Coronary Artery Vasospasm

Back

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).[1] Unlike 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.[3] In 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,[4] which 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[6] or intracoronary injection of the parasympathetic neurotransmitter acetylcholine[7] indicates 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.[8] Some have even been found to have prognostic value, including the -786T/C polymorphism.[9] However, 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.[11] In addition, coronary artery vasospasm is associated with increased markers of oxidative stress and inflammation, including thioredoxin, C-reactive protein (CRP), and monocyte levels.[4] Certain 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.[13] In 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,[15] whereas in Japan, where the greatest number of publications on coronary artery vasospasm originate, positive study rates are in the range of 30%.[16] The 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,[19, 20] although 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.[21] Among 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.[18] Patients 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.[4] In a study of 59 patients followed for an average of 5.9 years, 93% experienced rest angina and 19% sustained frank MIs.[23] However, there were no cardiac deaths.

Long-term survival is believed to be good, especially in patients who tolerate calcium antagonists and avoid smoking.[18] Predictors of poorer prognosis include the presence of concurrent coronary atherosclerosis,[24] ongoing 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.[27] Persistent 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:

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.[30]

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.[31] Notably, 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.[4] In 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,[15] which 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.[14] Spasm 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).

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,[5] but 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.[35] During 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.[39] A 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:

Relative contraindications include the following:

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.[44] Early experience with cilostazol has been positive but limited;[45] additional 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.[47] The results for surgical revascularization have been variable, but overall, bypass surgery appears to provide clinical benefit to less than 50% of patients.[24] The 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.[48]

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.

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

Clinical Context:  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)

Clinical Context:  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)

Clinical Context:  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.

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.

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

Clinical Context:  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)

Clinical Context:  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)

Clinical Context:  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)

Clinical Context:  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.

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.

What is coronary artery vasospasm?What is the pathophysiology of coronary artery vasospasm?What is the epidemiology of coronary artery vasospasm in the US?What is the global prevalence of coronary artery vasospasm?What are the demographic predilections in the prevalence of coronary artery vasospasm?What is the prognosis of coronary artery vasospasm?What is the Japanese Coronary Spasm Association (JCSA) risk score coronary artery vasospasm?What are complications of coronary artery vasospasm?What are the signs and symptoms of coronary artery vasospasm?How is coronary artery vasospasm differentiated from atherosclerotic coronary disease?What are the differential diagnoses for Coronary Artery Vasospasm?What is the role of lab studies in the workup of coronary artery vasospasm?What is the role of perfusion imaging and echocardiography in the workup of coronary artery vasospasm?What is the role of electrocardiography and monitoring in the workup of coronary artery vasospasm?What is the role of angiography in the workup of coronary artery vasospasm?What is the role of provocative testing in the workup of coronary artery vasospasm?What are contraindications to provocative testing in the evaluation of coronary artery vasospasm?What is included in the inial management of coronary artery vasospasm?What is included in pharmacologic therapy for coronary artery vasospasm?What is the role of percutaneous and surgical revascularization in the management of coronary artery vasospasm?What are the mainstays of medical therapy for coronary artery vasospasm?Which medications in the drug class Calcium Channel Blockers are used in the treatment of Coronary Artery Vasospasm?Which medications in the drug class Nitrates, Angina are used in the treatment of Coronary Artery Vasospasm?

Author

Stanley S Wang, JD, MD, MPH, Clinical Cardiologist, Austin Heart South; Director of Legislative Affairs, Austin Heart; Medical Director, Sleep Disorders Center at Heart Hospital of Austin; Assistant Professor of Medicine (Adjunct), University of North Carolina School of Medicine

Disclosure: Nothing to disclose.

Specialty Editors

Yasmine S Ali, MD, FACC, FACP, MSCI, President, LastSky Writing, LLC; Assistant Clinical Professor of Medicine, Vanderbilt University School of Medicine

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: MCG Health, LLC; LastSky Writing, LLC; Philips Healthcare; Cardiac Profiles, Inc.; BBN Cardio Therapeutics.

Chief Editor

Eric H Yang, MD, Associate Professor of Medicine, Director of Cardiac Catherization Laboratory and Interventional Cardiology, Mayo Clinic Arizona

Disclosure: Nothing to disclose.

Acknowledgements

Steven J Compton, MD, FACC, FACP Director of Cardiac Electrophysiology, Alaska Heart Institute, Providence and Alaska Regional Hospitals

Steven J Compton, MD, FACC, FACP is a member of the following medical societies: Alaska State Medical Association, American College of Cardiology, American College of Physicians, American Heart Association, American Medical Association, and Heart Rhythm Society

Disclosure: Nothing to disclose.

