Vasospastic (Prinzmetal) Angina: Provocation Testing and Treatment

Definition and pathophysiology

Vasospastic angina (VA), formerly termed Prinzmetal or variant angina, is myocardial ischaemia caused by transient abnormal vasoconstriction of one or more coronary arteries. Epicardial spasm produces a reversible functional occlusion and usually causes transmural ischaemia. The resulting abnormalities in left ventricular function may lead to myocardial infarction, ventricular tachycardia, ventricular fibrillation, or sudden cardiac death.

Spasm may involve the epicardial coronary arteries, the coronary microvasculature, or both. Epicardial and microvascular angina can coexist, and this combination is associated with a worse prognosis. VA may occur in the presence of obstructive coronary artery disease (CAD), in non-obstructive coronary arteries, or in patients with intermediate lesions that do not produce physiologically significant flow limitation.

The mechanisms are incompletely defined. Proposed contributors include hypercontractility or hypersensitivity of coronary vascular smooth muscle to vasoconstrictor stimuli, including adrenergic agonists, leukotrienes, and serotonin. In patients with CAD, endothelial disruption may convert normal vasodilator responses to vasoconstriction; however, endothelial dysfunction alone is not sufficient, and an additional trigger is required. Potential triggers include thrombus formation and sympathetic activation. Rho kinase may increase vascular smooth-muscle sensitivity to calcium by inhibiting myosin phosphatase activity.

Patients with VA are generally younger than those with atherosclerotic non-ST-elevation acute coronary syndromes. Cigarette smoking is a prominent association, whereas other conventional coronary risk factors may be absent. The condition is more prevalent in Japan and South Korea than in Western populations, and multiple-vessel spasm during provocation testing is also reported more frequently in East Asian populations.

VA can occur as part of a more generalized vasospastic syndrome with migraine or Raynaud phenomenon. Associations have also been described with aspirin-induced asthma, 5-fluorouracil, and cyclophosphamide. Ergot derivatives used for migraine and serotonin antagonists used for depression may precipitate episodes.

Clinical presentation and symptoms

The characteristic symptom is severe angina occurring at rest. Episodes frequently cluster between midnight and 8 AM and may be accompanied by transient ST-segment elevation. Symptoms can be dramatic, but many episodes are clinically silent and detected only by electrocardiographic monitoring.

Syncope may result from transient atrioventricular block, asystole, or ventricular tachycardia. Prolonged spasm can cause acute myocardial infarction, including myocardial infarction with non-obstructive coronary arteries (MINOCA). Ventricular fibrillation and sudden cardiac death are important potential complications.

Approximately one-third of patients may have severe fixed coronary obstruction. Such patients can have a mixed syndrome, with exertional angina and ST-segment depression related to fixed disease, together with rest angina and ST-segment elevation caused by spasm.

The absence of obstructive disease generally indicates a more favourable course than VA accompanied by severe fixed lesions. Nevertheless, patients who develop serious arrhythmias during spontaneous episodes represent a higher-risk subgroup.

Evaluation and physical examination

The cardiac examination is usually normal when the patient is not experiencing ischaemia. A minority of patients have clinical evidence of systemic vasospasm, particularly migraine or Raynaud phenomenon.

The history should define:

• Whether attacks occur at rest, particularly during the night or early morning.

• The severity, duration, clustering, and reproducibility of symptoms.

• Associated syncope or palpitations, which may indicate bradyarrhythmia or ventricular tachyarrhythmia.

• Smoking exposure.

• Symptoms or diagnoses suggestive of migraine or Raynaud phenomenon.

• Exposure to potential pharmacological precipitants, including ergot derivatives, serotonin antagonists, 5-fluorouracil, and cyclophosphamide.

• Previous myocardial infarction, documented ventricular fibrillation, or known obstructive CAD.

A resting 12-lead ECG should be obtained during an episode of angina whenever possible. Because many episodes are silent or intermittent, normal findings between attacks do not exclude VA.

Diagnostic criteria

The COVADIS diagnostic framework incorporates three domains:

• Nitrate-responsive angina, particularly during spontaneous episodes.

• Transient ischaemic ECG changes, consisting of ST-segment elevation or depression of at least 0.1 mV.

• Demonstration of coronary spasm, defined as transient coronary occlusion occurring with angina and ECG changes, either spontaneously or after a provocative stimulus.

A definitive diagnosis is strengthened when the clinical syndrome, transient ECG abnormality, and angiographic evidence of spasm are concordant. In patients with compatible symptoms and characteristic transient ECG changes, invasive functional angiography is used to confirm the diagnosis and assess the severity of accompanying atherosclerotic disease.

