Introduction

Vasospastic angina, variant angina, or Prinzmetal angina is a known clinical entity characterized by chest pain at rest with transient ischemic electrocardiographic changes in the ST segment, with a prompt response to nitrates. These symptoms are attributed to coronary arteries spasm.[1][2]

Etiology

Diffuse or segmental spasm in the coronary arteries causes Printzmetal angina. There is a decrease in blood supply to the myocardium, generating symptoms like chest pain. The coronary arteries may develop spasm as a result of exposure to cold weather, exercise, or a substance that promotes vasoconstriction, such as alpha-agonists (pseudoephedrine and oxymetazoline). Recreational drug use, for example, cocaine use, is associated with the development of vasospastic angina, especially when used concurrently with cigarette smoking.[3]

Epidemiology

The incidence or prevalence of Prinzmetal angina is still unknown. The reason for this is the possible misdiagnosis or confusion with other conditions that might present with the same symptoms, and further evaluation is not sought. Some studies show that the Japanese population has an increased risk of developing vasospastic angina when compared with the Caucasian population. The difference between the Japanese population and the Caucasian population is that the former has a three times higher risk. The average age of presentation of vasospastic angina is around the fifth decade of life. Females are more likely within the Japanese population to experience vasospastic angina.[4][5]

Pathophysiology

The underlying mechanism in the development of coronary artery spasm is multifactorial. One mechanism that might generate the spasm is an increased reactivity of the vessels to vasoconstrictive stimuli and subsequent high-grade stenosis in a segment of the coronary or diffusely, creating low coronary flow and, with this, myocardial injury due to ischemia. The etiology of the hyperreactivity of the coronary vessels is unclear but could be related to endothelial dysfunction and primary smooth muscle cells of the coronary vessels that might have impaired regulatory mechanism for vasoconstriction and vasodilation. Balances within the sympathetic and parasympathetic tone are also an important factor that regulates flow in the coronaries. Imbalance in this system can predispose exaggerated vasoconstriction under normal circumstances and during exposuretof acetylcholine and methacholine.[6][7]

Risk Factors

Typical cardiovascular risk factors have not directly been associated with the presence of vasospastic angina, except for cigarette smoking and inflammatory states determined by high hs-CRP levels. A metabolic disorder, such as insulin resistance, has also been associated with vasospastic angina.

Precipitating Factors

Multiple triggers have been associated with the development of vasospastic angina.

Several drugs, such as ephedrine and sumatriptan, can cause typical chest pain due to coronary spasm. Recreational drugs like cocaine, amphetamines, alcohol, and marijuana are also possible precipitating factors.

Environmental factors such as cold water can cause spasms in the coronaries. Valsalva maneuver, hyperventilation, and coronary manipulation through cardiac catheterization can also produce hyperreactivity of the coronaries.

History and Physical

Patients with vasospastic angina present with the following:

• A chronic pattern of episodes of chest pain at rest that last 5 to 15 minutes, from midnight to early morning.
• Pain decreases with the use of short-acting nitrates.
• Typically, these patients have ischemic ST-segment changes on an electrocardiogram during an episode of chest discomfort, which returns to baseline on symptom resolution.
• Typically, the chest pain is not triggered by exertion or alleviated with rest, as is typical of angina.
• Often, the patient is younger with few or no classical cardiovascular risk factors.

Other vasospastic disorders, like Raynaud phenomenon or migraine, can be associated with this subset of patients. Patients may complain of recent or past episodes with some symptom-free periods.

Evaluation

Clinical history and an electrocardiographic recording during a spontaneous episode are major elements in the clinical diagnosis of vasospastic angina.[8][9][10]

The international study group of coronary vasomotion disorders, known as COVADIS, created a diagnostic criterion to determine the presence of Prinzmetal angina. These include:

1. Clinical response to nitrates during a spontaneous anginal episode. 
2. Transient electrocardiographic changes with concern for ischemia during a spontaneous anginal episode. These include ST-segment elevation or depression = 0.1 mV or new U waves.
3. Evidence of coronary vasospasm during angiography. 

