Nifedipine therapy for refractory coronary arterial spasm

Nifedipine Therapy for Refractory Coronary Arterial Spasm

FREDERICK FACC WILLIAM

A.

HEUPLER,

L. PROUDFIT,

Jr.,

MD,

MD

Cleveland, Ohio

Nifedipine was evaluated in the management of eight patients with intractable coronary arterial spasm. All had Prinzmetal’s variant angina, normal or mildly abnormal coronary arteriograms, and a positive ergonovine maleate provocative test. Angina1 attacks occurred at least three times a week in all patients during isosorbide dinitrate therapy. All patients had a decrease in frequency of ischemic attacks with nifedipine. Seven patients underwent repeat Holter monitor evaluation, which confirmed the absence of ischemic changes while they were taking nifedipine. When nifedipine dosage was decreased or therapy discontinued in six patients, all experienced a recurrence of angina1 attacks. Two patients had minor side effects, which required a decrease in the dose of nifedipine. Nifedipine was well tolerated, and no major complications occurred with its use. Nifedipine appears to be effective in the management of patients with symptomatic coronary arterial spasm and normal or mildly abnormal coronary arteriograms. Our data justify further investigation of nifedipine for treatment of such patients.

Patients with normal or mildly abnormal coronary arteriograms may suffer from Prinzmetal’s variant angina due to coronary arterial spasm.1-5 These patients often do not respond to isosorbide or propranolol therapy,6,7 and coronary arterial bypass surgery is usually ineffective.3,7,s A few patients are refractory to all therapy and remain incapacitated. Several investigators have suggested that nifedipine, an experimental drug, is effective in treatment of patients with Prinzmetal’s variant angina and normal coronary arteriograms.g-ll Therefore, we undertook a pilot study of nifedipine for the management of patients with intractable symptomatic coronary arterial spasm. The effects of therapy were evaluated by symptomatic response and electrocardiographic monitoring. Methods

From the

Department of Cardiology, The Cleveland Clinic Foundation, Cleveland, Ohio. Manuscript received April 4. 1979; revised manuscript received July 16. 1979, accepted July 20, 1979. Address for reprints: Frederick A. Heupler, Jr., MD, The Department of Cardiology, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44106.

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Patients: The study group (Table I) consisted of eight patients with Prinzmetal’s variant angina due to spasm involving a normal or mildly abnormal coronary artery (less than 50 percent fixed narrowing of luminal diameter). Patients were included in this study only if they were unresponsive to isosorbide therapy (Table II). These patients were identified among approximately 27,000 patients who underwent coronary arteriography for suspected arteriosclerotic heart disease at the Cleveland Clinic between December 1972 and January 1979. During this period, a total of 21 patients were identified who had Prinzmetal’s variant angina and normal or mildly abnormal coronary arteriograms, and 14 of these patients were unresponsive to vasodilator therapy. The eight patients who participated in this pilot study included six women and two men whose ages

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NIFEDIPINEFOR CORONARY SPASM--HEU~LER AND PROUDFIT

TABLE I

Clinical and Catheterization Findings Catheterization Case no. 1 2

Age (yr)’ 8 Sex

Symptoms

Resting

Electrocardiogram During Spontaneous lschemia

Coronary Arteries After NTG

43. M

DRA, SA

Normal

S-T? II, Ill, aVF; 2: 1 A-V block; VT

37. F

DRA, SA

Normal

S-T? II, Ill, aVF; sinus arrest; CHB

3 4

36, F 52, F

NA, EA, Cl DRA, NA, EA,

Normal Normal

S-T II, Ill, aVF S-T ! II, Ill, aVF; VT; 2:l A-V block

f

37, F 39, F

Normal Normal

7

54, F

DR: DRA: Cl, DRA,

Normal

S-T? II, Ill, aVF; VT S-T? VI-Vs or T wave changes VI-Vs S-T? II, Ill, aVF; sinus arrest

8

65, M

DRA, SA

Normal

S-T? II, Ill. aVF; VT; VF

NA EA NA: EA, SA NA, SA

Ergonovine Test

20% LCx; 10% RCA 20% RCA: 10% LAD 10% RCA 40% RCA

100% RCA; S-T? II, Ill, aVF; angina S-T? II, Ill, aVF; angina; no repeat catheterization 100% RCA; S-T II, Ill, aVF; angina 100% RCA: S-T t II, Ill, aVF; 2:l A-V block 90% RCA; S-T? II, III, aVF; angina 100% AD; 50% RCA; S-Tt V leads; angina 100% RCA; 95% LAD, LCx; S-Tt II, Ill, aVF; sinus arrest; angina 95% RCA; S-T? II, Ill, aVF

