Carotid Stenosis

Complex MONDO:0001612 Pathograph 23 Show in embeddings browser Carotid artery disorder Vascular disorder Cerebrovascular Disease

Carotid stenosis is narrowing of the extracranial carotid arterial lumen, usually from atherosclerotic plaque at the bifurcation or proximal internal carotid artery. Plaque burden and plaque instability are distinct determinants of risk. Embolization and, in some severe lesions, inadequate perfusion can cause ipsilateral cerebral or retinal ischemia. Symptomatic status, stenosis severity, plaque characteristics, procedural risk, and contemporary medical therapy influence stroke-prevention decisions. Cognitive impairment is associated with severe disease, but randomized revascularization trials have not demonstrated cognitive benefit.

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Pathophysiology

Carotid Intimal ApoB Lipoprotein Retention

Mechanism confidence: Established

Endothelial dysfunction in the carotid arterial wall permits infiltration and retention of apoB-containing lipoproteins in the intima. Retained LDL is modified locally and initiates the inflammatory plaque-forming branch of atherosclerotic carotid stenosis.

endothelial cell CL:0000115

cholesterol homeostasis GO:0042632 ↕ DYSREGULATED

internal carotid artery UBERON:0001532

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 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 foam cell CL:0000891

foam cell differentiation GO:0090077 ↑ INCREASED inflammatory response GO:0006954 ↑ INCREASED

internal carotid artery UBERON:0001532

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 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 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

Vascular smooth-muscle-cell phenotypic switching, proliferation, and extracellular-matrix secretion assemble a fibrofatty plaque with a fibrous cap in the carotid arterial wall. Continued plaque growth progressively narrows the lumen.

vascular smooth muscle cell CL:0000359

smooth muscle cell proliferation GO:0048661 ↑ INCREASED extracellular matrix organization GO:0030198 ↑ INCREASED

Downstream

Flow-limiting carotid lumen narrowing Growth can encroach on the residual lumen.

Vulnerable plaque instability Inflammatory remodeling of an established plaque can enlarge its lipid core and thin its cap, producing a vulnerable state.

Fibrous-cap matrix degradation Inflammatory proteases can degrade the matrix of an established plaque.

Intraplaque neovascularization Advanced plaque can develop an immature microvascular network.

Show evidence (3 references)

PMID:37303351 SUPPORT 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 abstract supports fibrous-cap formation as part of the carotid atherosclerotic plaque branch.

PMID:37595697 SUPPORT REVIEW SYNTHESIS Other

"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."

This histopathology review supports the conserved smooth-muscle-cell switching and matrix-secretion program that builds the fibrous cap and enlarges the necrotic core of the carotid plaque.

PMID:39099701 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The characteristic lesion of atherosclerosis is the atherosclerotic plaque or atheromatous plaque, a complex lesion of the intimal layer of the vessel wall, consisting of a central core of cholesterol clefts, macrophages, and inflammatory cells, surrounded by layers of smooth muscle cells and..."

Describes the cellular and matrix architecture of carotid atheroma.

Flow-limiting carotid lumen narrowing

Mechanism confidence: Established

Plaque encroachment narrows the residual carotid lumen. Severe narrowing can limit distal flow, but percent stenosis alone does not determine plaque vulnerability or prove exhausted perfusion reserve.

internal carotid artery UBERON:0001532

Downstream

Carotid artery stenosis Lumen encroachment produces the defining imaging phenotype.

Hemodynamic cerebral perfusion impairment Severe stenosis can impair distal perfusion when compensatory flow is inadequate.

Show evidence (1 reference)

PMID:39099701 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The atherosclerotic plaque usually grows slowly, limiting the arterial lumen and causing a local stenosis that reduces blood flow to the distal vessels."

Connects plaque growth with narrowing and reduced distal flow.

Fibrous-cap matrix degradation

Mechanism confidence: Established

Proteolytic breakdown of extracellular matrix reduces cap structural integrity. Human plaque observations and broader atherogenesis work implicate matrix metalloproteinases; no single protease is assumed to explain every unstable plaque.

extracellular matrix disassembly GO:0022617 ↑ INCREASED

Downstream

Vulnerable plaque instability Loss of cap matrix increases vulnerability to rupture.

Show evidence (1 reference)

PMID:38673936 SUPPORT DIRECT REVIEW SYNTHESIS Other

"MMPs play a critical role in determining the instability of plaques because of their capability to degrade the cellular matrix, the vascular wall, and fibrotic caps, leading to a higher risk of rupture."

Review synthesis links proteolysis to weakened cap structure.

Intraplaque neovascularization

Mechanism confidence: Established

Endothelial sprouting creates immature microvessels within advanced plaque.

angiogenesis GO:0001525 ↑ INCREASED

Downstream

Intraplaque hemorrhage Fragile microvessels permit red-cell leakage into the plaque.

Show evidence (1 reference)

PMID:38673936 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Angiogenic sprouting entails the proliferation and migration of ECs into avascular areas. Pathological angiogenesis is a consistent feature of atherosclerotic plaque development,"

Defines intraplaque endothelial sprouting.

Intraplaque hemorrhage

Mechanism confidence: Established

Blood leakage into the plaque adds erythrocyte material and promotes inflammatory remodeling, contributing to a vulnerable plaque state.

Downstream

Vulnerable plaque instability Hemorrhagic plaque remodeling increases vulnerability.

Show evidence (2 references)

PMID:38673936 SUPPORT DIRECT REVIEW SYNTHESIS Other

"Additionally, these premature vessels have limited pericyte coverage and are prone to the leakage of circulating cells, leading to IPH"

Immature plaque microvessels permit intraplaque hemorrhage.

PMID:39099701 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The characteristics which define vulnerable plaque include a large lipid-rich core, a thin fibrous cap, inflammation in or around the plaque, intraplaque hemorrhage and vasa vasorum neovascularization."

Supports an advanced vulnerable plaque state distinct from percent stenosis.

Vulnerable plaque instability

Mechanism confidence: Established

An advanced carotid atheroma with a lipid-rich necrotic core and a weakened fibrous cap is susceptible to surface disruption. Intraplaque hemorrhage and immature microvessels are additional vulnerability features; severe lumen narrowing is not a prerequisite.

macrophage CL:0000235 endothelial cell CL:0000115 vascular smooth muscle cell CL:0000359

internal carotid artery UBERON:0001532

Downstream

Carotid plaque surface disruption A weakened cap is more susceptible to rupture or ulceration.

Show evidence (1 reference)

PMID:39099701 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

Supports an advanced vulnerable plaque state distinct from percent stenosis.

Carotid plaque surface disruption

Mechanism confidence: Established

Rupture or ulceration exposes thrombogenic plaque contents to circulating blood.

Downstream

Carotid plaque-surface thrombosis Surface injury provides the substrate for platelet adhesion and coagulation.

Show evidence (1 reference)

PMID:39099701 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The most frequent pathological process is plaque rupture, with its content extruded into the arterial lumen and taken by the bloodstream to the distal internal carotid artery and its branches to the brain and to the ipsilateral eye."

Connects disruption of carotid plaque with downstream cerebral and ocular embolic injury.

Carotid plaque-surface thrombosis

Mechanism confidence: Established

Platelet accumulation and fibrin deposition form thrombus on the disrupted carotid plaque surface.

platelet CL:0000233

platelet activation GO:0030168 ↑ INCREASED blood coagulation GO:0007596 ↑ INCREASED

Downstream

Artery-to-artery embolization Surface thrombus can fragment and travel distally.

Show evidence (2 references)

PMID:38673936 SUPPORT DIRECT REVIEW SYNTHESIS Other

"When the endothelium is damaged, platelets adhere to the vascular wall, inducing the formation of a platelet-rich thrombus"

Supports platelet-rich thrombus formation at a disrupted surface.

PMID:38673936 SUPPORT DIRECT REVIEW SYNTHESIS Other

"The exposition of subendothelial TF induces the activation of the coagulation system and the production of thrombin, which cleaves fibrinogen into fibrin, which stabilizes the platelets-rich thrombus"

Supports tissue-factor-mediated coagulation and fibrin stabilization.

Artery-to-artery embolization

Mechanism confidence: Established

Plaque or thrombotic fragments travel downstream into cerebral or retinal arteries.

Downstream

Thromboembolic cerebral and retinal ischemia Emboli obstruct downstream vessels and compromise tissue perfusion.

Show evidence (2 references)

PMID:39099701 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Another process resulting in embolization is the ulceration of atheromatous plaque, with the formation of thrombi on the plaque surface and the embolization of those thrombi to cerebral arterial vessels."

Distinguishes plaque-surface thrombosis from downstream embolization.

PMID:39099701 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

Connects disruption of carotid plaque with downstream cerebral and ocular embolic injury.

Thromboembolic cerebral and retinal ischemia

Mechanism confidence: Established

Distal embolic obstruction causes ischemia in ipsilateral cerebral or retinal territories. Injury can be transient or progress to infarction; cerebral hypoperfusion is a separate contributing route.

Downstream

Ischemic stroke Sustained cerebral ischemia can progress to infarction.

Transient ischemic attack Transient cerebral ischemia produces focal neurologic symptoms.

Amaurosis fugax Transient retinal ischemia produces transient monocular visual loss.

Show evidence (2 references)

PMID:39099701 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

Connects disruption of carotid plaque with downstream cerebral and ocular embolic injury.

PMID:38683353 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Carotid artery stenosis is considered symptomatic when correlated with findings like focal neurologic symptoms produced by ipsilateral transient ischaemic attacks, amaurosis fugax, or an ischaemic stroke in the carotid artery territory during the preceding six months."

Defines the clinical manifestations and recent symptomatic interval.

Hemodynamic cerebral perfusion impairment

Mechanism confidence: Established

High-grade carotid stenosis can produce delayed ipsilateral hemispheric perfusion. The degree of impairment depends on collateral supply and autoregulatory reserve. Its association with cognitive impairment does not establish reversibility by carotid revascularization.

brain UBERON:0000955

Downstream

Cerebral perfusion delay Hemodynamic impairment is measured as delayed contrast arrival.

Show evidence (2 references)

PMID:42747834 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Magnetic resonance or computed tomographic perfusion imaging tested for baseline hemodynamic impairment defined by delayed time-to-peak (TTP) arrival of intravenous contrast in the hemisphere ipsilateral minus contralateral to the stenotic artery."

CREST-H measured perfusion delay in severe unilateral asymptomatic stenosis; this is an organ-level observation, not evidence for a specific cellular hypoxia-response pathway.

PMID:42747834 SUPPORT DIRECT BACKGROUND Human Clinical

"Cerebral hemodynamic impairment in patients with asymptomatic internal carotid artery (ICA) stenosis is associated with reduced cognition."

The authors describe an association; a reversible causal mechanism is not established.

✶

Histopathology

Vulnerable carotid atherosclerotic plaque

Vulnerable carotid atheroma has abundant lipids, macrophages, and T lymphocytes with fewer vascular smooth muscle cells and less extracellular matrix than stable plaque. A lipid-rich core and weakened fibrous cap are central structural features; plaque composition is distinct from lumen severity.

Show evidence (2 references)

PMID:38673936 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Histologically, vulnerable plaques are characterized by a high amount of lipids, macrophages, and T lymphocytes and a lower accumulation of vascular smooth muscle cells (VSMCs) and extracellular matrix compounds"

Explicitly describes histologic cellular and matrix composition.

PMID:39099701 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

Describes the cellular and matrix architecture of carotid atheroma.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

Cardiovascular 3

Carotid artery stenosis HP:0100546

Show evidence (1 reference)

PMID:37303351 SUPPORT REVIEW SYNTHESIS Human Clinical

"Carotid stenosis (CS) is a buildup of atherosclerotic plaque within the artery leading to a wide range of symptoms, from mild symptoms, including blurred vision and confusion, to much more life-threatening presentations, including paralysis due to stroke."

This supports carotid stenosis as an atherosclerotic arterial lesion and links it to the symptom spectrum.

Ischemic stroke HP:0002140

Show evidence (1 reference)

PMID:38683353 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

Defines the clinical manifestations and recent symptomatic interval.

Transient ischemic attack HP:0002326

Show evidence (1 reference)

PMID:38683353 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

Defines the clinical manifestations and recent symptomatic interval.

Eye 1

Amaurosis fugax HP:0100576

Show evidence (1 reference)

PMID:38683353 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

Defines the clinical manifestations and recent symptomatic interval.

Nervous System 1

Cognitive impairment HP:0100543

Show evidence (1 reference)

PMID:42747834 SUPPORT DIRECT BACKGROUND Human Clinical

"Cerebral hemodynamic impairment in patients with asymptomatic internal carotid artery (ICA) stenosis is associated with reduced cognition."

The authors describe an association; a reversible causal mechanism is not established.

Other 1

Cerebral perfusion delay

Needs term: delayed cerebral perfusion. The OAK query `runoak -i ols:hp search 'l~perfusion' 'l~cerebral blood flow' 'l~hypoperfusion'` returned pulmonary perfusion defect, maternal vascular malperfusion, iris hypoperfusion, ophthalmic artery hypoperfusion, and cilioretinal arteriolar hypoperfusion, with no cerebral-perfusion term. A cerebral ischemia binding would overstate what contrast-arrival delay alone establishes.

