Vasospastic (Prinzmetal) angina

• Vasospastic (Prinzmetal) angina is chest pain caused by a sudden, severe, temporary spasm of a coronary artery, usually without a fixed high-grade narrowing.
• It classically occurs at rest, often at night or in the early morning, and can produce transient ST elevation that resolves within minutes.
• It is seen most often in younger people, especially heavy smokers (including young women).
• Diagnosis rests on the characteristic history plus, when needed, coronary angiography with acetylcholine or ergonovine provocation testing.
• Calcium channel blockers are the backbone of treatment; pure vasospasm is a reason to avoid non-selective beta-blockers.

By the end of this page you should be able to:

1. Define vasospastic angina and distinguish epicardial spasm, microvascular spasm and fixed obstructive coronary disease.
2. Explain the mechanisms that lower the threshold for coronary spasm.
3. Recognise the clinical picture, triggers and ECG changes, and list common mimics.
4. Plan investigations and weigh the risks of provocation testing.
5. Apply the COVADIS criteria and the management steps, including refractory disease and ICD decisions.
6. State the prognosis and the arrhythmic and sudden-death risk.

Described by Myron Prinzmetal in 1959; originally called variant angina. ^[1]

• About 68% of 187 people with angina and non-obstructive arteries had a positive acetylcholine test; more than half had microvascular abnormalities. ^[1]
• A Korean study of more than 52,000 hospitalised patients found about 75% of hospitalisations in ages 40-69, with advancing age linked to higher rehospitalisation risk. ^[1]
• Overall vasospasm prevalence did not differ significantly between women (28%) and men (25%; P = 0.654); microvascular spasm was more common in women (64% versus 36%) and epicardial spasm more common in men (61% versus 39%). ^[1]
• Vasospastic and multiterritory spasm appear more common in Japanese/Taiwanese than Caucasian patients. ^[1][2]

• Cigarette smoking is the most well-established risk factor and can both predispose to and acutely trigger spasm. ^[1]
• Heavy (especially binge) alcohol is another risk factor and precipitant. ^[1]
• Genetic predisposition: NOS3 polymorphisms and variants in Rho-associated kinase 2, ALDH2*2 and RNF213 are implicated. ^[1]
• Hypertension, dyslipidaemia and diabetes do not significantly drive vasospastic activity or alter long-term prognosis, although general risk-factor care remains good practice. ^[1]
• The syndrome clusters with migraine and Raynaud's phenomenon. ^[2]

• Endothelial dysfunction: impaired nitric oxide (NO) production leaves constrictor stimuli unopposed; endothelin-1 is raised. ^[1][2]
• Smooth-muscle hyperreactivity: RhoA/Rho-kinase increases calcium sensitivity; intracoronary fasudil abolishes triggered spasm. ^[1]
• Inflammation/oxidative stress: hs-CRP, interleukin-6 and pericoronary 18F-FDG uptake are higher. ^[1][2]
• Atherosclerosis overlay: OCT found plaque at 98.8% of assessed spasm sites, erosion in 26%, vulnerable plaques more prevalent at spasm sites (66% versus 38%, P = 0.04). ^[1]
• Autonomic imbalance: vagal predominance at night/rest; adrenergic surges in the morning or stress. ^[1]

• Sudden, short, crushing retrosternal discomfort radiating possibly, identical in quality to exertional angina but unrelated to effort. ^[1][2]
• Rest angina especially between night and early morning; marked diurnal variation in exercise tolerance with reduced morning tolerance; hyperventilation can precipitate attacks; rapid relief with glyceryl trinitrate. ^[1][2]
• Patients are often younger than those with atherosclerotic angina; heavy smokers are over-represented, including young women. ^[1][2]
• Arrhythmia during spasm: high-grade AV block, sinus node arrest, ventricular tachycardia or fibrillation; sudden cardiac death can be the first manifestation. ^[1][2]
• Between episodes the examination is usually normal. ^[2]

Cold-pressor provocation reproduces spasm in up to two-thirds of susceptible people (winter/spring excess). ^[1]

• Between episodes the ECG is often normal. ^[2]
• Transient ST-segment elevation of at least 0.1 mV or ST depression of at least 0.1 mV, and/or new negative U waves, in at least two contiguous leads. ^[2][3]
• Peaked T waves and transient conduction abnormalities are possible. ^[2]
• Changes resolve with spasm relaxation, usually within minutes of glyceryl trinitrate. ^[2]

ESC 2024 recommends a resting ECG during episodes of angina (Class I, level C) and ambulatory ST-segment monitoring in patients with frequent symptoms (Class IIa, level B). ^[1]

Exercise testing is often negative in pure vasospastic angina; hyperventilation or cold pressor may provoke spasm but sensitivity is low. ^[2]

If pain persists, measure troponin. A short attack with normal troponin supports spasm; persistent occlusion can infarct (MINOCA).