Because of the lack of electrocardiographic evidence, further studies might be considered. The initial workup should be to evaluate the possibility of fixed obstructive coronary artery disease.

If appropriate, a noninvasive stress test can be performed. Most of these patients will have a normal stress test or be negative for ischemia. However, a subgroup of patients (10% to 30%) can have exercise-induced spasms with electrocardiographic changes for ischemia that are not specific for vasospastic angina versus fixed coronary obstruction. This group of patients should undergo coronary catheterization to determine obstructive coronary disease. Also, a negative stress test with suspicion for coronary obstruction should be evaluated with cardiac catheterization.

During cardiac catheterization, coronary spasms can be visualized spontaneously or under drug induction.

Ergonovine, acetylcholine, and hyperventilation can be used in the catheterization laboratory in an attempt to confirm the diagnosis of coronary vasospasm. These tests are warranted only when the diagnosis of vasospastic angina is suspected but not firmly established. At present, provocative pharmacologic testing is not frequently performed.

An ambulatory electrocardiogram can also be used to record transient electrocardiographic changes during acute spontaneous events.

It is important to remember that when a patient has acute chest pain or angina, the focus is to evaluate for possible fixed coronary obstruction.

Treatment / Management

Treatment is focused on decreasing episodes of angina and preventing complications like myocardial injury and arrhythmia. Lifestyle modifications should be encouraged, especially smoking cessation. This is one of the critical interventions in reducing the frequency of episodes. Avoid medications or drugs that can trigger coronary vasospasm, for example, cocaine, marijuana, and ephedrine-based products. It is also important.[11][10]

Pharmacological Therapy

• Calcium antagonists play an important role in the management of vasospastic angina. It is a first-line treatment due to its vasodilating effect in the coronary vasculature. Calcium antagonist is effective in alleviating symptoms in 90% of patients. Moreover, one study demonstrated that the use of calcium channel blocker therapy was an independent predictor of myocardial infarct-free survival in vasospastic angina patients.
• The use of a long-acting calcium antagonist is recommended to be given at night, as the episodes of vasospasm are more frequent at midnight and early in the morning. A high dose of long-acting calcium antagonists like diltiazem, amlodipine, nifedipine, or verapamil is recommended, and titration should be done on an individual basis with an adequate response and minimal side effects. In some cases, the use of a two-calcium antagonist (dihydropyridine and non-dihydropyridine) can be effective in patients with poor response to one agent.
• The use of long-acting nitrates is also effective in preventing vasospastic events, but chronic use is associated with tolerance. In patients on calcium aantagonistswithout an adequate response to treatment, long-acting nitrates can be added.
• Nicorandil, a nitrate and K-channel activator, also suppresses vasospastic attacks.
• The use of beta-blockers, especially those with nonselective adrenoceptor blocking effects, should be avoided because these drugs can aggravate the symptoms.
• Treatment with guanethidine, clonidine, or cilostazol has been reported to be beneficial in patients taking calcium channel antagonists. However, these drugs are not well-studied in this setting.
• The use of fluvastatin is effective in preventing coronary spasm and may exert benefits via endothelial nitric oxide or direct effects on the vascular smooth muscle.

Differential Diagnosis

The differential diagnosis includes the following. 

• Acute pericarditis
• Angina pectoris
• Anxiety disorders
• Aortic dissection
• Cocaine toxicity
• Esophageal spasms
• Gastroesophageal reflux disease 
• Myocardial infarction
• Panic disorder
• Unstable angina

Complications

Complications include the following:

• Arrhythmia
• Sudden death
• Myocardial infarction

Enhancing Healthcare Team Outcomes

An interprofessional approach to Prinzmetal angina is recommended.

Prinzmetal angina is not an easy diagnosis to make and may require tests, including cardiac catheterization with provocation. An interprofessional team of healthcare workers best manages the disorder.

In general, the long-term prognosis for vasospastic angina is good if patients get adequate treatment. Overall, 75% of patients can be free of myocardial infarction at 5 years. The factor that might independently determine the free infarct survival includes the presence and severity of pre-existing coronary stenosis, the number of vessels with hyperreactivity or spasms, and the use of calcium channel blockers. Half of the patients with angina will have persistent symptoms.

