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Variant angina
Variant angina
Variant angina
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Variant angina
Other namesPrinzmetal's angina, vasospastic angina[1]
Illustration depicting angina
SpecialtyCardiology Edit this on Wikidata

Variant angina, also known as Prinzmetal angina, vasospastic angina, angina inversa, coronary vessel spasm, or coronary artery vasospasm,[2] is a syndrome typically consisting of angina (cardiac chest pain). Variant angina differs from stable angina in that it commonly occurs in individuals who are at rest or even asleep, whereas stable angina is generally triggered by exertion or intense exercise. Variant angina is caused by vasospasm, a narrowing of the coronary arteries due to contraction of the heart's smooth muscle tissue in the vessel walls.[3] In comparison, stable angina is caused by the permanent occlusion of these vessels by atherosclerosis, which is the buildup of fatty plaque and hardening of the arteries.[4]

Signs and symptoms

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In contrast to those with angina secondary to atherosclerosis, people with variant angina are generally younger and have fewer risk factors for coronary artery disease with the exception of smoking, which is a common and significant risk factor for both types of angina. Affected people usually have repeated episodes of unexplained (e.g., in the absence of exertion and occurring at sleep or in the early morning) chest pain, tightness in throat, chest pressure, light-headedness, excessive sweating, and/or reduced exercise tolerance that, unlike atherosclerosis-related angina, typically does not progress to myocardial infarction (heart attack). Unlike cases of atherosclerosis-related stable angina, these symptoms are often unrelated to exertion and occur in night or early morning.[4] However, individuals with atherosclerosis-related unstable angina may similarly exhibit night to early morning hour symptoms that are unrelated to exertion.[5]

Cardiac examination of individuals with variant angina is usually normal in the absence of current symptoms.[2][6] Two-thirds of these individuals do have concurrent atherosclerosis of a major coronary artery, but this is often mild or not in proportion to the degree of their symptoms. Persons who have atherosclerosis-based occlusion that is ≥70% in a single coronary artery or that involves multiple coronary arteries are predisposed to develop a variant angina form that has a poorer prognosis than most other forms of this disorder.[7] In these individuals but also in a small percentage of individuals without appreciable atherosclerosis of their coronary arteries, attacks of coronary artery spasm can have far more serious presentations such as fainting, shock, and cardiac arrest. Typically, these presentations reflect the development of a heart attack and/or a potentially lethal heart arrhythmia; they require immediate medical intervention as well as consideration for the presence of, and specific treatment regimens for, their disorder.[8][9]

Variant angina should be suspected by a cardiologist when a) an individual's symptoms occur at rest or during sleep; b) an individual's symptoms occur in clusters; c) an individual with a history of angina does not develop angina during treadmill stress testing (variant angina is exercise tolerant); d) an individual with a history of angina shows no evidence of other forms of cardiac disease; and/or e) an individual without features of coronary artery atherosclerotic heart disease has a history of unexplained fainting.[4][8]

Complaints of chest pain should be immediately checked for an abnormal electrocardiogram (ECG). ECG changes compatible but not indicative of variant angina include elevations rather than depressions of the ST segment or an elevated ST segment plus a widening of the R wave to create a single, broad QRS complex peak termed the "monophasic curve".[4] Associated with these ECG changes, there may be small elevations in the blood levels of cardiac damage marker enzymes, especially during long attacks. Some individuals with otherwise typical variant angina may show depressions, rather than elevations in the ST segments of their ECGs during angina pain; they may also show new U waves on ECGs during angina attacks.[4]

A significant percentage of those with variant angina have symptom-free episodes of coronary artery spasm. These episodes may be far more frequent than expected, cause myocardial ischemia (i.e. insufficient blood flow to portions of the heart), and be accompanied by potentially serious abnormalities in the rhythm of heart beats, i.e. arrhythmias. The only evidence of the presence of totally asymptomatic variant angina would be detection of diagnostic changes on fortuitously conducted ECGs.[4][9]

Risk factors

[edit]

The intake of certain agents have been reported to trigger an attack of variant angina. These agents include:

In addition, hyperventilation and virtually any stressful emotional or physical (e.g. cold exposure) event that is suspected of causing significant rises in the blood levels of catecholamines may trigger variant angina.[4][7]

Mechanism

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The mechanism that causes such intense vasospasm, as to cause a clinically significant narrowing of the coronary arteries is so far unknown, but there are three relevant hypotheses:

  1. Enhanced contractility of coronary vascular smooth muscle due to reduced nitric oxide bioavailability caused by a defect in the endothelial nitric oxide synthetase enzyme which leads to endothelial function abnormalities.[7][10][11]
    • Acetylcholine is normally released by the parasympathetic nervous system (PSNS) at rest, and causes dilation of the coronary arteries.[12] While acetylcholine induces vasoconstriction of vascular smooth muscle cells through a direct mechanism, acetylcholine also stimulates endothelial cells to produce nitric oxide (NO). NO then diffuses out of the endothelial cells, stimulating relaxation of the nearby smooth muscle cells. In healthy arterial walls, the overall indirect relaxation induced by acetylcholine (via nitric oxide) is of greater effect than any contraction that is induced.
    • When the endothelium is dysfunctional, stimulation with acetylcholine will fail to produce, or produce very little, nitric oxide. Thus, acetylcholine released by the PSNS at rest will simply cause contraction of the vascular smooth muscle.
  2. Thromboxane A2, serotonin, histamine, and endothelin are vasoconstrictor which activated platelets release and/or cause to be released. Abnormal platelet activation (e.g. by lipoprotein(a) interference with fibrinolysis by competing with plasminogen to thereby impair fibrinolysis and promote platelet activation) results in the release of these mediators and coronary vasospasm.[13][7][14]
  3. Increased alpha-adrenergic receptor activity in epicardial coronary arteries or the excessive release of the "flight or fight" catecholamines (e.g. norepinephrine) that activate these receptors may lead to coronary vasospasm.[4][7][15]

