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Refractory coronary artery spasm
lACC Vol. 4, No.3 September 1984:635-9
635
Refractory Coronary Artery Spasm VIRINDERJIT S. BAMRAH, MD, FACC, GREGORY J. SCHUCHARD, MD Milwaukee, Wisconsin
A patient with an episode of refractory myocardial ischemia induced by ergonovine is described. The patient underwent cardiac catheterization 2 weeks after an inferior wall myocardial infarction for evaluation of recurrent rest angina. He developed severe spasm of the proximal right coronary artery in response to ergonovine which was partially relieved with nitrates and calcium channel antagonists. However, myocardial ischemia per-
Coronary artery spasm has become a frequently recognized cause of angina as awareness and knowledge of this interesting disease entity has expanded. It has been identified in patients with and without obstructed coronary arteries and in vein grafts after coronary artery bypass surgery. The complications of coronary spasm include severe cardiac arrhythmias, such as ventricular tachycardia and fibrillation, conduction disturbances, acute myocardial infarction and sudden death. The administration of ergonovine has been used as a very sensitive and specific provocative test to document coronary spasm. Most patients with spontaneous or ergonovine-induced coronary artery spasm respond promptly, that is, within 3 to 5 minutes, to sublingual nitroglycerin 0-5). However, in a few patients ergonovine resulted in serious cardiovascular complications due to intractable coronary artery spasm (6,7). We report a case of severe and intractable myocardial ischemia that was induced by ergonovine and resulted in acute myocardial infarction.
Case Report Clinical history and findings. A 67 year old white man with known hypertension, peptic ulcer disease and chronic
From the Cardiovascular Section, Medical Service, Veterans Administration Medical Center, Wood (Milwaukee), Wisconsin and the Department of Medicine, The Medical College of Wisconsin, Milwaukee. Manuscript received January 18, 1984; revised manuscript received April 10, 1984, accepted April 16, 1984. Address for reprints: Virinderjit S. Barnrah, MD, Cardiovascular Section/I I 1M, Veterans Administration Medical Center, 5000 West National Avenue, Wood (Milwaukee), Wisconsin 53193. © 1984 by the American College of Cardiology
sisted, culminating in a new inferior wall infarction. The possible mechanism of continuing intense ischemia despite partial relief of the proximal right coronary spasm is discussed. It is suggested that ergonovine testing should perhaps be avoided during the early postinfarction period. Furthermore, if an ergonovine test is anticipated, beta-adrenergic blocking agents should be withheld.
obstructive pulmonary disease was hospitalized because of severe retrosternal chest pain radiating to both arms and the jaw and lasting approximately 1 hour. The pain was only slightly relieved with 1.2 mg of sublingual nitroglycerin and required 10 mg of intravenous morphine sulfate for complete control. Blood pressure was 142/94 mm Hg, pulse 70/min and regular and an S4 gallop was audible at the apex. The admission electrocardiogram showed sinus rhythm, 2 mm ST segment elevation in leads II, III and aVF and 1 mm ST segment depression in leads V I and V2' On the second hospital day, Q waves developed in leads II, III and aVF. The serial electrocardiograms and serum cardiac enzymes were compatible with the development of acute inferior wall myocardial infarction. The ST segments returned to baseline values by the third day. On the fourth hospital day, the patient developed another episode of severe retrosternal chest pain with ST segment elevation in leads II, III and aVF. The patient was started on treatment with oral nifedipine (30 mg every 6 hours), oral metoprolol (50 mg twice daily) and nitroglycerin paste (2 inches [5.08 em] every 6 hours topically). He had two additional similar episodes of chest pain that were controlled by morphine sulfate. Cardiac catheterization and angiography. Cardiac catheterization was performed on the 13th day after infarction because of the recurrent rest angina. Left ventricular end-diastolic pressure at rest was elevated at 20 mm Hg. The left ventriculogram showed moderate hypokinesia of the diaphragmatic and posterolateral segments in the 30° right and 60° left anterior oblique views, respectively. The right coronary artery was dominant and showed two areas of 20 and 40% narrowing, respectively, in its proximal segment and another 20% narrowing in its middle segment 0735-1097/84/$3.00
636
BAMRAH AND SCHUCHARD CORONARY SPASM
