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.     

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.     

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.     

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.     

Hyperventilation-echocardiography test for the diagnosis of myocardial ischaemia at rest

The purpose of this study was to assess the feasibility, safety,specificity and sensitivity of the hyperventilation test performedunder echocardiographic monitoring for the provocation of vasospasticischaemia. Hyperventilation (approximately 30 cycles.min^–1for 5 min) was performed in 104 hospitalized patients, referredfor pain typical of angina at rest, under 2-D echocardiographicand 12-lead electrocardiographic monitoring. All the tests werecompleted and no significant side effect was observed. In-hospitaldocumentation of spontaneous myocardial ischaemia and/or ergonovine-inducedischaemia was achieved in 38 patients (group I). A positivehyperventilation–echocardiography test (occurrence ofnew transient asynergies or worsening of basal ones) was obtainedin 32/38 patients. Among the group I patients, only 23 had diagnosticST-T changes and only 16 experienced chest pain during the hyperventilation-echotest. Of the 66 patients without evidence of myocardial ischaemiaat rest (negative ECG monitoring during hospitalization and/ornegative ergonovine maleate-echo test)—Group II, noneshowed echocardiographic changes, seven presented ST-T changesand six complained of typical chest pain during the test. Thus,in relation to in-hospital documentation of myocardial ischaemiaat rest, both spontaneous and/or ergonovine-induced episodes,the hyperventilation–echo test showed a specificity of100%, a sensitivity of 84%, a positive predictive value of 100%and a negative predictive value of 92%. In conclusion, hyperventilation performed under echocardiographicmonitoring is feasible and safe; it can be proposed as a screeningtest to unmask vasospastic myocardial ischaemia in patientswith angina at rest, in whom documentation of spontaneous episodesis not available.     

Time-related decrease in sensitivity to ergonovine in patients with variant angina

Eighteen patients with variant angina, a positive ergonovine test, and a favorable response to calcium antagonists were studied by serial ergonovine tests and Holter monitoring to assess the long-term changes in response to ergonovine and the relationship with the spontaneous activity of the disease. The number of patients with a positive test decreased from 18 of 18 in the acute phase to 12 of 18 (66%) at 3 months, 10 of 17 (59%) at 6 months, and five of 17 (29%) at 12 months. The mean dose level of ergonovine associated with a positive response and the percentage of positive tests with ST segment depression increased progressively during follow-up. The results of the ergonovine test were well correlated with the spontaneous activity of the disease in 94%, 83%, 76%, and 71% of the patients at initial observation and at 3, 6 and 12 months, respectively. Thus in patients with variant angina and a favorable response to calcium antagonists, a time-related decrease in sensitivity to ergonovine develops during follow-up. In most patients the response to ergonovine is well correlated with the spontaneous activity of the disease; thus the ergonovine test may be a useful tool in the assessment of the natural evolution of vasospastic angina.     

Similarities of ergonovine-induced and spontaneous attacks of variant angina.

Ergonovine has been shown to provoke attacks of variant angina, but a question remains whether spontaneous and ergonovine-induced attacks of variant angina are similar. Seven patients with variant angina undergoing cardiac catheterization were studied during transient episodes of spontaneous and ergonovine-induced rest angina with ST-segment elevation. Clinical, electrocardiographic, left ventricular hemodynamic and coronary angiographic observations were made before and repeated after ergonovine (0.05-0.2 mg I.V.). The character and duration of chest pain were similar during both spontaneous and ergonovine-induced episodes. ST-segment elevation (greater than 1 mm) was present inferiorly in three patients, anteriorly in three patients, and both inferiorly and anteriorly in one patient during both episodes. Mean heart rate and systolic arterial pressure changed little, while left ventricular end-diastolic pressure increased significantly during spontaneous or ergonovine-induced attacks. We observed subtotal or total dynamic obstruction in the left anterior descending (three patients), right coronary arteries (three patients) and both arteries in one patient during both attacks. Thus, in selected patients ergonovine-induced attacks of variant angina were remarkably similar to spontaneous episodes.     

Pathogenesis of unstable angina with 0- or 1-vessel disease. Important role of coronary artery spasm.

