INOCA: ischemia with non-obstructive coronary arteries

Article written and reviewed by Dr Luca Moretti

INOCA indicates the presence of myocardial ischemia in the absence of obstructive epicardial stenoses capable of explaining it. It does not identify a single disease and is not diagnosed merely because coronary angiography shows no obstruction: reliable evidence of ischemia and analysis of the mechanism are required; microvascular dysfunction and vasomotor disorders are the most relevant causes. Diffuse atherosclerosis, hemodynamic factors, and associated heart diseases may contribute.
The acronym differs from ANOCA, which begins with angina or equivalents without requiring documented ischemia. A patient with typical pain and non-obstructive coronary arteries remains in the ANOCA category if testing is negative or inconclusive; the patient also has INOCA when ECG, imaging, or physiology demonstrates a mismatch between flow and demand. The objective documentation must be consistent and technically valid. Artifacts and false positives must not be turned into chronic disease.

Ischemia may result from an inability of the microcirculation to increase flow, episodic constriction of a large vessel, arteriolar spasm, or combinations of these. Conventional coronary angiography describes the lumen but does not measure these functions; a complete diagnosis separates anatomy, perfusion, and vasoreactivity. This separation guides different drugs and limits procedures with no correctable target.
INOCA is not synonymous with a harmless prognosis. Observational studies show greater risk of events, heart failure, and hospitalizations than in populations without disease, but risk varies with reserve, atherosclerosis, ventricular function, and comorbidities; the greatest burden often consists of persistent angina and impaired quality of life. Individual stratification avoids both absolute reassurance and unsupported alarming predictions.

Etiology, risk factors, pathogenesis, and pathophysiology

During stress, coronary flow must increase several-fold above rest. Reduced CFR indicates that this capacity is limited, but may result from low hyperemic flow, high resting flow, or both; CFR is therefore an integrated index, not a pure measure of microvascular structure. Its interpretation requires epicardial anatomy, resistance, blood pressure, heart rate, and the measurement technique.
In structural CMD, arteriolar remodeling, thickening, perivascular fibrosis, and rarefaction increase minimal resistance. The subendocardium, exposed to greater extravascular pressure, is particularly vulnerable when diastole shortens; elevated IMR supports a resistive component under appropriate invasive conditions. Hypertension, diabetes, kidney disease, and hypertrophy are frequent but not necessary substrates.

In functional CMD, excessive resting flow may compress reserve despite less abnormal hyperemic resistance. Sympathetic activation, metabolic dysfunction, and abnormal regulation of tone contribute to varying degrees; the phenotype is not defined by tachycardia alone. Resting physiology must be measured under stable conditions without correctable confounders.
Epicardial spasm causes transient subtotal constriction of the large coronary arteries, accompanied by symptoms and ischemic changes when diagnostic criteria are met. It may produce transmural or subendocardial ischemia according to duration and severity; Rho-kinase and smooth-muscle hyperreactivity play a central role. Endothelial dysfunction and the autonomic nervous system modulate the phenomenon without fully explaining it.

Microvascular spasm causes symptoms and ischemic changes during acetylcholine administration without diagnostic epicardial constriction. The reduction in flow may be heterogeneous and does not always produce regional defects visible on standard tests; it may coexist with reduced CFR or elevated resistance. This combination makes classification based on a single result inadequate.
Non-obstructive diffuse atherosclerosis alters the endothelium and pressure distribution along the vessel. A series of mild narrowings may create a gradient without a focal 50% stenosis; plaque burden preserves an atherothrombotic risk. An FFR pullback distinguishes a distributed drop from a focal lesion. Abnormal epicardial physiology modifies the interpretation of CFR.