Show evidence (1 reference)

PMID:42747834 SUPPORT DIRECT PRIMARY RESULT Human Clinical

CREST-H measured perfusion delay in severe unilateral asymptomatic stenosis; this is an organ-level observation, not evidence for a specific cellular hypoxia-response pathway.

💊

Medical Actions

Optimal medical therapy and risk-factor modification

Action: Pharmacotherapy NCIT:C15986

Agent: aspirin CHEBI:15365 clopidogrel CHEBI:37941 atorvastatin CHEBI:39548

Intensive medical management is foundational whether or not revascularization is chosen: antiplatelet therapy, lipid lowering, blood-pressure and diabetes control, smoking cessation, diet, and physical activity. CREST-2 targeted systolic pressure below 130 mm Hg and LDL cholesterol below 70 mg/dL under protocol oversight. These trial targets do not replace individualized prescribing.

Mechanism Target:

INHIBITS Carotid plaque-surface thrombosis — The antiplatelet component reduces platelet-mediated thrombotic activity; other components address vascular risk.

Show evidence (1 reference)

PMID:38673936 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"These data confirm that platelet activation plays a crucial role in cerebral microembolism, as demonstrated by the efficacy of antiplatelet drugs in reducing the MES rate"

Links antiplatelet therapy to reduced microembolic signals; the surrogate is not itself a clinical stroke endpoint.

Target Phenotypes: Ischemic stroke HP:0002140

Show evidence (6 references)

PMID:39099701 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Optimal clinical management consists of three key elements: (1) adopting healthy eating habits and physical activity; (2) controlling comorbidities and risk factors; and (3) optimization of antithrombotic and lipid-lowering therapy."

Defines the components of carotid disease prevention.

PMID:41269206 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Primary targets were a systolic blood pressure of less than 130 mm Hg (the initial target of 140 mm Hg was reduced in 2018 after guideline changes) and a low-density lipoprotein (LDL) cholesterol level of less than 70 mg per deciliter"

Reports CREST-2 protocol targets.

PMID:39099701 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"For patients with asymptomatic ICA stenosis, lipid-lowering therapy with statins associated or not with ezetimibe to prevent cardiovascular events (AMI, stroke, cardiovascular death) is recommended"

Supports statin-based lipid lowering, with ezetimibe where appropriate.

+ 3 more references

Carotid endarterectomy

Action: Carotid Endarterectomy NCIT:C157807

Platform: Surgery

Carotid endarterectomy removes the atheromatous lesion. NASCET established benefit for selected recently symptomatic 70-99% stenosis; prompt assessment is important, with timing depending on neurologic stability and infarct burden. Older ACAS results supported selected asymptomatic patients, but in the separate modern CREST-2 endarterectomy trial the 4-year composite rate was 3.7% with surgery plus intensive management versus 5.3% with intensive management alone (P=.24). This neutral asymptomatic result does not negate symptomatic-trial benefit.

Mechanism Target:

INHIBITS Flow-limiting carotid lumen narrowing — Removal of the obstructing plaque restores the residual lumen.

Show evidence (1 reference)

PMID:37303351 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The artery is opened, and the plaque is removed."

Describes direct removal of the carotid atheroma.

INHIBITS Artery-to-artery embolization — Removal of the culprit plaque removes a local source of artery-to-artery emboli.

Show evidence (1 reference)

PMID:37303351 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The artery is opened, and the plaque is removed."

Describes direct removal of the carotid atheroma.

Target Phenotypes: Ischemic stroke HP:0002140 Transient ischemic attack HP:0002326

Show evidence (6 references)

PMID:1852179 SUPPORT PRIMARY RESULT Human Clinical

"Carotid endarterectomy is highly beneficial to patients with recent hemispheric and retinal transient ischemic attacks or nondisabling strokes and ipsilateral high-grade stenosis (70 to 99 percent) of the internal carotid artery."

This randomized trial abstract directly supports carotid endarterectomy for symptomatic high-grade carotid stenosis.

PMID:7723155 SUPPORT PRIMARY RESULT Human Clinical

"Patients with asymptomatic carotid artery stenosis of 60% or greater reduction in diameter and whose general health makes them good candidates for elective surgery will have a reduced 5-year risk of ipsilateral stroke if carotid endarterectomy performed with less than 3% perioperative morbidity..."

Historical ACAS benefit in selected asymptomatic patients predates contemporary intensive management; interpret alongside CREST-2.

PMID:41269206 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In the endarterectomy trial, the 4-year incidence of primary-outcome events was 5.3% (95% CI, 3.3 to 7.4) in the medical-therapy group and 3.7% (95% CI, 2.1 to 5.5) in the endarterectomy group"

The difference in the separate endarterectomy trial was not statistically significant (P=.24).

+ 3 more references

Carotid artery stenting

Action: Endovascular Stenting NCIT:C157840

Platform: Device

Carotid stenting with embolic protection is an alternative for selected patients. CREST found similar composite outcomes to endarterectomy but more periprocedural stroke with stenting and more myocardial infarction with endarterectomy, with age modifying relative outcomes. In the separate CREST-2 stenting trial for asymptomatic stenosis of at least 70%, transfemoral stenting plus intensive management reduced the 4-year composite from 6.0% to 2.8% (P=.02). Certified operators and trial selection limit generalization; CREST-2 did not include TCAR or directly compare stenting with endarterectomy.

Mechanism Target:

INHIBITS Artery-to-artery embolization — Stent coverage stabilizes the plaque surface; embolic protection reduces procedural embolization risk.

Show evidence (2 references)

PMID:38683353 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"It should be noted that the objective of CAS endpoint is not to achieve maximal luminal gain, but rather to attain complete plaque coverage."

Explains the plaque-coverage mechanism of stenting.

PMID:38683353 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"In order to mitigate this risk, embolic protection devices (EPDs) have been devised to capture and remove any fragments that may break off during the procedure."

Supports procedural embolic protection.

Target Phenotypes: Ischemic stroke HP:0002140

Show evidence (5 references)

PMID:20505173 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"the rates of the individual end points differed between the stenting group and the endarterectomy group (death, 0.7% vs. 0.3%; P = 0.18; stroke, 4.1% vs. 2.3%; P = 0.01; myocardial infarction, 1.1% vs. 2.3%; P = 0.03)"

Reports the opposing periprocedural stroke and myocardial-infarction differences in CREST.

PMID:41269206 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In the stenting trial, the 4-year incidence of primary-outcome events was 6.0% (95% confidence interval [CI], 3.8 to 8.3) in the medical-therapy group and 2.8% (95% CI, 1.5 to 4.3) in the stenting group"

CREST-2 stenting versus intensive medical management, not versus endarterectomy.

PMID:41269206 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The primary outcome was a composite of any stroke or death, assessed from randomization to 44 days, or ipsilateral ischemic stroke, assessed during the remaining follow-up period up to 4 years."

Defines the composite endpoint used for the two trial-specific estimates.

+ 2 more references

Transcarotid artery revascularization with flow reversal

Action: Endovascular Stenting NCIT:C157840

Platform: Device

TCAR combines direct cervical carotid access, flow reversal for embolic protection, and stent placement. ROADSTER-3 reported a 0.9% 30-day stroke/death/MI rate in 344 intention-to-treat standard-risk patients younger than 80 years. The study was single-arm and industry sponsored; it does not prove superiority to endarterectomy or benefit over medical therapy in asymptomatic disease.

Mechanism Target:

INHIBITS Artery-to-artery embolization — Reversed flow protects the cerebral circulation during stent delivery.

Show evidence (1 reference)

PMID:41277872 SUPPORT DIRECT BACKGROUND Human Clinical

"TCAR combines transcarotid arterial access and robust reversal of antegrade internal carotid artery flow to provide embolic protection during carotid angioplasty and stenting"

Defines the procedural protection mechanism.

Show evidence (3 references)

PMID:41277872 SUPPORT DIRECT BACKGROUND Human Clinical

"Transcarotid artery revascularization (TCAR) combines transcarotid arterial access and robust reversal of antegrade internal carotid artery flow to provide embolic protection during carotid angioplasty and stenting (CAS) for stroke prevention."

Defines TCAR access and protection mechanisms.

PMID:41277872 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The composite 30-day stroke/death/myocardial infarction rate was 0.6% (95% CI, 0.1-2.2%) for the per protocol population and 0.9% (95% CI, 0.2-2.5%) for the intent to treat population."

Single-arm ROADSTER-3 outcomes: 320 per-protocol and 344 intention-to-treat patients; not a randomized comparison.

PMID:41277872 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"ROADSTER 3 is a single-arm study without a comparative group, and potential bias can exist without randomization."

Explicit limitation of causal comparative efficacy inference.

🌍

Environmental Factors

Cardiometabolic comorbidities

Hypertension, diabetes, and chronic kidney disease contribute to carotid plaque development and overlap with broader atherosclerotic cardiovascular risk.

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."

This review abstract identifies these comorbidities as salient contributors to plaque development.

Smoking and diet

Smoking and diet are modifiable lifestyle risk factors that contribute to carotid plaque development and are targets of medical prevention.

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 plaque development.

Mechanism Target:

PREDISPOSES Atherosclerotic carotid plaque formation — Smoking and diet are named as the lifestyle factors playing the largest role in carotid plaque development, which is the node this exposure acts on.

Show evidence (1 reference)

PMID:37303351 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"lifestyle aspects, including smoking and diet, played the most salient role in plaque development."

Names plaque development specifically, rather than carotid stenosis as a whole, as what these lifestyle factors drive. The edge jumps the ApoB-retention and monocyte-recruitment nodes that sit between exposure and plaque in this file, and the study measures a combined lifestyle contribution without isolating the diet component.

🔬

Diagnosis

Duplex ultrasound with confirmatory CT angiography

Duplex ultrasonography is commonly used as first-line assessment of ICA stenosis. Significant stenosis is often confirmed or further characterized with CT angiography or another cross-sectional vascular imaging modality.

Diagnostic Imaging Testing NCIT:C16502

Results: Estimates stenosis severity and informs medical versus revascularization management.

Show evidence (1 reference)

PMID:38896635 SUPPORT PRIMARY RESULT Human Clinical

"Duplex ultrasonography (DUS) is the first line of investigation of ICA stenosis, but its accuracy varies in the literature and it is usual to complement the study with another more accurate exam when faced with significant stenosis."

This directly supports DUS as first-line imaging and confirmatory imaging for significant stenosis.

CT angiography for severe ICA stenosis

CT angiography can accurately diagnose severe internal carotid stenosis and is used to characterize anatomy for procedural planning.

computed tomography angiography NCIT:C202408

Results: High sensitivity and specificity for severe ICA stenosis in meta-analysis.

Show evidence (1 reference)

PMID:39143526 SUPPORT PRIMARY RESULT Human Clinical

"CTA demonstrated high sensitivity and specificity for diagnosing severe ICA stenosis."

This meta-analysis conclusion directly supports CTA for severe ICA stenosis diagnosis.

Vulnerable plaque risk stratification

Plaque composition, including intraplaque hemorrhage, lipid-rich core, and surface disruption, adds information beyond lumen stenosis. CT and MRI can identify vulnerable plaques against histology; these findings do not by themselves establish that a particular patient benefits from revascularization.

vascular imaging

Results: Identifies high-risk plaque composition and may refine stroke-risk stratification.

Show evidence (1 reference)

PMID:38953552 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"CT and MRI have a similar, high performance in detecting vulnerable carotid plaques, whereas US showed significantly less diagnostic accuracy."

Meta-analysis compares imaging against histology; it does not test treatment benefit.

NASCET and ECST stenosis measurement

Report the measurement convention. NASCET compares the narrowest residual lumen with the normal distal lumen; ECST uses the estimated original lumen at the lesion. The percentages are not interchangeable.

Show evidence (1 reference)

PMID:38683353 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The degree of the stenosis is calculated by either the NASCET criteria, that calculates the ratio of the stenosis to the normal lumen distal to the stenosis, or the ECST criteria, which characterises the degree of the stenosis in relation to the estimated normal lumen at the same level"

Explains the distinct denominator conventions.

Transcranial Doppler microembolic signals

Transcranial Doppler monitoring can detect microembolic signals associated with active embolization and plaque instability. Absence of detected signals does not exclude carotid disease.

Show evidence (2 references)

PMID:38673936 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Microembolisms from carotid plaques are one of the mechanisms responsible for cerebral ischemia."

Defines the process assessed by microembolic monitoring.

PMID:38673936 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Microembolic signals (MESs) can also be detected in asymptomatic patients,"

Supports detecting embolic activity even without recent symptoms.

Distinguishing near-occlusion from conventional stenosis and complete occlusion

Near-occlusion is a tight proximal ICA stenosis with distal lumen reduction, with or without a threadlike full collapse. Residual lumen distinguishes it from complete occlusion. The collapsed distal vessel is not a valid normal denominator for routine percentage stenosis; confirm this configuration before applying conventional thresholds.

Show evidence (2 references)

PMID:26316571 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Carotid near-occlusion is distal ICA luminal collapse beyond a tight stenosis, where the distal lumen should not be used for calculating percentage stenosis."

Defines near-occlusion and the measurement caveat.

PMID:41614493 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"When grading carotid stenosis, it is crucial to first assess if the case have CNO and only grade conventional stenoses with percent."

The contemporary systematic review maintains the distinction from conventional percentage stenosis.

🩻

Imaging Findings

Duplex evidence of carotid lumen narrowing

Duplex combines plaque morphology and flow velocities to estimate stenosis. Laboratory thresholds and near-occlusion interpretation vary, so a single velocity is not a universal substitute for complete vascular assessment.

