Ergonovine testing in a coronary care unit

This study describes the results of ergonovine testing in 100 consecutive patients who underwent this procedure in a coronary care unit. All patients had recently undergone coronary arteriography. A bolus injection of ergonovine was administered at 5 minute intervals in the following doses (mg): 0.0125, 0.025, 0.05, 0.1, 0.2, 0.3 and 0.4. The criterion for a positive test was the appearance of S-T elevation greater than 1 mm. The test was positive in all 17 patients known to have variant angina and in 18 (40 percent) of 45 patients who had a history of chest pain judged strongly suggestive of variant angina but who had no electrocardiogram recorded during pain. Of 38 patients with a history of chest pain classified as not entirely typical of variant angina, only 1 (2.6 percent) had a positive test.Of the 64 patients with a negative ergonovine test, 47 had chest pain and 25 had nausea but none had more serious complications. Ventricular arrhythmia accompanied S-T elevation in 18 of the 36 patients with a positive test but occurred in only 4 of the 64 with a negative test (p < 0.0005). No patient needed treatment with antiarrhythmic drugs. Four of the 36 patients with a positive test had serious complications: severe translent hypotension (2 patients), recurrent episodes of angina with S-T elevation (1 patient) and a subendocardial infarction (1 patient). Thus, ergonovine testing is useful in patients with a typical clinical history of variant angina but without an electrocardiogram recorded during pain. in this study, a small but definite incidence of serious complications occurred during a positive test.     

Ventricular arrhythmias during ergonovine-induced episodes of variant angina

Of 95 consecutive patients with active variant angina who underwent ergonovine testing in the coronary care unit while off treatment, 24 (25%) developed serious ventricular arrhythmias: ventricular tachycardia in eight, bigeminy in seven, pairs in five, and frequent ventricular extrasystoles in four. Ergonovine-induced arrhythmias were observed more often in patients with anterior than inferior ST segment elevation (p less than 0.05). ST segment elevation was significantly higher (10.3 +/- 8.1 vs 3.1 +/- 2.1 mm) in patients who developed arrhythmias. All ventricular arrhythmias began within 3 minutes after the onset of ST segment elevation. The intravenous administration of nitroglycerin eliminated arrhythmias in 22 of 24 cases; in only two patients did ventricular arrhythmias develop after the administration of nitroglycerin. Serious ventricular arrhythmias were found during spontaneous variant angina attacks in 14 of 24 patients with ergonovine-induced arrhythmias compared to 16 of 71 patients without ergonovine-induced arrhythmias (p less than 0.001). We conclude that arrhythmias during ergonovine testing are most often caused by ischemia and not reperfusion. Patients with arrhythmias during ergonovine-induced attacks are more likely to have arrhythmias during spontaneous attacks.     

Nifedipine therapy for refractory coronary arterial spasm.

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. Anginal 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 anginal 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.     

Clinical characteristics of patients with variant angina complicated by myocardial infarction or death within 1 month

Of 132 consecutive patients hospitalized during a 5 year period because of active variant angina, 18 died or had a myocardial infarction within 1 month. In 4 patients an episode of pain and S-T elevation unrelieved by calcium antagonist drugs and intravenous nitroglycerin persisted for more than 1 hour, inducing cardiogenic shock and death before the appearance of Q waves and elevated serum enzyme levels. In the other 14 patients myocardial infarction developed in the electrocardiographic leads in which S-T elevation had occurred during attacks of variant angina.Clinical features were not helpful in distinguishing the 18 patients with complications from the other 114. Angina at rest had been present for less than 1 month in 7 of the 18 patients with infarction compared with 31 of 114 in the other group (probability [p] not significant [NS]). Before infarction the artery presumed to be perfusing the involved territory contained a fixed stenosis of 70 percent or more of luminal diameter in 8 of the 14 patients with complications who had coronary arteriograms compared with 50 of 112 in the other group (p = NS). In 13 of the 18 patients, complications occurred in spite of large doses of calcium antagonist drugs. In 11 of these 13, attacks of variant angina were monitored for 3 to 17 days both before and during treatment. All 11 had fewer attacks with treatment and 5 had no attacks. Daily attacks per patient decreased from 4.6 ± 4.3 to 0.5 ± 0.7 (mean ± standard deviation) (p < 0.01). It is concluded that in variant angina of recent onset myocardial infarction occurs frequently and unpredictably. Myocardial infarction may occur in the absence of severe fixed lesions and in spite of apparent clinical improvement with administration of calcium antagonist drugs.     