In order to examine the possible role of coronary artery spasm in the pathogenesis of unstable angina, provocative testing for coronary spasm was performed in 43 patients with unstable angina who had 0- or 1-vessel disease. Coronary spasm was induced in 20 (65%) of 31 patients by hyperventilation testing (ST increases in 18, ST decreases in 2). Anginal attacks with either ST-segment elevation or ST-segment depression in patients without a significant organic stenosis were induced in 23 (55%) of 42 patients during treadmill exercise testing. Coronary artery spasm, showing severe (> or = 90%) vasoconstriction with angina and/or ischemic electrocardiographic ST-segment deviation, was also documented angiographically in 42 (98%) of 43 patients following intracoronary injection of acetylcholine. We conclude that dynamic coronary obstruction plays an important role in the genesis of attacks in patients with unstable angina who had 0- or 1-vessel organic coronary artery disease.     

Effect of magnesium on anginal attack induced by hyperventilation in patients with variant angina

To examine whether or not magnesium suppresses coronary spasm, the effect of magnesium infusion on anginal attacks induced by hyperventilation was studied in 20 patients with variant angina. In all patients, anginal attacks associated with ischemic ST segment changes on the electrocardiogram were repeatedly induced by hyperventilation. The study was performed in the early morning successively for 3 days. On days 1 and 3 (control studies), 50 minutes before the hyperventilation test, a 5% glucose solution was infused as a placebo. On day 2 (magnesium study), 50 minutes before the hyperventilation test, magnesium sulfate (0.27 mM/kg body wt) was infused during a 20-minute period. During the control studies, anginal attack was induced by hyperventilation in all 20 patients, whereas during the magnesium study, anginal attack was induced by hyperventilation in only six (30%) of the 20 patients (p less than 0.001 vs. control studies). The changes in arterial blood pH and PCO2 caused by hyperventilation were not significant between the control study and the magnesium study. Mean serum magnesium concentration increased from 2.2 +/- 0.2 to 6.0 +/- 0.5 mg/dl immediately after infusing magnesium and was 4.5 +/- 0.6 mg/dl before the hyperventilation test during the magnesium study. We conclude that magnesium suppresses anginal attacks induced by hyperventilation in patients with variant angina.     

Characteristics and clinical significance of silent myocardial ischemia in unstable angina

The frequency and duration of transient myocardial ischemia on Holter recordings, analyzed by the compact analog technique, were determined in 41 patients (all men, mean age 54) with unstable angina (33 with angiographic evidence). There were 781 episodes of ischemia: 392 (50%) with ST-segment depression, 242 (31%) with ST elevation, 45 (6%) with ST elevation and depression in different leads, 70 (9%) with pseudonormalization of T waves and 32 (4%) with T-wave augmentation. Ventricular arrhythmias were associated with 18% of the episodes. The mean duration of ischemic episodes was 14 minutes (range 30 seconds to almost 12 hours); most were less than 5 minutes. Only 154 (20%) of the 781 episodes of ischemia were associated with pain. Conversely, 77 episodes of chest pain were not associated with electrocardiographic changes. Analysis of the temporal sequence of heart rate during the development of ischemia (analyzed in 415 episodes) showed that in only 43 (10%) the heart rate at the beginning of ischemia was significantly (greater than 6 beats/min) higher than that at 5 minutes (baseline) before the onset of ischemia. At the peak of the ischemic abnormality, the mean heart rate increase was 10% and returned to baseline at the end of the ischemic episode. The data indicate that 80% of ischemic episodes in unstable angina are silent and over 90% are not triggered by increases in heart rate; apparently increased oxygen demand is an uncommon cause of ischemia in unstable angina. Although most of the episodes were short-lived, some were extremely protracted without the development of myocardial infarction. The findings are of therapeutic significance.     

Echocardiographic monitoring of left ventricular regional motion during hyperventilation and intravenous infusion of trometamol (tris) for detection of variant angina

BACKGROUND: In spite of constant progress and development of new diagnostic tests, the detection of variant angina, which occurs in approximately 30% of patients with ischaemic heart disease (IHD), remains challenging. AIM: To assess the sensitivity and specificity of echocardiographically monitored transient abnormalities of regional wall motion of left ventricle (LV) during hyperventilation after intravenous infusion of trometamol (TRIS-buffer) for the detection of coronary artery spasm. METHODS: The study group consisted of 72 patients (14 women and 58 men, aged from 32 to 69 years) with IHD. A control group was composed of 20 healthy men. Patients with IHD were divided into two groups. Group I consisted of 46 patients with Prinzmetal's angina whereas group II was composed of 26 patients with exertional angina and a history of myocardial infarction. Two-dimensional echocardiographic monitoring of LV contractility was carried out during hyperventilation after an intravenous infusion of 100 ml of trometamol. RESULTS: Transient abnormalities of regional LV wall motion during infusion of trometamol and hyperventilation occurred in 91% of patients from group I and in 8% of patients from group II (p<0.00001). Electrocardiographic ST-segment changes during hyperventilation-trometamol test were observed in 63% of patients from group I and in 23% of patients from group II (p<0.0001). No transient regional dyssynergy of LV nor ST-segment changes during hyperventilation-trometamol test in the control group were observed. The sensitivity and specificity of regional LV wall motion during hyperventilation-trometamol test in the identification of patients with variant angina were 91% and 92%, respectively, and the sensitivity and specificity of ST-segment changes - 63% and 76%, respectively. CONCLUSIONS: Echocardiographic monitoring of regional LV wall motion during hyperventilation after intravenous infusion of trometamol is a sensitive and specific test for detection of variant angina.     

