Vasospastic angina

INTRODUCTION — Vasospastic angina, which was previously referred to as Prinzmetal [1] or variant angina, is characterized by episodes of rest angina that promptly respond to short-acting nitrates and are attributable to coronary artery vasospasm. Following the original description by Prinzmetal, et al [1] of angina at rest and transient ST-segment elevation, the condition was initially called "variant angina" as it differed from the established description of classical angina (ie, effort angina associated with ST depression) [2]. In recent years, as coronary artery spasm has been shown to be associated with either ST elevations or depressions, the term "vasospastic angina" is currently more commonly used.

This topic will discuss the clinical presentation, diagnosis, and management of vasospastic angina. Other forms of myocardial infarction (MI) without obstructive coronary artery disease and other forms of (cardiac) angina are discussed in separate topic reviews. (See "Chronic coronary syndrome: Overview of care" and "Microvascular angina: Angina pectoris with normal coronary arteries" and "Acute coronary syndrome: Terminology and classification" and "Myocardial infarction with no obstructive coronary atherosclerosis".)

EPIDEMIOLOGY

●Prevalence – The prevalence of vasospastic angina is difficult to assess since provocative spasm testing is not widely performed in contemporary cardiology practice. Consequently, prevalence estimates are subject to patient selection bias for identifying vasospastic angina. Considering this limitation, in a recent meta-analysis of 24 studies in over 6500 patients with suspected coronary disease and no epicardial obstructive coronary lesions, the prevalence of epicardial artery vasospastic angina was 40 percent (95% CI 33-47 percent) [3].

Among all patients presenting with MI, 1 to 15 percent do not have obstructive coronary disease on angiography [4]. An estimated 30 percent of these individuals have documented coronary artery spasm [5,6].

•Sex differences – Some studies suggest that the prevalence of vasospastic angina is similar between men and women [7]. In some populations, the prevalence of vasospastic angina was shown to be higher in males versus females [8,9], though studies demonstrating this may be confounded by higher rates of smoking in males versus females.

•Younger ages – Patients with vasospastic angina are often younger than patients with angina related to obstructive coronary disease, with fewer classic cardiovascular risk factors (except for cigarette smoking) [10].

●Risk factors – Cigarette smoking is the only established atherosclerotic cardiovascular disease (ASCVD) risk factor that is also a major risk factor for vasospastic angina [11]. Hypertension and hypercholesterolemia do not accurately predict the development of vasospastic angina [12].

Other risk factors include the following:

•Genetic factors and insulin resistance [13-15]. (See "Overview of established risk factors for cardiovascular disease".)

•A history of recreational drug use (such as cocaine).

PATHOGENESIS — Vasospastic angina is caused by focal or diffuse spasm (of the arterial wall smooth muscle layer) of an epicardial coronary artery [16,17], resulting in a dynamic high-grade obstruction. Vascular smooth muscle hyperreactivity is thought to be central to the pathogenesis of vasospastic angina [1,16,17]. Spasm may occur in the absence of any preceding increase in myocardial oxygen demand (eg, exercise) and in normal or diseased vessels.

Spasm commonly occurs at the focal site of atherosclerotic plaques (of variable severity) even though it can also occur in angiographically normal coronary vessels. Vasospasm can also be diffuse rather than at a focal site of stenosis [18].

Possible mechanisms — The following pathogenic mechanisms contribute to vasospastic angina:

●Vascular smooth muscle hyperreactivity – Increased calcium sensitivity of the vascular myosin light chain has a role in spasm [19-21]. This is mediated by enhanced Rho kinase and phospholipase C activity [22]. Inhibition of smooth muscle contractile mechanisms using nonreceptor pathways (eg, nitrates, calcium channel blockers) is an effective treatment [23,24].

●Autonomic nervous system dysfunction – Increased vagal tone and hyperreactivity to sympathetic stimulation occur in vasospastic angina patients [25,26]. Vasospastic angina often occurs from midnight to early morning (when vagal tone is higher). Provocation of spasm by acetylcholine and methacholine suggests vagal and sympathetic tone imbalance [25,27-33].

●Endothelial dysfunction – This may be a predisposing factor but is not likely the sole reason for coronary spasm, given that typical coronary spasm is an uncommon condition, whereas endothelial dysfunction is more common. (See "Coronary endothelial dysfunction: Clinical aspects".)

Factors contributing to endothelial dysfunction in vasospastic angina patients are largely similar to those in patients without vasospastic angina (eg, oxidative stress and inflammation) [34-44]. (See "C-reactive protein in cardiovascular disease", section on 'Possible pathogenic role of CRP'.)

●Microvascular spasm – This refers to occlusive or subocclusive vasomotor changes in the coronary microvessels, leading to myocardial ischemia [45-47].

●Allergy – Allergic angina (also called Kounis syndrome) may be defined as any allergy-mediated acute coronary syndrome, including in-stent thrombosis resulting from anaphylactoid processes [48,49]. This entity has been described primarily in isolated case reports and case series [50,51]. Whether anaphylactoid mediators play a major role in coronary spasm is unclear, though an animal [52] and a small human study [53] have reported coronary spasm after intracoronary injection of histamine, and an autopsy study demonstrated adventitial mast cells in a patient with variant angina [54].

Whether allergic angina represents a distinct clinical entity or a subtype of vasospastic angina, plaque rupture, and thrombosis remains to be determined.

●Smooth muscle dysfunction, often coexisting with coronary spasm

•Microvascular dysfunction – Microvascular dysfunction has been demonstrated in some patients with epicardial coronary vasospastic angina and may additionally contribute to myocardial ischemia. In a study of 55 patients, epicardial spasm was provoked by maximal doses of intracoronary acetylcholine [47]. In 14 of these patients, submaximal doses of acetylcholine provoked microvascular dysfunction in the absence of epicardial coronary vasospasm. Patients with microvascular dysfunction were more likely women and to have reported prolonged (>30 min) chest pain.