Traditional factors promote plaque and CMD, while smoking is particularly relevant to vasospasm. Autoimmune diseases, inflammation, chemotherapy, migraine, and autonomic abnormalities may contribute in subgroups; the presence of a factor does not prove individual causality. Correcting it remains indicated when it reduces overall risk or documented triggers.
Perfusion pressure, anemia, heart rate, and ventricular pressures determine how much reserve is actually used. The same microcirculation may become ischemic during fever, tachyarrhythmia, or hypertension and remain adequate at rest; these hemodynamic modifiers are treated before the syndrome is defined as refractory. They must not, however, replace investigation for a persistent endotype when symptoms continue.

CMD is also observed in cardiomyopathies, aortic stenosis, amyloidosis, and heart failure. In these conditions, INOCA describes the ischemic phenomenon, but prognosis depends heavily on the underlying disease; secondary CMD requires treatment of the substrate. Transferring algorithms studied in primary INOCA without considering the heart disease may be inappropriate.
CFR and resistance do not describe the same property. Reduced CFR with normal IMR may result from high resting flow, diffuse epicardial disease, or a hyperemic limitation not captured by the resistance threshold; elevated IMR with preserved CFR may instead reflect high resistance compensated by a large increase from rest. Physiological discordances are not errors by definition. Absolute flow, blood pressure, heart rate, perfused mass, and curve quality are needed to establish their clinical meaning.

Pathological anatomy, classification, and progression

The most commonly used anatomical criterion defines stenosis below 50% as non-obstructive, but intermediate lesions must be assessed physiologically. FFR above 0.80 or iFR above 0.89 excludes significant epicardial flow limitation in the measured vessel; values at or below the respective thresholds require at least part of the ischemia to be attributed to epicardial disease. The anatomical threshold does not distinguish absent, minimal, or diffuse plaque; these categories have different risks and preventive implications.
The ischemic criterion may be met by ECG changes during pain or stress, perfusion defects, stress-induced wall-motion abnormalities, or quantitative reduction in flow. Each method measures one aspect and has false positives and false negatives; multimodal consistency increases certainty but does not require indiscriminate repetition of concordant tests. An equivocal finding is reviewed before diagnostic weight is assigned.

Requirements for classifying a syndrome as INOCA

• Objective and technically credible evidence of myocardial ischemia.
• Absence of obstructive or functionally significant epicardial stenoses.
• Exclusion of an acute event or mimics capable of explaining the finding.
• Investigation for microvascular dysfunction through flow and resistance.
• Assessment of epicardial or microvascular spasm when clinically appropriate.
• Definition of concomitant atherosclerosis, heart disease, and systemic conditions.

The principal endotypes are CMD with reduced reserve, CMD with increased resistance, epicardial spasm, microvascular spasm, and combined forms. ESC 2024 considers CFR below 2.5 abnormal with both Doppler and thermodilution; the threshold below 2.0 from the 2020 EAPCI consensus is a more restrictive historical criterion, while noninvasive cutoffs depend on tracer, software, and method. A mixed endotype may require drugs with different objectives. The report must state the value, technique, resistance, resting flow, and hemodynamic conditions, not merely the final label.
Definitive MVA according to COVADIS requires all four elements: ischemic symptoms, absence of obstruction defined by stenosis below 50% or FFR above 0.80, objective evidence of ischemia, and abnormal microvascular function. Suspected MVA requires the first two elements plus only one of documented ischemia or microvascular dysfunction. Definitive MVA is therefore not inferred from INOCA alone; this grading prevents ischemia without microvascular evidence from being called microvascular and recognizes cases in which one component is still missing.

For the fourth criterion, COVADIS accepts reduced CFR with a method-dependent threshold between 2.0 and 2.5, an abnormal resistance index such as IMR above 25, microvascular spasm, or slow coronary flow with a corrected TIMI frame count above 25. ESC 2024 harmonized clinical use toward CFR below 2.5 and IMR of 25 or greater. The microvascular criterion must be named explicitly. Slow flow and low CFR are not synonymous and may result from different mechanisms.

