Suppression of exercise-induced angina by magnesium sulfate in patients with variant angina

The effects of intravenous magnesium on exercise-induced angina were examined in 15 patients with variant angina and in 13 patients with stable effort angina and were compared with those of placebo. Symptom-limited bicycle exercise and thallium-201 myocardial scintigraphy were performed after intravenous administration of 0.27 mmol/kg body weight of magnesium sulfate and after placebo on different days. In all patients, serum magnesium levels after administration of magnesium sulfate were about twofold higher than levels after placebo. Exercise-induced angina associated with transient ST segment elevation occurred in 11 patients with variant angina receiving placebo and in only 2 of these patients receiving magnesium (p less than 0.005). On the other hand, exercise-induced angina was not suppressed by magnesium in any patient with stable effort angina. In these patients there was no significant difference in exercise duration after administration of placebo versus after administration of magnesium. The size of the perfusion defect as measured by thallium-201 scintigraphy was significantly less in patients with variant angina receiving magnesium than that in those receiving placebo (p less than 0.001), whereas it was not significantly different in patients with stable effort angina receiving placebo versus magnesium. In conclusion, exercise-induced angina is suppressed by intravenous magnesium in patients with variant angina but not in patients with stable effort angina. This beneficial effect of magnesium in patients with variant angina is most likely due to improvement of regional myocardial blood flow by suppression of coronary artery spasm.     

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.     

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.     

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.     

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.     

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.     

Variant angina due to deficiency of intracellular magnesium

A 51-year-old man was diagnosed as having variant angina by documentation of typical ST elevation during anginal attack and also by showing coronary arterial spasm (#2 and #12) during hyperventilation on coronary arteriography. Large quantities of calcium blocking agents and nitrates could not improve his symptoms. Lack of intracellular magnesium was suspected from a daily excretion of urine magnesium (5.3 mEq) and magnesium tolerance test (56.7%). After hourly infusion of magnesium sulfate (80 mEq), coronary spasm could not be induced by ergonovine.     

Relationship between the Degree of Intracellular Magnesium Deficiency and the Frequency of Chest Pain in Women with Variant Angina

OBJECTIVES: This study sought to clarify the relationship between the degree of intracellular magnesium deficiency and the frequency of anginal attacks in women with variant angina. PATIENTS AND METHODS: We evaluated the intracellular and extracellular magnesium status of twelve women with variant angina: group A (> or = 4 attacks/week, n = 5) and group B (< 4 attacks/week, n = 7). Magnesium levels were determined in serum, urine, and erythrocytes, and the 24-h magnesium retention rate was calculated by magnesium loading test. RESULTS: Group A showed a higher 24-h magnesium retention rate (58.2 +/- 9.1% vs. 31.3 +/- 4.4%; p < 0.01) and a lower intracellular concentration of magnesium in erythrocytes than group B (3.1 +/- 1.1 vs. 5.0 +/- 0.8 fg/cell; p < 0.05), demonstrating the presence of magnesium deficiency in group A. The 24-h magnesium retention rate and intracellular concentrations of magnesium in erythrocytes correlated well with the activity of variant angina (r = 0.61, p < 0.01; and r = -0.74, p < 0.01, respectively) for these patients. CONCLUSION: This study demonstrates that the degree of intracellular magnesium deficiency in women with variant angina is closely related to the frequency of chest pain.     

Coronary arteriography and left ventriculography during spontaneous and exercise-induced ST segment elevation in patients with variant angina

The present study is an angiographic demonstration of coronary artery spasm during both spontaneous and exercise-induced angina in three patients with variant angina. In each case, clinical, ECG, coronary angiographic, and left ventriculographic observations were made at rest, during spontaneous angina, and during exercise-induced angina. The character of chest pain was similar during spontaneous and exercise-induced episodes. ST segment elevation was present in the anterior ECG leads during both episodes. The left anterior descending coronary artery became partially or totally obstructed during both types of attacks. When coronary spasm was demonstrated during both types of attacks, left ventriculography disclosed akinetic or dyskinetic wall motion in the area supplied by the involved artery. In those patients with reproducible exercise-induced ST segment elevation and chest pain, thallium-201 scintigraphy showed areas of reversible anteroseptal hypoperfusion. Thus in selected patients exercise-induced attacks of angina were similar to spontaneous episodes.     

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.     

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.     

Circadian variation of exercise capacity in patients with Prinzmetal's variant angina: role of exercise-induced coronary arterial spasm.