In a separate study, the acetylcholine test triggered epicardial or microvascular coronary spasm in nearly two-thirds of patients with angina and normal coronary arteriograms [55]. In this prospective study of patients with exertional angina undergoing diagnostic angiography, 144 patients had normal or minimal coronary disease. Of these, 124 patients underwent intracoronary acetylcholine testing. Coronary artery spasm was elicited in 77 patients; 45 percent had epicardial coronary artery spasm, and 55 percent had microvascular vasoconstriction. (See "Coronary artery endothelial dysfunction: Basic concepts" and "Microvascular angina: Angina pectoris with normal coronary arteries", section on 'Pathogenesis'.)

•Bronchial hyperreactivity – The pathology underlying asthma (caused in part by bronchial smooth muscle contraction and relaxation or "spasm") may coexist with and possibly precede the development of vasospasm. A propensity-score matched analysis of 3000 subjects with coronary artery spasm (and 12000 control patients undergoing coronary intervention) was undertaken using a population database from Taiwan [56]. Asthma was associated with new-onset vasospasm (odds ratio  1.85; 95% CI 1.47-2.32). Use of insurance claims data rather than clinical ascertainment was a limitation of this study.

•Arterial spasm in noncardiac vascular beds – Raynaud's phenomenon and migraine headache or its treatment have been anecdotally associated with vasospastic angina [57-59]. Arterial spasm that occurs in different vascular beds may explain these observations.

CLINICAL PRESENTATION

History

Chest pain/angina characteristics — Patients with vasospastic angina typically present with a chronic pattern of recurrent episodes of chest pain that is nitrate responsive. The quality of the chest pain is indistinguishable from classical angina pectoris associated with obstructive coronary artery disease; however, the context in which it occurs differs. It is important to recognize that vasospastic angina can cause angina symptoms, be asymptomatic, can present with arrhythmias, and even with cardiac arrest.

Features that are specific to vasospastic angina (versus classical angina) [60]:

●Angina occurs predominantly at rest and may occur from midnight to early morning [60].

●Effort and exercise tolerance are usually preserved [61-63]. However, among patients who are very symptomatic during a "hot phase" of the condition, characterized by more frequent and intense episodes, spasm may be triggered by the elevated catecholamines associated with exercise.

●Each episode of chest pain generally lasts 5 to 15 minutes, but episodes may last longer in some cases that are refractory to initial medical therapy. (See "Approach to the patient with suspected angina pectoris".)

●Hyperventilation can precipitate vasospastic angina [64].

●The episodes appear in "clusters."

●Vasospastic angina often has a more rapid response to sublingual nitroglycerin.

Features that are shared between vasospastic angina and classical angina:

●"Discomfort" is more often given as a descriptor than "pain." Other common descriptors include squeezing, tightness, pressure, constriction, strangling, burning, heart burn, fullness in the chest, a band-like sensation, knot in the center of the chest, lump in the throat, ache, and heavy weight on chest.

●Episodes are typically gradual in onset and offset.

●There is no change in the quality of pain with respiration or position.

●Patients may have some difficulty in describing the location of the pain, although the substernal location is common. Radiation to the neck, throat, lower jaw, teeth, upper extremity, or shoulder is common.

●During the anginal episode, nausea, sweating, dizziness, dyspnea, and palpitations may be present.

As with stable angina from fixed obstructive coronary artery disease, asymptomatic episodes of ischemia can also occur in patients with vasospastic angina. In one study of over 1000 episodes in 240 patients, 92 percent of ischemic episodes were asymptomatic [65]. The role of screening for asymptomatic episodes is discussed below. (See 'Ambulatory ECG monitoring' below.)

Although angina is a common presenting symptom, vasospastic angina can also present with arrythmia and sudden cardiac arrest/death.

Acute triggers — Obtaining history of factors that trigger an episode of vasospastic angina may help define strategic treatments.

Possible triggers and their underlying mechanisms include:

●Changes in autonomic activity, eg, increased vagal tone (detected by heart rate variability monitoring) shortly before an episode [32]. (See "Evaluation of heart rate variability" and 'Possible mechanisms' above.)

●Recreational drugs – Cocaine, amphetamines, marijuana, alcohol, butane.

●Prescription drugs – Sympathomimetic agents (ephedrine-based products), migraine therapies (sumatriptan), chemotherapy agents (5-flurouracil), and ergot-derivatives (ergonovine in obstetrics) [33,66,67].

●Guide wire or balloon dilatation at the time of percutaneous coronary intervention [33].

●Food-born botulism [68]. (See "Botulism", section on 'Types of botulism and their sources'.)

●Magnesium deficiency [49,52-54]. (See 'Subsequent therapy' below.)

●Hyperventilation.

●Exposure to extreme cold.

●Allergic reactions.

Physical examination — Although a cardiovascular physical examination should be performed to establish baseline information, there are no findings unique to vasospastic angina. Findings that may be present during an episode are tachycardia, hypertension, diaphoresis, and an S4 gallop rhythm. Bradycardia and hypotension may be present if sinus nodal, atrioventricular nodal, and right ventricular arteries are involved during proximal right coronary artery vasospasm.

ECG changes — The electrocardiogram (ECG) is usually normal between episodes in patients with vasospastic angina. For patients evaluated during an acute spontaneous episode, ECG may reveal transient ST-segment elevation or depression in multiple leads. These are described in detail below. (See '12-lead ECG during chest pain' below.)

DIAGNOSIS

Diagnostic criteria — The Coronary Vasomotion Disorders International Study group has published diagnostic criteria for vasospastic angina (table 1) [60]. It includes the following core elements:

●Nitrate-responsive angina

●Transient ischemic ECG changes in the absence of obvious causes for increased myocardial oxygen demand

●Angiographic evidence of coronary artery spasm

Occasionally, a spontaneous episode may occur during diagnostic angiography so that all three elements may be documented. Provocative testing is needed if the diagnosis cannot be made during a spontaneous episode. During provocation testing, the diagnosis of vasospastic angina is confirmed if the provocative stimulus induced chest pain, transient ECG changes, and a >90 percent constrictor response.

Sometimes, the diagnosis is made on a clinical basis from the history and ECG without angiographic evidence of vasospasm.