Diagnostics

Electrocardiography

The key electrocardiographic abnormality is episodic ST-segment elevation during rest pain. ST-segment changes may occur in any leads, depending on the involved coronary artery. Transient ST-segment depression may also occur, particularly in the setting of microvascular spasm or fixed obstructive disease.

A resting 12-lead ECG during angina is recommended in patients with suspected VA. Because asymptomatic episodes are common, ambulatory ECG monitoring may identify clinically silent episodes, although the source material does not provide specific monitoring protocols.

Increased QT dispersion has been described as a marker associated with sudden cardiac death risk.

Coronary angiography

Transient coronary spasm during coronary angiography is the diagnostic hallmark. Angiography may demonstrate:

• Focal or diffuse transient narrowing.

• Spasm in one or more epicardial arteries.

• Fixed atherosclerotic plaques, which are present in approximately half of patients in some series.

• Severe proximal obstructive lesions in a substantial subgroup.

Spasm is reversible with nitrate administration. Angiography is therefore important not only for documenting dynamic obstruction but also for characterizing fixed CAD, which has major implications for prognosis and treatment.

Invasive coronary functional assessment

Invasive functional angiography is recommended in patients with suspected VA who have repetitive rest angina, transient ST-segment changes that resolve with nitrates or calcium-channel antagonists, and no clear diagnostic confirmation.

In patients with persistent symptoms and suspected ANOCA or INOCA, invasive coronary functional testing can identify treatable coronary vasomotor endotypes and improve symptom-directed management. Testing may include assessment of:

• Epicardial coronary spasm.

• Microvascular spasm.

• Coronary flow reserve.

• Microcirculatory resistance.

• Fractional flow reserve.

In patients with myocardial infarction and non-obstructive coronary arteries who are suspected of having coronary vasomotor abnormalities, provocative testing is endorsed to establish the cause, identify a higher-risk subgroup, and guide treatment.

Provocation testing

Provocation testing should be performed selectively. It is intended for patients in whom VA is suspected but not yet confirmed and who do not have obstructive CAD. It is also relevant in selected patients with MINOCA and suspected coronary vasomotor abnormalities.

The established provocative approaches are:

• Intracoronary acetylcholine.

• Intracoronary ergonovine.

• Hyperventilation testing.

Intracoronary acetylcholine is the most established method for exploring endothelium-dependent coronary vasomotor function. Incremental intracoronary acetylcholine or ergonovine doses may also be used when coronary spasm is being investigated as a cause of ventricular fibrillation in the absence of obstructive CAD or cardiomyopathy.

A positive test identifies transient spasm associated with angina and corresponding ECG changes. Provocation testing has been reported as safe in appropriately selected patients without obstructive coronary atherosclerosis and may reveal a high-risk subgroup.

Clinical role and limitations of provocation testing

Provocation testing should not be used indiscriminately. The source material specifically supports its use when:

• Symptoms are compatible with VA but the diagnosis remains unconfirmed.

• Obstructive CAD has been excluded or is not present.

• MINOCA is accompanied by suspected coronary vasomotor dysfunction.

• Ventricular fibrillation has occurred without obstructive CAD or cardiomyopathy and coronary spasm is a possible cause.

The principal clinical value is diagnostic clarification and selection of therapy according to the underlying pathophysiology. Testing may also distinguish epicardial spasm from microvascular dysfunction when combined with invasive coronary function assessment.

Biomarkers and laboratory findings

The source material does not specify a characteristic biomarker profile or laboratory test for VA. Prolonged spasm may result in acute myocardial infarction, in which case myocardial injury biomarkers may be elevated, but no specific biomarker thresholds or laboratory strategy are provided.

Treatment and management

Immediate treatment of an episode

Sublingual or intravenous nitroglycerin generally relieves coronary spasm and angina promptly. The source material does not provide a specific sublingual dose for VA.

Long-term nitrate therapy is less reliable because nitrate tolerance limits its efficacy. Nitrates may therefore be useful for acute relief but should not be regarded as the principal long-term preventive treatment.

Calcium-channel blockers

Calcium-channel blockers (CCBs) are the cornerstone of therapy. They are recommended for isolated VA to control symptoms, prevent recurrent ischaemia, and reduce the risk of potentially fatal complications.

The source material does not provide specific CCB agents, doses, titration schedules, or combinations. Treatment should therefore be individualized according to symptom control and tolerance.

Smoking cessation

Smoking cessation is a central component of management. Patients with VA should be strongly advised to stop smoking. Remission is more frequent among those who discontinue smoking.