Establishes whether fixed stenoses exist and defines the territory; OCT/IVUS helps where anatomy is ambiguous. A normal angiogram does not exclude spasm.

Reference test when spontaneous episodes are not documented. Positive test = typical angina + ischaemic ECG change + >= 90% transient vasoconstriction. ^[1][2][3]

• Incremental acetylcholine boluses (20/50/100 microgram in 5 mL over 20 seconds at 5-minute intervals) into the left coronary artery; reduced doses (20/50 microgram) into the right coronary artery, which may require a temporary pacemaker. ^[3]
• Medication washout: stop beta/alpha blockers, calcium channel blockers, nitrates, ACE inhibitors and diuretics 48 hours beforehand; caffeine 24 hours; nicotine 4 hours. ^[3]
• Overall complication rate below 1%; arrhythmic complications in about 3% (VT/VF or bradyarrhythmia), transient AV block 4.2%, sinus block 0.8%, paroxysmal atrial fibrillation 3.5%. ^[1][3]
• Ergonovine is more likely to provoke extended multivessel spasm and is used less often. ^[2][3]

Strong (Class I) indications include: suspicious history without documented episode; nitrate-responsive rest angina and/or marked diurnal variation; rest angina without obstructive disease; unresponsiveness to empiric therapy; ACS presentation without culprit; unexplained resuscitated cardiac arrest; unexplained syncope with antecedent chest pain; recurrent rest angina after successful PCI. Good (IIa), controversial (IIb) and contraindications (emergent ACS, severe fixed multivessel disease including left main, severe myocardial dysfunction, no suggestive symptoms) are described in the guideline. ^[1]

A provocation test is positive only when all three occur together: typical angina, ischaemic ECG change and at least 90% vasoconstriction; an incomplete response is equivocal. ^[1][2] Microvascular spasm is recognised by pain and ECG change at a constriction of less than 90%. ^[2]

• ESC 2024: resting ECG during angina (Class I, level C); ambulatory ST monitoring for frequent symptoms (Class IIa, level B); invasive functional testing to confirm suspected vasospastic angina and assess underlying atherosclerosis (Class I, level C). ^[1]
• COVADIS (2015/2017): the three-component criteria above and the provocative-testing indications. ^[1][3]
• JCS 2023: Class IIa, level C recommendation for pharmacological spasm provocation during elective angiography in patients with angina and demonstrated myocardial ischaemia without significant epicardial stenosis. ^[1] Refractory vasospasm (unresponsive to two vasodilators) affects about 10% of patients. ^[1]

• Stop exertion and remove triggers. Sublingual glyceryl trinitrate or isosorbide dinitrate spray relieves pain within 1-3 minutes; ECG normalisation with nitrates strongly supports spasm. ^[2]
• In the emergency department a suspected attack is assessed as for acute coronary syndrome until the diagnosis is clear; in established disease, agreed pathways of repeat short-acting nitrates and optimised prophylaxis are used. ^[2]

• Smoking cessation is particularly beneficial. ^[1][2]
• Alcohol moderation and avoidance of precipitants (cold exposure, emotional stress). ^[1][2]
• Activity planning, symptom diaries, and carefully titrated cardiac rehabilitation. ^[2]
• General vascular risk care (blood pressure, weight, glucose, lipids). ^[1][2]

Calcium channel blockers are first-line. They inhibit calcium influx in vascular smooth muscle, producing coronary vasodilation and reducing vasoreactivity; both ESC 2024 and JCS 2023 recommend CCBs as the cornerstone of therapy. ^[1]

Typical dosing recorded in a detailed VSA review (adults):

In severe disease, high-dose CCB regimens (for example 2 x 200 mg diltiazem daily) or a combination of a non-dihydropyridine with a dihydropyridine CCB may be needed. ^[2]

Second-generation CCBs (amlodipine, benidipine) were associated with a lower incidence of acute coronary syndrome than first-generation CCBs (diltiazem, nifedipine) in a recent study, and benidipine showed better angina control than diltiazem over 3 years. ^[2] Diltiazem up to 360 mg once daily did not improve coronary function testing, symptoms or quality of life in the 85-patient EDIT-CMD trial, so failure to improve invites re-evaluation rather than simple dose escalation. ^[2]

Nitrates provide rapid relief and chronic prophylaxis, but they are generally treated as add-on therapy:

