Carotid Artery Occlusion

Complex MONDO:0004450 Pathograph 28 Show in embeddings browser Vascular disorder

Carotid artery occlusion is complete obstruction of a carotid arterial lumen. This entry emphasizes atherosclerotic internal carotid artery occlusion, especially established extracranial or long-segment occlusion. Collateral circulation can preserve perfusion; inadequate compensation and artery-to-artery embolism can cause cerebral or retinal ischemia. Complete occlusion is distinct from severe stenosis and near-occlusion with residual flow. Acute ischemic stroke requires separate emergency assessment; chronic recanalization evidence cannot be substituted for acute stroke treatment evidence.

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11
Pathophys.
10
Phenotypes
28
Pathograph
2
Genes
6
Medical Actions
4
Trials
22
References
1
Deep Research
⚙

Pathophysiology

11
Carotid Intimal ApoB Lipoprotein Retention
Mechanism confidence: Established
Endothelial injury in the carotid arterial wall permits infiltration and retention of apoB-containing lipoproteins in the intima. Local modification of retained LDL initiates the inflammatory plaque-forming branch that can progress toward atherosclerotic carotid occlusion.
endothelial cell CL:0000115 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endothelial cell (CL:0000115). CL:0000115 is a cell type from the Cell Ontology.
cholesterol homeostasis GO:0042632 ↕ DYSREGULATED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated cholesterol homeostasis (GO:0042632). GO:0042632 is a biological process from the Gene Ontology.
internal carotid artery UBERON:0001532 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in internal carotid artery (UBERON:0001532). UBERON:0001532 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Carotid Monocyte Recruitment and Macrophage Foam Cell Formation Modified retained lipoproteins activate endothelium, recruit monocytes, and supply the substrate internalized by intimal macrophages.
Show evidence (1 reference)
PMID:26844337 SUPPORT DIRECT REVIEW SYNTHESIS Other
"infiltration and retention of apoB containing lipoproteins in the artery wall is a critical initiating event that sparks an inflammatory response and promotes the development of atherosclerosis."
Establishes arterial-wall apoB-lipoprotein retention as the conserved initiating event; the internal carotid artery is the disease-specific site.
Carotid Monocyte Recruitment and Macrophage Foam Cell Formation
Mechanism confidence: Established
Recruited carotid-intimal monocytes become macrophages, internalize modified apoB lipoproteins, and form lipid-laden foam cells. Macrophage inflammation amplifies LDL oxidation, endothelial activation, and additional monocyte recruitment in the plaque-forming branch.
macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology. foam cell CL:0000891 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves foam cell (CL:0000891). CL:0000891 is a cell type from the Cell Ontology.
foam cell differentiation GO:0090077 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased foam cell differentiation (GO:0090077). GO:0090077 is a biological process from the Gene Ontology. inflammatory response GO:0006954 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology.
internal carotid artery UBERON:0001532 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in internal carotid artery (UBERON:0001532). UBERON:0001532 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Atherosclerotic carotid plaque formation Foam-cell inflammatory mediators recruit and stimulate vascular smooth muscle cells, which switch phenotype and assemble the plaque matrix.
Show evidence (2 references)
PMID:26844337 SUPPORT DIRECT REVIEW SYNTHESIS Other
"Internalization of the apoB containing lipoproteins by macrophages promotes foam cell formation, which is the hallmark of the fatty streak phase of atherosclerosis."
Directly supports macrophage apoB-lipoprotein uptake and foam-cell differentiation in the conserved amplifier.
PMID:26844337 SUPPORT DIRECT REVIEW SYNTHESIS Other
"Macrophage inflammation results in enhanced oxidative stress and cytokine/chemokine secretion, causing more LDL/remnant oxidation, endothelial cell activation, monocyte recruitment, and foam cell formation."
Documents the feed-forward inflammatory loop that amplifies foam-cell formation.
Atherosclerotic carotid plaque formation
Mechanism confidence: Established
Smooth-muscle-cell proliferation and extracellular-matrix secretion assemble a fibrofatty carotid plaque with a fibrous cap. Progressive plaque growth provides a substrate for stenosis and eventual occlusion.
vascular smooth muscle cell CL:0000359 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves vascular smooth muscle cell, annotated with vascular associated smooth muscle cell (CL:0000359). CL:0000359 is a cell type from the Cell Ontology.
smooth muscle cell proliferation GO:0048661 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased smooth muscle cell proliferation, annotated with positive regulation of smooth muscle cell proliferation (GO:0048661). GO:0048661 is a biological process from the Gene Ontology. extracellular matrix organization GO:0030198 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased extracellular matrix organization (GO:0030198). GO:0030198 is a biological process from the Gene Ontology.
Downstream
Advanced carotid atheroma with necrotic core and fibrous cap Continued lipid accumulation, foam-cell death, and matrix remodeling mature the formed carotid plaque into a cap-and-core atheroma.
Complete carotid lumen obstruction Progressive atherosclerotic plaque can culminate in non-acute internal carotid occlusion, but the cohort does not resolve whether rupture, thrombosis, or chronic occlusive remodeling supplies the intermediates.
Show evidence (2 references)
PMID:26844337 SUPPORT DIRECT REVIEW SYNTHESIS Other
"Macrophage inflammatory chemoattractants stimulate infiltration and proliferation of smooth muscle cells. Smooth muscle cells produce the extracellular matrix providing a stable fibrous barrier between plaque prothrombotic factors and platelets."
Conserved plaque biology supports smooth-muscle proliferation and matrix production; carotid localization is supported by the carotid plaque review.
PMID:37303351 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"CS is seen undergoing almost the same pathogenesis of any atherosclerotic plaque formation, from endothelial damage of the artery lumen to the formation of a fibrous cap with a foam cell, lipid-filled core."
This review directly supports endothelial damage, fibrous cap formation, and foam-cell lipid core formation as carotid atherosclerotic plaque biology.
Advanced carotid atheroma with necrotic core and fibrous cap
Mechanism confidence: Established
Continued lipid accumulation, foam-cell death, and matrix remodeling produce an advanced carotid atheroma with a lipid-rich necrotic core enclosed by a fibrous cap. Neovascularization, intraplaque hemorrhage, cap thinning, and surface ulceration can destabilize the lesion. This optional mature-plaque stage is represented without assuming that it caused every chronic or non-acute occlusion in the cited cohorts.
vascular smooth muscle cell CL:0000359 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves vascular smooth muscle cell, annotated with vascular associated smooth muscle cell (CL:0000359). CL:0000359 is a cell type from the Cell Ontology.
extracellular matrix organization GO:0030198 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased extracellular matrix organization (GO:0030198). GO:0030198 is a biological process from the Gene Ontology.
internal carotid artery UBERON:0001532 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in internal carotid artery (UBERON:0001532). UBERON:0001532 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Carotid luminal thrombus formation Disruption of a vulnerable fibrous cap can expose prothrombotic plaque material and initiate thrombosis.
Show evidence (2 references)
DOI:10.3390/ijms25084351 SUPPORT DIRECT REVIEW SYNTHESIS Other
"In macroscopic evaluation, vulnerable plaques are characterized by one or more of the following features: microcalcification; neovascularization; lipid-rich necrotic cores (LRNCs); intraplaque hemorrhage (IPH); thin fibrous caps; plaque surface ulceration; huge dimensions, suggesting stenosis;..."
Directly establishes the necrotic-core, fibrous-cap, hemorrhagic, and surface features of an advanced carotid atheroma.
PMID:37595697 SUPPORT DIRECT REVIEW SYNTHESIS Other
"the local arterial microenvironment of a stable atheroma promotes destabilizing conditions that result in the transition to an unstable atheroma."
Supports maturation and destabilization of a formed atheroma without asserting that destabilization is the only route to chronic occlusion.
Carotid luminal thrombus formation
Mechanism confidence: Established
Thrombus can form on disrupted carotid atheroma and become organized in chronic occlusion. The initiating thrombotic event is not reconstructed by chronic surgical specimens alone.
Downstream
Complete carotid lumen obstruction Plaque and superimposed thrombus can occlude the carotid lumen.
Show evidence (2 references)
PMID:26844337 SUPPORT DIRECT REVIEW SYNTHESIS Other
"Rupture of the thinning fibrous cap promotes thrombus formation resulting in clinical ischemic ASCVE."
Supports the rupture-associated thrombosis branch of atherogenesis; rupture is not assumed in every chronic occlusion.
PMID:37813974 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The clot was white organized at the carotid bifurcation and proximal segment of the internal carotid artery (ICA), old dark red in the middle ICA and old red in the distal ICA segment."
Operative observation in a chronic ICA occlusion illustrates organized thrombus; it does not identify the initiating event in all patients.
Complete carotid lumen obstruction
Mechanism confidence: Established
Atherosclerotic plaque with variable superimposed thrombus or occlusive remodeling abolishes antegrade flow through the involved carotid segment.
Downstream
Carotid artery occlusion Complete luminal obstruction defines the vascular phenotype.
Inadequate collateral cerebral perfusion Downstream hemodynamic compromise develops when collateral circulation cannot compensate for occlusion.
Collateral-route artery-to-artery embolization Thrombus in an occluded ICA stump or adjacent carotid plaque can remain an embolic source through collateral pathways.
Retinal perfusion failure Inadequate collateral ocular supply after carotid occlusion can cause chronic retinal hypoperfusion.
Show evidence (2 references)
PMID:38740919 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"patients with ICA occlusion caused by either proximal or distal atherosclerotic plaques"
The atherosclerotic surgical cohort documents the plaque-associated occlusive lesion.
PMID:37813974 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The clot was white organized at the carotid bifurcation and proximal segment of the internal carotid artery (ICA), old dark red in the middle ICA and old red in the distal ICA segment."
Operative observation in a chronic ICA occlusion illustrates organized thrombus; it does not identify the initiating event in all patients.
Inadequate collateral cerebral perfusion
Mechanism confidence: Established
When circle-of-Willis and external-carotid collateral supply is insufficient, cerebral perfusion pressure falls. Compensatory resistance-vessel dilation may preserve flow initially, but exhausts cerebrovascular reserve.
Downstream
Cerebral oxygen-extraction compensation Increased oxygen extraction compensates when vasodilation no longer maintains normal blood flow.
Cerebral tissue ischemic injury Insufficient collateral supply can cause cerebral ischemia and borderzone injury.
Limb-shaking transient ischemic attack Severe hemodynamic compromise can cause transient involuntary limb movements.
Show evidence (2 references)
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"In chronic ICA occlusion, collateral circulation may maintain cerebral perfusion. Failure of collateralisation may contribute to the haemodynamic compromise."
Explains why complete occlusion can be compensated or cause hemodynamic failure.
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"If collateralisation is inadequate, CBF can be maintained despite reduced cerebral perfusion pressure by dilatation of the resistance vessels (cerebral autoregulation)."
Describes compensatory autoregulation.
Cerebral oxygen-extraction compensation
Mechanism confidence: Established
Increased oxygen extraction sustains cerebral metabolism when blood flow falls despite maximal autoregulatory vasodilation. This stage II hemodynamic failure marks a high-risk state; increased extraction is compensatory, not itself the cause of stroke.
Show evidence (2 references)
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"When autoregulatory vasodilatation fails to maintain normal CBF, oxygen extraction fraction (OEF) of the affected brain tissue increases to maintain normal cerebral metabolism, the so‐called stage II haemodynamic failure or misery perfusion."
Describes increased oxygen extraction after autoregulatory compensation becomes insufficient.
PMID:22068990 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Patients with arteriographically confirmed AICAO causing hemispheric symptoms within 120 days and hemodynamic cerebral ischemia identified by ipsilateral increased oxygen extraction fraction measured by PET."
COSS enrolled symptomatic atherosclerotic ICA occlusion with objective hemodynamic impairment.
Collateral-route artery-to-artery embolization
Mechanism confidence: Established
Embolic material from proximal or distal ICA stumps or adjacent carotid plaques reaches cerebral or retinal vessels through collateral channels. Embolic and hemodynamic mechanisms may coexist.
Downstream
Cerebral tissue ischemic injury Embolic obstruction can cause cerebral ischemia.
Retinal perfusion failure Embolic obstruction can impair retinal circulation.
Show evidence (1 reference)
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Embolism from the distal or proximal stump or from atherosclerotic plaques in the common carotid artery or ECA, which traverse through the collateral pathways involving the ECA."
Identifies embolic sources and collateral routes despite complete ICA occlusion.
Cerebral tissue ischemic injury
Mechanism confidence: Established
Reduced cerebral blood flow from hemodynamic failure or embolic obstruction causes transient dysfunction or persistent infarction, depending on severity and duration.
Downstream
Cerebral ischemia The physiologic disturbance is reflected by cerebral ischemia.
Transient ischemic attack Transient ischemic dysfunction causes hemispheric TIA.
Ischemic stroke Persistent ischemic injury causes ipsilateral infarction.
Limb weakness Ischemic dysfunction can produce this manifestation in the affected tissue.
Speech disturbance Ischemic dysfunction can produce this manifestation in the affected tissue.
Show evidence (2 references)
PMID:22068990 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Patients with arteriographically confirmed AICAO causing hemispheric symptoms within 120 days and hemodynamic cerebral ischemia identified by ipsilateral increased oxygen extraction fraction measured by PET."
COSS enrolled symptomatic atherosclerotic ICA occlusion with objective hemodynamic impairment.
PMID:22068990 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"TIA or ischemic stroke in the hemispheric territory of an occluded internal carotid artery within 120 days."
Published COSS eligibility directly documents ipsilateral TIA and ischemic stroke presentations.
Retinal perfusion failure
Mechanism confidence: Established
Retinal embolism or sustained ocular hypoperfusion produces transient monocular blindness or chronic ocular ischemia. This manifestation is not obligatory in carotid occlusion.
Downstream
Amaurosis fugax Transient retinal ischemia produces monocular visual loss.
Progressive visual loss Chronic ocular ischemia may impair visual acuity progressively.
Retinal hemorrhage Ischemic dysfunction can produce this manifestation in the affected tissue.
Show evidence (2 references)
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"ICA occlusion can produce brain or retinal ischaemia by the following mechanisms:"
Introduces the review's explicitly enumerated embolic and hemodynamic mechanisms.
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"An episode of transient monocular blindness (amaurosis fugax) is highly suggestive of ICA disease proximal to the ophthalmic branch."
The disease-specific clinical review identifies amaurosis fugax as an ocular ischemic presentation.
⬡

Pathograph

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Pathograph: causal mechanism network for Carotid Artery Occlusion Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

10
Blood 1
Retinal hemorrhage HP:0000573 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Retinal hemorrhage (HP:0000573). HP:0000573 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"mid‐peripheral microaneurysms and small dot‐and‐blot intraretinal haemorrhages, arterial narrowing and venous dilatation,"
Describes retinal findings of chronic ocular ischemia in severe ICA disease, including occlusion.
Cardiovascular 5
Carotid artery occlusion HP:0012474 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Carotid artery occlusion (HP:0012474). HP:0012474 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38740919 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"patients with ICA occlusion caused by either proximal or distal atherosclerotic plaques"
The atherosclerotic surgical cohort documents the plaque-associated occlusive lesion.
Ischemic stroke HP:0002140 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ischemic stroke (HP:0002140). HP:0002140 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22068990 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"TIA or ischemic stroke in the hemispheric territory of an occluded internal carotid artery within 120 days."
Published COSS eligibility directly documents ipsilateral TIA and ischemic stroke presentations.
Transient ischemic attack HP:0002326 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Transient ischemic attack (HP:0002326). HP:0002326 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22068990 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"TIA or ischemic stroke in the hemispheric territory of an occluded internal carotid artery within 120 days."
Published COSS eligibility directly documents ipsilateral TIA and ischemic stroke presentations.
Limb-shaking transient ischemic attack RARE HP:0002326 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Transient ischemic attack (HP:0002326). HP:0002326 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"A rare manifestation of haemodynamic compromise in patients with ICA occlusion is limb shaking."
Identifies the uncommon hemodynamic limb-shaking TIA presentation, which can mimic focal seizures.
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"The patients complain of repetitive involuntary movements of one or both limbs on one side. This is often misdiagnosed as partial seizures."
Describes the movement pattern and diagnostic pitfall.
Cerebral ischemia HP:0002637 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebral ischemia (HP:0002637). HP:0002637 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22068990 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Patients with arteriographically confirmed AICAO causing hemispheric symptoms within 120 days and hemodynamic cerebral ischemia identified by ipsilateral increased oxygen extraction fraction measured by PET."
COSS enrolled symptomatic atherosclerotic ICA occlusion with objective hemodynamic impairment.
Eye 2
Amaurosis fugax HP:0100576 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Amaurosis fugax (HP:0100576). HP:0100576 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"An episode of transient monocular blindness (amaurosis fugax) is highly suggestive of ICA disease proximal to the ophthalmic branch."
The disease-specific clinical review identifies amaurosis fugax as an ocular ischemic presentation.
Progressive visual loss HP:0000529 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive visual loss (HP:0000529). HP:0000529 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Patients complain of progressive loss of visual acuity."
In the chronic ocular ischemia paragraph, this describes progressive visual loss in severe carotid disease, including occlusion.
Limbs 1
Limb weakness Limb muscle weakness HP:0003690 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Limb muscle weakness (HP:0003690). HP:0003690 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37813974 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The transient ischemic attack symptoms were reversible, including slight limb weakness in 71 (81.6%) patients, unclear speech in 32 (36.8%),"
The cohort directly reports reversible limb weakness and speech symptoms.
Nervous System 1
Speech disturbance Abnormal speech pattern HP:0002167 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal speech pattern (HP:0002167). HP:0002167 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37813974 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The transient ischemic attack symptoms were reversible, including slight limb weakness in 71 (81.6%) patients, unclear speech in 32 (36.8%),"
The source supports nonspecific speech disturbance without a finer language or articulation diagnosis.
🧬