Statins

Statin treatment has been associated with a reduction in major adverse cardiovascular events in patients with VA. The mechanism is not established but may involve prevention of plaque development or progression and potentially beneficial effects on endothelial dysfunction, inflammation, and the Rho kinase pathway.

The source material does not specify statin choice or dose.

Aspirin

Aspirin should not be used routinely in isolated VA. It may worsen ischaemic episodes, possibly because relatively small alterations in prostacyclin synthesis can influence coronary tone. Aspirin should be reserved for patients with significant coronary stenosis or another clear indication related to substantial atherosclerotic disease.

Beta-blockers

The response to beta-blockers is variable. Patients with concomitant fixed obstructive disease and exertional angina may experience benefit because beta-blockade can reduce myocardial oxygen demand. Conversely, non-selective beta-blockers may aggravate spasm by blocking beta2-mediated coronary vasodilation and leaving alpha-mediated vasoconstriction unopposed.

The use of beta-blockers in isolated VA therefore requires particular caution, and the source material does not provide a specific preferred agent or dose.

Other anti-anginal agents

Cilostazol and nicorandil may prevent recurrent episodes. Nicorandil is not available in the United States according to the source material. Specific doses are not provided.

Revascularization

PCI, and occasionally CABG, may be considered when VA coexists with a discrete, proximal, fixed obstructive lesion that limits coronary flow. Revascularization is contraindicated for isolated coronary spasm without accompanying fixed obstructive disease, because intervention does not treat the underlying dynamic vasomotor disorder.

Implantable cardioverter-defibrillator

Patients who have experienced ischaemia-associated ventricular fibrillation despite maximal medical therapy should receive an implantable cardioverter-defibrillator (ICD). The indication is particularly relevant when recurrent ischaemic episodes persist despite treatment directed at coronary spasm.

Guideline recommendations

The principal recommendations contained in the source material are summarized below.

Provocative testing with acetylcholine, ergonovine, or hyperventilation is intended for appropriately selected patients without obstructive CAD when VA is suspected but not confirmed. In MINOCA with suspected vasomotor abnormalities, guidelines endorse provocative testing to establish the cause and guide therapy.

Acute and long-term management strategy

Management should combine treatment of the acute attack, suppression of recurrent spasm, modification of precipitating factors, and assessment for complications.

An integrated approach includes:

• Recognition of the characteristic rest-pain syndrome and acquisition of an ECG during symptoms.

• Prompt nitrate treatment for an acute episode.

• Institution of CCB therapy as the principal preventive strategy.

• Strong smoking-cessation counselling.

• Review of potentially precipitating drugs and exposures.

• Coronary angiographic assessment when indicated to define both spasm and fixed CAD.

• Selective provocative testing when the diagnosis is uncertain and obstructive CAD is absent.

• Assessment for ventricular arrhythmias, particularly in patients with syncope, documented ventricular tachycardia, or ventricular fibrillation.

• Revascularization only when a discrete flow-limiting fixed lesion coexists with VA.

• ICD implantation in patients with ischaemia-associated ventricular fibrillation despite maximal medical treatment.

Prognosis and follow-up

VA often has an active phase during the first six months after presentation, when angina and cardiac events may be frequent. Symptoms and events may subsequently diminish, although recurrent vasospastic activity can reappear after months or years of relative quiescence. Such recurrences generally respond to renewed or intensified CCB therapy.

Five-year survival is reported as approximately 90–95%, but myocardial infarction occurs in as many as 20% of patients. Prognosis is more favourable when there is no or only mild fixed coronary obstruction and less favourable when severe obstructive lesions coexist. The tempo of the syndrome and the extent and severity of underlying CAD substantially influence late mortality and infarction risk.

Patients who develop serious arrhythmias during spontaneous attacks have increased risk of sudden cardiac death. This group requires particularly careful follow-up, assessment for recurrent ischaemia and arrhythmia, and consideration of ICD therapy when ventricular fibrillation persists despite maximal medical treatment.

Follow-up should include reassessment of:

• Recurrent rest angina or nocturnal symptom clusters.

• Adherence to CCB therapy.

• Smoking status.

• Exposure to potential pharmacological triggers.

• Evidence of fixed CAD and its progression.

• Syncope, palpitations, ventricular tachycardia, or ventricular fibrillation.

• The need for repeat diagnostic evaluation if symptoms recur after a prolonged quiescent interval.

Clinical outcomes are especially favourable in isolated coronary spasm without significant CAD, although angina may remain frequent. Because relapse can occur after a symptom-free period, continued clinical surveillance remains appropriate even after apparent remission.