Other factors thought to be associated with the development of variant angina include: intrinsic hypercontractility of coronary artery smooth muscle; existence of significant atherosclerotic coronary artery disease; and reduced activity of the parasympathetic nervous system (which normally functions to dilate blood vessels).[6][7]

Diagnosis

[edit]
Prinzmetal angina

Although variant angina has been documented in approximately 2% to 10% of angina patients, it can be overlooked by cardiologists who stop further evaluations after ruling out typical angina. Individuals who develop cardiac chest pain are generally treated empirically as an "acute coronary syndrome", and are immediately tested for elevations in their blood levels of enzymes such as creatine kinase isoenzymes or troponin that are markers for cardiac damage. They are also tested by ECG which may suggest variant angina if it shows elevations in the ST segment or an elevated ST segment plus a widening of the R wave during symptoms that are triggered by a provocative agent (e.g. ergonovine or acetylcholine). The electrocardiogram may show depressions rather than elevations in ST segments but in all diagnosable cases clinical symptoms should be promptly relieved and ECG changes should be promptly reversed by rapidly acting sublingual or intravenous nitroglycerin. However, the gold standard for diagnosing variant angina is to visualize coronary arteries by angiography before and after injection of a provocative agent such as ergonovine, methylergonovine or acetylcholine to precipitate an attack of vasospasm. A positive test to these inducing agents is defined as a ≥90% (some experts require lesser, e.g. ≥70%) constriction of involved arteries. Typically, these constrictions are fully reversed by rapidly acting nitroglycerin.[4][16]

Individuals with variant angina may have many undocumented episodes of symptom-free coronary artery spasm that are associated with poor blood flow to portions of the heart and subsequent irregular and potentially serious heart arrhythmias. Accordingly, individuals with variant angina should be intermittently evaluated for this using long-term ambulatory cardiac monitoring.[4][9]

Prevention

[edit]

Numerous methods are recommended to avoid attacks of variant angina. Affected individuals should not smoke tobacco products. Smoke cessation significantly reduces the incidence of patient-reported variant angina attacks.[7] They should also avoid any trigger known to them to trigger these attacks such as emotional distress, hyperventilation, unnecessary exposure to cold, and early morning exertion. And, they should avoid any of the recreational and therapeutic drugs listed in the above signs and symptoms and risk factors sections as well as blockers of beta receptors such as propranolol which may theoretically worsen vasospasm by inhibiting beta-2 adrenergic receptor's vasodilation effect mediated by these receptors' naturally occurring stimulator i.e. epinephrine. In addition, aspirin should be used with caution and at low doses since at high doses it inhibits the production of the naturally occurring vasodilator, prostacyclin.[4][16]

Treatment

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See also: angina § treatment

Acute attacks

[edit]

During acute attacks, individuals typically respond well to fast-acting sublingual, intravenous, or spray nitroglycerin formulations. The onset of symptom relief in response to intravenous administration, which is used in more severe attacks of angina, occurs almost immediately while sublingual formulations of it act within 1–5 minutes. Spray formulations also require ~1–5 minutes to act.[17]

Maintenance

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As maintenance therapy, sublingual nitroglycerin tablets can be taken 3-5 min before conducting activity that causes angina by the small percentage of patients who experience angina infrequently and only when doing such activity.[17] For most affected individuals, antianginals are used as maintenance therapy to avoid attacks of variant angina. Calcium channel blockers of the dihydropyridine class (e.g. nifedipine, amlodipine)[18] or non-dihydropyridine class (e.g. verapamil, diltiazem) are regarded as first-line drugs to avoid angina attacks. Long-acting nitroglycerins such as isosorbide dinitrate or intermittent use of short-acting nitroglycerin (to treat acute symptoms) may be added to the calcium channel blocker regimen in individuals responding sub-optimally to the channel blockers.

However, individuals commonly develop tolerance, or resistance, to the efficacy of continuously used long-acting nitroglycerin formulations. One strategy to avoid this is to schedule nitroglycerin-free periods of between 12 and 14 hours between doses of long-acting nitroglycerin formulations.[17] Individuals whose symptoms are poorly controlled by a calcium blocker may benefit from addition of a long-acting nitroglycerin and/or a second calcium channel blocker of a different class than the blocker already in use. Nevertheless, about 20% of individuals fail to respond adequately to the two-drug calcium blocker plus long-acting nitroglycerin regimen. If these individuals have significant permanent occlusion of their coronary arteries, they may benefit by stenting their occluded arteries. However, coronary stenting is contraindicated in drug-refractory individuals who do not have significant organic occlusion of their coronary arteries.[16]

