Vasospastic angina

Article written and reviewed by Dr Luca Moretti

Vasospastic angina is an episodic ischemic syndrome in which an epicardial coronary artery transiently contracts until coronary flow is critically reduced. An attack may involve an angiographically normal segment, a site with non-obstructive atherosclerosis, or the margin of a significant stenosis; a normal lumen between episodes does not exclude the diagnosis. Duration, territory, and collateral response determine the intensity of ischemia. Prolonged constriction may produce necrosis and arrhythmias, not merely pain.
The historical term Prinzmetal angina primarily describes the variant with pain at rest and transient ST-segment elevation; the current definition of vasospastic angina is broader. It includes episodes with ST-segment elevation, depression, or other ischemic changes, provided the clinical and instrumental criteria can be verified. Not every instance of nocturnal angina is vasospastic. Not every response to nitrate demonstrates coronary spasm. Diagnosis integrates symptoms, ECG, and documentation of vasoconstriction.

This condition must be separated from microvascular spasm, in which acetylcholine reproduces symptoms and ECG ischemia without the epicardial constriction greater than 90 percent required by international criteria. It must also be distinguished from endothelial dysfunction, a physiological phenotype assessed with low-dose acetylcholine administered by slow infusion that may exist without anginal episodes. The mechanisms may coexist in the same patient. Overlap does not make the definitions interchangeable. Every result must state the dose, protocol, and compartment assessed.
Vasospasm is not uniformly benign. Many patients achieve good control with calcium channel blockers and removal of precipitating factors, but prolonged episodes may cause acute coronary syndrome, myocardial infarction, syncope, atrioventricular block, ventricular tachycardia, and cardiac arrest; prognostic stratification considers previous arrhythmias, multivessel spasm, organic stenoses, and adherence. Coronary angiography without obstruction does not justify absolute reassurance. Effective therapy must be continued and reassessed over time.

Etiology, risk factors, pathogenesis, and pathophysiology

The immediate mechanism is coronary smooth-muscle hyperreactivity. Increased sensitivity to calcium and phosphorylation of the myosin light chain permit contraction disproportionate to the stimulus. Activation of Rho-kinase inhibits myosin phosphatase and maintains tone even without a large increase in intracellular calcium; this pathway has been documented primarily in Japanese mechanistic studies. There is no routine clinical test of Rho-kinase. Provocation measures the resulting vasomotor phenotype.
Healthy endothelium releases nitric oxide, prostacyclin, and hyperpolarizing factors that counter vasoconstriction. When this function is impaired, acetylcholine may promote a constrictor response because direct muscarinic action on smooth muscle predominates. Endothelial modulation therefore lowers the threshold in some patients. It is neither necessary nor sufficient, however, to explain every spasm. High-dose testing primarily explores susceptibility to spasm. It must not automatically be described as a selective measure of the endothelium.

The autonomic nervous system contributes to circadian variability. Attacks often cluster between nighttime and early morning, when vagal tone, sympathetic activity, catecholamines, and vascular reactivity fluctuate. An abrupt autonomic transition may precede an episode more than the absolute heart rate does; experimental findings do not support a single universal autonomic profile. Mental stress and hyperventilation may provoke attacks in susceptible individuals. Sleep is not itself the cause of the disease.
Tobacco smoking is the modifiable factor most consistently associated with vasospasm. Oxidative stress, nitric oxide inactivation, inflammation, and increased vascular reactivity explain part of the risk. Complete cessation is a therapeutic measure, not ancillary advice; passive smoking and relapses must also be discussed. Hypertension, diabetes, and dyslipidemia retain general cardiovascular relevance. Their specific association with vasospasm is less consistent than that of smoking.

Large amounts of alcohol, cold, hyperventilation, severe stress, and sleep deprivation are reported triggers, but sensitivity is individual. Cocaine and amphetamines increase catecholamines and may cause severe vasoconstriction, thrombosis, and myocardial injury. Ergot derivatives, some triptans, and nasal sympathomimetics warrant caution in people with documented vasospasm. The temporal relationship must be reconstructed precisely. The patient must not stop essential therapies without guidance. Drug alternatives should be agreed with the prescriber.
Fluoropyrimidines, particularly 5-fluorouracil and capecitabine, may cause ischemia through vasospasm and other cardiotoxic mechanisms. An attack during infusion requires controlled interruption, urgent assessment, and cardio-oncology coordination; any rechallenge is a specialist decision. Iatrogenic vasospasm must not be dismissed as a harmless transient effect. The drug, dose, infusion, and ECG changes must be documented. Prophylaxis with vasodilators does not eliminate all risk. Oncological benefit and cardiac danger are balanced individually.

