Prinzmetal angina

A 20-year-old female presents with recurrent episodes of central chest pain that are non-exertional, sudden in onset, and last approximately 5 to 15 minutes. The pain is substernal and severe, radiates to the left arm, jaw, and neck, and is associated with nausea and diaphoresis. She has a history of Raynaud disease. Vital signs are normal between episodes. Electrocardiography during an ergonovine provocation test demonstrates transient ST-segment elevation. Coronary angiography demonstrates coronary vasospasm without significant obstructive atherosclerotic disease. Diagnosis?

Diagnosis is Prinzmetal (variant) angina, a classic form of vasospastic angina.

1. Definition

Prinzmetal angina, also called variant angina, is a classic form of vasospastic angina caused by transient constriction of an epicardial coronary artery, producing a dynamic reduction in coronary blood flow and transient myocardial ischemia.

Classic Prinzmetal angina is characterized by episodes of angina, usually occurring at rest, accompanied by transient ST-segment elevation.

Vasospastic angina may occur in patients with normal or near-normal coronary arteries, but the presence of coexisting coronary atherosclerosis does not exclude the diagnosis.

2. Etiology and Predisposing Factors

The underlying mechanism is abnormal coronary vasomotor reactivity. Important mechanisms and associated factors include:

1.       Hyperreactivity of coronary vascular smooth muscle

2.       Endothelial dysfunction

3.       Autonomic and vasomotor abnormalities

4.       Cigarette smoking

o    An important modifiable risk factor for coronary vasospasm

5.       Vasoconstrictive substances or drugs

o    Cocaine

o    Amphetamines and other sympathomimetics

o    Ergot derivatives

o    Other vasoconstrictive medications

6.       Potential precipitating factors

o    Cold exposure

o    Emotional stress

o    Hyperventilation

o    Alcohol in susceptible individuals

7.       Associated vasomotor disorders

o    Raynaud disease

o    Migraine

These associations may support a tendency toward abnormal vasomotor reactivity but are not diagnostic of vasospastic angina.

3. Pathophysiology

1.       A coronary artery undergoes transient intense vasoconstriction.

2.       The vasospasm causes a marked temporary reduction in the coronary arterial lumen.

3.       Coronary blood flow decreases, producing transient myocardial ischemia.

4.       Severe epicardial coronary spasm may produce transient myocardial ischemia with ST-segment elevation.

5.       When the vasospasm resolves spontaneously or after administration of a vasodilator such as a nitrate, coronary blood flow is restored and the ECG changes typically resolve.

6.       Prolonged or severe vasospasm can cause:

o    Myocardial infarction

o    Ventricular arrhythmias

o    Bradyarrhythmias

o    Sudden cardiac death

4. Clinical Features

4.1 Core Features

1.       Angina occurring predominantly at rest

2.       Sudden onset of chest pain

3.       Episodes often occur in a circadian pattern, particularly at night or in the early morning

4.       Exercise tolerance may be relatively preserved

5.       Episodes are usually brief but may recur in clusters

6.       Symptoms generally respond rapidly to short-acting nitrates

Although rest angina is characteristic, vasospastic angina is not absolutely restricted to rest and can occasionally occur during exertion.

4.2 Associated Features

During an episode, patients may experience:

1.       Diaphoresis

2.       Nausea

3.       Palpitations

4.       Presyncope or syncope if significant arrhythmia occurs

5.       Radiation of pain to the arm, shoulder, jaw, neck, or back

A history of a vasomotor disorder such as Raynaud disease may increase clinical suspicion but does not establish the diagnosis.

5. Diagnosis

The diagnosis is based on the characteristic clinical presentation together with documentation of transient myocardial ischemia or coronary artery spasm.

5.1 Electrocardiography

During an episode, the ECG may demonstrate:

1.       Transient ST-segment elevation

2.       Transient ST-segment depression

3.       Other transient ischemic changes

In classic Prinzmetal or variant angina, transient ST-segment elevation is characteristic.

The ECG may return completely to baseline after the vasospasm resolves.

5.2 Cardiac Biomarkers

1.       Cardiac biomarkers are often normal after brief episodes of reversible ischemia.

2.       Troponin may become elevated when vasospasm is prolonged or sufficiently severe to cause myocardial injury or infarction.

5.3 Coronary Angiography

Coronary angiography may show:

1.       No significant obstructive coronary artery disease

2.       Transient epicardial coronary vasospasm

3.       Resolution of the spasm after administration of an intracoronary nitrate

Vasospastic angina can also occur in patients with coexisting atherosclerotic coronary disease. Therefore, normal coronary arteries are not required for the diagnosis.

