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Variant angina

Variant angina, also known as Prinzmetal's angina or vasospastic angina, is a rare form of chest pain caused by sudden spasms in the coronary arteries that temporarily reduce blood flow to the heart muscle, typically occurring at rest rather than during physical exertion.^[1]^[2]^[3] Unlike stable angina, which results from fixed blockages due to atherosclerosis, variant angina arises primarily from vasospasm of the smooth muscle in artery walls, often without significant underlying plaque buildup.^[1]^[4] 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 sumatriptan.^[1]^[2]^[3] 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 nausea, sweating, or dizziness.^[1]^[4] The pain typically resolves spontaneously or with rest and medication, but recurrent attacks follow a predictable pattern, distinguishing it from other angina types.^[3] 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.^[1]^[4] 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.^[1]^[4] 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.^[1] Illicit drugs like cocaine or marijuana can provoke spasms, emphasizing the role of lifestyle in its onset.^[1]^[2] Diagnosis often involves electrocardiography (ECG) during an episode, which may show transient ST-segment elevation, alongside coronary angiography to visualize spasms, sometimes provoked by agents like acetylcholine.^[1]^[4] Ambulatory ECG monitoring or stress testing helps confirm the rest-related pattern.^[1] Treatment primarily relies on medications such as calcium channel blockers (e.g., diltiazem) and long-acting nitrates to prevent spasms, with statins like fluvastatin sometimes used for additional benefit.^[1]^[2] Lifestyle modifications, including smoking cessation and avoiding triggers, are essential, and in severe cases, procedures like stenting may be considered if fixed blockages coexist.^[1]^[2]^[4] With proper management, the prognosis is generally favorable, allowing most patients to lead normal lives.^[2]^[1]

Background and Epidemiology

Definition and Classification

Variant angina, also known as Prinzmetal's angina, is a form of angina pectoris caused by transient coronary artery spasm that leads to myocardial ischemia, typically occurring at rest in the absence of fixed obstructive coronary artery disease.^[5] This condition is characterized by episodes of reduced blood flow to the heart muscle due to focal or diffuse vasoconstriction of the coronary arteries, often without underlying atherosclerosis.^[6] 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 angina.^[7] Common synonyms for variant angina include vasospastic angina, coronary spastic angina, and angina inversa.^[1] 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.^[8] Unlike stable angina, which is provoked by physical exertion or increased myocardial demand, variant angina arises primarily from supply-side issues related to vasospasm.^[3] 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.^[9] This classification underscores its unique position among ischemic heart syndromes, separating it from demand ischemia or obstructive pathologies.^[10]

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 Japan, 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.^[11]^[12] Incidence rates in the general population are not well-established, but studies indicate it may contribute to 30-40% of cases of myocardial infarction with normal coronary angiograms, highlighting its underrecognized role in acute events.^[11] 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 smoking rates among affected men. The condition is strongly associated with smoking, present in up to 66% of cases in certain groups, and shows correlations with comorbidities such as migraine and Raynaud's phenomenon, which may share vasoreactive mechanisms.^[5]^[13]^[11] Geographic variations underscore a higher burden in East Asia, where genetic factors like the RNF213 p.R4810K variant (rs112735431) confer increased susceptibility, with odds ratios for vasospastic angina reaching 2-6 in carriers compared to non-carriers. This variant 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 angina and normal coronary angiograms on standard imaging may harbor undetected vasospasm without provocation testing.^[13]^[12]^[14]

Clinical Presentation

Signs and Symptoms

The primary symptom of variant angina is severe chest pain or discomfort, often described as squeezing, tightness, or pressure in the chest, typically occurring at rest and lasting 5 to 15 minutes.^[1]^[9] This pain frequently arises between midnight and early morning, such as during sleep or periods of relaxation.^[2]^[15] The chest pain may radiate to the arms, neck, jaw, back, shoulders, or upper abdomen, and is commonly accompanied by diaphoresis (sweating), nausea, dizziness, or dyspnea (shortness of breath).^[1]^[15]^[16] Episodes often follow a cyclical pattern, clustering over days or weeks, and can be provoked by factors such as hyperventilation, exposure to cold, or emotional stress, though they are not induced by physical exertion.^[9]^[15] Atypical presentations during attacks may include palpitations, syncope (fainting), or ventricular arrhythmias, which can arise due to the intensity of the spasm.^[17]^[18]^[19] Unlike exertional angina, the pain in variant angina is unrelated to physical activity, tends to resolve spontaneously, or responds rapidly to nitroglycerin.^[1]^[9]

