Coronary Artery Vasospasm

Background

Coronary artery vasospasm, or smooth muscle constriction of the coronary artery, is an important cause of chest pain syndromes that can lead to myocardial infarction (MI), ventricular arrhythmias, and sudden death. It also plays a key role in the development of atherosclerotic lesions.

In 1959, Prinzmetal et al described a syndrome of nonexertional chest pain with ST-segment elevation on electrocardiography (ECG). [1Unlike patients with typical angina, these patients characteristically had normal exercise tolerance, and their pain patterns tended to be cyclical, with most episodes occurring in the early morning hours without regard to cardiac workload. This syndrome became known as Prinzmetal or variant angina, and was believed to be due to vasospasm in coronary arteries without obstructive lesions.

Subsequently, Maseri et al described the clinical, ECG, and angiographic features of 138 patients with variant angina and concluded that the syndrome was considerably more polymorphic than was initially inferred by Prinzmetal. [2]

For patient education resources, see the Heart Health Center and Chest Pain.

Etiopathophysiology

The pathophysiologic mechanisms leading to coronary artery vasospasm are not yet completely understood. Coronary arterial tone varies normally via physiologic mechanisms, but the degree of vasoconstriction can range along a spectrum extending from undetectable constriction to complete arterial occlusion.

In some patients with partial vasoconstriction, symptoms can arise with activities that exceed a threshold of myocardial demand. [3In other patients, constriction may be so severe that myocardial ischemia develops at rest. Many observers use the presence of constriction-induced ischemia as the threshold for defining clinical coronary artery vasospasm, [4which has also been called vasospastic angina or variant angina.

In many cases, coronary artery vasospasm can occur spontaneously without an identifiable cause. Known triggers of spasm in susceptible patients include hyperventilation, cocaine or tobacco use, and administration of provocative agents such as acetylcholine, ergonovine, histamine, or serotonin. [5]

That coronary artery vasospasm can be induced through stimulation of alpha receptors [6or intracoronary injection of the parasympathetic neurotransmitter acetylcholine [7indicates that there are different mechanisms of action.

Acetylcholine causes coronary vasodilation in healthy coronary arteries through the release of endothelial nitric oxide (NO); however, in atherosclerotic arteries, vasoconstriction ensues instead. Patients with coronary artery vasospasm appear to have a heightened vasoconstrictor response to acetylcholine as well as an enhanced response to the vasodilator effects of nitrates, an observation that is consistent with a deficiency of endogenous NO activity. [4]

Thus, NO deficiency is believed to play an important role in the development of coronary artery vasospasm. This may also explain the correlation between coronary artery vasospasm and increased intimal thickening: NO deficiency results in enhanced activity of potent vasoconstrictors and stimulators of vascular smooth muscle proliferation, such as angiotensin II and endothelin 1. [4]

Several genetic polymorphisms that compromise endothelial NO production have been found to be significantly associated with coronary artery vasospasm. [8Some have even been found to have prognostic value, including the -786T/C polymorphism. [9However, additional studies showing that NO levels are not decreased at the sites of coronary artery vasospasm dispute the primacy of the role of NO. [10]

Alternative (or coexisting) mechanisms of coronary artery vasospasm include enhanced phospholipase C activity. [11In addition, coronary artery vasospasm is associated with increased markers of oxidative stress and inflammation, including thioredoxin, C-reactive protein (CRP), and monocyte levels. [4Certain behavioral traits (eg, type A personality, panic disorder, and severe anxiety) are also described as being associated with coronary artery vasospasm. [12]

Epidemiology

United States statistics

The reported prevalence of vasospastic angina varies considerably between clinical studies, depending in large part on the geographic location of the population studied, as well as on the criteria used to test and define the condition. [13In the United States, the frequency is among the lowest in the world, with about 4% of patients who undergo coronary angiography showing evidence of focal spasm (defined as a 75% reduction in artery diameter on the administration of ergonovine). [14]

International statistics

In France, about 12% of patients had positive ergonovine-based studies, [15whereas in Japan, where the greatest number of publications on coronary artery vasospasm originate, positive study rates are in the range of 30%. [16The incidence of coronary artery vasospasm may be increasing in Japan, at least on the basis of provocation of spasm by the administration of acetylcholine. [17]

Age-, sex-, and race-related demographics

The age at which symptoms first appear is highly variable, but on average, patients are in their 50s at symptom onset. [18]

Variant angina is believed to be more common in female patients, [1920although some prognostic studies of patients with variant angina suggest a male preponderance. A 2012 study of Korean patients showed that men were more likely to develop coronary artery vasospasm in response to an intracoronary acetylcholine challenge. [21Among women, variant angina may be relatively more common in white patients (22%) than in Japanese patients (11%).