Normal 20% LAD Normal 40% RCA; 40% LCX

Age at onset of symptoms. A-V = atrioventricular; CHB = complete heart block: Cl = coronary insufficiency; DRA = daytime resting angina; EA = exertion& angina; LAD = left anterior descending coronary artery; LCx = left circumflex coronary artery; NA = nocturnal angina; NTG = nitroglycerin; RCA = right coronary artery; SA = syncope with angina; VF = ventricular fibrillation; VT = ventricular tachycardia. l

ranged from 35 to 65 years, with an average age of 45 years. Prinzmetal’s variant angina was defined as: (1) recurrent episodes of angina at rest; (2) transient S-T segment elevation during angina1 attacks; and (3) normalization of the electrocardiogram between attacks, with no evidence of acute myocardial infarction.12 Diagnostic and therapeutic procedures: Coronary arteriography was performed with the Sones technique.‘3 The ergonovine maleate provocative test for coronary arterial spasm was performed in all patients as previously described.4 All patients were treated with isosorbide dinitrate, with a minimal dose of 30 mg sublingually or 40 mg orally a day. Seven patients received propranolol in doses of 80 to 160 mg/day. Five patients were treated with nitroglycerin ointment. Nifedipine was given initially in a dose of 10 mg orally four times a day. In two patients the dose was increased to 20 mg four times a day because of persistent angina. Informed consent was obtained from each patient before nifedipine was administered. Data analysis: Patients were evaluated for frequency of angina every 1 to 3 months after treatment was started. Seven patients underwent long-term ambulatory electrocardio-

TABLE

graphic monitoring while taking nifedipine. The response to therapy was considered poor if the patient did not have a sustained decrease in frequency of angina1 attacks for at least 1 month. The response was considered fair if less than a 50 percent reduction in the frequency of anginal attacks occurred and was considered good if angina1 attacks were reduced in frequency by more than 50 percent.

Results The results and II.

of the study are summarized

in Tables

I

Ergonovine test: This provocative test reproduced the attacks of myocardial ischemia with S-T segment elevation in all patients. During the ergonovine test, seven patients underwent repeat coronary arteriography. This demonstrated coronary spasm with 90 to 100 percent obstruction in the artery supplying the area exhibiting S-T segment elevation. In one patient, the ergonovine test was performed the day after coronary arteriography, and angina and S-T segment elevation developed, Coronary arteriography revealed either

II

Medical Treatment of Coronary Arterial Spasm Nifndioine

Case no. 1 : z 6 7 8

lsosorbide Dinitrate Dose/Day Effect (mg) 30. SI 30, sl 40, PO 30. sl 125, po 30, sl 30. sl 40, sl

Poor Poor Poor Poor Poor Fair Poor Poor

Nitroglycerin Ointment Dose/Day (inch) Effect None 8 None 3 r, None 6

Propranolol Dose/Day Effect (mg)

i&r bobr Poor Poor i&r

160 80 160 8”: 80 160 None

Poor Poor Fair Poor Poor Poor Poor

.

Dose/ Day (mg)

Additional Drugs

80

None Is0 None None None Is0 None None

t:

40 40 80 ::

Effect

Attacks/Month During Before Treatment Treatment

2: ~~ Good Good Good Good

120 60 12 80 120 120 200 150

8 : 1 3: 12 1

Iso = isosorbide dinitrate; po = orally; sl = sublingually.

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NIFEDIPINE FOR CORONARY SPASM-HEUPLER AND PROUDFIT

normal coronary arteries or only mild obstructions in all patients. Response to other drug therapy: None of the eight patients had a good response to isosorbide dinitrate or propranolol. A variety of other medications, including hydralazine, propantheline bromide, phenoxybenzamine, nylidrin, dipyridamole and clonidine, were tried unsuccessfully in these patients. In one patient, sublingual Hydergine@ produced a good response. Kesponse to nifedipine: The response was considered good in all eight patients. The average number of angina1 attacks decreased from 104 a month before niTwo fedipine therapy to 8 a month during therapy. patients continued to have angina1 attacks 8 to 30 times a month while taking nifedipine, 40 mg/day. Larger doses produced severe nausea in one patient, and the second patient had no further symptomatic improvement on 80 mg/day. One patient had a burning sensation in the hands and feet while taking 40 mgfday; these symptoms subsided when the dose was decreased to 30 mg/day. No symptoms of postural hypotension developed, and no serious side effects occurred in any patient. The duration of nifedipine therapy ranged from 2 to 38 months, averaging 21 months. Nifedipine was discontinued in two patients whose angina1 attacks had subsided while they were taking the drug. However, a rapid increase in symptoms developed, and both patients required hospitalization. The symptoms in these patients were again controlled by the patients’ resuming nifedipine therapy. The nifedipine dose was decreased in four patients, and all experienced an increased frequency of angina. Illustrative