Ultrasound

Show evidence (2 references)

PMID:38683353 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Duplex ultrasonography utilises blood velocity in addition to B-mode greyscale to detect the existence and degree of stenosis, as well as evaluation of plaque composition and characteristics."

Describes combined morphologic and hemodynamic assessment.

DOI:10.54522/jvsgbi.2024.156 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The criteria prioritised to grade a stenosis and how near occlusion was defined on duplex imaging was variable, and there were inconsistent practices on internal audits and quality assurance."

UK/Ireland practice survey documents variability; it is not a diagnostic-accuracy estimate.

Ipsilateral cerebral perfusion delay

CREST-H used perfusion MRI or CT to measure delayed contrast arrival in the hemisphere ipsilateral to severe stenosis. This imaging phenotype does not by itself establish infarction or reversible cognitive dysfunction.

Mri

Show evidence (1 reference)

PMID:42747834 SUPPORT DIRECT PRIMARY RESULT Human Clinical

CREST-H measured perfusion delay in severe unilateral asymptomatic stenosis; this is an organ-level observation, not evidence for a specific cellular hypoxia-response pathway.

📈

Progression

Asymptomatic high-grade stenosis

Age: Adult to older adult

High-grade asymptomatic stenosis may be found through targeted vascular assessment in high-risk patients and carries future stroke and cardiovascular event risk.

Show evidence (1 reference)

PMID:39319460 SUPPORT PRIMARY RESULT Human Clinical

"Significantly higher incidence rates of stroke (Ptrend<0.011) and CVD (Ptrend<0.0001) during follow-up were found with increasing PACAS risk groups."

This supports future stroke and cardiovascular event risk in higher predicted-risk asymptomatic carotid stenosis groups.

Symptomatic carotid-territory ischemia

Age: Adult to older adult

Symptomatic disease includes recent hemispheric or retinal TIA and nondisabling stroke in the territory of the stenotic carotid artery.

Show evidence (1 reference)

PMID:1852179 SUPPORT PRIMARY RESULT Human Clinical

"recent hemispheric and retinal transient ischemic attacks or nondisabling strokes and ipsilateral high-grade stenosis (70 to 99 percent) of the internal carotid artery."

This directly defines symptomatic high-grade carotid stenosis in the NASCET population.

📊

Prevalence

Adults aged 45-80 years in the REACH-derived validation cohort without prior carotid procedures

6.3% severe baseline asymptomatic carotid artery stenosis

This estimate applies to a high vascular-risk registry population, not to unselected population screening.

Show evidence (1 reference)

PMID:39319460 SUPPORT PRIMARY RESULT Human Clinical

"1662 (6.3%) had severe baseline ACAS."

This registry-derived cohort directly reports severe asymptomatic carotid stenosis prevalence in the studied population.

📊

Related Datasets

Possible association between the microbiota in subgingival and atherosclerotic plaque in patients with carotid stenosis. geo:GSE308470

Paired subgingival and carotid endarterectomy specimens from 25 patients (50 samples), profiled by V3-V4 16S rRNA amplicon sequencing. Oral and vascular bacterial DNA profiles differed; occasional overlap does not establish oral origin, viable infection, or microbial causation of stenosis.

human n=50

PMID:41908294

Cross-sectional, small surgical cohort. Low bacterial biomass makes vascular samples susceptible to reagent contamination and carryover. Amplicon sequencing cannot establish microbial viability and has limited species resolution. This is not shotgun metagenomics.

RNA-seq of human atherosclerotic carotid plaque tissue from diabetic patients geo:GSE311535

Bulk RNA sequencing of carotid plaques from 12 patients with diabetes undergoing endarterectomy: six recently symptomatic and six asymptomatic. Sex and insulin use explained substantial transcriptomic variation; the small observational study cannot establish that insulin causes plaque rupture. Spatial localization was inferred computationally using external single-cell and spatial references.

human BULK RNA SEQ n=12

PMID:41377472

Recently symptomatic samples were obtained about five days after events, so expression changes may follow rupture. No contemporaneous nondiabetic control group was included; batch effects prevented comparison with a historical cohort. Inferred fibrous-cap expression is not direct spatial transcriptomic measurement.

🔬

Clinical Trials

NCT00004732 NOT_APPLICABLE COMPLETED

CREST analyzed 2502 symptomatic or asymptomatic patients to stenting or endarterectomy. The estimated 4-year primary composite rates were 7.2% and 6.8% (P=.51), with opposing periprocedural stroke and myocardial-infarction differences. The comparison did not include a medical-therapy-only arm.

Target Phenotypes: Ischemic stroke HP:0002140

Show evidence (3 references)

clinicaltrials:NCT00004732 SUPPORT BACKGROUND Other

"The purpose of the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) is to compare the relatively new procedure of stent-assisted carotid angioplasty (CAS) to the traditional and accepted surgical approach of carotid endarterectomy (CEA) for the treatment of carotid artery..."

The trial summary directly supports CREST as a comparative stenting-versus-endarterectomy trial for symptomatic and asymptomatic carotid stenosis.

PMID:20505173 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"There was no significant difference in the estimated 4-year rates of the primary end point between carotid-artery stenting and carotid endarterectomy (7.2% and 6.8%, respectively;"

Reports the main randomized comparison.

PMID:20505173 SUPPORT DIRECT PRIMARY RESULT Human Clinical

Reports the opposing periprocedural stroke and myocardial-infarction differences in CREST.

NCT02089217 NOT_APPLICABLE COMPLETED

CREST-2 comprised two parallel randomized trials in asymptomatic stenosis of at least 70%: 1245 patients in the stenting comparison and 1240 in the endarterectomy comparison. At 4 years, the primary composite was lower with stenting plus intensive medical management (2.8% versus 6.0%, P=.02); the endarterectomy comparison was neutral (3.7% versus 5.3%, P=.24). Neither comparison showed cognitive benefit through 4 years in the prespecified secondary cognitive analysis. The trials do not directly compare stenting with endarterectomy.

Target Phenotypes: Ischemic stroke HP:0002140

Show evidence (5 references)

clinicaltrials:NCT02089217 SUPPORT BACKGROUND Other

"Carotid revascularization for primary prevention of stroke (CREST-2) is two independent multicenter, randomized controlled trials of carotid revascularization and intensive medical management versus medical management alone in patients with asymptomatic high-grade carotid stenosis."

The trial summary directly supports CREST-2 as a randomized comparison of revascularization plus intensive medical management versus medical management alone.

PMID:41269206 SUPPORT DIRECT PRIMARY RESULT Human Clinical

CREST-2 stenting versus intensive medical management, not versus endarterectomy.

PMID:41269206 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In the endarterectomy trial, the 4-year incidence of primary-outcome events was 5.3% (95% CI, 3.3 to 7.4) in the medical-therapy group and 3.7% (95% CI, 2.1 to 5.5) in the endarterectomy group"

The difference in the separate endarterectomy trial was not statistically significant (P=.24).

+ 2 more references

NCT03121209 PHASE_III COMPLETED

CREST-H enrolled 392 patients with severe asymptomatic stenosis; 291 had complete imaging and cognitive data. In the primary analysis of 51 with reduced baseline cognition, baseline perfusion impairment did not significantly modify the cognitive response to revascularization versus intensive medical management over one year (interaction P=.40). Small subgroup size and missing data limit inference.

Target Phenotypes: Cognitive impairment HP:0100543

Show evidence (3 references)

PMID:42747834 SUPPORT DIRECT PRIMARY RESULT Human Clinical

CREST-H measured perfusion delay in severe unilateral asymptomatic stenosis; this is an organ-level observation, not evidence for a specific cellular hypoxia-response pathway.

PMID:42747834 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In this substudy of a randomized clinical trial, there was no differential effect of revascularization vs IMM alone on cognition over 1 year by cerebral hemodynamic status among those with baseline reduced cognition,"

The CREST-H result does not support the proposed differential cognitive benefit from restoring flow; the reduced-cognition primary-analysis subgroup contained 51 participants.

PMID:42747834 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Of 392 participants enrolled (mean age, 71 years; 125 [32%] females), 61 were excluded for missing baseline imaging and 40 for missing cognitive examinations or other covariates, leaving 291 with complete data. Fifty-one had reduced cognition at baseline"

Defines attrition and the primary-analysis subgroup.

NCT05465122 NOT_APPLICABLE ACTIVE_NOT_RECRUITING

CREST-2 observational extension follows participants beyond the randomized trial follow-up to assess later stroke and death. It is follow-up research, not a new randomized treatment comparison.

Show evidence (1 reference)

clinicaltrials:NCT05465122 SUPPORT DIRECT BACKGROUND Other

"The purpose of this Long-Term Observational Extension of Participants in the CREST-2 Randomized Clinical Trial (C2LOE - ClinicalTrials.gov Identifier: NCT02089217) study is to study is to assess post-procedural efficacy of carotid endarterectomy and carotid stenting."

Registry summary defines the study design and purpose.

NCT06653387 NOT_APPLICABLE RECRUITING

Single-arm device study of the CGuard Prime carotid stent with ENROUTE transcarotid neuroprotection. Registry-reported recruitment does not establish comparative stroke-prevention efficacy.

Show evidence (1 reference)

clinicaltrials:NCT06653387 SUPPORT DIRECT BACKGROUND Other

"The objective of this study is to evaluate acute device and technical success of the CGuard Prime™ Carotid Stent System (80cm) when used in conjunction with the Enroute NPS during Transcarotid Artery Revascularization procedures in the treatment of carotid artery stenosis in spatients at high..."

Registry summary defines the study design and purpose.

NCT05365490 NOT_APPLICABLE COMPLETED

ROADSTER-3 is a prospective single-arm post-approval TCAR study in standard surgical-risk patients. Published early outcomes cover 344 intention-to-treat patients and 320 per-protocol patients; comparative efficacy cannot be inferred without a control group.

Show evidence (2 references)

clinicaltrials:NCT05365490 SUPPORT DIRECT BACKGROUND Other

"The study objective is to evaluate real world usage of the ENROUTE Transcarotid Stent when used with the ENROUTE Transcarotid Neuroprotection System in patients at standard risk for adverse events from carotid endarterectomy"

Registry summary defines the study design and purpose.

PMID:41277872 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The composite 30-day stroke/death/myocardial infarction rate was 0.6% (95% CI, 0.1-2.2%) for the per protocol population and 0.9% (95% CI, 0.2-2.5%) for the intent to treat population."

Single-arm ROADSTER-3 outcomes: 320 per-protocol and 344 intention-to-treat patients; not a randomized comparison.

ISRCTN97744893 NOT_APPLICABLE NOT_RECRUITING

ECST-2 randomized 429 asymptomatic or low/intermediate-risk symptomatic patients with at least 50% stenosis to optimized medical therapy with or without revascularization. One participant withdrew consent immediately. The two-year interim hierarchical composite included fatal/periprocedural events, nonfatal stroke, myocardial infarction, and silent imaging infarction; no benefit was detected (win ratio 1.01, 95% CI 0.60-1.70; P=.97).

Show evidence (3 references)

ICTRP:ISRCTN97744893 SUPPORT DIRECT BACKGROUND Other

"| Recruitment status | No longer recruiting |"

WHO ICTRP reports recruitment closed; this is not assumed to prove completion of all follow-up.

PMID:40252662 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"No evidence for a benefit of revascularisation in addition to OMT was found in the first 2 years following treatment for patients with asymptomatic or symptomatic carotid stenosis of 50% or greater with a low or intermediate predicted stroke risk (assessed by the CAR score)."

ECST-2 interim findings apply to low/intermediate predicted-risk patients and do not establish absence of benefit in high-risk symptomatic disease.

PMID:40252662 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"win ratio 1·01 [95% CI 0·60-1·70]; p=0·97"

Reports the interim hierarchical primary analysis.

