ANOCA: angina with non-obstructive coronary arteries

Article written and reviewed by Dr Luca Moretti

ANOCA is the acronym for angina with non-obstructive coronary arteries and indicates angina or equivalents compatible with a coronary origin without obstructive epicardial stenoses. It is a clinical-anatomical description, not a single disease: it includes microcirculatory disorders, vasospasm, diffuse atherosclerosis, and forms in which the mechanism has not yet been defined. The absence of obstructions does not make the symptoms imaginary. At the same time, it does not justify automatically attributing every pain to ischemia.
ANOCA differs from INOCA because, by definition, it does not require objective demonstration of ischemia. The patient may have a negative, equivocal, or unperformed stress test, or one unable to capture an episodic phenomenon; if ischemia is documented, the patient also falls within the INOCA spectrum. The distinction protects against falsely equating a symptom with ischemia. It also allows precise description of the stage reached in the diagnostic pathway.

Diagnosis does not end with a report of ‘unobstructed coronary arteries.’ CCTA and coronary angiography primarily show epicardial anatomy, while flow is regulated largely in vessels that are not visible and depends on vasomotion; functional assessment may identify microvascular dysfunction, epicardial or microvascular spasm, and mixed forms. When no endotype is demonstrated, alternative cardiac and noncardiac causes remain open.
Failure to recognize the condition leads to years of symptoms, urgent visits, repeated tests, and ineffective reassurance. ANOCA is more common among women undergoing coronary angiography, but also affects men and is not explained by hormonal status alone; quality of life and ability to work may be severely impaired. A mechanistic pathway allows random trials of therapy to be replaced by verifiable decisions.

Etiology, risk factors, pathogenesis, and pathophysiology

The most extensively studied cause is coronary microvascular dysfunction, in which the arteriolar bed does not adequately reduce resistance when demand rises. Low CFR may result from reduced hyperemic flow, high resting flow, or both; the structural phenotype often has elevated hyperemic resistance. The functional phenotype may show reduced reserve with less abnormal minimal resistance.
Epicardial spasm causes intense, transient constriction of the large coronary arteries, whereas microvascular spasm produces symptoms and ischemic changes without diagnostic epicardial narrowing. The two phenomena may occur in the same patient or coexist with nonspastic CMD; vasomotion depends on smooth muscle, endothelium, the autonomic nervous system, and local mediators. No single factor explains every episode.

Non-obstructive atherosclerosis and diffuse disease may alter flow and endothelial function without producing stenosis above the anatomical threshold. Positive remodeling may preserve the lumen while plaque burden increases; luminography therefore underestimates disease of the vessel wall. CCTA and intracoronary imaging answer anatomical questions but do not by themselves demonstrate the mechanism of pain.
Hypertension, diabetes, dyslipidemia, smoking, obesity, and kidney disease promote atherosclerosis and microvascular abnormalities, but their absence does not exclude ANOCA. Systemic inflammation and autoimmune diseases may impair the endothelium and microcirculation; traditional risk is useful for prevention, not as a diagnostic test for the symptom. A young person without risk factors may still have vasospasm or another endotype.

Smoking is particularly associated with spasm; cocaine, amphetamines, triptans, ergot derivatives, and some anticancer drugs may provoke vasoconstriction. Cold, hyperventilation, stress, and autonomic changes are possible but not universal triggers; a reproducible temporal relationship increases plausibility. Diagnosis is not made solely because a compatible exposure exists.
Women are more likely to have no obstruction on coronary angiography performed for angina. Coronary size, menopausal transition, inflammation, and differences in presentation may contribute, but the explanations remain multifactorial; biological sex modifies probability and phenotypes without defining the individual case. Premature attribution to anxiety is a documented source of underdiagnosis.