Diagnostic overview — The clinical diagnosis of vasospastic angina is made when a patient with recurrent episodes of nitrate-responsive chest pain, which generally occur at rest (or in early morning/night), is found to have transient ST-segment elevation or depression on an ECG at the time of these episodes (algorithm 1). These patients can have reduced exercise tolerance. Since vasospasm can often coexist with ischemia from obstructive coronary artery disease, it is important to consider both diagnoses. Therefore, in the patient with intermediate to high risk of atherosclerotic cardiovascular disease (ASCVD), we also assess for this possibility with noninvasive testing, and in some cases invasive coronary angiography. If these are unrevealing or equivocal for etiology of chest pain, angiography with provocative testing should be performed.

●In patients who have nitrate-responsive chest pain and meet other criteria consistent with coronary vasospasm, it is reasonable to give a trial of calcium channel blockers. If the symptoms are relieved, the diagnosis of vasospasm is very likely.

•If the patient is at low risk of ASCVD, usually no further evaluation is needed.

•If the patient is at intermediate to high risk of ASCVD, we would perform invasive angiography in order to exclude concomitant obstructive coronary artery disease. If obstructive coronary artery disease is present, we also administer therapies for secondary ASCVD prevention (eg, aspirin, statin, etc). (See "Cardiovascular disease risk assessment for primary prevention: Risk calculators" and "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach".)

●When an ECG during chest pain is unavailable, we use a stress test and/or coronary computed tomography angiography (CCTA) to first evaluate for obstructive coronary disease. An exercise ECG stress test is the preferred initial test as it is a functional test. (See "Stress testing for the diagnosis of obstructive coronary heart disease" and "Clinical use of coronary computed tomographic angiography".)

●If the stress test and/or CCTA are uninterpretable or equivocal, an ambulatory ECG monitor can detect episodes of ST-segment elevation/depression coincident with chest pain. (See 'Ambulatory ECG monitoring' below.)

●If all noninvasive tests are equivocal or uninterpretable, invasive coronary angiography can be performed to rule out obstructive coronary artery disease as a cause of the chest pain.

●If the diagnosis of vasospastic angina remains uncertain, the patients should undergo invasive coronary angiography with provocative testing. If local expertise is unavailable, the patient should be referred to a center that has expertise in performing provocative testing with angiography. (See 'Coronary arteriography and provocative testing' below.)

Our diagnostic approach is consistent with the 2019 European Society of Cardiology guidelines on the management of stable coronary artery disease [69].

Frequent underdiagnosis — We believe that vasospastic angina is underdiagnosed for two main reasons:

●Some patients do not present with typical symptoms of either stable ischemic heart disease due to fixed obstruction or vasospastic angina.

●Many clinicians are not sufficiently familiar with vasospastic angina to consider it as a diagnostic possibility. As fixed obstruction is significantly more common as a cause of angina, that diagnosis is pursued preferentially without the possibility of vasospasm.

Diagnostic evaluation

12-lead ECG during chest pain

●In all patients with angina, particularly patients suspected of having vasospastic angina, a 12-lead ECG should be performed during a spontaneous episode of pain.

●In addition, a "baseline" ECG should be obtained when the patient is not having pain for comparison.

ST-segment elevation or depression may be seen during an episode of chest discomfort. These changes are usually transient (less than 15 minutes) and may occur in multiple leads of a 12-lead ECG. Unlike most other causes of chest pain and ischemic ST changes, the ST segment returns to baseline rapidly upon resolution of symptoms. Occasionally, a transient period of T-wave inversion may be seen before return of the ECG to baseline.

Other reported ECG abnormalities include a tall and broad R wave, disappearance of the S wave, a taller T wave, and negative U waves [65].

Troponin levels — Patients evaluated during an acute spontaneous episode and who have ECG changes need to have an MI ruled out with serial troponin testing. In most cases, troponin values are in the normal range in patients with vasospastic angina, due to the relatively short duration of myocardial ischemia. However, with prolonged vasospasm, high-sensitivity troponin can be elevated [46].

Stress testing and coronary computed tomography angiography — Many patients with anginal chest pain with no available concurrent ECG or with an ECG that has no transient ischemic ST-segment changes during pain should undergo testing to screen for significant fixed coronary artery disease. (See 'Differential diagnoses' below.)

We prefer an exercise stress test as the initial diagnostic test rather than a pharmacologic stress test or CCTA. This is because an exercise stress test can quantify a patient's exercise tolerance, functional status, and provides prognostic information.

Most patients with vasospastic angina will have a normal noninvasive stress test. However, exercise-induced spasm with ST-segment elevation has been reported to occur in 10 to 30 percent of patients with vasospastic angina, particularly during the very symptomatic periods of this condition [62,63,70]. As ST-segment elevation during stress testing is not specific for vasospastic angina, these patients need to be screened for severe fixed disease with coronary arteriography.

We do not perform provocative testing with ergonovine during stress testing, including stress echocardiography, even though it has been used by others to diagnose vasospastic angina in specialized centers [71,72]. If this investigation is undertaken prior to excluding obstructive coronary artery disease, it may be associated with significant risk. Furthermore, ergonovine testing with ECG monitoring alone has been associated with significant morbidity and mortality [73].

A CCTA can be a reasonable alternative test to rule out obstructive coronary artery disease in patients at low to intermediate risk of acute coronary syndrome from fixed coronary artery disease. (See "Noninvasive testing and imaging for diagnosis in patients at low to intermediate risk for acute coronary syndrome", section on 'Coronary computed tomography angiography' and "Cardiac imaging with computed tomography and magnetic resonance in the adult", section on 'Cardiac CT'.)

Ambulatory ECG monitoring — Ambulatory ECG monitoring can detect episodes of ST-segment elevation/depression with or without angina and should be performed in patients in whom the diagnosis is being considered but not yet confirmed. Multi-lead ECG monitoring is more likely to detect ischemia compared with single-lead monitoring and is thus highly preferred. If a patient has had a negative stress test or CCTA, it is reasonable to perform ambulatory ECG monitoring. In patients with documented vasospastic angina, the ambulatory ECG monitoring can also be used to assess efficacy of therapy and monitor for arrhythmia.