Gregory J Dehmer, MD Director, Division of Cardiology, Scott & White Healthcare; Professor of Medicine, Texas A&M Health Science Center College of Medicine

Gregory J Dehmer, MD is a member of the following medical societies: American College of Cardiology, American Heart Association, Society for Cardiac Angiography and Interventions, and Society of Cardiac Angiography and Interventions

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Reference Salary Employment

References

  1. Prinzmetal M, Kennamer R, Merliss R, Wada T, Bor N. Angina pectoris. I. A variant form of angina pectoris; preliminary report. Am J Med. 1959 Sep. 27:375-88. [View Abstract]
  2. Maseri A, Severi S, Nes MD, et al. "Variant" angina: one aspect of a continuous spectrum of vasospastic myocardial ischemia. Pathogenetic mechanisms, estimated incidence and clinical and coronary arteriographic findings in 138 patients. Am J Cardiol. 1978 Dec. 42(6):1019-35. [View Abstract]
  3. Yasue H, Omote S, Takizawa A, Nagao M, Miwa K, Tanaka S. Circadian variation of exercise capacity in patients with Prinzmetal's variant angina: role of exercise-induced coronary arterial spasm. Circulation. 1979 May. 59(5):938-48. [View Abstract]
  4. Yasue H, Nakagawa H, Itoh T, Harada E, Mizuno Y. Coronary artery spasm--clinical features, diagnosis, pathogenesis, and treatment. J Cardiol. 2008 Feb. 51(1):2-17. [View Abstract]
  5. Ajani AE, Yan BP. The mystery of coronary artery spasm. Heart Lung Circ. 2007 Feb. 16(1):10-5. [View Abstract]
  6. Yasue H, Touyama M, Kato H, Tanaka S, Akiyama F. Prinzmetal's variant form of angina as a manifestation of alpha-adrenergic receptor-mediated coronary artery spasm: documentation by coronary arteriography. Am Heart J. 1976 Feb. 91(2):148-55. [View Abstract]
  7. Yasue H, Horio Y, Nakamura N, et al. Induction of coronary artery spasm by acetylcholine in patients with variant angina: possible role of the parasympathetic nervous system in the pathogenesis of coronary artery spasm. Circulation. 1986 Nov. 74(5):955-63. [View Abstract]
  8. Kaneda H, Taguchi J, Kuwada Y, et al. Coronary artery spasm and the polymorphisms of the endothelial nitric oxide synthase gene. Circ J. 2006 Apr. 70(4):409-13. [View Abstract]
  9. Nishijima T, Nakayama M, Yoshimura M, et al. The endothelial nitric oxide synthase gene -786T/C polymorphism is a predictive factor for reattacks of coronary spasm. Pharmacogenet Genomics. 2007 Aug. 17(8):581-7. [View Abstract]
  10. Egashira K, Katsuda Y, Mohri M, et al. Basal release of endothelium-derived nitric oxide at site of spasm in patients with variant angina. J Am Coll Cardiol. 1996 May. 27(6):1444-9. [View Abstract]
  11. Nakano T, Osanai T, Tomita H, Sekimata M, Homma Y, Okumura K. Enhanced activity of variant phospholipase C-delta1 protein (R257H) detected in patients with coronary artery spasm. Circulation. 2002 Apr 30. 105(17):2024-9. [View Abstract]
  12. Stern S, Bayes de Luna A. Coronary artery spasm: a 2009 update. Circulation. 2009 May 12. 119(18):2531-4. [View Abstract]
  13. Adlam D, Azeem T, Ali T, Gershlick A. Is there a role for provocation testing to diagnose coronary artery spasm?. Int J Cardiol. 2005 Jun 22. 102(1):1-7. [View Abstract]
  14. Harding MB, Leithe ME, Mark DB, et al. Ergonovine maleate testing during cardiac catheterization: a 10-year perspective in 3,447 patients without significant coronary artery disease or Prinzmetal's variant angina. J Am Coll Cardiol. 1992 Jul. 20(1):107-11. [View Abstract]
  15. Bertrand ME, LaBlanche JM, et al. Frequency of provoked coronary arterial spasm in 1089 consecutive patients undergoing coronary arteriography. Circulation. 1982 Jun. 65(7):1299-306. [View Abstract]
  16. Sueda S, Kohno H, Fukuda H, et al. Frequency of provoked coronary spasms in patients undergoing coronary arteriography using a spasm provocation test via intracoronary administration of ergonovine. Angiology. 2004 Jul-Aug. 55(4):403-11. [View Abstract]
  17. Sueda S, Kohno H, Oshita A, et al. Coronary abnormal response has increased in Japanese patients: Analysis of 17 years' spasm provocation tests in 2093 cases. J Cardiol. 2010 May. 55(3):354-361. [View Abstract]
