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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.

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 less than 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.

A subgroup of 22 patients with Prinzmetal angina and a good clinical response to treatment with calcium inhibitors was studied to determine whether the ergonovine provocation test could help decide when to stop treatment. Before treatment, all patients had ST elevation during the ergonovine test which was performed in the coronary care unit. After 9,4 +/- 4,7 months' treatment, all 22 patients were asymptomatic. Their treatment was discontinued and the ergonovine test repeated. Twelve of the 22 patients had no anginal pain or ST segment changes during the test. Without therapy, none of these 12 patients have experienced recurrence of angina during a follow up period of 4,2 +/- 2,9 months. Angina with ST elevation occurred in 7 patients during the ergonovine test, as observed during their initial provocation tests. In 3 other patients, ergonovine induced ST depression in the leads in which ST elevation had been recorded during their initial tests. Treatment was restarted in these 10 patients with positive tests. There were no complications. Spontaneous remissions of symptoms and negative ergonovine tests may be observed in some patients with Prinzmetal angina. Without treatment this group of patients may remain asymptomatic for several months.

A subgroup of 22 patients with variant angina who had responded well to calcium antagonist drugs were studied to determine if ergonovine testing could help assess the need for continued therapy. Before treatment all 22 patients exhibited angina with S-T elevation during ergonovine testing done in the coronary care unit according to a previously described protocol with sequential ergonovine doses of 0.0125, 0.025, 0.05, 0.1, 0.2, 0.3 and 0.4 mg administered at 5 minute intervals. After 9.4 +/- 4.7 (range 1 to 24) months of treatment (nifedipine 7 patients, diltiazem 3, verapamil 8, perhexiline 3, nifedipine and diltiazem 1), all patients were free from anginal attacks. Medication was discontinued and ergonovine testing repeated 24 to 48 hours later (3 weeks for perhexiline). In 12 of the 22 patients, angina or S-T segment shifts did not occur during the second ergonovine test to a maximal dose of 0.4 mg. Treatment was not restarted in these patients and all 12 remain free of variant anginal attacks 4.2 +/- 2.9 (range 1 to 13) months later. In seven patients angina and S-T elevation occurred during the second ergonovine test, in the same electrocardiographic leads as during the test before treatment. In three patients the ergonovine test induced angina with S-T depression in the leads where S-T elevation had occurred during the previous test. Treatment was reinstituted in these 10 patients with a positive test. No complications resulted from ergonovine testing in any patient. We conclude that in many patients with variant angina, symptoms will disappear spontaneously and the ergonovine test will revert to negative. Treatment with calcium antagonist drugs can probably be safely discontinued in some patients with variant angina; ergonovine testing appears to be helpful in identifying such patients. Longer periods of follow-up are required to confirm that symptoms do not recur.

Variant angina was diagnosed after coronary artery bypass surgery in six patients over a 22-month period. Although all six patients had at least occasional angina at rest preoperatively, all but one had predominantly exertional angina. After surgery, rest angina with transient ST-segment elevation appeared in all six after an asymptomatic interval of 1 week to 4 years. In two patients the involved artery had not been bypassed, in two patients it was perfused by a patent graft and in two patients the graft to the involved vessel was occluded. Treatment with calcium antagonist drugs (four cases) or isosorbide dinitrate (one case) eliminated symptoms; one patient spontaneously became asymptomatic. The diagnosis of variant angina should be considered when rest angina occurs after bypass surgery, particularly if exertional angina is absent and grafts are patent.