For drug-refractory individuals without blockage, other, less fully investigated drugs may provide symptom relief. Statins, e.g. fluvastatin, while not evaluated in large-scale double-blind studies, are reportedly helpful in reducing variant angina attacks and should be considered in patients when calcium channel blockers and nitroglycerin fail to achieve good results.[4] There is also interest in using rho-kinase inhibitors, such as fasudil (available in Japan and China but not the USA),[16] and blocker of alpha-1 adrenergic receptors such as prazosin (which when activated cause vasodilation) but studies are needed to support their clinical utility in variant angina.[4][6]

Emergency

[edit]

Individuals with certain severe complications of variant angina require immediate therapy. Individuals presenting with potentially lethal irregularities in the rhythm of their heart beating or a history of episodic fainting spells due to such arrhythmias require implantation of an internal defibrillator and/or cardiac pacemaker to stop such arrhythmias and restore normal heart beating.[8][9] Other rare but severe complications of variant angina, e. g. myocardial infarction, severe congestive heart failure, and cardiogenic shock require the same immediate medical interventions that are used for other causes of these extremis conditions. In all of these emergency cases, percutaneous coronary intervention to stent areas where coronary arteries evidence spasm is only useful in individuals who have concomitant coronary atherosclerosis on coronary angiogram.[4]

Prognosis

[edit]

Most individuals with variant angina have a favorable prognosis provided they are maintained on calcium channel blockers and/or long-acting nitrates; five-year survival rates in this group are estimated as over 90%.[4][19] The Japanese Coronary Spasm Association established a clinical risk scoring system to predict outcomes for variant angina. Seven major factors (i.e. history of out of hospital cardiac arrest [score = 4]; smoking, angina at rest, physically obstructive coronary artery disease, and spasm in multiple coronary arteries [score = 2]; and presence of ST segment elevations on ECG and history of using beta blockers [score = 1]) where assigned the indicated scores. Individuals with scores of 0 to 2, 3 to 5, and ≥6 experienced an incidence of a major cardiovascular event in 2.5, 7.0, and 13.0% of cases.[20]

History

[edit]

Dr. William Heberden is credited with being the first to describe in a 1768 publication the occurrence of chest pain attacks (i.e. angina pectoris) that appeared due to pathologically occluded coronary arteries. These attacks were triggered by exercise or other forms of exertion and relieved by rest and nitroglycerin. In 1959, Dr. Myron Prinzmetal described a type of angina that differed from the classic cases of Heberden angina in that it commonly occurred in the absence of exercise or exertion. Indeed, it often woke patients from their normal sleep. This variant angina differed from the classical angina described by Dr. Heberden in that it appeared due to episodic vasospasm of coronary arteries that were typically not occluded by pathological processes such as atherosclerosis, emboli, or spontaneous dissection (i.e. tears in the walls of coronary arteries).[4][19][13] Variant angina had been described twice in the 1930s by other authors[14][21] and was referred to as cardiac syndrome X (CSX) by Kemp in 1973, in reference to patients with exercise-induced angina who nonetheless had normal coronary angiograms.[22] CSX is now termed microvascular angina, i.e. angina caused by disease of the heart's small arteries.[4]

Some key features of variant angina are chest pain that is concurrently associated with elevations in the ST segment on electrocardiography recordings, that often occurs during the late evening or early morning in individuals who are at rest, doing non-strenuous activities, or asleep, and that is not associated with permanent occlusions of their coronary vessels. The disorder seems to occur more often in women than men, has a particularly high incidence in Japanese males as well as females, and affects individuals who may smoke tobacco products but exhibit few other cardiovascular risk factors.[4][23] However, individuals exhibiting angina symptoms that are associated with depressions in their electrocardiogram ST segments, that are triggered by exertion, and/or who have atherosclerotic coronary artery disease are still considered to have variant angina if their symptoms are caused by coronary artery spasms. Finally, rare cases may exhibit symptom-free coronary artery spasm that is nonetheless associated with cardiac muscle ischemia (i.e. restricted blood flow and poor oxygenation) along with concurrent ischemic electrocardiographic changes. The term vasospastic angina is sometimes used to include all of these atypical cases with the more typical cases of variant angina.[4] Here, variant angina is taken to include typical and atypical cases.

For a portion of patients, variant angina may be a manifestation of a more generalized episodic smooth muscle-contractile disorder such as migraine, Raynaud's phenomenon, or aspirin-induced asthma.[6] Variant angina is also the major complication of eosinophilic coronary periarteritis, an extremely rare disorder caused by extensive eosinophilic infiltration of the adventitia and periadventitia, i.e. the soft tissues, surrounding the coronary arteries.[24][25] Variant angina also differs from the Kounis syndrome (also termed allergic acute coronary syndrome) in which coronary artery constriction and symptoms are caused by allergic or strong immune reactions to a drug or other substance. Treatment of the Kounis syndrome very much differs from that for variant angina.[26]

See also

[edit]
  • Angina pectoris: the most common form of coronary artery spasm; it is due to atherosclerosis.
  • Kounis syndrome: coronary artery spasm due to an allergic reaction.
  • Eosinophilic coronary periarteritis: a very rare form of coronary artery spasm; it is due to non-allergic infiltration of coronary arteries by eosinophils.
  • Myocardial bridge, a common congenital heart anomaly in which one of the coronary arteries tunnels through the heart muscle (myocardium) itself.