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.^[1]^[20]^[21] Recreational drug use, particularly cocaine and marijuana, further heightens risk by promoting endothelial dysfunction and acute spasms, often leading to more severe episodes.^[1]^[2]^[20] 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.^[1]^[21] 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 angina that peaks later in life.^[20]^[21] Co-existing conditions such as variant migraine and Raynaud's phenomenon are strongly linked, likely due to shared vascular reactivity pathways.^[1]^[20] Additional associations include magnesium deficiency, which may impair vascular smooth muscle relaxation and contribute to spasm propensity.^[21] High cholesterol exhibits a mild association, unlike its dominant role in atherosclerotic angina, with lipid abnormalities potentially amplifying spasm risk without overt plaque buildup.^[1]^[21] Environmental exposures, such as cold temperatures or allergens, can provoke episodes in susceptible individuals by inducing vasoconstriction.^[1]^[2] Cohort studies underscore the impact of addressing modifiable factors, particularly smoking cessation, which has been shown to reduce the incidence and severity of variant angina by improving endothelial function and decreasing spasm frequency, with prognosis enhancements observed even in short-term follow-ups.^[22]^[23] Recent 2024 research highlights genetic predispositions, such as variants in the RNF213 gene, as conferring increased risk for vasospastic angina, though detailed mechanisms are explored elsewhere.^[13]

Pathophysiology

Mechanism of Coronary Vasospasm

Variant angina, also known as vasospastic angina, is characterized by transient, focal, or diffuse spasms of the epicardial coronary arteries that lead to partial or complete vessel occlusion, thereby reducing myocardial blood flow and inducing ischemia without reliance on underlying atherosclerotic plaques.^[24] These spasms typically occur at rest and are reversible upon resolution, distinguishing them from chronic ischemic conditions.^[5] A central contributor to these spasms is endothelial dysfunction, which diminishes nitric oxide (NO) bioavailability, thereby failing to counteract vasoconstrictive forces. This imbalance promotes unopposed action of potent vasoconstrictors such as endothelin-1, a peptide released by endothelial cells that binds to receptors on vascular smooth muscle to induce contraction, and thromboxane A2, a prostanoid derived from arachidonic acid that enhances platelet aggregation and further amplifies vasoconstriction.^[25] In patients with variant angina, this endothelial impairment can manifest even in non-spastic segments of the coronary vasculature, underscoring a systemic vasomotor abnormality.^[24] Hyperreactivity of vascular smooth muscle cells exacerbates the propensity for spasm, primarily through heightened Rho-kinase activity, which inhibits myosin light chain phosphatase 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.^[26] Such hypercontractility is a hallmark of the smooth muscle response in variant angina, enabling rapid and severe narrowing of the arterial lumen.^[25] Various triggers can initiate or propagate these spasms, including alpha-adrenergic stimulation from catecholamines like noradrenaline, which activates receptors on smooth muscle to promote constriction; serotonin release from aggregated platelets, acting via 5-HT2A receptors to heighten vasoreactivity; and oxidative stress, which generates reactive oxygen species that degrade NO and facilitate platelet activation, thereby sustaining the spasm.^[24]^[26] These events often occur at sites of minor atherosclerotic irregularities or arterial bifurcations, where local shear stress may sensitize the endothelium and smooth muscle.^[5] 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.^[24] This reversibility highlights the functional nature of the obstruction, often affecting angiographically normal arteries.^[25]