• Short-acting nitrates (sublingual glyceryl trinitrate) work within 1-3 minutes. ^[2]
• Long-acting nitrates added to a CCB gave additional benefit in roughly 40% of 1,429 patients. ^[1]
• Long-acting nitrates are recommended by ESC 2024 as second-line for vasospastic angina when CCBs are inadequate (Class IIa, level B), and JCS 2023 advises adjunct use with a nitrate-free interval. ^[1]
• ESC/JCS and other consensus documents advise a nitrate-free interval of about 10-14 hours to limit tolerance. ^[1][2]
• Long-term prophylactic nitrate benefit is uncertain: the VA-KOREA registry linked conventional nitrates to a higher 2-year acute coronary syndrome risk (HR 2.49; 95% CI 1.01-6.14), especially in low-risk patients. ^[2]

Nicorandil (10-20 mg twice daily, table) is an NO donor and potassium-channel opener; JCS 2023 gives a Class IIa, level B recommendation as add-on therapy after CCBs and nitrates. ^[1][2]

Statins are mechanistically attractive because endothelial dysfunction and plaque co-localise with spasm:

• Adding fluvastatin 30 mg daily to CCB therapy reduced acetylcholine-provoked spasm at 6 months (52% versus 21%; P reported as 0.231). ^[1]
• A meta-analysis of 10 cohort studies involving 9,333 patients found a 30% relative risk reduction in major adverse cardiac events on statins (RR 0.70; 95% CI 0.49-0.99). ^[1] Conflicting evidence remains, so expectation should be modest and the decision individual. ^[2]

Other add-ons (refractory or selected cases):

• Cilostazol 100 mg twice daily, with evidence from the STELLA trial (66.5% versus 17.6% greater chest-pain reduction; P = 0.009) and from real-world cohorts. ^[1][2]
• Cyproheptadine 4 mg three times daily for refractory spasm. ^[1]
• Bosentan 125 mg twice daily (last-line; monitor hepatotoxicity and teratogenicity). ^[1]
• IV magnesium, antioxidants (vitamin C/E), Rho-kinase inhibitors (IV fasudil, especially in East Asia, no oral formulation), alpha-blockers (conflicting evidence, not first-line), ACE inhibitors/ARBs (possible long-term benefit), and renin-angiotensin system inhibitors. ^[1][2]
• Aspirin: high doses (> 325 mg daily) may worsen spasm through prostacyclin inhibition; low doses (< 100 mg daily) may help, but large-scale data show no MACE benefit without concomitant obstructive disease, so reserve aspirin for patients with significant stenosis. ^[2]

Beta-blockers deserve special caution. Beta-blockers without alpha-1 activity can worsen pure vasospasm by unopposed alpha-1-mediated vasoconstriction and are best avoided; if one is indispensable, choose mixed alpha/beta agents (labetalol, carvedilol). ^[2] CorMicA-style VSA regimens therefore use a non-dihydropyridine CCB first, then add nitrates, then substitute or add nicorandil. ^[3] For mixed microvascular angina plus vasospasm, a non-dihydropyridine CCB first line, with nicorandil second line, is described. ^[3]

Percutaneous coronary intervention and surgery. Medical therapy is preferred. Stenting of spasm segments is strongly discouraged because endothelial dysfunction can persist or worsen distally and spasm tends to recur at adjacent segments; it is reserved for focal spasm with significant obstructive disease refractory to maximal therapy. Drug-coated balloon may preserve endothelial function better than drug-eluting stent (D5 study). ^[2] Surgery has variable results. ^[2]

Defined by JCS as unresponsiveness to two vasodilators (usually a CCB and a nitrate), affecting about 10% of patients; it can lead to sudden cardiac death. ^[1] Options include uptitrating and combining vasodilators, optimising CCB class, adding the adjuncts above (cilostazol, cyproheptadine, bosentan, IV magnesium, IV fasudil), and the research-level options being studied (vericiguat, spinal cord stimulation, immunomodulation). ^[1]

Vasospastic angina predisposes to ventricular arrhythmias, and ICDs do not suppress coronary spasm. No primary-prevention ICD recommendation exists for vasospastic angina. ICDs are indicated for secondary prevention in survivors of resuscitated cardiac arrest caused by spasm, because recurrent arrhythmia and death risk remain high despite vasodilator therapy; ESC ventricular-arrhythmia guidance supports this as Class IIa, level C. ^[2]

Recurrent angina occurs in 10-53% of patients. ^[2] Nonfatal myocardial infarction is more common with epicardial (4%) than microvascular spasm (0.7%). ^[2] Cardiovascular mortality is low; hospitalisation for unstable angina drives more than half (52-90%) of major adverse cardiac events. ^[2] Patients who survive sudden cardiac arrest have a worse long-term prognosis. ^[2]