References

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Variant angina

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from Grokipedia
Variant angina, also known as Prinzmetal's angina or vasospastic angina, is a rare form of caused by sudden spasms in the that temporarily reduce blood flow to the heart muscle, typically occurring at rest rather than during physical exertion. Unlike stable , which results from fixed blockages due to , variant angina arises primarily from of the in artery walls, often without significant underlying plaque buildup. These episodes usually happen between midnight and early morning, lasting 5 to 15 minutes, and can be triggered by factors such as smoking, cold exposure, emotional stress, or certain medications like . Symptoms of variant angina include severe chest discomfort or pressure, often described as squeezing or tightness, which may radiate to the arms, neck, jaw, or back, and is sometimes accompanied by , sweating, or . The pain typically resolves spontaneously or with rest and , but recurrent attacks follow a predictable pattern, distinguishing it from other types. Although not usually fatal, untreated variant angina can lead to serious complications like heart rhythm abnormalities, heart attacks, or sudden cardiac death due to prolonged spasms. Causes and Risk Factors involve coronary artery spasms, potentially linked to endothelial dysfunction or hypersensitivity of vascular smooth muscle, with higher prevalence in individuals with migraines, Raynaud's phenomenon, or a history of smoking. It affects both men and women equally and is more common in Japanese populations, accounting for about 2% of all angina cases, though it is not strongly hereditary. Illicit drugs like cocaine or marijuana can provoke spasms, emphasizing the role of lifestyle in its onset. Diagnosis often involves (ECG) during an episode, which may show transient ST-segment elevation, alongside coronary angiography to visualize spasms, sometimes provoked by agents like . Ambulatory ECG monitoring or helps confirm the rest-related pattern. Treatment primarily relies on medications such as (e.g., ) and long-acting nitrates to prevent spasms, with statins like sometimes used for additional benefit. Lifestyle modifications, including and avoiding triggers, are essential, and in severe cases, procedures like stenting may be considered if fixed blockages coexist. With proper , the prognosis is generally favorable, allowing most patients to lead normal lives.

Background and Epidemiology

Definition and Classification

Variant angina, also known as Prinzmetal's angina, is a form of pectoris caused by transient coronary artery spasm that leads to myocardial ischemia, typically occurring at rest in the absence of fixed obstructive . This condition is characterized by episodes of reduced blood flow to the heart muscle due to focal or diffuse of the , often without underlying . It was first described in 1959 by Myron Prinzmetal and colleagues, who identified it as a distinct clinical entity and named it "variant angina" to highlight its differences from traditional exertional . Common synonyms for variant angina include vasospastic angina, coronary spastic angina, and angina inversa. In terms of classification, it is regarded as a subtype of unstable angina because of its unpredictable rest-onset episodes and potential for acute presentation, yet it is mechanistically distinct from the typical unstable angina driven by atherosclerotic plaque rupture or thrombosis. Unlike stable angina, which is provoked by physical exertion or increased myocardial demand, variant angina arises primarily from supply-side issues related to vasospasm. Furthermore, variant angina is included within the spectrum of non-obstructive coronary artery disease, where coronary angiography typically reveals no significant stenoses, emphasizing its vasospastic etiology over structural blockages. This classification underscores its unique position among ischemic heart syndromes, separating it from demand ischemia or obstructive pathologies.

Epidemiology

Variant angina, also known as vasospastic angina or Prinzmetal angina, accounts for a small but significant proportion of angina cases globally, with estimates suggesting it represents approximately 2-4% of all patients undergoing evaluation for suspected myocardial ischemia in Western populations, though exact figures remain uncertain due to diagnostic challenges. In contrast, prevalence is notably higher in East Asian countries, particularly , where it affects up to 20-25% of patients with angina symptoms and non-obstructive coronary arteries, compared to around 5-10% in Caucasian cohorts. Incidence rates in the general population are not well-established, but studies indicate it may contribute to 30-40% of cases of with normal coronary angiograms, highlighting its underrecognized role in acute events. Demographically, variant angina predominantly affects middle-aged adults, with peak onset between 40 and 70 years, though presentations in the fifth decade are common. Gender distribution varies by region and study, but overall, it shows a slight male predominance (approximately 60-65% in large cohorts), potentially linked to higher rates among affected men. The condition is strongly associated with , present in up to 66% of cases in certain groups, and shows correlations with comorbidities such as and Raynaud's phenomenon, which may share vasoreactive mechanisms. Geographic variations underscore a higher burden in , where genetic factors like the RNF213 p.R4810K (rs112735431) confer increased susceptibility, with odds ratios for vasospastic reaching 2-6 in carriers compared to non-carriers. This is found in 1.5-2.5% of Japanese and Korean populations but is rare in Europeans, contributing to the observed ethnic disparities. Recent studies from 2023-2024 confirm stable incidence patterns but emphasize underdiagnosis, as up to 40-50% of patients with and normal coronary angiograms on standard imaging may harbor undetected without provocation testing.

Clinical Presentation

Signs and Symptoms

The primary symptom of variant angina is severe or discomfort, often described as squeezing, tightness, or pressure in the chest, typically occurring at rest and lasting 5 to . This pain frequently arises between midnight and early morning, such as during sleep or periods of relaxation. The may radiate to the arms, neck, jaw, back, shoulders, or upper abdomen, and is commonly accompanied by diaphoresis (sweating), , , or (shortness of breath). Episodes often follow a cyclical pattern, clustering over days or weeks, and can be provoked by factors such as , exposure to , or emotional stress, though they are not induced by physical . Atypical presentations during attacks may include , syncope (fainting), or ventricular arrhythmias, which can arise due to the intensity of the . Unlike exertional , the pain in variant angina is unrelated to , tends to resolve spontaneously, or responds rapidly to .