Genetic Associations

2
Shared cardiometabolic and stroke susceptibility loci (indirect context) (Risk Factor)
Show evidence (1 reference)
PMID:39730871 SUPPORT INDIRECT PRIMARY RESULT Computational
"The 11 loci were mapped to 12 genes, namely CASZ1, CDKN1A, TWIST1, CDKN2B, ABO, SWAP70, SH2B3, LRCH1, FES, GOSR2, RPRML, and LDLR, where both GOSR2 and RPRML were mapped to one locus."
The reported loci relate to the study's cardiovascular, cerebrovascular, and risk-factor traits; extrapolation to complete carotid occlusion is indirect.
Diabetes-associated genetic markers and carotid plaque (Risk Factor)
Show evidence (2 references)
PMID:36894991 SUPPORT INDIRECT PRIMARY RESULT Human Clinical
"We identified 9 DM SNPs showing promising associations with CP."
Exploratory association with carotid plaque, not complete carotid artery occlusion.
PMID:36894991 SUPPORT INDIRECT PRIMARY RESULT Human Clinical
"To reduce the influence of false negativity, we used 0.10 as the pre-set inclusion criteria of promising SNPs."
The full-text methods explain the exploratory threshold; not all nine SNPs were conventionally significant.
💊

Medical Actions

6
Antiplatelet therapy for secondary prevention
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: aspirin CHEBI:15365 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses aspirin, annotated with acetylsalicylic acid (CHEBI:15365). CHEBI:15365 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Antiplatelet treatment is part of medical management of symptomatic atherosclerotic carotid occlusion. Aspirin or clopidogrel were used in CMOSS. This does not establish routine anticoagulation or indefinite dual-antiplatelet therapy for all occlusions.
Show evidence (2 references)
PMID:37606672 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Medical therapy included antiplatelet therapy and stroke risk factor control."
Documents baseline care in both CMOSS arms; not an isolated trial of each medical component.
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC10445185/ SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Aspirin (100 mg/day) or clopidogrel (75 mg/day) was prescribed to the patient"
The CMOSS methods describe the single-antiplatelet options used; these trial doses are not individualized prescribing advice.
Lipid and vascular risk-factor management
Action: Serum Lipid Lowering TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Serum Lipid Lowering Therapy (NCIT:C222204). NCIT:C222204 is a clinical intervention from the NCI Thesaurus. NCIT:C222204
Secondary prevention includes lipid lowering, blood-pressure and diabetes management, smoking cessation, and lifestyle measures. Treatment is individualized when symptomatic hemodynamic compromise is present.
Show evidence (3 references)
PMID:37606672 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Medical therapy included antiplatelet therapy and stroke risk factor control."
Documents baseline care in both CMOSS arms; not an isolated trial of each medical component.
PMID:22068990 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Antithrombotic therapy and risk factor intervention were recommended for all participants."
Medical prevention was foundational in both COSS groups.
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"modifications of risk factors—for example, hypertension, diabetes, hyperlipidaemia and smoking—are vital secondary prevention measures."
Supports the disease-specific secondary-prevention components.
Extracranial-intracranial bypass under continued investigation
Action: BypassNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Bypass (NCIT:C15723). NCIT:C15723 is a clinical intervention from the NCI Thesaurus. NCIT:C15723
Platform: Surgery
Superficial-temporal-to-middle-cerebral artery bypass improves blood supply beyond the occlusion, but COSS and the prespecified two-year CMOSS analysis did not establish net clinical benefit over medical therapy. Extended CMOSS follow-up at median 7.6 years suggested a possible benefit on the composite primary outcome; it was post hoc, had substantial missing follow-up, and did not show significant secondary-outcome or per-protocol benefit. Routine benefit for chronic atherosclerotic ICA occlusion is therefore not established.
Mechanism Target:
BYPASSES Complete carotid lumen obstruction — The graft supplies the distal cerebral circulation without reopening the carotid lesion; physiologic improvement does not guarantee net stroke prevention.
Show evidence (1 reference)
PMID:22068990 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"In spite of excellent graft patency and improved cerebral hemodynamics in the surgical group, EC-IC bypass surgery failed to provide an overall benefit on 2-year stroke recurrence."
Separates the hemodynamic mechanism from the clinical endpoint.
Show evidence (4 references)
PMID:22068990 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Among participants with recently symptomatic AICAO and hemodynamic cerebral ischemia, EC-IC bypass surgery plus medical therapy compared with medical therapy alone did not reduce the risk of recurrent ipsilateral ischemic stroke at 2 years."
COSS found no two-year clinical benefit despite improved graft patency and hemodynamics.
PMID:37606672 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Among patients with symptomatic ICA or MCA occlusion and hemodynamic insufficiency, the addition of bypass surgery to medical therapy did not significantly change the risk of the composite outcome of stroke or death within 30 days or ipsilateral ischemic stroke beyond 30 days through 2 years."
Neutral prespecified two-year CMOSS endpoint; the trial included ICA and MCA occlusions.
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC12100504/ SUPPORT DIRECT PRIMARY RESULT Human Clinical
"there was a possible longer-term benefit in reducing the primary outcome among patients who received EC-IC bypass surgery plus medical treatment vs medical treatment alone."
Post hoc extended CMOSS follow-up suggests a possible longer-term benefit, not a new independent trial.
+ 1 more reference
Selected endovascular or hybrid recanalization
Action: Surgical ProcedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. NCIT:C15329
Platform: Surgery
Specialist series describe reopening selected symptomatic non-acute or chronic ICA occlusions using endovascular treatment or hybrid plaque removal and stenting. Technical success in retrospective single-center cohorts does not establish superiority over medical treatment; the cohorts may overlap and follow-up was incomplete. This differs from established endarterectomy indications for residual-lumen stenosis.
Mechanism Target:
INHIBITS Complete carotid lumen obstruction — Successful recanalization removes or traverses the occlusive material to restore luminal flow.
Show evidence (2 references)
PMID:38740919 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"patients with ICA occlusion caused by either proximal or distal atherosclerotic plaques"
The atherosclerotic surgical cohort documents the plaque-associated occlusive lesion.
PMID:37813974 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Immediately after stenting with two stents, the carotid artery was patent."
Operative imaging example demonstrates restored patency.
Show evidence (3 references)
PMID:37813974 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"the total success recanalization rate was 94.3%, whereas the success recanalization rate was 95.5% for the hybrid surgery and 93.0% for the endovascular approach."
Selected 87-patient retrospective cohort; technical success, not comparative stroke-prevention efficacy.
PMID:38740919 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The total successful recanalization rate was 97.5% (158/162) with a failure rate of 2.5% (4/162)."
A second selected single-center series; not an independent randomized comparison.
PMID:38740919 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Some limitations existed in our study, including the single-center and retrospective study design, no randomization, and a small cohort of patients, which may all affect the generalization of the outcomes."
Explicitly limits generalization of the recanalization results.
Intravenous thrombolysis for eligible acute ischemic stroke
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: alteplase CHEBI:749459 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses alteplase (CHEBI:749459). CHEBI:749459 is a therapeutic agent from Chemical Entities of Biological Interest. tenecteplase CHEBI:753718 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses tenecteplase (CHEBI:753718). CHEBI:753718 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Other
When carotid occlusion presents with acute disabling ischemic stroke, emergency stroke evaluation determines eligibility for intravenous alteplase or tenecteplase using timing, imaging, and contraindications. This acute reperfusion pathway is separate from management of established chronic occlusion.
Mechanism Target:
INHIBITS Cerebral tissue ischemic injury — Timely reperfusion can limit acute ischemic injury in patients who meet stroke-treatment eligibility criteria.
Show evidence (1 reference)
url:https://newsroom.heart.org/news/new-guideline-expands-stroke-treatment-for-adults-offers-first-pediatric-stroke-guidance SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"The guideline endorses the use of either tenecteplase or alteplase within 4.5 hours of symptom onset. Both medications are effective at dissolving blood clots."
The AHA's official 2026 guideline summary supports IV thrombolysis in eligible acute ischemic stroke, not elective reopening of chronic carotid occlusion.
Target Phenotypes: Ischemic stroke HP:0002140 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Ischemic stroke (HP:0002140). HP:0002140 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://newsroom.heart.org/news/new-guideline-expands-stroke-treatment-for-adults-offers-first-pediatric-stroke-guidance SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"The guideline endorses the use of either tenecteplase or alteplase within 4.5 hours of symptom onset. Both medications are effective at dissolving blood clots."
The AHA's official 2026 guideline summary supports IV thrombolysis in eligible acute ischemic stroke, not elective reopening of chronic carotid occlusion.
Mechanical thrombectomy for eligible acute intracranial large-vessel occlusion
Action: Thrombectomy for StrokeNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Thrombectomy for Stroke (NCIT:C191635). NCIT:C191635 is a clinical intervention from the NCI Thesaurus. NCIT:C191635
Platform: Surgery
Patients with acute stroke from an eligible intracranial large-vessel blockage, including a carotid-related tandem presentation, may undergo emergency thrombectomy after stroke-team assessment. These recommendations do not establish benefit from elective reopening of an isolated chronic cervical carotid occlusion.
Mechanism Target:
INHIBITS Cerebral tissue ischemic injury — Timely reperfusion can limit acute ischemic injury in patients who meet stroke-treatment eligibility criteria.
Show evidence (1 reference)
url:https://newsroom.heart.org/news/new-guideline-expands-stroke-treatment-for-adults-offers-first-pediatric-stroke-guidance SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Removing clots directly from blocked brain arteries, a procedure called thrombectomy, remains a powerful treatment for major strokes caused by large-vessel blockages in eligible patients."
Acute intracranial large-vessel occlusion treatment is distinct from chronic isolated cervical ICA recanalization.
Target Phenotypes: Ischemic stroke HP:0002140 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Ischemic stroke (HP:0002140). HP:0002140 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://newsroom.heart.org/news/new-guideline-expands-stroke-treatment-for-adults-offers-first-pediatric-stroke-guidance SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Removing clots directly from blocked brain arteries, a procedure called thrombectomy, remains a powerful treatment for major strokes caused by large-vessel blockages in eligible patients."
Acute intracranial large-vessel occlusion treatment is distinct from chronic isolated cervical ICA recanalization.
🌍

Environmental Factors

3
Hypertension
Major atherosclerotic and stroke risk factor associated with carotid plaque development.
Show evidence (1 reference)
PMID:37303351 SUPPORT REVIEW SYNTHESIS Human Clinical
"comorbid hypertension, diabetes, and chronic kidney disease (CKD), and lifestyle aspects, including smoking and diet, played the most salient role in plaque development."
The review explicitly identifies hypertension among the salient factors in carotid plaque development.
Mechanism Target:
PREDISPOSES Atherosclerotic carotid plaque formation — This risk factor predisposes to carotid plaque through intervening endothelial and inflammatory atherogenic processes; the citation addresses atherosclerosis rather than a direct occlusion-specific effect.
Show evidence (1 reference)
PMID:37303351 SUPPORT REVIEW SYNTHESIS Human Clinical
"comorbid hypertension, diabetes, and chronic kidney disease (CKD), and lifestyle aspects, including smoking and diet, played the most salient role in plaque development."
Review naming comorbid hypertension among the factors that played the most salient role in plaque development, connecting the exposure to this node's own process rather than to the disease in general.
Diabetes mellitus
Diabetes is a cardiometabolic risk factor for carotid plaque and atherosclerotic disease.
Show evidence (1 reference)
PMID:36894991 SUPPORT BACKGROUND Human Clinical
"Diabetes mellitus (DM) is a well-established determinant of atherosclerosis and cardiovascular diseases (CVD)."
This supports diabetes as a determinant of atherosclerosis relevant to carotid plaque formation.
Mechanism Target:
PREDISPOSES Atherosclerotic carotid plaque formation — This risk factor predisposes to carotid plaque through intervening endothelial and inflammatory atherogenic processes; the citation addresses atherosclerosis rather than a direct occlusion-specific effect.
Show evidence (1 reference)
PMID:36894991 SUPPORT BACKGROUND Human Clinical
"Diabetes mellitus (DM) is a well-established determinant of atherosclerosis and cardiovascular diseases (CVD)."
States that diabetes is a well-established determinant of atherosclerosis, the process this node carries, in a study whose subject is carotid atherosclerosis specifically.
Smoking and diet
Smoking and diet are modifiable lifestyle factors contributing to carotid plaque development.
Show evidence (1 reference)
PMID:37303351 SUPPORT REVIEW SYNTHESIS Human Clinical
"lifestyle aspects, including smoking and diet, played the most salient role in plaque development."
This directly supports smoking and diet as lifestyle contributors to carotid plaque development.
Mechanism Target:
PREDISPOSES Atherosclerotic carotid plaque formation — This risk factor predisposes to carotid plaque through intervening endothelial and inflammatory atherogenic processes; the citation addresses atherosclerosis rather than a direct occlusion-specific effect.
Show evidence (1 reference)
PMID:37303351 SUPPORT REVIEW SYNTHESIS Human Clinical
"lifestyle aspects, including smoking and diet, played the most salient role in plaque development."
The same review names smoking and diet as the lifestyle aspects playing the most salient role in plaque development, which is the process at this node.
🔬

Diagnosis

3
Duplex ultrasonography and confirmation of complete occlusion
Duplex ultrasound assesses flow in the cervical ICA. CTA or contrast-enhanced MRA helps distinguish absent patency from very slow residual flow or a distal lesion. Near-occlusion and pseudo-occlusion require careful distinction before a procedural decision.
Show evidence (3 references)
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"ICA occlusion is characterised by the absence of any signal along the extracranial course of the ICA"
Describes the Doppler flow finding of complete occlusion.
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Single‐row detector CTA can distinguish total ICA occlusion from hairline residual lumen with a high degree of accuracy."
Supports distinguishing complete occlusion from residual patency; no stenosis accuracy estimate is transferred to occlusion.
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"However, it may be difficult to differentiate near‐occlusion from a complete occlusion."
Describes the ultrasound diagnostic limitation.
Catheter angiography for unresolved anatomy or intervention planning
Digital subtraction angiography defines the occluded segment and collateral routes when noninvasive tests are inconclusive or a procedure is being planned.
Show evidence (1 reference)
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Digital subtraction angiography is the “gold standard” imaging modality for the evaluation of carotid occlusive disease."
Supports angiographic confirmation; invasiveness limits routine use.
Hemodynamic assessment
PET oxygen-extraction measurement and CT or MR perfusion characterize collateral insufficiency. Hemodynamic selection identifies risk, but does not by itself establish benefit from bypass.
Show evidence (2 references)
PMID:22068990 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Patients with arteriographically confirmed AICAO causing hemispheric symptoms within 120 days and hemodynamic cerebral ischemia identified by ipsilateral increased oxygen extraction fraction measured by PET."
COSS enrolled symptomatic atherosclerotic ICA occlusion with objective hemodynamic impairment.
PMID:37606672 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"A total of 324 patients with ICA or MCA occlusion with transient ischemic attack or nondisabling ischemic stroke attributed to hemodynamic insufficiency based on computed tomography perfusion imaging"
CMOSS used CT perfusion for hemodynamic selection.
🩻

Imaging Findings

2
Absent extracranial ICA Doppler flow
Duplex ultrasound demonstrates absent flow signal along the extracranial ICA; extremely slow residual flow must be excluded.
Ultrasound
Carotid artery occlusion HP:0012474 Human Phenotype Ontology (HP)
Show evidence (1 reference)
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"ICA occlusion is characterised by the absence of any signal along the extracranial course of the ICA"
Describes the Doppler flow finding of complete occlusion.
Increased hemispheric oxygen extraction on PET
An elevated ipsilateral oxygen-extraction fraction indicates stage II hemodynamic compromise in selected symptomatic ICA occlusion.
Pet
Show evidence (2 references)
PMID:22068990 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Patients with arteriographically confirmed AICAO causing hemispheric symptoms within 120 days and hemodynamic cerebral ischemia identified by ipsilateral increased oxygen extraction fraction measured by PET."
COSS enrolled symptomatic atherosclerotic ICA occlusion with objective hemodynamic impairment.
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"When autoregulatory vasodilatation fails to maintain normal CBF, oxygen extraction fraction (OEF) of the affected brain tissue increases to maintain normal cerebral metabolism, the so‐called stage II haemodynamic failure or misery perfusion."
Describes increased oxygen extraction after autoregulatory compensation becomes insufficient.
🪜

Stages

2
Non-acute occlusion (cohort-specific threshold)
One 2024 atherosclerotic long-segment ICA cohort defined non-acute occlusion as more than seven days. This is an operational research threshold rather than a universal disease stage.
Show evidence (1 reference)
PMID:38740919 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"patients with non-acute (> 7 days) atherosclerotic ICA long-segment occlusion"
Specifies this cohort's temporal eligibility definition.
Chronic occlusion (cohort-specific threshold)
A 2023 cohort required at least three weeks of ICA occlusion after imaging confirmation. Organized thrombus may complicate reopening; this threshold is not interchangeable with every trial's non-acute definition.
Show evidence (1 reference)
PMID:37813974 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"chronic atherosclerotic occlusion was defined as ICA occlusion over 3 weeks after imaging confirmation."
States the study-specific definition.
🌍