Exercise-induced angina provoked by aspirin administration in patients with variant angina

The effects of aspirin (4.0 g/day) given orally to eight patients with variant angina were observed. An exercise stress test performed in the morning was positive in two of seven patients during placebo administration, whereas a test performed in the afternoon at the same exercise work load resulted in negative findings. During aspirin administration, the afternoon exercise test repeatedly provoked anginal attacks associated with electrocardiographic changes (S-T segment elevation in five and S-T depression in two). Rate-pressure product at the end of the exercise test during aspirin administration was significantly lower than that during placebo administration (p <0.01). During aspirin administration, the frequency of angina increased markedly, and the attacks occurred not only during the night or early morning but also in the daytime in six of the eight patients. Our observations suggest that aspirin, in this large dose, reduces the capacity for exercise and provokes exercise-induced coronary arterial spasm in patients with variant angina.     

Comparative study of myocardial ischemia during angina at rest and on exertion using thallium-201 scintigraphy

To compare the results of thallium-201 myocardial scintigraphy during angina at rest with those observed during effort angina, 81 patients were selected in whom the existence of acute myocardial ischemia was indicated both by typical transient S-T segment or T wave changes and by typical anginal pain. In these patients, scintigrams were obtained during 58 attacks of angina on effort (group 1) and during 40 attacks of angina at rest (group 2); 16 patients were studied during both types of angina. The attack at rest was spontaneous in 20 patients and induced by ergonovine maleate in 20 patients.In the presence of S-T segment elevation or transient normalization of inverted T waves, scintigrams were positive in all 24 studies at rest and in 19 of 20 studies during exercise. By contrast, in the presence of S-T segment depression scintigrams were positive in 14 (95 percent) of 15 studies during angina at rest, but in only 20 (53 percent) of 38 during angina on effort. Neither the degree of S-T segment changes nor their duration after injection of thallium was significantly different in resting studies relative to exercise studies, but the heart rate and double product were consistently higher during exercise.The marked difference in sensitivity in detecting ischemia in angina at rest with S-T segment depression compared with detection during exertional angina, even in the same patients, suggests that different pathogenetic mechanisms are responsible for the attack. Conversely, a similar mechanism operating in angina at rest and on exertion during S-T segment elevation and normalization of T waves is suggested by the similarity of thallium-201 scintigraphic findings in this situation. The findings are compatible with the hypothesis of a regional reduction in myocardial blood flow in angina at rest, independently of the direction of S-T segment change, and in exertional angina with S-T segment elevation or normalization of inverted T waves; they suggest an inadequate increase in myocardial blood flow in angina on effort with S-T segment depression.     

Circadian variation in variant angina

Thirteen hospitalized patients with variant angina were studied to assess circadian variation in disease activity. Over 48 hours, all angina attacks were noted, a continuous Holter electrocardiogram was recorded and 2 ergonovine tests were performed 12 hours apart, 1 at 4 AM and the other at 4 PM. Only 2 patients gave a clearcut history of more frequent nocturnal or early morning attacks. During the study period, 1.8 +/- 1.6 AM and 0.62 +/- 1.2 PM angina episodes per patient were reported (p less than 0.02), but a circadian pattern was apparent in only 4 patients. However, Holter analysis revealed 5.3 +/- 13.8 AM and 2.6 +/- 8.5 PM episodes of ST elevation per patient (p less than 0.05) and 8.1 +/- 13.9 AM and 3.2 +/- 8.5 PM episodes of ST elevation, ST depression or T-wave pseudonormalization (p less than 0.01). Ten of 11 patients with Holter abnormalities had more frequent AM than PM attacks (p less than 0.01). ST elevation developed during all 13 of the 4-AM and 12 of 13 of the 4-PM ergonovine tests. In 10 cases the ergonovine threshold at which the attack occurred was lower in the morning, in no case was it lower in the afternoon, and in 3 patients the morning and afternoon doses were identical (p less than 0.01). Thus, circadian variation in disease activity both for spontaneous and provoked attacks is present in most patients with variant angina, even though it is often not clinically apparent.     

Nifedipine in the treatment of Prinzmetal's (variant) angina.