Risk Factors

Variant angina, also known as Prinzmetal's angina, is influenced by a combination of modifiable and non-modifiable risk factors that predispose individuals to coronary artery spasms. Modifiable risk factors play a significant role in triggering vasospasm, with smoking emerging as the strongest association, exhibiting a dose-dependent relationship where heavier tobacco use correlates with higher incidence rates. Recreational drug use, particularly cocaine and marijuana, further heightens risk by promoting endothelial dysfunction and acute spasms, often leading to more severe episodes. States prone to hyperventilation, such as those associated with anxiety or stress, can exacerbate susceptibility by altering respiratory patterns and autonomic tone, thereby facilitating spasm induction. Non-modifiable risk factors include demographic and comorbid elements that elevate baseline vulnerability. The condition typically manifests between ages 40 and 60, distinguishing it from age-related atherosclerotic that peaks later in life. Co-existing conditions such as variant migraine and Raynaud's phenomenon are strongly linked, likely due to shared vascular reactivity pathways. Additional associations include , which may impair vascular relaxation and contribute to spasm propensity. High exhibits a mild association, unlike its dominant role in atherosclerotic , with lipid abnormalities potentially amplifying spasm risk without overt plaque buildup. Environmental exposures, such as cold temperatures or allergens, can provoke episodes in susceptible individuals by inducing . Cohort studies underscore the impact of addressing modifiable factors, particularly , which has been shown to reduce the incidence and severity of variant angina by improving endothelial function and decreasing frequency, with enhancements observed even in short-term follow-ups. Recent research highlights genetic predispositions, such as variants in the RNF213 gene, as conferring increased risk for vasospastic angina, though detailed mechanisms are explored elsewhere.

Pathophysiology

Mechanism of Coronary Vasospasm

Variant angina, also known as vasospastic angina, is characterized by transient, focal, or diffuse spasms of the epicardial that lead to partial or complete vessel occlusion, thereby reducing myocardial blood flow and inducing ischemia without reliance on underlying atherosclerotic plaques. These spasms typically occur at rest and are reversible upon resolution, distinguishing them from chronic ischemic conditions. A central contributor to these spasms is , which diminishes (NO) bioavailability, thereby failing to counteract vasoconstrictive forces. This imbalance promotes unopposed action of potent vasoconstrictors such as endothelin-1, a released by endothelial cells that binds to receptors on vascular to induce contraction, and , a derived from that enhances platelet aggregation and further amplifies . In patients with variant angina, this endothelial impairment can manifest even in non-spastic segments of the coronary vasculature, underscoring a systemic abnormality. Hyperreactivity of vascular smooth muscle cells exacerbates the propensity for , primarily through heightened Rho-kinase activity, which inhibits myosin light chain and increases the sensitivity of contractile apparatus to calcium ions. This mechanism allows for intense contraction even at relatively low intracellular calcium levels, independent of elevated calcium influx alone. Such hypercontractility is a hallmark of the response in variant angina, enabling rapid and severe narrowing of the arterial lumen. Various triggers can initiate or propagate these spasms, including alpha-adrenergic stimulation from catecholamines like noradrenaline, which activates receptors on to promote constriction; serotonin release from aggregated platelets, acting via 5-HT2A receptors to heighten vasoreactivity; and , which generates that degrade NO and facilitate platelet activation, thereby sustaining the spasm. These events often occur at sites of minor atherosclerotic irregularities or arterial bifurcations, where local may sensitize the and . In contrast to fixed stenoses caused by atherosclerotic plaques, which impose persistent mechanical obstruction and demand increased myocardial oxygen supply during exertion, coronary spasms in variant angina are dynamic and fully reversible, frequently resolving spontaneously or with vasodilators like nitrates, and they provoke ischemia at rest without proportional increases in oxygen demand. This reversibility highlights the functional nature of the obstruction, often affecting angiographically normal arteries.

Genetic and Molecular Factors

Variant angina, also known as vasospastic angina, has been linked to specific genetic variants that predispose individuals to . A key genetic factor is the RNF213 p.R4810K polymorphism (rs112735431), an East Asian-specific rare deleterious variant, which is associated with a 2.34-fold increased (95% CI, 1.99-2.74) of vasospastic angina, reaching genome-wide significance in large-scale genetic association studies. This variant promotes vascular cell dysfunction, particularly in younger males (OR: 3.06; 95% CI, 2.24-4.19), and homozygous carriers face an even higher (OR: 18.34; 95% CI, 5.15-65.22). The polymorphism's prevalence is higher in East Asian populations (1.5-2.5% in Japanese and Korean cohorts), contributing to the geographic variation in disease susceptibility. Other genetic contributors include variants in the NOS3 gene, which encodes endothelial . Polymorphisms such as T-786C and Glu298Asp in NOS3 reduce production, impairing and increasing susceptibility to coronary spasm by exacerbating . At the molecular level, upregulation of inflammatory cytokines like interleukin-6 (IL-6) plays a critical role; the IL-6 promoter -634C/G polymorphism is associated with coronary vasospastic angina, with the G allele independently increasing risk in populations. Susceptible individuals also exhibit elevated oxidative stress markers, such as nitrotyrosine and malondialdehyde-modified , which aggravate and hyperreactivity. Epigenetic modifications further modulate these genetic risks. Smoking, a major trigger for variant angina, induces DNA methylation changes that exacerbate endothelial dysfunction, as demonstrated in models where cigarette smoke extract alters methylation patterns leading to apoptotic and inflammatory responses in endothelial cells. Recent studies from 2023 to 2025 have advanced understanding by linking these factors to clinical outcomes. A 2023 nationwide family study in Sweden revealed familial clustering of vasospastic angina, underscoring heritable genetic contributions beyond sporadic cases (adjusted hazard ratio for siblings: 2.09; 95% CI, 1.12-3.89). The 2024 JAMA Cardiology analysis of RNF213 variants not only confirmed risk elevation but also associated carriers with higher spasm severity and fatal myocardial infarction rates (HR: 2.71; 95% CI, 1.57-4.65). These insights suggest potential for genotype-guided therapies to mitigate spasm severity.