Genetic and Molecular Factors

Variant angina, also known as vasospastic angina, has been linked to specific genetic variants that predispose individuals to coronary vasospasm. 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 risk (95% CI, 1.99-2.74) of vasospastic angina, reaching genome-wide significance in large-scale genetic association studies.^[13] 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 risk (OR: 18.34; 95% CI, 5.15-65.22).^[13] 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.^[27] Other genetic contributors include variants in the NOS3 gene, which encodes endothelial nitric oxide synthase. Polymorphisms such as T-786C and Glu298Asp in NOS3 reduce nitric oxide production, impairing vasodilation and increasing susceptibility to coronary spasm by exacerbating endothelial dysfunction.^[28] 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 Han Chinese populations.^[29] Susceptible individuals also exhibit elevated oxidative stress markers, such as nitrotyrosine and malondialdehyde-modified low-density lipoprotein, which aggravate endothelial dysfunction and smooth muscle hyperreactivity.^[30]^[31] 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.^[32] 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).^[33] 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).^[13] These insights suggest potential for genotype-guided therapies to mitigate spasm severity.

Diagnosis

Initial Evaluation

The initial evaluation of a patient suspected of having variant angina begins with a detailed history to identify characteristic patterns of symptoms. Patients typically report recurrent episodes of chest pain occurring at rest, often lasting 5 to 15 minutes and predominantly between midnight and early morning.^[5] These episodes may be triggered by emotional stress, exposure to cold, or hyperventilation, and they usually resolve promptly with sublingual nitroglycerin.^[6] A history of associated vasospastic conditions, such as Raynaud phenomenon or migraine, can further support suspicion.^[5] Physical examination is often unremarkable in the absence of an active episode, as findings between attacks are typically normal in patients without significant underlying coronary artery disease.^[5] During an acute episode, however, patients may exhibit signs of distress, including tachycardia, hypertension, or diaphoresis.^[18] Initial laboratory tests focus on excluding myocardial infarction and assessing contributing factors. Cardiac troponin levels are measured serially to rule out acute injury, as they are usually normal in uncomplicated vasospasm but may elevate if ischemia progresses to infarction.^[34] A lipid profile is obtained to evaluate for coexisting atherosclerotic risk, while serum magnesium levels are checked due to associations between hypomagnesemia and coronary spasm susceptibility.^[35] Resting electrocardiography (ECG) is performed promptly; it is often normal or shows nonspecific ST-T changes at baseline, but capturing an episode may reveal transient ST-segment elevation.^[5] 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 angina.^[5] 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 cardiac arrest, multivessel spasm, and nitrate-unresponsive symptoms, to guide urgency of further assessment.^[36]

Confirmatory Tests

Confirmatory tests for variant angina, also known as vasospastic angina, aim to demonstrate transient coronary vasospasm, typically through electrocardiographic changes or inducible spasm during invasive procedures.^[5] Electrocardiography 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 chest pain and reciprocal ST depression in opposing leads.^[5] Ambulatory Holter monitoring is particularly useful for capturing spontaneous episodes in patients with infrequent symptoms, documenting ischemic ST changes during rest-associated events.^[37] Coronary angiography remains the gold standard for confirmation, frequently showing normal or near-normal arteries at rest but enabling provocation testing to induce spasm.^[38] Intracoronary administration of acetylcholine (20–100 μg) or ergonovine (20–64 μg) during angiography reproduces symptoms, ECG changes, and ≥90% luminal narrowing, with positivity rates of 80–90% in suspected cases.^[37] Acetylcholine tends to provoke diffuse or distal spasms, while ergonovine elicits more focal ones, though acetylcholine is increasingly favored for its higher sensitivity (90–94%) and specificity (99%).^[37] Non-invasive alternatives support diagnosis by excluding fixed coronary lesions or paradoxically provoking spasm. Computed tomography angiography effectively rules out obstructive disease prior to invasive testing, providing anatomical reassurance in low-risk patients.^[5] Exercise stress ECG, while not routine, may induce vasospasm in up to 50% of cases, sometimes paradoxically during recovery rather than peak exertion, manifesting as ST elevation.^[39] The 2023 Japanese Circulation Society (JCS)/Cardiovascular Imaging and Therapeutics (CVIT)/Japanese Association for Coronary Artery Disease (JCC) guidelines recommend provocation testing (Class I) in patients with high clinical suspicion, normal resting angiography, and low bleeding risk, prioritizing acetylcholine over ergonovine due to its superior safety profile and efficacy in daily-life spasm simulation.^[40] The 2024 European Society of Cardiology (ESC) Guidelines for Chronic Coronary Syndromes similarly recommend invasive vasoreactivity testing with intracoronary acetylcholine or ergonovine (Class I, Level B) during coronary angiography for patients with suspected vasospastic angina and no obstructive coronary artery disease.^[41] Testing is advised against in the acute phase post-myocardial infarction or when severe complications are anticipated.^[40] 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 chest pain or bradycardia occur.^[42] Contraindications include severe bronchial asthma (due to acetylcholine's bronchospastic potential) and recent myocardial infarction.^[43]