Overall, Japanese patients are much more likely to develop coronary artery vasospasm than Caucasian patients. When evaluated by the same team, Japanese patients had a 3-fold higher incidence of spasm than their Caucasian counterparts even though the 2 groups of patients had similar average basal coronary tone. [22]

Prognosis

The natural history of patients undergoing medical therapy for coronary vasospasm may involve significant morbidity, but mortality is low in most cases, even on long-term follow-up. [18Patients often have 3- to 6-month clusters of recurrent attacks, separated by relatively asymptomatic periods, with a gradual reduction of symptoms in the long term. [4In a study of 59 patients followed for an average of 5.9 years, 93% experienced rest angina and 19% sustained frank MIs. [23However, there were no cardiac deaths.

Long-term survival is believed to be good, especially in patients who tolerate calcium antagonists and avoid smoking. [18Predictors of poorer prognosis include the presence of concurrent coronary atherosclerosis, [24ongoing smoking, intolerance of calcium antagonists, and spasm of multiple coronary arteries. [25]

In patients with no or even single-vessel atherosclerosis, the prognosis is benign, with survival rates as high as 99% at 1 year and 94% at 5 years. On the other hand, survival in patients with multivessel atherosclerotic disease fell to 87% at 1 year and 77% at 5 years. Survival rates were also lower in patients with multivessel spasm. [26]

A 3-year follow-up to the Coronary Artery Spasm as a Frequent Cause for Acute Coronary Syndrome (CASPAR) study concluded that patients with acute coronary syndrome (ACS) who do not have a culprit lesion have a better prognosis than patients with obstructive ACS. [27Persistent angina is challenging, and repeated coronary angioplasty may be required.

The Japanese Coronary Spasm Association (JCSA) derived the "JCSA risk score" to guide prognostication for patients with coronary vasospasm. Elements of the score include the following:

  • History of out-of-hospital cardiac arrest (4 points)

  • Smoking, angina at rest alone, organic coronary stenosis, multivessel spasm (2 points each)

  • Beta blocker use, ST elevation during angina (1 point each)

Stratification of patients by score led to differentiation in their risk of major adverse cardiac events (MACE). Patients with a low score of 0-2 had a MACE of 2.5%. Those with an intermediate score of 3-5 had a MACE of 7%, and those whose scores were 6 or higher had a MACE of 13%. [28]

Complications

Myocardial infarction (MI) is a potential complication of variant angina, especially in the myocardial territory corresponding to the location of the electrocardiographic (ECG) changes during previous anginal attacks. The incidence of MI depends on diagnostic criteria, but has been reported to be as high as 30% in some series.

The incidence and prognosis of MI in patients with variant angina appear to be associated with the extent and severity of any underlying atherosclerotic coronary stenoses. Adverse outcomes are more likely and survival poorer in patients with multivessel atherosclerotic CAD. [24]

Arrhythmias may occur with severe vasospastic angina. Both atrioventricular conduction abnormalities and ventricular arrhythmias can cause life-threatening hemodynamic deterioration and syncope. Coronary vasospasm has been identified as an important cause of out-of-hospital cardiac arrest. [29 The risk of sudden death is approximately 2% and is most common in patients with multivessel spasm [26 and prior serious arrhythmia during anginal attacks. In extreme cases, defibrillator implantation may be considered.


History and Physical Examination

Patients with coronary artery vasospasm typically describe anginal symptoms, including retrosternal pain or pressure with radiation to the neck, jaw, left shoulder, or arm. This may be particularly true if there is significant coexistent atherosclerosis. [31Notably, symptoms associated with vasospastic angina often occur at rest and may exhibit a circadian pattern, with most episodes occurring in the early hours of the morning. [4In severe cases, associated arrhythmias may be present, ranging from heart block to ventricular tachycardia. [32]

Distinguishing unstable angina pectoris related to coronary atherosclerosis from variant angina may be difficult and require special investigations for diagnosis, including coronary angiography. In some patients, the distinction may be an arbitrary one because it is likely that vasospasm is both a cause and a consequence of plaque rupture and thrombosis in patients with unstable angina pectoris.

In addition, many patients with variant angina have obstructive coronary artery disease (CAD). Indeed, in as many as 60% of cases, coronary artery vasospasm occurs at a site with preexisting coronary atherosclerosis, [15which suggests that underlying arterial dysfunction may be a predisposing factor for spasm.