{ }

Source YAML

click to show

name: Carotid Stenosis
creation_date: '2026-05-06T18:58:50Z'
description: >-
  Carotid stenosis is narrowing of the extracranial carotid arterial lumen, usually from atherosclerotic
  plaque
  at the bifurcation or proximal internal carotid artery. Plaque burden and plaque instability
  are distinct determinants
  of risk. Embolization and, in some severe lesions, inadequate perfusion can cause ipsilateral
  cerebral or retinal
  ischemia. Symptomatic status, stenosis severity, plaque characteristics, procedural risk,
  and contemporary medical
  therapy influence stroke-prevention decisions. Cognitive impairment is associated with severe
  disease, but randomized
  revascularization trials have not demonstrated cognitive benefit.
category: Complex
disease_term:
  preferred_term: carotid stenosis
  term:
    id: MONDO:0001612
    label: carotid stenosis
parents:
- Carotid artery disorder
- Vascular disorder
- Cerebrovascular Disease
synonyms:
- Carotid artery stenosis
- Internal carotid artery stenosis
- Extracranial carotid stenosis
- Carotid atherosclerotic stenosis
- Asymptomatic carotid artery stenosis
- Symptomatic carotid stenosis
references:
- reference: DOI:10.1007/s00270-024-03707-y
  title: CIRSE Standards of Practice on Carotid Artery Stenting
  found_in:
  - Carotid_Stenosis-deep-research-falcon.md
  findings: []
- reference: DOI:10.1016/j.ejvs.2022.04.011
  title: Editor's Choice - European Society for Vascular Surgery (ESVS) 2023 Clinical Practice Guidelines on the Management of Atherosclerotic Carotid and Vertebral Artery Disease
  found_in:
  - Carotid_Stenosis-deep-research-falcon.md
  findings: []
- reference: DOI:10.1055/a-2175-4029
  title: Elective carotid stenting fulfills quality standards defined in guidelines
  found_in:
  - Carotid_Stenosis-deep-research-falcon.md
  findings: []
- reference: DOI:10.1093/cvr/cvad135
  title: 'Stroke risk management in carotid atherosclerotic disease: a clinical consensus statement of the ESC Council on Stroke and the ESC Working Group on Aorta and Peripheral Vascular Diseases'
  found_in:
  - Carotid_Stenosis-deep-research-falcon.md
  findings: []
- reference: DOI:10.1136/jnis-2022-018732
  title: 'Asymptomatic carotid artery stenosis: a summary of current state of evidence for revascularization and emerging high-risk features'
  found_in:
  - Carotid_Stenosis-deep-research-falcon.md
  findings: []
- reference: DOI:10.1161/str.0000000000000475
  title: '2024 Guideline for the Primary Prevention of Stroke: A Guideline From the American Heart Association/American Stroke Association'
  found_in:
  - Carotid_Stenosis-deep-research-falcon.md
  findings: []
- reference: DOI:10.1161/strokeaha.123.046894
  title: Prediction of Severe Baseline Asymptomatic Carotid Stenosis and Subsequent Risk of Stroke and Cardiovascular Disease
  found_in:
  - Carotid_Stenosis-deep-research-falcon.md
  findings: []
- reference: PMID:39099701
  title: Brazilian Angiology and Vascular Surgery Society Guidelines for the treatment of extracranial cerebrovascular disease.
  found_in:
  - Carotid_Stenosis-deep-research-falcon.md
  findings: []
- reference: DOI:10.3390/ijms25084351
  title: 'Molecular Pathways of Vulnerable Carotid Plaques at Risk of Ischemic Stroke: A Narrative Review'
  found_in:
  - Carotid_Stenosis-deep-research-falcon.md
  findings: []
- reference: DOI:10.54522/jvsgbi.2024.156
  title: Current practice in ultrasound grading of carotid artery stenosis in the UK and Ireland
  found_in:
  - Carotid_Stenosis-deep-research-falcon.md
  findings: []
- reference: PMID:1852179
  title: Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis.
- reference: PMID:20505173
  title: Stenting versus endarterectomy for treatment of carotid-artery stenosis.
- reference: PMID:26844337
  title: The Role of Lipids and Lipoproteins in Atherosclerosis.
- 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:38673936
  title: 'Molecular Pathways of Vulnerable Carotid Plaques at Risk of Ischemic Stroke: A Narrative Review.'
- reference: PMID:38683353
  title: CIRSE Standards of Practice on Carotid Artery Stenting.
- reference: PMID:38896635
  title: Accuracy of duplex ultrasonography versus angiotomography for the diagnosis of extracranial internal carotid stenosis.
- reference: PMID:38953552
  title: 'Diagnostic accuracy of carotid plaque instability by noninvasive imaging: a systematic review and meta-analysis.'
- reference: PMID:39143526
  title: Systematic review and meta-analysis of the diagnostic value of computed tomography angiography for severe internal carotid artery stenosis.
- reference: PMID:39319460
  title: Prediction of Severe Baseline Asymptomatic Carotid Stenosis and Subsequent Risk of Stroke and Cardiovascular Disease.
- reference: PMID:41269206
  title: Medical Management and Revascularization for Asymptomatic Carotid Stenosis.
- reference: PMID:41277872
  title: 'Prospective, Multicenter Evaluation of Transcarotid Artery Revascularization in Standard-Risk Patients: 30-Day Outcomes of the ROADSTER 3 Study.'
- reference: PMID:41377472
  title: Insulin use promotes pro-inflammatory changes in the transcriptome of atherosclerotic plaques in patients with diabetes mellitus.
- reference: PMID:41908294
  title: Possible association between the microbiota in subgingival and atherosclerotic plaque in a cohort of patients with carotid stenosis.
- reference: PMID:42747834
  title: 'Revascularization in Asymptomatic Carotid Artery Stenosis With Hemodynamic Impairment and Cognitive Outcomes: The CREST-H Substudy of the CREST-2 Randomized Clinical Trial.'
- reference: PMID:42747844
  title: 'Revascularization of Asymptomatic Carotid Artery Stenosis: Cognitive Results of the CREST-2 Randomized Trials.'
- reference: PMID:7723155
  title: Endarterectomy for asymptomatic carotid artery stenosis. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study.
- reference: clinicaltrials:NCT00004732
  title: Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST)
- reference: clinicaltrials:NCT02089217
  title: Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial
- reference: clinicaltrials:NCT05365490
  title: Post-approval Study of Transcarotid Artery Revascularization in Standard Risk Patients With Significant Carotid Artery Disease. The ROADSTER 3 Study
- reference: clinicaltrials:NCT05465122
  title: Long-Term Observational Extension of Participants in the CREST-2 Randomized Clinical Trial
- reference: clinicaltrials:NCT06653387
  title: A Multicenter, Single-arm, Pivotal Study to Evaluate Acute Device and Technical Success of the CGuard Prime Carotid Stent System (80cm) When Used in Conjunction With the FDA-cleared ENROUTE Transcarotid Neuroprotection System (NPS) in Patients at High Risk for Adverse Events From Carotid Endarterectomy Undergoing Carotid Artery Stenting Via the Transcarotid Artery Revascularization (TCAR) Approach.
- reference: PMID:40252662
  title: 'Optimised medical therapy alone versus optimised medical therapy plus revascularisation for asymptomatic or low-to-intermediate risk symptomatic carotid stenosis (ECST-2): 2-year interim results of a multicentre randomised trial.'
- reference: ICTRP:ISRCTN97744893
  title: European Carotid Surgery Trial 2
- reference: PMID:26316571
  title: 'Carotid Near-Occlusion: A Comprehensive Review, Part 1--Definition, Terminology, and Diagnosis.'
- reference: PMID:41614493
  title: 'Carotid near-occlusion diagnostics and its consequences: A systematic review.'
prevalence:
- population: Adults aged 45-80 years in the REACH-derived validation cohort without prior carotid procedures
  percentage: 6.3% severe baseline asymptomatic carotid artery stenosis
  notes: >-
    This estimate applies to a high vascular-risk registry population, not to
    unselected population screening.
  evidence:
  - reference: PMID:39319460
    reference_title: Prediction of Severe Baseline Asymptomatic Carotid Stenosis and Subsequent Risk of Stroke and Cardiovascular Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 1662 (6.3%) had severe baseline ACAS.
    explanation: This registry-derived cohort directly reports severe asymptomatic carotid stenosis prevalence in the studied population.
    quote_role: PRIMARY_RESULT
pathophysiology:
- name: Carotid Intimal ApoB Lipoprotein Retention
  role: trigger
  conforms_to: atherogenesis#Endothelial Dysfunction and Subendothelial LDL Retention
  description: >-
    Endothelial dysfunction in the carotid arterial wall permits infiltration
    and retention of apoB-containing lipoproteins in the intima. Retained LDL is
    modified locally and initiates the inflammatory plaque-forming branch of
    atherosclerotic carotid stenosis.
  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
  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.
      quote_role: REVIEW_SYNTHESIS
  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
  - 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
  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.
      quote_role: REVIEW_SYNTHESIS
  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: >-
    Vascular smooth-muscle-cell phenotypic switching, proliferation, and
    extracellular-matrix secretion assemble a fibrofatty plaque with a fibrous
    cap in the carotid arterial wall. Continued plaque growth progressively
    narrows the lumen.
  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
    term:
      id: GO:0048661
      label: positive regulation of smooth muscle cell proliferation
    modifier: INCREASED
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  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: >-
      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 abstract supports fibrous-cap formation as part of the carotid atherosclerotic plaque branch.
    quote_role: REVIEW_SYNTHESIS
  - 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: >-
      This histopathology review supports the conserved smooth-muscle-cell
      switching and matrix-secretion program that builds the fibrous cap and
      enlarges the necrotic core of the carotid plaque.
    quote_role: REVIEW_SYNTHESIS
  - &id003
    reference: PMID:39099701
    reference_title: Brazilian Angiology and Vascular Surgery Society Guidelines for the treatment of extracranial cerebrovascular disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: The characteristic lesion of atherosclerosis is the atherosclerotic plaque or atheromatous plaque, a complex lesion of the intimal layer of the vessel wall, consisting of a central core of cholesterol clefts, macrophages, and inflammatory cells, surrounded by layers of smooth muscle cells and connective tissue as well as a fibrous cap separating the core from the arterial lumen.
    explanation: Describes the cellular and matrix architecture of carotid atheroma.
  downstream:
  - target: Flow-limiting carotid lumen narrowing
    description: Growth can encroach on the residual lumen.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39099701
      reference_title: Brazilian Angiology and Vascular Surgery Society Guidelines for the treatment of extracranial cerebrovascular disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: The atherosclerotic plaque usually grows slowly, limiting the arterial lumen and causing a local stenosis that reduces blood flow to the distal vessels.
      explanation: Connects plaque growth with narrowing and reduced distal flow.
  - target: Vulnerable plaque instability
    description: Inflammatory remodeling of an established plaque can enlarge its lipid core and thin its cap, producing a vulnerable state.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38673936
      reference_title: 'Molecular Pathways of Vulnerable Carotid Plaques at Risk of Ischemic Stroke: A Narrative Review.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: IFN-γ, TNF-α, and IL-1β promote the apoptosis of macrophages and foam cells, leading to lipid core enlargement. Moreover, these cytokines induce the apoptosis of SMCs, resulting in the thinning of the fibrous cap
      explanation: The cached review identifies inflammatory-cell and smooth-muscle-cell loss as intermediates connecting advanced plaque remodeling to lipid-core enlargement and cap thinning.
    intermediate_mechanisms:
    - inflammatory cytokine signaling
    - macrophage and smooth-muscle-cell apoptosis
    - lipid-core enlargement and cap thinning
  - target: Fibrous-cap matrix degradation
    description: Inflammatory proteases can degrade the matrix of an established plaque.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38673936
      reference_title: 'Molecular Pathways of Vulnerable Carotid Plaques at Risk of Ischemic Stroke: A Narrative Review.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: MMPs play a critical role in determining the instability of plaques because of their capability to degrade the cellular matrix, the vascular wall, and fibrotic caps, leading to a higher risk of rupture.
      explanation: Review synthesis links proteolysis to weakened cap structure.
    intermediate_mechanisms:
    - inflammatory-cell protease production
  - target: Intraplaque neovascularization
    description: Advanced plaque can develop an immature microvascular network.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38673936
      reference_title: 'Molecular Pathways of Vulnerable Carotid Plaques at Risk of Ischemic Stroke: A Narrative Review.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Angiogenic sprouting entails the proliferation and migration of ECs into avascular areas. Pathological angiogenesis is a consistent feature of atherosclerotic plaque development,
      explanation: Defines intraplaque endothelial sprouting.
    intermediate_mechanisms:
    - local angiogenic signaling
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
- name: Flow-limiting carotid lumen narrowing
  description: >-
    Plaque encroachment narrows the residual carotid lumen. Severe narrowing can limit distal
    flow, but percent
    stenosis alone does not determine plaque vulnerability or prove exhausted perfusion reserve.
  locations:
  - preferred_term: internal carotid artery
    term:
      id: UBERON:0001532
      label: internal carotid artery
  evidence:
  - reference: PMID:39099701
    reference_title: Brazilian Angiology and Vascular Surgery Society Guidelines for the treatment of extracranial cerebrovascular disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: The atherosclerotic plaque usually grows slowly, limiting the arterial lumen and causing a local stenosis that reduces blood flow to the distal vessels.
    explanation: Connects plaque growth with narrowing and reduced distal flow.
  downstream:
  - target: Carotid artery stenosis
    description: Lumen encroachment produces the defining imaging phenotype.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39099701
      reference_title: Brazilian Angiology and Vascular Surgery Society Guidelines for the treatment of extracranial cerebrovascular disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: The atherosclerotic plaque usually grows slowly, limiting the arterial lumen and causing a local stenosis that reduces blood flow to the distal vessels.
      explanation: Connects plaque growth with narrowing and reduced distal flow.
  - target: Hemodynamic cerebral perfusion impairment
    description: Severe stenosis can impair distal perfusion when compensatory flow is inadequate.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39099701
      reference_title: Brazilian Angiology and Vascular Surgery Society Guidelines for the treatment of extracranial cerebrovascular disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: The atherosclerotic plaque usually grows slowly, limiting the arterial lumen and causing a local stenosis that reduces blood flow to the distal vessels.
      explanation: Connects plaque growth with narrowing and reduced distal flow.
    intermediate_mechanisms:
    - insufficient collateral and autoregulatory compensation