(Fig. lA). The left main trunk, anterior descending and proximal circumflex vessels were normal. The second marginal branch of the left circumflex vessel was totally occluded as its origin and opacified slowly by means of collateral vessels. Ergonovine study. The recurrent postinfarction angina appeared to be somewhat out of proportion to the extent and severity of atherosclerotic coronary artery disease. The occluded second marginal branch was considered to be responsible for the inferior wall myocardial infarction, but coronary artery spasm was considered as a possible explanation for the postinfarction angina. To evaluate the possible role of coronary artery spasm, 0.05 mg of ergonovine maleate was given intravenously while pulmonary and systemic arterial pressures and cardiac rhythm were monitored continuously. The patient developed his typical severe retrostemal chest pain with ST segment elevation in leads II, III and aVF, and ST segment depression in leads I, aVL and V4 to V6 within 5 minutes of ergonovine administration (Fig. 2). Repeat angiography showed further narrowing of the two proximal right coronary artery lesions to 80 and 50% stenosis, respectively (Fig. 18). Five minutes after 0.8 mg of sublingual nitroglycerin, the 80% proximal narrowing decreased to 60% (Fig. lC). Despite the partial relief of proximal right coronary artery spasm, intense chest pain and ST segment changes persisted. Sublingual nifedipine (20 mg), intracoronary nitroglycerin (up to 700 ug), intravenous nitroglycerin infusion (up to 100 ug/min), morphine sulfate (4 mg), meperidine hydrochloride (Demerol) (25 mg) and atropine (2 mg) were administered without any relief of chest pain or electrocardiographic changes. The intensity of chest pain and ST segment elevation actually became progressively worse. In response to nitroglycerin, the systolic aortic pressure decreased slightly from the pre-ergonovine level of 145 mm Hg but remained above 90 mm Hg throughout the study. The pulmonary artery diastolic pressure also remained below 15 mm Hg in response to nitroglycerin infusion. The heart rate was unchanged during the first 12 minutes after ergonovine administration, and then it increased to a maximal level of 120 beats/min. ST segment elevation progressively increased to a maximum of 6 mm from the baseline value. The patient then developed three episodes of ventricular fibrillation which were successfully cardioverted. Right and left coronary angiography was repeated several times and showed no further reduction in the proximal right coronary artery narrowing. The left coronary artery was unchanged from the pre-ergonovine angiogram. The patient continued to have chest pain, elevation of ST segments in the inferior leads and ST segment depression in the anterolateral leads. Subsequent hospital course. The patient was transferred to the coronary care unit after placement of a SwanGanz catheter and a temporary pacemaker. After completion
JACC Vol. 4, No.3 September 1984:635-9
Figure 1. Right coronary artery angiograms in left anterior oblique view. A, Proximal segment of right coronary artery shows two separate lesions causing 20 and 40% narrowing, respectively. B, After ergonovine administration, the severity of narrowing increases in both lesions to 80 and 50%, respectively. C, After sublingual nitroglycerin (0.8 mg), the severity of the proximal lesion decreases from 80 to 60%. The second lesion persists as 50% stenosis.
of the catheterization procedure, two-dimensional echocardiography showed reduced wall motion in the inferior and posterolateral segments. Over the next 48 hours, serum enzyme measurements (creatine kinase of 1,853 IV/liter with MB fraction of 16%) were diagnostic of a new myocardial infarction. The patient was free from further episodes of
BAMRAH AND SCHUCHA RD CORONARY SPASM
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angin a on a medical regimen of oral verapamil ( 120 mg four times dail y) and nitroglycerin paste (2 inche s [5.0 8 em] topically four times daily) . A repeat echocardiogram I month later demonstrated con siderable impro vement in the left ventricular segmental wall motion with residual hypokine sia present only in the apical segment. A symptom-limited exercise stress test was performed 21/2 month s later. Th e patient exercised for 660 seconds , achie ving a maximal age-predicted heart rate of 128 beat sl min. Mild angina and premature ventricular complexes developed; howe ver , there was no ST segment change . The radionuclide angiogram at this time showed an ejection fraction of 0.54 at rest, decreasing to 0.49 during maximal exercise .
Discussion The primary purpose of this report is to illustrate that some episodes of ergonovine-induced coronary artery spasm may be unusually prolonged and relatively intractable to commonly available vasod ilator s. Refractory coronary artery spasm. In view of onl y a mode st degree of fixed coronary artery disease (total occlusion of second marg inal branch ) in our case, coro nary vasospasm was considered as a mechanism underlying post-
. .l
637
Figure 2. Serial 12 lead electrocardiograms. A, Control electrocardiogramshowing Q wave in leads II and aVF and T wave inversion in leads II, III, aVF, Vs and V6 , indicating recent inferior wall myocardial infarction . B, Electro card iogram 5 minutes after the administration of ergonovine , showing marked ST segment elevation in leads II, III and aVF and reciprocal ST seg ment depression in leads aVL and V I to V4 . C, Electrocardiogram 2 days after ergonovine study, showing deep Q waves, ST segment elevation and T wave inversion in leads II, III, aVF and V6 · There is reciprocal ST segment depression in leads V I to V4' Compari son with the control electrocardiogram (A) indicates development of acute inferior wall myocardial infarction.