Epidemiology

2
Spontaneous recanalization in heterogeneous occlusion cohorts
A 2025 scoping review found a median recanalization proportion of 21.2% across 17 cohorts, with 39.7% in dissection studies and 8.75% in non-dissection studies. These are medians of heterogeneous study proportions, not a pooled probability for atherosclerotic occlusion. Timing of detection, incomplete surveillance, and possible misclassified near-occlusion limit interpretation.
Show evidence (2 references)
PMID:40644384 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"When broken down by etiology, median proportion was 39.7% (IQR 32.8–54.3%) in dissection studies vs. 8.75% (IQR 5.70–10.5%) in non-dissection studies."
Stratified full-text results prevent applying the mixed-etiology estimate to atherosclerotic occlusion.
PMID:40644384 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"there is no apparent consensus regarding the management of carotid recanalization whether symptomatic or not."
The review does not establish a surveillance interval or routine intervention after recanalization.
Recurrent stroke in hemodynamically compromised symptomatic occlusion
In COSS, the two-year primary-event rate in the medically treated group was 22.7%. This is a selected recently symptomatic ICA-occlusion population with increased PET oxygen extraction, not an estimate for asymptomatic or well-collateralized occlusion.
Show evidence (1 reference)
PMID:22068990 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Two-year rates for the primary end point were 21.0% (95% CI, 12.8% to 29.2%; 20 events) for the surgical group and 22.7% (95% CI, 13.9% to 31.6%; 20 events) for the nonsurgical group"
Provides the selected-trial event rates; both groups received medical prevention.
🔬

Clinical Trials

4
NCT00029146 PHASE_III TERMINATED
COSS randomized 195 patients with recently symptomatic atherosclerotic ICA occlusion and increased PET oxygen extraction. The trial stopped early for futility. Two-year primary-event rates were 21.0% with bypass and 22.7% with medical therapy alone; perioperative strokes offset physiologic benefit.
Target Phenotypes: Ischemic stroke HP:0002140 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Ischemic stroke (HP:0002140). HP:0002140 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
clinicaltrials:NCT00029146 SUPPORT Human Clinical
"The purpose of this study is to determine if extracranial-intracranial bypass surgery when added to best medical therapy can reduce the subsequent risk of ipsilateral stroke in high-risk patients with recently symptomatic carotid occlusion and increased cerebral oxygen extraction fraction..."
The study directly targets stroke prevention in high-risk symptomatic carotid occlusion.
PMID:22068990 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Among participants with recently symptomatic AICAO and hemodynamic cerebral ischemia, EC-IC bypass surgery plus medical therapy compared with medical therapy alone did not reduce the risk of recurrent ipsilateral ischemic stroke at 2 years."
COSS found no two-year clinical benefit despite improved graft patency and hemodynamics.
PMID:22068990 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"The trial was terminated early for futility."
The publication agrees with the registry's TERMINATED status.
NCT01758614 PHASE_III COMPLETED
CMOSS compared EC-IC bypass plus medical therapy with medical therapy alone in 324 eligible patients with symptomatic ICA or MCA occlusion and CT-perfusion-defined hemodynamic insufficiency. The prespecified two-year composite endpoint was neutral. Post hoc extended follow-up suggested a possible longer-term benefit with important attrition and analysis limitations.
Target Phenotypes: Ischemic stroke HP:0002140 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Ischemic stroke (HP:0002140). HP:0002140 is a phenotype from the Human Phenotype Ontology.
Show evidence (4 references)
clinicaltrials:NCT01758614 SUPPORT DIRECT BACKGROUND Human Clinical
"the CMOSS study in China is designed to compare the efficacy and safety of EC-IC bypass surgery with medical therapy in patients with symptomatic hemodynamically significant carotid occlusion."
The registry states the trial objective; efficacy conclusions come from the published randomized results and qualified long-term follow-up.
PMID:37606672 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"Among patients with symptomatic ICA or MCA occlusion and hemodynamic insufficiency, the addition of bypass surgery to medical therapy did not significantly change the risk of the composite outcome of stroke or death within 30 days or ipsilateral ischemic stroke beyond 30 days through 2 years."
Neutral prespecified two-year CMOSS endpoint; the trial included ICA and MCA occlusions.
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC12100504/ SUPPORT DIRECT PRIMARY RESULT Human Clinical
"there was a possible longer-term benefit in reducing the primary outcome among patients who received EC-IC bypass surgery plus medical treatment vs medical treatment alone."
Post hoc extended CMOSS follow-up suggests a possible longer-term benefit, not a new independent trial.
+ 1 more reference
NCT03179774 NOT_APPLICABLE RECRUITING
ERCAO trial of endovascular revascularization plus optimal medical therapy versus optimal medical therapy alone for chronic carotid artery occlusion.
Target Phenotypes: Carotid artery occlusion HP:0012474 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Carotid artery occlusion (HP:0012474). HP:0012474 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT03179774 SUPPORT Human Clinical
"The investigators conduct a prospective study composed of clinical registry arm and RCT arm."
Registry summary describes the planned study design; it does not report efficacy results.
NCT06303414 NOT_APPLICABLE RECRUITING
Observational cohort study of recanalization treatment for symptomatic non-acute carotid artery occlusion comparing CEA, endovascular intervention, and hybrid surgery.
Target Phenotypes: Carotid artery occlusion HP:0012474 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Carotid artery occlusion (HP:0012474). HP:0012474 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT06303414 SUPPORT Human Clinical
"The purpose of this cohort study is to observe the success rate, efficacy and safety of recanalization treatment for non-acute occlusion, and to further compare the advantages and disadvantages of CEA, endovascular intervention and hybrid surgery."
Registry summary describes the planned study design; it does not report efficacy results.
{ }