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
- name: Fibrous-cap matrix degradation
  description: Proteolytic breakdown of extracellular matrix reduces cap structural integrity. Human plaque observations and broader atherogenesis work implicate matrix metalloproteinases; no single protease is assumed to explain every unstable plaque.
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:38673936
    reference_title: 'Molecular Pathways of Vulnerable Carotid Plaques at Risk of Ischemic Stroke: A Narrative Review.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: MMPs play a critical role in determining the instability of plaques because of their capability to degrade the cellular matrix, the vascular wall, and fibrotic caps, leading to a higher risk of rupture.
    explanation: Review synthesis links proteolysis to weakened cap structure.
  downstream:
  - target: Vulnerable plaque instability
    description: Loss of cap matrix increases vulnerability to rupture.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38673936
      reference_title: 'Molecular Pathways of Vulnerable Carotid Plaques at Risk of Ischemic Stroke: A Narrative Review.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: MMPs play a critical role in determining the instability of plaques because of their capability to degrade the cellular matrix, the vascular wall, and fibrotic caps, leading to a higher risk of rupture.
      explanation: Review synthesis links proteolysis to weakened cap structure.
  biological_processes:
  - preferred_term: extracellular matrix disassembly
    term:
      id: GO:0022617
      label: extracellular matrix disassembly
    modifier: INCREASED
- name: Intraplaque neovascularization
  description: Endothelial sprouting creates immature microvessels within advanced plaque.
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:38673936
    reference_title: 'Molecular Pathways of Vulnerable Carotid Plaques at Risk of Ischemic Stroke: A Narrative Review.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Angiogenic sprouting entails the proliferation and migration of ECs into avascular areas. Pathological angiogenesis is a consistent feature of atherosclerotic plaque development,
    explanation: Defines intraplaque endothelial sprouting.
  downstream:
  - target: Intraplaque hemorrhage
    description: Fragile microvessels permit red-cell leakage into the plaque.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38673936
      reference_title: 'Molecular Pathways of Vulnerable Carotid Plaques at Risk of Ischemic Stroke: A Narrative Review.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Additionally, these premature vessels have limited pericyte coverage and are prone to the leakage of circulating cells, leading to IPH
      explanation: Immature plaque microvessels permit intraplaque hemorrhage.
  biological_processes:
  - preferred_term: angiogenesis
    term:
      id: GO:0001525
      label: angiogenesis
    modifier: INCREASED
- name: Intraplaque hemorrhage
  description: Blood leakage into the plaque adds erythrocyte material and promotes inflammatory remodeling, contributing to a vulnerable plaque state.
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:38673936
    reference_title: 'Molecular Pathways of Vulnerable Carotid Plaques at Risk of Ischemic Stroke: A Narrative Review.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Additionally, these premature vessels have limited pericyte coverage and are prone to the leakage of circulating cells, leading to IPH
    explanation: Immature plaque microvessels permit intraplaque hemorrhage.
  - &id001
    reference: PMID:39099701
    reference_title: Brazilian Angiology and Vascular Surgery Society Guidelines for the treatment of extracranial cerebrovascular disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: The characteristics which define vulnerable plaque include a large lipid-rich core, a thin fibrous cap, inflammation in or around the plaque, intraplaque hemorrhage and vasa vasorum neovascularization.
    explanation: Supports an advanced vulnerable plaque state distinct from percent stenosis.
  downstream:
  - target: Vulnerable plaque instability
    description: Hemorrhagic plaque remodeling increases vulnerability.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39099701
      reference_title: Brazilian Angiology and Vascular Surgery Society Guidelines for the treatment of extracranial cerebrovascular disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: The characteristics which define vulnerable plaque include a large lipid-rich core, a thin fibrous cap, inflammation in or around the plaque, intraplaque hemorrhage and vasa vasorum neovascularization.
      explanation: Supports an advanced vulnerable plaque state distinct from percent stenosis.
    intermediate_mechanisms:
    - erythrocyte breakdown and inflammatory remodeling
- name: Vulnerable plaque instability
  role: effector
  conforms_to: atherogenesis#Advanced Atheroma with Necrotic Core and Fibrous Cap
  description: >-
    An advanced carotid atheroma with a lipid-rich necrotic core and a weakened fibrous cap
    is susceptible to surface
    disruption. Intraplaque hemorrhage and immature microvessels are additional vulnerability
    features; severe lumen
    narrowing is not a prerequisite.
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  - 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
  evidence:
  - *id001
  downstream:
  - target: Carotid plaque surface disruption
    description: A weakened cap is more susceptible to rupture or ulceration.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38673936
      reference_title: 'Molecular Pathways of Vulnerable Carotid Plaques at Risk of Ischemic Stroke: A Narrative Review.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: MMPs play a critical role in determining the instability of plaques because of their capability to degrade the cellular matrix, the vascular wall, and fibrotic caps, leading to a higher risk of rupture.
      explanation: Review synthesis links proteolysis to weakened cap structure.
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
- name: Carotid plaque surface disruption
  description: Rupture or ulceration exposes thrombogenic plaque contents to circulating blood.
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  evidence:
  - &id002
    reference: PMID:39099701
    reference_title: Brazilian Angiology and Vascular Surgery Society Guidelines for the treatment of extracranial cerebrovascular disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: The most frequent pathological process is plaque rupture, with its content extruded into the arterial lumen and taken by the bloodstream to the distal internal carotid artery and its branches to the brain and to the ipsilateral eye.
    explanation: Connects disruption of carotid plaque with downstream cerebral and ocular embolic injury.
  downstream:
  - target: Carotid plaque-surface thrombosis
    description: Surface injury provides the substrate for platelet adhesion and coagulation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38673936
      reference_title: 'Molecular Pathways of Vulnerable Carotid Plaques at Risk of Ischemic Stroke: A Narrative Review.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: When the endothelium is damaged, platelets adhere to the vascular wall, inducing the formation of a platelet-rich thrombus
      explanation: Supports platelet-rich thrombus formation at a disrupted surface.
- name: Carotid plaque-surface thrombosis
  description: Platelet accumulation and fibrin deposition form thrombus on the disrupted carotid plaque surface.
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:38673936
    reference_title: 'Molecular Pathways of Vulnerable Carotid Plaques at Risk of Ischemic Stroke: A Narrative Review.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: When the endothelium is damaged, platelets adhere to the vascular wall, inducing the formation of a platelet-rich thrombus
    explanation: Supports platelet-rich thrombus formation at a disrupted surface.
  - reference: PMID:38673936
    reference_title: 'Molecular Pathways of Vulnerable Carotid Plaques at Risk of Ischemic Stroke: A Narrative Review.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: The exposition of subendothelial TF induces the activation of the coagulation system and the production of thrombin, which cleaves fibrinogen into fibrin, which stabilizes the platelets-rich thrombus
    explanation: Supports tissue-factor-mediated coagulation and fibrin stabilization.
  downstream:
  - target: Artery-to-artery embolization
    description: Surface thrombus can fragment and travel distally.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39099701
      reference_title: Brazilian Angiology and Vascular Surgery Society Guidelines for the treatment of extracranial cerebrovascular disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Another process resulting in embolization is the ulceration of atheromatous plaque, with the formation of thrombi on the plaque surface and the embolization of those thrombi to cerebral arterial vessels.
      explanation: Distinguishes plaque-surface thrombosis from downstream embolization.
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  biological_processes:
  - preferred_term: platelet activation
    term:
      id: GO:0030168
      label: platelet activation
    modifier: INCREASED
  - preferred_term: blood coagulation
    term:
      id: GO:0007596
      label: blood coagulation
    modifier: INCREASED
- name: Artery-to-artery embolization
  description: Plaque or thrombotic fragments travel downstream into cerebral or retinal arteries.
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:39099701
    reference_title: Brazilian Angiology and Vascular Surgery Society Guidelines for the treatment of extracranial cerebrovascular disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Another process resulting in embolization is the ulceration of atheromatous plaque, with the formation of thrombi on the plaque surface and the embolization of those thrombi to cerebral arterial vessels.
    explanation: Distinguishes plaque-surface thrombosis from downstream embolization.
  - *id002
  downstream:
  - target: Thromboembolic cerebral and retinal ischemia
    description: Emboli obstruct downstream vessels and compromise tissue perfusion.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39099701
      reference_title: Brazilian Angiology and Vascular Surgery Society Guidelines for the treatment of extracranial cerebrovascular disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: The most frequent pathological process is plaque rupture, with its content extruded into the arterial lumen and taken by the bloodstream to the distal internal carotid artery and its branches to the brain and to the ipsilateral eye.
      explanation: Connects disruption of carotid plaque with downstream cerebral and ocular embolic injury.
    intermediate_mechanisms:
    - distal arterial obstruction
- name: Thromboembolic cerebral and retinal ischemia
  role: consequence
  conforms_to: atherogenesis#Plaque Rupture, Thrombosis, and Ischemic Events
  description: >-
    Distal embolic obstruction causes ischemia in ipsilateral cerebral or retinal territories.
    Injury can be transient
    or progress to infarction; cerebral hypoperfusion is a separate contributing route.
  evidence:
  - *id002
  - reference: PMID:38683353
    reference_title: CIRSE Standards of Practice on Carotid Artery Stenting.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Carotid artery stenosis is considered symptomatic when correlated with findings like focal neurologic symptoms produced by ipsilateral transient ischaemic attacks, amaurosis fugax, or an ischaemic stroke in the carotid artery territory during the preceding six months.
    explanation: Defines the clinical manifestations and recent symptomatic interval.
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  downstream:
  - target: Ischemic stroke
    description: Sustained cerebral ischemia can progress to infarction.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38683353
      reference_title: CIRSE Standards of Practice on Carotid Artery Stenting.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Carotid artery stenosis is considered symptomatic when correlated with findings like focal neurologic symptoms produced by ipsilateral transient ischaemic attacks, amaurosis fugax, or an ischaemic stroke in the carotid artery territory during the preceding six months.
      explanation: Defines the clinical manifestations and recent symptomatic interval.
    intermediate_mechanisms:
    - irreversible cerebral tissue injury
  - target: Transient ischemic attack
    description: Transient cerebral ischemia produces focal neurologic symptoms.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38683353
      reference_title: CIRSE Standards of Practice on Carotid Artery Stenting.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Carotid artery stenosis is considered symptomatic when correlated with findings like focal neurologic symptoms produced by ipsilateral transient ischaemic attacks, amaurosis fugax, or an ischaemic stroke in the carotid artery territory during the preceding six months.
      explanation: Defines the clinical manifestations and recent symptomatic interval.
  - target: Amaurosis fugax
    description: Transient retinal ischemia produces transient monocular visual loss.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38683353
      reference_title: CIRSE Standards of Practice on Carotid Artery Stenting.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: Carotid artery stenosis is considered symptomatic when correlated with findings like focal neurologic symptoms produced by ipsilateral transient ischaemic attacks, amaurosis fugax, or an ischaemic stroke in the carotid artery territory during the preceding six months.
      explanation: Defines the clinical manifestations and recent symptomatic interval.
- name: Hemodynamic cerebral perfusion impairment
  description: >-
    High-grade carotid stenosis can produce delayed ipsilateral hemispheric perfusion. The
    degree of impairment
    depends on collateral supply and autoregulatory reserve. Its association with cognitive
    impairment does not
    establish reversibility by carotid revascularization.
  evidence:
  - &id005
    reference: PMID:42747834
    reference_title: 'Revascularization in Asymptomatic Carotid Artery Stenosis With Hemodynamic Impairment and Cognitive Outcomes: The CREST-H Substudy of the CREST-2 Randomized Clinical Trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Magnetic resonance or computed tomographic perfusion imaging tested for baseline hemodynamic impairment defined by delayed time-to-peak (TTP) arrival of intravenous contrast in the hemisphere ipsilateral minus contralateral to the stenotic artery.
    explanation: CREST-H measured perfusion delay in severe unilateral asymptomatic stenosis; this is an organ-level observation, not evidence for a specific cellular hypoxia-response pathway.
  - &id004
    reference: PMID:42747834
    reference_title: 'Revascularization in Asymptomatic Carotid Artery Stenosis With Hemodynamic Impairment and Cognitive Outcomes: The CREST-H Substudy of the CREST-2 Randomized Clinical Trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: Cerebral hemodynamic impairment in patients with asymptomatic internal carotid artery (ICA) stenosis is associated with reduced cognition.
    explanation: The authors describe an association; a reversible causal mechanism is not established.
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  downstream:
  - target: Cerebral perfusion delay
    description: Hemodynamic impairment is measured as delayed contrast arrival.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:42747834