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infarction rest ang ina. We there fore felt justified in performing the ergonovine test. The ergonovine-provoked coronary artery spasm and the resultant myocardial ischemia in our patient were totall y refractory to sublingual, intrave nous and intracoronary nitroglycerin, sublingual nifedipine and atropine. This prolonged ischemic epi sode resulted in acute inferior wall myocardi al infarction . Crevey et al. (6) reported on a patient who also developed in response to ergonovine intract able right coronary artery spasm that resulted in acute inferior wall myo card ial infarction . The ir patient and several others who either developed myocardial infarction or died after an ergonovine test were reported (6-8) to have severe two or three vessel atherosclero tic coronary artery disease. Even though our patient also had athero sclerot ic coronary artery disease , the significant obstruction was limited to only the second marginal bran ch of the left circumflex vessel. In several patients recently reported (6-8) on , ergonovine-provoked coronary artery spasm was resi stant to commonly employed vasodilators. Multiple factor s, such as specific vasodilator used , route of administration and dose of ergonovine used , should be discussed regarding ergonovine testing . The right coronary artery spasm in the case reported by Crevey et al. (6) was intrac table to sublingual nitroglycerin. These investigators did not admini ster
638
BAMRAH AND SCHUCHARD CORONARY SPASM
intravenous or intracoronary nitroglycerin, calcium channel blocking drugs or alpha-adrenolytic agents to reverse the spasm. Buxton et al. (7) reported on five patients with serious ischemic complications (including three deaths) secondary to ergonovine testing. In the two patients who survived, the ergonovine-induced spasm was reversed only by large doses of intracoronary nitroglycerin; sublingual and intravenous nitroglycerin were ineffective. Of the three patients who died of irreversible coronary spasm, all received sublingual nitroglycerin, one received intravenous nitroglycerin, one received a small (100 I-Lg) dose of intracoronary nitroglycerin and two received phentolamine without any effect on the spasm. Our patient received 700 I-Lg of intracoronary nitroglycerin that did not completely relieve the coronary artery spasm. Buxton et al. (7) also recommended that ergonovine be given in small and equal serial doses (0.025 or 0.05 mg each) and that the total dose should not exceed 0.2 mg. Our patient and that of Crevey et al. (6) received only 0.05 mg and developed drug-resistant spasm. Mechanism of ergonovine-induced myocardial ischemia. In our patient, the exact mechanism of the prolonged ischemic episode is not clear. The spasm of the proximal right coronary artery probably was not responsible for persistent ischemia since the maximal obstruction in response to ergonovine was 80%, which promptly decreased to 60% after sublingual nitroglycerin. This modest degree of obstruction usually does not cause intense ischemia in the absence of a markedly augmented myocardial oxygen demand. The oxygen demand in our patient was not significantly increased since the heart rate and blood pressure after ergonovine administration were unchanged. There was no evidence of air or blood clot embolism or dissection involving the right coronary artery. Collapse of this artery was unlikely because the systolic blood pressure remained above 90 mm Hg despite substantial amounts of nitroglycerin. Persistent spasm of the resistance vessels in the right coronary artery vascular bed, despite partial reversal of focal spasm of the proximal segment of the right coronary artery, may have contributed to the continuation of an ischemic event. A high arteriolar resistance would be anticipated to curtail the nutrient flow, even if the spasm of the epicardial portion of the vessel was reversed. Orlick et al. (9) showed that ergonovine may provoke the syndrome of coronary spasm, not only by augmenting resistance in the epicardial segment of the coronary artery, but also by limiting the capacity of coronary arterioles to dilate in response to increased metabolic demands or ischemia. Recently, Cannon et al. (10,11) also demonstrated that abnormal arteriolar constriction in the coronary vascular bed (reduced arteriolar vasodilatory reserve) may result in myocardial ischemia, either spontaneously or in response to ergonovine. Nitroglycerin is a potent dilator of large (epicardial) coro-
lACC Vol. 4, No.3 September 1984:635-9