Although spasm is more likely to occur in the presence of atherosclerotic lesions, the absence of traditional risk factors for atherosclerotic CAD may make vasospastic angina more likely; the exception is cigarette smoking, which is a common risk factor for both clinical syndromes. [14Spasm is found more often in patients with symptoms that occur at rest (55.5%) than in those with exertional angina (27.7%). [16]

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. [33]

No features on physical examination are specific for vasospastic angina. Signs may be absent between symptomatic episodes. During periods of angina, physical findings relating to ischemia and ventricular dysfunction may be present, including rales, jugular venous distention, peripheral edema, extra heart sounds, ectopy or other arrhythmia (eg, tachycardia or bradycardia), and murmurs (such as occur with ischemic mitral regurgitation

Diagnostic Considerations

Coronary artery vasospasm is an important cause of chest pain but not the exclusive cause. Atherosclerotic coronary disease is much more common, and its presence confers a worse prognosis, regardless of the cause of symptoms. Therefore, appropriate evaluation and interventions for both diseases should be considered in most of these patients.

Technical limitations of both noninvasive and invasive coronary evaluations may lead to misleading results. For example, a coronary event caused by rupture of a nonobstructive atherosclerotic plaque with thrombosis, followed by spontaneous reperfusion, may lead to a seemingly normal or innocuous coronary evaluation. In this situation, a diagnosis of vasospastic angina may be incorrectly applied, and important interventions to treat and prevent further atherosclerotic events may be delayed.

A full reevaluation of the clinical syndrome should follow an unexpected angiographic or other diagnostic result.

Differential Diagnoses


Laboratory Studies

Evaluation of the standard hematology, serum chemistry, and lipid profiles is appropriate for excluding anemia, infection, primary platelet disorders, renal failure, hyperglycemia, electrolyte abnormalities, and dyslipidemia. Serial measurement of cardiac enzyme and troponin levels should be performed to assess for evidence of ischemia.

Magnesium levels may be checked; magnesium deficiency can heighten sensitivity to acetylcholine- and hyperventilation-induced spasm. Magnesium supplementation may be a potentially useful therapy. [5]

Perfusion Imaging and Echocardiography

Myocardial perfusion imaging may be helpful in ruling out obstructive atherosclerotic disease between episodes of coronary artery vasospasm. During episodes, myocardial perfusion imaging may help identify and quantify ischemia and localize it to the culprit artery.

Standard transthoracic echocardiography should be considered to evaluate for stigmata of other causes of nonexertional chest pain (eg, pericarditis or abnormalities of the aorta). Preliminary data suggest a potential role for hyperventilation and cold-pressor stress echocardiography as a noninvasive means for detecting coronary artery vasospasm, though this method may not be as sensitive as using intracoronary acetylcholine as the provocative agent. [34]

Electrocardiography and Monitoring

Transient ST-segment elevation on electrocardiography (ECG) is a characteristic finding in patients with variant angina, [5but it may only be present during symptomatic episodes and typically resolves completely within minutes. However, in more severe cases, ST elevation may be followed by T-wave inversions for hours to days. [35During recovery, U-wave inversions may be present, particularly in lead V5. [36]

Many episodes of coronary artery vasospasm are brief and may be asymptomatic; however, ST-segment changes may be detected by ambulatory electrocardiography, which may allow for more accurate characterization of the frequency and duration of attacks.

Severe vasospastic angina may result in heart block or potentially fatal ventricular arrhythmias. Inpatient telemetry monitoring serves an important role in acutely ill patients. In outpatients, Holter monitoring may facilitate detection of nonsustained arrhythmias.

Angiography

Coronary angiography may reveal focal spasm of a coronary artery; when coupled with typical symptoms, ECG changes, and even ventricular dysfunction, this spasm may be pathognomonic for the condition.

Most patients with variant angina and documented coronary artery vasospasm have some angiographic evidence of atherosclerotic coronary artery disease (CAD), which is typically mild. Focal spasm more commonly occurs within 1 cm of an angiographically apparent obstruction. If minimal or no angiographic evidence of CAD is found in a patient who has recently had angina at rest with transient ST-segment elevation, variant angina is the more likely diagnosis, and further testing is unnecessary.

The angiographic demonstration of a myocardial bridge may have prognostic implications as well. Not only are myocardial bridges associated with a higher likelihood of more severe coronary artery vasospasm in response to an intracoronary acetylcholine challenge, but a 2012 study suggested that these patients may have greater related morbidity and mortality. [37]

Provocative Testing

Provocative testing is infrequently used in clinical practice but may facilitate identification of patients with coronary artery vasospasm.