Adventitial inflammation, oxidative stress, magnesium, genetic variants, and differences in vascular signaling have been studied as modifiers. No single biomarker has sufficient accuracy to confirm or exclude the disease. Historically higher prevalence in East Asian populations suggests a combination of biological susceptibility, exposures, and diagnostic practice. Western estimates increase when provocation is applied systematically. Ethnicity does not replace clinical assessment. Diagnosis cannot be based on a commercial genetic profile.

Pathological anatomy, classification, and progression

Spasm may be focal, involving a circumscribed segment, or diffuse along an extended portion of the vessel. The COVADIS consensus requires transient total or subtotal constriction greater than 90 percent, associated with angina and ECG ischemia. Japanese guidelines also include diffuse constriction of 90 percent in at least two contiguous segments with ischemic signs. The percentage is compared with diameter after nitrate. Visual impression alone is less reliable than quantification. A smaller reduction does not satisfy the standard epicardial criterion.
One vessel or multiple coronary arteries may respond during the same procedure or at different times. Multivessel vasospasm exposes a larger myocardial mass to ischemia and is among the adverse prognostic determinants in Japanese cohorts. The site affects the type of arrhythmia: right coronary involvement may promote bradycardia and block, whereas large anterior territories facilitate ventricular instability; these associations are not deterministic. Collateral anatomy and duration modify the outcome. Every report must state the vessel, segment, dose, and reversibility.

The vessel wall may appear normal on angiography, but intracoronary imaging often identifies subclinical atherosclerosis, intimal thickening, or irregularities at the reactive site. Spasm and plaque are not mutually exclusive: an organic stenosis may increase risk and make interpretation of the attack more complex; revascularization treats a flow-limiting lesion, not a diffuse vasomotor predisposition. Stenting is not standard treatment for spasm without significant stenosis. Vasodilators remain necessary if the phenotype persists.
Classification is based on the COVADIS criteria. The first element is nitrate-responsive angina with at least one feature among rest angina, circadian variation in tolerance, hyperventilation, or suppression by calcium channel blockers but not beta-blockers. The second is a transient ischemic ECG change during pain: ST-segment elevation or depression of at least 0.1 mV, or new negative U waves, in at least two contiguous leads. The third element is documented spasm. Recording must coincide temporally with the symptom. Chronic abnormalities do not satisfy the episodic criterion.

Vasospastic angina is definitive when nitrate-responsive angina is present together with at least one of transient ischemic ECG changes or documented spasm. It is suspected when angina is compatible but the ECG is inconclusive and spasm is undocumented, or when one element remains ambiguous according to the classification. A definitive diagnosis does not necessarily require all three components. Provocation becomes valuable when spontaneous episodes are not captured. A positive provocation result requires the test triad. Response to nitrate alone remains nonspecific.
Microvascular spasm reproduces the usual pain and ischemic changes during acetylcholine administration without epicardial constriction greater than 90 percent. It is an endotype of microvascular angina, not an angiographically invisible form of epicardial spasm. The compartmental distinction changes interpretation and the strength of therapeutic evidence. Both phenomena may occur in the same patient. A sequence of doses may reveal different responses. The report must not label every provoked pain as a positive test.

The course frequently alternates periods of activity, with episodes grouped in clusters, and asymptomatic intervals. Temporary disappearance of pain does not demonstrate cure, and abrupt withdrawal of vasodilators may promote recurrences. Vasospastic activity may change with smoking, medications, stress, and autonomic state. Follow-up and adherence remain important even after stable months. Routine repeat provocation is unnecessary. A relevant clinical change requires a new differential assessment.

Clinical manifestations

The typical presentation is constricting pain at rest, often between midnight and early morning, lasting several minutes and responding rapidly to nitrate. Episodes may recur at the same time for several days; this circadian periodicity increases suspicion but lacks absolute diagnostic specificity. Reflux, esophageal disorders, and panic attacks may also follow a nocturnal pattern. The history must describe duration, radiation, and associated symptoms. ECG recording during the attack remains decisive.
Transient ST-segment elevation often reflects transmural ischemia from nearly complete occlusion, but ST-segment depression and negative U waves are included in the criteria. Alternating territories and rapidly reversible changes suggest dynamic vasomotion. The interictal ECG may be completely normal. A normal tracing in the emergency department after resolution does not exclude the episode. Serial tracings or prolonged monitoring are needed when appropriate. Persistent abnormalities require investigation for myocardial infarction or other disease.