According to COVADIS, definitive VSA requires nitrate-responsive angina and at least one of transient ischemic ECG changes during a spontaneous episode or documented spasm. Spontaneous changes include ST-segment elevation or depression of at least 0.1 mV in at least two contiguous leads, or new negative U waves. A positive provocation test requires the usual pain, ECG ischemia, and near-occlusive epicardial constriction: COVADIS describes it as greater than 90%, whereas ESC 2024 uses at least 90%; narrowing below the threshold with the other two elements diagnoses microvascular spasm. A negative test reduces probability under the conditions assessed. Medications, doses, territory, and episodic nature preclude interpreting it as lifelong absolute exclusion.

Over time, plaque and risk factors may progress while physiology and symptoms change nonparallelly. CFR may vary with therapy, blood pressure, and method; repeat testing is not routine if it does not change decisions. Clinical stability is assessed through symptoms, function, and risk. Marked worsening requires epicardial disease or a new condition to be excluded again.
Diffuse subendocardial ischemia may not cause a clear regional defect but may contribute to diastolic dysfunction and intolerance. The link with HFpEF is supported by prospective associations, not by an obligatory sequence in every patient; functional progression depends on blood pressure, metabolism, kidney function, and inflammation. Follow-up treats these determinants even when coronary physiology is not repeated.

Myocardial injury with non-obstructive coronary arteries, MINOCA, is a distinct acute working diagnosis: it does not require definitive confirmation of myocardial infarction and initiates a specific etiological investigation. A patient with INOCA may subsequently have MINOCA, but the acronyms are not interchangeable; normal troponin is compatible with chronic INOCA. A dynamic increase requires reassessment as an acute event.

Clinical manifestations

Exertional angina and dyspnea are common manifestations, but intensity does not correlate linearly with reduction in flow. Microvascular pain may last longer, occur after exertion, or respond incompletely to nitrates; the symptom pattern helps select tests. It is not sufficiently specific to distinguish elevated resistance, spasm, or diffuse ischemia.
Epicardial spasm often causes pain at rest, at night, or in the morning, accompanied by transient ST-segment elevation or depression. Attacks may occur in clusters and alternate with long symptom-free periods; syncope during an episode increases concern for arrhythmias. A normal ECG between attacks does not substantially reduce suspicion.

Microvascular spasm may reproduce pain and ST-segment changes without marked angiographic constriction. The presentation may be indistinguishable from nonspastic MVA and requires functional testing. Episodicity makes a negative stress test between attacks possible. An inconclusive result is not compensated for by a diagnosis based solely on drug response.
Ischemia may be paucisymptomatic or silent, especially with diabetes and neuropathy, and present as reduced capacity or an instrumental abnormality. INOCA does not necessarily require angina, but the finding must be interpreted clinically; indiscriminate screening of asymptomatic people is not justified merely by the possibility of INOCA. Tests are performed when the result can change management.

The Seattle Angina Questionnaire measures frequency, limitation, and perception of disease; cardiopulmonary exercise testing quantifies capacity and may reveal multiple limitations. These instruments describe impact but do not demonstrate the ischemic mechanism; a baseline measurement allows therapeutic benefit to be assessed. Symptom improvement remains important even if physiological indices are not repeated.
Women with INOCA may have symptoms considered less typical, but variability exists in both sexes. Nausea, fatigue, and back pain must neither be excluded nor considered automatically cardiac; a detailed history avoids diagnostic stereotypes. Sex and age modify probability together with risk factors, ECG, and anatomy.

Migraine, Raynaud phenomenon, autoimmune diseases, and mood disorders may coexist; these associations guide the history and assessment of comorbidities but do not replace documented ischemia and function. A systemic phenotype may require rheumatology, neurology, or internal medicine. Care remains coordinated to avoid drugs with opposing vascular effects.
New or different prolonged pain with dyspnea, diaphoresis, or instability is treated as a possible acute event. The known diagnosis of INOCA may create anchoring and delay recognition of myocardial infarction or dissection; a change in pattern is essential clinical information. Serial ECG and troponin are used according to current risk.