The most commonly used provocative agent is ergonovine maleate, an ergot alkaloid that stimulates both alpha-adrenergic and serotonergic receptors, exerting a direct constrictive effect on vascular smooth muscle. Normal coronary arteries respond to ergonovine maleate with a mild diffuse spasm, whereas abnormal arteries may respond with an intense focal spasm. Acetylcholine and hyperventilation have also been used to provoke spasm.

In one study, Sueda et al performed both acetylcholine (ACh) and ergonovine (ER) spasm provocation tests in 461 patients. They found evidence that, as a spasm provocation test, ACh is more sensitive than ER in both sexes, especially in females. [38]

Intravenous (IV) administration of incremental doses of methylergonovine, starting at 0.05 mg and increasing to a maximum of 0.40 mg, is both sensitive and specific, and there is an inverse relation between the dose required to provoke spasm in the laboratory and the frequency of 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. The intracoronary route of administering methylergonovine is preferable for provocation of spasm and affords the opportunity to evaluate the left and right coronary circulations separately. Small dosing increments (ie, 5-10 µg) are used, with the total dose not to exceed 50 µg.

Intracoronary nitrates should be readily available. Complication rates during provocative testing are relatively low with either ergonovine or acetylcholine, provided that intracoronary nitrates are on hand for use to relieve induced spasms. [39A 2012 study showed that use of beta blockers during the intracoronary acetylcholine provocation test in patients with vasospastic angina is not associated with a worsening of clinical and angiographic parameters. [40]

A 2015 study suggests that left-ventricular end diastolic pressure (LVEDP) may be effective in identifying myocardial ischemia during ergonovine provocation testing. [41 

Absolute contraindications to provocative testing with methylergonovine include the following:

  • Pregnancy

  • Severe hypertension

  • Severe left ventricular dysfunction

  • Moderate-to-severe aortic stenosis

  • High-grade left main coronary stenosis

  • Significant stenoses in epicardial coronary vessels

Relative contraindications include the following:

  • Uncontrolled or unstable angina

  • Uncontrolled ventricular arrhythmia

  • Recent MI

  • Advanced coronary disease

Treatment & Management

Initial Measures

Patients with vasospastic angina presenting with active symptoms of ischemia often require admission. Initial evaluation should include 12-lead electrocardiography (ECG), continuous telemetry monitoring, and serial cardiac enzyme and troponin measurements. Further evaluation should include assessment for coexisting or contributory atherosclerotic coronary artery disease (CAD). This may involve stress testing with myocardial perfusion imaging or even coronary angiography (see Workup).

Because atherosclerosis is common in patients with vasospastic angina, medical and lifestyle interventions for preventing or treating atherosclerosis should be implemented when appropriate.

Pharmacologic Therapy

Initial medical treatment should include sublingual, topical, or intravenous (IV) nitrate therapy. Nitroglycerin administered by any route (intracoronary, IV, topical, or sublingual) effectively treats episodes of angina and myocardial ischemia within minutes, and long-acting nitrate preparations reduce the frequency of recurrent events.

Until atherosclerotic coronary disease (a much more frequent cause of chest pain) is excluded, standard therapies, including antiplatelet or antithrombotic agents, statins, and beta blockers, may be administered. Statin therapy appears to improve clinical outcomes in patients with coronary spasm–induced acute myocardial infarction with nonobstructive coronary arteries. [42]

Once the diagnosis of coronary artery vasospasm is made, calcium channel blockade and long-acting nitrates may be used for long-term prophylaxis.

The calcium channel blockers nifedipine, amlodipine, verapamil, and diltiazem effectively prevent coronary vasospasm and variant angina, and they should be administered in preference to beta blockers. Amlodipine may be preferable because of its long half-life. [43]

Bet -blockers are beneficial in most patients with atherosclerotic coronary stenoses and exertional angina pectoris and are sometimes helpful in combination with the above drugs to achieve control of symptoms in these patients. 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 and may worsen vasospastic angina in selected cases.

Other agents have been tried with variable success, including endothelin antagonists such as bosentan. [44Early experience with cilostazol has been positive but limited; [45additional research is needed to validate its clinical use.