Although rest is characteristic, some patients have attacks during exercise, particularly in the morning or during a phase of high disease activity. The threshold may vary from day to day, unlike the more predictable angina caused by fixed stenosis; this threshold variability is part of the COVADIS clinical criteria. A negative exercise test does not exclude vasospasm. A positive exercise test does not prove its mechanism. The relationship with time of day and nitrate must be analyzed together.
Palpitations, dizziness, and syncope during pain are signs of possible electrical instability or conduction block. Loss of consciousness must not automatically be attributed to a vagal reaction. A syncopal event requires rhythm correlation, assessment of ischemia, and investigation for alternatives; ambulatory monitoring may capture ST changes and rhythm during symptoms. A loop recorder is selected according to event frequency. Documented arrhythmia changes prognosis and strategy.

Some attacks are silent and recognized as transient ST-segment deviations during monitoring, sometimes accompanied by arrhythmias. Ischemic burden therefore does not always coincide with the number of perceived episodes. Silent ischemia is particularly relevant after cardiac arrest or unexplained arrhythmias; indiscriminate screening of asymptomatic people is not indicated. Monitoring must answer a defined clinical question. Postural artifacts may mimic ST-segment changes.
Nausea, diaphoresis, dyspnea, and a sense of impending death may accompany an intense attack. In women and older adults, the description may be less classic, but no symptom profile can replace the criteria. Clinical phenotyping must avoid sex- or age-based stereotypes; vasomotor factors such as migraine and Raynaud phenomenon may coexist. Their presence supports only the context. It does not confirm a coronary cause of pain.

Pain lasting beyond the usual pattern, resistant to nitrate, or associated with instability must be treated as a possible acute coronary syndrome. Vasospasm, thrombosis, dissection, and unstable plaque may overlap. A symptomatic change precludes using a previous diagnosis as an automatic explanation. ECG and troponin must be obtained promptly. Coronary angiography may be necessary according to risk. Response to nitrate does not exclude an evolving myocardial infarction.

Investigations and diagnosis

Diagnosis begins with documentation of episodes. A twelve-lead ECG during pain is preferable; Holter monitoring with ST-segment analysis may be useful when attacks are frequent or nocturnal. Temporal correlation among symptoms, the ST segment, and rhythm makes the finding interpretable; blood pressure, heart rate, and medications taken must be recorded. A baseline ECG assesses scars and conduction disorders. Echocardiography assesses structural abnormalities or impaired function.
CCTA or coronary angiography defines atherosclerosis, stenoses, and alternative diagnoses. An intermediate lesion requires physiological assessment when its significance is unclear because spasm and fixed obstruction may coexist. Non-obstructive anatomy does not by itself demonstrate vasomotor disease; intracoronary imaging is reserved for uncertainty about dissection, plaque, or a lesion. Provocation is planned after major hazards have been excluded. Informed consent specifies benefits and risks.

In the Japanese intracoronary acetylcholine protocol, 20, 50, and 100 micrograms are administered in the left coronary artery and 20 and 50 micrograms in the right, generally over approximately twenty seconds with intervals of at least five minutes. Temporary pacing at 40-50 beats per minute reduces the risk associated with bradycardia and block. Angiography, ECG, and symptoms are recorded after each dose. Doses and sequence may vary according to validated protocols. Final intracoronary nitrate documents reversibility and reference diameter.
An acetylcholine test is positive for epicardial spasm when constriction greater than 90 percent, reproduction of the usual angina, and ischemic ECG changes occur together. An incomplete diagnostic triad must not be called definitive epicardial spasm. Symptoms and ECG changes without such constriction define microvascular spasm when technical conditions are adequate. Constriction without symptoms or ECG changes remains a nondiagnostic angiographic response. Quantification uses the diameter after nitrate. The report must distinguish complete, equivocal, and negative results.

Ergonovine stimulates serotonergic and alpha-adrenergic receptors on smooth muscle. Japanese guidelines describe total intracoronary doses of 20-60 micrograms per vessel, administered slowly over two to five minutes. Compared with acetylcholine, ergonovine-induced spasm tends to resolve less readily on its own and requires more prompt nitrate administration. Protocols are not completely standardized among centers. Intravenous administration is less controllable. Testing must be performed only in a prepared laboratory.
According to the JCS/CVIT/JCC update, provocation is indicated in patients with suspicious symptoms not documented noninvasively, class I with level B, and may be considered when empirical therapy is inadequate or the diagnosis changes strategy. The clinical question must precede the procedure; it provides no benefit for screening asymptomatic people. As a provocative procedure, it is contraindicated in high-risk acute presentations, severe cardiac dysfunction, or uncontrolled heart failure. Stabilization takes priority over phenotyping.