Thirteen patients with Prinzmetal's variant angina performed treadmill exercise tests in the early morning and in the afternoon of the same day. The attacks with ST elevation were induced repeatedly in all 13 patients in the early morning, but in only two patients in the afternoon. Propranolol did not suppress the exercise-induced attacks in all 13 patients. Diltiazem suppressed the attacks in all 13 patients and phentolamine in eight of the nine patients. Coronary arteriograms demonstrated that spasm occluding completely or almost completely the large coronary artery supplying the area of myocardium showing ST elevation appeared during the attacks and disappeared along with the attacks after nitroglycerin administration in all four patients in whom the attacks were induced by arm exercise in the catheterization laboratory. We conclude that there is circadian variation of exercise capacity in patients with Prinzmetal's variant angina caused by coronary arterial spasm induced by exercise in the early morning but not in the afternoon.     

变异型心绞痛胸痛发作频率与细胞内镁离子浓度的相关性探讨

目的:探讨变异型心绞痛患者胸痛发作频率与细胞内镁离子浓度的相关性。方法:18例临床诊断为变异性心绞痛患者,男6例,女12例,分为两组:A组(n=9,胸痛发作频率≥4次/周),B组(n=9,胸痛发作频率4次/周),测定患者血清、尿、红细胞内镁离子浓度,通过镁离子负荷试验测定24小时镁离子潴留率。结果:A组24小时镁离子潴留率明显高于B组(58.2±9.1%vs31.1±4.4%,P0.01);红细胞内镁离子浓度A组却明显低于B组(3.1±1.1%vs5.0±0.8fg/cell,P0.05);胸痛发作频率与24h镁离子潴留率呈正相关(r=0.69,P0.01),与红细胞内镁离子浓度呈负相关(r=-0.70,P0.01)。结论:变异型心绞痛患者胸痛发作频率与细胞内镁离子浓度高低有一定相关性。     

Vasospastic ischemic mechanism of frequent asymptomatic transient ST-T changes during continuous electrocardiographic monitoring in selected unstable angina patients

Asymptomatic episodes of ST segment and/or T wave changes are often reported during Holter monitoring in patients with angina pectoris. However, the interpretation of such changes is debated relative to silent myocardial ischemia. We studied 11 patients admitted to the CCU because of frequent episodes of unstable anginal attacks who had undergone repeated periods of Holter monitoring, characterized by predominantly occurring asymptomatic episodes of ST segment and/or T wave changes associated with less frequent typical anginal attacks. In a total of 89 days of Holter monitoring, the patients evidenced 520 episodes of transient ECG changes including 180 of ST elevation, 73 of ST depression, and 267 of T wave alterations. Only 12% of episodes were symptomatic. Coronary injection during asymptomatic ST-T changes was performed in eight patients. In six it was possible to document spontaneous coronary spasm. In seven patients ergonovine administration induced anginal pain, ST-T changes, and coronary spasm. In all patients the anginal attacks completely disappeared with medical treatment and the asymptomatic episodes were abolished in six and reduced in four. Our findings support the hypothesis that in certain selected unstable anginal patients, transient asymptomatic ECG changes are caused by acute myocardial ischemia.     

Estradiol supplementation suppresses hyperventilation-induced attacks in postmenopausal women with variant angina.

OBJECTIVES: We sought to examine whether estradiol (E2) supplementation suppresses anginal attacks in women with variant angina. BACKGROUND: Estrogen is known to improve endothelial function. Coronary spasm plays an important role in the pathogenesis of not only variant angina but also ischemic heart disease in general, and endothelial dysfunction seems to be involved in the pathogenesis of coronary spasm. METHODS: Fifteen postmenopausal women with variant angina (mean age 54.2 years) were given a hyperventilation (HV) test, a provocation test for coronary spasm, in the early morning of day 1 (baseline), day 3 (after 2-day transdermal E2 supplementation, 4 mg) and day 5 (after 2-day placebo administration). We measured the flow-mediated (endothelium-dependent) dilation (FMD) of the brachial artery with the ultrasound technique before each HV test. RESULTS: The anginal attacks with ST segment elevation were induced by HV in all patients on days 1 and 5. However, no attacks were induced on day 3. Supplementation with E2 augmented FMD (3.5 +/- 0.6*, 8.9 +/- 0.7 and 4.0 +/- 0.5* on days 1, 3 and 5, respectively; *p < 0.01 vs. day 3). The serum E2 levels on days 1, 3 and 5 were 22.7 +/- 2.8*, 96.2 +/- 9.2 and 30.7 +/- 7.1* pg/ml, respectively (*p < 0.01 vs. day 3). CONCLUSIONS: The present results demonstrated for the first time, to our knowledge, that E2 supplementation suppresses the HV-induced attacks in women with variant angina, in part because of the improvement of endothelial function.     