Myocardial bridging may cause compression and alter diastolic flow during tachycardia, but is also a common incidental finding. Cardiomyopathies, aortic stenosis, and hypertrophy cause secondary CMD and must be recognized separately; a structural cause changes prognosis and treatment. Its presence may explain the mechanism without making the label of primary ANOCA appropriate.
Anemia, tachyarrhythmias, hyperthyroidism, hypertension, or hypotension modify demand and perfusion and may lower the symptom threshold. Elevated filling pressures reduce the subendocardial gradient and mimic or amplify exercise intolerance; the supply-demand relationship is corrected alongside coronary physiology. A response to systemic treatment does not exclude coexisting microvascular vulnerability.

Nociceptive perception, attention, and sensitization may modulate pain intensity and persistence; these mechanisms are not alternatives to ischemia and may develop after repeated episodes or prolonged diagnostic pathways. Chronic pain requires a biopsychosocial assessment that does not erase cardiac data. Treating anxiety or depression improves care without automatically making them the primary cause.
The response to acetylcholine spans preserved endothelium-dependent dilation, paradoxical vasoconstriction, and overt spasm. The EAPCI consensus described a flow increase of less than 50%, equivalent to less than 1.5 times baseline, as attenuated, but this criterion is protocol-dependent and does not coincide with the three elements needed to diagnose provoked spasm. The endothelial response is therefore not synonymous with vasospasm. The dose, infusion rate, territory assessed, and vasoactive therapy explain some heterogeneity among laboratories.

Pathological anatomy, classification, and progression

To be non-obstructive, the anatomy must not show an epicardial stenosis of 50% or greater capable of explaining the clinical picture; physiology clarifies the significance of intermediate lesions. FFR greater than 0.80 or iFR greater than 0.89 makes important focal flow limitation unlikely, but does not exclude a diffuse gradient. Mixed disease combines modest stenoses, diffuse plaque, and vasomotor dysfunction. The report must separate percentage stenosis, physiology, and atherosclerotic burden.
ANOCA includes exertional, rest, or mixed angina and equivalents such as dyspnea, provided the clinical assessment maintains the plausibility of a coronary origin. The category is intentionally broader than microvascular angina and vasospastic angina; a defined endotype progressively replaces the umbrella label. Persistent ANOCA does not mean that every test should be repeated without a precise question.

Elements required for correct assessment of ANOCA

• Angina or equivalents described and quantified in a clinically credible manner.
• Exclusion of acute coronary syndrome and other urgent conditions.
• Absence of obstructive or functionally significant epicardial stenoses.
• Assessment of non-obstructive atherosclerosis and associated heart disease.
• Selective investigation for CMD, epicardial spasm, and microvascular spasm.
• Positive consideration of noncoronary causes and mixed mechanisms.

Functional classification distinguishes reduced CFR with elevated resistance, reduced CFR with preserved resistance, epicardial spasm, microvascular spasm, and no demonstrated abnormality. The last category does not mean simulation: it may reflect protocol limitations, episodicity, or a different cause; diagnostic certainty is graded. Each conclusion specifies which test supports the mechanism and which evidence remains missing.
In the ILIAS ANOCA trial, reproduction of the usual pain with acetylcholine without ischemic ECG changes or diagnostic epicardial vasoconstriction was classified as functional angina, whereas the noncardiac pain category required normal responses to both adenosine and acetylcholine. This was an operational classification for the protocol, not a new universal criterion. An indeterminate endotype remains possible in practice; these labels do not replace targeted investigation for esophageal, musculoskeletal, pulmonary, or neuropathic causes.

The term “cardiac syndrome X” is historical and ambiguous because it included different populations and unmeasured mechanisms. ANOCA/INOCA nomenclature and COVADIS criteria better describe symptoms, ischemia, and function; abandoning a label does not mean ignoring the historical literature. Rather, it requires reinterpretation of its results in light of modern definitions.
Over time, a person with ANOCA may be reclassified as INOCA after ischemia is documented, as MVA after CMD is demonstrated, or as VSA after positive provocation. A more convincing noncoronary diagnosis may also be reached; reclassification is progress in the pathway, not a contradiction. The patient should understand why the name changes while the symptom remains similar.

