Role of coronary artery spasm in ischemic heart disease. Therapeutic implications

The term coronary artery spasm should not be used interchangeably with the specific clinical syndrome "variant angina" since it does occur in other acute and chronic ischemic heart disease syndromes. The term coronary artery spasm should not be applied to patients with ischemic heart disease unless there is clinical, angiographic, and physiologic evidence of its presence. The diagnosis of coronary artery spasm is confirmed by angiography, i.e. change in caliber of the coronary arteries plus evidence of ischemia. Probable diagnosis is in patients who have the syndrome of variant angina, i.e. rest angina associated with ST segment elevation on the electrocardiogram. One can be highly suspicious that the spasm is at work in patients who have rest angina, especially those with unstable angina. One can be suspicious of patients who have variable effort angina or walk-through angina. Coronary artery spasm is a possibility in patients with an acute myocardial infarction or acute re-infarction and is also possible that sudden death in patients with normal coronary arteries can be related to coronary artery spasm. Coronary artery spasm is the usual cause of myocardial ischemia in patients with rest angina without effort angina. This has also commonly been documented in patients with rest and effort angina. There are isolated reports suggesting that patients with effort angina pectoris also develop coronary artery spasm. Coronary artery spasm has been documented to occur in association with acute myocardial infarction. Whether coronary artery spasm is the cause or the result of myocardial infarction has not been determined at this time. However, the recent combined use of intracoronary nitroglycerin and intracoronary streptokinase in patients with acute myocardial infarction has shown reversal of totally obstructed arteries and suggests the relationship between coronary artery disease, coronary artery spasm, and in situ coronary thrombosis. The incidence of sudden death in patients with documented coronary artery spasm is unknown. But, since complete heart block and/or ventricular tachycardia occur during episodes of coronary artery spasm, it is not unreasonable to assume that some patients have died as a result of these rhythm disturbances. The prognosis of patients with coronary artery spasm seems to depend on the presence or absence of severe coronary atherosclerosis, i.e. those with severe disease have a worse prognosis. Current therapy of patients with coronary artery spasm involves the use of nitrates and calcium antagonists.(ABSTRACT TRUNCATED AT 400 WORDS)     

Endothelial function and coronary spastic angina

Coronary spasm plays an important role in the pathogenesis of not only variant angina but also coronary heart disease in general including acute coronary syndromes, especially in the Japanese population. The vascular endothelium has been reported to be a multifunctional organ whose integrity is essential for normal vascular physiology. Vascular endothelial dysfunction can be a critical factor in the pathogenesis of ischemic heart disease. Acetylcholine and methacholine cause vasodilation by endothelium-derived relaxing factor when the endothelium is functioning normally, whereas they cause vasoconstriction when the endothelium is removed or damaged. Coronary spasm can be induced by a variety of stimuli with different mechanisms of action, including acetylcholine and methacholine. Patients with coronary spasm may have a disturbance in endothelial function as well as local hyperreactivity of the coronary arteries.     

Accelerated coronary atherosclerosis revealed by arrhythmogenic coronary spasm

Coronary artery spasm is sometimes associated with life-threatening ventricular arrhythmias. Based on intravascular ultrasound findings, it appears that coronary artery spasm promotes negative arterial remodeling, suggesting that patients with coronary artery spasm might be at higher risk of accelerated coronary atherosclerosis. We report the cases of 3 patients with ventricular arrhythmia secondary to coronary artery spasm complicated by accelerated coronary atherosclerosis. Consequently, coronary disease progression should be considered in the case of angina pectoris recurrence in patients with coronary artery spasm, especially in those with coronary artery spasm complicated by ventricular arrhythmia.     

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.     

Successful Use of Continuous Erector Spinae Plane Blocks in a Patient With Variant Angina After Large Ventral Hernia Repair

Coronary artery spasm constitutes the primary underlying pathology of variant angina. Because provocation of coronary artery spasm may occur with both excess sympathetic and excess parasympathetic stimulation, patients with this disorder have extremely limited options for perioperative pain control. This is especially true for procedures involving extensive abdominal incision/manipulation. Whereas neuraxial analgesia might otherwise be appropriate in these cases, several studies have demonstrated that coronary artery spasm can occur as a result of epidural placement, and therefore, that this may not be an optimal choice for patients with variant angina. This report discusses the case of a patient with a preexisting diagnosis of variant angina who underwent an exploratory laparotomy with large ventral hernia repair and for whom continuous erector spinae plane blocks were successfully used as analgesic adjuncts without triggering coronary artery spasm.     