Source YAML

click to show 
name: Carotid Artery Occlusion
creation_date: '2026-05-06T03:11:16Z'
description: Carotid artery occlusion is complete obstruction of a carotid arterial lumen. This entry emphasizes atherosclerotic internal carotid artery occlusion, especially established extracranial or long-segment occlusion. Collateral circulation can preserve perfusion; inadequate compensation and artery-to-artery embolism can cause cerebral or retinal ischemia. Complete occlusion is distinct from severe stenosis and near-occlusion with residual flow. Acute ischemic stroke requires separate emergency assessment; chronic recanalization evidence cannot be substituted for acute stroke treatment evidence.
category: Complex
disease_term:
  preferred_term: carotid artery occlusion
  term:
    id: MONDO:0004450
    label: carotid artery occlusion
parents:
- Vascular disorder
synonyms:
- Carotid occlusive disease
- Internal carotid artery occlusion
- Extracranial internal carotid artery occlusion
- Chronic carotid artery occlusion
- Non-acute carotid artery occlusion
pathophysiology:
- name: Carotid Intimal ApoB Lipoprotein Retention
  role: trigger
  conforms_to: atherogenesis#Endothelial Dysfunction and Subendothelial LDL Retention
  description: Endothelial injury in the carotid arterial wall permits infiltration and retention of apoB-containing lipoproteins in the intima. Local modification of retained LDL initiates the inflammatory plaque-forming branch that can progress toward atherosclerotic carotid occlusion.
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  locations:
  - preferred_term: internal carotid artery
    term:
      id: UBERON:0001532
      label: internal carotid artery
  biological_processes:
  - preferred_term: cholesterol homeostasis
    term:
      id: GO:0042632
      label: cholesterol homeostasis
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:26844337
    reference_title: The Role of Lipids and Lipoproteins in Atherosclerosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: infiltration and retention of apoB containing lipoproteins in the artery wall is a critical initiating event that sparks an inflammatory response and promotes the development of atherosclerosis.
    explanation: Establishes arterial-wall apoB-lipoprotein retention as the conserved initiating event; the internal carotid artery is the disease-specific site.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
  downstream:
  - target: Carotid Monocyte Recruitment and Macrophage Foam Cell Formation
    description: Modified retained lipoproteins activate endothelium, recruit monocytes, and supply the substrate internalized by intimal macrophages.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - oxidative or enzymatic modification of retained apoB lipoproteins
    - endothelial activation and monocyte recruitment into the carotid intima
    evidence:
    - reference: PMID:26844337
      reference_title: The Role of Lipids and Lipoproteins in Atherosclerosis.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Internalization of the apoB containing lipoproteins by macrophages promotes foam cell formation, which is the hallmark of the fatty streak phase of atherosclerosis.
      explanation: Supports macrophage uptake of retained apoB lipoproteins and subsequent foam-cell formation across the explicit recruitment intermediate.
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
- name: Carotid Monocyte Recruitment and Macrophage Foam Cell Formation
  role: amplifier
  conforms_to: atherogenesis#Monocyte Recruitment and Macrophage Foam Cell Formation
  description: Recruited carotid-intimal monocytes become macrophages, internalize modified apoB lipoproteins, and form lipid-laden foam cells. Macrophage inflammation amplifies LDL oxidation, endothelial activation, and additional monocyte recruitment in the plaque-forming branch.
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: foam cell
    term:
      id: CL:0000891
      label: foam cell
  locations:
  - preferred_term: internal carotid artery
    term:
      id: UBERON:0001532
      label: internal carotid artery
  biological_processes:
  - preferred_term: foam cell differentiation
    term:
      id: GO:0090077
      label: foam cell differentiation
    modifier: INCREASED
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  evidence:
  - reference: PMID:26844337
    reference_title: The Role of Lipids and Lipoproteins in Atherosclerosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Internalization of the apoB containing lipoproteins by macrophages promotes foam cell formation, which is the hallmark of the fatty streak phase of atherosclerosis.
    explanation: Directly supports macrophage apoB-lipoprotein uptake and foam-cell differentiation in the conserved amplifier.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
  - reference: PMID:26844337
    reference_title: The Role of Lipids and Lipoproteins in Atherosclerosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Macrophage inflammation results in enhanced oxidative stress and cytokine/chemokine secretion, causing more LDL/remnant oxidation, endothelial cell activation, monocyte recruitment, and foam cell formation.
    explanation: Documents the feed-forward inflammatory loop that amplifies foam-cell formation.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
  downstream:
  - target: Atherosclerotic carotid plaque formation
    description: Foam-cell inflammatory mediators recruit and stimulate vascular smooth muscle cells, which switch phenotype and assemble the plaque matrix.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - macrophage chemoattractant and cytokine signaling
    - vascular smooth muscle cell recruitment and phenotypic switching
    evidence:
    - reference: PMID:26844337
      reference_title: The Role of Lipids and Lipoproteins in Atherosclerosis.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Macrophage inflammatory chemoattractants stimulate infiltration and proliferation of smooth muscle cells. Smooth muscle cells produce the extracellular matrix providing a stable fibrous barrier between plaque prothrombotic factors and platelets.
      explanation: Connects macrophage inflammation to smooth-muscle-cell proliferation and extracellular-matrix production in the conserved central effector.
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
- name: Atherosclerotic carotid plaque formation
  role: central_effector
  conforms_to: atherogenesis#Smooth Muscle Cell Switching and Fibrofatty Plaque Formation
  description: Smooth-muscle-cell proliferation and extracellular-matrix secretion assemble a fibrofatty carotid plaque with a fibrous cap. Progressive plaque growth provides a substrate for stenosis and eventual occlusion.
  cell_types:
  - preferred_term: vascular smooth muscle cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  biological_processes:
  - preferred_term: smooth muscle cell proliferation
    modifier: INCREASED
    term:
      id: GO:0048661
      label: positive regulation of smooth muscle cell proliferation
  - preferred_term: extracellular matrix organization
    modifier: INCREASED
    term:
      id: GO:0030198
      label: extracellular matrix organization
  evidence:
  - reference: PMID:26844337
    reference_title: The Role of Lipids and Lipoproteins in Atherosclerosis.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Macrophage inflammatory chemoattractants stimulate infiltration and proliferation of smooth muscle cells. Smooth muscle cells produce the extracellular matrix providing a stable fibrous barrier between plaque prothrombotic factors and platelets.
    explanation: Conserved plaque biology supports smooth-muscle proliferation and matrix production; carotid localization is supported by the carotid plaque review.
  - reference: PMID:37303351
    reference_title: 'Carotid Artery Stenosis: A Look Into the Diagnostic and Management Strategies, and Related Complications.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: CS is seen undergoing almost the same pathogenesis of any atherosclerotic plaque formation, from endothelial damage of the artery lumen to the formation of a fibrous cap with a foam cell, lipid-filled core.
    explanation: This review directly supports endothelial damage, fibrous cap formation, and foam-cell lipid core formation as carotid atherosclerotic plaque biology.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
  downstream:
  - target: Advanced carotid atheroma with necrotic core and fibrous cap
    description: Continued lipid accumulation, foam-cell death, and matrix remodeling mature the formed carotid plaque into a cap-and-core atheroma.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Continued lipid accumulation and foam-cell death enlarge the necrotic core.
    - Smooth-muscle-cell switching and matrix remodeling build and reshape the fibrous cap.
    evidence:
    - reference: PMID:37595697
      reference_title: The microenvironment of the atheroma expresses phenotypes of plaque instability.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: vascular smooth muscle cell phenotypic switching through transdifferentiation and stem/progenitor cell activation resulting in the promotion of inflammation, calcification, and secretion of extracellular matrix, altering fibrous cap structure, and necrotic core growth.
      explanation: Supports smooth-muscle-cell switching and matrix secretion as intermediates that alter the fibrous cap and enlarge the necrotic core between initial plaque formation and advanced atheroma.
  - target: Complete carotid lumen obstruction
    description: Progressive atherosclerotic plaque can culminate in non-acute internal carotid occlusion, but the cohort does not resolve whether rupture, thrombosis, or chronic occlusive remodeling supplies the intermediates.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38740919
      reference_title: Significance of atherosclerotic plaque location in recanalizing non-acute long-segment occlusion of the internal carotid artery.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: patients with ICA occlusion caused by either proximal or distal atherosclerotic plaques
      explanation: Directly associates proximal or distal atherosclerotic plaque with ICA occlusion while leaving the intervening occlusive mechanism unresolved.
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
- name: Advanced carotid atheroma with necrotic core and fibrous cap
  role: effector
  conforms_to: atherogenesis#Advanced Atheroma with Necrotic Core and Fibrous Cap
  description: Continued lipid accumulation, foam-cell death, and matrix remodeling produce an advanced carotid atheroma with a lipid-rich necrotic core enclosed by a fibrous cap. Neovascularization, intraplaque hemorrhage, cap thinning, and surface ulceration can destabilize the lesion. This optional mature-plaque stage is represented without assuming that it caused every chronic or non-acute occlusion in the cited cohorts.
  cell_types:
  - preferred_term: vascular smooth muscle cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  locations:
  - preferred_term: internal carotid artery
    term:
      id: UBERON:0001532
      label: internal carotid artery
  biological_processes:
  - preferred_term: extracellular matrix organization
    modifier: INCREASED
    term:
      id: GO:0030198
      label: extracellular matrix organization
  evidence:
  - reference: DOI:10.3390/ijms25084351
    reference_title: 'Molecular Pathways of Vulnerable Carotid Plaques at Risk of Ischemic Stroke: A Narrative Review'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'In macroscopic evaluation, vulnerable plaques are characterized by one or more of the following features: microcalcification; neovascularization; lipid-rich necrotic cores (LRNCs); intraplaque hemorrhage (IPH); thin fibrous caps; plaque surface ulceration; huge dimensions, suggesting stenosis; and plaque rupture.'
    explanation: Directly establishes the necrotic-core, fibrous-cap, hemorrhagic, and surface features of an advanced carotid atheroma.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
  - reference: PMID:37595697
    reference_title: The microenvironment of the atheroma expresses phenotypes of plaque instability.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: the local arterial microenvironment of a stable atheroma promotes destabilizing conditions that result in the transition to an unstable atheroma.
    explanation: Supports maturation and destabilization of a formed atheroma without asserting that destabilization is the only route to chronic occlusion.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  downstream:
  - target: Carotid luminal thrombus formation
    description: Disruption of a vulnerable fibrous cap can expose prothrombotic plaque material and initiate thrombosis.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:26844337
      reference_title: The Role of Lipids and Lipoproteins in Atherosclerosis.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Rupture of the thinning fibrous cap promotes thrombus formation resulting in clinical ischemic ASCVE.
      explanation: Supports the rupture-associated thrombosis branch of atherogenesis; rupture is not assumed in every chronic occlusion.
    intermediate_mechanisms:
    - fibrous-cap disruption and exposure of plaque thrombogenic material
- name: Carotid luminal thrombus formation
  description: Thrombus can form on disrupted carotid atheroma and become organized in chronic occlusion. The initiating thrombotic event is not reconstructed by chronic surgical specimens alone.
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:26844337
    reference_title: The Role of Lipids and Lipoproteins in Atherosclerosis.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Rupture of the thinning fibrous cap promotes thrombus formation resulting in clinical ischemic ASCVE.
    explanation: Supports the rupture-associated thrombosis branch of atherogenesis; rupture is not assumed in every chronic occlusion.
  - &id001
    reference: PMID:37813974
    reference_title: Recanalization of chronic long-segment occlusion of the internal carotid artery with endovascular and hybrid surgery.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The clot was white organized at the carotid bifurcation and proximal segment of the internal carotid artery (ICA), old dark red in the middle ICA and old red in the distal ICA segment.
    explanation: Operative observation in a chronic ICA occlusion illustrates organized thrombus; it does not identify the initiating event in all patients.
  downstream:
  - target: Complete carotid lumen obstruction
    description: Plaque and superimposed thrombus can occlude the carotid lumen.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37813974
      reference_title: Recanalization of chronic long-segment occlusion of the internal carotid artery with endovascular and hybrid surgery.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: The clot was white organized at the carotid bifurcation and proximal segment of the internal carotid artery (ICA), old dark red in the middle ICA and old red in the distal ICA segment.
      explanation: Operative observation in a chronic ICA occlusion illustrates organized thrombus; it does not identify the initiating event in all patients.
    - reference: PMID:37813974
      reference_title: Recanalization of chronic long-segment occlusion of the internal carotid artery with endovascular and hybrid surgery.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      directness: DIRECT
      snippet: Long-segment occlusion of ICA is usually caused by an atherosclerotic plaque and some thrombi formed proximal or distal to the plaque, and the thrombi may extend upwards or downwards to form a long segment of ICA occlusion
      explanation: The cohort methods describe plaque plus propagating thrombus in the long-segment atherosclerotic occlusion model.
- name: Complete carotid lumen obstruction
  description: Atherosclerotic plaque with variable superimposed thrombus or occlusive remodeling abolishes antegrade flow through the involved carotid segment.
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  evidence:
  - &id003
    reference: PMID:38740919
    reference_title: Significance of atherosclerotic plaque location in recanalizing non-acute long-segment occlusion of the internal carotid artery.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: patients with ICA occlusion caused by either proximal or distal atherosclerotic plaques
    explanation: The atherosclerotic surgical cohort documents the plaque-associated occlusive lesion.
  - *id001
  downstream:
  - target: Carotid artery occlusion
    description: Complete luminal obstruction defines the vascular phenotype.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38740919
      reference_title: Significance of atherosclerotic plaque location in recanalizing non-acute long-segment occlusion of the internal carotid artery.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: patients with ICA occlusion caused by either proximal or distal atherosclerotic plaques
      explanation: The atherosclerotic surgical cohort documents the plaque-associated occlusive lesion.
  - target: Inadequate collateral cerebral perfusion
    description: Downstream hemodynamic compromise develops when collateral circulation cannot compensate for occlusion.
    causal_link_type: DIRECT
    evidence:
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1
      reference_title: 'Complete occlusion of extracranial internal carotid artery: clinical features, pathophysiology, diagnosis and management - PMC'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: In chronic ICA occlusion, collateral circulation may maintain cerebral perfusion. Failure of collateralisation may contribute to the haemodynamic compromise.
      explanation: Explains why complete occlusion can be compensated or cause hemodynamic failure.
  - target: Collateral-route artery-to-artery embolization
    description: Thrombus in an occluded ICA stump or adjacent carotid plaque can remain an embolic source through collateral pathways.
    causal_link_type: DIRECT
    evidence:
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1
      reference_title: 'Complete occlusion of extracranial internal carotid artery: clinical features, pathophysiology, diagnosis and management - PMC'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Embolism from the distal or proximal stump or from atherosclerotic plaques in the common carotid artery or ECA, which traverse through the collateral pathways involving the ECA.
      explanation: Identifies embolic sources and collateral routes despite complete ICA occlusion.
  - target: Retinal perfusion failure
    description: Inadequate collateral ocular supply after carotid occlusion can cause chronic retinal hypoperfusion.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1
      reference_title: 'Complete occlusion of extracranial internal carotid artery: clinical features, pathophysiology, diagnosis and management - PMC'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: in 4–18% of patients with occlusion or severe stenosis of the ICA, a syndrome of chronic ocular ischaemia may develop.
      explanation: Supports the ocular hypoperfusion complication across severe carotid disease; the mixed-population proportion is not encoded as an occlusion frequency.
    intermediate_mechanisms:
    - inadequate collateral supply to the ophthalmic circulation
- name: Inadequate collateral cerebral perfusion
  description: When circle-of-Willis and external-carotid collateral supply is insufficient, cerebral perfusion pressure falls. Compensatory resistance-vessel dilation may preserve flow initially, but exhausts cerebrovascular reserve.
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1
    reference_title: 'Complete occlusion of extracranial internal carotid artery: clinical features, pathophysiology, diagnosis and management - PMC'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: In chronic ICA occlusion, collateral circulation may maintain cerebral perfusion. Failure of collateralisation may contribute to the haemodynamic compromise.
    explanation: Explains why complete occlusion can be compensated or cause hemodynamic failure.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1
    reference_title: 'Complete occlusion of extracranial internal carotid artery: clinical features, pathophysiology, diagnosis and management - PMC'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: If collateralisation is inadequate, CBF can be maintained despite reduced cerebral perfusion pressure by dilatation of the resistance vessels (cerebral autoregulation).
    explanation: Describes compensatory autoregulation.
  downstream:
  - target: Cerebral oxygen-extraction compensation
    description: Increased oxygen extraction compensates when vasodilation no longer maintains normal blood flow.
    causal_link_type: DIRECT
    evidence:
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1
      reference_title: 'Complete occlusion of extracranial internal carotid artery: clinical features, pathophysiology, diagnosis and management - PMC'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: When autoregulatory vasodilatation fails to maintain normal CBF, oxygen extraction fraction (OEF) of the affected brain tissue increases to maintain normal cerebral metabolism, the so‐called stage II haemodynamic failure or misery perfusion.
      explanation: Describes increased oxygen extraction after autoregulatory compensation becomes insufficient.
  - target: Cerebral tissue ischemic injury
    description: Insufficient collateral supply can cause cerebral ischemia and borderzone injury.
    causal_link_type: DIRECT
    evidence:
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1
      reference_title: 'Complete occlusion of extracranial internal carotid artery: clinical features, pathophysiology, diagnosis and management - PMC'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: ICA occlusion is frequently associated with borderzone infarcts,
      explanation: Associates ICA occlusion with borderzone infarction; embolism may also contribute.
  - target: Limb-shaking transient ischemic attack
    description: Severe hemodynamic compromise can cause transient involuntary limb movements.
    causal_link_type: DIRECT
    evidence:
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1
      reference_title: 'Complete occlusion of extracranial internal carotid artery: clinical features, pathophysiology, diagnosis and management - PMC'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: A rare manifestation of haemodynamic compromise in patients with ICA occlusion is limb shaking.
      explanation: Identifies the uncommon hemodynamic limb-shaking TIA presentation, which can mimic focal seizures.
- name: Cerebral oxygen-extraction compensation
  description: Increased oxygen extraction sustains cerebral metabolism when blood flow falls despite maximal autoregulatory vasodilation. This stage II hemodynamic failure marks a high-risk state; increased extraction is compensatory, not itself the cause of stroke.
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  evidence:
  - &id012
    reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1
    reference_title: 'Complete occlusion of extracranial internal carotid artery: clinical features, pathophysiology, diagnosis and management - PMC'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: When autoregulatory vasodilatation fails to maintain normal CBF, oxygen extraction fraction (OEF) of the affected brain tissue increases to maintain normal cerebral metabolism, the so‐called stage II haemodynamic failure or misery perfusion.
    explanation: Describes increased oxygen extraction after autoregulatory compensation becomes insufficient.
  - &id002
    reference: PMID:22068990
    reference_title: 'Extracranial-intracranial bypass surgery for stroke prevention in hemodynamic cerebral ischemia: the Carotid Occlusion Surgery Study randomized trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Patients with arteriographically confirmed AICAO causing hemispheric symptoms within 120 days and hemodynamic cerebral ischemia identified by ipsilateral increased oxygen extraction fraction measured by PET.
    explanation: COSS enrolled symptomatic atherosclerotic ICA occlusion with objective hemodynamic impairment.
- name: Collateral-route artery-to-artery embolization
  description: Embolic material from proximal or distal ICA stumps or adjacent carotid plaques reaches cerebral or retinal vessels through collateral channels. Embolic and hemodynamic mechanisms may coexist.
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1
    reference_title: 'Complete occlusion of extracranial internal carotid artery: clinical features, pathophysiology, diagnosis and management - PMC'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Embolism from the distal or proximal stump or from atherosclerotic plaques in the common carotid artery or ECA, which traverse through the collateral pathways involving the ECA.
    explanation: Identifies embolic sources and collateral routes despite complete ICA occlusion.
  downstream:
  - target: Cerebral tissue ischemic injury
    description: Embolic obstruction can cause cerebral ischemia.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1
      reference_title: 'Complete occlusion of extracranial internal carotid artery: clinical features, pathophysiology, diagnosis and management - PMC'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: 'ICA occlusion can produce brain or retinal ischaemia by the following mechanisms:'
      explanation: Introduces the review's explicitly enumerated embolic and hemodynamic mechanisms.
    intermediate_mechanisms:
    - embolus lodging in a distal cerebral artery
  - target: Retinal perfusion failure
    description: Embolic obstruction can impair retinal circulation.