  18. Bory M, Pierron F, Panagides D, Bonnet JL, Yvorra S, Desfossez L. Coronary artery spasm in patients with normal or near normal coronary arteries. Long-term follow-up of 277 patients. Eur Heart J. 1996 Jul. 17(7):1015-21. [View Abstract]
  19. Mayer S, Hillis LD. Prinzmetal's variant angina. Clin Cardiol. 1998 Apr. 21(4):243-6. [View Abstract]
  20. Selzer A, Langston M, Ruggeroli C, Cohn K. Clinical syndrome of variant angina with normal coronary arteriogram. N Engl J Med. 1976 Dec 9. 295(24):1343-7. [View Abstract]
  21. Rha SW, Park JY, Ryu SK, et al. TCT-437 The impact of gender difference on angiographic characteristics during intracoronary acetylcholine provocation test in Korean patients. J Am Coll Cardiol. 2012 Oct 23. 60(17 Supp B):B124.
  22. Pristipino C, Beltrame JF, Finocchiaro ML, et al. Major racial differences in coronary constrictor response between Japanese and Caucasians with recent myocardial infarction. Circulation. 2000 Mar 14. 101(10):1102-8. [View Abstract]
  23. Bott-Silverman C, Heupler FA Jr. Natural history of pure coronary artery spasm in patients treated medically. J Am Coll Cardiol. 1983 Aug. 2(2):200-5. [View Abstract]
  24. Mishra PK. Variations in presentation and various options in management of variant angina. Eur J Cardiothorac Surg. 2006 May. 29(5):748-59. [View Abstract]
  25. Yasue H, Takizawa A, Nagao M, et al. Long-term prognosis for patients with variant angina and influential factors. Circulation. 1988 Jul. 78(1):1-9. [View Abstract]
  26. Onaka H, Hirota Y, Shimada S, et al. Prognostic significance of the pattern of multivessel spasm in patients with variant angina. Jpn Circ J. 1999 Jul. 63(7):509-13. [View Abstract]
  27. Ong P, Athanasiadis A, Borgulya G, Voehringer M, Sechtem U. 3-year follow-up of patients with coronary artery spasm as cause of acute coronary syndrome: the CASPAR (coronary artery spasm in patients with acute coronary syndrome) study follow-up. J Am Coll Cardiol. 2011 Jan 11. 57(2):147-52. [View Abstract]
  28. Takagi Y, Takahashi J, Yasuda S, et al. Prognostic stratification of patients with vasospastic angina: a comprehensive clinical risk score developed by the Japanese Coronary Spasm Association. J Am Coll Cardiol. 2013 Sep 24. 62(13):1144-53. [View Abstract]
  29. Kobayashi N, Hata N, Shimura T, et al. Characteristics of patients with cardiac arrest caused by coronary vasospasm. Circ J. 2013. 77(3):673-8. [View Abstract]
  30. Hendriks ML, Allaart CP, Bronzwaer JG, Res JJ, de Cock CC. Recurrent ventricular fibrillation caused by coronary artery spasm leading to implantable cardioverter defibrillator implantation. Europace. 2008 Dec. 10(12):1456-7. [View Abstract]
  31. Figueras J, Cortadellas J, Gil CP, Domingo E, Soler JS. Comparison of clinical and angiographic features and longterm follow-up events between patients with variant angina and patients with ST elevation myocardial infarction. Int J Cardiol. 2006 Aug 10. 111(2):256-62. [View Abstract]
  32. Previtali M, Klersy C, Salerno JA, et al. Ventricular tachyarrhythmias in Prinzmetal's variant angina: clinical significance and relation to the degree and time course of S-T segment elevation. Am J Cardiol. 1983 Jul. 52(1):19-25. [View Abstract]
  33. Rosamond W. Are migraine and coronary heart disease associated? An epidemiologic review. Headache. 2004 May. 44 Suppl 1:S5-12. [View Abstract]
  34. Hirano Y, Uehara H, Nakamura H, et al. Diagnosis of vasospastic angina: comparison of hyperventilation and cold-pressor stress echocardiography, hyperventilation and cold-pressor stress coronary angiography, and coronary angiography with intracoronary injection of acetylcholine. Int J Cardiol. 2007 Apr 4. 116(3):331-7. [View Abstract]
  35. Miwa K, Kambara H, Kawai C, Murakami T. Two electrocardiographic patterns with or without transient T-wave inversion during recovery periods of variant anginal attacks. Jpn Circ J. 1983 Dec. 47(12):1415-22. [View Abstract]
  36. Miwa K, Murakami T, Kambara H, Kawai C. U wave inversion during attacks of variant angina. Br Heart J. 1983 Oct. 50(4):378-82. [View Abstract]
  37. Im SI, Rha SW, Choi BG, et al. TCT-436 Association of myocardial bridge and acetylcholine dose response in patients with vasospastic angina. J Am Coll Cardiol. 2012 Oct. 60(17 Supp B):B124.