Diagnosis

Initial Evaluation

The initial evaluation of a suspected of having variant angina begins with a detailed history to identify characteristic patterns of symptoms. typically report recurrent episodes of occurring at rest, often lasting 5 to 15 minutes and predominantly between midnight and early morning. These episodes may be triggered by emotional stress, exposure to cold, or , and they usually resolve promptly with sublingual . A history of associated vasospastic conditions, such as Raynaud phenomenon or , can further support suspicion. Physical examination is often unremarkable in the absence of an active , as findings between attacks are typically normal in patients without significant underlying . During an acute , however, patients may exhibit signs of distress, including , , or diaphoresis. Initial laboratory tests focus on excluding and assessing contributing factors. Cardiac levels are measured serially to rule out acute injury, as they are usually normal in uncomplicated but may elevate if ischemia progresses to . A is obtained to evaluate for coexisting atherosclerotic risk, while serum magnesium levels are checked due to associations between hypomagnesemia and coronary spasm susceptibility. Resting (ECG) is performed promptly; it is often normal or shows nonspecific ST-T changes at baseline, but capturing an may reveal transient ST-segment elevation. Variant angina should be suspected in patients presenting with recurrent rest angina and normal exercise stress testing results, particularly if symptoms do not align with exertional patterns of stable . Risk stratification uses the Japanese Coronary Spasm Association (JCSA) risk score, which categorizes patients into low, intermediate, or high risk based on clinical features such as history of out-of-hospital , multivessel , and nitrate-unresponsive symptoms, to guide urgency of further assessment.

Confirmatory Tests

Confirmatory tests for variant angina, also known as vasospastic angina, aim to demonstrate transient , typically through electrocardiographic changes or inducible spasm during invasive procedures. plays a central role, with 12-lead ECG during an acute episode revealing transient ST-segment elevation (focal or global, ≥0.1 mV) that resolves after the attack, often accompanied by and reciprocal in opposing leads. Holter monitoring is particularly useful for capturing spontaneous episodes in patients with infrequent symptoms, documenting ischemic ST changes during rest-associated events. Coronary remains the gold standard for confirmation, frequently showing normal or near-normal arteries at rest but enabling provocation testing to induce . Intracoronary administration of (20–100 μg) or ergonovine (20–64 μg) during reproduces symptoms, ECG changes, and ≥90% luminal narrowing, with positivity rates of 80–90% in suspected cases. tends to provoke diffuse or distal , while ergonovine elicits more focal ones, though is increasingly favored for its higher sensitivity (90–94%) and specificity (99%). Non-invasive alternatives support diagnosis by excluding fixed coronary lesions or paradoxically provoking spasm. effectively rules out obstructive disease prior to invasive testing, providing anatomical reassurance in low-risk patients. Exercise stress ECG, while not routine, may induce in up to 50% of cases, sometimes paradoxically during recovery rather than peak exertion, manifesting as . The 2023 Japanese Circulation Society (JCS)/Cardiovascular Imaging and Therapeutics (CVIT)/Japanese Association for (JCC) guidelines recommend provocation testing (Class I) in patients with high clinical suspicion, normal resting , and low bleeding risk, prioritizing over ergonovine due to its superior safety profile and efficacy in daily-life spasm simulation. The 2024 (ESC) Guidelines for Chronic Coronary Syndromes similarly recommend invasive vasoreactivity testing with intracoronary or ergonovine (Class I, Level B) during coronary for patients with suspected vasospastic angina and no obstructive . Testing is advised against in the acute phase post-myocardial infarction or when severe complications are anticipated. Safety during provocation requires continuous ECG monitoring for arrhythmias, with intracoronary routes preferred over intravenous to minimize systemic effects; overall major complication rates are low (≈5.5%), though transient issues like or occur. Contraindications include severe bronchial asthma (due to acetylcholine's bronchospastic potential) and recent .