●The finding of transient ischemic ST changes on the ambulatory monitor, combined with a typical history, may confirm the diagnosis.

●Since episodes of vasospastic angina may be infrequent, longer-term monitoring (7 to 14 days) with an event recorder or even an insertable cardiac monitor (also sometimes referred to as implantable cardiac monitor or implantable loop recorder) may be required to make the diagnosis. (See "Ambulatory ECG monitoring".)

●In patients with confirmed vasospastic angina, ambulatory ECG monitoring should be performed to assess the efficacy of therapy. This is important given that asymptomatic episodes are common and sometimes associated with significant arrhythmias [74]. In one report using 24-hour ambulatory ECG monitoring, 79 percent of episodes were asymptomatic [65,75]. Recording of a left precordial lead and an inferior lead is able to identify the majority of transient ischemic episodes, although it may not identify episodes caused by spasm of the circumflex artery or a small coronary artery branch.

●In patients with confirmed vasospasm, ambulatory ECG monitoring should also be performed to exclude arrythmia, which has a worse prognosis and more aggressive management. (See 'Prognosis' below.)

Coronary arteriography and provocative testing — Although catheter-induced coronary spasm is frequent, it is neither sensitive nor specific for the diagnosis of vasospastic angina. As such, the primary purpose of coronary arteriography in patients with suspected vasospastic angina is to perform provocative testing that will elicit vasospasm if present. If obstructive coronary artery disease is seen, resolution of obstruction after intracoronary nitroglycerin is diagnostic of coronary spasm. The diagnosis is even more certain if ECG changes resolve with resolution of pain.

We recognize that in some centers, provocative testing will not be available due to lack of expertise.

If a patient with suspected vasospasm has an intermediate to high risk of ASCVD, invasive angiography may be indicated for the diagnosis of obstructive coronary artery disease. The criteria for obtaining an angiogram would be the same for any patient with chronic coronary syndrome.

●We perform provocation to solidify the diagnosis of vasospasm. Three provocative tests (ergonovine, acetylcholine, and hyperventilation) can be performed in the catheterization laboratory in an attempt to confirm the diagnosis (see 'Diagnostic criteria' above). These tests are performed only when the diagnosis of vasospastic angina is suspected but not firmly established. At present, pharmacologic provocative testing is not frequently performed and should be employed only by experienced teams [72].

Acetylcholine – Provocation with intracoronary acetylcholine is a useful provocative test [27,30,76] and can also provide useful prognostic information. The dose of acetylcholine administered can widely differ between countries and specific centers.

-Diagnosis – Acetylcholine is preferred over ergonovine and hyperventilation by most but not all of our experts. There are low incidence rates of serious complications with acetylcholine. In a study of 847 patients without high-grade coronary disease (no lesion ≥50 percent diameter stenosis) who received high-dose acetylcholine, epicardial spasm was reported in one-third, yet serious complications occurred in less than 1 percent of patients [77]. This was similar to prior studies [76].

-Prognosis - Acetylcholine-provoked spasm at sites of significant organic stenosis was a predictor of major adverse cardiac events at five years [78]. A 2015 retrospective study of 1760 patients with typical or atypical angina-like chest pain who underwent acetylcholine-provocation testing found that if spasm was located further from a hemodynamically significant stenosis or occurred in the absence of a hemodynamically significant stenosis, patients had a better prognosis.

Ergonovine – Ergonovine is not available in the United States and it is not used as commonly as it was in the past in Europe [64,72,79-81]. It is currently used in a few selected centers in Korea and Japan.

Hyperventilation – Hyperventilation is rarely used as a provocative test during coronary arteriography. Testing for vasospastic angina with hyperventilation has been evaluated in studies of ECG-monitored patients and had a high specificity (100 percent) in one study [64] and a sensitivity ranging between 55 and 95 percent, depending on the frequency of daily attacks [64,82].

Differential diagnoses — Chest pain is a common presenting symptom for a variety of clinical conditions, thus a number of other diagnoses must be considered in the differential diagnosis of vasospastic angina. The likelihood of specific diagnoses depends on the type of the chest pain (typical or atypical) and the presence and type of ECG changes.

●Cardiac ischemia with obstructive coronary artery disease – In patients with typical anginal chest pain and ECG ST elevations, acute ST-elevation MI (STEMI) must first be ruled out. Vasospastic angina may occur in the presence or absence of obstructive coronary artery disease. Even if ST elevations are not present, patients with typical angina must still undergo a thorough evaluation for severe coronary artery disease.

•STEMI – In patients with STEMI, chest pain and ECG ST elevations are usually present for more than 15 minutes. Acute therapy with nitroglycerin or calcium channel blocker does not usually resolve symptoms and ST elevation. (See "Diagnosis of acute myocardial infarction", section on 'ST elevation' and "Overview of the acute management of ST-elevation myocardial infarction".)

•Severe coronary artery disease – We suggest excluding severe coronary artery disease due to the significantly greater likelihood of fixed obstructive coronary disease compared with vasospastic angina. This evaluation often involves stress testing in patients with normal troponin values. (See "Stress testing for the diagnosis of obstructive coronary heart disease" and "Selecting the optimal cardiac stress test".)

However, for many patients in whom unstable angina is suspected or for all those in whom a 12-lead ECG has shown transient ischemic ST-segment changes with an episode of pain, coronary arteriography should be performed to exclude severe fixed coronary artery disease. If this is found, revascularization is often indicated. (See "Non-ST-elevation acute coronary syndromes: Selecting an approach to revascularization", section on 'Summary and recommendations'.)

Stress testing should not be done for patients in whom there is high suspicion for unstable angina.

●Other cardiac causes that result in ischemia or ECG changes without obstructive coronary artery disease – The conditions below cause chest pain from myocardial ischemia without obstructive coronary arteries and can be ruled out with coronary angiography. Unlike vasospastic angina, most of these conditions are not chronic disorders. However, 1 to 2 percent of cases recur in the 12 months following their initial presentation. Microvascular angina is an exception; it has a chronic course.