nary arteries, but it has a weak vasodilatory action on the arterioles (12). Thus, it is possible that, even if the proximal right coronary artery spasm was partially relieved, myocardial ischemia persisted because of ergonovine-induced high resistance in the arterioles. Metoprolol, a beta-adrenergic blocking agent that our patient was taking, could have also contributed to his prolonged ischemic episode. Kern et al. (13) demonstrated that beta-adrenergic blockade can potentiate coronary artery vasoconstriction in some patients with coronary artery disease, probably on the basis of unopposed alpha-adrenergic vasomotor tone. Several other studies (14-18) have also shown prolongation of ischemic episodes of beta-adrenergic blockade in patients with documented vasospastic angina. Our patient was probably resistant to nifedipine since he had experienced rest angina in the immediate post-myocardial infarction period while he was receiving oral nifedipine therapy. Although nifedipine has a more generalized vasodilatory effect on the coronary vascular bed, it was ineffective in this patient. Ergonovine test after recent myocardial infarction. The safety of an ergonovine test during the early post-myocardial infarction period is not known. Several authors (1922) have suggested that the test should be avoided during this period. The augmented myocardial oxygen demand occurring secondary to ergonovine-induced elevation of blood pressure and the reduction of myocardial blood flow secondary to ergonovine-induced spasm would be potentially detrimental to recently necrotic myocardium and might even enlarge the infarct size (19,20). Moreover, the ergonovineinduced coronary spasm may be unresponsive to nitroglycerin, as was seen in our patient. Recently, however, Moran et al. (21) and Koiwaya et al. (22) reported that ergonovineinduced spasm was promptly relieved with sublingual nitroglycerin in some patients while others required intracoronary nitroglycerin. There were no ergonovine-related complications in their patients. Clinical implications. Whereas most episodes of ergonovine-provoked vasospastic angina promptly respond to sublingual nitroglycerin, occasional episodes may be unusually prolonged or totally refractory to sublingual nitroglycerin. In these patients, alternate routes for nitroglycerin administration, that is intravenous or preferably intracoronary, and other agents such as calcium channel blocking drugs should be employed without undue delay. In some patients, these episodes may be totally refractory. Ergonovine testing should probably be avoided in patients during the early post-myocardial infarction period. Moreover, if an ergonovine test is anticipated, beta-adrenergic blocking agents should be discontinued beforehand. We gratefully acknowledge the secretarial assistance of Donna Shaughnessy and the editorial assistance of Catherine Walther in the preparation of this manuscript.
lACC Vol. 4, No.3
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References I. Schroeder JS, Bolen JL, Quint RA, et al. Provocation of coronary spasm with ergonovine maleate. Am J Cardiol 1977;40:487-91. 2. Curry RC, Pepine CJ, Sabom MB, Feldman RL, Christie LG, Conti CR. Effects of ergonovine in patients with and without coronary artery disease. Circulation 1977;58:803-9. 3. Heupler F, Proudfit W, Rajavi M, Shirey EK, Greenstreet R, Sheldon We. Ergonovine maleate provocative test for coronary arterial spasm. Am J Cardiol 1978;41:631-40. 4. Curry RC, Pepine CJ, Sabom MB, Conti CR. Similarities of ergonovine-induced and spontaneous attacks of variant angina. Circulation 1979;59:307-12. 5. Cipriano PR, Guthaner DF, Orlick AE, Ricci DR, Wexler L, Silverman JF. The effects of ergonovine maleate on coronary arterial size. Circulation 1979;59:82-9. 6. Crevey BJ, Owen SF, Pitt B. Irreversible coronary occlusion related to administration of ergonovine. Circulation 1981;64:853-6. 7. Buxton A, Goldberg S, Hirshfeld JW, et al. Refractory ergonovineinduced coronary vasospasm: importance of intracoronary nitroglycenn, Am J Cardiol 1980;46:329-34. 8. Waters DD, Chaitman BR, Dupras G, Theroux P, Mizgala HF. Coronary artery spasm during exercise in patients with variant angina. Circulation 1979;59:580-5. 9. Orlick AE, Ricci DR, Cipriano PR, Guthaner DF, Harrison De. Coronary hemodynamic effects of ergonovine maleate in human subjects. Am J Cardiol 1980;45:48-52. 10. Cannon RO, Watson RM, Rosing DR, Epstein SE. Angina caused by abnormal coronary arteriolar vasoconstriction in patients with insignificant fixed coronary artery disease (abstr). Circulation 1982;66(suppl 11):11-44. II. Cannon RO, Watson RM, Rosing DR, Epstein SE. Small vessel coronary constriction as a cause of atypical angina: pitfalls of ergonovine testing (abstr). Circulation 1982;66(suppl 11):11-248.