Management

Prevention and Lifestyle Modifications

Smoking cessation is a cornerstone of prevention for variant angina, as tobacco use is a major trigger for coronary vasospasm. Quitting smoking significantly decreases the frequency of anginal episodes by eliminating a key endothelial disruptor and spasm inducer. Counseling, nicotine replacement therapy, and support programs are emphasized to facilitate long-term abstinence, with observational data indicating substantial reductions in spasm occurrence among former smokers.^[44] Avoiding identifiable triggers is essential to minimize episode risk. Patients should limit exposure to cold temperatures, which can provoke vasospasm through sympathetic activation, by dressing warmly during outdoor activities. Stress management techniques, such as mindfulness or relaxation exercises, help mitigate emotional or physical stressors that exacerbate endothelial dysfunction. Additionally, recreational drugs like cocaine and ergotamine derivatives must be strictly avoided, as they directly induce coronary vasoconstriction.^[1]^[5] Dietary modifications support vascular health and counter potential deficiencies linked to vasospasm. 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 caffeine is best limited due to its potential to heighten vasoconstriction.^[45] Regular moderate exercise promotes endothelial function and overall cardiovascular resilience, reducing the likelihood of spasms through improved nitric oxide bioavailability. Activities like walking or cycling 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 therapy, with observational studies demonstrating reductions in episode frequency through combined interventions like smoking cessation and trigger avoidance.^[40]

Pharmacological Treatment

The mainstay of long-term pharmacological treatment for variant angina, also known as vasospastic angina, is calcium channel blockers (CCBs), which relax vascular smooth muscle and prevent recurrent coronary vasospasm.^[5] Dihydropyridine CCBs such as amlodipine (5-10 mg daily) and non-dihydropyridine CCBs such as diltiazem (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 nifedipine, diltiazem, and verapamil.^[46] These agents are recommended by the Japanese Circulation Society (JCS) 2023 guidelines as Class I therapy for prophylaxis (Level B evidence).^[40] Long-acting nitrates, such as isosorbide dinitrate (20-40 mg twice daily) or isosorbide mononitrate (20-40 mg daily), provide additional vasodilation and are used as adjuncts when CCB monotherapy is insufficient, particularly in patients with frequent episodes.^[47] Sublingual nitroglycerin (0.3-0.6 mg as needed) can be employed for breakthrough symptoms alongside chronic therapy.^[48] For refractory cases, combination therapy with a CCB and long-acting nitrate is effective, as endorsed in the JCS 2023 guidelines, though tolerance may develop, necessitating nitrate-free intervals.^[40] Beta-blockers should be avoided, as they can exacerbate vasospasm by unopposed alpha-adrenergic activity.^[49] In patients with concomitant atherosclerosis, 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.^[50] Statins, such as atorvastatin or rosuvastatin, serve as adjuncts for endothelial protection, reducing major adverse cardiovascular events by improving vascular function independent of lipid-lowering effects.^[51] For severe, refractory variant angina in Japan, the JCS 2023 guidelines support rho-kinase inhibitors like fasudil (typically 30-60 mg three times daily intravenously or orally in specialized settings) as an emerging option, targeting hypercontractility in vascular smooth muscle with demonstrated suppression of acetylcholine-induced spasm.^[52] All therapies require monitoring for side effects, including hypotension, headache, and reflex tachycardia with dihydropyridines.^[40]