Among 268 patients undergoing percutaneous transluminal coronary angioplasty between February 1980 and January 1983, a total of 21 patients had variant angina, documented before angioplasty in 14 and after angioplasty in 7. Before angioplasty, all 21 patients had rest angina and 17 also had effort angina; single vessel coronary artery disease with 60 to 95% stenosis was present in all patients and the left anterior descending coronary artery was involved in all but 3 patients. Coronary angioplasty was successful in 19 patients (90%). Eight of the 19 patients remained symptom-free without coronary restenosis after successful angioplasty; in the other 11 patients, angina reappeared within 4 months, usually in association with restenosis. Of the nine patients with coronary restenosis, six had repeat angioplasty (five successful procedures and one failure), two received medical therapy and one underwent coronary bypass surgery. Patients in whom calcium channel antagonists were discontinued immediately after angioplasty had an exceedingly high coronary restenosis rate (8 [80%] of 10 successful attempts), but when calcium antagonists were continued for an average of 6 +/- 4 months after angioplasty, the restenosis rate was low (3 [21%] of 14 successful attempts). After a mean (+/- SD) follow-up period of 33 +/- 13 months, 1 patient had died and the 20 others (95%) were symptom-free; among these 20, 15 patients (75%) had been taking no antianginal drugs for more than 1 year, 2 still received calcium channel antagonists and 3 had had coronary bypass surgery. Repeat coronary arteriography performed 14 +/- 7 months after angioplasty in the 17 patients without angioplasty-related infarction or surgery showed 50% or less coronary stenosis in 13 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Among the first 83 patients treated with percutaneous transluminal coronary angioplasty (PTCA) at our institution, typical variant angina was recognized beforehand in five cases and was discovered within 4 months of PTCA in six others. All patients had a 65-95% proximal left anterior descending coronary artery stenosis and only one had a coronary lesion greater than 50% in other coronary arteries. Before PTCA, all patients were premedicated with calcium-antagonist drugs. Thirteen of 15 PTCAs, including three of four repeat PTCAs, were technically successful. However, variant angina recurred after successful PTCA in three of the five patients in whom it was documented beforehand and in an additional two of two patients with variant angina before a successful repeat PTCA. Overall, among the nine patients with variant angina after successful PTCA, five had restenosis at the site of PTCA and two others developed severe lesions adjacent to the site of PTCA within 4 months of the procedure. The three patients without restenosis have been treated with calcium-antagonist drugs from soon after PTCA and have remained angina-free. These results suggest that PTCA is technically feasible in patients with variant angina who have organic lesions, but symptoms due to coronary spasm usually persist or recur, often with restenosis.

A patient with Prinzmetal angina and ST segment elevation in the anterior ECG leads became asymptomatic after a 50% left anterior descending coronary artery stenosis was bypassed. However, seven years later Prinzmetal angina recurred but with ST segment elevation in the inferior ECG leads. Although the coronary bypass graft had remained patent, the proximal and distal left anterior descending coronary artery was occluded. No significant stenosis was present in the right coronary artery. Perhexiline maleate controlled his symptoms but when the drug was stopped because of side effects an acute inferior myocardial infarction occurred.

To assess the prevalence of spontaneous remission in variant angina, 100 patients with this diagnosis who had undergone coronary arteriography in the hospital and a follow-up of at least 1 year were studied. Patients with coronary bypass surgery or myocardial infarction were excluded. Remission was diagnosed in 45 of the 100 patients who had been angina-free and had had no treatment for more than 3 months (mean 18.3). The other 55 patients were receiving medical treatment; 37 had been angina-free for at least 6 months (mean 22.5) and angina persisted in 18. The persistent angina group had a lower prevalence of organic coronary stenoses 70% or greater: 4 of 18 versus 22 of 45 and 22 of 37 for the other two groups (p less than 0.05), and a longer history of rest angina before admission. The remission group contained more patients (17 of 45 versus 4 of 55 [p less than 0.001]) whose attacks had been documented only by provocative testing. Rest angina recurred when calcium antagonist drugs were discontinued in 15 of 51 instances, within 1 month in 11 patients and later in 4 patients. Remission was eventually attained in 35 of the 38 patients in whom these drugs were stopped. These results indicate that remission is a frequent outcome of variant angina. This fact should be considered in the evaluation of the long-term results of treatment and in the planning of care for an individual patient.

Seven patients with typical variant angina without coronary stenoses greater than 50% developed angina and ST-segment elevation during treadmill exercise testing. In all cases the ST-segment elevation occurred in the same leads during exercise testing as during spontaneous attacks at rest. Five of the patients had developed spontaneous coronary spasm during coronary arteriography, in each case in the artery corresponding to the site of ST-segment elevation. In five patients, thallium was injected during the exercise test during which angina and ST-segment elevation occurred. In each case, a large perfusion defect not present at rest was found in the zone corresponding to the site of ST-segment elevation. These findings suggest that coronary artery spasm may occur during exercise in patients with variant angina.