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12. Abrams J. Nitroglycerin and long acting nitrates. N Engl J Med 1980;302:1234-7. 13. Kern MJ, Ganz P, Horowitz JD, et al. Potentiation of coronary vasoconstriction by beta-adrenergic blockade in patients with coronary artery disease. Circulation 1983;67:1178-85. 14. Yasue H, Touyama M, Kato H, Tanaka S, Akiyama F. Prinzmetal's variant form of angina as a manifestation of alpha-adrenergic receptormediated coronary artery spasm: documentation by coronary arteriography. Am Heart J 1976;91:148-55. 15. Robertson D, Robertson RM, Nies AS, Oates JA, Friesinger GC. Variant angina pectoris: investigation of indexes of sympathetic nervous system function. Am J Cardiol 1979;43:1080-5. 16. Robertson RM, Wood AJJ, Vaughn WK, Robertson D. Exacerbation of vasotonic angina pectoris by propranolol. Circulation 1982;65: 281-5. 17. Yasue H, Omote S, Takizawa A, et al. Pathogenesis and treatment of angina pectoris at rest as seen from its response to various drugs. Jpn Circ J 1978;42:1-10. 18. Cannon RO, Watson RM, Rosing DR, Epstein SE. Detrimental effect of propranolol on anginal threshold of patients with angina and insignificant epicardial coronary artery disease (abstr). J Am CoIl Cardiol 1983;1:595. 19. Madias JE. The syndrome of variant angina culminating in acute myocardial infarction. Circulation 1979;59:297-306. 20. Heupler FA Jr. Provocative testing for coronary arterial spasm: risk, method and rationale. Am J Cardiol 1980;46:335-7. 21. Moran TJ, French WJ, Abrams HF, Criley JM. Postmyocardial infarction angina and coronary spasm. Am J CardioI1982;50:197-202. 22. Koiwaya Y, Torii S, Takeshita A, Nakagaki 0, Nakamura M. Postinfarction angina caused by coronary arterial spasm. Circulation 1982;65:275-80.
635
Refractory Coronary Artery Spasm VIRINDERJIT S. BAMRAH, MD, FACC, GREGORY J. SCHUCHARD, MD Milwaukee, Wisconsin
A patient with an episode of refractory myocardial ischemia induced by ergonovine is described. The patient underwent cardiac catheterization 2 weeks after an inferior wall myocardial infarction for evaluation of recurrent rest angina. He developed severe spasm of the proximal right coronary artery in response to ergonovine which was partially relieved with nitrates and calcium channel antagonists. However, myocardial ischemia per-
Coronary artery spasm has become a frequently recognized cause of angina as awareness and knowledge of this interesting disease entity has expanded. It has been identified in patients with and without obstructed coronary arteries and in vein grafts after coronary artery bypass surgery. The complications of coronary spasm include severe cardiac arrhythmias, such as ventricular tachycardia and fibrillation, conduction disturbances, acute myocardial infarction and sudden death. The administration of ergonovine has been used as a very sensitive and specific provocative test to document coronary spasm. Most patients with spontaneous or ergonovine-induced coronary artery spasm respond promptly, that is, within 3 to 5 minutes, to sublingual nitroglycerin 0-5). However, in a few patients ergonovine resulted in serious cardiovascular complications due to intractable coronary artery spasm (6,7). We report a case of severe and intractable myocardial ischemia that was induced by ergonovine and resulted in acute myocardial infarction.
Case Report Clinical history and findings. A 67 year old white man with known hypertension, peptic ulcer disease and chronic
From the Cardiovascular Section, Medical Service, Veterans Administration Medical Center, Wood (Milwaukee), Wisconsin and the Department of Medicine, The Medical College of Wisconsin, Milwaukee. Manuscript received January 18, 1984; revised manuscript received April 10, 1984, accepted April 16, 1984. Address for reprints: Virinderjit S. Barnrah, MD, Cardiovascular Section/I I 1M, Veterans Administration Medical Center, 5000 West National Avenue, Wood (Milwaukee), Wisconsin 53193. © 1984 by the American College of Cardiology
sisted, culminating in a new inferior wall infarction. The possible mechanism of continuing intense ischemia despite partial relief of the proximal right coronary spasm is discussed. It is suggested that ergonovine testing should perhaps be avoided during the early postinfarction period. Furthermore, if an ergonovine test is anticipated, beta-adrenergic blocking agents should be withheld.
