Cimetidine induces coronary artery spasm in patients with vasospastic angina

We have previously reported that cimetidine, a histamine H2-receptor blocker, augments the histamine-induced coronary vasoconstriction at the site of spastic segments in the atherosclerotic coronary arteries of swine. To elucidate whether cimetidine has a coronary vasoconstrictive effect in humans, 14 patients with vasospastic angina (group 1) and 14 controls with atypical chest pain (group 2) were examined angiographically. Nitroglycerin-effective spontaneous angina with electrocardiographic ST-T changes and ergonovine-induced coronary artery spasm were confirmed in group 1, but not in group 2. Cimetidine was administered intravenously in a dose of 200 mg. Cimetidine induced coronary artery spasm in 4 patients in group 1 but none in group 2(29% vs. 0%, p less than 0.01). The extent of coronary vasoconstriction induced by cimetidine was greater at the site of spastic coronary segments than that at the site of non-spastic segments in group 1 or all segments in group 2 [14% vs. 4%, (p less than 0.01) or 14% vs. 2%, (p less than 0.01)] as well as the extent of ergonovine-induced coronary vasoconstriction [46% vs. 14%, (p less than 0.01) or 46% vs. 14%, (p less than 0.01)] and nitroglycerin-induced coronary vasodilatation [58% vs. 25%, (p less than 0.01) or 58% vs. 17%, (p less than 0.01)]. As it was suggested that cimetidine has potential vasoconstrictive effects in patients with coronary artery spasm, it should be administered with caution in patients with the vasospastic angina pectoris.     

Long-term prognosis of vasospastic angina without significant atherosclerotic coronary artery disease

Long-term prognosis of 90 patients with vasospastic angina without significant coronary artery disease (less than 50% reduction in luminal diameter) was examined for a mean follow-up period of 4 years. All patients had episodes of angina at rest and were treated with calcium antagonists. One patient developed myocardial infarction and 2 died suddenly during the follow-up period. In the patient with myocardial infarction, there was an abrupt worsening of angina prior to the infarction despite therapy with a calcium antagonist. One of the sudden death patients discontinued his calcium antagonist before his death. Of the sudden death patients, one had ventricular tachycardia and the other had a complete atrioventricular block during an anginal attack. The incidence of such serious arrhythmias was higher (p less than 0.01) in sudden death patients (2/2) than that in survivors (6/88). The treatment with calcium antagonists reduced the severity and frequency of angina in all patients. These results suggest that long-term prognosis of vasospastic angina without significant coronary artery disease is good as characterized by the low incidence of myocardial infarction and death and the favorable response to treatment with calcium antagonists.     

Cardiac arrest related to coronary spasm in patients with variant angina: a three-case study

We present three patients with variant angina pectoris and episodes of cardiac arrest. All of them had typical clinical symptoms, ST-segment changes in electrocardiogram, and coronary artery spasm confirmed by arteriography. They were treated with high doses of calcium antagonists and nitrates. An automatic cardioverter-defibrillator was implanted in the patient who developed ventricular fibrillation despite therapy with calcium antagonists. In another patient a DDD pacemaker was implanted because of high-degree atrioventricular block.     

Abnormal heart rate response to exercise in vasospastic angina: pathophysiologic mechanism in the provocation of coronary spasm

To examine the alteration in control function of the heart, which may account for the pathophysiologic condition precipitating coronary arterial spasm, the dynamic property of heart rate response to exercise in vasospastic angina was evaluated by using our previously developed frequency analytic procedure. We studied 21 patients with vasospastic angina, divided into two groups (active angina and inactive angina) and 12 normal control subjects. When compared with the transfer function of the heart rate control system in normal control subjects, the transfer function in patients with active vasospastic angina showed moderately lower gain, especially in the middle frequency range, and significantly delayed phase angle over the whole frequency range, especially in the middle and high frequency ranges. These abnormalities were not observed in inactive vasospastic angina. The present exercise test to detect abnormal heart rate control can feasibly be used in the detection and management of vasospastic angina.     

Significance of coronary artery tone in patients with vasospastic angina

To investigate the relation between basal coronary artery diameter and development of coronary artery spasm, the diameters of the proximal, middle and distal segments of the three major coronary artery branches, together with that of the left main trunk, were measured on a control angiogram and after ergonovine and nitrate administration in 30 patients with vasospastic angina without significant organic stenosis, and in 35 patients without ischemic heart disease. The percent change in coronary diameter after ergonovine and nitrate administration compared with the control diameter was used as an index of coronary vasoreactivity. In patients with vasospastic angina, coronary artery responses to both ergonovine and nitrate were greater in the spastic segments than in the other segments (p less than 0.05), and those of the coronary arteries without spasm were greater than those of the coronary arteries in patients without ischemic heart disease (p less than 0.01). There were no significant differences between the coronary artery diameters in the two groups after nitrate administration, and the control diameters were less in patients with vasospastic angina than in patients without ischemic heart disease. These observations indicate that a coronary vasomotion disorder, which involves increased basal coronary artery tone and hypersensitivity to vasoconstrictive stimuli, not only at a localized segment but also in the entire coronary artery tree, is present in patients with vasospastic angina. Clinically, evaluation of basal coronary artery tone may be useful for predicting the occurrence and location of coronary artery spasm.     

