Prinzmetal's angina
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Synonyms and keywords: Variant angina; angina inversa; vasospastic angina

# Overview
Vasospastic angina was previously referred to as Prinzmetal or variant angina. Vasospastic angina is a syndrome typically consisting of angina (cardiac chest pain) at rest that occurs in periodic cycles. Vasospastic angina is caused by vasospasm, a narrowing of the coronary arteries caused by contraction of the smooth muscle tissue in the vessel walls rather than fixed narrowings of the coronary arteries due to atherosclerosis (buildup of fatty plaque and hardening of the arteries).

# Historical Perspective
Printzmetal's angina was first described as a variant form in 1959 by the  American cardiologist Dr. Myron Prinzmetal.
It was first documented by coronary arteriography in 1973.

# Classification

## Classification by Location
Coronary artery spasm can be classified according to the location of vasoconstriction:

### Focal coronary spasm
Focal coronary spasm is limited to a localized segment of the coronary artery.

### Multifocal coronary spasm
Multifocal coronary spasm involves several localized segments of the same coronary artery.

### Multivessel coronary spasm
Multivessel coronary spasm involves several coronary arteries.

## Classification by Clinical Syndrome
Coronary artery vasospasm can be classified into either spontaneous or iatrogenic.

### Spontaneous
- A subtype of epicardial coronary artery spasm is known as Prinzmetal's angina.  Prinzmetal's angina is characterized by the sudden onset of chest pain at rest with ST elevation on ECG. Click here for more information about Prinzmetal's angina.

### Iatrogenic
- Coronary vasospasm can be secondary to PCI.  Click here for more information about PCI-induced coronary vasospasm.

# Pathophysiology
- The exact pathogenesis of coronary vasospasm is not well understood, but some causes and contributing factors are known.
- Coronary spasm can be explained by a hyperreactivity to vasoconstrictor stimuli that results from endothelial dysfunction or primary hyperreactivity of smooth muscle cells.  Vasoconstrictor stimuli include changes in the autonomic nervous system, inflammation, and calcium availability in the myocardium.  Dysfunction of the autonomic nervous system and endothelial dysfunction can lead to chronic intermittent vasospasm, which usually occurs where a fixed, non-calcified stenosis is located.
- A significant group of patients with variant angina have underlying obstructive coronary artery disease.

# Epidemiology and Demographics
- Incidence or prevalence of Prinzmetal angina is still unknown.
- Young patients with fewer cardiovascular risk factors (with the exception of smoking) are at a higher risk for coronary vasospasm, as are noncalcified lesions and eccentric plaques.
- Some studies show that the Japanese population has an increased risk of developing vasospastic angina when compared with Caucasian populations.
- The average age of presentation of vasospastic angina is around the fifth decade of life.

# Risk Factors
- Smoking
- Genetic factors and insulin resistance
There is some evidence that genetic factors and insulin resistance are associated with vasospastic angina
- There is some evidence that genetic factors and insulin resistance are associated with vasospastic angina
- Patients with vasospastic angina are often younger and exhibit fewer classic cardiovascular risk factors (except smoking).
- Vasospastic angina may be associated with other vasospastic disorders, such as Raynaud's phenomenon and migraine headache or its treatment .
- A history of drug abuse such as cocaine may be present.
- Hyperventilation can precipitate attacks of vasospastic angina .

# Differential diagnosis
Vasopastic angina must be differentiated from other diseases that cause chest pain, view chest pain differential diagnosis for more.

# Natural History, Complications and Prognosis
- There are no findings characteristic for vasospastic angina. However, during an episode, tachycardia, hypertension, diaphoresis, and a gallop rhythm may be present.
- Bradycardia and hypotension can be observed if the sinus nodal, atrioventricular nodal, and right ventricular arteries are involved during proximal right coronary artery vasospasm.
- If left untreated, 25% of patients with prinzmetal angina may progress to develop myocardial infarction and life threatening arrhythmias.
- Two-thirds of patients have concurrent atherosclerosis of a major coronary artery. This is often mild or not in proportion to the degree of symptoms.
- Coronary vasospasm can lead to life-threatening arrhythmias, depending on the vessel that is involved.
Right coronary artery spasm can lead to sinus arrest or complete heart block.
Left anterior descending artery spasm can lead to ventricular tachycardia or fibrillation.
Multivessel spasm can also lead to ventricular arrhythmias.
- Right coronary artery spasm can lead to sinus arrest or complete heart block.
- Left anterior descending artery spasm can lead to ventricular tachycardia or fibrillation.
- Multivessel spasm can also lead to ventricular arrhythmias.
- Once detected, aggressive management of coronary vasospasm is necessary, as vasospasm can provoke fatal arrhythmias or myocardial infarction.
- Patients who have coronary artery disease in addition to coronary vasospasm have an overall worse prognosis.
- The prognosis of vasospastic angina depends on the extent of underlying  coronary artery disease (CAD).