After hospital discharge, 114 patients with variant angina were followed for a mean period of 26 months. Six died suddenly and 13 others were resuscitated from sudden cardiac death. The extent of coronary disease and the prevalence of left ventricular dysfunction in these 19 "sudden death" patients were similar to those in the patients who did not experience sudden death ("survivors"). During spontaneous episodes of ST elevation recorded in hospital, 56 of the 114 patients had serious arrhythmias: ventricular fibrillation in two, ventricular tachycardia in 28, ventricular couplets or bigeminy in 17, second- or third-degree atrioventricular block in six and asystole in three. Patients with and those without these arrhythmias during attacks were similar with respect to extent of coronary disease, left ventricular function and most other clinical variables. The maximal ST elevation, however, was higher in the arrhythmia group (7.5 +/- 5.7 vs 3.3 +/- 2.3 mm, p less than 0.01). Serious arrhythmias were detected in 16 of the 19 sudden death patients, compared with 36 of the 86 survivors (p less than 0.01). Sudden death occurred during follow-up in 15 of the 36 patients (42%) with ventricular fibrillation, ventricular tachycardia, high-degree atrioventricular block or asystole during attacks, compared with only four of 69 (6%) without these arrhythmias (p less than 0.001). We conclude that variant angina patients with serious arrhythmias during spontaneous attacks differ from other variant angina patient only in the degree of ischemia during attacks, as reflected by maximal ST elevation, but are at a much higher risk for sudden death.

Eighty-two patients with variant angina underwent a treadmill exercise test using 14 ECG leads, and 67 also underwent exercise thallium-201 scans. The test induced ST elevation in 25 patients (30%), ST depression in 21 (26%) and no ST-segment abnormality in 36 (44%). ST elevation during exercise occurred in the same ECG leads as during spontaneous attacks at rest, and was always associated with a large perfusion defect on the exercise thallium scan. In contrast, exercise-induced ST depression often did not occur in the leads that exhibited ST elevation during episodes at rest. The ST-segment response to exercise did not accurately predict coronary anatomy: Coronary stenoses greater than or equal to 70% were present in 14 of 25 patients (56%) with ST elevation, in 13 of 21 (62%) with ST depression and in 14 of 36 (39%) with no ST-segment abnormality (NS). However, the degree of disease activity did correlate with the result of the exercise test: ST elevation occurred during exercise in 11 of 14 patients who had an average of more than two spontaneous attacks per day, in 12 of 24 who had between two attacks per day and two per week, and in only two of 31 who had fewer than two attacks per week (p less than 0.005). St elevation during exercise was reproducible in five of five patients retested during an active phase of their disease, but not in three of three patients who had been angina-free for at least 1 month before the repeat test. Twelve patients wih exercise-induced ST elevation were retested during treatment with calcium antagonist drugs; in 10 of 12, ST elevation did not occur with the second test. During a mean follow-up of 20.3 +/- 14.5 months, death or myocardial infarction occurred in three of the 25 patients with ST elevation during exercise, none of 21 with ST depression and two of 36 with no ST abnormality. We conclude that in variant angina patients, the results of an exercise test correlate well with the degree of disease activity but not with coronary anatomy, and do not define a high-risk subgroup.

We compared the sensitivity of three commonly used provocative tests, exercise, ergonovine and the cold pressor test, in a series of 34 hospitalized patients with well-documented, active variant angina. All tests were performed off medication at the same time of day, usually on 3 consecutive days. Angina was provoked by ergonovine in all 34 patients, by exercise in 17 and by the cold pressor test in only 5 (p less than 0.005). ST elevation developed during the ergonovine test in 32 (94%), during exercise in 10 (29%) and during the cold pressor test in only 3 (9%). With ergonovine one patient had ST depression only and one had no ECG changes. During the cold pressor test two patients had pseudonormalization of abnormally negative T waves and 29 had no ECG changes. Exercise induced T wave pseudonormalization in 4 patients, ST depression in 9 others and no ECG changes in 11. Thus, in patients with active variant angina, the sensitivity of the cold pressor test and exercise are too low to be useful clinically. Other studies suggest that the sensitivity of hyperventilation or provoked alkalosis is higher, but not as high as ergonovine administration. In patients who have become asymptomatic, either with treatment or spontaneously, the sensitivity of all tests decreases markedly. If such patients no longer have coronary spasm, the test is not a 'false negative' but a 'true negative'. Deaths have been reported following ergonovine administration and for this reason the test is not universally accepted.(ABSTRACT TRUNCATED AT 250 WORDS)