Coronary artery vasoregulation and left ventricular function in patients with angina pectoris-like pain and normal coronary angiograms

Twenty patients with angina pectoris-like pain, normal coronary angiography and abnormal exercise 201Tl scans were investigated by means of haemodynamic, coronary sinus blood flow and lactate determinations before and after cold provocation, pacing and dipyridamole infusion. Radionuclide angiography, a new exercise 201Tl scan and noninvasive hyperventilation and ergonovine tests were performed. Intracoronary infusions of acetylcholine were given in increasing doses and a second coronary angiogram in combination with a 201Tl scintigram was performed. Despite a previously pathological 201Tl scintigram, with reversible perfusion defects, only ten of the patients had reversible perfusion defects at the second investigation. Hyperventilation and ergonovine tests did not result in ECG signs indicative of coronary spasm. Intracoronary infusion of acetylcholine resulted in a diffuse coronary constriction in 3 of 14 patients, and in one patient a perfusion defect was observed on thallium scintigram. In conclusion, although most of the common methods for inducing coronary vasospasm were used, no consistent pattern of reaction was found to explain the chest pains experienced in this group of patients.     

Autopsy findings of the coronary arteries of variant angina with Raynaud's phenomenon of the tongue

A 42 year old man with variant angina occasionally associated with syncopal attacks died of acute myocardial infarction 17 months after the onset of angina. Prior to the onset of variant angina, he had Raynaud's phenomenon of the tongue for 2 years. Both Valsalva maneuver and hyperventilation could repeatedly provoke chest pain and ST segment elevation in leads II, III and aVF. The infusion of prostaglandin E1 at a rate of 0.05 microgram/kg/min, was able to prevent the attack of variant angina induced by these maneuvers. Although coronary angiography performed 15 months prior to death revealed no organic lesions except for complete spastic occlusion at segment 1 following intravenous ergonovine, autopsy revealed marked intimal proliferation and accumulation of abundant glycosaminoglycans in three coronary vessels, as well as in small and muscular arteries of other organs. This suggests that a rapid systemic progression of narrowing due to proliferation of the intima might occur in some cases of variant angina.     

Two electrocardiographic patterns with or without transient T-wave inversion during recovery periods of variant anginal attacks

Continuous electrocardiographic recordings during anginal attacks in patients with variant angina were reviewed. Twenty-seven attacks in 15 patients were associated with transient T-wave inversion during recovery periods of angina (type A), while in another 69 attacks in 28 patients there was no T-wave inversion (type B). In none of the patients was there an ischemic T-wave inversion during angina-free periods. Both the maximum elevation (0.79 +/- 0.57 mV) and duration (5.3 +/- 1.2 min) of ST-segment deviation of type A attacks were significantly higher and longer than those of type B (0.44 +/- 0.27 mV, 2.8 +/- 1.4 min). Ten patients who had both type A and type B attacks one time or the other were selected for further evaluation. In these 10, the duration of ST-segment elevation was significantly longer during type A attacks (5.2 +/- 1.2 min, n = 18) than during type B attacks (2.7 +/- 1.2 min, n = 20) but there was no significant difference in the maximum ST-segment elevation. Giant U-wave inversion appeared in 15% of the type A attacks, but never in type B. Therefore, the T-wave abnormality related to ischemic episodes in patients with variant angina seems to be associated with more severe ischemia of longer duration than milder episodes of transient ischemia.     