      reference_title: 'Revascularization in Asymptomatic Carotid Artery Stenosis With Hemodynamic Impairment and Cognitive Outcomes: The CREST-H Substudy of the CREST-2 Randomized Clinical Trial.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Magnetic resonance or computed tomographic perfusion imaging tested for baseline hemodynamic impairment defined by delayed time-to-peak (TTP) arrival of intravenous contrast in the hemisphere ipsilateral minus contralateral to the stenotic artery.
      explanation: CREST-H measured perfusion delay in severe unilateral asymptomatic stenosis; this is an organ-level observation, not evidence for a specific cellular hypoxia-response pathway.
histopathology:
- name: Vulnerable carotid atherosclerotic plaque
  description: >-
    Vulnerable carotid atheroma has abundant lipids, macrophages, and T lymphocytes with fewer
    vascular smooth muscle
    cells and less extracellular matrix than stable plaque. A lipid-rich core and weakened
    fibrous cap are central
    structural features; plaque composition is distinct from lumen severity.
  evidence:
  - reference: PMID:38673936
    reference_title: 'Molecular Pathways of Vulnerable Carotid Plaques at Risk of Ischemic Stroke: A Narrative Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Histologically, vulnerable plaques are characterized by a high amount of lipids, macrophages, and T lymphocytes and a lower accumulation of vascular smooth muscle cells (VSMCs) and extracellular matrix compounds
    explanation: Explicitly describes histologic cellular and matrix composition.
  - *id003
phenotypes:
- category: Cardiovascular
  name: Carotid artery stenosis
  diagnostic: true
  description: >-
    Narrowing of the carotid artery is the defining vascular lesion and is
    usually assessed by duplex ultrasonography, CT angiography, MR angiography,
    or catheter angiography.
  phenotype_term:
    preferred_term: Carotid artery stenosis
    term:
      id: HP:0100546
      label: Carotid artery stenosis
  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: >-
      Carotid stenosis (CS) is a buildup of atherosclerotic plaque within the artery leading
      to a wide range of
      symptoms, from mild symptoms, including blurred vision and confusion, to much more life-threatening
      presentations,
      including paralysis due to stroke.
    explanation: This supports carotid stenosis as an atherosclerotic arterial lesion and links it to the symptom spectrum.
    quote_role: REVIEW_SYNTHESIS
- category: Neurological
  name: Ischemic stroke
  description: >-
    Symptomatic carotid stenosis may cause ipsilateral ischemic stroke through
    artery-to-artery embolism, local thrombosis, or impaired cerebral perfusion.
  phenotype_term:
    preferred_term: Ischemic stroke
    term:
      id: HP:0002140
      label: Ischemic stroke
  evidence:
  - reference: PMID:38683353
    reference_title: CIRSE Standards of Practice on Carotid Artery Stenting.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Carotid artery stenosis is considered symptomatic when correlated with findings like focal neurologic symptoms produced by ipsilateral transient ischaemic attacks, amaurosis fugax, or an ischaemic stroke in the carotid artery territory during the preceding six months.
    explanation: Defines the clinical manifestations and recent symptomatic interval.
- category: Neurological
  name: Transient ischemic attack
  description: >-
    Transient focal neurologic symptoms can occur when carotid plaque emboli or
    flow limitation cause short-lived cerebral or retinal ischemia.
  phenotype_term:
    preferred_term: Transient ischemic attack
    term:
      id: HP:0002326
      label: Transient ischemic attack
  evidence:
  - reference: PMID:38683353
    reference_title: CIRSE Standards of Practice on Carotid Artery Stenting.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Carotid artery stenosis is considered symptomatic when correlated with findings like focal neurologic symptoms produced by ipsilateral transient ischaemic attacks, amaurosis fugax, or an ischaemic stroke in the carotid artery territory during the preceding six months.
    explanation: Defines the clinical manifestations and recent symptomatic interval.
- category: Ophthalmological
  name: Amaurosis fugax
  description: >-
    Transient monocular visual loss can occur when embolic or hemodynamic
    compromise affects the ipsilateral retinal circulation.
  phenotype_term:
    preferred_term: Amaurosis fugax
    term:
      id: HP:0100576
      label: Amaurosis fugax
  evidence:
  - reference: PMID:38683353
    reference_title: CIRSE Standards of Practice on Carotid Artery Stenting.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Carotid artery stenosis is considered symptomatic when correlated with findings like focal neurologic symptoms produced by ipsilateral transient ischaemic attacks, amaurosis fugax, or an ischaemic stroke in the carotid artery territory during the preceding six months.
    explanation: Defines the clinical manifestations and recent symptomatic interval.
- category: Neurological
  name: Cognitive impairment
  description: >-
    Cognitive impairment is associated with severe asymptomatic carotid disease in some patients.
    This association is not proof that carotid narrowing is the sole cause or that the impairment
    is reversible by revascularization.
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - *id004
- name: Cerebral perfusion delay
  category: Neurological
  description: Perfusion MRI or CT can show delayed ipsilateral hemispheric contrast arrival in a subset with severe stenosis. Delay alone does not establish infarction or a reversible cause of cognitive impairment.
  evidence:
  - *id005
  phenotype_term:
    preferred_term: Delayed cerebral perfusion
  notes: "Needs term: delayed cerebral perfusion. The OAK query `runoak -i ols:hp search 'l~perfusion' 'l~cerebral blood flow' 'l~hypoperfusion'` returned pulmonary perfusion defect, maternal vascular malperfusion, iris hypoperfusion, ophthalmic artery hypoperfusion, and cilioretinal arteriolar hypoperfusion, with no cerebral-perfusion term. A cerebral ischemia binding would overstate what contrast-arrival delay alone establishes."
progression:
- phase: Asymptomatic high-grade stenosis
  age_range: Adult to older adult
  notes: >-
    High-grade asymptomatic stenosis may be found through targeted vascular
    assessment in high-risk patients and carries future stroke and cardiovascular
    event risk.
  evidence:
  - reference: PMID:39319460
    reference_title: Prediction of Severe Baseline Asymptomatic Carotid Stenosis and Subsequent Risk of Stroke and Cardiovascular Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Significantly higher incidence rates of stroke (Ptrend<0.011) and CVD (Ptrend<0.0001)
      during follow-up were
      found with increasing PACAS risk groups.
    explanation: This supports future stroke and cardiovascular event risk in higher predicted-risk asymptomatic carotid stenosis groups.
    quote_role: PRIMARY_RESULT
- phase: Symptomatic carotid-territory ischemia
  age_range: Adult to older adult
  notes: >-
    Symptomatic disease includes recent hemispheric or retinal TIA and
    nondisabling stroke in the territory of the stenotic carotid artery.
  evidence:
  - reference: PMID:1852179
    reference_title: Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      recent hemispheric and retinal transient ischemic attacks or nondisabling strokes and
      ipsilateral high-grade
      stenosis (70 to 99 percent) of the internal carotid artery.
    explanation: This directly defines symptomatic high-grade carotid stenosis in the NASCET population.
    quote_role: PRIMARY_RESULT
environmental:
- name: Cardiometabolic comorbidities
  presence: Positive
  description: >-
    Hypertension, diabetes, and chronic kidney disease contribute to carotid
    plaque development and overlap with broader atherosclerotic cardiovascular
    risk.
  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: This review abstract identifies these comorbidities as salient contributors to plaque development.
    quote_role: REVIEW_SYNTHESIS
- name: Smoking and diet
  presence: Positive
  description: >-
    Smoking and diet are modifiable lifestyle risk factors that contribute to
    carotid plaque development and are targets of medical prevention.
  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 plaque development.
    quote_role: REVIEW_SYNTHESIS
  influences_mechanisms:
  - target: Atherosclerotic carotid plaque formation
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Smoking and diet are named as the lifestyle factors playing the largest role in carotid plaque development, which is the node this exposure acts on.
    evidence:
    - reference: PMID:37303351
      reference_title: 'Carotid Artery Stenosis: A Look Into the Diagnostic and Management Strategies, and Related Complications.'
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: lifestyle aspects, including smoking and diet, played the most salient role in plaque development.
      explanation: Names plaque development specifically, rather than carotid stenosis as a whole, as what these lifestyle factors drive. The edge jumps the ApoB-retention and monocyte-recruitment nodes that sit between exposure and plaque in this file, and the study measures a combined lifestyle contribution without isolating the diet component.
      quote_role: REVIEW_SYNTHESIS
diagnosis:
- name: Duplex ultrasound with confirmatory CT angiography
  description: >-
    Duplex ultrasonography is commonly used as first-line assessment of ICA
    stenosis. Significant stenosis is often confirmed or further characterized
    with CT angiography or another cross-sectional vascular imaging modality.
  diagnosis_term:
    preferred_term: Diagnostic Imaging Testing
    term:
      id: NCIT:C16502
      label: Diagnostic Imaging Testing
  results: Estimates stenosis severity and informs medical versus revascularization management.
  evidence:
  - reference: PMID:38896635
    reference_title: Accuracy of duplex ultrasonography versus angiotomography for the diagnosis of extracranial internal carotid stenosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Duplex ultrasonography (DUS) is the first line of investigation of ICA stenosis, but
      its accuracy varies in
      the literature and it is usual to complement the study with another more accurate exam
      when faced with significant
      stenosis.
    explanation: This directly supports DUS as first-line imaging and confirmatory imaging for significant stenosis.
    quote_role: PRIMARY_RESULT
- name: CT angiography for severe ICA stenosis
  description: >-
    CT angiography can accurately diagnose severe internal carotid stenosis and
    is used to characterize anatomy for procedural planning.
  diagnosis_term:
    preferred_term: computed tomography angiography
    term:
      id: NCIT:C202408
      label: Computed Tomography Angiography
  results: High sensitivity and specificity for severe ICA stenosis in meta-analysis.
  evidence:
  - reference: PMID:39143526
    reference_title: Systematic review and meta-analysis of the diagnostic value of computed tomography angiography for severe internal carotid artery stenosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CTA demonstrated high sensitivity and specificity for diagnosing severe ICA stenosis.
    explanation: This meta-analysis conclusion directly supports CTA for severe ICA stenosis diagnosis.
    quote_role: PRIMARY_RESULT
- name: Vulnerable plaque risk stratification
  description: >-
    Plaque composition, including intraplaque hemorrhage, lipid-rich core, and surface disruption,
    adds information
    beyond lumen stenosis. CT and MRI can identify vulnerable plaques against histology; these
    findings do not by
    themselves establish that a particular patient benefits from revascularization.
  diagnosis_term:
    preferred_term: vascular imaging
  results: Identifies high-risk plaque composition and may refine stroke-risk stratification.
  evidence:
  - reference: PMID:38953552
    reference_title: 'Diagnostic accuracy of carotid plaque instability by noninvasive imaging: a systematic review and meta-analysis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: CT and MRI have a similar, high performance in detecting vulnerable carotid plaques, whereas US showed significantly less diagnostic accuracy.
    explanation: Meta-analysis compares imaging against histology; it does not test treatment benefit.
- name: NASCET and ECST stenosis measurement
  description: Report the measurement convention. NASCET compares the narrowest residual lumen with the normal distal lumen; ECST uses the estimated original lumen at the lesion. The percentages are not interchangeable.
  evidence:
  - reference: PMID:38683353
    reference_title: CIRSE Standards of Practice on Carotid Artery Stenting.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: The degree of the stenosis is calculated by either the NASCET criteria, that calculates the ratio of the stenosis to the normal lumen distal to the stenosis, or the ECST criteria, which characterises the degree of the stenosis in relation to the estimated normal lumen at the same level
    explanation: Explains the distinct denominator conventions.
- name: Transcranial Doppler microembolic signals
  description: Transcranial Doppler monitoring can detect microembolic signals associated with active embolization and plaque instability. Absence of detected signals does not exclude carotid disease.
  evidence:
  - reference: PMID:38673936
    reference_title: 'Molecular Pathways of Vulnerable Carotid Plaques at Risk of Ischemic Stroke: A Narrative Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Microembolisms from carotid plaques are one of the mechanisms responsible for cerebral ischemia.
    explanation: Defines the process assessed by microembolic monitoring.
  - reference: PMID:38673936
    reference_title: 'Molecular Pathways of Vulnerable Carotid Plaques at Risk of Ischemic Stroke: A Narrative Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Microembolic signals (MESs) can also be detected in asymptomatic patients,
    explanation: Supports detecting embolic activity even without recent symptoms.
- name: Distinguishing near-occlusion from conventional stenosis and complete occlusion
  description: Near-occlusion is a tight proximal ICA stenosis with distal lumen reduction, with or without a threadlike full collapse. Residual lumen distinguishes it from complete occlusion. The collapsed distal vessel is not a valid normal denominator for routine percentage stenosis; confirm this configuration before applying conventional thresholds.
  evidence:
  - reference: PMID:26316571
    reference_title: 'Carotid Near-Occlusion: A Comprehensive Review, Part 1--Definition, Terminology, and Diagnosis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Carotid near-occlusion is distal ICA luminal collapse beyond a tight stenosis, where the distal lumen should not be used for calculating percentage stenosis.
    explanation: Defines near-occlusion and the measurement caveat.
  - reference: PMID:41614493
    reference_title: 'Carotid near-occlusion diagnostics and its consequences: A systematic review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: When grading carotid stenosis, it is crucial to first assess if the case have CNO and only grade conventional stenoses with percent.
    explanation: The contemporary systematic review maintains the distinction from conventional percentage stenosis.
treatments:
- name: Optimal medical therapy and risk-factor modification
  description: >-
    Intensive medical management is foundational whether or not revascularization is chosen:
    antiplatelet therapy,
    lipid lowering, blood-pressure and diabetes control, smoking cessation, diet, and physical
    activity. CREST-2
    targeted systolic pressure below 130 mm Hg and LDL cholesterol below 70 mg/dL under protocol
    oversight. These