Possible complications include prolonged spasm, hypotension, atrial fibrillation, bradycardia, atrioventricular block, and ventricular arrhythmias. A meta-analysis of 12,585 patients estimated major complications at approximately 0.5 percent, with no procedural deaths in the included studies. The documented safety applies to experienced centers and selected patients. Nitrates, atropine, pacing, defibrillation, and resuscitation must be immediately available. Asthma or severe bronchospasm warrants caution with acetylcholine. Severe impulse formation or conduction disorders require appropriate protection.
The differential diagnosis includes atherothrombotic acute coronary syndrome, spontaneous dissection, embolism, myocardial bridging, pericarditis, myocarditis, Takotsubo syndrome, reflux, and musculoskeletal pain. Cardiac magnetic resonance is useful when troponin and the clinical picture suggest unexplained myocardial injury. An alternative diagnosis is not excluded by positive provocation because concomitant conditions may exist. A negative test does not automatically invalidate well-documented spontaneous episodes. Vasodilator drugs may reduce sensitivity. Preparation and washout must follow the center's protocol.

Treatment and prognosis

During an attack, sublingual nitroglycerin or spray is the usual treatment when no contraindication exists. Persistent pain requires urgent care because myocardial infarction and arrhythmias cannot be excluded at home. A rapid-acting nitrate relieves constriction but does not replace prevention; the patient must know the prescribed dose and when to call emergency services. In hospital, intracoronary nitrate treats documented spasm. Hypotension and recent use of PDE5 inhibitors affect safety.
Calcium channel blockers are the cornerstone of prevention. The 2024 ESC guidelines recommend a calcium channel blocker for isolated vasospastic angina, class I and level A. Diltiazem, verapamil, amlodipine, and long-acting dihydropyridines are selected according to heart rate, blood pressure, and tolerability. Therapeutic titration must reach an effective dose without bradycardia or hypotension. Nocturnal attacks guide administration timing. Edema and constipation may limit adherence. Severe forms may require a combination of different classes.

Long-acting nitrates may be added when a calcium channel blocker does not control symptoms; ESC assigns this strategy class IIa and level B. A daily nitrate-free interval reduces tolerance but must cover the time of greatest risk. Symptomatic benefit is better established than benefit for major events; headache and hypotension are common. Nicorandil is an alternative where available, with less robust evidence. None of these drugs justifies continued smoking.
Smoking cessation, moderation of alcohol, and removal of precipitating substances are part of therapy. JCS assigns smoking cessation class I and level A. Cocaine, amphetamines, and ergot derivatives should be avoided; triptans and decongestants require review. Trigger prevention must be specific and realistic. Cold and hyperventilation do not require isolation or inactivity. Regular exercise is appropriate after stabilization. Cardiac rehabilitation improves adherence and functional capacity.

Beta-blockers, especially nonselective agents without alpha-blocking activity, may leave alpha-adrenergic vasoconstriction unopposed and worsen pure epicardial spasm. They are therefore not therapy for isolated vasospastic angina; this pharmacological caution is not an absolute ban on every drug or indication. Heart failure, arrhythmias, or associated stenoses may require different decisions. The choice must be specialist-led and monitored. Abrupt discontinuation may be dangerous.
Aspirin is not specific therapy for vasospasm and, in the absence of organic stenosis or another indication, JCS classifies it as not useful, class III with level B. High doses may increase vasoconstriction through prostacyclin inhibition. Antiplatelet therapy should be prescribed for atherosclerosis, a stent, or an appropriate event, not solely for a positive test. Statins follow risk and the presence of plaque. Small studies suggest vasomotor effects but do not establish a universal indication. Blood pressure, lipids, and diabetes must nevertheless be treated.

In refractory cases, diagnosis, adherence, doses, timing, smoking, and precipitating drugs are checked first. Two calcium channel blockers and a nitrate or nicorandil may be necessary, with monitoring of blood pressure and conduction. Intracoronary fasudil, a Rho-kinase inhibitor, receives class IIa and level B in Japanese guidelines for refractory spasm during the procedure, but availability and use are limited. It is not standard international chronic therapy. Sympathetic interventions are exceptional. Stenting without a fixed lesion does not resolve a diffuse predisposition.