Non-obstructive plaque may progress and cause a stenosis or a future atherothrombotic event; the course of angina does not necessarily follow the anatomical course, however, because vasomotion and perception vary independently. Anatomical follow-up is not serial by definition. It is scheduled when a clinical or risk change makes a decision-making benefit likely.
Symptoms may persist after PCI performed for a concomitant lesion, revealing a preexisting microvascular or vasospastic component. Restenosis, progression, and stent problems must also be excluded before the clinical picture is attributed to ANOCA. Residual angina requires concordance among territory, physiology, and symptom. A new procedure without a target does not correct a functional endotype.

The association between CMD and heart failure with preserved ejection fraction is plausible and documented in cohorts, but may reflect shared factors and bidirectional relationships. ANOCA must not be presented as an inevitable precursor of heart failure; the onset of diastolic dysfunction is assessed using its own criteria. Blood pressure, obesity, diabetes, kidney disease, and atrial fibrillation contribute independently.

Clinical manifestations

Pain may be pressure-like, constricting, burning, or felt as heaviness and occur with exertion, emotion, cold, or after a meal. In MVA, it may last longer than classic angina and resolve slowly after exertion; pain quality modifies probability but does not identify the mechanism. Stabbing, positional, or reproducible pain points toward alternatives without excluding coexistence.
In vasospasm, episodes at rest, at night, or in the morning predominate, sometimes in clusters separated by asymptomatic periods. A rapid response to nitrates is suggestive but not specific; a circadian pattern and transient ECG changes strengthen suspicion. Spasm may also be induced by exertion, especially at certain times of day.

Dyspnea, fatigue, reduced endurance, and tightness without pain are possible equivalents. Limitation is measured through daily activities and validated instruments rather than inferred only from episode frequency; a symptom diary records triggers, duration, response, and medications. It helps distinguish overlapping patterns in the same patient.
Palpitations and syncope require attention for possible arrhythmias, especially with vasospasm. Syncope is not attributed to angina alone without documentation because neurological, orthostatic, and rhythm causes are common; ECG monitoring is tailored to episode frequency. Ischemic changes during pain increase the probability of a coronary phenomenon.

Symptoms may begin or worsen during the menopausal transition, but there is no exclusive clinical signature. Migraine and Raynaud phenomenon may accompany vasomotor disorders without being necessary or sufficient; the gynecological history complements the assessment of risk and therapies. Hormone therapy is not prescribed to test the vascular nature of pain.
Many patients report previous reassurance based on non-obstructive angiograms and develop mistrust. Reviewing the data and limitations of each test avoids setting organic and psychological diagnoses against each other; validating the symptom is not the same as confirming ischemia. It enables a new rigorous assessment without blame.

Rapid worsening, prolonged pain, diaphoresis, severe dyspnea, or instability requires urgent assessment. Chronic ANOCA does not exclude a new myocardial infarction, SCAD, embolism, myocarditis, or Takotsubo syndrome; dynamic troponin change identifies myocardial injury but not its cause. Each acute episode is assessed according to the current presentation and not dismissed as a usual recurrence.
Fear of pain leads to avoidance, deconditioning, and early exertional tachycardia, creating a cycle of limitation. Rehabilitation and support help patients resume activity safely; deconditioning is a treatable complication, not evidence of a noncardiac origin. Stability, thresholds, and signs requiring cessation are defined before exercise.

Esophageal disorders, reflux, muscular pain, asthma, and panic attacks may mimic ANOCA. The presence of a coronary endotype does not automatically make every subsequent episode ischemic; the differential diagnosis remains active during follow-up. Multiple patterns are described separately to avoid unnecessary treatment and visits.
Daily variability is clinically relevant: sleep, temperature, circadian cycle, meals, stress, blood pressure, and medications may change the threshold without changing anatomy. A test performed on an asymptomatic day does not necessarily reproduce an episodic disorder, but this possibility does not turn a negative examination into a positive one. The temporal context is recorded precisely. Comparing the usual symptom with the provoked symptom is more informative than merely noting generic pain during the test.