The clinical response to therapy with the calcium-blocking agent nifedipine was assessed in 12 patients with variant angina pectoris who were 44 to 67 years old. Five patients had vasospasm of the left anterior descending coronary artery, and seven had spasm of a dominant right coronary artery. Before nifedipine therapy, the frequency of anginal attacks per 24 hour period ranged from 1 to 12, with ventricular tachycardia accompanying ischemic episodes in 7 of 12 patients and high grade atrioventricular block occurring in 2 patients. After therapy with nifedipine, 11 of 12 patients had initial relief of symptoms, and 7 of the 11 had long-term relief. Withdrawal of nifedipine led to recurrence of angina on six occasions in four patients. Provocative testing in the cardiac catheterization laboratory by means of the cold pressor test in one patient and ergonovine maleate in another before and after nifedipine administration showed that this agent can block both alpha adrenergic- and regonovine-induced vasospasm. Nifedipine may have a significant role in the therapy of angina caused by coronary spasm.     

Comparison of coronary arteriographic findings during angina pectoris associated with S-T elevation or depression

Coronary arteriographic findings during an attack of angina pectoris associated with S-T segment elevation and angina associated with S-T depression were compared in 54 patients. Thirty-eight attacks with S-T segment elevation included 2 that were spontaneous, 6 induced by methacholine, 4 by epinephrine with or without propranolol, 9 by arm exercise, 5 by hyperventilation with or without Tris-buffer infusion and 12 by ergonovine maleate. Twenty-nine of the 38 attacks were associated with total occlusion, 8 with subtotal occlusion and 1 with diffuse narrowing of a major coronary artery caused by spasm.Twenty-six attacks with S-T segment depression included 3 induced by methacholine, 13 by arm exercise, 3 by hyperventilation with or without Tris-buffer infusion and 7 by ergonovine maleate. Eight of the 26 attacks were associated with subtotal occlusion and 9 with diffuse narrowing of a major coronary artery caused by spasm; 3 attacks were associated with total occlusion of a major coronary artery well supplied with collateral vessels and 2 with total occlusion of a small coronary branch caused by spasm. Four attacks were associated not with spasm but with fixed subtotal occlusion of a major coronary artery (3 attacks) or total occlusion of a major coronary artery receiving collateral vessels (1 attack).Only 2 of the 31 patients with S-T segment elevation had collateral vessels compared with 8 of the 16 patients with S-T segment depression (p < 0.001). It is concluded that angina pectoris associated with S-T segment elevation usually indicates more severe myocardial ischemia than angina associated with S-T segment depression.     

S-T segment elevation and coronary spasm in response to exercise

The prevalence rate of exercise-induced S-T segment elevation of 0.1 mV or greater in symptomatic patients is 3.0 to 6.5 percent in most studies. S-T segment elevation is associated with a more severe degree of myocardial ischemia than depression and frequently implies a high grade coronary stenosis in the vessel that supplies the site of ischemia. Leads V₄ to V₆ and bipolar lead CM₅ have been found to be relatively insensitive in detecting exercise-induced S-T segment elevation.

The pathogenesis of S-T segment elevation is different in three clinical patient subsets reviewed. In patients after infarction, the largest of the three subgroups, exercise-induced S-T segment elevation usually appears in leads with Q waves, is more common after anterior myocardial infarction and implies underlying akinetic or dyskinetic wall motion. Of patients with variant angina, 10 to 30 percent have during exercise S-T segment elevation that is most likely provoked by coronary arterial spasm. The natural history of variant angina is cyclic, and clinical observations and laboratory findings are dependent on particular phases in the disease process and treatment. Finally, 0.2 to 1.7 percent of symptomatic patiënts without infarction or variant angina have exercise-induced S-T segment elevation. Although most of the latter have fixed high grade coronary arterial stenoses at angiography, the exact pathogenetic mechanism of S-T segment shift in this patient group is not yet fully understood.     

Variable threshold of exertional angina: a clue to a vasospastic component

A patient with a history of exertional angina occurring at variablelevels of effort underwent three consecutive exercise stresstests to evaluate his coronary reserve. The first test was negative,the second was positive with S-T segment depression, and thethird showed S-Tsegment depression at the beginning of eachstage with a return to normal at the end of each stage and S-Tsegment elevation in lead V₂ at the maximal level of effort.Coronary arteriography during a stress test revealed incompletespasm with asymptomatic S-T segment depression at the site ofa 75% stenosis and the complete occlusion of the vessel at ahigher level of effort associated with symptomatic S-T segmentelevation. A similar electrocardio–graphic and angiographicpattern was observed both during ergonovine maleate injectionand during a cold pressor test. Changes in coronary vasomotortone may play an important role in anginal attacks occurringat a variable level of exertion and during cold exposure     

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Two patients complained of chest pain while at rest and during physical activities. However there seemed to be no direct relation between exertional angina and an increasing level of work performed, indicating that these patients had a variable threshold of angina during exercise. In one patient spontaneous chest pain was associated with transient S-T segment changes in precordial leads, and during coronary arteriography the administration of ergonovine induced spasm of the left anterior descending coronary artery. The other patient showed S-T segment elevation in inferior leads during an ergonovine-induced anginal attack and coronary arteriography revealed a spontaneous spasm of the right coronary artery. In both patients repeated exercise tests yielded different results, because the chest pain and S-T segment depression occurred at different work loads with large differences in heart rate-systolic blood pressure product.It is concluded that a variable threshold of angina during exercise is a clinical manifestation in some patients with vasospastic angina and is probably due to the difference in coronary arterial tone at the onset of exercise.     