•Spontaneous coronary artery dissection – Spontaneous coronary artery dissection (SCAD) is a nontraumatic and noniatrogenic separation of the coronary arterial wall and is an infrequent cause of acute MI. SCAD should be considered in any young patient, especially a female, without a history of coronary heart disease or risk factors, who presents with an acute MI or cardiac arrest. (See "Spontaneous coronary artery dissection".)

•Coronary artery anomaly – Congenital anomalies of the coronary circulation can cause compression and myocardial ischemia, depending on the specific course of the anomalous coronary artery between the great vessels, the intramural myocardial course, or acute angle of take-off from its origin. The clinical presentation of a patient may be anginal chest pain, syncope (especially with exercise), and sudden cardiac arrest/death. (See "Congenital and pediatric coronary artery abnormalities".)

•Takotsubo syndrome – This is a syndrome characterized by transient regional left (and often right) ventricular dysfunction in the absence of significant coronary artery disease. The most common presenting symptom is acute substernal chest pain, and some patients have dyspnea or syncope. Unlike vasospastic angina, a physical or emotional trigger is often present in stress cardiomyopathy. (See "Clinical manifestations and diagnosis of stress (takotsubo) cardiomyopathy".)

•Pericarditis – In patients with pericarditis, the chest pain is often dissimilar to that of vasospastic angina, with individuals often complaining of sharp pain that is affected by position or breathing and can last continuously for hours to days. Vasospastic angina episodes are generally brief and intermittent. Echocardiography is often abnormal in these individuals. (See "Acute pericarditis: Clinical presentation and diagnosis".)

•Myocarditis – Myocarditis should be suspected in patients with or without cardiac signs and symptoms who present with a rise in cardiac biomarker levels, change in ECG suggestive of acute myocardial injury, arrhythmia, or abnormalities of ventricular systolic function, particularly if these clinical findings are new and unexplained. Chest pain is not always a presenting symptom and when present is often pleuritic and can last continuously for hours to days.(See "Clinical manifestations and diagnosis of myocarditis in adults".)

•Microvascular angina – Microvascular angina (MVA) results from vascular dysfunction of the microvascular coronary bed and in a subset of patients, microvascular vasospasm (or vasoconstriction) can be an underlying mechanism. In this case, the pattern of MVA is similar to that of vasospastic angina in that it can occur either at rest or in a mixed rest/effort pattern. When vasoconstriction or vasospasm is not an underlying mechanism, MVA is usually effort related. Vasospastic angina, on the other hand, is far less likely to present with effort. MVA is associated with less marked ST-segment changes as compared with vasospastic angina. The clinical features, diagnosis, and treatment of MVA are discussed separately. (See "Microvascular angina: Angina pectoris with normal coronary arteries" and "Microvascular angina: Angina pectoris with normal coronary arteries", section on 'Clinical presentation'.)

●Causes of nitrate-responsive chest pain – If obstructive and other forms of nonobstructive epicardial coronary artery disease are ruled out, and nitrate responsive chest pain is present, both MVA and esophageal dysmotility (also referred to as esophageal spasm) should be considered.

•MVA – MVA typically responds to nitroglycerin. (See "Microvascular angina: Angina pectoris with normal coronary arteries" and "Microvascular angina: Angina pectoris with normal coronary arteries", section on 'Clinical presentation'.)

•Esophageal dysmotility – Patients with esophageal dysmotility (or esophageal spasm) may present with dysphagia, noncardiac chest pain, heartburn, and/or regurgitation. If the patient has absent or well-controlled gastrointestinal esophageal reflux disease, the chest pain from esophageal dysmotility can be relieved by nitroglycerin. (See "Distal esophageal spasm and hypercontractile esophagus".)

●Other conditions with chest pain and ECG abnormalities

•Pulmonary embolism – The most common presenting symptom of a pulmonary embolism is dyspnea followed by chest pain (classically but not always pleuritic) and cough. (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism" and "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism", section on 'Electrocardiography'.)

●In some cases, patients will present with noncardiac chest pain and have incidental ECG changes. Comparing old ECGs to the present one can be useful to establish these diagnoses, which include:

•Early repolarization – This refers to an ECG J-point elevation of ≥0.1 mV in two adjacent leads with either a slurred or notched morphology. This pattern can be mistaken for ST elevation. More common in young athletes, this pattern is nearly always a benign incidental ECG finding, with no specific signs or symptoms attributed to it. (See "Early repolarization".)

•Patients with classic angina who have chronic ST elevation on their ECG – Patients with classic angina from obstructive coronary disease can have abnormal ECGs, most commonly as a result of a prior left ventricular aneurysm. (See "Approach to the patient with suspected angina pectoris" and "ECG tutorial: ST and T wave changes", section on 'Persistent ST elevation compatible with an aneurysm'.)

MANAGEMENT — The primary goals of treatment of vasospastic angina are to reduce the frequency of symptomatic episodes and to decrease the frequency of serious complications (MI, arrhythmias, and aborted cardiac arrest). (See 'Prognosis' below.)

Initial therapy — Initial therapy consists of prescribing sublingual nitroglycerin as needed for angina, smoking cessation counseling, atherosclerotic cardiovascular disease (ASCVD) risk-factor modification as relevant, and calcium channel blocker medication [83].

●Sublingual nitroglycerin – Although episodes may terminate spontaneously, sublingual nitroglycerin may reduce the duration of each episode. We suggest that patients use sublingual nitroglycerin with the onset of each episode, both to decrease the duration of symptoms and ischemia.

●Smoking cessation – We strongly encourage smoking cessation in all patients with vasospastic angina who smoke. Smoking cessation removes one of the triggers for vasospastic angina and leads to a substantial decrease in the frequency of episodes [84]. (See 'Epidemiology' above.)

●ASCVD prevention – Aggressive ASCVD risk-factor modification is important, since coronary vasospasm and ASCVD often coexist. (See "Overview of primary prevention of cardiovascular disease".).