The long-term prognosis of variant angina and the factors influencing it were assessed in 217 consecutive patients hospitalized in our coronary care unit and followed for a mean of 65 months (range 2 to 123). Cardiac death occurred in 30 patients and an additional 54 experienced a nonfatal myocardial infarction. Survival at 1 and 5 years was 95% and 89%, respectively; survival without infarction was 83% and 69%. Coronary disease and the degree of disease activity were strong predictors of survival by Cox analysis. Survival at 1 year was 99%, and that at 5 years was 95% and 94%, respectively, for patients with one-vessel disease (n = 81) and for those without stenoses of 70% or greater (n = 87). Survival at 1 and 5 years was only 87% and 77% for those with multivessel disease (n = 40). The Cox analysis selected left ventricular function, initial treatment, extent score, duration of angina at rest, and disease activity as multivariate predictors of survival without infarction. Coronary disease was a strong predictor (p less than .0001) of survival without infarction by univariate analysis. Treatment with nifedipine, diltiazem, or verapamil improved survival without infarction compared with other medical treatment (p = .002). Myocardial infarction occurred most commonly soon after diagnosis in patients with a short history of angina at rest. Late coronary events were almost never preceded by resting angina.

A young man with a single left coronary artery and refractory variant angina is described. Spontaneous coronary artery spasm developed during coronary arteriography at the site of a 50% fixed left anterior descending coronary artery stenosis. Frequent episodes of rest angina with transient ST segment elevation persisted in hospital in spite of treatment with three different calcium antagonist drugs. Symptoms disappeared only when the combination of nifedipine, diltiazem, isosorbide dinitrate, and nitroglycerin ointment were given. Ergonovine testing was used to objectively assess the response to treatment.

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.

To determine the prognosis of variant angina and the factors influencing it, 169 consecutive patients hospitalized in our coronary unit were followed for a mean of 15.3 months (range 1 to 68). Survival at 1, 2, and 3 years was 95%, 90%, and 87%, respectively; survival without myocardial infarction was 80%, 78%, and 75%. Twenty of the 22 myocardial infarctions and eight of the 14 deaths occurred within the first 3 months. Mantel-Haenszel log-rank analysis demonstrated that coronary disease, ventricular function, and the degree of disease activity were significant interdependent variables that influenced both survival and survival without infarction. At 1, 2, and 3 years, survival for patients with multivessel disease was 81%, 76%, and 66%; for patients with one-vessel disease, 97%, 92%, and 92%; and for patients without stenoses greater than or equal to 70%, 98% at each year (p = .0003). Survival without infarction at 1 year was 88% in patients with no stenoses greater than or equal to 70% and 82% in patients with single-vessel disease; it did not change thereafter in either group, but was 62%, 58%, and 50% at 1, 2, and 3 years in patients with multivessel disease (p = .001). Treatment did not influence survival in any subgroup (only 14 patients died overall) or survival without infarction in patients with multivessel disease. However, in patients without multivessel disease, treatment with nifedipine, diltiazem, and verapamil improved survival without infarction compared to treatment with perhexiline maleate or long-acting nitrates alone (92% vs 67% at 1, 2, and 3 years; p less than .005). Thus in addition to preventing angina, nifedipine, diltiazem, and verapamil appear to reduce complications in patients with variant angina without multivessel disease.

The prevalence rate of exercise- 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 afer 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 of 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 patients 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.

Exercise, ergonovine and the cold pressor test have been used to provoke variant angina attacks. The sensitivity of these three tests was compared in 34 hospitalized patients with well documented, active variant angina who had recently undergone coronary arteriography. The three tests were usually performed on three consecutive days, and 28 of the 34 had the three tests within 1 week. Angina was provoked by ergonovine in all 34 patients, by exercise in 17 and by cold pressor test in only five (p less than 0.005). ST elevation developed during the ergonovine test in 32 (94%), during exercise in 10 (29%) and during the cold pressor test in only three (9%). With ergonovine, one patient had only ST depression and one had no ECG changes. During the cold pressor test two patients had pseudonormalization of abnormally negative T waves and 29 had no ECG changes. Exercise induced T-wave pseudonormalization in four patients, ST depression in nine others and no ECG changes in 11. ST elevation was more frequent with ergonovine than with either of the other tests (p less than 0.0001). ST elevation or T-wave pseudonormalization occurred more often with exercise than with cold (p less than 0.05), but both occurred less often than with ergonovine (p less than 0.0001). We conclude that the sensitivity of the ergonovine test is very high in patients with active variant angina and that exercise will provoke angina with ST elevation in about 30% of these cases. In contrast, the sensitivity of the cold pressor test is too low to be of much clinical value in the diagnosis of variant angina.