Management

Prevention and Lifestyle Modifications

Smoking cessation is a cornerstone of prevention for variant angina, as tobacco use is a major trigger for . Quitting smoking significantly decreases the frequency of anginal episodes by eliminating a key endothelial disruptor and inducer. Counseling, , and support programs are emphasized to facilitate long-term abstinence, with observational data indicating substantial reductions in occurrence among former smokers. Avoiding identifiable triggers is essential to minimize episode risk. Patients should limit exposure to cold temperatures, which can provoke through sympathetic activation, by dressing warmly during outdoor activities. techniques, such as or relaxation exercises, help mitigate emotional or physical stressors that exacerbate . Additionally, recreational drugs like and ergotamine derivatives must be strictly avoided, as they directly induce coronary . Dietary modifications support vascular health and counter potential deficiencies linked to . Consuming magnesium-rich foods, including nuts, leafy greens, and whole grains, addresses observed hypomagnesemia that may worsen spasm susceptibility, with evidence suggesting benefits for symptom control. Alcohol intake should be moderated to prevent magnesium depletion and dehydration-related triggers, while excessive is best limited due to its potential to heighten . Regular moderate exercise promotes endothelial function and overall cardiovascular resilience, reducing the likelihood of spasms through improved bioavailability. Activities like walking or for 30 minutes most days are recommended, but intense workouts in cold environments should be avoided to prevent trigger activation. The 2023 Japanese Circulation Society guidelines endorse lifestyle modifications as a first-line adjunct to , with observational studies demonstrating reductions in episode frequency through combined interventions like and trigger avoidance.

Pharmacological Treatment

The mainstay of long-term pharmacological treatment for variant angina, also known as vasospastic angina, is (CCBs), which relax vascular and prevent recurrent . Dihydropyridine CCBs such as amlodipine (5-10 mg daily) and non-dihydropyridine CCBs such as (120-360 mg daily, often administered at bedtime due to nocturnal symptom predominance) are first-line options, demonstrating 80-90% efficacy in reducing angina attacks based on multicenter surveys of , , and verapamil. These agents are recommended by the Japanese Circulation Society (JCS) 2023 guidelines as Class I therapy for prophylaxis (Level B evidence). Long-acting nitrates, such as (20-40 mg twice daily) or (20-40 mg daily), provide additional and are used as adjuncts when CCB monotherapy is insufficient, particularly in patients with frequent episodes. Sublingual (0.3-0.6 mg as needed) can be employed for symptoms alongside chronic . For refractory cases, with a CCB and long-acting nitrate is effective, as endorsed in the JCS 2023 guidelines, though tolerance may develop, necessitating nitrate-free intervals. Beta-blockers should be avoided, as they can exacerbate by unopposed alpha-adrenergic activity. In patients with concomitant , low-dose aspirin (81 mg daily) may be added cautiously to mitigate thrombotic risk, though it carries potential to worsen spasm and is not routinely recommended without fixed stenoses. Statins, such as or , serve as adjuncts for endothelial protection, reducing by improving vascular function independent of lipid-lowering effects. For severe, refractory variant angina in , the JCS 2023 guidelines support rho-kinase inhibitors like (typically 30-60 mg three times daily intravenously or orally in specialized settings) as an emerging option, targeting hypercontractility in vascular with demonstrated suppression of acetylcholine-induced spasm. All therapies require monitoring for side effects, including , , and reflex with dihydropyridines.

Acute and Emergency Management

The acute management of variant angina focuses on rapidly reversing to alleviate and prevent complications such as arrhythmias or myocardial ischemia. The first-line intervention for an ongoing attack is sublingual , administered at a dose of 0.3-0.6 mg every 5 minutes for up to three doses, which provides rapid and symptom relief in most cases. If symptoms persist after initial doses, intravenous infusion should be initiated, starting at 5-10 mcg/min and titrated upward to achieve hemodynamic stability while monitoring for . For severe or refractory attacks in a setting, intravenous , such as verapamil at 5-10 mg administered over 2 minutes, or , can be used to directly counteract the , often in combination with infusion. Adjunctive therapies include sulfate (2-5 mg IV) for persistent pain unresponsive to nitrates and supplemental oxygen if the patient is hypoxic (oxygen saturation <90%). Serial electrocardiograms (ECGs) are essential to differentiate transient ST-segment elevation from ST-elevation (STEMI), guiding further evaluation such as urgent coronary if infarction is suspected. In emergency scenarios involving arrhythmias or hemodynamic instability, immediate resuscitation takes precedence; direct current (DC) cardioversion is indicated for ventricular tachycardia or fibrillation, while antiarrhythmic agents like lidocaine (1-1.5 mg/kg IV bolus) may be used for ventricular arrhythmias refractory to spasm reversal. If hemodynamic compromise persists, such as profound hypotension or shock, cautious vasopressor support may be required alongside spasmolytic therapy, avoiding pure alpha-agonists like phenylephrine that can exacerbate vasospasm; agents like norepinephrine may be considered with close monitoring, and emergent coronary angiography with possible intracoronary nitroglycerin is recommended to confirm and treat focal spasm. Recent guidelines emphasize the urgency of spasm reversal to mitigate risks like ventricular fibrillation, which can arise from severe ischemia during attacks. Nitroglycerin effectively relieves symptoms in over 90% of variant angina episodes within minutes by promoting relaxation in . While long-term is key for prevention, acute management prioritizes these on-demand interventions to stabilize the patient rapidly.