Case Report

Case 4: A 53 year old woman was evaluated in February 1977 for a 6 month history of substernal tightness both at rest

and on exertion. Her symptoms were relieved in 2 minutes by nitroglycerin. She had undergone lobectomy for squamous cell carcinoma of the lung in 1975. An electrocardiogram was normal. An X-ray film of the chest showed an elevated right hemidiaphragm. Propranolol and isosorbide dinitrate were administered, but the patient’s chest pain subsequently increased in frequency, usually causing her to awaken at night. An exercise stress test showed normal findings. Cardiac catheterization in May 1977 demonstrated 40 percent narrowing in the right coronary artery (Fig. 1A) and a normal left coronary artery and left ventricle. The next day, an electrocardiogram during angina at rest demonstrated S-T segment elevation in leads II, III and aVF (Fig. 2). After nitroglycerin was taken, the patient’s chest pain subsided, and the electrocardiogram returned to normal. Continuous electrocardiographic monitoring revealed S-T segment elevation, sinus bradycardia, second degree atrioventricular block, and ventricular tachycardia during angina1 attacks, which occurred eight times in 24 hours (Fig. 3). An ergonovine test during repeat coronary arteriography produced total obstruction of the “dominant” right coronary artery (Fig. 1B) and precipitated an attack of variant angina. The coronary spasm, symptoms and electrocardiographic changes subsided promptly after nitroglycerin was given. Angina1 attacks temporarily decreased to one a day when sublingual isosorbide dinitrate and nitroglycerin ointment were used. During the next 2 months, the angina1 attacks increased to three a day. Nylidrin, 36 mg/day, and clonidine, 0.4 mg/day, did not relieve the symptoms. While the patient was taking Hydergine, 6 mglday, the angina1 attacks decreased to three a week. This drug (a combination of dihydroergocornine, dihydroergocristine and dihydroergokryptine) was discontinued because of expense. Nifedipine, 10 mg four times a day, was started in August 1977, and all other medications were gradually discontinued. The patient remained nearly free of angina for 15 months, In November 1978, she had recurrent angina one or two times a day, beginning 1 week after she began to take imipramine hydrochloride, 75 mg/day, for depression. After this drug was

FIGURE 1. Case 4. Arteriograms of right coronary artery in left anterior oblique projection demonstrate localized 40 percent narrowing in the proximal right coronary artery (arrow) after nitroglycerin (A) and total obstruction in the same area (arrow) after ergonovine maleate (6). Angina and S-T segment elevation in the inferior electrocardiographic leads developed during spasm.

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discontinued, the angina1 attacks again subsided to less than one a month. A repeat 12 hour Holter monitor recording while

ANGINA

NO ANGINA

the patient was receiving nifedipine revealed no episodes of S-T segment elevation or arrhythmia. Discussion

This study was undertaken as a preliminary trial to evaluate nifedipine therapy for recurrent and intractable symptomatic coronary arterial spasm in patients with no fixed severe coronary obstructions. Our results suggest that nifedipine is safe, well tolerated, and effective in preventing ischemic attacks produced by coronary arterial spasm. The study group: The study group comprised a homogeneous subset of patients with myocardial ischemia. All patients had Prinzmetal’s variant angina, normal or mildly abnormal coronary arteriograms and a positive ergonovine maleate provocative test. This test, in patients with normal or nearly normal coronary arteriograms, has shown a high degree of specificity in detecting those who suffer from symptomatic coronary arterial spasm.4J4-17 The ischemic attacks induced by the ergonovine maleate test in this study were similar to those that occurred spontaneously. Because all patients had normal or mildly abnormal coronary arteriograms, the symptoms in these patients cannot be attributed to a fixed severe coronary obstruction. The patients in this study are not representative of typical patients with symptomatic coronary arterial spasm. Rather, they represent one extreme of the clinical spectrum, that is, patients with recurrent intractable angina. Nitrate and beta adrenergic blocking drug therapy for coronary spasm: Long-acting nitrates are generally used for the treatment of patients with symptomatic coronary arterial spasm and no fixed severe coronary obstructions. Isolated case reports indicate that isosorbide dinitrate often appears effective in preventing attacks of Prinzmetal’s variant angina in