Intracoronary verapamil for reversal of refractory coronary vasospasm during percutaneous transluminal coronary angioplasty

Coronary artery spasm unresponsive to intracoronary nitroglycerin was observed in eight patients undergoing percutaneous transluminal coronary angioplasty for unstable ischemic symptoms (unstable angina or recent nontransmural infarction, or both). All patients manifested eccentric lesions angiographically with the right coronary artery involved in four, circumflex artery in two and left anterior descending in two. Severe coronary spasm was documented angiographically in all patients after angioplasty and resulted in symptomatic and electrocardiographic evidence of ischemia. Multiple sites of spasm were present in the dilated vessel in three patients. Coronary artery spasm persisted despite the infusion of large doses of intracoronary nitroglycerin (200 to 2,000 micrograms, mean 850 micrograms) over 10 min. Administration of intracoronary verapamil (1 to 1.5 mg over 10 min) resulted in complete relief of spasm with restoration of brisk anterograde flow in all patients. These findings suggest that intracoronary verapamil may be a useful agent for the relief of coronary spasm occurring in the setting of coronary angioplasty.     

Calcium channel blockers for the treatment of coronary artery spasm: rationale, effects, and nursing responsibilities

Coronary artery spasm is recognized as a cause of ischemic heart disease, producing a syndrome of the variant form of angina that occurs at rest. Spasm also may play a role in other types of rest angina (unstable angina) and exertional angina. Calcium is essential for the basic tonus of vascular smooth muscle. The accentuated contraction that occurs in coronary artery spasm is the result of an increase in intracellular calcium ions. Current therapy is aimed at blocking the slow calcium currents that are responsible for electrical activation and contraction of smooth muscle cells. A marked coronary vasodilatation is produced with calcium channel blockers, thus demonstrating effective therapy for coronary artery spasm. A similar effect is achieved by nitrates, and these agents will continue to have a role in the therapy of spasm. Calcium channel blockers produce beneficial effects on myocardial oxygen supply and demand and, therefore, are also useful in the prevention of classic exertional angina caused by fixed obstruction. Verapamil and diltiazem possess electrophysiologic effects and have, in addition, proved useful in the treatment of supraventricular dysrhythmias.     

Coronary Artery Spasm*

Summary: Coronary artery spasm. S. B. Freedman and D. R. Richmond. Aust. N.Z. J. Med., 1980. 10 , pp. 69–72. Variant angina with ST elevation indicates transmural myocardial ischaemia and is due to spasm of a large epicardial coronary artery. Spasm occurs in arteries with varying degrees of fixed obstruction, giving rise to different clinical profiles of variant angina. However, coronary angiography is required to differentiate between those with minor coronary disease, and those with significant (>70%) obstruction. In patients with minor coronary disease or normal arteries, β-blockers are contraindicated, and treatment with calcium antagonist vasodilators should be commenced after documentation of spontaneous or ergo-novine induced spasm. Patients with significant fixed coronary obstructions require bypass grafting if technically feasible. The role of coronary spasm is not confined to variant angina, as it causes angina at rest with ST depression, and may also cause myocardial infarction and sudden death.     

冠脉痉挛与变异型心绞痛和急性心肌梗死的关系

目的 探讨冠脉痉挛与变异型心绞痛(VA)和急性心肌梗死(AMI)的关系。方法 对30例AMI和14例VA患者施行冠状动脉造影(CAG),以冠脉狭窄>50％为CAG阳性。结果 在30例AMI患者中有4例CAG正常,在14例VA中,CAG正常2例,狭窄程度在50％～90％的12例。结论 本文结果提示,冠脉痉挛在VA和AMI的发病中起着十分重要的作用。冠脉痉挛不仅可以发生在有严重狭窄的冠状动脉,亦可以发生于造影正常的冠状动脉。     

Coronary spasm: It’s common,but it’s still unsolved

Coronary spasm is caused by a transient coronary narrowing due to the constriction of epicardial coronary artery, which leads to myocardial ischemia. More than 50 years have passed since the first recognition of coronary spasm, and many findings on coronary spasm have been reported. Coronary spasm has been considered as having pivotal roles in the cause of not only rest angina but also exertional angina, acute coronary syndrome, and heart failure. In addition, several new findings of the mechanism of coronary spasm have emerged recently. The diagnosis based mainly on coronary angiography and spasm provocation test and the mainstream treatment with a focus on a calcium-channel blocker have been established. At a glance, coronary spasm or vasospastic angina (VSA) has become a common disease. On the contrary, there are several uncertain or unsolved problems regarding coronary spasm, including the presence of medically refractory coronary spasm (intractable VSA), or an appropriate use of implantable cardioverter defibrillator in patients with cardiac arrest who have been confirmed as having coronary spasm. This editorial focused on coronary spasm, including recent topics and unsolved problems.     