Acute and Emergency Management

The acute management of variant angina focuses on rapidly reversing coronary vasospasm to alleviate chest pain and prevent complications such as arrhythmias or myocardial ischemia. The first-line intervention for an ongoing attack is sublingual nitroglycerin, administered at a dose of 0.3-0.6 mg every 5 minutes for up to three doses, which provides rapid vasodilation and symptom relief in most cases.^[53]^[54] If symptoms persist after initial doses, intravenous nitroglycerin infusion should be initiated, starting at 5-10 mcg/min and titrated upward to achieve hemodynamic stability while monitoring for hypotension.^[55] For severe or refractory attacks in a hospital setting, intravenous calcium channel blockers, such as verapamil at 5-10 mg administered over 2 minutes, or diltiazem, can be used to directly counteract the vasospasm, often in combination with nitroglycerin infusion.^[56]^[48] Adjunctive therapies include morphine sulfate (2-5 mg IV) for persistent pain unresponsive to nitrates and supplemental oxygen if the patient is hypoxic (oxygen saturation <90%).^[57] Serial electrocardiograms (ECGs) are essential to differentiate transient ST-segment elevation from ST-elevation myocardial infarction (STEMI), guiding further evaluation such as urgent coronary angiography if infarction is suspected.^[44] 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.^[58] 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.^[40]^[59] Recent guidelines emphasize the urgency of spasm reversal to mitigate risks like ventricular fibrillation, which can arise from severe ischemia during attacks.^[52] Nitroglycerin effectively relieves symptoms in over 90% of variant angina episodes within minutes by promoting smooth muscle relaxation in coronary arteries.^[60] While long-term calcium channel blocker therapy is key for prevention, acute management prioritizes these on-demand interventions to stabilize the patient rapidly.^[47]

Prognosis and Complications

Prognosis

The prognosis for patients with variant angina is generally favorable when managed with appropriate medical therapy, 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 vasospasm and associated ischemic events. Several factors influence long-term prognosis. Persistent cigarette smoking doubles the risk of adverse cardiovascular events, underscoring the importance of smoking cessation, which has been shown to improve outcomes even in short-term follow-up. Concurrent coronary atherosclerosis significantly worsens prognosis, elevating the annual event rate to 10-15% due to combined vasospastic and fixed obstructive mechanisms. Common event rates include recurrent angina episodes in 20-30% of patients despite treatment, myocardial infarction in 5-10%, and sudden death from ventricular fibrillation in less than 2%. Studies have shown that adherence to guideline-directed therapy with calcium channel blockers and nitrates significantly reduces major adverse cardiac events.^[40] Additionally, genetic variants such as those in RNF213 are associated with increased susceptibility to vasospastic angina and higher risks of fatal myocardial infarction; a 2024 study confirmed that RNF213 variants increase the risk of vasospastic angina and fatal myocardial infarction, particularly in East Asian populations.^[13] 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.^[61]^[5] Prolonged spasms exceeding 20 minutes may result in myocardial infarction through ischemic necrosis, with nonfatal acute myocardial infarction reported in 5-10% of cases.^[62] Heart failure is a rare complication, typically arising from recurrent ischemia leading to myocardial stunning or scarring, and may be accompanied by conduction abnormalities such as atrioventricular block.^[63]^[64] Other potential sequelae include syncope due to bradycardia or severe arrhythmias during spasms.^[65] In some patients, variant angina coexists with or progresses to atherosclerosis, potentially evolving into chronic coronary syndrome with fixed stenotic lesions.^[5] Early initiation of appropriate treatment, such as calcium channel blockers, significantly reduces the risk of these complications, as emphasized in the 2023 Japanese Circulation Society guidelines on vasospastic angina.^[40] The incidence of complications is notably higher in individuals using cocaine, which exacerbates coronary vasospasm and increases the likelihood of arrhythmias and infarction.^[66]