FIGURE 2. Case 4. Electrocardiograms demonstrating S-T segment elevation in inferior leads during Prinzmetal’s variant angina (left) and return to normal afler the angina subsided (right).

patients with normal coronary arteriograms.l,5J8-21 However, in a larger number of case reports, such patients have not responded to isosorbide dinitrate.1*gJ2-27 Among reports describing five or more patients treated with isosorbide dinitrate, a good response to therapy occurred in less than 50 percent of patients.6f7,28 The reports of therapy in patients with symptomatic coronary arterial spasm may be biased toward those with the more malignant and persistent forms of coronary spasm, because these are more obvious clinically and are more likely to be detected. This may account, in part, for the observation that isosorbide dinitrate does not appear

12: IO AM ANGINA

2:00 AM ANGINA FIGURE 3. Case 4. Continuous electrocardiographic monitor recording of lead II. Top, during angina, S-T segment elevation, sinus arrest with junctional escape rhythm and premature ventricular complexes occurred. Middle, during another episode of angina, S-T segment elevation, Wenckebach phenomenon (atrioventricular block) and ventricular tachycardia occurred. Bottom, the electrocardiogram returned to normal when the patient was free of pain.

6:ooAM NO ANGINA

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to be a satisfactory treatment for many patients with symptomatic coronary arterial spasm and normal coronary arteriograms. Among 21 patients with Prinzmetal’s’ variant angina and normal or nearly normal coronary arteriograms evaluated at the Cleveland Clinic, only 7 (33 percent) had a good response to isosorbide dinitrate therapy. However, it is possible that more patients would have responded to isosorbide dinitrate if larger doses had been used. Most, patients with coronary arterial spasm do not respond to propranolol therapy,1,3,g,22,24-27,2g although occasionally patients showed improvement, especially when propranolol was used in conjunction with isosorbide dinitrate.18*30,31 In a few patients, propranolol therapy was associated with an increase in symptoms.1gr32T33 We believe that propranolol should be avoided or used with caution in patients with symptomatic coronary arterial spasm. Other drugs for therapy of coronary spasm: Most patients with symptomatic coronary arterial spasm do not respond to phenoxybenzamine (Dibenzyline@)1p25,86,31or atropine, l,g although occasional successes have been reported with these drugs. Among the patients in this study, a variety of drugs, including hydralazine, propantheline bromide, nylidrin, clonidine, phenoxybenzamine and dipyridamole, were tried without success. Hydergine produced a marked decrease in symptoms in one patient (Case 4), but conclusions cannot be drawn from this one case. Patients in whom ventricular tachycardia or fibrillation develops during coronary arterial spasm often fail to respond to lidocaine, quinidine sulfate or procainamide.gJ4*25 One patient in this study (Case 8) had recurrent ventricular tachycardia refractory to antiarrhythmic therapy. His attacks of ventricular tachycardia, which occurred only during episodes of S-T segment elevation, were controlled only when the episodes of coronary spasm and S-T segment elevation were prevented by administration of nifedipine. One patient (Case 4) had a dramatic increase in angina coinciding with imipramine therapy. This finding suggests that imipramine, a tricyclic antidepressant, may provoke coronary arterial spasm. This effect could be due to the vasoconstrictor effect of tricyclic antidepressants, which block the uptake of norepinephrine at the cell membrane of adrenergic neurons,34 or it may be produced by a drug interaction with nifedipine. Tricyclic antidepressants should be used with caution in patients who have symptomatic coronary arterial spasm. Nifedipine and other calcium flux antagonists: Nifedipine is one of a group of calcium flux antagonists that also includes perhexiline maleate, verapamil and