Investigations and diagnosis

The initial work-up assesses characteristics, physical examination, ECG, complete blood count, kidney function, glucose, lipids, and other targeted tests. Echocardiography assesses ventricular function, valvular heart disease, hypertrophy, and alternative causes; a normal baseline assessment does not exclude ANOCA. It defines safety and probability before coronary testing.
CCTA is often appropriate to exclude stenosis and describe plaque in suitable patients. A high-quality examination shows anatomy but does not directly measure vasospasm or arteriolar function; non-obstructive plaque modifies prevention and prognosis. On its own, it does not demonstrate that the observed lesion caused the symptom.

Invasive coronary angiography is used when probability, symptoms, or tests warrant it and allows physiology and provocation in the same session. Intermediate lesions are assessed with FFR or nonhyperemic indices before functionally significant disease is declared absent. FFR and iFR above 0.80 and 0.89, respectively, primarily exclude the focal target measured. Diffuse disease and the microcirculation require additional tools.
Stress tests document ischemia when positive, but sensitivity for diffuse or episodic phenomena is imperfect. Quantitative CMR and PET may measure perfusion and global reserve; echocardiography and SPECT depend on regional differences and quality. A negative result does not by definition turn ANOCA into noncardiac pain. It reduces the probability of ischemia detectable with that specific method.

CFR and microvascular resistance assess the hyperemic response. The 2024 ESC guidelines consider CFR below 2.5 abnormal with both thermodilution and Doppler; the threshold below 2.0 in the 2020 EAPCI consensus is a more restrictive historical reference and must not be transferred automatically to every technique. IMR of 25 or greater and HMR above 2.5 mmHg/(cm/s) indicate elevated resistance according to ESC, whereas EAPCI also reported an HMR threshold of 1.9. The technique used must always be reported. Resting flow, blood pressure, heart rate, medications, caffeine, and the quality of hyperemia may shift a value around the threshold.
Acetylcholine is administered in escalating doses to reproduce the usual symptom and observe the ECG and vessel caliber. The 2024 ESC guidelines require pain, ischemic ECG changes, and at least 90% epicardial narrowing for macrovascular spasm; COVADIS formally uses constriction greater than 90%. Pain and ECG changes with narrowing below the threshold point toward microvascular spasm. Coronary provocation requires an experienced laboratory. Isolated reproduction of pain without ECG ischemia is insufficient to define a positive spasm response.

The illustrative 2024 ESC protocol for the left coronary artery uses escalating intracoronary acetylcholine doses of 2, 20, 100, and 200 micrograms over approximately 60 seconds, stopping escalation when spasm occurs and then administering nitroglycerin. The guideline proposes withholding calcium channel blockers and nitrates for at least 24 hours; ILIAS ANOCA instead demonstrated feasibility with a pragmatic approach that did not mandate withdrawal. Medication preparation primarily affects sensitivity. The protocol, continued medications, and tested territory must appear in the report to make a negative result interpretable.

The COVADIS criteria prevent ANOCA from being confused with already defined microvascular angina. Definitive MVA requires all four elements: ischemic symptoms, absence of obstruction, objective ischemia, and microvascular dysfunction; suspected MVA requires the first two plus only one of the last two. Definitive VSA requires nitrate-responsive angina and spontaneous ischemic ECG changes or documented spasm. Diagnostic grading makes missing data visible. ANOCA remains the appropriate description when the symptom is present but ischemia or an endotype has not yet been demonstrated.
Coronary angiography without functional tests may leave the patient in the unphenotyped ANOCA category. The 2024 ESC guidelines give invasive testing a greater role when symptoms persist despite therapy and the diagnosis remains uncertain; test selection depends on whether the result can change treatment. Procedural risk, comorbidities, and preferences enter the decision.