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.     

Alcohol-induced variant angina and considerations of its mechanism: a case report]

A 64-year-old man had episodes of angina pectoris several hours after ingestion of alcohol. Otherwise, anginal attacks never occurred. He was diagnosed as having variant angina based on the typical ST elevation in leads II, III and aVF during the anginal attacks. We performed an alcohol challenge test on his 4th admission day. He was given 540 ml of "sake" at 6:00 p.m. and anginal attacks with ST elevations occurred 9.5 hours after its ingestion. The peak value of plasma ethanol was 136 mg/dl at 9:00 p.m. and it returned to 0 when angina occurred. By alcohol ingestion, urinary excretion of Mg increased in association with a slight decrease in serum Mg. The ratio of serum Ca to Mg was increased from 4.0 at the control state before taking alcohol to 4.5 at the occurrence of anginal attack. Mg content in red blood cells and in plasma catecholamines did not differ between before and after ingesting alcohol. We concluded that the change in the extracellular Ca-Mg equilibrium may contribute to the mechanism of alcohol-induced variant angina.     

Relation Between Severity of Magnesium Deficiency and Frequency of Anginal Attacks in Men With Variant Angina

Objectives. We evaluated whether the severity of magnesium deficiency was correlated with the frequency of attacks of variant angina.Background. Magnesium deficiency may be associated with the development of variant angina. However, the relation between the activity of variant angina and magnesium deficiency remains to be elucidated.Methods. We assessed the body magnesium status of 18 men with variant angina: Group 1 (≥4 attacks/week, n = 7) and Group 2 (<4 attacks/week, n = 11). Concentrations of magnesium were determined in serum, urine, mononuclear cells and erythrocytes, and the 24-h magnesium retention rate was determined.Results. Group 1 showed a higher 24-h magnesium retention rate (mean ± SEM 63.5 ± 7.6% vs. 24.9 ± 2.7%, p < 0.01) and a lower intracellular concentration of magnesium in mononuclear cells and erythrocytes than did Group 2 (respectively, 156.3 ± 13.5 vs. 212.1 ± 6.9 fg/cell, p < 0.01; and 3.5 ± 0.5 vs. 5.2 ± 0.4 fg/cell, p < 0.05), demonstrating the presence of magnesium deficiency in Group 1. The 24-h magnesium retention rate and intracellular concentrations of magnesium in mononuclear cells and erythrocytes correlated well with the frequency of anginal attacks (r = 0.78, p < 0.01; r = −0.78, p < 0.01; r = −0.62, p < 0.01, respectively) for all patients.Conclusions. Data suggest that the magnesium status of men with variant angina is closely related to disease activity.     

Myocardial ischemia due to coronary artery spasm during dobutamine stress echocardiography

Dobutamine stress echocardiography (DSE) is a useful and safe provocation test for myocardial ischemia. Until now, the test has been focused only on the organic lesion in the coronary artery, and positive DSE has indicated the presence of significant fixed coronary artery stenosis. The aim of the present study is to examine whether myocardial ischemia due to coronary spasm is induced by dobutamine. We performed DSE on 51 patients with coronary spastic angina but without significant fixed coronary artery stenosis. All patients had anginal attacks at rest with ST elevation on the electrocardiogram (variant angina). Coronary spasm was induced by intracoronary injection of acetylcholine, and no fixed coronary artery stenosis was documented on angiograms in all patients. DSE was performed with intravenous dobutamine infusion with an incremental doses of 5, 10, 20, 30, and 40 microg/kg/min every 5 minutes. Of the 51 patients, 7 patients showed asynergy with ST elevation. All 7 patients (13.7%) had chest pain during asynergy, and both chest pain and electrocardiographic changes were preceded by asynergy. These findings indicate that dobutamine can provoke coronary spasm in some patients with coronary spastic angina. When DSE is performed to evaluate coronary artery disease, not only fixed coronary stenosis, but also coronary spasm should be considered as a genesis of asynergy.     

Usefulness of massive oral nicorandil in a patient with variant angina refractory to conventional treatment

A 67-year-old man, who was previously diagnosed with vasospastic angina and treated with standard therapy, was admitted to our hospital because of recurrent chest pain refractory to sublingual nitroglycerin. Admission electrocardiography revealed ST segment elevation in II, III and aV(F), and his symptoms were relieved by intravenous bolus administration of nicorandil. He was diagnosed to have active variant angina, and remained symptomatic even after treatment with calcium antagonists and nitrates at optimal doses. Intravenous bolus administration of nicorandil was consistently effective to relieve his symptoms. Anginal attack was finally prevented by massive oral nicorandil in addition to conventional treatment.