obstructive pulmonary disease was hospitalized because of severe retrosternal chest pain radiating to both arms and the jaw and lasting approximately 1 hour. The pain was only slightly relieved with 1.2 mg of sublingual nitroglycerin and required 10 mg of intravenous morphine sulfate for complete control. Blood pressure was 142/94 mm Hg, pulse 70/min and regular and an S4 gallop was audible at the apex. The admission electrocardiogram showed sinus rhythm, 2 mm ST segment elevation in leads II, III and aVF and 1 mm ST segment depression in leads V I and V2' On the second hospital day, Q waves developed in leads II, III and aVF. The serial electrocardiograms and serum cardiac enzymes were compatible with the development of acute inferior wall myocardial infarction. The ST segments returned to baseline values by the third day. On the fourth hospital day, the patient developed another episode of severe retrosternal chest pain with ST segment elevation in leads II, III and aVF. The patient was started on treatment with oral nifedipine (30 mg every 6 hours), oral metoprolol (50 mg twice daily) and nitroglycerin paste (2 inches [5.08 em] every 6 hours topically). He had two additional similar episodes of chest pain that were controlled by morphine sulfate. Cardiac catheterization and angiography. Cardiac catheterization was performed on the 13th day after infarction because of the recurrent rest angina. Left ventricular end-diastolic pressure at rest was elevated at 20 mm Hg. The left ventriculogram showed moderate hypokinesia of the diaphragmatic and posterolateral segments in the 30° right and 60° left anterior oblique views, respectively. The right coronary artery was dominant and showed two areas of 20 and 40% narrowing, respectively, in its proximal segment and another 20% narrowing in its middle segment 0735-1097/84/$3.00
636
BAMRAH AND SCHUCHARD CORONARY SPASM
(Fig. lA). The left main trunk, anterior descending and proximal circumflex vessels were normal. The second marginal branch of the left circumflex vessel was totally occluded as its origin and opacified slowly by means of collateral vessels. Ergonovine study. The recurrent postinfarction angina appeared to be somewhat out of proportion to the extent and severity of atherosclerotic coronary artery disease. The occluded second marginal branch was considered to be responsible for the inferior wall myocardial infarction, but coronary artery spasm was considered as a possible explanation for the postinfarction angina. To evaluate the possible role of coronary artery spasm, 0.05 mg of ergonovine maleate was given intravenously while pulmonary and systemic arterial pressures and cardiac rhythm were monitored continuously. The patient developed his typical severe retrostemal chest pain with ST segment elevation in leads II, III and aVF, and ST segment depression in leads I, aVL and V4 to V6 within 5 minutes of ergonovine administration (Fig. 2). Repeat angiography showed further narrowing of the two proximal right coronary artery lesions to 80 and 50% stenosis, respectively (Fig. 18). Five minutes after 0.8 mg of sublingual nitroglycerin, the 80% proximal narrowing decreased to 60% (Fig. lC). Despite the partial relief of proximal right coronary artery spasm, intense chest pain and ST segment changes persisted. Sublingual nifedipine (20 mg), intracoronary nitroglycerin (up to 700 ug), intravenous nitroglycerin infusion (up to 100 ug/min), morphine sulfate (4 mg), meperidine hydrochloride (Demerol) (25 mg) and atropine (2 mg) were administered without any relief of chest pain or electrocardiographic changes. The intensity of chest pain and ST segment elevation actually became progressively worse. In response to nitroglycerin, the systolic aortic pressure decreased slightly from the pre-ergonovine level of 145 mm Hg but remained above 90 mm Hg throughout the study. The pulmonary artery diastolic pressure also remained below 15 mm Hg in response to nitroglycerin infusion. The heart rate was unchanged during the first 12 minutes after ergonovine administration, and then it increased to a maximal level of 120 beats/min. ST segment elevation progressively increased to a maximum of 6 mm from the baseline value. The patient then developed three episodes of ventricular fibrillation which were successfully cardioverted. Right and left coronary angiography was repeated several times and showed no further reduction in the proximal right coronary artery narrowing. The left coronary artery was unchanged from the pre-ergonovine angiogram. The patient continued to have chest pain, elevation of ST segments in the inferior leads and ST segment depression in the anterolateral leads. Subsequent hospital course. The patient was transferred to the coronary care unit after placement of a SwanGanz catheter and a temporary pacemaker. After completion
JACC Vol. 4, No.3 September 1984:635-9
Figure 1. Right coronary artery angiograms in left anterior oblique view. A, Proximal segment of right coronary artery shows two separate lesions causing 20 and 40% narrowing, respectively. B, After ergonovine administration, the severity of narrowing increases in both lesions to 80 and 50%, respectively. C, After sublingual nitroglycerin (0.8 mg), the severity of the proximal lesion decreases from 80 to 60%. The second lesion persists as 50% stenosis.
