AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

In 1959, Prinzmetal et al described a syndrome of chest pain at rest secondary to myocardial ischemia associated with ST-segment elevation. Exercise tolerance was characteristically normal in these individuals, who experienced a cyclical pain pattern with most episodes occurring in the early morning hours. This syndrome, known as Prinzmetal or variant angina, is due to focal coronary artery vasospasm and may be associated with acute myocardial infarction (MI), serious ventricular arrhythmias, and sudden death.

More recently, Maseri et al described the clinical, electrocardiographic, and angiographic features of 138 patients with variant angina and concluded that the syndrome is considerably more polymorphic than initially inferred by Prinzmetal et al. Variant angina is defined by the angiographic demonstration of spontaneous or induced coronary spasm in patients with rest pain. Electrocardiographic features may include ST-segment elevation or depression.

Note that coronary vasoconstriction and dynamic coronary obstruction are also components of atherosclerotic coronary artery disease, which can present as stable and unstable angina pectoris. This suggests a spectrum of clinical, electrocardiographic, and angiographic manifestations that share a common pathophysiology.

A Japanese variant of variant angina (termed vasospastic angina) may constitute a more diffuse disorder of large vessel vasomotor reactivity.

Pathophysiology

Prinzmetal angina is caused by focal coronary artery vasospasm, and a generalized abnormality of coronary artery vasomotor reactivity is not present. Focal coronary artery spasm typically occurs at the site of or adjacent to a fixed stenosis. A substantial number of patients have seemingly normal coronary angiogram results, although many within this subgroup have evidence of early atherosclerosis demonstrated by intravascular ultrasonographic examination or at autopsy.

Nitric oxide is a potent endothelium-derived relaxing factor responsible for maintaining the coronary arteries in a state of relative vasodilatation. Nitric oxide is synthesized from the amino acid L-arginine in a biochemical reaction catalyzed by the enzyme nitric oxide synthase. Nitric oxide is also a potent inhibitor of platelet activation, adhesion, and aggregation. Activated platelets are responsible for the release of several potent vasoconstrictors, including thromboxane A2. Abnormalities of nitric oxide synthase and reduced bioavailability of nitric oxide may result in increased basal vascular tone, vasoconstriction, vasospasm, and in activation, adhesion, and aggregation of platelets with release of additional vasoconstrictors.

Elevated serum low-density lipoprotein (LDL) cholesterol, especially the oxidized form of this lipid moiety, is responsible for the decreased production of nitric oxide due to down-regulation of endogenous nitric oxide synthase and the oxidative inactivation of nitric oxide by oxygen free radicals. Since focal coronary artery spasm in Prinzmetal angina typically occurs at or adjacent to endothelium that overlies a fatty streak of early atherosclerosis or a fibrous plaque of advanced atherosclerosis, focal endothelial dysfunction seems likely. The role of endothelial vasodilator function in the genesis of coronary artery vasospasm remains controversial.

Experimental evidence from porcine models of this disorder suggests that spasm is caused primarily by vascular smooth muscle cell hypercontraction and not by local endothelial vasodilatory dysfunction. The molecular mechanism(s) of this smooth muscle cell abnormality remains unclear. Low levels of intracellular magnesium and increased retained magnesium after an intravenous load in patients with this disorder suggest that magnesium metabolism is abnormal in patients with coronary artery vasospasm. This may occur with vitamin E as well. Hyperinsulinemia and insulin resistance are probable risk factors for variant angina, although the pathogenic mechanisms of these apparent associations have not been defined.

The role of the autonomic nervous system in the pathogenesis of variant angina is controversial. Withdrawal of parasympathetic activity before the onset of angina has been suggested, but Japanese investigators actually found an increase in parasympathetic and sympathetic activity. Whether this discrepancy is due to methodological flaws or to racial vasomotor heterogeneity in vasomotor angina is unclear.

Frequency

United States

Estimates are that 2-3% of all patients undergoing diagnostic cardiac catheterization for chest pain in the United States will subsequently be classified as having variant angina. This percentage may vary depending on the criteria applied to make the diagnosis of variant angina and the intensity of electrocardiographic surveillance for transient ST-segment elevation during episodes of chest pain.

International

In Italy, where rigorous inpatient electrocardiographic monitoring is frequently used, the incidence of variant angina in patients admitted with chest pain is approximately 10%. Variant angina is particularly common in Japan with 20-30% of patients who undergo coronary angiography for chest pain assigned a diagnosis of vasospastic angina (see Background). Of these patients, 40-80% have angiographically normal coronary arteries.

