medium12 and may constitutean unnecessary risk . After the angiographic documentation of normal

PROVOCATIVE TESTING FOR CORONARY SPASM-NELSON ET AL .

FIGURE 1 . Case 1 . Electrocardiograms during provoca-tive testing . A, 9 :55 AM ; 0 .2 mg of ergonovine maleategiven . B, 10:05 AM ; chest pain, 0 .4 mg of nitroglyceringiven . C, 10:10 AM; continuing pain, second degree A-Vblock. Another 0 .4 mg of nitroglycerin and 0 .8 mg of at-ropine given intravenously . D, 10 :17 AM; pain relieved,electrocardiogram returned to control state .


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coronary arteries, provocative testing for coronaryspasm might be carried out more appropriately in thecoronary care unit, where more sophisticated safetyprocedures and multichannel electrocardiography areavailable. Furthermore, the absence of a catheter in thecoronary artery eliminates the potentially confusingpossibility of catheter-induced spasm. We emphasizethat provocative testing should be done only after ar-teriographic demonstration of normal coronary arteriesbecause only then does such testing become necessaryfor diagnosis . Provocative testing may be both unwiseand unnecessary in the many patients with S-T eleva-tion during chest pain who have anatomic proximalstenosis with or without coronary spasm . 7 ' 13

Two cases are presented of coronary spasm provokedby the intravenous administration of ergonovine ma-leate in the coronary care unit .

Case ReportsCase 1

A 43 year old woman, an electronics factory worker, wastransferred to our coronary care unit for the evaluation ofchest pain . She had a 6 month history of substernal chest painradiating to the neck and both arms accompanied by dyspnea,diaphoresis and palpitations- These symptoms often occurredin relation to exertion, large meals or stress but most fre-quently occurred at night, waking her from sleep . After 2weeks of increasingly frequent pain culminating in two par-ticularly severe nocturnal episodes, she was admitted to an-other hospital so that the possibility of infarction could beruled out. Electrocardiograms at that time showed only Twave inversion in V i and V 2 . The chest pain was recurrent andinconsistently relieved with nitroglycerin . Oral cholecysto-gram and upper gastrointestinal X-ray series were obtained ;the latter showed Instal hernia . After 1 week, an episode ofchest pain occurred which was unrelieved with nitroglycerin,and an electrocardiogram showed T wave inversion in leadsII, III, aVF and V 3 to V6 . Serum enzyme levels were normaland the patient was transferred to this hospital for coronaryarteriography .

Cardiac risk factors included untreated mild hypertensionfirst noted 2 years earlier, a 100 pack-year smoking history anda positive family history of heart disease . Her mother died,allegedly of myocardial infarction, at age 44 years . Of ninesiblings, one brother has chest pain and is to undergo coronaryarteriography in Chicago . One sister died suddenly at age 23years and another sister died of rheumatic heart disease at age33 years . The patient had fasting serum cholesterol and tri-glyceride levels of 198 and 108 mg/100 ml, respectively .

Physical examination revealed an obese anxious woman .Blood pressure was 130/90 mm Hg, pulse 80/min and regular,height 160 cm and weight 79 .2 kg . There were no xanthelas-mas, xanthomas, arcus cornea or retinopathy. Carotid up-strokes were normal without bruits . Cardiac examinationrevealed no abnormality except for an intermittent fourthheart sound .

Left uentricalography and coronary arteriography dis-closed a slightly elevated left ventricular end-diastolic pres-sure at rest (13 mm Hg) but normal contraction and normalejection fraction (0.68) . A minor spasm of a 1 cm segment ofthe right coronary artery 1 cm from its origin was accompaniedby marked sinus bradycardia and the patient's usual chestpain. The administration of nitroglycerin sublingually andatropine intravenously slowly reversed the spasm . There wasno change in the monitored lead II electrocardiogram during

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pain or spasm. The coronary arteries were otherwise nor-mal.

Ergonovine testing : On the following day, the patient wasbrought to the coronary care unit where she was placed on acardiac monitor and an intravenous infusion started . Theresting electrocardiogram was normal (Fig . IA). With Tho-razine® , atropine, nitroglycerin and phentolamine (Regitine ®)available at the bedside, 0.2 mg of ergonovine maleate wasadministered intravenously . After 4 minutes, typical chestpain occurred with marked S-T elevation in leads II, III andaVF, depression in leads V 1 to V 3 (Fig. 113) and transient A-Vblock (Fig . 1C). When nitroglycerin and atropine were ad-ministered, the pain stopped and the electrocardiogram re-turned to normal within 5 minutes (Fig . 1D) . Because thefollow-up electrocardiograms, plasma creatine kinase levelsand MB fractions were all normal, myocardial infarction wasruled out . Propanthelene bromide and nitroglycerin ointmentwere prescribed and the patient was discharged .