Chronic suffering may cause avoidance and depression, while repeated explanations of ‘normality’ increase mistrust. A precise diagnosis acknowledges the mechanism without promising that every episode will disappear; quality of life is treated as a clinical outcome. Psychological support and rehabilitation supplement control of ischemia.
Instrumental evidence may precede or exceed the symptom: diabetic neuropathy, spontaneous reduction in activity, and diffuse ischemia may attenuate pain without normalizing physiology. Conversely, a high angina burden does not necessarily imply a more severe flow defect or greater immediate risk. Ischemic burden and symptom burden are described separately; this distinction allows both capacity and quality of life and prognostic indicators to be measured without using one as an automatic surrogate for the other.

Investigations and diagnosis

The first step confirms that the finding represents ischemia rather than artifact, scar, cardiomyopathy, or an acute imbalance. ECG, echocardiography, and laboratory tests define the context; CMR may characterize tissue when the diagnosis is uncertain. Validation of the finding precedes investigation for the endotype. An isolated low-quality test does not support a permanent diagnosis.
CCTA or coronary angiography excludes obstructive anatomy and describes plaque. Intermediate stenoses undergo FFR or nonhyperemic assessment because visual percentage may be misleading. FFR and iFR above 0.80 and 0.89, respectively, exclude a significant epicardial component in the assessed vessel. Diffuse disease, a distributed gradient, and the microcirculation remain to be assessed separately.

Exercise ECG may demonstrate ischemic changes but has limited accuracy and false positives. Echocardiography and SPECT seek regional abnormalities; uniform microvascular ischemia may not produce a clear difference among territories. Global balance is a known limitation of relative techniques. An examination is interpreted with the workload achieved, symptoms, ECG, and image quality.
PET measures absolute flow and myocardial reserve and is a validated method for CMD; radiation, availability, and tracer affect its use. Stress CMR assesses perfusion, function, and tissue without radiation but requires expertise and has specific limitations; quantification reduces dependence on regional comparison. Thresholds and software are not fully interchangeable across platforms.

Transthoracic Doppler of the left anterior descending artery may measure CFR in expert hands, with advantages of cost and no radiation. The acoustic window and assessment of a single territory limit generalizability; abnormal noninvasive CFR alone does not localize the epicardial or arteriolar component. The result is integrated with CCTA or other anatomical imaging.
In the laboratory, thermodilution or Doppler measures CFR and resistance during hyperemia. ESC 2024 uses CFR below 2.5 for both techniques; the value below 2.0 in the 2020 EAPCI consensus must be recognized as a previous criterion, not the sole current threshold. IMR of 25 or greater and HMR above 2.5 mmHg/(cm/s) indicate elevated resistance; EAPCI also reported 1.9 for HMR, while MRR below 2.7 is a less established emerging index. Adequate hyperemia is essential. Caffeine, medications, insufficient adenosine, blood pressure, and signal instability may produce misleading results, especially near the cutoff.

CFR is a continuous variable, and its prognostic significance does not appear suddenly when a threshold is crossed. A value between 2.0 and 2.5 may be classified differently under EAPCI 2020 and ESC 2024; PET, CMR, and transthoracic Doppler also require ranges validated for the platform and population. The borderline zone requires consistency among symptoms, ischemia, absolute flow, and resistance. Repeating a technically inadequate measurement is more appropriate than assigning biological precision to an unstable decimal.
Acetylcholine assesses the vasomotor response by integrating the usual symptom, twelve-lead ECG, angiographic caliber, and, when available, Doppler flow. The illustrative 2024 ESC protocol for the left coronary artery administers 2 and 20 micrograms for the low-dose response, then 100 and 200 micrograms to provoke spasm, each dose over approximately 60 seconds, and concludes with 200 micrograms of nitroglycerin. Symptom reproduction without ischemic changes is insufficient for a positive test. Escalation is stopped as soon as spasm occurs, and the laboratory must be ready to treat bradycardia, arrhythmias, and persistent constriction.