Mortality/Morbidity

Overall, the prognosis of patients with variant angina is favorable. Three-year survival rates vary between 84-98%, and MI-free survival at 3 years varies between 63-98%, depending on application of the relevant diagnostic criteria and the study population. Early and late mortality and morbidity are related to the degree of underlying atherosclerotic coronary artery disease. Patients without a stenosis of 70% or more have a 93% 1-year MI-free survival rate, while patients with multivessel atherosclerotic coronary artery disease and variant angina only have a 65% 1-year MI-free survival rate. Patients who develop serious arrhythmias during episodes of pain and/or who have evidence of diminished left ventricular ejection fraction are at increased risk of early mortality.

Race

Racial heterogeneity probably exists in coronary artery vasomotor reactivity. Japanese patients have a higher relative incidence of variant angina. They may exhibit a more diffuse abnormality of vasomotor tone compared to whites, and angiography may show segmental or diffuse coronary artery spasm. The incidence of variant angina in African Americans is not well defined.

Sex

The major prognostic studies of patients with variant angina confirm that 69-91% are male. Variant angina may be relatively more common in white female patients (22%) than in Japanese patients (11%).

Age

The mean age of patients with variant angina is 51-57 years.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Angina pectoris is the chest pain experienced by patients with variant angina and usually is described as a retrosternal pressure with radiation to the neck, jaw, left shoulder, or arm. Variant angina occurs at rest and exhibits a circadian pattern, with most episodes occurring in the early hours of the morning. The pain commonly is severe and may be associated with palpitations, presyncope, or syncope secondary to arrhythmia.

• Distinguishing unstable angina pectoris related to coronary atherosclerosis from variant angina may be difficult and requires special investigations, including coronary angiography. This may be an arbitrary distinction in some patients because it is likely that vasospasm is both a cause and a consequence of plaque rupture and thrombosis in patients with unstable angina pectoris, and many patients with variant angina have obstructive coronary artery disease.
• The absence of risk factors for atherosclerotic coronary artery disease suggests variant angina, although cigarette smoking is a common risk factor for both clinical syndromes and is reported in most patients with variant angina.
• A minority of patients with variant angina may have a more systemic abnormality of vasomotor tone; this may include symptoms of migraine headache and Raynaud phenomenon. Although in one series, 30% of patients reported a familial incidence of variant angina, there is no convincing evidence for a genetic predisposition to arterial spasm. It has been suggested that an examination of hereditary pathological and polymorphic variations in factors elaborated by endothelial cells, platelets, and leukocytes responsible for maintaining the patency of blood vessels (eg, nitric oxide, prostacyclin, endothelin-1) may prove enlightening.

Physical

The cardiac examination findings in patients with variant angina typically are normal, although a fourth heart sound or mitral regurgitation may be heard during episodes. Tachycardia or bradycardia may accompany episodes of prolonged chest pain, particularly with marked ST-segment elevation. Noninvasive imaging studies may show regional wall motion abnormalities and even segmental dyskinesis during episodes of pain. Finding other evidence of diffuse atherosclerotic disease does not differentiate patients with variant angina from those with unstable angina pectoris, and the physical examination does not reliably discriminate patients with variant angina who have no obstructive coronary artery disease from those with multivessel disease.

Causes

The pathophysiology of this syndrome is most likely related to an abnormality of normal vasodilator function within the coronary arteries and/or a hypersensitivity of the coronary arteries to normal mediators of vasoconstriction. The underlying cause of these abnormalities of vasomotor function is unknown. Subclinical or clinical atherosclerosis is almost ubiquitous in patients with variant angina, although the reason this subgroup of patients should present with focal coronary artery vasospasm remains unclear. Smoking, hyperinsulinemia, and insulin resistance are probable risk factors for variant angina.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Evaluation of the standard hematology, serum chemistry, and lipid profiles to exclude anemia, infection, primary platelet disorder, renal failure, hyperglycemia, electrolyte abnormality, and dyslipidemia is appropriate. Serial cardiac enzyme determination is appropriate if MI is suspected.