diltiazem. It is a dihydropyridine derivative that is structurally unrelated to existing antianginal drugs. It acts by blocking the transmembrane flux of calcium ions into the myocardial ce11.s5 This, in turn, reduces the availability of intracellular free calcium ions, which are necessary for activation of the enzyme adenosine triphosphatase. Because the energy for muscle contraction is derived from the splitting of adenosine triphosphate by adenosine triphosphatase, nifedipine reduces contractility of the myocardial cell. It apparently acts in a similar manner on the smooth muscle of coronary arteries, causing coronary vasodilatation by inhibition of smooth muscle contraction. It produces preferential dilatation of coronary, cutaneous and muscular arteries. Nifedipine is supplied in capsules containing 10 mg of the drug in solution. Approximately 90 percent of an orally administered dose is absorbed. It is excreted primarily by the kidneys, and its elimination half-life from serum is approximately 4 to 5 hours. The main side effects are headache (6 percent), vomiting (4 percent) and dizziness (3 percent). Nifedipine has been widely used in Europe, South America and Asia for patients with typical angina as well as Prinzmetal’s variant angina. Several investigators have evaluated nifedipine for treatment of patients with Prinzmetal’s variant angina and normal coronary arteriograms. Hosoda and Kimura’l found nifedipine effective in 12 of 17 patients; Goldberg et al.1° reported good relief in three patients, partial relief in one and no effect in two; and Endo et al9 reported good results with nifedipine in 25 patients with Prinzmetal’s variant angina, including 19 with no fixed severe obstructions. Three other calcium flux antagonists have been investigated for therapy of symptomatic coronary arterial spasm. Verapamil,seJs perhexiline maleate,32T37 and diltiazemss have been reported to be effective in the treatment of patients with Prinzmetal’s variant angina an-d no fixed severe obstructions. Implications: Our experience with nifedipine in eight patients with symptomatic coronary spasm who were unresponsive to other medications is encouraging. This drug was highly effective in controlling symptoms and preventing S-T segment elevation in all patients. However, three patients continued to have attacks of angina from 8 to 30 times a month. No major side effects occurred as a result of nifedipine therapy, although one patient experienced nausea when the dose was increased to 80 mg/day, and another complained of a burning sensation in the hands and feet on a dosage of 40 mg/ day. The data accumulated in this pilot study justify further trials of nifedipine for the management of patients with symptomatic coronary arterial spasm.

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angina of Prinzmetal with normal coronary arteriograms: a variant of the variant. Circulation 47:476-485, 1973 3. Dhurandhar RW, Watt DL, Silver MD, Trimble AS, Adelman AG: Prinzmetal’s variant form of angina with arteriographic evidence of coronary arterial spasm. Am J Cardiol 30:902-905, 1972

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4. Heupler FA Jr, Proudfit WL, Razavi M, Shirey EK, Greenstreet R, Sheldon WC: Ergonovine maleate provocative test for coronary arterial spasm. Am J Cardiol 41631-640, 1978 5. Oliva PB, Potts DE, Pluss RG: Coronary arterial spasm in Prinzmetal angina: documentation by coronary arteriography. N Engl J Med 288:745-75 1, 1973 6. Johnson AD, Stroud HA, Vieweg VR, Ross J Jr: Variant angina pectoris: clinical presentations, coronary angiographic patterns, and the results of medical and surgical management in 42 consecutive patients. Chest 73:706-794, 1978 7. Pasternak RC, Hutter AM Jr, DeSanctis RW, Jaro MF, Flynn T, Buckley MJ: Variant angina: management and followup (abstr). Circulation 57-58:Suppl ll:ll-133, 1978 8. Gaasch WH, Lufshanowski R, Leachman RD, Alexander JK: Surgical management of Prinzmetal’s variant angina. Chest 66: 614-621, 1974 9. Endo M, Kanda I, Hosoda S, Hayashi H, Hirosawa K, Konno S: Prinzmetal’s variant form of angina pectoris: re-evaluation of mechanisms. Circulation 52:33-37, 1975 IO. Goldberg S, Reichek N, Muller J, Gunther S, Kastor JA: Nifedipine: a useful new agent for the therapy of variant angina (abstr). Circulation 57-58:Suppl ll:ll-101, 1978 11. Hosoda S, Kimura E: Efficacy of nifedipine in the variant form of angina pectoris. In, New Therapy of lschemic Heart Disease, Third International Adalat Symposium (Jatene AD, Lichtlen PR, ed). Amsterdam, Excerpta Medica, 1976, p 195- 199 12. PriRzmetal M, Kennamer R, Merliss R, Wada T, Bor N: Angina pecforis: a variant form of angina pectoris. Am J Med 27:375-388, 1959 13. Sones FM Jr, Shirey EK: Cine coronary arteriography. Mod Concepts Cardiovasc Dis 31:735-738. 1962 14. Curry RC, Pepine CJ, Sabom MB, Feldman RL, Christie LG, Varhell JH, Conti CR: Hemodynamic and myocardial metabolic effects of ergonovine in patients with chest pain. Circulation 58: 648-654, 1978 15. Higgins CB, Wexler L, Silverman JF, Hayden WG, Anderson WL, Schroeder JH: Spontaneously and pharmacologically provoked coronary arterial spasm in Prinzmetal variant angina. Radiology l&521-527, 1976 16. Specchia G, Angoli L, DeServi S, Mussini A, Bramucci E, Marinoni G, Ray M, Montemarfini C, DiGuglielmo L, Bobba L: Spasm0 coronarico indotto dalla somministrazione di ergonovina maleato in soggetti affetti da angina spontanea. G ltal Cardiol6:1177-1183, 1976 17. 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 40:487-491, 1977 18. Allaire BI, Schroeder JS: Prinzmetal’s angina. West J Med 122: 187-193, 1975 19. Black MM, Black A, Huntington P: Prinzmetal’s variant angina with syncope: treatment with permanent demand pacemaker. NY State J Med 76~255-258, 1976 20. Christian N, Botti RE: Prinzmetal’s variant angina pectoris with prolonged electrocardiographic changes in the absence of ob-