Magnesium deficiency detected by intravenous loading test in variant angina pectoris

To study whether magnesium (Mg) deficiency is present in patients with variant angina, 24-hour Mg retention of low dose Mg (0.2 mEq/kg lean body weight) administered intravenously over 4 hours in 20 patients with variant angina was examined. No patient had received calcium antagonists before or during the study. All had attacks of chest pain associated with ST elevation on electrocardiograms. Twenty-one subjects without ischemic heart disease were studied as control subjects. Ten patients with variant angina were restudied 10 to 529 days (mean 235 +/- 30) after the treatment with calcium antagonists (diltiazem 120 to 240 or nifedipine 40 to 80 mg/day), which resulted in complete suppression of anginal attacks. The mean serum Mg concentrations in the patients with variant angina and the control subjects were 2.1 +/- 0.05 and 2.1 +/- 0.03 mg/dl, respectively (difference not significant). However, 24-hour Mg retention in the patients with variant angina was 60 +/- 5%, while that in the control subjects was 36 +/- 3% (p less than 0.001), suggesting that Mg deficiency is present in at least some patients with variant angina. The mean serum Mg concentrations before and after calcium antagonist treatment in 10 patients with variant angina were 2.1 +/- 0.09 and 2.1 +/- 0.07 mg/dl, respectively (difference not significant). However, 24-hour Mg retention decreased significantly (p less than 0.01) from 60 +/- 6 to 34 +/- 7% after the treatment. There is Mg deficiency in many patients with variant angina and it is corrected after treatment with calcium antagonists.     

Prinzmetal's angina during 5-fluorouracil chemotherapy

Variant angina developed during intravenous 5-fluorouracil therapy in a patient without prior history of angina pectoris. Ambulatory electrocardiography demonstrated S-T segment elevation and ventricular ectopy during pain, whereas no symptoms or S-T segment changes occurred during placebo therapy. Prophylaxis with both nifedipine and diltiazem was successful in preventing recurrence. It is believed that 5-fluorouracil induced coronary vasospasm and that this was prevented by prophylactic calcium antagonist therapy. Drug-induced coronary artery spasm may be the cause of 5-fluorouracil-associated chest pain.     

Symptomatic coronary artery spasm following radiotherapy for Hodgkin's disease

Four years after mediastinal radiation for Hodgkin's lymphoma, a 32-year-old man developed angina at rest and with varying levels of physical activity. At coronary arteriography, 40 percent to 50 percent stenoses were seen in the left coronary artery; ergonovine induced severe coronary spasm. Treatment with diltiazem eliminated all anginal attacks.     

Coronary arterial spasm as a cause of exercise-induced ST-segment elevation in patients with variant angina.

Four patients with variant angina pectoris exhibited reproducible exercise-induced chest pain and ST-segment elevation. Coronary arterial spasm was documented with arteriography during exercise-induced ST-segment elevation (three patients) or after intravenous administration of ergonovine maleate (one patient). Our observations show that in patients with variant angina exercise can trigger coronary arterial spasm, thus inducing anginal pain and ST-segment elevation.     

Increased fibrinopeptide A during anginal attacks in patients with variant angina

It is not known whether coronary vasospasm is associated with coronary thrombosis. In this study, plasma levels of fibrinopeptide A during anginal attacks in 24 patients with variant angina were examined. A hyperventilation test was used to induce angina. Hyperventilation induced angina and ST segment elevation (AST: 0.32 +/- 0.14 mV, p less than 0.01) in eight patients with variant angina. Fibrinopeptide A increased from 0.75 +/- 0.27 at control to 7.8 +/- 4.4 ng/ml (p less than 0.01) during anginal attacks in these eight patients. In addition, four patients had spontaneous attacks of angina; they also had elevated levels of fibrinopeptide A during attacks (from 2.0 +/- 1.2 at control to 21.9 +/- 18.0 ng/ml [p less than 0.01] during attacks). Hyperventilation did not induce either angina or ST segment elevation in 12 of the patients with variant angina. Fibrinopeptide A levels did not change with hyperventilation in these patients. To determine whether elevated plasma levels of fibrinopeptide A were associated with angina, the plasma levels of fibrinopeptide A were examined during exercise-induced angina in seven additional patients with stable effort angina. They all developed angina with treadmill exercise; however, plasma fibrinopeptide A did not change. Therefore, only the patients with variant angina demonstrated elevated levels of fibrinopeptide A during anginal attacks. These findings suggest that coronary vasospasm associated with myocardial ischemia may induce stasis of blood, resulting in fibrinogen-fibrin conversion in the coronary vessels.     