Imaging Studies

• Thallium scintigraphy has been used to localize the myocardial perfusion defect to an area perfused by a coronary artery in which spasm can be demonstrated by angiography. This was a valuable research tool and helped define the syndromes of coronary artery vasospasm; however, the routine clinical utility of this test is uncertain.
• Coronary angiography is the criterion standard for the diagnosis of variant angina when coupled with the clinical syndrome of angina pectoris at rest with transient ST-segment elevation. Focal spasm of the proximal portion of a major coronary artery not preceded by an increase in heart rate or blood pressure that is followed by chest pain, ST-segment elevation, and ventricular dysfunction is pathognomonic.
• • Most patients with variant angina and documented coronary artery vasospasm have some angiographic evidence of atherosclerotic coronary artery disease, although evidence is mild in many patients. Spasm typically occurs within 1 cm of an angiographically apparent obstruction. If minimal or no angiographic evidence of coronary artery disease is found in a patient who has recently had angina at rest with transient ST-segment elevation, variant angina is the likely diagnosis, and further testing is unnecessary. In some patients, it may be necessary to perform provocative testing to induce coronary artery spasm.
  • Ergonovine maleate is an ergot alkaloid that stimulates both alpha-adrenergic and serotonergic receptors and thus exerts a direct constrictive effect on vascular smooth muscle. Coronary arteries, which constrict spontaneously, appear to be abnormally sensitive to this agent. The response of normal coronary arteries to ergonovine maleate is a mild, diffuse spasm.
  • Of the provocative test agents shown to induce coronary artery spasm in susceptible patients, ergonovine maleate, methylergonovine maleate, acetylcholine, or hyperventilation are the most useful. Ergonovine maleate for injection is no longer available, and the availability of methylergonovine is limited. The intravenous administration of incremental doses of methylergonovine starting at 0.05 mg to a maximum of 0.40 mg is both sensitive and specific, and there is an inverse relationship between the dose required to provoke spasm in the laboratory and the frequency or spontaneous episodes experienced by the patient.
  • To ensure a valid test, nitrates and calcium antagonists must be withdrawn for at least 48 hours before testing. Women are more sensitive than men to methylergonovine. The intracoronary route of administration of methylergonovine for provocation of spasm is relatively safe, sensitive, and specific, but rarely used today. This route is preferable in hypertensive patients and affords the opportunity to evaluate the left and right coronary circulations separately. Small dosing increments of 5-10 mcg are used, with a total dose not to exceed 50 mcg and with intracoronary nitroglycerine available.
  • Absolute contraindications to methylergonovine include pregnancy, severe hypertension, severe left ventricular dysfunction, moderate-to-severe aortic stenosis, high-grade left main coronary stenosis, and significant stenoses in epicardial coronary vessels. Relative contraindications include uncontrolled or unstable angina, uncontrolled ventricular arrhythmia, recent MI, and advanced coronary disease. Alternatively, intracoronary acetylcholine can be used as a provocative test for spasm, and its effectiveness is comparable to methylergonovine. In patients with more than 1 episode of variant angina per day, the hyperventilation provocative test is nearly as effective as methylergonovine in causing vasospasm. In patients with less frequent attacks, hyperventilation is less sensitive.

Other Tests

• Electrocardiography: Transient ST-segment elevation is the characteristic finding in patients with variant angina. If the patient is fortunate, this is detected during the initial evaluation of a patient with chest pain. Until the diagnosis is firmly established, a 12-lead electrocardiograph should be performed during each and every episode of chest pain. As previously noted, ST-segment elevation and depression and T-wave inversion or pseudonormalization may follow episodes of ST-elevation.
• • Ambulatory electrocardiography: Many episodes of coronary artery vasospasm are brief and may be asymptomatic; however, ST-segment changes may be detected by ambulatory electrocardiography and may better characterize the frequency and duration of myocardial ischemia.
  • Holter monitoring: Variant angina, which is associated with ventricular dysrhythmia and sudden cardiac death, may be detected during inpatient telemetry observation or ambulatory Holter monitoring.
• Exercise tolerance testing is controversial and of questionable utility. Prinzmetal originally described patients who had chest pain at rest and preserved exercise tolerance. However, we now know that many patients with coronary artery vasospasm experience exertional angina pectoris due to fixed coronary artery stenoses; furthermore, we know that exercise may precipitate coronary artery vasospasm in some patients. The results of exercise testing in patients with variant angina therefore are highly variable, and approximately equal numbers of patients show ST-segment depression, elevation, or no change during exercise testing.

Histologic Findings

In one report, increased numbers of mast cells were found in the adventitial layer of the coronary artery in a patient who died from coronary artery spasm.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Patients with angina pectoris at rest are routinely admitted to a hospital for observation, evaluation, and initiation of medical therapy. This should include a 12-lead electrocardiograph (which should be repeated with each episode of chest pain), telemetry monitoring for the initial 24-48 hours, and serial cardiac enzyme assays.