structive coronary disease. Am J Med Sci 263:225-232, 1972 21. Owlia D, Prabhu R, Pierce JA, Stoughton PV, Shankar KR, Nino A: Variant angina pectoris due to coronary artery spasm: Chest 671727-729. 1975 22. Combs DT, Wilkin JH, Blewett C, Gregoratos G: Spasm of the left coronary artery with aortocoronary bypass (communication to the editor). Chest 66:737-738, 1974 23. Chahlne RA, Rairner AE, lshimori T, Luchi RJ, McIntosh HD: The incidence and clinical implications of coronary artery spasm. Circulation 52:972-978, 1975 24. Hart NJ, Silverman ME, King SB: Variant angina pectoris caused by coronary artery spasm. Am J Med 56:269-274, 1974 25. Muller JE, Gunther SJ: Nifedipine therapy for Prinzmetal’s angina. Circulation 57:137-139, 1978 26. Solberg LE, Nissen RG, Vlietstra RE, Callahan JA: Prinzmetal’s variant angina: response to verapamil. Mayo Clin Proc 53:256-259, 1978 27. Wiener L, Kasparian H, Duca PR, Walinsky P, Gottlieb RS, Hanckel F, Brest AN: Spectrum of coronary arterial spasm: clinical, angiographic, and myocardial metabolic experience in 29 cases. Am J Cardiol 38:945-955, 1976 28. Higgins CB, Wexler L, Silverman JF, Schroeder JS: Clinical and arteriographic features of Prinzmetal’s variant angina: docum&tation of etiologic factors. Am J Cardiol 37:831-839, 1976 29. Whiting RB, Klein MD, Veer JV, Lown B: Variant angina pectoris. N Engl J Med 282:709-712. 1970 30. Donsky MS, Harris MD, Curry GC, Blomqvist CG, Willerson JT, Mullins CB: Variant angina pectoris: a clinical and coronary arteriographic spectrum. Am Heart J 89:571-578, 1975 3 1. Marcus HR, Easley RM Jr: The effectiveness of high dose beta blockade in patients with variant angina pectoris. RI Med J 61: 159-163, 1976 32. Curry RC Jr: Prinzmetal’s angina: provocative test and current therapy. JAMA 240:677-679, 1978 33. Yasue H, Touyama M, Shimamoto M, Kato H, Tanaka S, Akiyama F: Role of autonomic nervous system in the pathogenesis of Prinzmetal’s variant form of angina. Circulation 50:534-539, 1974 34. Jefferson JW: A review of the cardiovascular effects and toxicity of tricyclic antidepressants. Psychosom Med 37:160-179. 1975 35. Fleckenstein A: On the basic pharmacological mechanism of nifedipine and its relation to therapeutic efficacy. In Ref 11, p 1-13 36. Lipton SA, Markis JE, Pine MB, Paulin S, Lindsay HE: Cessation of smoking followed by Prinzmetal’s variant angina and diffuse esophageal spasm (communication to the editor). N Engl J Med 299:775, 1978 37. Mirgala HF, Chaitman BR, Theroux P, Convert G: Successful treatment of “variant angina” with oral perhexilene maleate (abstr). Circulation 53-54:Suppl ll:ll-72, 1976 38. Yasue H, Nagao M, Omote S, Takirawa A, Miwa K, Tanaka S: Coronary arterial spasm and Prinzmetal’s variant form of angina induced by hyperventilation and Tris-buffer infusion. Circulation 58:56-62, 1978

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