of the catheterization procedure, two-dimensional echocardiography showed reduced wall motion in the inferior and posterolateral segments. Over the next 48 hours, serum enzyme measurements (creatine kinase of 1,853 IV/liter with MB fraction of 16%) were diagnostic of a new myocardial infarction. The patient was free from further episodes of
BAMRAH AND SCHUCHA RD CORONARY SPASM
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angin a on a medical regimen of oral verapamil ( 120 mg four times dail y) and nitroglycerin paste (2 inche s [5.0 8 em] topically four times daily) . A repeat echocardiogram I month later demonstrated con siderable impro vement in the left ventricular segmental wall motion with residual hypokine sia present only in the apical segment. A symptom-limited exercise stress test was performed 21/2 month s later. Th e patient exercised for 660 seconds , achie ving a maximal age-predicted heart rate of 128 beat sl min. Mild angina and premature ventricular complexes developed; howe ver , there was no ST segment change . The radionuclide angiogram at this time showed an ejection fraction of 0.54 at rest, decreasing to 0.49 during maximal exercise .
Discussion The primary purpose of this report is to illustrate that some episodes of ergonovine-induced coronary artery spasm may be unusually prolonged and relatively intractable to commonly available vasod ilator s. Refractory coronary artery spasm. In view of onl y a mode st degree of fixed coronary artery disease (total occlusion of second marg inal branch ) in our case, coro nary vasospasm was considered as a mechanism underlying post-
. .l
637
Figure 2. Serial 12 lead electrocardiograms. A, Control electrocardiogramshowing Q wave in leads II and aVF and T wave inversion in leads II, III, aVF, Vs and V6 , indicating recent inferior wall myocardial infarction . B, Electro card iogram 5 minutes after the administration of ergonovine , showing marked ST segment elevation in leads II, III and aVF and reciprocal ST seg ment depression in leads aVL and V I to V4 . C, Electrocardiogram 2 days after ergonovine study, showing deep Q waves, ST segment elevation and T wave inversion in leads II, III, aVF and V6 · There is reciprocal ST segment depression in leads V I to V4' Compari son with the control electrocardiogram (A) indicates development of acute inferior wall myocardial infarction.
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infarction rest ang ina. We there fore felt justified in performing the ergonovine test. The ergonovine-provoked coronary artery spasm and the resultant myocardial ischemia in our patient were totall y refractory to sublingual, intrave nous and intracoronary nitroglycerin, sublingual nifedipine and atropine. This prolonged ischemic epi sode resulted in acute inferior wall myocardi al infarction . Crevey et al. (6) reported on a patient who also developed in response to ergonovine intract able right coronary artery spasm that resulted in acute inferior wall myo card ial infarction . The ir patient and several others who either developed myocardial infarction or died after an ergonovine test were reported (6-8) to have severe two or three vessel atherosclero tic coronary artery disease. Even though our patient also had athero sclerot ic coronary artery disease , the significant obstruction was limited to only the second marginal bran ch of the left circumflex vessel. In several patients recently reported (6-8) on , ergonovine-provoked coronary artery spasm was resi stant to commonly employed vasodilators. Multiple factor s, such as specific vasodilator used , route of administration and dose of ergonovine used , should be discussed regarding ergonovine testing . The right coronary artery spasm in the case reported by Crevey et al. (6) was intrac table to sublingual nitroglycerin. These investigators did not admini ster
638
BAMRAH AND SCHUCHARD CORONARY SPASM
intravenous or intracoronary nitroglycerin, calcium channel blocking drugs or alpha-adrenolytic agents to reverse the spasm. Buxton et al. (7) reported on five patients with serious ischemic complications (including three deaths) secondary to ergonovine testing. In the two patients who survived, the ergonovine-induced spasm was reversed only by large doses of intracoronary nitroglycerin; sublingual and intravenous nitroglycerin were ineffective. Of the three patients who died of irreversible coronary spasm, all received sublingual nitroglycerin, one received intravenous nitroglycerin, one received a small (100 I-Lg) dose of intracoronary nitroglycerin and two received phentolamine without any effect on the spasm. Our patient received 700 I-Lg of intracoronary nitroglycerin that did not completely relieve the coronary artery spasm. Buxton et al. (7) also recommended that ergonovine be given in small and equal serial doses (0.025 or 0.05 mg each) and that the total dose should not exceed 0.2 mg. Our patient and that of Crevey et al. (6) received only 