In a study of 3349 patients diagnosed with coronary artery spasm (CAS), Choi et al divided patients into 2 groups according to whether their prescriptions included renin-angiotensin system (RAS) inhibitor or not, and they investigated the effect of renin-angiotensin system inhibitors on long-term clinical outcomes. Following propensity score matching analysis, two matched groups (524 pairs, n=1048 patients) were generated and their baseline characteristics were balanced. Compared with the non-RAS inhibitor group, the RAS inhibitor group had a lower incidence of recurrent angina, total death, and total major adverse cardiovascular events during the 5-year clinical follow-up. [46]

Spontaneous remission may occur, and some patients may be able to wean or reduce their drug therapy after an initial 3-month symptom-free period.

Percutaneous and Surgical Revascularization

Up to one fifth of patients may continue to have vasospasm despite medical therapy. Mechanical revascularization has been used successfully in patients with medically resistant vasospasm. Scattered reports of coronary stenting suggest that a percutaneous strategy may be feasible in such patients. [47The results for surgical revascularization have been variable, but overall, bypass surgery appears to provide clinical benefit to less than 50% of patients. [24The efficacy of surgical treatment is greater in patients who also have significant obstructive atherosclerotic lesions. In patients without baseline obstruction, however, the risk of early graft closure is elevated.

For patients who continue to have significant symptoms or signs of coronary vasospasm despite maximally tolerated medical therapy, in whom the culprit segment can be identified, coronary stenting may be considered on a case-by-case basis. However, bypass grafting of arteries without baseline obstruction should be reserved for patients with life-threatening ischemia that is refractory to maximal medical therapy. In these patients, adding complete plexectomy to the procedure may provide additional benefit



Medication Summary

Nitrates and calcium channel blockers are the mainstays of medical therapy for vasospastic angina. Other agents have been tried with variable success, including endothelin antagonists such as bosentan.

Nitrates, Angina

Class Summary

Nitrates produce a direct, endothelium-independent vasodilatation of the large coronary arteries. In addition, they reduce preload by dilating venous capacitance vessels, which results in decreased 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.

Nitroglycerin (Nitrolingual, Nitrostat, Minitran, Nitro-Bid, Nitro-Dur)

Nitroglycerin causes relaxation of vascular smooth muscle by stimulating intracellular cyclic guanosine monophosphate (GMP). The result is a decrease in blood pressure. Dosage forms include sublingual, transdermal, and intravenous (IV) preparations. The distinction between short-acting preparations for treatment of acute attacks and long-acting preparations for prevention of recurrent episodes is important.

Isosorbide dinitrate (Isordil, Dilatrate SR)

Isosorbide dinitrate relaxes vascular smooth muscle by stimulating intracellular cyclic GMP. It decreases preload and afterload, causing decreased myocardial oxygen demand. Isosorbide dinitrate is used for the treatment and prevention (sustained-release preparations) of variant angina. The onset of action is approximately 3.5 minutes, and the antianginal effect lasts about 2 hours.

Isosorbide mononitrate (ISMO, Imdur, Monoket)

Isosorbide mononitrate is used for the prevention of variant angina. The onset of action of oral isosorbide mononitrate is not sufficiently quick to permit its use as an acute antianginal agent. The half-life is approximately 5 hours.

Calcium Channel Blockers

Class Summary

Calcium antagonists relax coronary smooth muscle and produce coronary vasodilation, which in turn improves myocardial oxygen delivery. Dihydropyridines (eg, amlodipine and felodipine) exhibit greater vascular selectivity than nondihydropyridines (eg, verapamil and diltiazem), which also inhibit impulse conduction within the sinoatrial and atrioventricular nodes.

Nifedipine (Nifediac CC, Adalat CC, Procardia, Procardia XL)

Nifedipine is the prototypical dihydropyridine, indicated for treatment of acute attacks and prevention of recurrent attacks. Sublingual administration is generally safe, despite theoretical concerns.

Amlodipine (Norvasc)

Amlodipine is generally regarded as a dihydropyridine, though experimental evidence suggests that it may also bind to nondihydropyridine binding sites. It has a substantially longer half-life than nifedipine and is administered daily. It is appropriate for prophylaxis of variant angina.

Verapamil (Calan, Calan SR, Covera HS, Isoptin, Verelan)

Verapamil is a nondihydropyridine that is appropriate for prophylaxis of variant angina. It is recommended for rate control in atrial fibrillation or flutter. During depolarization, verapamil inhibits the entry of calcium ions into slow channels or voltage-sensitive areas of the vascular smooth muscle and myocardium.

Diltiazem (Cardizem, Cardizem CD, Cartia XT, Dilacor XR, Tiazac)

Diltiazem is a nondihydropyridine that is appropriate for prophylaxis of variant angina. During depolarization, it inhibits the entry of calcium ions into slow channels or voltage-sensitive areas of the vascular smooth muscle and myocardium.


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