●Calcium channel blockers – These agents are the mainstay of therapy for vasospastic angina. Calcium channel blockers alleviate symptoms by preventing vasoconstriction and promoting vasodilation in the coronary vasculature. One study demonstrated that the use of calcium channel blocker therapy was an independent predictor of MI-free survival in patients with vasospastic angina [85]. (See "Calcium channel blockers in the management of chronic coronary syndrome", section on 'Mechanism of action' and "Nitrates in the management of chronic coronary syndrome", section on 'Mechanism of action'.)

•We often start treatment with diltiazem 240 to 360 mg daily or amlodipine 5 to 10 mg daily. Higher doses of calcium channel blocker (eg, diltiazem up to a dose of 960 mg per day) can be used in patients with refractory vasospastic angina [86].

•Long-acting nifedipine (30 to 90 mg daily) is an option that is used less commonly than the calcium channel blockers listed above. Of note, long-acting nifedipine can cause severe hypotension and reflex tachycardia.

•Short-acting formulations of nifedipine should not be used because they are more likely to result in rebound symptoms.

•The combination of dihydropyridine and nondihydropyridine calcium channel blockers may be useful for management of severe symptoms [87].

Subsequent therapy — Subsequent therapy to treat vasospastic angina includes addition of long-acting nitroglycerin, statins, and other less commonly used medications.

●Long-acting nitroglycerin – For patients who do not have acceptable improvement in symptoms on calcium channel blocker therapy, we add a long-acting nitrate (eg, isosorbide mononitrate starting at 60 mg once daily). Optimally, isosorbide mononitrate should be titrated up to 120 mg once daily. Long-acting nitrates may be effective in alleviating symptoms [88] and can relieve vasospasm [89]. However, there is a relatively high occurrence of nitrate tolerance, and long-acting nitrates may trigger endothelial dysfunction [90]. (See "Nitrates in the management of chronic coronary syndrome", section on 'Nitrate tolerance'.).

Other long-term risks and benefits of adding long-acting nitrates to calcium channel blocker in patients with vasospastic angina are unclear, and data are limited. In an observational study of 1429 individuals with vasospastic angina, 90 percent of whom were receiving treatment with a calcium channel blocker, a propensity-score-matched analysis found that rates of major adverse cardiac events (MACE; ie, cardiac death, non-fatal MI, unstable angina, heart failure, and implantable cardioverter-defibrillator [ICD] shocks) were similar in patients receiving nitrate treatment and those receiving no nitrate therapy (11 versus 8 percent at five years) [91]. Furthermore, use of patch nitrates (hazard ratio [HR] 1.69, 95% CI 1.17-2.45) and combining oral and patch nitrates (HR 2.18, 95% CI 1.52–3.11) were associated with higher risk of MACE. Among the nitrates, nitroglycerin in combination with nicorandil (a non-nitrate antianginal medication) was associated with increased risk of MACE (HR 4.47, 95% CI 1.47-13.6). The nonrandomized nature of these analyses makes interpretation of these findings difficult since patients with more active vasospastic angina may have been selectively prescribed the incremental nitrate and other antianginal therapy. 

●Additional agents for persistent symptoms – If there is persistent chest pain on calcium channel blocker and long-acting nitrates, some medications may be beneficial, though supportive evidence is limited.

•Statins have been shown to be effective in preventing coronary spasm and may exert their benefits via endothelial nitric oxide or direct effects on the vascular smooth muscle. (See "Mechanisms of benefit of lipid-lowering drugs in patients with coronary heart disease", section on 'Reversal of endothelial dysfunction'.)

Statins may be beneficial for vasospastic angina when given in addition to a calcium channel blocker. The benefit of fluvastatin 30 mg daily added to a calcium channel blocker was evaluated in a randomized, open-label trial in 64 patients with possible vasospastic angina (assessed by acetylcholine provocation on angiography) [92]. After six months, the percentage of patients with acetylcholine-induced spasm was lower in the group who received fluvastatin compared with those who did not (48 versus 79 percent). Further studies are required to assess clinical outcomes before we recommend routine statin therapy in vasospastic angina patients who do not have other indications.

•Treatment with guanethidine, clonidine, or cilostazol has been reported to be of benefit when administered with a calcium channel blocker [93,94]. However, these drugs have not been extensively studied.

●Additional therapies for refractory angina

•Magnesium deficiency may play a role in coronary vasospasm [95]. In one study of 22 patients with vasospastic angina, those administered intravenous magnesium (n = 14) compared with placebo (n = 8) exhibited coronary vasodilation [96]. When re-challenged with intracoronary acetylcholine, they had less severe chest pain and ST-segment elevation. We do not routinely recommend magnesium as routine therapy for patients with vasospastic angina.

•Percutaneous coronary intervention (PCI) is not routinely indicated for patients with focal spasm and minimal obstructive disease. However, PCI may be helpful if significant obstructive coronary disease is present and thought to be a potential trigger for focal spasm. Still, effective medical therapy, such as calcium channel blockers, should be continued after PCI.

Results are variable in this setting and depend, in part, on the severity of the fixed obstruction [97,98]. Coronary artery stenting may be an effective therapy for selected patients with medically refractory vasospasm that is associated with mild to moderate coronary disease and in whom the vasospastic segment can be clearly identified [99].

Many patients with vasospastic angina have multivessel spasm; the role of revascularization in this setting is uncertain. This was addressed in a study of 45 patients with documented coronary vasospasm and severe stenosis who underwent balloon only angioplasty or stenting [100]. After seven months, there was no restenosis, and repeat provocative testing with intracoronary acetylcholine did not induce spasm at the site of the initial stenosis; however, spasm at a different site in the dilated vessel and/or in another vessel occurred in 77 percent, and multivessel spasm occurred in 62 percent of patients.

•Surgical sympathetic denervation may be an effective therapy in medically refractory patients [31,69,101].

•Fasudil is a rho kinase inhibitor that has been shown to inhibit acetylcholine-induced spasm [21], but it is available only in Japan and China for the indication of coronary vasospasm and associated ischemic symptoms after surgery for subarachnoid hemorrhage. Another potential limitation of the use of this medication for vasospasm treatment is that it is only available intravenously.