Usefulness and limitations of the ergonovine maleate test in the evaluation of calcium-antagonist therapy in Prinzmetal variant angina

Ergonovine testing was carried out in a selected group of 25 patients with Prinzmetal's variant angina treated with calcium-antagonists in order to: define its usefulness in the evaluation of the short-term effectiveness of calcium-antagonist treatment; compare the results of the test with those of Holter monitoring; verify if the results of the test during the acute phase are correlated with the long-term response to treatment. In all patients a control period lasting 2-6 days was carried out, after which a treatment period with calcium-antagonists (nifedipine, diltiazem, verapamil), lasting 2-8 days, was instituted. In 20 patients only 1 calcium-antagonist was evaluated, in 1 patient 2 calcium-antagonists and in 4 all of them. Scalar ergonovine test was carried out in control conditions and repeated during each calcium-antagonist treatment period. During both control and treatment periods all patients underwent Holter monitoring for evaluation of frequency of the spontaneous attacks. After the acute phase 21 of the 25 patients were discharged on calcium-antagonist treatment and followed-up for a mean period of 11 +/- 7 months. In control conditions ergonovine test was positive in 24 patients at a mean dose of 0.11 +/- 0.09 mg.(ABSTRACT TRUNCATED AT 250 WORDS)     

Long-term follow-up of verapamil and nitrate treatment for coronary artery spasm

Thirty-seven patients with coronary artery spasm and minor coronary atherosclerosis (34) or normal coronary arteries (3) were followed up long-term. All had angina at rest, 32 had nocturnal angina, and 13 had a positive exercise test with S-T elevation. Three had a previous subendocardial infarction; 10 had had serious arrhythmias, which caused syncope in 7. At last review, 21 months (range 1 to 61) after starting therapy, 27 patients continued on verapamil, 314 (120 to 600) mg/day; 4 who did not respond to verapamil were taking nifedipine, 58 (30 to 80) mg/day; and 16 were also taking isosorbide dinitrate, 41 (20 to 80) mg/day. Of the 31 patients on therapy, 21 were asymptomatic, 9 were improved (1 to 4 attacks/month), and 1 had an average of 8 anginal attacks/month; the remaining 6 had stopped therapy and 5 were asymptomatic a mean of 10 (3 to 18) months after stopping. The exercise test became negative in all 12 patients tested on therapy, although 3 required nitrates in addition to verapamil or nifedipine.In 26 supervised treatment withdrawals in the hospital, a mean of 15 (1 to 55) months on therapy, 10 developed angina in less than 48 hours. Angina recurred in all 6 unsupervised, patient-initiated withdrawals. Failure to stop smoking was positively associated with recurrence of angina on treatment withdrawal (p < 0.02).Long-term treatment of coronary artery spasm with verapamil or nifedipine together with isosorbide dinitrate was well tolerated and effectively relieved angina. No documented serious arrhythmias, syncopal episodes, myocardial infarction, or death occurred during follow-up.     

Failure of ketanserin, a serotonin inhibitor, to prevent spontaneous or ergonovine-induced attacks of variant angina

Six patients hospitalized with active variant angina were treated for 3 days with the serotonin antagonist ketanserin after a 3 day control period on no medication. The number of variant angina episodes per patient per day was 1.52 +/- 1.42 during the control period and 2.05 +/- 2.30 during ketanserin therapy (p = NS). Ergonovine was administered in incremental doses of 0.0125 mg to 0.4 mg in the control period, during intravenous ketanserin administration and after 3 days of oral treatment. All 6 patients developed ST elevation during all 3 ergonovine tests. The ergonovine dose at which ST elevation developed was similar in each of the 3 periods. It is concluded that ketanserin is of no value in the treatment of variant angina and that both spontaneous and ergonovine-induced coronary spasm in man are unlikely to be mediated by a serotonergic mechanism.