Thallium scintigraphy and coronary angiography may be required for diagnostic, prognostic, and therapeutic reasons. Ambulatory electrocardiography and Holter monitoring may increase the sensitivity of the aforementioned in-hospital evaluation if the diagnosis of variant angina remains elusive.

Medical therapy initially should include intravenous or sublingual nitroglycerin and an oral calcium channel antagonist. Long-acting oral nitrates are appropriate for the prevention of recurrent episodes and may be used in combination with the calcium channel antagonist for long-term prophylaxis.

Surgical Care

Percutaneous coronary revascularization and coronary artery bypass surgery may be helpful in patients with a mixed presentation, including both rest and limiting exertional angina with suitable proximal coronary artery stenoses.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Nitrates and calcium channel blockers (CCBs) are the mainstays of medical therapy for variant angina. Nitroglycerin effectively treats episodes of angina and myocardial ischemia within minutes of administration, and the long-acting nitrate preparations reduce the frequency of recurrent events.

Nifedipine, amlodipine, verapamil, and diltiazem effectively prevent coronary vasospasm and variant angina, and they should be administered in preference to beta-blockers.

Beta-blockers can be beneficial in patients with fixed coronary artery stenoses and exertional angina pectoris and are sometimes necessary in combination with the aforementioned drugs to achieve control of symptoms, especially in patients with significant fixed stenoses. However, nonselective beta-blockers may be detrimental in some patients because blockade of the beta-receptors, which mediate vasodilation, allows unopposed alpha-receptor–mediated coronary vasoconstriction to occur, thus possibly causing an actual worsening of symptoms.

Spontaneous remission following an early period of acute activity is not infrequent; therefore, it is reasonable to carefully reduce the dose of medications after an initial 3-month symptom-free period.

Because atherosclerosis is common in patients with variant angina, the dietary and medical treatment of dyslipidemia is appropriate.

Drug Category: Nitrates

Affect direct endothelium-independent vasodilatation of the large coronary arteries. In addition, a reduction of preload occurs due to dilatation of venous capacitance vessels, resulting in a decrease in myocardial oxygen consumption. Nitrates act as an exogenous source of nitric oxide, which causes vascular smooth muscle relaxation and may have a modest effect on platelet aggregation and thrombosis.

Drug Category: Calcium channel blockers

Relax coronary smooth muscle and produce coronary vasodilation, which in turn improves myocardial oxygen delivery. Dihydropyridines exhibit greater vascular selectivity over nondihydropyridines (verapamil and diltiazem), which also inhibit the impulse conduction within the sinoatrial and atrioventricular nodes.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Complications

• MI is a complication of variant angina. It typically develops in the region corresponding to the location of the electrocardiographic changes during prior anginal attacks, which supports the theory that coronary artery vasospasm is the primary mechanism. Incidence depends on the relevant diagnostic criteria, but it is as high as 30% in some series. The incidence and prognosis of MI in patients with variant angina appears to be associated with the extent and severity of any underlying fixed atherosclerotic coronary stenoses.
• Arrhythmias: Syncope and presyncope are recognized symptoms that are not infrequently associated with variant angina and are likely due to significant arrhythmias, which cause hemodynamic deterioration. An increased incidence of sudden cardiac death, ventricular tachycardia, ventricular fibrillation, and complete atrioventricular block have been observed during episodes of variant angina and myocardial ischemia. The risk of sudden death is approximately 2% and is most common in patients with multivessel spasm and prior serious arrhythmia during anginal attacks.

Patient Education

• For excellent patient education resources, visit eMedicine's Heart Center. Also, see eMedicine's patient education article Chest Pain.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• The absence of obstructive atherosclerotic coronary artery disease (stenosis of 70% or more) should not lead the physician to conclude that the patient is at no risk of future morbidity and mortality.
• Technical limitations of the 2-dimensional coronary angiogram, operator and interpreter error, variant angina, and rupture of a nonobstructive atherosclerotic plaque with endogenous fibrinolysis of the endovascular thrombus may render the results of this apparently objective test of coronary artery anatomy misleading.
• A full reevaluation of the clinical syndrome should follow an unexpected angiographic result, and consideration of the aforementioned entities, including variant angina, is appropriate.
• Addressing risk factors for future coronary heart disease events, including the lowering of cholesterol, almost invariably is appropriate. Full and accurate documentation of this decision-making process is essential.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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• Pristipino C, Beltrame JF, Finocchiaro ML, et al. Major racial differences in coronary constrictor response between japanese and caucasians with recent myocardial infarction. Circulation. Mar 14 2000;101(10):1102-8. [Medline].
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Article Last Updated: Nov 8, 2005