Most patients are controlled on a CCB, often with a long-acting nitrate. Prognosis is generally good provided spasm is recognised and treated and the (common) trigger of smoking is addressed. A missed or untreated diagnosis leaves a risk of acute myocardial infarction, lethal arrhythmia and syncope. ^[1][2]

• Recurrent angina; acute coronary syndrome; arrhythmia (AV block, VT/VF); sudden cardiac death. ^[1][2]
• Acute myocardial infarction when occlusion is prolonged. ^[2]
• Medication intolerance or uncontrolled symptoms in refractory disease. ^[1]

• Where provocative testing is unavailable, rely on the clinical pattern (rest pain at night, smoker, nitrate responsiveness) and try to record an ECG during symptoms. ^[1][2]
• Where angiography is unavailable, a presumptive diagnosis with a therapeutic trial of a CCB is reasonable in the right clinical picture, while arranging referral if attacks recur or biomarkers suggest infarction.
• Smoking-cessation support, cold-avoidance and alcohol moderation are the cheapest and most effective interventions.
• Calcium channel blockers and short-acting nitrates are widely available; long-acting formulations and add-on drugs may be difficult to source; arrange follow-up and referral for recurrent symptoms.

• Vasospastic angina is transient, severe (> 90%) coronary spasm, classically at rest at night or in the early morning, in a smoker. ^[1][2]
• The strongest risk factor is cigarette smoking; heavy alcohol, cold, stress and hyperventilation also trigger attacks. ^[1][2]
• ECG shows transient ST elevation/depression >= 0.1 mV in >= 2 contiguous leads, with new negative U waves possible. ^[2][3]
• Resting ECG and ambulatory ST monitoring are ESC 2024 Class I/IIa recommendations; confirm with angiography and, if needed, provocation testing. ^[1]
• COVADIS defines definite (Criterion 1 plus 2 or 3) and suspected (1 with equivocal 2 or 3) disease; provocation positive only with symptoms + ECG change + >= 90% constriction. ^[1][2]
• CCBs are first-line; combine or up-titrate in severe disease; use a nitrate-free interval with long-acting nitrates; second-generation CCBs may carry a lower ACS risk. ^[1][2]
• Avoid non-alpha beta-blockers in pure vasospasm; use mixed alpha/beta agents if a beta-blocker is essential. ^[2]
• Statins have mechanistic and evidence support (RR 0.70; 95% CI 0.49-0.99 in cohort meta-analysis), though evidence remains mixed. ^[1][2]
• Refractory disease affects about 10% of patients and can cause sudden death; add cilostazol, cyproheptadine and, last-line, bosentan. ^[1]
• Angioplasty of spasm segments is discouraged; reserve ICDs for survivors of spasm-related cardiac arrest (secondary prevention). ^[2]
• Most patients do well once diagnosed; untreated disease carries a risk of infarction and sudden death. ^[1][2]

1. What defines a positive acetylcholine provocation test for vasospastic angina? It must reproduce the patient's usual angina, produce ischaemic ECG changes, and cause at least 90% coronary vasoconstriction; missing any one makes it equivocal. ^[1][2]

2. Why should non-selective beta-blockers be avoided in pure vasospastic angina? They block beta-2-mediated vasodilation, leaving alpha-1-mediated vasoconstriction unopposed, which can worsen spasm. ^[2]

3. A 42-year-old man, a heavy smoker, wakes at 3 a.m. with crushing chest pain relieved by glyceryl trinitrate within minutes. His resting ECG is normal and troponin is negative. Name the diagnosis and the test that would confirm it if episodes recur. Vasospastic angina. Coronary angiography with acetylcholine provocation testing if the diagnosis is not yet confirmed and episodes recur. ^[1][2]

4. According to COVADIS, what is the difference between "definite" and "suspected" vasospastic angina? Definite disease requires nitrate-responsive angina plus either transient ischaemic ECG changes or angiographic spasm; suspected disease has the characteristic angina history while the objective documentation is equivocal or unavailable. ^[1][2]

5. Which of the following is NOT recommended in vasospastic angina? Routine primary-prevention ICD implantation (secondary prevention is appropriate only after resuscitated cardiac arrest), and stenting of spasm segments. ^[2]

6. A patient with vasospastic angina remains symptomatic on diltiazem and long-acting nitrate. What pharmacological step is consistent with guideline advice? Add nicorandil (JCS 2023 Class IIa, level B) and consider cilostazol, while reassessing the diagnosis if spasm is not confirmed. ^[1][2]

• ECG interpretation
• Cardiac physical examination
• Approach to tachyarrhythmias
• Ventricular arrhythmias
• Atrial fibrillation and flutter
• Unstable angina and NSTEMI (related topic)
• Chronic coronary syndrome (related topic)
• Heart failure