Long-term prognosis of coronary artery spasm

This study analyses the long-term prognosis of 210 patients with coronary spasm documented at coronary angiography. All patients with a previous history of myocardial infarction or who had undergone coronary angioplasty were excluded. The average follow-up was 55 months and only 11 patients were lost to follow-up. The actuarial survival figures showed the 1 year, 2 year and 5 year survival rates to be 95, 92 and 89 per cent respectively. Extracardiac mortality was mainly related to smoking (lung cancer, laryngeal cancer, etc.) and was higher than cardiac mortality. More than half of the cardiovascular events (sudden death, myocardial infarcts) occurred during the first year of follow-up. Ten patients (4.7%) died suddenly. The predictive factors of this event were: previous syncopal episodes or syncopal angina due to coronary spasm, percritical arrhythmias and the documentation of multiple spasms at coronary angiography. Myocardial infarction was observed in 10.6 per cent of patients. Only those with significant coronary arterial lesions developed this complication. At the end of the follow-up period, 75 per cent of patients were asymptomatic or had only atypical chest pain. No significant differences were observed between the two groups treated medically, by aortocoronary bypass or by the association of coronary bypass and plexectomy with the exception of non-lethal myocardial infarcts being significantly less common in patients treated medically. Therefore, the long-term prognosis of patients with coronary spams is relatively satisfactory.     

The preventive effect of magnesium on coronary spasm in patients with vasospastic angina

STUDY OBJECTIVES: Previous studies have reported that magnesium (Mg) deficiency is associated with coronary spasm. However, little is known about the preventive effect of Mg on coronary spasm. The present study investigated whether Mg prevents coronary spasm in patients with vasospastic angina (VSA). DESIGN: Effectiveness trial. SETTING: University medical center. PATIENTS: Twenty-two patients with VSA. INTERVENTION: Coronary spasm was induced with an intracoronary infusion of acetylcholine (Ach). After spontaneous relief of the coronary spasm, Mg sulfate (0.27 mmol/kg body weight) was infused IV over 20 min in 14 patients and isotonic glucose was infused in 8 patients as control subjects. Intracoronary infusion of Ach was then repeated, and the diameter of the coronary arteries was measured quantitatively. MEASUREMENTS AND RESULTS: Mg infusion caused coronary artery dilatation at baseline in both the spastic (5. 9 +/- 2.3%) and nonspastic segments (5.5 +/- 1.5%). Mg infusion reduced the severity of chest pain and ST-segment deviations during coronary spasm. After the Mg infusion, the percent change in the diameter of the spastic segments improved from - 62.8 +/- 2.6% to - 43.7 +/- 4.7% during coronary spasm. Overall, 10 of 14 patients (71%) responded favorably to Mg infusion. Isotonic glucose infusion did not elicit changes in chest pain severity, ST-segment deviations, or the diameter of the coronary arteries during spasm. CONCLUSIONS: Mg infusion produces nonsite-specific basal coronary dilatation and suppresses Ach-induced coronary spasm in patients with VSA.     

Clinical characteristics and prognosis of patients with postinfarction angina caused by coronary artery spasm

Clinical features and the course of 15 patients with postinfarction angina caused by coronary artery spasm are described. Episodes of postinfarction angina in the patients recurred at rest in the early recovery phase and were accompanied by transient ST-segment elevation. The area where ST-segment elevations were demonstrated on a 12-lead ECG always included the leads with newly developed abnormal Q waves. Pain resolved spontaneously or after sublingual nitroglycerin in several minutes. Holter ECGs during a 24-h period demonstrated frequent episodes of ST-segment elevation that were not always associated with chest pain. Treatment with calcium antagonist and/or nitrates effectively suppressed angina, and only one patient developed reinfarction. The patient's subjective symptoms were abolished by diltiazem and isosorbide dinitrate. A Holter ECG of the patient revealed silent ST-segment elevations before and after the reinfarction and an increase of the drugs completely suppressed the recurrence of silent ischemic ECG changes. Coronary arteriograms were obtained from 8 patients, which demonstrated more than 75% segmental stenosis on one coronary artery in 5 patients and no significant obstruction in the remaining 3. All patients performed a treadmill exercise stress test before discharge and most demonstrated excellent tolerance. All patients experienced no form of chest pain for an average of 25 months follow-up under medication. We conclude that among patients with postinfarction angina, those cases caused by coronary artery spasm have a relatively good prognosis.     