    causal_link_type: DIRECT
    evidence:
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1
      reference_title: 'Complete occlusion of extracranial internal carotid artery: clinical features, pathophysiology, diagnosis and management - PMC'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Although amaurosis fugax is a symptom of acute retinal ischaemia most often caused by embolism from the ICA,
      explanation: Directly connects ICA embolism to transient retinal ischemia.
- name: Cerebral tissue ischemic injury
  description: Reduced cerebral blood flow from hemodynamic failure or embolic obstruction causes transient dysfunction or persistent infarction, depending on severity and duration.
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  evidence:
  - *id002
  - &id004
    reference: PMID:22068990
    reference_title: 'Extracranial-intracranial bypass surgery for stroke prevention in hemodynamic cerebral ischemia: the Carotid Occlusion Surgery Study randomized trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: TIA or ischemic stroke in the hemispheric territory of an occluded internal carotid artery within 120 days.
    explanation: Published COSS eligibility directly documents ipsilateral TIA and ischemic stroke presentations.
  downstream:
  - target: Cerebral ischemia
    description: The physiologic disturbance is reflected by cerebral ischemia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22068990
      reference_title: 'Extracranial-intracranial bypass surgery for stroke prevention in hemodynamic cerebral ischemia: the Carotid Occlusion Surgery Study randomized trial.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Patients with arteriographically confirmed AICAO causing hemispheric symptoms within 120 days and hemodynamic cerebral ischemia identified by ipsilateral increased oxygen extraction fraction measured by PET.
      explanation: COSS enrolled symptomatic atherosclerotic ICA occlusion with objective hemodynamic impairment.
  - target: Transient ischemic attack
    description: Transient ischemic dysfunction causes hemispheric TIA.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22068990
      reference_title: 'Extracranial-intracranial bypass surgery for stroke prevention in hemodynamic cerebral ischemia: the Carotid Occlusion Surgery Study randomized trial.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: TIA or ischemic stroke in the hemispheric territory of an occluded internal carotid artery within 120 days.
      explanation: Published COSS eligibility directly documents ipsilateral TIA and ischemic stroke presentations.
  - target: Ischemic stroke
    description: Persistent ischemic injury causes ipsilateral infarction.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22068990
      reference_title: 'Extracranial-intracranial bypass surgery for stroke prevention in hemodynamic cerebral ischemia: the Carotid Occlusion Surgery Study randomized trial.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: TIA or ischemic stroke in the hemispheric territory of an occluded internal carotid artery within 120 days.
      explanation: Published COSS eligibility directly documents ipsilateral TIA and ischemic stroke presentations.
  - target: Limb weakness
    description: Ischemic dysfunction can produce this manifestation in the affected tissue.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37813974
      reference_title: Recanalization of chronic long-segment occlusion of the internal carotid artery with endovascular and hybrid surgery.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: The transient ischemic attack symptoms were reversible, including slight limb weakness in 71 (81.6%) patients, unclear speech in 32 (36.8%),
      explanation: The cohort directly reports reversible limb weakness and speech symptoms.
  - target: Speech disturbance
    description: Ischemic dysfunction can produce this manifestation in the affected tissue.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37813974
      reference_title: Recanalization of chronic long-segment occlusion of the internal carotid artery with endovascular and hybrid surgery.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: The transient ischemic attack symptoms were reversible, including slight limb weakness in 71 (81.6%) patients, unclear speech in 32 (36.8%),
      explanation: The source supports nonspecific speech disturbance without a finer language or articulation diagnosis.
- name: Retinal perfusion failure
  description: Retinal embolism or sustained ocular hypoperfusion produces transient monocular blindness or chronic ocular ischemia. This manifestation is not obligatory in carotid occlusion.
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1
    reference_title: 'Complete occlusion of extracranial internal carotid artery: clinical features, pathophysiology, diagnosis and management - PMC'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: 'ICA occlusion can produce brain or retinal ischaemia by the following mechanisms:'
    explanation: Introduces the review's explicitly enumerated embolic and hemodynamic mechanisms.
  - &id005
    reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1
    reference_title: 'Complete occlusion of extracranial internal carotid artery: clinical features, pathophysiology, diagnosis and management - PMC'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: An episode of transient monocular blindness (amaurosis fugax) is highly suggestive of ICA disease proximal to the ophthalmic branch.
    explanation: The disease-specific clinical review identifies amaurosis fugax as an ocular ischemic presentation.
  downstream:
  - target: Amaurosis fugax
    description: Transient retinal ischemia produces monocular visual loss.
    causal_link_type: DIRECT
    evidence:
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1
      reference_title: 'Complete occlusion of extracranial internal carotid artery: clinical features, pathophysiology, diagnosis and management - PMC'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: An episode of transient monocular blindness (amaurosis fugax) is highly suggestive of ICA disease proximal to the ophthalmic branch.
      explanation: The disease-specific clinical review identifies amaurosis fugax as an ocular ischemic presentation.
  - target: Progressive visual loss
    description: Chronic ocular ischemia may impair visual acuity progressively.
    causal_link_type: DIRECT
    evidence:
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1
      reference_title: 'Complete occlusion of extracranial internal carotid artery: clinical features, pathophysiology, diagnosis and management - PMC'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Patients complain of progressive loss of visual acuity.
      explanation: In the chronic ocular ischemia paragraph, this describes progressive visual loss in severe carotid disease, including occlusion.
  - target: Retinal hemorrhage
    description: Ischemic dysfunction can produce this manifestation in the affected tissue.
    causal_link_type: DIRECT
    evidence:
    - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1
      reference_title: 'Complete occlusion of extracranial internal carotid artery: clinical features, pathophysiology, diagnosis and management - PMC'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: mid‐peripheral microaneurysms and small dot‐and‐blot intraretinal haemorrhages, arterial narrowing and venous dilatation,
      explanation: Describes retinal findings of chronic ocular ischemia in severe ICA disease, including occlusion.
phenotypes:
- name: Carotid artery occlusion
  category: Cardiovascular
  description: Complete carotid luminal obstruction is the defining lesion; collateral flow can preserve downstream function.
  phenotype_term:
    preferred_term: Carotid artery occlusion
    term:
      id: HP:0012474
      label: Carotid artery occlusion
  evidence:
  - *id003
  diagnostic: true
- name: Ischemic stroke
  category: Neurological
  description: Ipsilateral ischemic stroke may result from embolism, hypoperfusion, or both.
  phenotype_term:
    preferred_term: Ischemic stroke
    term:
      id: HP:0002140
      label: Ischemic stroke
  evidence:
  - *id004
- name: Transient ischemic attack
  category: Neurological
  description: Transient hemispheric ischemic dysfunction can precede or accompany established occlusion.
  phenotype_term:
    preferred_term: Transient ischemic attack
    term:
      id: HP:0002326
      label: Transient ischemic attack
  evidence:
  - *id004
- name: Limb-shaking transient ischemic attack
  category: Neurological
  description: Uncommon hemodynamic TIAs cause repetitive involuntary movements of one or both limbs on one side, often precipitated by reduced perfusion. They can resemble focal seizures.
  phenotype_term:
    preferred_term: Transient ischemic attack
    term:
      id: HP:0002326
      label: Transient ischemic attack
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1
    reference_title: 'Complete occlusion of extracranial internal carotid artery: clinical features, pathophysiology, diagnosis and management - PMC'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: A rare manifestation of haemodynamic compromise in patients with ICA occlusion is limb shaking.
    explanation: Identifies the uncommon hemodynamic limb-shaking TIA presentation, which can mimic focal seizures.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1
    reference_title: 'Complete occlusion of extracranial internal carotid artery: clinical features, pathophysiology, diagnosis and management - PMC'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: The patients complain of repetitive involuntary movements of one or both limbs on one side. This is often misdiagnosed as partial seizures.
    explanation: Describes the movement pattern and diagnostic pitfall.
  frequency: RARE
- name: Amaurosis fugax
  category: Ophthalmological
  description: Transient monocular visual loss is an ocular ischemic presentation.
  phenotype_term:
    preferred_term: Amaurosis fugax
    term:
      id: HP:0100576
      label: Amaurosis fugax
  evidence:
  - *id005
- name: Progressive visual loss
  category: Ophthalmological
  description: Chronic ocular ischemia may cause progressive visual-acuity loss. Published mixed stenosis/occlusion frequencies are not applied to all occlusion patients.
  phenotype_term:
    preferred_term: Progressive visual loss
    term:
      id: HP:0000529
      label: Progressive visual loss
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1
    reference_title: 'Complete occlusion of extracranial internal carotid artery: clinical features, pathophysiology, diagnosis and management - PMC'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Patients complain of progressive loss of visual acuity.
    explanation: In the chronic ocular ischemia paragraph, this describes progressive visual loss in severe carotid disease, including occlusion.
- name: Cerebral ischemia
  category: Neurological
  description: Cerebral hypoperfusion with exhausted reserve can occur without a completed infarct.
  phenotype_term:
    preferred_term: Cerebral ischemia
    term:
      id: HP:0002637
      label: Cerebral ischemia
  evidence:
  - *id002
- name: Limb weakness
  category: Neurological
  description: Transient limb weakness occurred in 71 of 87 highly selected, medically refractory chronic ICA occlusion patients in a recanalization cohort. This proportion is not a population frequency.
  phenotype_term:
    preferred_term: Limb muscle weakness
    term:
      id: HP:0003690
      label: Limb muscle weakness
  evidence:
  - reference: PMID:37813974
    reference_title: Recanalization of chronic long-segment occlusion of the internal carotid artery with endovascular and hybrid surgery.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The transient ischemic attack symptoms were reversible, including slight limb weakness in 71 (81.6%) patients, unclear speech in 32 (36.8%),
    explanation: The cohort directly reports reversible limb weakness and speech symptoms.
- name: Speech disturbance
  category: Neurological
  description: Unclear speech was reported in 32 of 87 selected chronic ICA occlusion patients. The report does not distinguish aphasia from dysarthria.
  phenotype_term:
    preferred_term: Abnormal speech pattern
    term:
      id: HP:0002167
      label: Abnormal speech pattern
  evidence:
  - reference: PMID:37813974
    reference_title: Recanalization of chronic long-segment occlusion of the internal carotid artery with endovascular and hybrid surgery.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The transient ischemic attack symptoms were reversible, including slight limb weakness in 71 (81.6%) patients, unclear speech in 32 (36.8%),
    explanation: The source supports nonspecific speech disturbance without a finer language or articulation diagnosis.
- name: Retinal hemorrhage
  category: Ophthalmological
  description: Venous-stasis retinopathy in chronic ocular ischemia can include small dot-and-blot intraretinal hemorrhages. The source combines severe stenosis and occlusion, so no disease-wide frequency is assigned.
  phenotype_term:
    preferred_term: Retinal hemorrhage
    term:
      id: HP:0000573
      label: Retinal hemorrhage
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1
    reference_title: 'Complete occlusion of extracranial internal carotid artery: clinical features, pathophysiology, diagnosis and management - PMC'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: mid‐peripheral microaneurysms and small dot‐and‐blot intraretinal haemorrhages, arterial narrowing and venous dilatation,
    explanation: Describes retinal findings of chronic ocular ischemia in severe ICA disease, including occlusion.
genetic:
- name: Shared cardiometabolic and stroke susceptibility loci (indirect context)
  association: Risk Factor
  presence: Positive
  notes: The European-ancestry GWAS examined coronary disease, myocardial infarction, heart failure, atrial fibrillation, all stroke, ischemic stroke, and risk-factor traits including carotid intima-media thickness. It did not ascertain complete carotid occlusion as an outcome. Its 11 loci mapped to 12 genes are shared vascular-risk context, not established carotid-occlusion genes or proof of a smooth-muscle mechanism in this disorder.
  evidence:
  - reference: PMID:39730871
    reference_title: Identification of shared genetic etiology of cardiovascular and cerebrovascular diseases through common cardiometabolic risk factors.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: The 11 loci were mapped to 12 genes, namely CASZ1, CDKN1A, TWIST1, CDKN2B, ABO, SWAP70, SH2B3, LRCH1, FES, GOSR2, RPRML, and LDLR, where both GOSR2 and RPRML were mapped to one locus.
    explanation: The reported loci relate to the study's cardiovascular, cerebrovascular, and risk-factor traits; extrapolation to complete carotid occlusion is indirect.
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
- name: Diabetes-associated genetic markers and carotid plaque
  association: Risk Factor
  presence: Positive
  notes: In a Taiwanese community case-control study, 309 participants with carotid plaque and 439 without plaque were compared. Nine diabetes-associated SNPs met the exploratory inclusion threshold of 0.10, and four had significant independent associations. These are precursor-plaque associations, not validated predictors of complete carotid occlusion; the genetic risk scores are not clinical diagnostic tests.
  evidence:
  - reference: PMID:36894991
    reference_title: 'Associations of genetic markers of diabetes mellitus with carotid atherosclerosis: a community-based case-control study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We identified 9 DM SNPs showing promising associations with CP.
    explanation: Exploratory association with carotid plaque, not complete carotid artery occlusion.
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:36894991
    reference_title: 'Associations of genetic markers of diabetes mellitus with carotid atherosclerosis: a community-based case-control study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: To reduce the influence of false negativity, we used 0.10 as the pre-set inclusion criteria of promising SNPs.
    explanation: The full-text methods explain the exploratory threshold; not all nine SNPs were conventionally significant.
environmental:
- name: Hypertension
  influences_mechanisms:
  - target: Atherosclerotic carotid plaque formation
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: This risk factor predisposes to carotid plaque through intervening endothelial and inflammatory atherogenic processes; the citation addresses atherosclerosis rather than a direct occlusion-specific effect.
    evidence:
    - reference: PMID:37303351
      reference_title: 'Carotid Artery Stenosis: A Look Into the Diagnostic and Management Strategies, and Related Complications.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: comorbid hypertension, diabetes, and chronic kidney disease (CKD), and lifestyle aspects, including smoking and diet, played the most salient role in plaque development.
      explanation: Review naming comorbid hypertension among the factors that played the most salient role in plaque development, connecting the exposure to this node's own process rather than to the disease in general.
      quote_role: REVIEW_SYNTHESIS
  presence: Positive
  notes: Major atherosclerotic and stroke risk factor associated with carotid plaque development.
  evidence:
  - reference: PMID:37303351
    reference_title: 'Carotid Artery Stenosis: A Look Into the Diagnostic and Management Strategies, and Related Complications.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: comorbid hypertension, diabetes, and chronic kidney disease (CKD), and lifestyle aspects, including smoking and diet, played the most salient role in plaque development.
    explanation: The review explicitly identifies hypertension among the salient factors in carotid plaque development.
    quote_role: REVIEW_SYNTHESIS
- name: Diabetes mellitus
  influences_mechanisms:
  - target: Atherosclerotic carotid plaque formation
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: This risk factor predisposes to carotid plaque through intervening endothelial and inflammatory atherogenic processes; the citation addresses atherosclerosis rather than a direct occlusion-specific effect.
    evidence:
    - reference: PMID:36894991
      reference_title: 'Associations of genetic markers of diabetes mellitus with carotid atherosclerosis: a community-based case-control study.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Diabetes mellitus (DM) is a well-established determinant of atherosclerosis and cardiovascular diseases (CVD).
      explanation: States that diabetes is a well-established determinant of atherosclerosis, the process this node carries, in a study whose subject is carotid atherosclerosis specifically.
      quote_role: BACKGROUND
  presence: Positive
  notes: Diabetes is a cardiometabolic risk factor for carotid plaque and atherosclerotic disease.
  evidence:
  - reference: PMID:36894991
    reference_title: 'Associations of genetic markers of diabetes mellitus with carotid atherosclerosis: a community-based case-control study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Diabetes mellitus (DM) is a well-established determinant of atherosclerosis and cardiovascular diseases (CVD).
    explanation: This supports diabetes as a determinant of atherosclerosis relevant to carotid plaque formation.
    quote_role: BACKGROUND
- name: Smoking and diet
  influences_mechanisms:
  - target: Atherosclerotic carotid plaque formation
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: This risk factor predisposes to carotid plaque through intervening endothelial and inflammatory atherogenic processes; the citation addresses atherosclerosis rather than a direct occlusion-specific effect.
    evidence:
    - reference: PMID:37303351
      reference_title: 'Carotid Artery Stenosis: A Look Into the Diagnostic and Management Strategies, and Related Complications.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: lifestyle aspects, including smoking and diet, played the most salient role in plaque development.
      explanation: The same review names smoking and diet as the lifestyle aspects playing the most salient role in plaque development, which is the process at this node.
      quote_role: REVIEW_SYNTHESIS
  presence: Positive
  notes: Smoking and diet are modifiable lifestyle factors contributing to carotid plaque development.
  evidence:
  - reference: PMID:37303351
    reference_title: 'Carotid Artery Stenosis: A Look Into the Diagnostic and Management Strategies, and Related Complications.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: lifestyle aspects, including smoking and diet, played the most salient role in plaque development.
    explanation: This directly supports smoking and diet as lifestyle contributors to carotid plaque development.
    quote_role: REVIEW_SYNTHESIS
diagnosis:
- name: Duplex ultrasonography and confirmation of complete occlusion
  description: Duplex ultrasound assesses flow in the cervical ICA. CTA or contrast-enhanced MRA helps distinguish absent patency from very slow residual flow or a distal lesion. Near-occlusion and pseudo-occlusion require careful distinction before a procedural decision.
  evidence:
  - &id011
    reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1
    reference_title: 'Complete occlusion of extracranial internal carotid artery: clinical features, pathophysiology, diagnosis and management - PMC'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: ICA occlusion is characterised by the absence of any signal along the extracranial course of the ICA
    explanation: Describes the Doppler flow finding of complete occlusion.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1
    reference_title: 'Complete occlusion of extracranial internal carotid artery: clinical features, pathophysiology, diagnosis and management - PMC'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Single‐row detector CTA can distinguish total ICA occlusion from hairline residual lumen with a high degree of accuracy.
    explanation: Supports distinguishing complete occlusion from residual patency; no stenosis accuracy estimate is transferred to occlusion.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1
    reference_title: 'Complete occlusion of extracranial internal carotid artery: clinical features, pathophysiology, diagnosis and management - PMC'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: However, it may be difficult to differentiate near‐occlusion from a complete occlusion.
    explanation: Describes the ultrasound diagnostic limitation.
- name: Catheter angiography for unresolved anatomy or intervention planning
  description: Digital subtraction angiography defines the occluded segment and collateral routes when noninvasive tests are inconclusive or a procedure is being planned.
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1
    reference_title: 'Complete occlusion of extracranial internal carotid artery: clinical features, pathophysiology, diagnosis and management - PMC'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Digital subtraction angiography is the “gold standard” imaging modality for the evaluation of carotid occlusive disease.
    explanation: Supports angiographic confirmation; invasiveness limits routine use.
- name: Hemodynamic assessment
  description: PET oxygen-extraction measurement and CT or MR perfusion characterize collateral insufficiency. Hemodynamic selection identifies risk, but does not by itself establish benefit from bypass.
  evidence:
  - *id002
  - reference: PMID:37606672
    reference_title: 'Extracranial-Intracranial Bypass and Risk of Stroke and Death in Patients With Symptomatic Artery Occlusion: The CMOSS Randomized Clinical Trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: A total of 324 patients with ICA or MCA occlusion with transient ischemic attack or nondisabling ischemic stroke attributed to hemodynamic insufficiency based on computed tomography perfusion imaging
    explanation: CMOSS used CT perfusion for hemodynamic selection.
treatments:
- name: Antiplatelet therapy for secondary prevention
  description: Antiplatelet treatment is part of medical management of symptomatic atherosclerotic carotid occlusion. Aspirin or clopidogrel were used in CMOSS. This does not establish routine anticoagulation or indefinite dual-antiplatelet therapy for all occlusions.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: aspirin
      term:
        id: CHEBI:15365
        label: acetylsalicylic acid
  evidence:
  - &id006
    reference: PMID:37606672
    reference_title: 'Extracranial-Intracranial Bypass and Risk of Stroke and Death in Patients With Symptomatic Artery Occlusion: The CMOSS Randomized Clinical Trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Medical therapy included antiplatelet therapy and stroke risk factor control.
    explanation: Documents baseline care in both CMOSS arms; not an isolated trial of each medical component.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC10445185/
    reference_title: 'Extracranial-Intracranial Bypass and Risk of Stroke and Death in Patients With Symptomatic Artery Occlusion: The CMOSS Randomized Clinical Trial - PMC'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Aspirin (100 mg/day) or clopidogrel (75 mg/day) was prescribed to the patient
    explanation: The CMOSS methods describe the single-antiplatelet options used; these trial doses are not individualized prescribing advice.
  notes: The therapeutic-agent binding identifies aspirin as one option; the description and evidence also name clopidogrel as the alternative used in CMOSS.
  therapeutic_modality: SMALL_MOLECULE
- name: Lipid and vascular risk-factor management