ESC proposes withholding calcium channel blockers and nitrates for at least 24 hours before vasomotor testing because these drugs may reduce sensitivity. The ILIAS ANOCA trial instead used a pragmatic protocol without mandatory withdrawal and demonstrated feasibility and high diagnostic yield; the two approaches prioritize different objectives and do not make results interchangeable. Pretest therapy must be documented. A negative examination during vasodilator treatment calls for more cautious interpretation, not necessarily another procedure.
The integrated diagnosis states whether ischemia is caused by CMD, spasm, diffuse disease, or a combination. If functional tests are normal, the validity of the ischemic evidence and alternative diagnoses are reassessed. Incongruence is not resolved by arbitrarily choosing the preferred finding. It may require image review or a genuinely discriminating complementary test.

CMR is essential when troponin or the clinical picture suggests myocarditis, Takotsubo syndrome, or previous myocardial infarction, conditions that do not automatically belong to chronic INOCA. Anemia, valvular heart disease, cardiomyopathies, and pulmonary disease may also produce stress findings; the differential diagnosis prevents a catch-all category. Each condition is treated according to its own criteria and prognosis.

Treatment and prognosis

The strategy combines prevention, control of ischemia, functional recovery, and treatment of associated conditions. The patient receives a description of the endotype and what remains uncertain; a measurable objective may be fewer episodes, a longer walking distance, or a better SAQ score. Normalization of a single test is not the only criterion of success.
Atherosclerosis and risk determine the use of statins, antiplatelet agents, and other preventive drugs. INOCA without plaque or an event does not automatically entail the same antithrombotic treatment as established atherosclerotic coronary artery disease; bleeding risk is balanced against expected benefit. Blood pressure, diabetes, kidney disease, and smoking are treated intensively according to specific indications.

In the phenotype with reduced CFR and elevated resistance, beta-blockers may reduce demand and improve perfusion time; ACE inhibitors, angiotensin receptor blockers, and statins address risk factors and may support vascular function. Calcium channel blockers or ranolazine are assessed according to response; evidence for microvascular therapy remains heterogeneous. Selection is individualized and does not imply a proven prognostic benefit for every drug.
In vasospasm, calcium channel blockers are the cornerstone; short-acting nitrates treat episodes and long-acting formulations may be added. Nonselective beta-blockers are avoided in pure epicardial spasm because they may accentuate vasoconstriction; smoking cessation is a priority. Precipitating drugs and substances are replaced when clinically possible.

Microvascular spasm may respond to calcium channel blockers, but results and doses vary. Combined forms require titration that avoids hypotension and bradycardia and controls multiple mechanisms; therapy guided by functional testing improves symptoms compared with unstratified management in CorMicA. It has not yet been demonstrated that this algorithm reduces major events.
ESC 2024 recommends invasive functional testing with class I, level B in persistently symptomatic patients despite therapy, with suspected ANOCA/INOCA and impaired quality of life. Therapy based on test results has class IIa, level A for improving symptoms and quality of life; calcium channel blockers for isolated vasospastic angina have class I, level A, while nitrates to prevent recurrences have class IIa, level B. The ESC classes concern specific questions and outcomes. They are not equivalent to evidence that the pathway reduces mortality or myocardial infarction in every endotype.

WARRIOR enrolled 2,476 women with suspected ANOCA/INOCA and compared a high-intensity statin, an ACE inhibitor or angiotensin receptor blocker, and aspirin with usual care. At approximately two and a half years, the composite outcome did not differ, with a hazard ratio of 1.13 and a confidence interval of 0.94 to 1.37; underenrollment, frequent preventive therapy in the control group, and contamination reduce the ability to exclude benefit. The WARRIOR result does not support an automatic preventive combination based solely on the acronym. The presence of plaque, a previous event, blood pressure, lipids, and bleeding risk retain their own indications.
In the ILIAS ANOCA trial, 153 patients were randomized after functional testing: a vasomotor disorder was present in 78%, and guided therapy improved the SAQ summary score by 9.4 points at six months. A 2026 CMR trial involving 250 patients achieved diagnostic reclassification in 53% and an adjusted 20.9-point advantage in the SAQ at twelve months. The available outcomes are primarily symptomatic and patient-reported. Neither study was powered to demonstrate fewer events, and CMR does not replace acetylcholine when vasospasm is the principal question.