5.4 Provocation Testing

When spontaneous episodes have not been adequately documented, coronary vasospasm may be assessed during invasive coronary angiography using pharmacologic provocation.

Common provocative agents include:

1.       Acetylcholine

2.       Ergonovine

A positive test for epicardial coronary vasospasm typically requires:

1.       Reproduction of the patient's characteristic chest pain

2.       Ischemic ECG changes

3.       Severe transient epicardial coronary constriction

Severe epicardial coronary vasospasm is generally defined by approximately 90% or greater angiographic constriction together with characteristic symptoms and ischemic ECG changes.

Contemporary ESC criteria use at least 90% reduction in coronary lumen diameter, COVADIS criteria use greater than 90% constriction, and JCS criteria specify greater than 90% focal stenosis or 90% diffuse vasoconstriction involving at least two contiguous coronary segments.

Provocation testing should be performed in an appropriately equipped cardiac catheterization laboratory by experienced clinicians because significant bradyarrhythmias, ventricular arrhythmias, or prolonged vasospasm can occur.

In this patient, transient ST-segment elevation during provocation together with angiographically demonstrated coronary vasospasm strongly supports the diagnosis.

6. Management

6.1 Acute Treatment

Short-acting nitrates are used for rapid relief of an acute vasospastic episode.

Examples include:

1.       Sublingual nitroglycerin

2.       Sublingual or other rapidly acting nitrate preparations

Nitrates relax coronary vascular smooth muscle and usually relieve the vasospasm rapidly.

6.2 Long-Term Prevention

Calcium channel blockers are the first-line preventive treatment for vasospastic angina.

Examples include:

1.       Diltiazem

2.       Verapamil

3.       Amlodipine

4.       Nifedipine

In patients with severe or persistent vasospastic angina, higher doses or a combination of a dihydropyridine and non-dihydropyridine calcium channel blocker may be required under appropriate clinical supervision.

6.3 Nitrates for Prevention

Long-acting nitrates may be added when symptoms remain inadequately controlled with calcium channel blockers.

They are generally used as adjunctive therapy rather than as the sole first-line preventive treatment.

6.4 Risk Factor and Trigger Modification

Patients should be advised to:

1.       Stop smoking

2.       Avoid cocaine and other sympathomimetic recreational drugs

3.       Avoid medications or substances known to precipitate coronary vasospasm when possible

4.       Manage conventional cardiovascular risk factors when present

6.5 Beta Blockers

Beta blockers are generally avoided in isolated vasospastic angina, particularly agents without alpha-1 adrenergic blocking activity, because they may exacerbate coronary vasospasm in susceptible patients.

This is particularly relevant to nonselective beta blockers.

If a beta blocker is required for another compelling indication, treatment should be individualized rather than considering all beta blockers absolutely contraindicated.

7. Complications

Vasospastic angina can occasionally produce serious complications, particularly when vasospasm is prolonged or involves a major coronary artery.

Complications include:

1.       Ventricular tachycardia or ventricular fibrillation

2.       Bradyarrhythmias or atrioventricular block

3.       Syncope

4.       Myocardial infarction

5.       Sudden cardiac death

8. Key Clinical Insight

Rest angina + transient ST-segment elevation + angiographically demonstrated reversible coronary vasospasm strongly indicates Prinzmetal or variant angina.

In this patient, the combination of recurrent non-exertional chest pain, transient ST-segment elevation during pharmacologic provocation, and angiographically demonstrated coronary vasospasm without significant obstructive coronary disease establishes the diagnosis of Prinzmetal (variant) angina, a classic form of vasospastic angina.

Her history of Raynaud disease provides an additional clue to abnormal vasomotor reactivity but is not itself diagnostic.

References

1.       Vrints C, Andreotti F, Koskinas KC, et al. 2024 ESC Guidelines for the management of chronic coronary syndromes. European Heart Journal. 2024;45(36):3415-3537. doi:10.1093/eurheartj/ehae177.

2.       Hokimoto S, Kaikita K, Yasuda S, et al. JCS/CVIT/JCC 2023 Guideline Focused Update on Diagnosis and Treatment of Vasospastic Angina (Coronary Spastic Angina) and Coronary Microvascular Dysfunction. Circulation Journal. 2023;87(6):879-936. doi:10.1253/circj.CJ-22-0779.

3.       Beltrame JF, Crea F, Kaski JC, et al. International standardization of diagnostic criteria for vasospastic angina. European Heart Journal. 2017;38(33):2565-2568. doi:10.1093/eurheartj/ehv351.