Assessment of efficacy — Irrespective of therapy chosen, it is important to document suppression of both symptomatic and asymptomatic episodes with ambulatory ECG monitoring. Persistence of asymptomatic episodes should prompt intensification of therapy with an aim to reduce the risk of ventricular arrhythmias. (See 'Clinical presentation' above and 'Ambulatory ECG monitoring' above.)

Management of high-risk sequelae

Myocardial infarction — MI in patients with vasospastic angina is often due to concurrent obstructive coronary artery disease [8,102]. With vasospastic angina alone, coronary vasospasm may trigger thrombus formation. Lipoprotein(a) may play a role in this setting [103]. (See "Lipoprotein(a)".)

The diagnosis and management of acute MI are discussed separately. (See "Diagnosis of acute myocardial infarction" and "Overview of the acute management of ST-elevation myocardial infarction".)

Arrhythmia — Arrhythmias are common and may be life threatening during an episode of coronary spasm. Arrhythmias may present as palpitations, presyncope, or syncope [104]. Patients should be screened with ambulatory ECG monitoring. (See 'Ambulatory ECG monitoring' above.)

●Multidisciplinary team – The management of patients with arrhythmias should be carried out by a multidisciplinary team with expertise in the care of patients with coronary vasospasm and this complication. In some cases, seeking expert opinion may be useful.

●Location of spasm site – The type of arrhythmia is determined in part by the vessel involved and the territory that has become ischemic. As an example, bradycardia and hypotension can be observed if the sinus nodal, atrioventricular nodal, and right ventricular arteries are involved during proximal right coronary artery vasospasm.

●Implantable cardiac defibrillator – At present, there are no consistent guidelines to help clinicians decide whether to implant an ICD in patients for primary prevention. We consider referral of patients for placement of an ICD if there are the following high-risk features [105]:

•Aborted cardiac arrest. (See "Implantable cardioverter-defibrillators: Overview of indications, components, and functions".)

•Obstructive coronary artery disease.

•Large ST-segment elevations.

•Focal proximal epicardial coronary artery spasm.

•Frequent vasospastic and arrhythmic activity.

•Patients with multivessel coronary artery spasm who are on maximal or submaximal doses of calcium channel blockers.

For patients without such high-risk features who are on submaximal doses of calcium channel blocker, some of our contributors maximize calcium channel blocker and refer the patient for an ICD, while others maximize the dose of calcium channel blocker and monitor the patient carefully for ventricular arrhythmia. There are not sufficient data to guide therapy for these patients.

The value of muti-drug therapy among vasospastic angina patients who have had aborted sudden cardiac death has not been determined. In a meta-analysis of 17 studies, including 137 patients with vasospastic angina and with ICD placed for aborted cardiac arrest, therapy with multiple medications (ie, calcium channel blockers and nitrates) was not related to the number appropriate shocks [106].

Aborted cardiac arrest — The optimal management of patients with aborted cardiac arrest as the presentation of vasospastic angina is not known. In the absence of prospective outcome studies evaluating therapeutic intervention in these patients, we suggest the following:

●ICD Placement – Placement of an ICD is indicated for any patient with aborted cardiac arrest. (See "Implantable cardioverter-defibrillators: Overview of indications, components, and functions".)

Studies on the efficacy of an ICD to improve survival after cardiac arrest in patients with vasospastic angina are both limited and mixed. Placement of an ICD was not associated with improved survival in one study [107]. However, in another observational study of 23 patients with vasospastic angina in whom an ICD was placed after resuscitation from cardiac arrest due to a documented ventricular arrhythmia, all patients were alive during a median follow-up of 2.1 years (four ventricular fibrillations and one pulseless electrical activity events occurred in five patients) [108].

●Initiate a calcium channel blocker ± nitroglycerin – We initiate calcium channel blockers for patients not already taking them. Nitrate therapy is added for persistent symptoms or evidence of ischemia or ventricular arrhythmia on ambulatory ECG monitoring or ICD interrogation, respectively. Medical therapy with a calcium channel blocker in survivors of sudden cardiac arrest due to spasm may not be sufficient since this therapy reduces but does not prevent episodes of spasm.

●Start a statin – We start statin therapy, particularly in patients with evidence of atherosclerosis on angiography.

●Avoid PCI – For intermediate lesions that remain after intracoronary administration of nitroglycerin or calcium channel blocker, we avoid PCI. This is to avoid potential multivessel and diffuse spasm during and after PCI. These possibilities complicate the procedure and make identification and treatment of the culprit lesion causing ventricular arrhythmia challenging. Moreover, stent thrombosis may result if there is subsequent sustained spasm distal to the stent.

We use PCI if there is evidence that medical therapy has failed to prevent ventricular arrhythmia and if there is a reasonable target lesion seen on angiography.

Medications to avoid — These are medications that can precipitate vasospastic angina and therefore should be avoided:

●Nonselective beta blockers such as propranolol can exacerbate vasospasm and should be avoided [109].

●Aspirin should be used with caution and at low doses, as it is an inhibitor of prostacyclin production at high doses [110]. Prostacyclin inhibits platelet aggregation, relaxes smooth muscle, and is a vasodilator [111]. However, for patients with ASCVD, we give aspirin 75 to 81 mg daily.

●Oral sumatriptan is used to treat acute migraine headache. However, its use has been associated with coronary vasospasm and MI. We suggest avoiding all medications of the triptan class in patients with known or suspected coronary artery vasospasm [66,112]. (See "Acute treatment of migraine in adults", section on 'Triptans' and "Acute treatment of migraine in adults", section on 'Triptans with NSAIDs'.)

●Fluorouracil (also known as 5-fluorouracil) is a chemotherapy agent that can also induce coronary artery spasm [113].

PROGNOSIS — In the absence of high-risk sequelae, the long-term survival of patients with vasospastic angina is good, particularly in patients receiving medical therapy [102,114]. Survival at five years may be as high as 94 percent [102,114-116].

However, many patients will still have symptoms. One study showed that half of patients with vasospastic angina continue to experience angina at three years [115].