History

Discovery

Early observations of angina occurring at rest, accompanied by transient electrocardiographic changes such as ST-segment elevation, were documented in the 1930s through clinical studies that highlighted reversible ischemic patterns without evidence of infarction.^[67] These findings, including reports of dynamic ST deviations during spontaneous chest pain episodes, suggested mechanisms beyond fixed atherosclerotic obstructions, though they were not initially linked to coronary vasospasm.^[68] The distinct entity of variant angina was formally identified in 1959 by Myron Prinzmetal and colleagues, who described 20 cases characterized by recurrent episodes of severe chest pain at rest, associated with transient ST-segment elevation on electrocardiography, and often occurring in a cyclical pattern, typically at night or early morning.^[69] In several of these patients, postmortem examinations revealed normal or near-normal coronary arteries without significant atherosclerosis, providing crucial evidence that the symptoms arose from transient functional alterations rather than permanent blockages.^[70] This work challenged the prevailing view that angina 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 angina could manifest independently of physical exertion or fixed coronary stenoses, implying a role for dynamic vasomotor phenomena in myocardial ischemia.^[71]

Key Developments

In the 1970s and 1980s, significant advancements in diagnostic standardization 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 Cleveland Clinic, enabling reproducible induction of coronary spasm for definitive diagnosis in patients suspected of variant angina.^[72] This intracoronary approach marked a shift toward safer, targeted testing compared to earlier intravenous methods that carried higher risks. Building on this, the acetylcholine provocation test was pioneered in the late 1980s by Yasue and colleagues, who demonstrated its high sensitivity (90%) and specificity (99%) for inducing multivessel spasms in variant angina patients, further refining diagnostic protocols.^[73] The 1990s brought deeper insights into the pathophysiological mechanisms, particularly the role of endothelial dysfunction. Studies highlighted deficient nitric oxide activity in spasm-prone arteries, linking reduced endothelial nitric oxide synthase (NOS3) bioavailability to heightened vascular reactivity and spasm susceptibility.^[74] Concurrently, the adoption of long-acting calcium channel blockers (CCBs), such as sustained-release diltiazem formulations, improved therapeutic outcomes by providing consistent vasodilation and reducing angina episodes, with early trials showing marked efficacy in preventing recurrent spasms.^[75] During the 2000s and 2010s, genetic research illuminated hereditary factors contributing to variant angina. A key finding was the association of NOS3 gene polymorphisms, such as the T-786C variant, with increased spasm risk due to impaired nitric oxide production, as evidenced in studies from the early 2000s.^[76] In 2013, the Japanese Circulation Society (JCS) issued comprehensive guidelines for vasospastic angina, recognizing it as a significant public health concern in East Asia and standardizing provocation testing, risk stratification, and CCB-based management to address its underdiagnosis and morbidity.^[77] In the 2020s, updates have integrated novel therapies and genetic insights. The 2023 JCS/CVIT/JCC focused update endorsed rho-kinase inhibitors like fasudil for refractory cases unresponsive to CCBs, based on evidence of its spasm-suppressing effects, alongside recommendations for genetic testing in high-risk populations to guide personalized care.^[78] 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 myocardial infarction risk in affected individuals.^[13] Recent 2025 reviews have emphasized diagnostic complexities in patients with non-obstructive coronary arteries, advocating integrated approaches combining provocation testing with functional assessments to differentiate vasospasm from microvascular dysfunction.^[79] Overall, these developments have transformed variant angina from a rare, enigmatic entity—first described in 1959—into a manageable condition, with modern therapies achieving symptom control in over 90% of cases through targeted vasodilation and risk factor modification.^[80]

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Angina, or angina pectoris, is temporary chest pain or a sensation of pressure that occurs when the heart's need for oxygen is not satisfied by the amount ...
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