After out-of-hospital cardiac arrest or ventricular tachycardia/fibrillation attributed to spasm, intensive vasodilator therapy remains mandatory. JCS considers an implantable cardioverter-defibrillator when the previous spasm-associated ventricular arrhythmia is refractory to medical therapy, class IIa level B; implantation may also be considered when medical therapy is effective, class IIb level C. The implantable cardioverter-defibrillator terminates arrhythmias but does not prevent ischemia. The decision, comorbidities, and preferences require an expert team. Angina alone without arrhythmia is not an indication. Follow-up checks recurrences and inappropriate therapies.

Prognosis depends on extent, associated stenoses, adherence, and previous cardiac arrest. The Japanese Coronary Spasm Association score combines seven variables and identified groups with major-event rates of approximately 2.5, 7, and 13 percent during follow-up of the original cohort. Geographical validation remains limited and precludes rigid individual estimates. Multivessel spasm, continued smoking, and previous cardiac arrest worsen the profile. Symptom control does not equal zero risk. Good adherence markedly improves the clinical course.

Complications

Complete and sufficiently prolonged spasm may cause myocardial infarction even without obstructive plaque. Troponin, ECG, and imaging define the extent of injury; if coronary angiography shows no obstruction, the case may present as MINOCA until the cause is identified. Vasospastic myocardial infarction requires treatment of the acute event and prevention of recurrences. Not every positive troponin during pain results from spasm. Myocarditis and Takotsubo syndrome must be excluded when relevant. Cardiac magnetic resonance clarifies tissue and distribution.
Transmural ischemia creates dispersion of refractoriness and slowed conduction, predisposing to polymorphic ventricular tachycardia and ventricular fibrillation; these arrhythmias may precede hospitalization and be the first manifestation. Sudden death is rare compared with uncomplicated attacks but represents the most serious risk. Early defibrillation determines immediate survival. The link with vasospasm must subsequently be demonstrated. Concomitant inherited or scar-related causes must not be ignored.

Right coronary spasm may cause ischemia of the sinoatrial or atrioventricular node, producing marked bradycardia, pauses, or complete block. A vagal reflex may also contribute. This bradyarrhythmic complication explains some episodes of syncope and requires documentation before a permanent pacemaker is considered; control of spasm may eliminate the transient disorder. Independent conduction disease changes the choice. Monitoring and electrophysiological study are individualized.
Multivessel or prolonged spasm may abruptly reduce ventricular function and cause pulmonary edema, cardiogenic shock, or electromechanical arrest; this hemodynamic instability requires nitrates when tolerated, advanced support, and rapid exclusion of thrombotic occlusion or a mechanical complication. Blood pressure may limit vasodilators. Circulatory support is reserved for extreme presentations. Recovery of function does not exclude residual injury.

Repeated episodes may cause small areas of necrosis, scar, and an arrhythmic substrate, although the most common course is not a progressive cardiomyopathy. When persistent ventricular dysfunction occurs, myocardial infarctions, tachycardia, myocarditis, or another cause must be sought. Post-ischemic remodeling must not be attributed by exclusion to attacks that were never documented. Echocardiography and magnetic resonance quantify function and scar. Secondary prevention follows the actual injury. Complete recovery improves but does not eliminate recurrence risk.
Recurrent angina, fear of sleep, urgent visits, and activity limitation may profoundly impair quality of life. An intermittent clinical picture is sometimes minimized when tests between attacks are normal. Vasospastic disability requires a written plan and measurable objectives; excessive monitoring may instead increase anxiety and false alarms. Education recognizes dangerous symptoms without medicalizing every sensation. Psychological support complements, but does not replace, vascular therapy.

Calcium channel blockers and nitrates may cause hypotension, edema, headache, constipation, and bradycardia. High-dose combinations increase the risk of syncope or conduction disorders, especially with verapamil or diltiazem. Treatment toxicity may mimic weakness or disease instability; blood pressure, heart rate, and ECG guide adjustments. Interactions with PDE5 inhibitors make nitrates dangerous. Adherence improves when adverse effects are addressed openly.
Invasive provocation may cause resistant spasm, arrhythmia, or vascular complications; for this reason, it is not performed without a clinically useful result. A false negative caused by preparation or medications may delay diagnosis, while a false positive interpreted without the triad may lead to unnecessary therapy. Diagnostic quality is therefore part of complication prevention. Protocols, doses, and criteria must be explicit. Center experience modifies safety and reliability. Review of the tracings resolves many equivocal cases.