Case 2This 45 year old woman was admitted to Mount Au-

burn Hospital for evaluation of chest pain of 6 months'duration that was precipitated by emotion and occa-sionally occurred at-rest . She also complained of or-thopnea, occasional paroxysmal nocturnal dyspnea,dyspnea on exertion, palpitations and light-headedspells . She had a 24 pack-year smoking history, elevatedserum triglycerides and a family history of coronarydisease. A resting electrocardiogram showed T waveinversion in the precordial leads V 1 to V4 ; tracingsduring pain showed peaked T waves and S-T elevationsanteriorly with premature ventricular contractions . Herangina was not relieved by propranolol (40 mg fourtimes a day), long-acting nitrates or prophylactic ni-troglycerin .

Physical examination and routine laboratory eval-uation including thyroid function tests revealed noabnormalities . Results of an exercise test given while thepatient was taking antianginal medications were nor-mal.

Cardiac catheterization revealed normal left ven-tricular contraction with an ejection fraction of 0.70 andnormal coronary arteries . Left ventricular end-diastolicpressure was 12 mm Hg at rest and was unchangedduring isometric hand exercise. Selective coronary ar-teriography without atropine or nitroglycerin pre-medication revealed normal left and right coronaryvessels. No spontaneous spasm or chest pain occurredduring the procedure .

Ergonovine maleate testing : On the following day,the patient was taken to the coronary care unit where,using multiple lead electrocardiography and with at-ropine, nitroglycerin, phentolamine and lidocaine ready,she was given 0 .2 mg of ergonovine maleate intrave-nously. The resting electrocardiogram was normal (Fig .2A) . After 4 minutes, severe chest pain occurred, ac-companied by S-T elevation in the precordial leads (Fig .2B) and occasional premature ventricular beats (Fig .2C). Administration of nitroglycerin, 0 .6 mg sub-lingually, produced remission of pain and electrocar-diographic abnormalities within 4 minutes (Fig . 2D) .Follow-up electrocardiograms and serum enzyme levelswere normal . The patient was discharged taking iso-

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FIGURE 2. Case 2 . Electrocardiograms during provoca-tive testing . A, 10 :45 AM : 0 .2 mg of ergonovine maleategiven . B, 10 :50 AM; onset of chest pain. C, 10:52 AM;premature ventricular contractions, S-T elevations, ni-troglycerin given . 0, 11 :00 AM; pain relieved, electro-cardiogram returned to control state .


627


sorbide, 5 mg sublingually every 4 hours, and 2 percentnitroglycerin ointment, 1 inch (2 .54 cm) at bedtime .

Discussion

Ergonovine maleate is an amine ergot alkaloid . Likeother ergot alkaloids, it is a potent direct constrictor ofsmooth muscle, but unlike some ergot alkaloids, it doesnot act as an adrenergic blocking agent. 14 Ergonovinemaleate has been reportedly administered to 57 patientsincluding 13 with known Prinzmetal's variant angina .All patients with variant angina, but none of the controlsubjects, showed characteristic S-T elevations, andcoronary arterial spasm was demonstrated angio-graphically in all but one patient 6-8 Ergotamine tartratehas also been administered without reported compli-cations to 40 patients with suspected variant angina,producing coronary spasm in eight. 5 Thus, availabledata indicate that ergonovine maleate (and possibly alsoergotamine tartrate) is a relatively sensitive and specificagent for provoking coronary spasm in patients withPrinzmetal's variant angina and anatomically normalcoronary arteries . However, since angina pectoris is arecognized side effect of ergot administration, questionsabout the safety as well as sensitivity and specificity ofthe use of ergot preparations in provoking coronaryarterial spasm must be considered .

Potential risks of provocative test: As with manytests designed to stimulate pathologic reactions, risk isinherent in the provocation of coronary spasm . Thearrhythmias encountered in our two patients suggestthat the complications of major spasm of a given vesselare similar to the complications seen during acute oc-clusion of the same vessel . One episode of nonfatalventricular tachycardia with ergonovine administrationduring coronary arteriography has been reported .8When provocative testing is performed during coronaryarteriography, the risk of the test is increased by thesmall but definite risk of coronary arteriography alone,particularly if drugs commonly used as safety precau-tions, such as atropine or nitroglycerin, are withheld . Anonfatal myocardial infarction during coronary arteri-ography, thought to be caused by coronary spasm, hasbeen reported . 15 Furthermore, patients with clinicallyimportant coronary spasm may or may not be more

1 . Levy R, Patterson J, Clark T, at al : The anoxemia test as an indexof coronary reserve . JAMA 117:2113--2119,1941

2 . Likoff W, Segal BL, Kasparlan H : Paradox of normal selectivecoronary arteriograms in patients considered to have unmistakablecoronary heart disease . N Engl J Mod 276:1063-1066, 1967