0.05 mg and developed drug-resistant spasm. Mechanism of ergonovine-induced myocardial ischemia. In our patient, the exact mechanism of the prolonged ischemic episode is not clear. The spasm of the proximal right coronary artery probably was not responsible for persistent ischemia since the maximal obstruction in response to ergonovine was 80%, which promptly decreased to 60% after sublingual nitroglycerin. This modest degree of obstruction usually does not cause intense ischemia in the absence of a markedly augmented myocardial oxygen demand. The oxygen demand in our patient was not significantly increased since the heart rate and blood pressure after ergonovine administration were unchanged. There was no evidence of air or blood clot embolism or dissection involving the right coronary artery. Collapse of this artery was unlikely because the systolic blood pressure remained above 90 mm Hg despite substantial amounts of nitroglycerin. Persistent spasm of the resistance vessels in the right coronary artery vascular bed, despite partial reversal of focal spasm of the proximal segment of the right coronary artery, may have contributed to the continuation of an ischemic event. A high arteriolar resistance would be anticipated to curtail the nutrient flow, even if the spasm of the epicardial portion of the vessel was reversed. Orlick et al. (9) showed that ergonovine may provoke the syndrome of coronary spasm, not only by augmenting resistance in the epicardial segment of the coronary artery, but also by limiting the capacity of coronary arterioles to dilate in response to increased metabolic demands or ischemia. Recently, Cannon et al. (10,11) also demonstrated that abnormal arteriolar constriction in the coronary vascular bed (reduced arteriolar vasodilatory reserve) may result in myocardial ischemia, either spontaneously or in response to ergonovine. Nitroglycerin is a potent dilator of large (epicardial) coro-
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nary arteries, but it has a weak vasodilatory action on the arterioles (12). Thus, it is possible that, even if the proximal right coronary artery spasm was partially relieved, myocardial ischemia persisted because of ergonovine-induced high resistance in the arterioles. Metoprolol, a beta-adrenergic blocking agent that our patient was taking, could have also contributed to his prolonged ischemic episode. Kern et al. (13) demonstrated that beta-adrenergic blockade can potentiate coronary artery vasoconstriction in some patients with coronary artery disease, probably on the basis of unopposed alpha-adrenergic vasomotor tone. Several other studies (14-18) have also shown prolongation of ischemic episodes of beta-adrenergic blockade in patients with documented vasospastic angina. Our patient was probably resistant to nifedipine since he had experienced rest angina in the immediate post-myocardial infarction period while he was receiving oral nifedipine therapy. Although nifedipine has a more generalized vasodilatory effect on the coronary vascular bed, it was ineffective in this patient. Ergonovine test after recent myocardial infarction. The safety of an ergonovine test during the early post-myocardial infarction period is not known. Several authors (1922) have suggested that the test should be avoided during this period. The augmented myocardial oxygen demand occurring secondary to ergonovine-induced elevation of blood pressure and the reduction of myocardial blood flow secondary to ergonovine-induced spasm would be potentially detrimental to recently necrotic myocardium and might even enlarge the infarct size (19,20). Moreover, the ergonovineinduced coronary spasm may be unresponsive to nitroglycerin, as was seen in our patient. Recently, however, Moran et al. (21) and Koiwaya et al. (22) reported that ergonovineinduced spasm was promptly relieved with sublingual nitroglycerin in some patients while others required intracoronary nitroglycerin. There were no ergonovine-related complications in their patients. Clinical implications. Whereas most episodes of ergonovine-provoked vasospastic angina promptly respond to sublingual nitroglycerin, occasional episodes may be unusually prolonged or totally refractory to sublingual nitroglycerin. In these patients, alternate routes for nitroglycerin administration, that is intravenous or preferably intracoronary, and other agents such as calcium channel blocking drugs should be employed without undue delay. In some patients, these episodes may be totally refractory. Ergonovine testing should probably be avoided in patients during the early post-myocardial infarction period. Moreover, if an ergonovine test is anticipated, beta-adrenergic blocking agents should be discontinued beforehand. We gratefully acknowledge the secretarial assistance of Donna Shaughnessy and the editorial assistance of Catherine Walther in the preparation of this manuscript.
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