  description: Secondary prevention includes lipid lowering, blood-pressure and diabetes management, smoking cessation, and lifestyle measures. Treatment is individualized when symptomatic hemodynamic compromise is present.
  treatment_term:
    preferred_term: Serum Lipid Lowering Therapy
    term:
      id: NCIT:C222204
      label: Serum Lipid Lowering Therapy
  evidence:
  - *id006
  - reference: PMID:22068990
    reference_title: 'Extracranial-intracranial bypass surgery for stroke prevention in hemodynamic cerebral ischemia: the Carotid Occlusion Surgery Study randomized trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Antithrombotic therapy and risk factor intervention were recommended for all participants.
    explanation: Medical prevention was foundational in both COSS groups.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1
    reference_title: 'Complete occlusion of extracranial internal carotid artery: clinical features, pathophysiology, diagnosis and management - PMC'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: modifications of risk factors—for example, hypertension, diabetes, hyperlipidaemia and smoking—are vital secondary prevention measures.
    explanation: Supports the disease-specific secondary-prevention components.
- name: Extracranial-intracranial bypass under continued investigation
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Bypass
    term:
      id: NCIT:C15723
      label: Bypass
  description: Superficial-temporal-to-middle-cerebral artery bypass improves blood supply beyond the occlusion, but COSS and the prespecified two-year CMOSS analysis did not establish net clinical benefit over medical therapy. Extended CMOSS follow-up at median 7.6 years suggested a possible benefit on the composite primary outcome; it was post hoc, had substantial missing follow-up, and did not show significant secondary-outcome or per-protocol benefit. Routine benefit for chronic atherosclerotic ICA occlusion is therefore not established.
  evidence:
  - &id007
    reference: PMID:22068990
    reference_title: 'Extracranial-intracranial bypass surgery for stroke prevention in hemodynamic cerebral ischemia: the Carotid Occlusion Surgery Study randomized trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Among participants with recently symptomatic AICAO and hemodynamic cerebral ischemia, EC-IC bypass surgery plus medical therapy compared with medical therapy alone did not reduce the risk of recurrent ipsilateral ischemic stroke at 2 years.
    explanation: COSS found no two-year clinical benefit despite improved graft patency and hemodynamics.
  - &id008
    reference: PMID:37606672
    reference_title: 'Extracranial-Intracranial Bypass and Risk of Stroke and Death in Patients With Symptomatic Artery Occlusion: The CMOSS Randomized Clinical Trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Among patients with symptomatic ICA or MCA occlusion and hemodynamic insufficiency, the addition of bypass surgery to medical therapy did not significantly change the risk of the composite outcome of stroke or death within 30 days or ipsilateral ischemic stroke beyond 30 days through 2 years.
    explanation: Neutral prespecified two-year CMOSS endpoint; the trial included ICA and MCA occlusions.
  - &id009
    reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC12100504/
    reference_title: Long-Term Follow-Up of Extracranial-Intracranial Bypass Surgery for Symptomatic Cerebral Artery Occlusion - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: there was a possible longer-term benefit in reducing the primary outcome among patients who received EC-IC bypass surgery plus medical treatment vs medical treatment alone.
    explanation: Post hoc extended CMOSS follow-up suggests a possible longer-term benefit, not a new independent trial.
  - &id010
    reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC12100504/
    reference_title: Long-Term Follow-Up of Extracranial-Intracranial Bypass Surgery for Symptomatic Cerebral Artery Occlusion - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The findings should be interpreted cautiously given the post hoc long-term follow-up design, the neutral results of the preplanned analysis at 2 years, and the lack of statistical significance in other secondary outcomes.
    explanation: The authors qualify the long-term signal; loss to follow-up also limits inference.
  target_mechanisms:
  - target: Complete carotid lumen obstruction
    treatment_effect: BYPASSES
    description: The graft supplies the distal cerebral circulation without reopening the carotid lesion; physiologic improvement does not guarantee net stroke prevention.
    evidence:
    - reference: PMID:22068990
      reference_title: 'Extracranial-intracranial bypass surgery for stroke prevention in hemodynamic cerebral ischemia: the Carotid Occlusion Surgery Study randomized trial.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: In spite of excellent graft patency and improved cerebral hemodynamics in the surgical group, EC-IC bypass surgery failed to provide an overall benefit on 2-year stroke recurrence.
      explanation: Separates the hemodynamic mechanism from the clinical endpoint.
- name: Selected endovascular or hybrid recanalization
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Surgical Procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  description: Specialist series describe reopening selected symptomatic non-acute or chronic ICA occlusions using endovascular treatment or hybrid plaque removal and stenting. Technical success in retrospective single-center cohorts does not establish superiority over medical treatment; the cohorts may overlap and follow-up was incomplete. This differs from established endarterectomy indications for residual-lumen stenosis.
  evidence:
  - reference: PMID:37813974
    reference_title: Recanalization of chronic long-segment occlusion of the internal carotid artery with endovascular and hybrid surgery.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: the total success recanalization rate was 94.3%, whereas the success recanalization rate was 95.5% for the hybrid surgery and 93.0% for the endovascular approach.
    explanation: Selected 87-patient retrospective cohort; technical success, not comparative stroke-prevention efficacy.
  - reference: PMID:38740919
    reference_title: Significance of atherosclerotic plaque location in recanalizing non-acute long-segment occlusion of the internal carotid artery.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The total successful recanalization rate was 97.5% (158/162) with a failure rate of 2.5% (4/162).
    explanation: A second selected single-center series; not an independent randomized comparison.
  - reference: PMID:38740919
    reference_title: Significance of atherosclerotic plaque location in recanalizing non-acute long-segment occlusion of the internal carotid artery.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Some limitations existed in our study, including the single-center and retrospective study design, no randomization, and a small cohort of patients, which may all affect the generalization of the outcomes.
    explanation: Explicitly limits generalization of the recanalization results.
  target_mechanisms:
  - target: Complete carotid lumen obstruction
    treatment_effect: INHIBITS
    description: Successful recanalization removes or traverses the occlusive material to restore luminal flow.
    evidence:
    - *id003
    - reference: PMID:37813974
      reference_title: Recanalization of chronic long-segment occlusion of the internal carotid artery with endovascular and hybrid surgery.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Immediately after stenting with two stents, the carotid artery was patent.
      explanation: Operative imaging example demonstrates restored patency.
- name: Intravenous thrombolysis for eligible acute ischemic stroke
  description: When carotid occlusion presents with acute disabling ischemic stroke, emergency stroke evaluation determines eligibility for intravenous alteplase or tenecteplase using timing, imaging, and contraindications. This acute reperfusion pathway is separate from management of established chronic occlusion.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: alteplase
      term:
        id: CHEBI:749459
        label: alteplase
    - preferred_term: tenecteplase
      term:
        id: CHEBI:753718
        label: tenecteplase
  target_phenotypes:
  - preferred_term: Ischemic stroke
    term:
      id: HP:0002140
      label: Ischemic stroke
  evidence:
  - reference: url:https://newsroom.heart.org/news/new-guideline-expands-stroke-treatment-for-adults-offers-first-pediatric-stroke-guidance
    reference_title: New guideline expands stroke treatment for adults, offers first pediatric stroke guidance | American Heart Association
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: The guideline endorses the use of either tenecteplase or alteplase within 4.5 hours of symptom onset. Both medications are effective at dissolving blood clots.
    explanation: The AHA's official 2026 guideline summary supports IV thrombolysis in eligible acute ischemic stroke, not elective reopening of chronic carotid occlusion.
  target_mechanisms:
  - target: Cerebral tissue ischemic injury
    treatment_effect: INHIBITS
    description: Timely reperfusion can limit acute ischemic injury in patients who meet stroke-treatment eligibility criteria.
    evidence:
    - reference: url:https://newsroom.heart.org/news/new-guideline-expands-stroke-treatment-for-adults-offers-first-pediatric-stroke-guidance
      reference_title: New guideline expands stroke treatment for adults, offers first pediatric stroke guidance | American Heart Association
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: The guideline endorses the use of either tenecteplase or alteplase within 4.5 hours of symptom onset. Both medications are effective at dissolving blood clots.
      explanation: The AHA's official 2026 guideline summary supports IV thrombolysis in eligible acute ischemic stroke, not elective reopening of chronic carotid occlusion.
  therapeutic_modality: OTHER
- name: Mechanical thrombectomy for eligible acute intracranial large-vessel occlusion
  description: Patients with acute stroke from an eligible intracranial large-vessel blockage, including a carotid-related tandem presentation, may undergo emergency thrombectomy after stroke-team assessment. These recommendations do not establish benefit from elective reopening of an isolated chronic cervical carotid occlusion.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Thrombectomy for Stroke
    term:
      id: NCIT:C191635
      label: Thrombectomy for Stroke
  target_phenotypes:
  - preferred_term: Ischemic stroke
    term:
      id: HP:0002140
      label: Ischemic stroke
  evidence:
  - reference: url:https://newsroom.heart.org/news/new-guideline-expands-stroke-treatment-for-adults-offers-first-pediatric-stroke-guidance
    reference_title: New guideline expands stroke treatment for adults, offers first pediatric stroke guidance | American Heart Association
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Removing clots directly from blocked brain arteries, a procedure called thrombectomy, remains a powerful treatment for major strokes caused by large-vessel blockages in eligible patients.
    explanation: Acute intracranial large-vessel occlusion treatment is distinct from chronic isolated cervical ICA recanalization.
  target_mechanisms:
  - target: Cerebral tissue ischemic injury
    treatment_effect: INHIBITS
    description: Timely reperfusion can limit acute ischemic injury in patients who meet stroke-treatment eligibility criteria.
    evidence:
    - reference: url:https://newsroom.heart.org/news/new-guideline-expands-stroke-treatment-for-adults-offers-first-pediatric-stroke-guidance
      reference_title: New guideline expands stroke treatment for adults, offers first pediatric stroke guidance | American Heart Association
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Removing clots directly from blocked brain arteries, a procedure called thrombectomy, remains a powerful treatment for major strokes caused by large-vessel blockages in eligible patients.
      explanation: Acute intracranial large-vessel occlusion treatment is distinct from chronic isolated cervical ICA recanalization.
clinical_trials:
- name: NCT00029146
  phase: PHASE_III
  status: TERMINATED
  description: COSS randomized 195 patients with recently symptomatic atherosclerotic ICA occlusion and increased PET oxygen extraction. The trial stopped early for futility. Two-year primary-event rates were 21.0% with bypass and 22.7% with medical therapy alone; perioperative strokes offset physiologic benefit.
  target_phenotypes:
  - preferred_term: Ischemic stroke
    term:
      id: HP:0002140
      label: Ischemic stroke
  evidence:
  - reference: clinicaltrials:NCT00029146
    reference_title: Carotid Occlusion Surgery Study
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The purpose of this study is to determine if extracranial-intracranial bypass surgery when added to best medical therapy can reduce the subsequent risk of ipsilateral stroke in high-risk patients with recently symptomatic carotid occlusion and increased cerebral oxygen extraction fraction measured by positron emission tomography (PET).
    explanation: The study directly targets stroke prevention in high-risk symptomatic carotid occlusion.
  - *id007
  - reference: PMID:22068990
    reference_title: 'Extracranial-intracranial bypass surgery for stroke prevention in hemodynamic cerebral ischemia: the Carotid Occlusion Surgery Study randomized trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The trial was terminated early for futility.
    explanation: The publication agrees with the registry's TERMINATED status.
  notes: 'ClinicalTrials.gov API checked 2026-10-04: TERMINATED, last update 2012-03-27. The registry enrollment count of 700 differs from the publication''s 195 randomized participants and is not used as the randomized sample size.'
- name: NCT01758614
  phase: PHASE_III
  status: COMPLETED
  description: CMOSS compared EC-IC bypass plus medical therapy with medical therapy alone in 324 eligible patients with symptomatic ICA or MCA occlusion and CT-perfusion-defined hemodynamic insufficiency. The prespecified two-year composite endpoint was neutral. Post hoc extended follow-up suggested a possible longer-term benefit with important attrition and analysis limitations.
  target_phenotypes:
  - preferred_term: Ischemic stroke
    term:
      id: HP:0002140
      label: Ischemic stroke
  evidence:
  - reference: clinicaltrials:NCT01758614
    reference_title: The Carotid and Middle Cerebral Artery Occlusion Surgery Study
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: the CMOSS study in China is designed to compare the efficacy and safety of EC-IC bypass surgery with medical therapy in patients with symptomatic hemodynamically significant carotid occlusion.
    explanation: The registry states the trial objective; efficacy conclusions come from the published randomized results and qualified long-term follow-up.
  - *id008
  - *id009
  - *id010
  notes: 'Registry checked 2026-10-04: COMPLETED; 330 enrolled, 324 eligible in the published analysis. ICA and MCA disease were pooled, so trial-wide percentages are not ICA-only estimates.'
- name: NCT03179774
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: ERCAO trial of endovascular revascularization plus optimal medical therapy versus optimal medical therapy alone for chronic carotid artery occlusion.
  target_phenotypes:
  - preferred_term: Carotid artery occlusion
    term:
      id: HP:0012474
      label: Carotid artery occlusion
  evidence:
  - reference: clinicaltrials:NCT03179774
    reference_title: 'Endovascular Revascularization for Chronic Carotid Artery Occlusion Trial (ERCAO Trial) Part 1: Prospective Clinical Registry Study Part 2: Prospective Randomized Control Trial Study'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The investigators conduct a prospective study composed of clinical registry arm and RCT arm.
    explanation: Registry summary describes the planned study design; it does not report efficacy results.
  notes: Registry-reported RECRUITING status checked 2026-10-04; this records the submitted status rather than independently confirming active enrollment. Last update 2025-07-28; estimated enrollment 200.
- name: NCT06303414
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: Observational cohort study of recanalization treatment for symptomatic non-acute carotid artery occlusion comparing CEA, endovascular intervention, and hybrid surgery.
  target_phenotypes:
  - preferred_term: Carotid artery occlusion
    term:
      id: HP:0012474
      label: Carotid artery occlusion
  evidence:
  - reference: clinicaltrials:NCT06303414
    reference_title: Revascularization for Symptomatic Non-acute Carotid Artery Occlusion
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The purpose of this cohort study is to observe the success rate, efficacy and safety of recanalization treatment for non-acute occlusion, and to further compare the advantages and disadvantages of CEA, endovascular intervention and hybrid surgery.
    explanation: Registry summary describes the planned study design; it does not report efficacy results.
  notes: Registry-reported RECRUITING status checked 2026-10-04; this records the submitted status rather than independently confirming active enrollment. Last update 2024-03-12; estimated enrollment 1000. This is an observational cohort, not an RCT.
notes: Atherosclerosis is the principal mechanism modeled here. Dissection-related occlusion and other arteriopathies have distinct etiologies and are not represented as atherosclerotic subtypes. Acute, non-acute, and chronic are temporal descriptions with study-specific thresholds, not genetically distinct disorders. No population frequency is inferred from stenosis registries or intervention-selected cohorts. The full-text sources PMC2805948, PMC10445185, and PMC12100504 correspond to PMID:17308211, PMID:37606672, and PMID:40402492, respectively.
epidemiology:
- name: Spontaneous recanalization in heterogeneous occlusion cohorts
  description: A 2025 scoping review found a median recanalization proportion of 21.2% across 17 cohorts, with 39.7% in dissection studies and 8.75% in non-dissection studies. These are medians of heterogeneous study proportions, not a pooled probability for atherosclerotic occlusion. Timing of detection, incomplete surveillance, and possible misclassified near-occlusion limit interpretation.
  evidence:
  - reference: PMID:40644384
    reference_title: 'Spontaneous recanalization of extracranial internal carotid occlusion: A systematic scoping review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: When broken down by etiology, median proportion was 39.7% (IQR 32.8–54.3%) in dissection studies vs. 8.75% (IQR 5.70–10.5%) in non-dissection studies.
    explanation: Stratified full-text results prevent applying the mixed-etiology estimate to atherosclerotic occlusion.
  - reference: PMID:40644384
    reference_title: 'Spontaneous recanalization of extracranial internal carotid occlusion: A systematic scoping review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: there is no apparent consensus regarding the management of carotid recanalization whether symptomatic or not.
    explanation: The review does not establish a surveillance interval or routine intervention after recanalization.
- name: Recurrent stroke in hemodynamically compromised symptomatic occlusion
  description: In COSS, the two-year primary-event rate in the medically treated group was 22.7%. This is a selected recently symptomatic ICA-occlusion population with increased PET oxygen extraction, not an estimate for asymptomatic or well-collateralized occlusion.
  evidence:
  - reference: PMID:22068990
    reference_title: 'Extracranial-intracranial bypass surgery for stroke prevention in hemodynamic cerebral ischemia: the Carotid Occlusion Surgery Study randomized trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Two-year rates for the primary end point were 21.0% (95% CI, 12.8% to 29.2%; 20 events) for the surgical group and 22.7% (95% CI, 13.9% to 31.6%; 20 events) for the nonsurgical group
    explanation: Provides the selected-trial event rates; both groups received medical prevention.
references:
- reference: DOI:10.3390/ijms25084351
  title: 'Molecular Pathways of Vulnerable Carotid Plaques at Risk of Ischemic Stroke: A Narrative Review'
- reference: PMID:22068990
  title: 'Extracranial-intracranial bypass surgery for stroke prevention in hemodynamic cerebral ischemia: the Carotid Occlusion Surgery Study randomized trial.'
- reference: PMID:26844337
  title: The Role of Lipids and Lipoproteins in Atherosclerosis.
- reference: PMID:36894991
  title: 'Associations of genetic markers of diabetes mellitus with carotid atherosclerosis: a community-based case-control study.'
- reference: PMID:37303351
  title: 'Carotid Artery Stenosis: A Look Into the Diagnostic and Management Strategies, and Related Complications.'
- reference: PMID:37595697
  title: The microenvironment of the atheroma expresses phenotypes of plaque instability.
- reference: PMID:37606672
  title: 'Extracranial-Intracranial Bypass and Risk of Stroke and Death in Patients With Symptomatic Artery Occlusion: The CMOSS Randomized Clinical Trial.'
- reference: PMID:37813974
  title: Recanalization of chronic long-segment occlusion of the internal carotid artery with endovascular and hybrid surgery.
- reference: PMID:38740919
  title: Significance of atherosclerotic plaque location in recanalizing non-acute long-segment occlusion of the internal carotid artery.
- reference: PMID:39730871
  title: Identification of shared genetic etiology of cardiovascular and cerebrovascular diseases through common cardiometabolic risk factors.
- reference: PMID:40644384
  title: 'Spontaneous recanalization of extracranial internal carotid occlusion: A systematic scoping review.'
- reference: clinicaltrials:NCT00029146
  title: Carotid Occlusion Surgery Study
- reference: clinicaltrials:NCT01758614
  title: The Carotid and Middle Cerebral Artery Occlusion Surgery Study
- reference: clinicaltrials:NCT03179774
  title: 'Endovascular Revascularization for Chronic Carotid Artery Occlusion Trial (ERCAO Trial) Part 1: Prospective Clinical Registry Study Part 2: Prospective Randomized Control Trial Study'
- reference: clinicaltrials:NCT06303414
  title: Revascularization for Symptomatic Non-acute Carotid Artery Occlusion
- reference: url:https://newsroom.heart.org/news/new-guideline-expands-stroke-treatment-for-adults-offers-first-pediatric-stroke-guidance
  title: New guideline expands stroke treatment for adults, offers first pediatric stroke guidance | American Heart Association
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC10445185/
  title: 'Extracranial-Intracranial Bypass and Risk of Stroke and Death in Patients With Symptomatic Artery Occlusion: The CMOSS Randomized Clinical Trial - PMC'
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC12100504/
  title: Long-Term Follow-Up of Extracranial-Intracranial Bypass Surgery for Symptomatic Cerebral Artery Occlusion - PMC
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1
  title: 'Complete occlusion of extracranial internal carotid artery: clinical features, pathophysiology, diagnosis and management - PMC'
- reference: PMID:17308211
  title: 'Complete occlusion of extracranial internal carotid artery: clinical features, pathophysiology, diagnosis and management.'
- reference: PMID:40402492
  title: Long-Term Follow-Up of Extracranial-Intracranial Bypass Surgery for Symptomatic Cerebral Artery Occlusion.
- reference: PMID:41582814
  title: '2026 Guideline for the Early Management of Patients With Acute Ischemic Stroke: A Guideline From the American Heart Association/American Stroke Association.'
imaging_findings:
- name: Absent extracranial ICA Doppler flow
  description: Duplex ultrasound demonstrates absent flow signal along the extracranial ICA; extremely slow residual flow must be excluded.
  phenotype_term:
    preferred_term: Carotid artery occlusion
    term:
      id: HP:0012474
      label: Carotid artery occlusion
  evidence:
  - *id011
  modality: ULTRASOUND
- name: Increased hemispheric oxygen extraction on PET
  modality: PET
  description: An elevated ipsilateral oxygen-extraction fraction indicates stage II hemodynamic compromise in selected symptomatic ICA occlusion.
  evidence:
  - *id002
  - *id012
stages:
- name: Non-acute occlusion (cohort-specific threshold)
  description: One 2024 atherosclerotic long-segment ICA cohort defined non-acute occlusion as more than seven days. This is an operational research threshold rather than a universal disease stage.
  evidence:
  - reference: PMID:38740919
    reference_title: Significance of atherosclerotic plaque location in recanalizing non-acute long-segment occlusion of the internal carotid artery.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: patients with non-acute (> 7 days) atherosclerotic ICA long-segment occlusion
    explanation: Specifies this cohort's temporal eligibility definition.
- name: Chronic occlusion (cohort-specific threshold)
  description: A 2023 cohort required at least three weeks of ICA occlusion after imaging confirmation. Organized thrombus may complicate reopening; this threshold is not interchangeable with every trial's non-acute definition.
  evidence:
  - reference: PMID:37813974
    reference_title: Recanalization of chronic long-segment occlusion of the internal carotid artery with endovascular and hybrid surgery.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: chronic atherosclerotic occlusion was defined as ICA occlusion over 3 weeks after imaging confirmation.
    explanation: States the study-specific definition.
📚

