Sudden death in two patients with variant angina and apparently minimal fixed coronary stenoses.
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Biomedical subjects
Publications and source records attributed to D D Waters.
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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.
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.
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.
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.
Angina pectoris results from an imbalance between the oxygen supply and the oxygen needs of the myocardium. While the classic form of angina is usually caused by demands exceeding supply, a primary and transient decrease in coronary blood flow is more and more often recognised as an aetiological factor of myocardial ischaemia. Calcium antagonists, although new in cardiovascular therapeutics, are already recognised as the treatment of choice for some forms of angina and as useful therapeutic adjuncts in others. Few contraindications to their use exist. They are potent vasodilators and they can prevent the occurrence of coronary artery spasm responsible for the Prinzmetal's variant form of angina. They can also reduce coronary artery tone, which if high, can compromise flow through a narrowed coronary artery. Nifedipine, diltiazem and verapamil can also influence the various determinants of myocardial oxygen consumption to reduce myocardial oxygen needs. Their effects on heart rate, blood pressure and on the inotropic state of the left ventricle is, in vivo, the balance between their direct effects on the vascular wall and myocardial muscular cells and their indirect effects represented by the reflex physiological responses. Significant variations in these effects exist between the 3 calcium antagonists such that treatment can be individualised to a particular patient's needs. Precautions with their use as well as most of their side effects can be understood from a knowledge of their direct and indirect properties. Other pharmacological effects of these drugs include a regional redistribution of coronary blood flow, cardioprotection, delay in cell death and possibly in the progression of atherosclerosis. The clinical significance of these properties remains to be investigated.
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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.
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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.
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.
The diagnostic accuracy of 14-lead exercise electrocardiography was evaluated in 112 women who had no history of myocardial infarction and underwent coronary angiography. The sensitivity of ST-segment displacement of 0.1 mV or more in any of 14 ECG leads was 0.79 for coronary artery stenosis of at least 70%; the specificity was 0.66. Results were similar using bipolar ECG leads CC5 and CM5 or 11 standard ECG leads. The ST-segment shifts that occurred only during exercise were associated with a 77% false-positive rate (10 of 13). Downsloping ST-segment depression did not provide more diagnostic information than horizontal ST-segment depression in the three clinical subsets of women. In women with typical angina pectoris, ST-segment depression of at least 0.15 mV for 0.08 second after the J point or a final treadmill time less than 360 seconds was predictive of proximal left or multivessel coronary artery disease. In the women with probable angina or nonspecific chest pain, this finding was not of diagnostic value. ST-segment elevation of 0.1 mV or more in leads V1-2 or a VL predicted proximal stenosis of at lest 80% in the left anterior descending coronary artery in all six women with typical angina pectoris. Maximal exercise testing in women with typical angina provides important diagnostic information when 11 standard ECG leads are recorded. In women with probable angina or nonspecific chest pain, diagnostic exercise testing is less useful and bipolar leads CC5 and CM5 are sufficient for most clinical purposes.
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.
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.
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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.
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.