  38. Sueda S, Miyoshi T, Sasaki Y, Sakaue T, Habara H, Kohno H. Gender differences in sensitivity of acetylcholine and ergonovine to coronary spasm provocation test. Heart Vessels. 2016 Mar. 31(3):322-9. [View Abstract]
  39. Sueda S, Kohno H, Fukuda H, et al. Clinical impact of selective spasm provocation tests: comparisons between acetylcholine and ergonovine in 1508 examinations. Coron Artery Dis. 2004 Dec. 15(8):491-7. [View Abstract]
  40. Im SI, Choi BG, Choi SY, et al. TCT-433 Impact of beta-blocker on angiographic and clinical parameters during intracoronary acetylcholine provocation test. J Am Coll Cardiol. 2012 Oct 23. 60(17 Supp B):B123.
  41. Jang HJ, Kim TH, Kwon SW, et al. Left ventricular end diastolic pressure for detection of intracoronary ergonovine-induced myocardial ischemia. Herz. 2016 Jun. 41(4):320-5. [View Abstract]
  42. Piao ZH, Jeong MH, Li Y, et al, for the Other Korea Acute Myocardial Infarction Registry (KAMIR) Investigators. Benefit of statin therapy in patients with coronary spasm-induced acute myocardial infarction. J Cardiol. 2016 Jul. 68(1):7-12. [View Abstract]
  43. Taylor SH. Usefulness of amlodipine for angina pectoris. Am J Cardiol. 1994 Jan 27. 73(3):28A-33A. [View Abstract]
  44. Krishnan U, Win W, Fisher M. First report of the successful use of bosentan in refractory vasospastic angina. Cardiology. 2010. 116(1):26-8. [View Abstract]
  45. Yoo SY, Song SG, Lee JH, et al. Efficacy of cilostazol on uncontrolled coronary vasospastic angina: a pilot study. Cardiovasc Ther. 2013 Jun. 31(3):179-85. [View Abstract]
  46. Choi BG, Jeon SY, Rha SW, et al. Impact of renin-angiotensin system inhibitors on long-term clinical outcomes of patients with coronary artery spasm. J Am Heart Assoc. 2016 Jul 21. 5(7):[View Abstract]
  47. Khitri A, Jayasuriya S, Habibzadeh MR, Movahed MR. Coronary stenting in patients with medically resistant vasospasm. Rev Cardiovasc Med. 2010 Fall. 11(4):264-70. [View Abstract]
  48. Bertrand ME, Lablanche JM, Rousseau MF, Warembourg HH Jr, Stankowtak C, Soots G. Surgical treatment of variant angina: use of plexectomy with aortocoronary bypass. Circulation. 1980 May. 61(5):877-82. [View Abstract]
  49. Lee EM, Choi MH, Seo HS, et al. Impact of vasomotion type on prognosis of coronary artery spasm induced by acetylcholine provocation test of left coronary artery. Atherosclerosis. 2017 Feb. 257:195-200. [View Abstract]
  50. Kim H, Cho SH, Cho KI, Kim BJ, Im SI, Heo JH. Blunted heart rate recovery is associated with coronary artery spasm in patients with suspected vasospastic angina. Clin Hypertens. 2017. 23:24. [View Abstract]
  51. Montone RA, Niccoli G, Fracassi F, et al. Patients with acute myocardial infarction and non-obstructive coronary arteries: safety and prognostic relevance of invasive coronary provocative tests. Eur Heart J. 2018 Jan 7. 39(2):91-8. [View Abstract]
  52. Kondo T, Terada K. Coronary-artery vasospasm. N Engl J Med. 2017 Jun 22. 376(25):e52. [View Abstract]

This electrocardiogram (ECG) is from a patient who underwent urgent cardiac catheterization, which revealed diffuse severe coronary spasm (most marked in the left circumflex system) without any fixed obstructive lesions. Severe left ventricular wall motion abnormalities were present, involving the anterior and inferior segments. A question of so-called takotsubo cardiomyopathy (left ventricular apical ballooning syndrome) is also raised (see Bybee et al. Systematic review: transient left ventricular apical ballooning: a syndrome that mimics ST-segment elevation myocardial infarction. Ann Int Med 2004:141:858-65). The latter is most often reported in postmenopausal, middle-aged to elderly women in the context of acute emotional stress and may cause ST elevations acutely with subsequent T wave inversions. A cocaine-induced cardiomyopathy (possibly related to coronary vasospasm) is a consideration but was excluded here. Myocarditis may also be associated with this type of ECG and the cardiomyopathic findings shown here. No fixed obstructive epicardial coronary lesions were detected by coronary arteriography. The findings in this ECG include low-amplitude QRS complexes in the limb leads (with an indeterminate QRS axis), loss of normal precordial R wave progression (leads V1-V3), and prominent anterior/lateral T wave inversions. Image courtesy of http://ecg.bidmc.harvard.edu .