Independent predictors of a better prognosis (eg, infarct-free survival) include:

●Less severe coronary artery disease

●Absence of multivessel spasm

●Use of calcium channel blockers

Factors associated with a worse prognosis include:

●Obstructive coronary artery disease – Patients with vasospastic angina who also have obstructive coronary artery disease have a worse prognosis. This is in large part determined by the severity of the underlying disease. Patients with vasospastic angina and one-vessel disease or <70 percent stenosis in any major coronary artery had one- and five-year survival rates of 99 and 95 percent [8]. By comparison, patients with multivessel disease had one- and five-year survival rates of 87 and 77 percent.

●Acetylcholine-provoked spasm at a site of significant stenosis – A 2015 retrospective study of 1760 patients with typical or atypical angina-like chest pain who underwent acetylcholine-provocation testing found that acetylcholine-provoked spasm at sites of significant organic stenosis was a predictor of MACE at five years [78]. Patients whose spasm was remote to a tight stenosis or in the absence of any tight stenosis had a better prognosis.

●High-risk sequelae – MI and life-threatening arrhythmias may occur in approximately 25 percent of untreated patients with vasospastic angina. The incidence of aborted sudden cardiac death may be as high as 9 percent [107]. Therapy that reduces the frequency of symptomatic episodes appears to decrease the frequency of life-threatening events, but the evidence is not robust [117].

Patients with vasospastic angina who experience aborted sudden cardiac arrest (ASCA) may have increased risks of cardiac death despite therapy compared with patients without ASCA. In a retrospective study of 2000 patients, 9 percent presented with ASCA [107]. The incidence of cardiac death at eight years was higher in those with ASCA versus no ASCA (24 versus 3 events per 1000 patients-years) [107]. Other studies had too few patients (ie, <10) to draw reliable conclusions regarding ASCA prognosis in vasospastic angina [118,119].

Risk score for cardiac events — A prognostic risk score for vasospastic angina was developed in 1429 patients from a Japanese registry [105]. During 32 months of follow-up, 6 percent had a primary MACE (cardiac death, nonfatal MI, unstable angina, heart failure, or ICD shock). Of these, 1 percent suffered death or nonfatal MI. Seven significant predictors of MACE (smoking, angina at rest alone, history of out-of-hospital cardiac arrest, organic coronary stenosis, multivessel spasm, ST-segment elevation during angina, and beta blocker use) were identified and used for a risk score (Japanese Coronary Spasm Association Clinical Risk Score). Low-, intermediate-, and high-risk patients were defined based on the score, and the incidence of MACE in these groups was 2.5, 7, and 13 percent, respectively. External validation of this score is needed before recommending its widespread usage.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic coronary syndrome".)

SUMMARY AND RECOMMENDATIONS

●Definition – Vasospastic angina is characterized by spontaneous episodes of angina accompanied by transient electrocardiogram (ECG) ischemic ST changes. There is abrupt, marked reduction in the luminal diameter of an epicardial coronary artery due to spasm, leading to transient myocardial ischemia. (See 'Introduction' above and 'Pathogenesis' above.)

●Epidemiology – The prevalence of vasospastic angina is difficult to determine due to underdiagnosis. The only consistent risk factor associated with vasospastic angina is smoking. (See 'Epidemiology' above.)

●Angina characteristics – Patients have a chronic pattern of chest pain episodes, with many symptoms similar to classical angina (ie, from obstructive coronary artery disease), including nitrate-responsiveness. However, many patients report that their episodes are mainly at rest, often occur from midnight to early morning, and last for 5 to 15 minutes. Patients with vasospastic angina typically have ischemic ST-segment changes on 12-lead or ambulatory electrocardiogram (ECG) during an episode of chest discomfort, which returns to baseline on symptom resolution. (See 'Clinical presentation' above.)

●Diagnostic criteria – Diagnostic criteria for vasospastic angina include:

•Nitrate-responsive angina, typically occurring at rest and often at night.

•Associated transient ischemic ST changes such as transient ST-segment elevation or depression.

•Coronary artery spasm on angiography, defined as >90 percent constriction. (See 'Diagnostic criteria' above.)

●Diagnostic evaluation – Obstructive coronary disease must be excluded for all patients with angina (algorithm 1). (See 'Diagnostic evaluation' above.)

•Ambulatory ECG – If significant fixed obstructive disease is excluded, we perform ambulatory ECG monitoring to assess for symptomatic or asymptomatic ischemic changes and arrhythmias. (See 'Ambulatory ECG monitoring' above.)

•Coronary angiography – We recommend diagnostic coronary arteriography (computed tomography [CT] or invasive angiography) for patients in whom the diagnosis is likely or confirmed (based on a typical history and findings of ST-segment elevation on ECG) to assess for obstructive coronary disease, and in some patients, to allow provocative testing. (See 'Coronary arteriography and provocative testing' above.)

●Management – Initial therapy includes cessation of smoking and pharmacologic therapy with calcium channel blockers and sublingual nitroglycerin (see 'Management' above):

•We suggest initiating therapy with a calcium channel blocker (Grade 2C). All calcium channel blockers appear effective; we often start with diltiazem at a dose of 240 to 360 mg per day and use higher doses for refractory spasm.

•We suggest the use of sublingual nitroglycerin to relieve angina and decrease the frequency of myocardial infarction (MI) and life-threatening arrhythmias associated with these episodes (Grade 2C). (See 'Prognosis' above.)

•Addition of long-acting nitrates to calcium channel blockers may be useful in controlling angina symptoms but may not protect against major adverse cardiac events (MACE).

•Nonselective beta blockers such as propranolol should be avoided. In addition, aspirin should be used with caution, since at high doses it is an inhibitor of prostacyclin production. (See 'Medications to avoid' above.)

●Prognosis and sequelae – Patients without obstructive coronary disease have a good long-term prognosis. (See 'Prognosis' above.)

Arrhythmias, MI, and aborted sudden cardiac death are potentially life-threatening complications of vasospastic angina, and thus treatment and monitoring may be more aggressive in patients with these sequelae. (See 'Prognosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Duane Pinto, MD, MPH, who contributed to earlier versions of this topic review.