Half of the patients with vasospastic angina will have recurring symptoms, even during treatment, within the first 3 years after onset. The development of arrhythmias with episodes of vasospastic angina has been associated with a poor prognosis, with the main associationbeing with ventricular fibrillation and sudden cardiac death.[12][13]

Review Questions

• Access free multiple choice questions on this topic.
• Click here for a simplified version.
• Comment on this article.

References

1.

Picard F, Sayah N, Spagnoli V, Adjedj J, Varenne O. Vasospastic angina: A literature review of current evidence. Arch Cardiovasc Dis. 2019 Jan;112(1):44-55. [PubMed: 30197243]

2.

Cenko E, Bergami M, Varotti E, Bugiardini R. Vasospastic Angina and its Relationship with the Coronary Microcirculation. Curr Pharm Des. 2018;24(25):2906-2910. [PubMed: 29938613]

3.

Swarup S, Patibandla S, Grossman SA. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Jul 4, 2023. Coronary Artery Vasospasm. [PubMed: 29261899]

4.

Kim HL, Lee SH, Kim J, Kim HJ, Lim WH, Seo JB, Chung WY, Kim SH, Zo JH, Kim MA, Lee JY. Incidence and Risk Factors Associated With Hospitalization for Variant Angina in Korea. Medicine (Baltimore). 2016 Mar;95(13):e3237. [PMC free article: PMC4998556] [PubMed: 27043695]

5.

Sueda S, Kohno H. Differential incidence and type of spasm according to coronary arterial location. Coron Artery Dis. 2016 Jun;27(4):273-6. [PubMed: 26901444]

6.

Castelein T, Tavernier R, Muyldermans L. Prinzmetal Angina can kill twice. Acta Cardiol. 2018 Jan 03;73(6):592-593. [PubMed: 29298643]

7.

Kishimoto N, Kato M, Nakanishi Y, Hasegawa A, Momota Y. Recurrent Coronary Artery Spasm Induced by Vasopressors During Two Operations in the Same Patient Under General Anesthesia. Anesth Prog. 2018 Spring;65(1):44-49. [PMC free article: PMC5841482] [PubMed: 29509526]

8.

Sueda S, Kohno H, Ochi T, Uraoka T. Overview of the Acetylcholine Spasm Provocation Test. Clin Cardiol. 2015 Jul;38(7):430-8. [PMC free article: PMC6711022] [PubMed: 26175183]

9.

Halna du Fretay X, Blanchard-Lemoine B, Schnebert B, Viossat J. [Variant angina: what to think in 2011?]. Ann Cardiol Angeiol (Paris). 2011 Dec;60(6):317-23. [PubMed: 22055431]

10.

American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina). ACC/AHA guidelines for the management of patients with unstable angina and non-ST segment elevation myocardial infarction: executive summary and recommendations. Catheter Cardiovasc Interv. 2000 Dec;51(4):505-21. [PubMed: 11108692]

11.

Sueda S, Izoe Y, Kohno H, Fukuda H, Uraoka T. Need for documentation of guidelines for coronary artery spasm: an investigation by questionnaire in Japan. Circ J. 2005 Nov;69(11):1333-7. [PubMed: 16247207]

12.

Kim HL, Kim J, Kim HJ, Lim WH, Lee JY. Incidence and factors associated with mortality in 2,476 patients with variant angina in Korea. Sci Rep. 2017 Apr 06;7:46031. [PMC free article: PMC5382575] [PubMed: 28383055]

13.

Cho SW, Park TK, Gwag HB, Lim AY, Oh MS, Lee DH, Seong CS, Yang JH, Song YB, Hahn JY, Choi JH, Lee SH, Gwon HC, Choi SH. Clinical Outcomes of Vasospastic Angina Patients Presenting With Acute Coronary Syndrome. J Am Heart Assoc. 2016 Nov 16;5(11) [PMC free article: PMC5210370] [PubMed: 27852592]

Disclosure: Mary Rodriguez Ziccardi declares no relevant financial relationships with ineligible companies.

Disclosure: Jason Hatcher declares no relevant financial relationships with ineligible companies.