# History and Symptoms
While the symptoms of chronic stable angina occur with exertion, the symptoms of Prinzmetal's angina typically occur at rest.  The symptoms may occur reproducibly at certain times of the day or night. In the classic description, the symptoms often come on at night.
Characteristic pain features for vasospastic angina include:
- Discomfort better describes the spasms than pain. Other common ways to describe the episodes: squeezing, tightness, pressure, constriction, strangling, burning, heart burn, fullness in the chest, a band-like sensation, knot in the center of the chest, lump in the throat, ache, and heavy weight on chest.
- Each episode is typically gradual in onset and offset.
- There is no change in the quality of pain with respiration or position.
- The patient may have some difficulty in describing the location of the pain, although the substernal location is common. Radiation to the neck, throat, lower jaw, teeth, upper extremity, or shoulder is common.
- During each episode, symptoms of nausea, sweating, dizziness, dyspnea, and palpitations may be present.

# Diagnosis
- Physicians should suspect vasospasm if ST segment elevation is detected in patients experiencing angina, and if the ECG completely returns to baseline upon resolution of symptoms.
These changes are usually transient (less than 15 minutes) and may occur in multiple leads of a 12-lead ECG.
- These changes are usually transient (less than 15 minutes) and may occur in multiple leads of a 12-lead ECG.
- Patients who develop cardiac chest pain are generally treated empirically as an "acute coronary syndrome" patient, and are generally evaluated with serial testing of  cardiac enzymes such as creatine kinase isoenzymes or troponin I or T. These may in some cases be abnormal or  positive, as coronary spasm can lead to  myocardial necrosis in severe cases.
- The gold standard test is coronary angiography including the administration  of provocative agents, such as acetylcholine or ergonovine, via the intracoronary route.   The definitive diagnosis of coronary vasospasm is made angiographically by demonstration of reduction of luminal diameter in a discrete segment of the vessel, which is proven to be reversible.  Reversibility may be demonstrated by previous or subsequent enlargement of luminal diameter, often after the administration of intracoronary vasodilators.
- It should be noted that two-thirds of patients with Prinzmetal's angina have concurrent atherosclerosis of a major coronary artery, but the extent  of the atherosclerosis is generally  mild, and the symptoms are out of proportion to the extent of disease. Depending on the local protocol, provocative testing may utilize either ergonovine, methylergonovine or acetylcholine. Exaggerated spasm is diagnostic of Prinzmetal's angina.  Care should be taken to have nitrates and calcium channel agents readily available to reverse the spasm.

# Electrocardiogram
Prinzmetal's angina is associated with transmural injury and ST segment elevation rather than ST segment depression.
The most important ECG change during a focal proximal coronary spasm is in around 50% of cases the appearance of peaked and symmetrical T wave that is followed, if the spasm persist, by progressive ST-segment elevation that last for a few minutes, and later progressively resolve.
The most frequent ECG changes associated with ST-segment elevation are:
- Increased height of the R wave
- Coincident S-wave diminution
- Upsloping TQ in many cases
- Alternans of the elevated ST-segment
- Negative T wave deepness
In 20% of cases.
- In 20% of cases.