Clinical documentation must distinguish ANOCA, INOCA, suspected or definitive MVA, suspected or definitive VSA, and absence of an endotype. Avoiding the generic term ‘microcirculation’ when it has not been measured prevents unjustified treatment; the integrated report states anatomy, physiology, and vasoreactivity. It also identifies limitations that might make a result falsely negative.
The differential diagnosis is investigated in parallel, not only after negative coronary tests. Anemia, arrhythmias, valvular disease, cardiomyopathies, pulmonary disease, esophageal disease, and chest-wall disorders require investigations guided by the history; a positive alternative diagnosis is more useful than an indiscriminate list. Cardiac and noncardiac mechanisms may be simultaneous.

Treatment and prognosis

The first treatment is an accurate explanation of the result: no obstructions requiring revascularization are present, but the symptoms warrant functional investigation and treatment. A plan defines trial medications, objectives, and reassessment intervals; communication reduces repetitive use of coronary angiography as the only answer. The patient receives separate instructions for usual recurrences and warning signs.
Blood pressure, lipids, glucose, smoking, weight, sleep, and activity are managed according to risk. Statins are indicated when atherosclerosis or a profile warranting their use is present; antiplatelet agents are not automatic in ANOCA without atherosclerotic disease or an event. Prevention avoids generalizations derived from obstructive coronary artery disease. Bleeding risk and absolute benefits are discussed.

If the endotype is not yet known, empirical therapy is chosen according to the pattern and safety, with a structured assessment of response. Beta-blockers may be useful for exertional symptoms and tachycardia, but are unsuitable as a blind choice in suspected epicardial spasm; calcium channel blockers better cover a vasospastic phenotype. Short-acting nitrates may be prescribed for episodes, with an explanation of their limitations and interactions.
In the nonspastic microvascular phenotype, beta-blockers, calcium channel blockers, ranolazine, and drugs addressing causal factors may be tried individually. The average response in studies is variable and does not support a universal sequence; titration accounts for heart rate, blood pressure, QT interval, and comorbidities. A drug is continued if it produces clinically meaningful benefit without disproportionate adverse effects.

In documented vasospasm, calcium channel blockers are the main treatment and nitrates are used for episodes or additional control. Smoking, cocaine, and vasoconstrictor drugs are eliminated where possible; abrupt withdrawal of effective therapy may promote recurrences. Persistent cases require checking adherence, dose, triggers, and a mixed diagnosis.
The CorMicA trial demonstrated that therapy guided by coronary function improves angina and quality of life compared with management without disclosure of the endotype. It was not large enough to demonstrate a definite benefit for mortality or myocardial infarction; the symptomatic benefit is nonetheless clinically important. The evidence supports phenotyping, not every individual drug in the algorithm.

ILIAS ANOCA randomized 153 patients without obstruction after coronary angiography: functional testing identified a vasomotor disorder in 78%, and disclosure of the endotype with dedicated therapy improved the Seattle Angina Questionnaire summary score by 9.4 points at six months. No procedural events occurred in the study, but its size and duration do not permit conclusions about major events. The ILIAS result strengthens the evidence for symptomatic efficacy of the strategy. It does not demonstrate that every laboratory or protocol will produce the same diagnostic yield.
A 2026 trial involving 250 patients used quantitative CMR to guide classification and therapy: the diagnosis was reclassified in 53%, and the adjusted advantage in the SAQ score was 20.9 points at twelve months. The noninvasive strategy may characterize flow and tissue, but does not accurately measure propensity to spasm without acetylcholine and has not demonstrated fewer events. Noninvasive endotyping expands the options at experienced centers. The choice among CMR, PET, and invasive testing depends on the question that remains open.