Application and safety of outpatient ergonovine testing in accurately detecting coronary spasm in patients with possible variant angina

We analyzed the results of 61 consecutive outpatient ergonovine provocation tests to determine the safety and efficacy of such outpatient testing for detecting coronary artery spasm (CAS). Criteria for outpatient testing included: clinical history suggestive of variant angina, noncritical coronary artery disease documented by coronary arteriography, normal exercise treadmill test, no symptomatic arrhythmias, and no history of recent myocardial infarction. All antianginal medications were tapered and stopped. Ergonovine maleate was given as a bolus at 3-minute intervals in consecutive doses of 0.05, 0.10, and 0.25 mg. A positive test was defined as chest pain accompanied by > 0.1 mV ST segment elevation on 12-lead ECG. If pain and ST-segment elevation occurred, intravenous and sublingual nitroglycerin were immediately administered for rellef of myocardial ischemia. Of the 61 patients studied, 10 had positive tests; there were no complications. Follow-up of the 51 patients with negative studies has not revealed cardiac etiology for their chest pain. We conclude that outpatient ergonovine testing is a safe and accurate diagnostic test for identifying CAS in a highly selected population of patients with possible variant angina when performed under carefully controlled conditions.     

Different susceptibility to myocardial ischemia provoked by hyperventilation and cold pressor test in exertional and variant angina pectoris

Coronary constriction at the site of atherosclerotic stenoses has been suggested to play an important role in modulating the frequency of symptoms in patients with exertional angina. To investigate whether stimuli triggering coronary constriction have similar effects in patients with exertional and variant angina, responses to hyperventilation (HV) and cold pressor test (CPT) were evaluated. Twenty patients with chronic exertional angina, positive exercise test results and coronary heart disease were compared with 14 patients with variant angina and ST-segment elevation during an ergonovine test. In patients with exertional angina, the CPT produced diagnostic ST-segment depression in 6 of 20 patients (30%) at levels of rate-pressure product much lower than those during the exercise test; all patients had low effort tolerance and severe coronary artery disease. HV produced diagnostic ST-segment depression in only 1 of 20 patients (5%) (p less than 0.05 compared to that with CPT). Conversely, in patients with variant angina, HV produced ST-segment elevation in 11 of 14 patients (78%) and CPT produced elevation in only 2 of 14 (14%) (p less than 0.01). Thus, coronary constriction can provoke myocardial ischemia not only in patients with variant angina but also in some patients with exertional angina. Furthermore, the 2 groups of patients have a different susceptibility to stimuli known to produce coronary constriction.     

Significance of T-wave pseudonormalization during exercise. A radionuclide angiographic study

In 84 consecutive patients with resting T-wave inversion, radionuclide angiography revealed significant new wall motion abnormalities in 13 (28 percent) of the 47 patients with persistent T-wave inversion and in 23 (62 percent) of the 37 patients with T-wave pseudonormalization during exercise (p less than 0.01). The response of the ejection fraction to exercise was better in patients with persistent T-wave inversion than in those with pseudonormalization (p less than 0.04). Mechanical evidence of ischemia was seen in 14 (61 percent) of the 23 patients with T-wave pseudonormalization but without ST-segment depression. In patients with resting T-wave inversion, pseudonormalization was slightly more sensitive but less specific than a positive exercise test for predicting significant new wall motion abnormalities or decreases in the ejection fraction with exercise. Although pseudonormalization is not extremely useful alone, the presence or absence of this finding can increase the diagnostic accuracy of exercise electrocardiography in patients with resting T-wave inversion and suspected ischemic heart disease.     

Variant angina due to deficiency of intracellular magnesium by anorexia nervosa

A 51-year-old man who had a past history of gastric resection for medically uncontrollable gastric ulcer has loss of appetite that recurs periodically. And he has frequently presented spontaneous angina early in the morning since 1984. He was diagnosed as having variant angina by the documentation of typical ST elevation during anginal attack and also by showing coronary artery spasm (#2 and #12) during hyperventilation on coronary arteriography. A large quantity of calcium blocking agents and nitrates could not improve his symptoms. Lack of intracellular magnesium by loss of appetite was suspected from a daily excretion of urine magnesium (5.3 mEq) and magnesium tolerance test (56.7%). To confirm the effect of magnesium administration, the second coronary arteriography was performed. After magnesium sulphate (80 mEq, hourly) was injected, coronary artery spasm could not be induced by ergonovine. And orally magnesium oxide, calcium blocking agents and nitrates were started. Anginal attack disappeared with increasing urine magnesium.     

Vasospastic angina in thyrotoxicosis--case reports

We encountered 2 patients with thyrotoxicosis accompanied at its onset by progressive angina. The ST segment was elevated in one patient and depressed in the other patient during the spontaneous attacks. Coronary arteriographic findings were normal during control, and spasm was induced by ergonovine. No patients had chest pain even without antianginal medication after successful treatment of thyrotoxicosis. The coronary artery may become sensitive to spasm during thyroid hormone excess even in cases without significant coronary artery disease and previous chest pain.     

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.