    trial targets do not replace individualized prescribing.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: aspirin
      term:
        id: CHEBI:15365
        label: acetylsalicylic acid
    - preferred_term: clopidogrel
      term:
        id: CHEBI:37941
        label: clopidogrel
    - preferred_term: atorvastatin
      term:
        id: CHEBI:39548
        label: atorvastatin
  target_phenotypes:
  - preferred_term: Ischemic stroke
    term:
      id: HP:0002140
      label: Ischemic stroke
  evidence:
  - reference: PMID:39099701
    reference_title: Brazilian Angiology and Vascular Surgery Society Guidelines for the treatment of extracranial cerebrovascular disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: 'Optimal clinical management consists of three key elements: (1) adopting healthy eating habits and physical activity; (2) controlling comorbidities and risk factors; and (3) optimization of antithrombotic and lipid-lowering therapy.'
    explanation: Defines the components of carotid disease prevention.
  - reference: PMID:41269206
    reference_title: Medical Management and Revascularization for Asymptomatic Carotid Stenosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Primary targets were a systolic blood pressure of less than 130 mm Hg (the initial target of 140 mm Hg was reduced in 2018 after guideline changes) and a low-density lipoprotein (LDL) cholesterol level of less than 70 mg per deciliter
    explanation: Reports CREST-2 protocol targets.
  - reference: PMID:39099701
    reference_title: Brazilian Angiology and Vascular Surgery Society Guidelines for the treatment of extracranial cerebrovascular disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: For patients with asymptomatic ICA stenosis, lipid-lowering therapy with statins associated or not with ezetimibe to prevent cardiovascular events (AMI, stroke, cardiovascular death) is recommended
    explanation: Supports statin-based lipid lowering, with ezetimibe where appropriate.
  - &id012
    reference: PMID:40252662
    reference_title: 'Optimised medical therapy alone versus optimised medical therapy plus revascularisation for asymptomatic or low-to-intermediate risk symptomatic carotid stenosis (ECST-2): 2-year interim results of a multicentre randomised trial.'
    snippet: No evidence for a benefit of revascularisation in addition to OMT was found in the first 2 years following treatment for patients with asymptomatic or symptomatic carotid stenosis of 50% or greater with a low or intermediate predicted stroke risk (assessed by the CAR score).
    explanation: ECST-2 interim findings apply to low/intermediate predicted-risk patients and do not establish absence of benefit in high-risk symptomatic disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:39099701
    reference_title: Brazilian Angiology and Vascular Surgery Society Guidelines for the treatment of extracranial cerebrovascular disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: There is no proven benefit from dual antiplatelet therapy for asymptomatic individuals, and clopidogrel should be used as monotherapy in case of intolerance to ASA.
    explanation: Distinguishes long-term prevention in asymptomatic stenosis from periprocedural dual antiplatelet therapy for stenting.
  - reference: PMID:39099701
    reference_title: Brazilian Angiology and Vascular Surgery Society Guidelines for the treatment of extracranial cerebrovascular disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: 'statins: atorvastatin 40-80 mg/day or rosuvastatin 20-40 mg/day.'
    explanation: The guideline explicitly names atorvastatin as a lipid-lowering option; doses are source context, not individualized instructions.
  notes: Aspirin, clopidogrel, and atorvastatin are examples of antiplatelet and lipid-lowering agents; the intensive-management trial results do not isolate the effect of an individual drug. ECST-2 found no added benefit from revascularization on its two-year hierarchical endpoint in selected patients with at least 50% stenosis and predicted five-year ipsilateral stroke risk below 20%; this differs from the CREST-2 population and endpoint. Antiplatelet choice and duration depend on symptoms, intervention, and bleeding risk; the listed agents do not imply that all should be prescribed together.
  target_mechanisms:
  - target: Carotid plaque-surface thrombosis
    treatment_effect: INHIBITS
    description: The antiplatelet component reduces platelet-mediated thrombotic activity; other components address vascular risk.
    evidence:
    - reference: PMID:38673936
      reference_title: 'Molecular Pathways of Vulnerable Carotid Plaques at Risk of Ischemic Stroke: A Narrative Review.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: These data confirm that platelet activation plays a crucial role in cerebral microembolism, as demonstrated by the efficacy of antiplatelet drugs in reducing the MES rate
      explanation: Links antiplatelet therapy to reduced microembolic signals; the surrogate is not itself a clinical stroke endpoint.
- name: Carotid endarterectomy
  description: >-
    Carotid endarterectomy removes the atheromatous lesion. NASCET established benefit for
    selected recently symptomatic
    70-99% stenosis; prompt assessment is important, with timing depending on neurologic stability
    and infarct burden.
    Older ACAS results supported selected asymptomatic patients, but in the separate modern
    CREST-2 endarterectomy
    trial the 4-year composite rate was 3.7% with surgery plus intensive management versus
    5.3% with intensive management
    alone (P=.24). This neutral asymptomatic result does not negate symptomatic-trial benefit.
  treatment_term:
    preferred_term: Carotid Endarterectomy
    term:
      id: NCIT:C157807
      label: Carotid Endarterectomy
  target_phenotypes:
  - preferred_term: Ischemic stroke
    term:
      id: HP:0002140
      label: Ischemic stroke
  - preferred_term: Transient ischemic attack
    term:
      id: HP:0002326
      label: Transient ischemic attack
  evidence:
  - reference: PMID:1852179
    reference_title: Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Carotid endarterectomy is highly beneficial to patients with recent hemispheric and
      retinal transient ischemic
      attacks or nondisabling strokes and ipsilateral high-grade stenosis (70 to 99 percent)
      of the internal carotid
      artery.
    explanation: This randomized trial abstract directly supports carotid endarterectomy for symptomatic high-grade carotid stenosis.
    quote_role: PRIMARY_RESULT
  - reference: PMID:7723155
    reference_title: Endarterectomy for asymptomatic carotid artery stenosis. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with asymptomatic carotid artery stenosis of 60% or greater reduction in diameter
      and whose general
      health makes them good candidates for elective surgery will have a reduced 5-year risk
      of ipsilateral stroke
      if carotid endarterectomy performed with less than 3% perioperative morbidity and mortality
      is added to aggressive
      management of modifiable risk factors.
    explanation: Historical ACAS benefit in selected asymptomatic patients predates contemporary intensive management; interpret alongside CREST-2.
    quote_role: PRIMARY_RESULT
  - &id010
    reference: PMID:41269206
    reference_title: Medical Management and Revascularization for Asymptomatic Carotid Stenosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In the endarterectomy trial, the 4-year incidence of primary-outcome events was 5.3% (95% CI, 3.3 to 7.4) in the medical-therapy group and 3.7% (95% CI, 2.1 to 5.5) in the endarterectomy group
    explanation: The difference in the separate endarterectomy trial was not statistically significant (P=.24).
  - &id006
    reference: PMID:41269206
    reference_title: Medical Management and Revascularization for Asymptomatic Carotid Stenosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The primary outcome was a composite of any stroke or death, assessed from randomization to 44 days, or ipsilateral ischemic stroke, assessed during the remaining follow-up period up to 4 years.
    explanation: Defines the composite endpoint used for the two trial-specific estimates.
  - reference: PMID:38683353
    reference_title: CIRSE Standards of Practice on Carotid Artery Stenting.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Intervention within two weeks of TIA onset is most beneficial for symptomatic patients with ≥50% stenosis (NASCET)
    explanation: Supports prompt intervention assessment after TIA in eligible symptomatic patients.
  - reference: PMID:41614493
    reference_title: 'Carotid near-occlusion diagnostics and its consequences: A systematic review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: Symptomatic CNO have no benefit with revascularization in studies with "good" CNO diagnostics, which foremost applies to the moderate subtype (without full collapse).
    explanation: The review separates near-occlusion definitions; these findings do not prove equivalence for the sparsely studied full-collapse subgroup.
  therapeutic_modality: SURGERY
  notes: Conventional high-grade stenosis results should not be extrapolated to near-occlusion. Contemporary evidence for benefit in near-occlusion is limited, especially for the full-collapse subgroup; individualized specialist assessment is required.
  target_mechanisms:
  - target: Flow-limiting carotid lumen narrowing
    treatment_effect: INHIBITS
    description: Removal of the obstructing plaque restores the residual lumen.
    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
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: The artery is opened, and the plaque is removed.
      explanation: Describes direct removal of the carotid atheroma.
  - target: Artery-to-artery embolization
    treatment_effect: INHIBITS
    description: Removal of the culprit plaque removes a local source of artery-to-artery emboli.
    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
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: The artery is opened, and the plaque is removed.
      explanation: Describes direct removal of the carotid atheroma.
- name: Carotid artery stenting
  description: >-
    Carotid stenting with embolic protection is an alternative for selected patients. CREST
    found similar composite
    outcomes to endarterectomy but more periprocedural stroke with stenting and more myocardial
    infarction with
    endarterectomy, with age modifying relative outcomes. In the separate CREST-2 stenting
    trial for asymptomatic
    stenosis of at least 70%, transfemoral stenting plus intensive management reduced the
    4-year composite from
    6.0% to 2.8% (P=.02). Certified operators and trial selection limit generalization; CREST-2
    did not include
    TCAR or directly compare stenting with endarterectomy.
  treatment_term:
    preferred_term: Endovascular Stenting
    term:
      id: NCIT:C157840
      label: Endovascular Stenting
  target_phenotypes:
  - preferred_term: Ischemic stroke
    term:
      id: HP:0002140
      label: Ischemic stroke
  evidence:
  - &id008
    reference: PMID:20505173
    reference_title: Stenting versus endarterectomy for treatment of carotid-artery stenosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: the rates of the individual end points differed between the stenting group and the endarterectomy group (death, 0.7% vs. 0.3%; P = 0.18; stroke, 4.1% vs. 2.3%; P = 0.01; myocardial infarction, 1.1% vs. 2.3%; P = 0.03)
    explanation: Reports the opposing periprocedural stroke and myocardial-infarction differences in CREST.
  - &id009
    reference: PMID:41269206
    reference_title: Medical Management and Revascularization for Asymptomatic Carotid Stenosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In the stenting trial, the 4-year incidence of primary-outcome events was 6.0% (95% confidence interval [CI], 3.8 to 8.3) in the medical-therapy group and 2.8% (95% CI, 1.5 to 4.3) in the stenting group
    explanation: CREST-2 stenting versus intensive medical management, not versus endarterectomy.
  - *id006
  - reference: PMID:41269206
    reference_title: Medical Management and Revascularization for Asymptomatic Carotid Stenosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: revascularization was performed only by well-trained and certified high-volume operators, so the results in CREST-2 may not reflect practice more broadly.
    explanation: Limits extrapolation of trial results.
  - &id007
    reference: PMID:38683353
    reference_title: CIRSE Standards of Practice on Carotid Artery Stenting.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: It should be noted that the objective of CAS endpoint is not to achieve maximal luminal gain, but rather to attain complete plaque coverage.
    explanation: Explains the plaque-coverage mechanism of stenting.
  therapeutic_modality: DEVICE
  target_mechanisms:
  - target: Artery-to-artery embolization
    treatment_effect: INHIBITS
    description: Stent coverage stabilizes the plaque surface; embolic protection reduces procedural embolization risk.
    evidence:
    - *id007
    - reference: PMID:38683353
      reference_title: CIRSE Standards of Practice on Carotid Artery Stenting.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
      snippet: In order to mitigate this risk, embolic protection devices (EPDs) have been devised to capture and remove any fragments that may break off during the procedure.
      explanation: Supports procedural embolic protection.
- name: Transcarotid artery revascularization with flow reversal
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: Endovascular Stenting
    term:
      id: NCIT:C157840
      label: Endovascular Stenting
  description: TCAR combines direct cervical carotid access, flow reversal for embolic protection, and stent placement. ROADSTER-3 reported a 0.9% 30-day stroke/death/MI rate in 344 intention-to-treat standard-risk patients younger than 80 years. The study was single-arm and industry sponsored; it does not prove superiority to endarterectomy or benefit over medical therapy in asymptomatic disease.
  evidence:
  - reference: PMID:41277872
    reference_title: 'Prospective, Multicenter Evaluation of Transcarotid Artery Revascularization in Standard-Risk Patients: 30-Day Outcomes of the ROADSTER 3 Study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: Transcarotid artery revascularization (TCAR) combines transcarotid arterial access and robust reversal of antegrade internal carotid artery flow to provide embolic protection during carotid angioplasty and stenting (CAS) for stroke prevention.
    explanation: Defines TCAR access and protection mechanisms.
  - &id011
    reference: PMID:41277872
    reference_title: 'Prospective, Multicenter Evaluation of Transcarotid Artery Revascularization in Standard-Risk Patients: 30-Day Outcomes of the ROADSTER 3 Study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: The composite 30-day stroke/death/myocardial infarction rate was 0.6% (95% CI, 0.1-2.2%) for the per protocol population and 0.9% (95% CI, 0.2-2.5%) for the intent to treat population.
    explanation: 'Single-arm ROADSTER-3 outcomes: 320 per-protocol and 344 intention-to-treat patients; not a randomized comparison.'
  - reference: PMID:41277872
    reference_title: 'Prospective, Multicenter Evaluation of Transcarotid Artery Revascularization in Standard-Risk Patients: 30-Day Outcomes of the ROADSTER 3 Study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: ROADSTER 3 is a single-arm study without a comparative group, and potential bias can exist without randomization.
    explanation: Explicit limitation of causal comparative efficacy inference.
  target_mechanisms:
  - target: Artery-to-artery embolization
    treatment_effect: INHIBITS
    description: Reversed flow protects the cerebral circulation during stent delivery.
    evidence:
    - reference: PMID:41277872