Prognosis and Complications

Prognosis

The prognosis for patients with variant angina is generally favorable when managed with appropriate medical , with 5-year survival rates exceeding 90% and 10-year survival rates around 93%. Annual cardiovascular mortality is low, typically less than 1% in treated patients, compared to higher rates of 3-5% in those without optimal treatment. These outcomes reflect the effectiveness of vasodilator therapies in preventing recurrent and associated ischemic events. Several factors influence long-term . Persistent cigarette smoking doubles the risk of adverse cardiovascular events, underscoring the importance of , which has been shown to improve outcomes even in short-term follow-up. Concurrent coronary significantly worsens , elevating the annual event rate to 10-15% due to combined vasospastic and fixed obstructive mechanisms. Common event rates include recurrent episodes in 20-30% of patients despite treatment, in 5-10%, and sudden death from in less than 2%. Studies have shown that adherence to guideline-directed with and nitrates significantly reduces major adverse cardiac events. Additionally, genetic variants such as those in RNF213 are associated with increased susceptibility to vasospastic and higher risks of fatal ; a 2024 study confirmed that RNF213 variants increase the risk of vasospastic and fatal , particularly in East Asian populations. Follow-up management emphasizes symptom-guided care rather than routine annual coronary angiography, with at least yearly clinical evaluations recommended to monitor for recurrent symptoms and adjust therapy as needed.

Complications

Variant angina, also known as vasospastic angina, can lead to serious complications due to transient but severe myocardial ischemia caused by coronary artery spasm. One of the primary risks is the development of life-threatening arrhythmias, particularly ventricular tachycardia or ventricular fibrillation, which occur frequently during ischemic episodes and are associated with a poor prognosis, including sudden cardiac death. Prolonged spasms exceeding 20 minutes may result in through ischemic , with nonfatal acute reported in 5-10% of cases. is a rare complication, typically arising from recurrent ischemia leading to or scarring, and may be accompanied by conduction abnormalities such as . Other potential sequelae include syncope due to or severe arrhythmias during spasms. In some patients, variant angina coexists with or progresses to , potentially evolving into chronic coronary with fixed stenotic lesions. Early initiation of appropriate treatment, such as , significantly reduces the risk of these complications, as emphasized in the 2023 Japanese Circulation Society guidelines on vasospastic angina. The incidence of complications is notably higher in individuals using , which exacerbates and increases the likelihood of arrhythmias and .

History

Discovery

Early observations of angina occurring at rest, accompanied by transient electrocardiographic changes such as ST-segment elevation, were documented in through clinical studies that highlighted reversible ischemic patterns without evidence of . These findings, including reports of dynamic ST deviations during spontaneous episodes, suggested mechanisms beyond fixed atherosclerotic obstructions, though they were not initially linked to . The distinct entity of variant angina was formally identified in by Myron Prinzmetal and colleagues, who described 20 cases characterized by recurrent episodes of severe at rest, associated with transient ST-segment elevation on , and often occurring in a cyclical pattern, typically at night or early morning. In several of these patients, postmortem examinations revealed normal or near-normal without significant , providing crucial evidence that the symptoms arose from transient functional alterations rather than permanent blockages. This work challenged the prevailing view that pectoris was solely due to exertional demand exceeding supply from atherosclerotic vessels, introducing the concept of a "variant" form driven by episodic coronary artery narrowing at rest. A key insight from these early descriptions was the recognition that could manifest independently of physical or fixed coronary stenoses, implying a role for dynamic phenomena in myocardial ischemia.

Key Developments

In the and , significant advancements in diagnostic occurred with the introduction of pharmacological provocation testing. The first use of ergonovine maleate as a provocative agent during coronary arteriography was reported in 1973 at the , enabling reproducible induction of coronary spasm for definitive diagnosis in patients suspected of variant . This intracoronary approach marked a shift toward safer, targeted testing compared to earlier intravenous methods that carried higher risks. Building on this, the provocation test was pioneered in the late by Yasue and colleagues, who demonstrated its high sensitivity (90%) and specificity (99%) for inducing multivessel spasms in variant patients, further refining diagnostic protocols. The 1990s brought deeper insights into the pathophysiological mechanisms, particularly the role of . Studies highlighted deficient activity in spasm-prone arteries, linking reduced endothelial (NOS3) bioavailability to heightened vascular reactivity and spasm susceptibility. Concurrently, the adoption of long-acting (CCBs), such as sustained-release formulations, improved therapeutic outcomes by providing consistent and reducing episodes, with early trials showing marked efficacy in preventing recurrent spasms. During the 2000s and 2010s, genetic research illuminated hereditary factors contributing to angina. A key finding was the association of NOS3 polymorphisms, such as the T-786C variant, with increased risk due to impaired production, as evidenced in studies from the early 2000s. In 2013, the Japanese Circulation Society (JCS) issued comprehensive guidelines for vasospastic angina, recognizing it as a significant concern in and standardizing provocation testing, risk stratification, and CCB-based management to address its underdiagnosis and morbidity. In the , updates have integrated novel therapies and genetic insights. The 2023 JCS/CVIT/JCC focused update endorsed rho-kinase inhibitors like for refractory cases unresponsive to CCBs, based on evidence of its spasm-suppressing effects, alongside recommendations for in high-risk populations to guide personalized care. A 2024 multicenter study identified RNF213 gene variants, particularly the East Asian-specific p.R4810K polymorphism, as strongly associated with vasospastic angina prevalence and increased fatal risk in affected individuals. Recent 2025 reviews have emphasized diagnostic complexities in patients with non-obstructive , advocating integrated approaches combining provocation testing with functional assessments to differentiate from microvascular dysfunction. Overall, these developments have transformed variant angina from a rare, enigmatic entity—first described in —into a manageable condition, with modern therapies achieving symptom control in over 90% of cases through targeted and risk factor modification.

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