Supervised exercise, weight control, sleep, and stress management improve capacity and risk factors. Activity is not generally prohibited because of ischemia, but prescribed according to stability and threshold; rehabilitation counters deconditioning and fear. In vasospasm with arrhythmias or syncope, the program is adapted after stabilization.
Follow-up reassesses symptoms, function, adherence, and new risk factors. A new stress test or coronary angiogram is indicated when the presentation changes and the result can modify therapy, not at fixed intervals for every patient; clinical surveillance includes signs of heart failure and arrhythmias. Unified documentation prevents repetition and enables reliable comparisons.

Severely reduced CFR is associated with events and mortality in PET and WISE studies, even without obstruction. Atherosclerosis, diabetes, kidney disease, ventricular function, and capacity complete the prognostic profile. The prognostic association does not demonstrate that correcting CFR eliminates risk. Prevention acts on determinants with proven benefit.
Angina frequency and risk of death do not coincide: a patient may be highly symptomatic with relatively limited risk or paucisymptomatic with severely abnormal physiology. Both dimensions are treated; communicated prognosis separates event risk from the expectation of relief. This avoids minimizing disability or overstating immediate danger.

Complications

Persistent angina, dyspnea, and reduced activity are frequent complications and drive hospitalizations and absence from work. Uncertainty may lead to repeated procedures that do not modify the mechanism; an endotype-specific diagnosis reduces the cycle of anatomical exclusion alone. Benefit is also measured through quality of life and resource use.
Myocardial infarction and cardiovascular death may occur, particularly with plaque, severe spasm, or diffuse dysfunction. Percentages depend on the population and cannot be transferred without context; stratification is updated when new factors or dysfunction appear. A previous coronary angiogram does not replace assessment of an acute event.

Prolonged epicardial spasm may cause necrosis, atrioventricular block, ventricular tachycardia or fibrillation, and arrest. Syncope and documented arrhythmia require intensive specialist management; prevention of recurrences remains fundamental even if a device is considered. A defibrillator does not treat the vasomotor cause.
CMD and low reserve are associated with diastolic dysfunction and risk of HFpEF. The relationship is bidirectional: elevated filling pressures may in turn impair the perfusion gradient; the appearance of congestion requires assessment and treatment for heart failure. It is not automatically attributed to microvascular ischemia.

Antianginal drugs may cause hypotension, bradycardia, edema, headache, constipation, and QT prolongation; these effects may further reduce capacity and confound assessment of progression. Tolerability is checked through blood pressure, heart rate, ECG, and symptoms. Combinations are simplified when benefit cannot be demonstrated.
Invasive tests and provocation carry vascular, arrhythmic, and kidney risks that are low but real. An experienced laboratory applies protocols, exclusion criteria, and immediate treatment of spasm; informed consent explains which decision depends on the result. A procedure is not performed if the answer would not change management.

Depression, anxiety, and catastrophizing may result from chronic pain and a fragmented diagnostic pathway. Treating them improves adherence and function without invalidating documented ischemia; mental health is assessed directly. Suicidal ideation or severe impairment requires prompt intervention.
A false-positive imaging result may lead to unnecessary diagnosis and therapy; a false negative may leave an endotype untreated. Review of quality and consistency among tests reduces both errors; pretest probability affects predictive value. Tests are not added indiscriminately to obtain the desired answer.

The diagnosis of INOCA must not obscure new or concomitant causes. Myocarditis, Takotsubo syndrome, embolism, SCAD, valvular heart disease, and pulmonary disease require distinct pathways; a clinical change reopens the differential diagnosis. Continuity of care enables rapid recognition of what does not belong to the previous pattern.