# Treatment
Prinzmetal angina typically responds to  nitrates and calcium channel blockers.  Patients with multivessel spasm, refractory spasm, spasm that results in sudden death may benefit from dual calcium channel blocker therapy.
- Calcium channel blockers:
Generally, well tolerated and can aid with hypertension control.
A combination of dihyropyridine and non-dihydropyridine calcium channel blockers should be used in patients with refractory coronary vasospasm, particularly if it has resulted in ventricular arrhythmia.
Multiple calcium channel blockers may be required in patients with refractory or multi-vessel spasm.
A patient who has suffered ventricular tachycardia or ventricular fibrillation due to spontaneous vasospasm (not due to acute infarction) should also likely undergo ICD placement.
Diltiazem 240-360 mg PO qd
Verapamil 240-480 mg PO qd
Nifedipine XL 60-120 mg PO qd
Nicardipine 40-160 mg PO qd
- Generally, well tolerated and can aid with hypertension control.
- A combination of dihyropyridine and non-dihydropyridine calcium channel blockers should be used in patients with refractory coronary vasospasm, particularly if it has resulted in ventricular arrhythmia.
- Multiple calcium channel blockers may be required in patients with refractory or multi-vessel spasm.
- A patient who has suffered ventricular tachycardia or ventricular fibrillation due to spontaneous vasospasm (not due to acute infarction) should also likely undergo ICD placement.
Diltiazem 240-360 mg PO qd
Verapamil 240-480 mg PO qd
Nifedipine XL 60-120 mg PO qd
Nicardipine 40-160 mg PO qd
- Diltiazem 240-360 mg PO qd
- Verapamil 240-480 mg PO qd
- Nifedipine XL 60-120 mg PO qd
- Nicardipine 40-160 mg PO qd
- Long-acting nitrates:
Generally, well tolerated and can aid with hypertension control.
Isosorbide mononitrate (Imdur) 60-240 mg PO qd
Isosorbide dinitrate (Isordil) 20-40 mg PO tid
- Generally, well tolerated and can aid with hypertension control.
Isosorbide mononitrate (Imdur) 60-240 mg PO qd
Isosorbide dinitrate (Isordil) 20-40 mg PO tid
- Isosorbide mononitrate (Imdur) 60-240 mg PO qd
- Isosorbide dinitrate (Isordil) 20-40 mg PO tid
- Statins:
May improve endothelial dysfunction and lower inflammation.  A small, randomized control trial showed that fluvastatin 30 mg daily reduced rates of vasospasm.  Statins also provide benefits of LDL lowering and plaque stabilization.
Fluvastatin 30 mg PO qd
- May improve endothelial dysfunction and lower inflammation.  A small, randomized control trial showed that fluvastatin 30 mg daily reduced rates of vasospasm.  Statins also provide benefits of LDL lowering and plaque stabilization.
Fluvastatin 30 mg PO qd
- Fluvastatin 30 mg PO qd
- Hormone replacement therapy:
This remains controversial, particularly due to the risk of concern of increased cardiac events.
- This remains controversial, particularly due to the risk of concern of increased cardiac events.
- Smoking cessation:
Should be emphasized in all patients, as it contains non-cardiac benefits as well.  It lowers future event rates of vasospasm and acute coronary syndromes.
- Should be emphasized in all patients, as it contains non-cardiac benefits as well.  It lowers future event rates of vasospasm and acute coronary syndromes.
- Percutaneous coronary intervention:
While resolution occurs following PTCA/stenting in some cases, spasm can propagate to a new location, proximal or distal to the stented site.
PCI is not commonly indicated for patients with focal spasm and minimal obstructive disease. However, it may be helpful if significant obstructive coronary disease is present and thought to be a potential trigger for focal spasm.
- While resolution occurs following PTCA/stenting in some cases, spasm can propagate to a new location, proximal or distal to the stented site.
- PCI is not commonly indicated for patients with focal spasm and minimal obstructive disease. However, it may be helpful if significant obstructive coronary disease is present and thought to be a potential trigger for focal spasm.
- ICD placement:
As described above for patients with ventricular tachycardia or ventricular fibrillation due to spontaneous coronary vasospasm without other provocation that may be treated.
- As described above for patients with ventricular tachycardia or ventricular fibrillation due to spontaneous coronary vasospasm without other provocation that may be treated.
- Surgical autonomic denervation/plexectomy:
Can be useful in cases that are refractory to medical therapy or percutaneous intervention.  It's reserved only for the most refractory cases.
- Can be useful in cases that are refractory to medical therapy or percutaneous intervention.  It's reserved only for the most refractory cases.

## Making a Selection
- Treatment of chronic vasospasm should be performed in this order (step-wise fashion): medical therapy, percutaneous intervention, and then, surgery.

### Medical Therapy
- Risk factor modification (smoking cessation, lipid control) is recommended for all patients.
- Begin pharmacologic therapy with oral calcium channel blockers (diltiazem, verapamil, nifedipine) and/or nitrates.  If monotherapy is ineffective, begin combination therapy which is generally well tolerated (10% of patients may require 2 calcium channel blockers). If refractory or multi-vessel spasm is present, multiple CCBs are likely necessary, as these patients are at high risk for ventricular arrhythmias. Alpha blockers may also be useful if there is incomplete response to CCB and nitrates.
- Due to their ability to improve endothelial function, statins should be considered for vasospasm.
- Certain medications should be avoided: nonselective beta blockers, aspirin, and sumatriptan can exacerbate vasospasm. Hormone replacement therapy (estrogen-progestin) have been associated with an increase in cardiac events (HERS-II and WHI trials) and should also be avoided.

### Percutaneous Intervention (PCI)
- If vasospasm has a clearly definable area that is associated with coronary artery disease and refractory to medical therapy, stenting may be an effective strategy. However, stenting may simply propagate the spasm to a proximal or distal location in the vessel.
- Following any PCI, adjunctive medical therapy must be continued.
- Resolution of symptoms, ECG changes, and angiographic vasospasm is usually apparent within one minute post-procedure.
- Refractory spasm occurring during PCI is likely secondary to dissection, which requires stenting unless the artery is small and the patient is clinically stable.
- The role of revascularization in the setting of multivessel vasospasm is uncertain.

### Surgery
- In the rare circumstance that a patient is refractory to pharmacologic and percutaneous therapy, surgical denervation and plexectomy have been effective.

# 2014 AHA/ACC Guideline for the Management of Patients With NonST-Elevation Acute Coronary Syndromes (DO NOT EDIT) 

## Recommendations for Prizmental's angina

# ESC Guidelines for Diagnostic Tests in Suspected Vasospastic Angina (DO NOT EDIT)

# ESC Guidelines for Pharmacological Therapy of Vasospastic Angina (DO NOT EDIT)