WARRIOR compared a high-intensity statin, an ACE inhibitor or angiotensin receptor blocker, and aspirin with usual care in 2,476 women with suspected ANOCA/INOCA. At approximately two and a half years, there was no reduction in the composite outcome, with a hazard ratio of 1.13 and a confidence interval of 0.94 to 1.37; underenrollment, already high use of the drugs in the control group, and contamination limit inference. The WARRIOR finding does not support automatic triple therapy based solely on the acronym. Nor does it justify discontinuing a statin, ACE inhibitor, or antiplatelet agent when plaque, blood pressure, a previous event, or individual risk provides an independent indication.
Progressive exercise and rehabilitation improve capacity, risk factors, and confidence, with intensity tailored to the clinical profile. Sleep, anemia, thyroid function, menopause, and inflammatory diseases are managed according to their own indications; psychological support treats fear, depression, and catastrophizing without denying the coronary mechanism. A multidisciplinary strategy is particularly useful for chronic and mixed symptoms.

Follow-up measures days with angina, nitrate use, activity, SAQ scores, adverse effects, and adherence. New tests are requested when the pattern changes or the result can modify therapy; there is no universal interval for stress imaging in every stable case of ANOCA. Periodic review avoids both inertia and overdiagnosis. New risk factors or ventricular dysfunction change stratification.
Prognosis depends on the endotype and associated disease. Non-obstructive plaque, reduced CFR, elevated resistance, multivessel spasm, diabetes, kidney disease, and ventricular function identify different profiles. ANOCA is not automatically benign, but neither is it synonymous with an imminent event. Risk is expressed in understandable terms and linked to concrete preventive actions.

Complications

Persistent angina may reduce activity, work, sleep, and relationships even when no major events occur. Fragmented consultations and conflicting messages amplify uncertainty and healthcare use; a longitudinal plan centralizes results and objectives. Quality of life is a primary outcome of care, not an ancillary variable.
Non-obstructive atherosclerosis may progress and cause events; CMD and spasm are associated with cardiovascular risk in selected cohorts. Absolute risk varies and cannot be inferred from the ANOCA acronym alone; risk prevention is based on anatomy, physiology, and comorbidities. Unnecessarily frequent reassessments do not replace continuous risk-factor control.

Spasm may be complicated by myocardial infarction, arrhythmias, syncope, and cardiac arrest. A nocturnal episode with palpitations or loss of consciousness requires rhythm documentation and intensive treatment of vasospasm; arrhythmic risk is not estimated from pain frequency alone. Multivessel spasm and previous cardiac arrest identify more severe scenarios.
Reduced CFR is associated with a worse prognosis and, in some populations, heart failure with preserved ejection fraction. It is not, however, an individual destiny or sufficient evidence of causality; progressive dyspnea is assessed with echocardiography, natriuretic peptides, and other appropriate tests. Blood pressure, volume, rhythm, and systemic diseases must be treated in parallel.

Repeated angiograms expose patients to bleeding, kidney injury, radiation, and vascular complications. An incomplete functional diagnosis may also lead to unnecessary stents for stenoses that are not responsible for symptoms; appropriateness requires a question capable of changing the decision. Each new examination is compared with available imaging and physiology.
Empirical polypharmacy may cause hypotension, bradycardia, edema, headache, constipation, fatigue, and interactions; these effects reduce activity and may resemble progression of angina. Medication reconciliation includes over-the-counter products and vasoactive substances. Discontinuations or changes are planned to avoid rebound and confusing interpretations.

Minimizing symptoms may promote depression, anxiety, and mistrust; excessive medicalization may produce fear of exertion and dependence on testing. Balanced communication recognizes the disorder and the limits of evidence; mental health is treated directly when impaired. Support is not presented as evidence that the pain is not coronary in origin.
An ANOCA label may become obsolete if symptoms or risk change. Myocardial infarction, SCAD, embolism, myocarditis, and aortic disease remain possible and require dedicated pathways; acute reassessment is not avoided for fear of repeating tests. It is based on new features, ECG, troponin, stability, and the urgent differential diagnosis.

The absence of an endotype after adequate testing may leave symptoms without a complete explanation. In these cases, the physician avoids both indefinite coronary therapy and a dismissive conclusion; explicit uncertainty allows follow-up, pain assessment, and review if new data emerge. Care remains active even when the taxonomy is not definitive.