References & Deep Research

References

22
DOI:10.3390/ijms25084351
Molecular Pathways of Vulnerable Carotid Plaques at Risk of Ischemic Stroke: A Narrative Review
No top-level findings curated for this source.
PMID:22068990
Extracranial-intracranial bypass surgery for stroke prevention in hemodynamic cerebral ischemia: the Carotid Occlusion Surgery Study randomized trial.
No top-level findings curated for this source.
PMID:26844337
The Role of Lipids and Lipoproteins in Atherosclerosis.
No top-level findings curated for this source.
PMID:36894991
Associations of genetic markers of diabetes mellitus with carotid atherosclerosis: a community-based case-control study.
No top-level findings curated for this source.
PMID:37303351
Carotid Artery Stenosis: A Look Into the Diagnostic and Management Strategies, and Related Complications.
No top-level findings curated for this source.
PMID:37595697
The microenvironment of the atheroma expresses phenotypes of plaque instability.
No top-level findings curated for this source.
PMID:37606672
Extracranial-Intracranial Bypass and Risk of Stroke and Death in Patients With Symptomatic Artery Occlusion: The CMOSS Randomized Clinical Trial.
No top-level findings curated for this source.
PMID:37813974
Recanalization of chronic long-segment occlusion of the internal carotid artery with endovascular and hybrid surgery.
No top-level findings curated for this source.
PMID:38740919
Significance of atherosclerotic plaque location in recanalizing non-acute long-segment occlusion of the internal carotid artery.
No top-level findings curated for this source.
PMID:39730871
Identification of shared genetic etiology of cardiovascular and cerebrovascular diseases through common cardiometabolic risk factors.
No top-level findings curated for this source.
PMID:40644384
Spontaneous recanalization of extracranial internal carotid occlusion: A systematic scoping review.
No top-level findings curated for this source.
clinicaltrials:NCT00029146
Carotid Occlusion Surgery Study
No top-level findings curated for this source.
clinicaltrials:NCT01758614
The Carotid and Middle Cerebral Artery Occlusion Surgery Study
No top-level findings curated for this source.
clinicaltrials:NCT03179774
Endovascular Revascularization for Chronic Carotid Artery Occlusion Trial (ERCAO Trial) Part 1: Prospective Clinical Registry Study Part 2: Prospective Randomized Control Trial Study
No top-level findings curated for this source.
clinicaltrials:NCT06303414
Revascularization for Symptomatic Non-acute Carotid Artery Occlusion
No top-level findings curated for this source.
url:https://newsroom.heart.org/news/new-guideline-expands-stroke-treatment-for-adults-offers-first-pediatric-stroke-guidance
New guideline expands stroke treatment for adults, offers first pediatric stroke guidance | American Heart Association
No top-level findings curated for this source.
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC10445185/
Extracranial-Intracranial Bypass and Risk of Stroke and Death in Patients With Symptomatic Artery Occlusion: The CMOSS Randomized Clinical Trial - PMC
No top-level findings curated for this source.
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC12100504/
Long-Term Follow-Up of Extracranial-Intracranial Bypass Surgery for Symptomatic Cerebral Artery Occlusion - PMC
No top-level findings curated for this source.
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC2805948/?pdf=1
Complete occlusion of extracranial internal carotid artery: clinical features, pathophysiology, diagnosis and management - PMC
No top-level findings curated for this source.
PMID:17308211
Complete occlusion of extracranial internal carotid artery: clinical features, pathophysiology, diagnosis and management.
No top-level findings curated for this source.
PMID:40402492
Long-Term Follow-Up of Extracranial-Intracranial Bypass Surgery for Symptomatic Cerebral Artery Occlusion.
No top-level findings curated for this source.
PMID:41582814
2026 Guideline for the Early Management of Patients With Acute Ischemic Stroke: A Guideline From the American Heart Association/American Stroke Association.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Falcon ▸
Carotid Artery Occlusion (CAO): Comprehensive Disease Characteristics Report
Edison Scientific Literature 52 citations 2026-05-05T23:38:21.989151

Carotid Artery Occlusion (CAO): Comprehensive Disease Characteristics Report

Executive summary

Carotid artery occlusion (CAO)—most commonly occlusion of the extracranial internal carotid artery (ICA)—is typically the end stage of carotid atherosclerotic disease and can cause transient ischemic attack (TIA), ischemic stroke, ocular ischemic syndrome, or remain asymptomatic depending on collateral circulation. Contemporary research emphasizes (i) careful phenotyping of acute vs non-acute/chronic occlusions, (ii) improved patient selection using perfusion/hemodynamic markers, and (iii) a shift toward less invasive or hybrid revascularization strategies for selected symptomatic chronic/non-acute ICA occlusion, while optimized medical therapy remains foundational. (zhao2024significanceofatherosclerotic pages 1-2, ren2023recanalizationofchronic pages 8-9, NCT06303414 chunk 2)

Evidence snapshot table (recent quantitative findings)

Domain Key metric (exact number) Population/study Year PMID (if available; otherwise DOI) URL
Epidemiology/Risk Severe baseline asymptomatic carotid artery stenosis (ACAS) prevalence 6.3%; 1,662/26,384 patients; 1,124 strokes and 2,484 CVD events over ~70,000 patient-years; among PACAS score ≥14 (27.7% of cohort), severe ACAS prevalence 11.4%, accounting for 56.6% of incident strokes and 64.9% of incident CVD events (poorthuis2024predictionofsevere pages 1-2) REACH validation cohort, Poorthuis et al., Stroke 2024 DOI: 10.1161/STROKEAHA.123.046894 https://doi.org/10.1161/strokeaha.123.046894
Epidemiology/Risk Early recurrence after neurologic index event: 6.4% at 2–3 days, 19.5% at 7 days, 26.1% at 14 days; pooled analysis 5,893 patients, 33,000 patient-years; benefit greatest when revascularization performed within 2 weeks (musialek2025strokeriskmanagement pages 28-29) Symptomatic carotid stenosis, ESC consensus cited systematic review 2025 DOI: 10.1093/cvr/cvad135 https://doi.org/10.1093/cvr/cvad135
Imaging diagnostics DUS vs CTA for extracranial ICA stenosis 50–94%: accuracy 69%, sensitivity 89%, specificity 63%; for 70–94%: accuracy 84%, sensitivity 61%, specificity 93%; CTA inter-observer variation 14% vs DUS 3% (daolio2024accuracyofduplex pages 1-2, daolio2024accuracyofduplex pages 4-6, daolio2024accuracyofduplex pages 2-4) 45 patients, 84 arteries, Daolio et al. 2024 DOI: 10.1590/0100-6991e-20243632-en https://doi.org/10.1590/0100-6991e-20243632-en
Imaging diagnostics CTA meta-analysis for severe ICA stenosis (70–99%): sensitivity 0.93 (95% CI 0.88–0.96), specificity 0.99 (95% CI 0.96–1.00), PLR 92.0, NLR 0.07, DOR 1302, AUC 0.98 (zeng2024systematicreviewand pages 1-2, zeng2024systematicreviewand pages 6-6) 16 studies, 2,368 vascular segments, Zeng et al. 2024 DOI: 10.1186/s12880-024-01390-6 https://doi.org/10.1186/s12880-024-01390-6
Imaging diagnostics Color Doppler ultrasound vs DSA: Kappa 0.823, sensitivity 97.67%, specificity 88.24%, accuracy 95.00%; MRA vs DSA: Kappa 0.657, sensitivity 97.30%, specificity 65.22%, accuracy 85.00% (li2026comparativediagnosticvalue pages 1-2) 120 patients, Li et al. 2026 DOI: 10.11152/mu-4590 https://doi.org/10.11152/mu-4590
Chronic ICA occlusion revascularization outcomes Chronic long-segment ICA occlusion recanalization: overall success 94.3% (82/87); endovascular-only 93.0% (40/43); hybrid 95.5% (42/44); type I 100%, type II 87.8%; favorable mRS 0–2 in 79.3% overall; overall complications 6.9%; re-occlusion 4.9% overall, 0% in type I vs 9.8–11.1% in type II (ren2023recanalizationofchronic pages 1-2, ren2023recanalizationofchronic pages 7-8, ren2023recanalizationofchronic pages 3-5) 87 patients, Ren et al., Scientific Reports 2023 DOI: 10.1038/s41598-023-44406-x https://doi.org/10.1038/s41598-023-44406-x
Chronic ICA occlusion revascularization outcomes Symptomatic non-acute long-segment ICA occlusion hybrid recanalization: overall success 97.5% (158/162); proximal plaque 99.2% (119/120); distal plaque 92.9% (39/42); complications 4.2% proximal and 4.8% distal; re-occlusion 2.8% proximal vs 13.3% distal; medically treated annual ipsilateral ischemic stroke risk 3%, rising to 10–20% with severe hemodynamic compromise (zhao2024significanceofatherosclerotic pages 1-2) 162 patients, Zhao et al., Scientific Reports 2024 DOI: 10.1038/s41598-024-61938-y https://doi.org/10.1038/s41598-024-61938-y
CAS standards/complications Recommended independently assessed in-hospital stroke/death risk after CAS: ≤4% for symptomatic and ≤2% for asymptomatic disease; 30-day rates should not exceed 6% symptomatic and 3% asymptomatic (spiliopoulos2024cirsestandardsof pages 9-10, spiliopoulos2024cirsestandardsof pages 10-11) CIRSE Standards of Practice on CAS 2024 DOI: 10.1007/s00270-024-03707-y https://doi.org/10.1007/s00270-024-03707-y
CAS standards/complications Transcervical CAS systematic review: technical success 96.3%, open conversion 3.0%, access complications 2.9%, stroke 1.1–1.2%, TIA 2.7%, MI 0.14%, death 0.41%; transradial CAS registry: major access complications 0% vs transfemoral 1.1%, peri-procedural stroke/death 3.3% vs 2.4% (spiliopoulos2024cirsestandardsof pages 9-10) CAS access-strategy studies summarized in CIRSE guideline 2024 DOI: 10.1007/s00270-024-03707-y https://doi.org/10.1007/s00270-024-03707-y
Genetics/molecular Shared CVD/CeVD/cIMT genetics: 11 colocalized loci, 12 mapped genes (CASZ1, CDKN1A, TWIST1, CDKN2B, ABO, SWAP70, SH2B3, LRCH1, FES, GOSR2, RPRML, LDLR); genetic correlation rg ≈ 0.59; MiXeR estimates ~1.5K causal variants for CAD, ~1.0K for atherosclerosis, with ~0.9K shared variants; methylation signals implicated for CASZ1 and LRCH1 (ding2024identificationofshared pages 1-2, ding2024identificationofshared pages 14-15) Ding et al., Communications Biology 2024 DOI: 10.1038/s42003-024-07417-6 https://doi.org/10.1038/s42003-024-07417-6
Genetics/molecular Diabetes-GWAS markers and carotid plaque: 9 SNPs associated (rs4712524, rs1150777, rs10842993, rs2858980, rs9583907, rs1077476, rs7180016, rs4383154, rs9937354); 9-GRS mean 9.19 ± 1.53 vs 8.62 ± 1.63; OR per 1.0 increase in 9-GRS 1.30 (95% CI 1.18–1.44, p=4.7×10^-7); 4-GRS mean 4.02 ± 0.81 vs 3.78 ± 0.92; OR 1.47 (reported 95% CI 1.74–9.40, p=6.1×10^-5) (wu2023associationsofgenetic pages 1-2) 309 carotid plaque cases, 439 controls, Wu et al. 2023 DOI: 10.1186/s12933-023-01787-7 https://doi.org/10.1186/s12933-023-01787-7

Table: This table compiles the main quantitative findings identified across recent carotid occlusion/stenosis literature, spanning epidemiology, imaging accuracy, chronic ICA occlusion revascularization outcomes, carotid stenting standards, and genetics. It is useful as a compact evidence summary for a disease knowledge base entry.

1. Disease Information

1.1 Definition and current understanding

Carotid artery occlusion (CAO) refers to near-complete or complete obstruction of a carotid artery lumen; in clinical cerebrovascular practice, this most often means extracranial internal carotid artery occlusion (ICAO), sometimes including common carotid artery (CCA) occlusion. Definitions vary by imaging modality and clinical context:

  • Angiographic complete occlusion: ClinicalTrials.gov protocols for symptomatic non-acute CAO define occlusion using DSA confirmation with mTICI=0, i.e., no antegrade perfusion through the occluded carotid segment. (NCT06303414 chunk 2)
  • “Non-acute” vs “chronic” occlusion is operationalized differently across studies:
  • Non-acute ICA occlusion defined as >7 days in a hybrid-recanalization cohort. (zhao2024significanceofatherosclerotic pages 1-2)
  • Chronic ICA occlusion defined as >3 weeks after imaging confirmation in an endovascular/hybrid recanalization cohort. (ren2023recanalizationofchronic pages 8-9)
  • A clinical trial defines non-acute CAO as occlusion ≥24 hours. (NCT06303414 chunk 2)

Key concept: Clinical consequences depend strongly on collateral flow (circle of Willis/external carotid pathways). Consensus sources note presentations range from asymptomatic to catastrophic depending on collateral capacity. (musialek2025strokeriskmanagement pages 15-16)

1.2 Key identifiers (ontologies/codes)

  • MeSH (from trial metadata): ClinicalTrials.gov records include MeSH identifiers for related interventions/conditions (e.g., “Endarterectomy, Carotid” D016894; “Stroke” D020521; “Ischemic Attack, Transient” D002546; “Cerebral Infarction” D002544; “Cerebral Revascularization” D002548). (NCT06303414 chunk 2, NCT00029146 chunk 2)
  • MONDO / OMIM / Orphanet identifiers: Not identified in the retrieved evidence set. This is expected because CAO is typically a phenotype within atherosclerotic or thromboembolic disease rather than a monogenic disorder. (zhao2024significanceofatherosclerotic pages 1-2, ren2023recanalizationofchronic pages 8-9)
  • ICD-10/ICD-11 codes: Not present in the retrieved sources.

1.3 Synonyms / alternative names

Common terms used in recent literature: * Internal carotid artery occlusion (ICAO) / extracranial ICA occlusion (zhang2025spontaneousrecanalizationof pages 1-3) * Chronic ICA occlusion, non-acute ICA occlusion, chronic long-segment ICA occlusion (zhao2024significanceofatherosclerotic pages 1-2, ren2023recanalizationofchronic pages 8-9) * Carotid artery disease / carotid atherosclerotic disease when CAO is treated as the end-stage of stenosis/plaque (musialek2025strokeriskmanagement pages 28-29)

1.4 Evidence source type

The evidence synthesized here is from aggregated disease-level resources: cohort studies, systematic reviews/meta-analyses, consensus statements, procedure standards, and ClinicalTrials.gov protocols—not individual EHR case extraction. (ren2023recanalizationofchronic pages 8-9, spiliopoulos2024cirsestandardsof pages 5-6, NCT06303414 chunk 2)

2. Etiology

2.1 Primary causal factors

Atherosclerotic plaque progression with superimposed thrombosis is the leading cause of extracranial ICA occlusion in older populations, and is conceptually an extreme on the carotid stenosis continuum. Mechanistically, plaques arise via endothelial dysfunction and inflammatory lipid accumulation with fibrous cap formation; advanced lesions can thrombose and occlude. (ismail2023carotidarterystenosis pages 8-10, ren2023recanalizationofchronic pages 8-9)

Non-atherosclerotic etiologies include carotid dissection and other less common arteriopathies (examples appear in related occlusion literature and trial inclusion allowing various etiologies). (zhang2025spontaneousrecanalizationof pages 1-3)

2.2 Risk factors (representative, evidence-based)

Risk factors align with systemic atherosclerosis and stroke prevention frameworks: * Hypertension and diabetes are common comorbidities in chronic occlusion intervention cohorts (e.g., hypertension 75.7%, diabetes 31.1% reported in a chronic cerebral artery occlusion recanalization cohort that included ICA occlusion cases). (zhao2024significanceofatherosclerotic pages 1-2) * Smoking is both a risk factor for carotid atherosclerotic progression and is a predictor in some recanalization success models; in one chronic occlusion cohort 36.9% had smoking history and smoking history was independently associated with recanalization success. (zhao2024significanceofatherosclerotic pages 1-2)

2.3 Protective factors

Direct protective factors specifically for CAO are not consistently quantified in the retrieved 2023–2024 CAO-focused evidence. However, guideline-consensus sources emphasize aggressive risk factor control and modern medical therapy to lower carotid-related stroke risk. (musialek2025strokeriskmanagement pages 57-58)

2.4 Gene–environment interactions

Direct gene×environment interaction studies for CAO were not captured in the retrieved set. Nonetheless, several genetic studies implicate pathways (BP regulation, lipid biology, inflammation) whose phenotypic expression is strongly modified by lifestyle and medical therapy, supporting a systems-level G×E view. (ding2024identificationofshared pages 1-2, wu2023associationsofgenetic pages 1-2)

3. Phenotypes

3.1 Core clinical phenotypes and suggested HPO terms

Below are common CAO-associated phenotypes; frequencies are variable and depend on collateral circulation and the presence of embolic sources.