What is the long-term prognosis of patients with coronary spasm and normal coronary arteries?

The clinical course of patients with pure coronary artery apasm is variable. Some patients have a chronic sourse characterized by recurrent angina at rest. Others develop spontaneous remission of symptoms. Most patients have a poor response to long-acting nitrate therapy and a good response to calcium antagonists. Despite the morbidity associated with this syndrome, cardiac mortality is low. When death occurs, it is usually sudden and probably secondary to an arrhythmia.     

Usefulness of intracoronary injection of acetylcholine as a provocative test for coronary artery spasm in patients with vasospastic angina

Summary In order to examine both the sensitivity and specificity of coronary artery spasm induced by intracoronary injection of acetylcholine in patients with vasospastic angina, incremental doses of acetylcholine (20, 30, and 50 µg) were injected directly into each coronary artery in 21 patients with variant angina (group A), in 28 patients with other types of vasospastic angina (group B), and in 20 patients without any significant coronary artery disease (group C). Coronary artery spasm was defined as severe vasoconstriction (90% of reduction in luminal diameter) with chest pain and/or ischemic changes in the electrocardiogram. Intracoronary injection of acetylcholine induced spasm of at least one coronary artery in 20 patients (95%) of group A, in 27 patients (96%) of group B, and in only 2 patients (10%) of group C. The low dose of acetylcholine (20 µg) induced coronary spasm more frequently in group A patients (81%) than in group B patients (43%) (P<0.05). ST-segment elevation associated with anginal attacks was significantly (P<0.05) more frequent in group A (71%) than in group B (39%). When acetylcholine was injected separately into the left and right coronary arteries, spasm of both coronary arteries was observed in 7 out of 14 of group A (50%), in 8 out of 22 of group B (36%), and in none of the 20 of group C. We concluded that intracoronary injection of acetylcholine is a sensitive and reliable method for the induction of coronary spasm in patients with vasospastic angina as well as in those with variant angina.     

A case of vasospastic angina: development of transient collateral circulation lessen the degree of myocardial ischemia during coronary artery spasm

A 57-year-old man was admitted to our hospital because he had had attacks of chest pain at rest for more than a year, in spite of daily oral diltiazem (90 mg/day) and isosorbide dinitrate (15 m/day). The diagnosis of variant angina was made for him based on ST elevation in chest leads of the electrocardiogram during his first attack. However, one year later, the electrocardiograms during attacks showed only ST depression or T wave inversion in chest leads. The coronary arteriogram during spontaneous chest pain revealed that the left anterior descending artery was totally occluded at its middle portion, and that its peripheral portion was perfused by collateral circulation from the right coronary artery. The coronary arteriograms after administration of nitroglycerin were apparently normal, and no signs of collateral circulation were observed. These findings indicated that the transient collateral circulation could develop after repetitive coronary artery spasms even in the absence of significant coronary stenosis, and that it could lessen the degree of myocardial ischemia during coronary artery spasm.     

Administration of the Rho-kinase inhibitor, fasudil, following nitroglycerin additionally dilates the site of coronary spasm in patients with vasospastic angina

BACKGROUND: The Rho/Rho-kinase signaling pathway is known to be involved in the pathogenesis of coronary artery spasm. Previous studies reported the efficacy of the Rho-kinase inhibitor, fasudil, in the prevention and relief of coronary spasm. The usefulness of fasudil in combination with conventional vasodilating agents, however, has not been fully examined in patients with vasospastic angina. METHODS AND RESULTS: A total of 26 patients (mean age, 61+/-11 years) with documented vasospasm in the left anterior descending coronary artery were examined by the acetylcholine stress test. Coronary diameter at the spasm site was measured at baseline and after the administration of vasodilator agents in the following order: intracoronary nitroglycerin (NTG) (300 microg), intravenous fasudil (30 mg, n=15, fasudil group) or saline (n=11, saline group), and again NTG during coronary angiography. The increase in diameter observed following the first NTG administration was found to be similar in the fasudil and saline groups (38.3+/-23.5% and 42.3+/-17.1%, respectively). The additional change in diameter on fasudil treatment (16.9+/-11.2% increase over the diameter after the first NTG administration) was significantly larger than that with saline (-2.8+/-7.6%, P<0.001). The second administration of NTG did not affect the diameter of the spasm site in either group. CONCLUSIONS: Fasudil further dilated the site of coronary spasm, which had already been treated with NTG in patients with vasospastic angina. These findings support and extend the previous results that showed the feasibility of employing fasudil as a novel therapeutic approach for coronary spasm.     