      reference_title: 'Prospective, Multicenter Evaluation of Transcarotid Artery Revascularization in Standard-Risk Patients: 30-Day Outcomes of the ROADSTER 3 Study.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      directness: DIRECT
      snippet: TCAR combines transcarotid arterial access and robust reversal of antegrade internal carotid artery flow to provide embolic protection during carotid angioplasty and stenting
      explanation: Defines the procedural protection mechanism.
clinical_trials:
- name: NCT00004732
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: >-
    CREST analyzed 2502 symptomatic or asymptomatic patients to stenting or endarterectomy.
    The estimated 4-year
    primary composite rates were 7.2% and 6.8% (P=.51), with opposing periprocedural stroke
    and myocardial-infarction
    differences. The comparison did not include a medical-therapy-only arm.
  target_phenotypes:
  - preferred_term: Ischemic stroke
    term:
      id: HP:0002140
      label: Ischemic stroke
  evidence:
  - reference: clinicaltrials:NCT00004732
    reference_title: Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The purpose of the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST)
      is to compare the
      relatively new procedure of stent-assisted carotid angioplasty (CAS) to the traditional
      and accepted surgical
      approach of carotid endarterectomy (CEA) for the treatment of carotid artery stenosis
      to prevent recurrent
      strokes in those patients who have had a TIA (transient ischemic attack) or a mild stroke
      within the past
      6 months (symptomatic) and in those patients who have not had any symptoms within the
      past 6 months (asymptomatic).
    explanation: The trial summary directly supports CREST as a comparative stenting-versus-endarterectomy trial for symptomatic and asymptomatic carotid stenosis.
    quote_role: BACKGROUND
  - reference: PMID:20505173
    reference_title: Stenting versus endarterectomy for treatment of carotid-artery stenosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: There was no significant difference in the estimated 4-year rates of the primary end point between carotid-artery stenting and carotid endarterectomy (7.2% and 6.8%, respectively;
    explanation: Reports the main randomized comparison.
  - *id008
  notes: ClinicalTrials.gov registry checked 2026-10-04; last posted update 2017-05-17.
- name: NCT02089217
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: >-
    CREST-2 comprised two parallel randomized trials in asymptomatic stenosis of at least
    70%: 1245 patients in
    the stenting comparison and 1240 in the endarterectomy comparison. At 4 years, the primary
    composite was lower
    with stenting plus intensive medical management (2.8% versus 6.0%, P=.02); the endarterectomy
    comparison was
    neutral (3.7% versus 5.3%, P=.24). Neither comparison showed cognitive benefit through
    4 years in the prespecified
    secondary cognitive analysis. The trials do not directly compare stenting with endarterectomy.
  target_phenotypes:
  - preferred_term: Ischemic stroke
    term:
      id: HP:0002140
      label: Ischemic stroke
  evidence:
  - reference: clinicaltrials:NCT02089217
    reference_title: Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Carotid revascularization for primary prevention of stroke (CREST-2) is two independent
      multicenter, randomized
      controlled trials of carotid revascularization and intensive medical management versus
      medical management
      alone in patients with asymptomatic high-grade carotid stenosis.
    explanation: The trial summary directly supports CREST-2 as a randomized comparison of revascularization plus intensive medical management versus medical management alone.
    quote_role: BACKGROUND
  - *id009
  - *id010
  - *id006
  - reference: PMID:42747844
    reference_title: 'Revascularization of Asymptomatic Carotid Artery Stenosis: Cognitive Results of the CREST-2 Randomized Trials.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: revascularization with either CAS or CEA plus IMM, compared with IMM alone, did not significantly improve cognitive function at up to 4 years of follow-up.
    explanation: Prespecified secondary cognitive outcomes in CREST-2 were neutral.
  notes: ClinicalTrials.gov registry checked 2026-10-04; last posted update 2025-10-01. The registry lists 2486 enrolled; the publication reports 2485 randomized, which is the denominator used here. TCAR was not included.
- name: NCT03121209
  phase: PHASE_III
  status: COMPLETED
  description: >-
    CREST-H enrolled 392 patients with severe asymptomatic stenosis; 291 had complete imaging
    and cognitive data.
    In the primary analysis of 51 with reduced baseline cognition, baseline perfusion impairment
    did not significantly
    modify the cognitive response to revascularization versus intensive medical management
    over one year (interaction
    P=.40). Small subgroup size and missing data limit inference.
  target_phenotypes:
  - preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - *id005
  - reference: PMID:42747834
    reference_title: 'Revascularization in Asymptomatic Carotid Artery Stenosis With Hemodynamic Impairment and Cognitive Outcomes: The CREST-H Substudy of the CREST-2 Randomized Clinical Trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: In this substudy of a randomized clinical trial, there was no differential effect of revascularization vs IMM alone on cognition over 1 year by cerebral hemodynamic status among those with baseline reduced cognition,
    explanation: The CREST-H result does not support the proposed differential cognitive benefit from restoring flow; the reduced-cognition primary-analysis subgroup contained 51 participants.
  - reference: PMID:42747834
    reference_title: 'Revascularization in Asymptomatic Carotid Artery Stenosis With Hemodynamic Impairment and Cognitive Outcomes: The CREST-H Substudy of the CREST-2 Randomized Clinical Trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Of 392 participants enrolled (mean age, 71 years; 125 [32%] females), 61 were excluded for missing baseline imaging and 40 for missing cognitive examinations or other covariates, leaving 291 with complete data. Fifty-one had reduced cognition at baseline
    explanation: Defines attrition and the primary-analysis subgroup.
  notes: ClinicalTrials.gov registry checked 2026-10-04; last posted update 2026-08-18.
- name: NCT05465122
  phase: NOT_APPLICABLE
  status: ACTIVE_NOT_RECRUITING
  description: CREST-2 observational extension follows participants beyond the randomized trial follow-up to assess later stroke and death. It is follow-up research, not a new randomized treatment comparison.
  evidence:
  - reference: clinicaltrials:NCT05465122
    reference_title: Long-Term Observational Extension of Participants in the CREST-2 Randomized Clinical Trial
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: 'The purpose of this Long-Term Observational Extension of Participants in the CREST-2 Randomized Clinical Trial (C2LOE - ClinicalTrials.gov Identifier: NCT02089217) study is to study is to assess post-procedural efficacy of carotid endarterectomy and carotid stenting.'
    explanation: Registry summary defines the study design and purpose.
  notes: Registry checked 2026-10-04; last posted update 2026-05-28.
- name: NCT06653387
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: Single-arm device study of the CGuard Prime carotid stent with ENROUTE transcarotid neuroprotection. Registry-reported recruitment does not establish comparative stroke-prevention efficacy.
  evidence:
  - reference: clinicaltrials:NCT06653387
    reference_title: A Multicenter, Single-arm, Pivotal Study to Evaluate Acute Device and Technical Success of the CGuard Prime Carotid Stent System (80cm) When Used in Conjunction With the FDA-cleared ENROUTE Transcarotid Neuroprotection System (NPS) in Patients at High Risk for Adverse Events From Carotid Endarterectomy Undergoing Carotid Artery Stenting Via the Transcarotid Artery Revascularization (TCAR) Approach.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: The objective of this study is to evaluate acute device and technical success of the CGuard Prime™ Carotid Stent System (80cm) when used in conjunction with the Enroute NPS during Transcarotid Artery Revascularization procedures in the treatment of carotid artery stenosis in spatients at high risk for adverse events from carotid endarterectomy.
    explanation: Registry summary defines the study design and purpose.
  notes: Registry checked 2026-10-04; last posted update 2025-05-31.
- name: NCT05365490
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: ROADSTER-3 is a prospective single-arm post-approval TCAR study in standard surgical-risk patients. Published early outcomes cover 344 intention-to-treat patients and 320 per-protocol patients; comparative efficacy cannot be inferred without a control group.
  evidence:
  - reference: clinicaltrials:NCT05365490
    reference_title: Post-approval Study of Transcarotid Artery Revascularization in Standard Risk Patients With Significant Carotid Artery Disease. The ROADSTER 3 Study
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: The study objective is to evaluate real world usage of the ENROUTE Transcarotid Stent when used with the ENROUTE Transcarotid Neuroprotection System in patients at standard risk for adverse events from carotid endarterectomy
    explanation: Registry summary defines the study design and purpose.
  - *id011
  notes: Registry checked 2026-10-04; last posted update 2025-07-30.
- name: ISRCTN97744893
  phase: NOT_APPLICABLE
  status: NOT_RECRUITING
  description: ECST-2 randomized 429 asymptomatic or low/intermediate-risk symptomatic patients with at least 50% stenosis to optimized medical therapy with or without revascularization. One participant withdrew consent immediately. The two-year interim hierarchical composite included fatal/periprocedural events, nonfatal stroke, myocardial infarction, and silent imaging infarction; no benefit was detected (win ratio 1.01, 95% CI 0.60-1.70; P=.97).
  evidence:
  - reference: ICTRP:ISRCTN97744893
    reference_title: European Carotid Surgery Trial 2
    snippet: '| Recruitment status | No longer recruiting |'
    explanation: WHO ICTRP reports recruitment closed; this is not assumed to prove completion of all follow-up.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    directness: DIRECT
  - *id012
  - reference: PMID:40252662
    reference_title: 'Optimised medical therapy alone versus optimised medical therapy plus revascularisation for asymptomatic or low-to-intermediate risk symptomatic carotid stenosis (ECST-2): 2-year interim results of a multicentre randomised trial.'
    snippet: win ratio 1·01 [95% CI 0·60-1·70]; p=0·97
    explanation: Reports the interim hierarchical primary analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  notes: ICTRP record checked 2026-10-04; source last refreshed 10 August 2026. The registry target sample size of 200 is not substituted for the publication randomized count of 429. The publication describes ongoing follow-up; NOT_RECRUITING records the registry recruitment state.
datasets:
- accession: geo:GSE308470
  title: Possible association between the microbiota in subgingival and atherosclerotic plaque in patients with carotid stenosis.
  description: Paired subgingival and carotid endarterectomy specimens from 25 patients (50 samples), profiled by V3-V4 16S rRNA amplicon sequencing. Oral and vascular bacterial DNA profiles differed; occasional overlap does not establish oral origin, viable infection, or microbial causation of stenosis.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  sample_count: 50
  publication: PMID:41908294
  notes: Cross-sectional, small surgical cohort. Low bacterial biomass makes vascular samples susceptible to reagent contamination and carryover. Amplicon sequencing cannot establish microbial viability and has limited species resolution. This is not shotgun metagenomics.
- accession: geo:GSE311535
  title: RNA-seq of human atherosclerotic carotid plaque tissue from diabetic patients
  description: 'Bulk RNA sequencing of carotid plaques from 12 patients with diabetes undergoing endarterectomy: six recently symptomatic and six asymptomatic. Sex and insulin use explained substantial transcriptomic variation; the small observational study cannot establish that insulin causes plaque rupture. Spatial localization was inferred computationally using external single-cell and spatial references.'
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 12
  publication: PMID:41377472
  notes: Recently symptomatic samples were obtained about five days after events, so expression changes may follow rupture. No contemporaneous nondiabetic control group was included; batch effects prevented comparison with a historical cohort. Inferred fibrous-cap expression is not direct spatial transcriptomic measurement.
notes: This entry models atherosclerotic extracranial carotid stenosis. Dissection, carotid web, vasculitis, radiation injury, and complete carotid occlusion have distinct mechanisms and management. Symptomatic and asymptomatic disease are clinical states, not obligate sequential stages or separate inherited subtypes. Stenosis percentages depend on the measurement method; NASCET uses the normal distal lumen whereas ECST estimates the original lumen at the lesion. Trial findings apply to their selected populations and endpoints; CREST-2 comprised two parallel trials and was not a direct stenting-versus-endarterectomy comparison.
imaging_findings:
- name: Duplex evidence of carotid lumen narrowing
  modality: ULTRASOUND
  description: Duplex combines plaque morphology and flow velocities to estimate stenosis. Laboratory thresholds and near-occlusion interpretation vary, so a single velocity is not a universal substitute for complete vascular assessment.
  evidence:
  - reference: PMID:38683353
    reference_title: CIRSE Standards of Practice on Carotid Artery Stenting.
    snippet: Duplex ultrasonography utilises blood velocity in addition to B-mode greyscale to detect the existence and degree of stenosis, as well as evaluation of plaque composition and characteristics.
    explanation: Describes combined morphologic and hemodynamic assessment.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
  - reference: DOI:10.54522/jvsgbi.2024.156
    reference_title: Current practice in ultrasound grading of carotid artery stenosis in the UK and Ireland
    snippet: The criteria prioritised to grade a stenosis and how near occlusion was defined on duplex imaging was variable, and there were inconsistent practices on internal audits and quality assurance.
    explanation: UK/Ireland practice survey documents variability; it is not a diagnostic-accuracy estimate.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Ipsilateral cerebral perfusion delay
  modality: MRI
  description: CREST-H used perfusion MRI or CT to measure delayed contrast arrival in the hemisphere ipsilateral to severe stenosis. This imaging phenotype does not by itself establish infarction or reversible cognitive dysfunction.
  evidence:
  - reference: PMID:42747834
    reference_title: 'Revascularization in Asymptomatic Carotid Artery Stenosis With Hemodynamic Impairment and Cognitive Outcomes: The CREST-H Substudy of the CREST-2 Randomized Clinical Trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Magnetic resonance or computed tomographic perfusion imaging tested for baseline hemodynamic impairment defined by delayed time-to-peak (TTP) arrival of intravenous contrast in the hemisphere ipsilateral minus contralateral to the stenotic artery.
    explanation: CREST-H measured perfusion delay in severe unilateral asymptomatic stenosis; this is an organ-level observation, not evidence for a specific cellular hypoxia-response pathway.

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