Inpatient treatment of unstable angina: Clinical perspective and sequential management

In the last decade, increasing information has become available to the effect that an increase in coronary artery tone and coronary artery spasm play an important role in patients with various ischemic heart disease syndromes. Coronary spasm may be superimposed on a coronary vessel already severely obstructed by atherosclerosis. Conversely, spasm may occur in an artery that is only minimally involved with atherosclerosis. The majority of patients studied in the United States with both stable and unstable angina pectoris have underlying severe organic obstructive coronary artery disease. There has now emerged a considerable amount of information from several centers showing that the calcium-channel blockers or calcium-flux antagonists are highly effective in the treatment of stable and unstable angina pectoris. This report focuses on the uses and limitations of one of these agents, nifedipine, in patients with unstable angina and provides a sequential approach to their management.     

Multivessel coronary spasm as a cause of ischemic syncope in angina at rest

Two patients with vasospastic angina at rest developed ST segmentelevation both in the anterior and inferior leads during spontaneousand ergonovine-induced attacks. In both cases the acute myocardialischemia secondary to multivessel coronary spasm led to reversibleelectromechanical dissociation. Coronary arteriography showednormal coronary arteries in one case and severe three-vesseldisease in the other; spasm of the right coronary artery wasdemonstrated in both patients. These cases show that in patientswith vasospastic angina coronary spasm may simultaneously involvedifferent arteries and lead to ischemic electromechanical dissociation.Ergonovine testing is contraindicated in those patients withsuspected or proved multivessel coronary spasm.     

The sensitivity of intracoronary injection of acetylcholine in inducing coronary spasm differs in patients with stable and unstable angina.

In an attempt to clarify the role of coronary artery spasm in the pathogenesis of unstable angina, acetylcholine (20 and 50 micrograms) was injected directly into the coronary arteries of 19 patients with unstable effort angina (group 1), 30 patients with unstable spontaneous angina (group 2), and 15 patients with stable effort angina due to coronary artery organic stenosis (greater than or equal to 75%) (group 3). Coronary spasm was defined as severe vasoconstriction (greater than or equal to 90% of luminal diameter) with chest pain and/or ischemic ST-segment changes. Intracoronary injection of acetylcholine induced spasm of at least one coronary artery in 19 patients (100%) of group 1 and 28 (93%) of group 2 but only 3 (20%) of group 3 (p less than 0.01). When acetylcholine was injected into the left and right coronary arteries separately, multivessel spasm (spasm of both coronary arteries) was induced in 5 of 12 (42%) patients of group 1 and in 9 of 23 (39%) patients of group 2. In contrast, intracoronary acetylcholine did not cause multivessel coronary spasm in any of 15 patients of group 3 (0%). These results suggest that coronary arteries in patients with unstable effort angina as well as spontaneous angina are susceptible to spasm and that coronary artery spasm may be responsible at least in part for the genesis of attacks in these patients.     

Spontaneous coronary artery spasm in variant angina is caused by a local hyperreactivity to a generalized constrictor stimulus

To assess whether spontaneous coronary artery spasm in patients with variant angina results from local coronary hyperreactivity to a generalized constrictor stimulus or from a stimulus generated only at the site of the hyperreactive segment, the behavior of spastic and nonspastic coronary segments was studied in six patients with variant angina in whom focal coronary spasm developed spontaneously during cardiac catheterization. None of the patients had critical (greater than 50% luminal diameter reduction) organic coronary stenoses. Coronary diameters were measured by computerized quantitative arteriography during control, spontaneous spasm and ergonovine-induced spasm and after intracoronary nitrates were given. During spontaneous spasm, the luminal diameter of spastic and both proximal and distal nonspastic coronary segments was significantly reduced from control values, 64.2%, 13.2% and 14.8%, respectively. Average diameter reduction of unrelated arteries was 12.3%. Ergonovine, which was also administered to four patients, provoked focal spasm at the same site as spontaneous spasm. During intravenous ergonovine, luminal diameter of spastic segments was reduced by 91.5%, that of nonspastic proximal segments by 17.8% and that of nonspastic distal segments by 11.5%. Luminal diameter of unrelated arteries during ergonovine-induced spasm was reduced by 17.7%. Constriction of spastic segments was greater during ergonovine-induced spasm (p less than 0.05), whereas the extent of diameter reduction of nonspastic segments was not significantly different during spontaneous spasm and ergonovine-induced spasm. Intracoronary isosorbide dinitrate dilated spastic and nonspastic coronary segments to a similar extent from control (20.7%, 18% and 16.5%, respectively; p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)     

Angina in thyrotoxicosis. Thyroid-related coronary artery spasm

Ischemic heart disease is a common complication of thyrotoxicosis, although the exact mechanism has not been defined. A case is reported of angina and thyrotoxicosis in which the angina was reproduced by coronary artery spasm induced by ergonovine maleate, relieved by thyroid ablation, and reactivated by postablative thyroid replacement. Coronary arteriography did not show significant stenoses prior to ergonovine injection. Possible mechanisms of coronary artery spasm in thyrotoxicosis are briefly discussed. Hyperthyroidism should be considered as a cause of angina in any patient with rest pain and normal coronary arteries.     