Hibernating myocardium associated with coronary artery dissection and vasospastic angina.

Hibernating myocardium is an uncommon clinical state involving persistently impaired myocardial function. A 61-year-old man was admitted because of vasospastic angina. Coronary angiography revealed coronary artery dissection in the midportion of the right coronary artery, and segmental vasoconstriction was evoked by acetylcholine. In this patient, hibernating myocardium in the dissected region was clearly demonstrated by dipyridamole thallium-201 imaging. This report describes the first documented case of hibernating myocardium associated with coronary artery dissection, and the usefulness of dipyridamole thallium-201 imaging in the assessment of this state. Coronary artery spasm might be relevant to the etiology of coronary artery dissection.     

Induction of coronary arterial spasm by intracoronary administration of acetylcholine in patients with vasospastic angina

To examine whether intracoronary injections of acetylcholine induce coronary artery spasm in patients with vasospastic angina, incremental doses (20, 30 and 50 micrograms) were injected directly into the coronary arteries in 12 patients with variant angina (Group A: rest angina with electrocardiographic ST-segment elevation during attacks), 19 with vasospastic angina (Group B: rest angina and/or effort angina with variable threshold in the treadmill exercise stress test), 11 with organic coronary artery stenosis but without angina (Group C), and 14 without coronary artery disease (Group D). A temporary cardiac pacemaker was positioned in the right ventricle. Coronary artery spasm was defined as severe vasoconstriction (greater than or equal to 90% of reduction in the luminal diameter) with chest pain and/or ischemic changes in the electrocardiogram. Intracoronary injection of acetylcholine induced spasm of at least one coronary artery in all 12 patients (100%) of Group A, in 18 (95%) of Group B, in two (18%) of Group C, and in two (14%) of Group D. Thus, the sensitivity of this method for inducing coronary spasm was 100% in group A, 95% in Group B, and 97% in Group A plus Group B. The specificity for inducing spasm was 86% in Group D, and 84% in Group C and Group D. When acetylcholine was injected separately into the left and right coronary arteries, spasm of both the coronary arteries was observed in two (40%) of Group A, in five (33%) of Group B, and none (0%) of Group C and Group D. Acetylcholine (20 micrograms) induced coronary spasm in 10 (83%) of Group A and only in nine (47%) of Group B.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of risk factors in vasospastic angina without significant fixed coronary narrowing to significant fixed coronary narrowing and no vasospastic angina

To determine the importance of usual risk factors of coronary artery disease (CAD) in patients with coronary artery spasm, 40 patients with vasospastic angina (VA), normal or nearly normal coronary arteries and without previous myocardial infarction were compared with 2 control groups of 40 patients each, matched for age and sex: 1 group with CAD and 1 without heart disease. Ninety percent of patients with VA were cigarette smokers and 70% were heavy smokers (more than 20 cigarettes daily), compared with 53% and 33% in patients with CAD (p less than 0.001) and 30% and 15% in those without heart disease (p less than 0.001). Except for cigarette smoking, the risk factor profile of patients with VA appeared more like the profile of patients without heart disease than that of patients with CAD. The results suggest that cigarette smoking may play a role in CAD independent of atherosclerosis and possibly favoring coronary artery spasm.     

Differences between coronary hyperresponsiveness to ergonovine and vasospastic angina

The objective of the present study was to investigate the differences between coronary hyperresponsiveness without ischemia and vasospastic angina in an ergonovine provocation test using multivariate analysis. We have sometimes experienced a more than 50% narrowing response of vascular diameter without ischemia in a coronary response to ergonovine. We studied 107 patients with less than 50% stenosis in a coronary arteriogram. Their vascular responses to ergonovine were measured and the patients were divided into three groups, as follows: Group 1 had 50% or less vascular narrowing response without ischemia; Group 2 had a vascular hyperresponsiveness of more than 50% narrowing response without ischemia; and Group 3 experienced a hyperresponsiveness with ischemia. The degree of coronary response was found to be related to smoking, inpaired glucose tolerance (IGT) and the Gensini score by multiple regression analysis. A multiple logistic analysis revealed that the Gensini score and smoking were significant predictive factors for Group 3 (odds ratio: 1.20 and 8.97). The only factor different between Group 2 and Group 1 was gender. The coronary hyperresponsiveness to ergonovine without ischemia differs from vasospastic angina in the degree of coronary atherosclerosis and smoking habits. The patients with hyperresponsiveness had similar characteristics to those with atypical chest pain rather than vasospastic angina, except for a gender difference.