1) Ischemic stroke / cerebral infarction (often carotid-territory) * Phenotype type: clinical event * HPO: Cerebral infarction (HP:0001344), Ischemic stroke (HP:0002140) * Notes: Chronic ICA occlusion is associated with substantial recurrent ipsilateral stroke risk despite medical therapy in historical cohorts (6–20%/year cited) and procedure series cite this as rationale for intervention in selected cases. (ren2023recanalizationofchronic pages 1-2)

2) Transient ischemic attack (TIA) including hemodynamic presentations * Phenotype type: symptom complex * HPO: Transient ischemic attack (HP:0002326) * Special phenotype: limb-shaking TIA is described as hemodynamic, related to carotid stenosis/occlusion and impaired perfusion. (musialek2025strokeriskmanagement pages 15-16)

3) Ocular ischemic phenomena (amaurosis fugax/ocular ischemic syndrome) * Phenotype type: symptom/sign * HPO: Amaurosis fugax (HP:0001105) (term usage may vary) * Notes: Some carotid stenosis/occlusion cohorts emphasize retinal ischemia as a marker of symptomatic carotid disease. (daolio2024accuracyofduplex pages 2-4)

4) Hemodynamic impairment / hypoperfusion * Phenotype type: imaging/physiology abnormality * HPO: Cerebral hypoperfusion (closest HPO term may differ by ontology version) * Notes: Non-acute CAO interventional trials require perfusion-confirmed hypoperfusion for enrollment. (NCT06303414 chunk 2)

3.2 Temporal phenotype features

  • Onset: typically adult/older adult for atherosclerotic CAO; can be younger in dissection-related occlusion. (zhang2025spontaneousrecanalizationof pages 1-3)
  • Course: can be asymptomatic chronic if collaterals are robust; otherwise progressive/episodic ischemic symptoms with hemodynamic instability. (musialek2025strokeriskmanagement pages 15-16)

3.3 Quality of life impact

Quality of life impact is driven by stroke disability and recurrent ischemia. Clinical trial outcomes for surgical bypass in symptomatic ICA occlusion include disability and stroke-specific QOL instruments (e.g., Rankin, Barthel, SS-QOL). (NCT00029146 chunk 2)

4. Genetic / Molecular Information

4.1 Causal genes

CAO is not typically monogenic; it is usually a downstream vascular phenotype of polygenic atherosclerosis risk, thrombosis risk, or arteriopathy (e.g., dissection, moyamoya-spectrum in selected populations).

4.2 Susceptibility loci / candidate genes (recent evidence)

Shared cardiometabolic genetics relevant to carotid atherosclerosis (proxy: cIMT): A 2024 multi-trait genetic study identified 11 colocalized loci mapped to CASZ1, CDKN1A, TWIST1, CDKN2B, ABO, SWAP70, SH2B3, LRCH1, FES, GOSR2, RPRML, LDLR, and suggested methylation of CASZ1 and LRCH1 as potentially causal mediators. Quantitative overlap estimates reported high genetic sharing (rg ≈ 0.59; ~0.9K shared causal variants). (ding2024identificationofshared pages 1-2, ding2024identificationofshared pages 14-15)

Diabetes-GWAS markers linked to carotid plaque: A 2023 community-based case–control analysis associated 9 diabetes GWAS SNPs with carotid plaque and reported polygenic risk score odds ratios (e.g., OR 1.30 per 1.0 increase in 9-locus GRS). (wu2023associationsofgenetic pages 1-2)

Endothelial/plaque biology candidates and epigenetic mechanisms (systematic review): Endothelial genetics/transcriptomics evidence emphasizes matrix remodeling and plaque progression pathways with candidates including MMP1 and ADAM9/15/17, and highlights flow/shear-stress–driven epigenetic regulation (DNA methylation, chromatin remodeling) and histone deacetylase biology (HDAC9). (richter2025endothelialcellgenetics pages 6-7, richter2025endothelialcellgenetics pages 14-15)

4.3 Epigenetics

Epigenetic regulation is implicated at two levels in the retrieved evidence: * Genetic multi-omics analyses suggesting methylation-mediated pleiotropy (CASZ1, LRCH1). (ding2024identificationofshared pages 1-2, ding2024identificationofshared pages 14-15) * Endothelial shear-stress–induced epigenetic changes (flow-dependent methylation and chromatin remodeling) in atherosclerosis biology. (richter2025endothelialcellgenetics pages 14-15)

4.4 Model organism genetics

Mouse vascular integrity genes (e.g., COL4A1) appear in broader cerebrovascular atherosclerosis genetics reviews but were not directly tied to CAO as a discrete phenotype in the retrieved set. (richter2025endothelialcellgenetics pages 11-12)

5. Environmental Information

5.1 Lifestyle and environmental factors

The disease is tightly linked to modifiable atherosclerosis risk factors (smoking, diet, activity) and metabolic disease burden. Intervention cohorts and reviews highlight smoking and cardiometabolic comorbidities as common features. (zhao2024significanceofatherosclerotic pages 1-2, ismail2023carotidarterystenosis pages 8-10)

5.2 Infectious agents

No infectious causal triggers were identified in the retrieved evidence set for CAO.

6. Mechanism / Pathophysiology

6.1 Causal chain (upstream → downstream)

  1. Upstream triggers: dyslipidemia, hypertension, diabetes, smoking → endothelial dysfunction and inflammation. (ismail2023carotidarterystenosis pages 8-10)
  2. Plaque formation and remodeling: lipid deposition, inflammatory infiltration, extracellular matrix remodeling (MMP/ADAM family), fibrous cap changes → plaque growth and vulnerability. (richter2025endothelialcellgenetics pages 6-7, richter2025endothelialcellgenetics pages 14-15)
  3. Occlusion event: plaque rupture/erosion and thrombosis or progressive luminal compromise → complete ICA/CCA occlusion. (ren2023recanalizationofchronic pages 8-9)
  4. Downstream ischemia mechanisms:
  5. Embolic: artery-to-artery embolism from carotid plaque/thrombus. (musialek2025strokeriskmanagement pages 50-51)
  6. Hemodynamic: reduced perfusion pressure with inadequate collaterals → hypoperfusion symptoms (e.g., limb-shaking TIA) and watershed infarcts. (musialek2025strokeriskmanagement pages 15-16, NCT06303414 chunk 2)

6.2 Cell types (suggested CL terms)

Key involved cell types (by current atherosclerosis biology and retrieved endothelial-focused evidence): * Endothelial cell (CL:0000115) (richter2025endothelialcellgenetics pages 1-2) * Vascular smooth muscle cell (CL:0000192) (implicated by vascular remodeling and gene expression enrichment) (ding2024identificationofshared pages 1-2) * Macrophage (CL:0000235) (ADAM genes upregulated in advanced plaques) (richter2025endothelialcellgenetics pages 14-15)

6.3 Suggested GO biological process terms

  • Inflammatory response (GO:0006954) (richter2025endothelialcellgenetics pages 6-7)
  • Extracellular matrix organization / collagen catabolic process (e.g., GO:0030198 / GO:0030574) (richter2025endothelialcellgenetics pages 6-7)
  • Response to shear stress / blood flow (GO:0034616) (richter2025endothelialcellgenetics pages 14-15)

6.4 Recent mechanistic developments (2023–2024 emphasis)

  • Increasing emphasis on lesion morphology/location and recanalization feasibility in chronic/non-acute ICA occlusion, with location-based classification affecting success and re-occlusion risk. (zhao2024significanceofatherosclerotic pages 1-2, ren2023recanalizationofchronic pages 8-9)
  • Multi-omics genetics continues to connect carotid intermediate phenotypes (cIMT, plaque) to shared cardiometabolic pathways (BP/lipid biology). (ding2024identificationofshared pages 1-2)

7. Anatomical Structures Affected

7.1 Organ/tissue level (UBERON suggestions)

  • Internal carotid artery (UBERON:0000945)
  • Common carotid artery (UBERON:0001456)
  • Brain (ischemic territories) (UBERON:0000955)
  • Retina/ocular circulation in ocular ischemic presentations (UBERON:0000966)

7.2 Localization and laterality

  • Often unilateral ICA occlusion; bilateral disease occurs and is clinically high risk. (NCT00029146 chunk 2)
  • Long-segment occlusion descriptions use Bouthillier ICA segments (C1–C7) for localization. (zhao2024significanceofatherosclerotic pages 1-2)

8. Temporal Development

8.1 Onset patterns

  • Acute ICA occlusion may present as large vessel occlusion stroke.
  • Non-acute/chronic occlusions may present with recurrent TIAs or progressive symptoms, or be incidentally discovered.

Operational definitions in recent chronic/non-acute cohorts: >7 days (non-acute) and >3 weeks (chronic). (zhao2024significanceofatherosclerotic pages 1-2, ren2023recanalizationofchronic pages 8-9)

8.2 Progression and staging

In practice, clinicians distinguish: * severe stenosis → near-occlusion → occlusion; * acute thrombotic occlusion vs chronic organized occlusion (recanalization feasibility differs).

9. Inheritance and Population

9.1 Epidemiology (available from retrieved evidence)

Direct population incidence/prevalence of ICA occlusion was not captured in the retrieved 2023–2024 primary epidemiology set. However, related high-quality epidemiology for severe asymptomatic carotid stenosis (a major precursor phenotype) is available: * Severe baseline ACAS prevalence 6.3% in 26,384 patients (REACH registry validation), with risk concentrated in high PACAS score strata. (poorthuis2024predictionofsevere pages 1-2)

CAO/ICAO recurrence risk under medical therapy is often cited from historical cohorts: * Annual ipsilateral stroke risk ~3% in medically treated chronic CAO, increasing to 10–20% with severe hemodynamic compromise (cited in a 2024 intervention series). (zhao2024significanceofatherosclerotic pages 1-2)

9.2 Genetic architecture

The genetic architecture is polygenic/multifactorial. Recent multi-trait analyses suggest thousands of causal variants for related atherosclerosis phenotypes and substantial sharing with CAD. (ding2024identificationofshared pages 1-2)

10. Diagnostics

10.1 Imaging-based diagnosis (core modalities)

  • Duplex ultrasound (DUS): commonly first-line; accuracy varies by stenosis threshold.
  • Example 2024 tertiary-center accuracy study vs CTA reference: accuracy 69% (50–94% stenosis) and 84% (70–94% stenosis). (daolio2024accuracyofduplex pages 1-2)
  • CTA: high accuracy for severe stenosis vs DSA in a 2024 meta-analysis (sensitivity 0.93, specificity 0.99, AUC 0.98). (zeng2024systematicreviewand pages 1-2)
  • MRA: may overestimate mild stenosis; 2026 study reports moderate agreement with DSA (Kappa 0.657). (li2026comparativediagnosticvalue pages 1-2)
  • DSA: invasive reference standard; used for procedural planning and trial enrollment confirmation. (NCT06303414 chunk 2)

Measurement caveat: Consensus sources stress that stenosis severity can be center- and modality-dependent; one cited comparison indicates that with DUS, “1 out of 6 arteries would be reclassified by CTA.” (musialek2025strokeriskmanagement pages 18-19)

10.2 Hemodynamic/perfusion assessment

For symptomatic non-acute CAO intervention selection, protocols require perfusion evidence of hypoperfusion and exclude large new infarcts on MRI DWI/ADC. (NCT06303414 chunk 2)

10.3 Differential diagnosis

  • Dissection-related occlusion
  • Intracranial occlusion patterns (tandem lesions)
  • Moyamoya-spectrum disease (RNF213-associated in East Asian ancestry contexts)

11. Outcome / Prognosis

11.1 Natural history (selected quantified estimates)

Chronic ICA occlusion is cited as carrying substantial recurrent stroke risk despite medical therapy: * Yearly ipsilateral recurrent stroke risk 6–20% is cited in a 2023 chronic ICA occlusion series as background rationale. (ren2023recanalizationofchronic pages 1-2)

11.2 Prognostic modifiers

  • Collateral circulation adequacy (circle of Willis/external carotid pathways) strongly influences symptom severity and outcome. (musialek2025strokeriskmanagement pages 15-16)
  • Occlusion anatomy/location predicts technical success and re-occlusion after recanalization (type I vs type II; proximal vs distal plaque). (zhao2024significanceofatherosclerotic pages 1-2, ren2023recanalizationofchronic pages 1-2)

12. Treatment

12.1 Medical therapy (baseline for all patients)

Modern carotid consensus emphasizes aggressive risk factor management (“goal-directed triple medical therapy” plus lifestyle modification), recognizing residual stroke risk remains in selected high-risk patients. (musialek2025strokeriskmanagement pages 57-58)

12.2 Surgical/interventional treatments

A) Carotid endarterectomy (CEA) and carotid artery stenting (CAS) for stenosis (precursor/related disease)

A 2023 review summarizes that guidelines recommend revascularization in symptomatic stenosis >50% and note comparative trial evidence between CEA and CAS with similar long-term ipsilateral stroke rates but different periprocedural risks; selected numeric trial outcomes are reported (e.g., NASCET perioperative stroke/death 6.5%). (ismail2023carotidarterystenosis pages 8-10)

CIRSE 2024 CAS SOP (practice standards): * Recommends structured procedural technique and embolic protection usage. * Provides quality thresholds (from ESO expert consensus) suggesting in-hospital stroke/death risk after CAS should not exceed 4% symptomatic and 2% asymptomatic, with 30-day rates ≤6% and ≤3% respectively. (spiliopoulos2024cirsestandardsof pages 9-10)

The SOP’s indications/contraindications are captured in the retrieved cropped guideline text images. (spiliopoulos2024cirsestandardsof media 6e47be29, spiliopoulos2024cirsestandardsof media 55399623)

B) Revascularization/recanalization for chronic/non-acute ICA occlusion (CAO-specific)

Hybrid or endovascular recanalization is increasingly reported in selected symptomatic chronic/non-acute long-segment ICA occlusion cohorts: * 2023 cohort: overall success 94.3% (82/87); complications 6.9%; re-occlusion 4.9%. (ren2023recanalizationofchronic pages 3-5) * 2024 cohort: overall success 97.5% (158/162); low reported periprocedural complications (~4–5%); re-occlusion differed by plaque location (2.8% vs 13.3%). (zhao2024significanceofatherosclerotic pages 1-2)

MAXO suggestions (interventions): * Carotid endarterectomy (MAXO:??) * Carotid artery stenting / endovascular recanalization (MAXO:??) * Extracranial–intracranial bypass (MAXO:??)

(Exact MAXO IDs were not available in retrieved sources and would require ontology lookup.)

12.3 Clinical trials (CAO-specific; ClinicalTrials.gov)

  • NCT03179774 (ERCAO trial; National Taiwan University Hospital): rater-blinded RCT of endovascular revascularization + OMT vs OMT alone for chronic CAO; primary endpoints include neurocognitive measures (ADAS-Cog, MMSE, etc.) with safety endpoints including death/ipsilateral stroke within 30 days and up to 1 year. (NCT03179774 chunk 1)
  • NCT06303414 (Xuanwu Hospital, Beijing): observational trial of revascularization for symptomatic non-acute CAO; requires DSA-confirmed mTICI=0 occlusion and perfusion-confirmed hypoperfusion; tracks technical success, stroke/death, cranial nerve injury, and re-occlusion (>99%) through 12 months. (NCT06303414 chunk 2)
  • NCT00029146 (COSS): EC–IC bypass trial framework for symptomatic ICA occlusion with hemodynamic compromise; includes disability/QOL endpoints at 2 years (Rankin, Barthel, SS-QOL). (NCT00029146 chunk 2)

13. Prevention

13.1 Primary prevention

Risk-factor modification to prevent carotid atherosclerosis progression (BP control, diabetes management, smoking cessation) is central; evidence is consistent with broader stroke prevention consensus emphasizing medical therapy uptake and lifestyle modification. (musialek2025strokeriskmanagement pages 57-58)

13.2 Secondary prevention

Selective screening for severe asymptomatic stenosis may be guided by risk models; a 2024 validation study suggests high PACAS risk groups concentrate stroke/CVD events and may support targeted screening strategies. (poorthuis2024predictionofsevere pages 1-2)

13.3 Tertiary prevention

In established symptomatic disease, timely revascularization for stenosis can reduce recurrent stroke risk, and selected chronic occlusion patients may be considered for recanalization trials or specialized interventions. (musialek2025strokeriskmanagement pages 28-29, NCT03179774 chunk 1)

14. Other species / natural disease

Non-human naturally occurring ICA occlusion is reported in veterinary anatomical studies (e.g., Japanese Black cattle ICA occlusion/closure patterns), but this is not a translational disease model for human atherosclerotic CAO. (musialek2025strokeriskmanagement pages 57-58)

15. Model organisms

Common experimental models relevant to CAO mechanisms (not comprehensively retrieved here) include bilateral common carotid artery occlusion (BCCAO) in rodents used for chronic hypoperfusion studies. (musialek2025strokeriskmanagement pages 57-58)

Direct abstract quotes (as required; limited by available abstracts in retrieved set)

  • Poorthuis et al., Stroke (Nov 2024): “Among 26 384 patients… 1662 (6.3%) had severe baseline ACAS.” (poorthuis2024predictionofsevere pages 1-2)
  • Zhang et al., PLOS One (Jul 2025; scoping review of ICA occlusion recanalization): “The proportion of recanalization was reported in 17 cohort studies for a median of 21.2% (IQR 9.2–37.5%).” (zhang2025spontaneousrecanalizationof pages 1-3)
  • ERCAO trial (ClinicalTrials.gov NCT03179774): protocol states it compares “endovascular revascularization plus optimal medical therapy… versus optimal medical therapy alone” for chronic CAO with neurocognitive primary endpoints. (NCT03179774 chunk 1)

(Additional verbatim abstract quotes from older landmark RCTs such as NASCET/CREST/ACST were not retrieved as full abstracts in this evidence set; the numeric summaries reported in secondary sources should be verified against primary trial abstracts/PMIDs for a production-grade knowledge base.) (ismail2023carotidarterystenosis pages 8-10)

Notes on evidence gaps vs requested template

  • MONDO/ICD identifiers, MAXO IDs, and some HPO/GO exact IDs were not present in the retrieved sources and would require direct ontology database lookup.
  • 2023–2024 ICAO/CAO population prevalence/incidence was not captured in retrieved primary epidemiology papers; current evidence here provides (i) severe asymptomatic stenosis epidemiology (2024) and (ii) recurrence risk estimates and intervention cohort outcomes for chronic/non-acute occlusion.

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