Clinical studies of patients with coronary spasm

Coronary artery spasm may cause myocardial ischemia in patients without severe coronary atherosclerotic obstruction. Spontaneous rest angina, particularly at night, is the predominant symptom; most patients are smokers. Ergonovine tests have high sensitivity and specificity for the diagnosis of coronary spasm, but should be used when vasospasm is suspected but no electrocardiogram was recorded during spontaneous angina. Arterial constriction measured during ergonovine testing suggests that the arterial hypersensitivity to vasoconstrictors at sites of atherosclerotic lesions is independent of the severity of the lesion. Coronary vasospasm may also be provoked by exercise, possibly through an alpha-adrenergic mechanism. Both spontaneous and exercise-induced attacks of vasospasm are prevented by calcium-antagonist drugs that remain effective during longer-term treatment. The cyclic nature of the condition is demonstrated when successful therapy is discontinued without recurrence of symptoms and may be due to alteration of arterial hypersensitivity.     

Induction of coronary artery spasm by a direct local action of ergonovine

To investigate whether ergonovine acts directly on coronary arteries or via remote neurohumoral reflexes, we administered small titrated increments of intracoronary ergonovine up to a maximum cumulative dose of 50 micrograms to 15 patients. In six patients with variant angina (group 1), ischemic electrocardiographic ST changes, angina, and localized coronary spasm (local coronary diameter reduction of 87.8 +/- 18.9% [mean +/- SD]) followed after 6 to 50 micrograms (mean 20.7) cumulative intracoronary ergonovine. In nine patients with atypical chest pain, normal baseline coronary arteriograms, and no evidence of variant angina (group 2), there was no ischemic ST segment change or localized coronary spasm after 6 to 50 micrograms (mean 31.6) intracoronary ergonovine. Coronary diameter of proximal vessels of patients in group 2 was reduced by 16.2 +/- 6.5% and did not differ from the response of nonspastic vessels of comparable size of group 1 (20.5 +/- 13.8%; p = .7). There was no significant difference in the median effective dose values in the dose-response curves of the spastic and nonspastic segments between groups 1 and 2. Ergonovine causes coronary spasm by a direct local effect, which seems to be caused by localized arterial hyperreactivity rather than supersensitivity. Intracoronary delivery may be safer than intravenous administration because negligible drug recirculation may prevent perpetuation of spasm and selective coronary administration can avoid branches with critical stenoses.     

Coronary artery spasm.

Coronary artery spasm is an important pathogenetic mechanism in some forms of myocardial ischemic disease. Factors that may be important in the genesis of spasm include the autonomic nervous system, prostaglandins, endoperoxides, thromboxanes, and the calcium availability to the contractile apparatus. Spasm results in myocardial ischemia with attendant chest pain and electrocardiographic and hemodynamic changes; it is the primary pathogenetic mechanism in Prinzmetal's variant angina and has been found in association with classic angina pectoris and acute myocardial infarction. Diagnosis of coronary artery spasm is firmly made only by coronary angiography. Treatment includes the use of both short- and long-acting nitrates and the slow-channel blocking agents such as verapamil, nifedipine, and perhexiline.     

Comparative sensitivity of intracoronary injection of acetylcholine for the induction of coronary spasm in patients with various types of angina pectoris

To elucidate the possible contribution of coronary artery spasm to the pathogenesis of angina pectoris, coronary arterial responses to intracoronary injection of acetylcholine were examined in patients with various types of angina pectoris. Coronary artery spasm with chest pain and/or electrocardiographic ischemic changes was angiographically demonstrated in 50 (85%) of 59 patients with angina pectoris. The sensitivity for coronary spasm was 92% (24 of 26) in patients with rest angina, 100% (16 of 16) in patients with both rest and effort angina, and 59% (10 of 17) in patients with effort angina, while it was only 6% (1 of 16) in patients without coronary artery disease. When patients with effort angina were subdivided according to the variability of anginal threshold for exertional angina, the sensitivity for coronary spasm was as high as 90% (9 out of 10) in patients with variable-threshold angina. In contrast, coronary spasm was less frequently (p less than 0.05) induced in patients with fixed-threshold angina (1 of 7, 14%). These results suggest that coronary arteries in patients with angina pectoris are quite susceptible to acetylcholine except in those patients with stable exercise tolerance or anginal threshold. Thus coronary artery spasm appears to play a significant role for the pathogenesis of angina pectoris in a large proportion of patients with effort angina as well as in patients with rest angina.     

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.