3. Kemp HG, EIIIOH WC, Gorlin R : The anginal syndrome with normalcoronary arteriography . Trans Assoc Am Physicians 80:59-70,1967

4. Endo M, Hirosawa K, Kaneko N, at al: Prinzmetal's variant angina .N Engl J Mad 294:252-255, 1976

5. Clark DA, Quint RA, Satan J, at at The angiographic demonstrationof coronary artery =palm in patients with suspected variant angina :method and therapeutic implications (abstr) . Am J Cardiol 35:127,1975

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References


prone than normal subjects to the development ofspasm secondary to the mechanical stimulation of thecoronary artery by a catheter . When such spasm doesoccur during coronary arteriography, its clinical importcannot be predicted. Finally, spontaneous coronaryspasm carries its own risk . Patients with Prinzmetal'svariant angina are known to experience serious ar-rhythmias during attacks, in addition to incapacitatingand often puzzling atypical pain . 16,17 A nonfatal myo-cardial infarction followed months later by suddendeath has been reported in a patient with documentedcoronary spasm . 18

Indications for testing: The frequency of coronaryspasm in patients with myocardial infarction and an-giographically normal coronary arteries is not known .At present a diagnosis of coronary spasm in the absenceof fixed coronary lesions favors the use of short- andlong-acting nitrates in management . Propranolol, whichhas been shown to increase coronary vascular resistance,may be contraindicated, 19 and therefore a pathophys-iologic diagnosis is desirable . The autonomic regulationof coronary vascular resistance in healthy and diseasedstates may be more complex than is presently recog-nized. Agents other than ergot have been shown toprovoke coronary spasm 20 A variety of mechanismscausing coronary spasm, each with its own appropriateand specific therapy, may be uncovered by more ex-tensive provocative testing. Just as the patient withsuspected Herberden's angina pectoris and a normalresting electrocardiogram needs exercise testing as alogical step toward the diagnosis of his pain, so the pa-tient with chest pain and arteriographically normalcoronary arteries needs pharmacologic provocativetesting to provide a diagnosis and aid in managementdecisions .

That provoking coronary spasm carries risk appearscertain. However, available evidence suggests that pa-tients with Prinzmetal's variant angina are alreadysubject to spontaneous risks . 1 S When carried out in thecoronary care unit with appropriate safety precautions,free of the potential additional complications of contrastinjection and the possible confusion of catheter-inducedspasm, provocative testing can take its place as a usefuldiagnostic tool for patients with angina pectoris andanatomically normal coronary arteries .

6. Haupler F, Proudfl W, Slegal W, at al: The ergonovine maleatetest for the diagnosis of coronary arterial spasm (abstr). Circulation52: Suppl 11:11-11, 1975

7 . Higgins C, Wexler L, Silverman J, at al : Coronary arteriographyin Prinzmetal variant angina : documentation of coronary arterialspasm (abstr) . Circulation 52:Suppl 11 :11-28, 1975

8. Cheng TO : Ergotrate in coronary artery spasm . Circulation 53 :585-586,1976

9. Demany MA, Tante A, Zimnemwn HA: Coronary arterial spasm .Dis Chest 53:714-721, 1968

10. Gensini G : Coronary Arteriography . Future, Mt . Kisco, New York,1975, p 431-435

11 . O'Reilly RJ, spellberg RD, King TW: Recognition of proximal rightcoronary artery spasm during coronary arteriography . Radiology

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of angina at rest (abstr) . Circulation 52:Suppl Il :11-89, 197514. Goodman LS, Gilman A: The Pharmacological Basis of Thera-

peutics . New York, Macmillan, 1975, p 540-541, 872-87815. Chang TO, Bashour T, Singer BK, et al : Myocardial infarction with

absence of coronary atherosclerosis : caused by coronary spasm(7) . Am J Cardiol 30 :680-682, 1972

16 . Prinzmetal M, Kennamer R, Kerliss R, et at : Angina pectoris . I .A variant form of angina pectoris. Preliminary report. Am J Mad27:375-376, 1959


17 . Higgins C, Wexler L, Silverman J, et al : Clinical and arteriographicfeatures of Prinzmetal's variant angina : documentation of etiologicfactors . Am J Cardiol 37 :831-839, 1976

18. Wiener L, Kasparlan H, Duca P, et al : Spectrum of coronary ar-terial spasm . Clinical, anglographic and myocardial metabolicexperience in 29 cases . Am J Cardiol 38 :945-955, 1976

19 . Whitsitt LS, Succhesl BR : Effects of propranolol and its stereo-isomers upon coronary vascular resistance . Circ Res 21 :305-317,1967

20. Yasue H, Touyama M, Shimamolo M, et al: Role of autonomicnervous system in the pathogenesis of Prinzmetal's variant formof angina . Circulation 50 :534-539, 1974

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Provocative testing for coronary arterial spasm: Rationale, risk and clinical illustrations