Ischemic Stroke

Complex MONDO:1060198 Pathograph 14 Show in embeddings browser Cerebrovascular disorder stroke disorder

Ischemic stroke is an acute symptomatic central nervous system infarction caused by interruption of cerebral blood flow, usually from thrombosis, embolism, or proximal large-vessel occlusion, leading to ischemic tissue injury and focal neurological deficits.

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9
Pathophys.
5
Phenotypes
14
Pathograph
5
Medical Actions
6
Datasets
1
Deep Research
⚙

Pathophysiology

9
Chronic Low-Grade Systemic Inflammation
Persistently raised circulating inflammatory markers, chiefly interleukin-6 and C-reactive protein, mark a higher risk of a first ischemic stroke and of recurrence after one. Genetic evidence that lower IL-6 signaling lowers the risk of large-artery and small-vessel stroke, but not cardioembolic stroke, suggests the IL-6 axis is causal rather than only a marker. In aged mice, age-related changes in blood-cell production generate atypical neutrophils that worsen the inflammatory response to stroke, and related neutrophil subsets track with worse reperfusion in elderly patients. Most of the human evidence concerns inflammation in general rather than inflammation driven by ageing, so this node is a disease-specific use of the inflammaging module. Anti-inflammatory treatment has not yet been shown to prevent stroke: low-dose colchicine did not reduce early recurrence in a large trial.
Inflammatory response GO:0006954 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. Cytokine production GO:0001816 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Cytokine production (GO:0001816). GO:0001816 is a biological process from the Gene Ontology.
Downstream
Cerebral arterial occlusion Chronic IL-6-driven inflammation is associated with large-artery and small-vessel ischemic stroke, plausibly through atherosclerosis and small-vessel disease. The causal link rests on genetic evidence, and anti-inflammatory treatment has not yet been shown to prevent recurrence.
Neurovascular inflammation and barrier disruption In ageing, the bone-marrow response to stroke produces atypical, pro-oxidant and procoagulant neutrophils that plug the ischemic microcirculation and worsen injury.
Show evidence (2 references)
PMID:20031199 SUPPORT Human Clinical
"CRP concentration has continuous associations with the risk of coronary heart disease, ischaemic stroke, vascular mortality, and death from several cancers and lung disease that are each of broadly similar size."
Pooled prospective data link higher CRP to ischemic stroke risk. The association is shared with non-vascular deaths and depends considerably on conventional risk factors, so on its own it does not show that inflammation causes stroke.
PMID:37026458 SUPPORT Human Clinical
"Blood markers of inflammation were independently associated with vascular recurrence after stroke"
In pooled individual-patient data, baseline IL-6 and high-sensitivity CRP predicted recurrent vascular events and recurrent stroke after adjustment for vascular risk factors and treatment.
Cerebral arterial occlusion
In situ thrombosis, artery-to-artery embolism, cardioembolism, or proximal large-vessel occlusion interrupts cerebral blood flow and initiates the ischemic cascade.
endothelial cell CL:0000115 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endothelial cell (CL:0000115). CL:0000115 is a cell type from the Cell Ontology.
blood coagulation GO:0007596 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased blood coagulation (GO:0007596). GO:0007596 is a biological process from the Gene Ontology. platelet aggregation GO:0070527 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased platelet aggregation (GO:0070527). GO:0070527 is a biological process from the Gene Ontology.
Downstream
Ischemic penumbra and energy failure Occlusion creates a severely hypoperfused core and a potentially salvageable penumbra with residual perfusion.
Show evidence (1 reference)
PMID:20670828 SUPPORT Human Clinical
"This can develop either as a consequence of thrombosis in situ or following embolic occlusion of a cerebral blood vessel"
This review supports thrombosis and embolic vascular occlusion as proximal ischemic-stroke mechanisms.
Ischemic penumbra and energy failure
Severe flow deficits rapidly deplete ATP in the ischemic core, while residual perfusion in the surrounding penumbra allows slower active cell death and creates a time-sensitive target for reperfusion therapy.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology. astrocyte CL:0000127 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves astrocyte (CL:0000127). CL:0000127 is a cell type from the Cell Ontology. endothelial cell CL:0000115 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endothelial cell (CL:0000115). CL:0000115 is a cell type from the Cell Ontology.
response to hypoxia GO:0001666 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased response to hypoxia (GO:0001666). GO:0001666 is a biological process from the Gene Ontology. cell death GO:0008219 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cell death (GO:0008219). GO:0008219 is a biological process from the Gene Ontology.
Downstream
Post-Ischemic Mitochondrial Dysfunction Energy failure and the return of oxygen at reperfusion load neuronal mitochondria with calcium and reactive oxygen species.
Excitotoxic and oxidative neuronal injury Energy failure disrupts ionic gradients and glutamate handling, triggering calcium overload, oxidative injury, and cell death.
Neurovascular inflammation and barrier disruption Ischemic injury activates vascular, glial, and immune responses in the neurovascular unit.
Post-Ischemic Autophagic-Lysosomal Dysfunction Energy failure activates macroautophagy within hours of occlusion, with autophagosome numbers and autophagy-marker levels in the ischemic penumbra rising over the following days.
Astrocyte and Cerebral Endothelial Cell Senescence Astrocytes and cerebral endothelial cells within the ischemic territory undergo acute cellular senescence following arterial occlusion.
Show evidence (2 references)
PMID:21628695 SUPPORT Human Clinical
"In ischemic strokes, severe blood flow deficits in the core rapidly decrease ATP levels and energy stores."
This supports energy failure as an early consequence of ischemic core hypoperfusion.
PMID:20670828 SUPPORT Human Clinical
"The ischemic penumbra then denotes an “at risk” region that is functionally impaired, but potentially salvageable."
This supports the penumbra as an at-risk but potentially salvageable tissue compartment.
Excitotoxic and oxidative neuronal injury
Energy failure and impaired glutamate reuptake promote excitotoxic calcium influx, oxidative and nitrative stress, mitochondrial dysfunction, and apoptotic-like cell death in neurons and neighboring neurovascular cells.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
response to oxidative stress GO:0006979 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased response to oxidative stress (GO:0006979). GO:0006979 is a biological process from the Gene Ontology. apoptotic process GO:0006915 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased apoptotic process (GO:0006915). GO:0006915 is a biological process from the Gene Ontology.
Show evidence (2 references)
PMID:21628695 SUPPORT Human Clinical
"accumulated data over the past two decades have implicated excitotoxicity, oxidative stress and in some circumstances, apoptotic-like pathways"
This supports excitotoxic, oxidative, and apoptotic-like injury processes in acute stroke cell death.
PMID:28417216 SUPPORT Human Clinical
"Brain injury following stroke results from a complex series of pathophysiological events including excitotoxicity, oxidative and nitrative stress, inflammation, and apoptosis."
This review independently supports the multi-mechanism cellular injury cascade after ischemic stroke.
Post-Ischemic Mitochondrial Dysfunction
After arterial occlusion and reperfusion, neuronal mitochondria generate reactive oxygen species and open the permeability transition pore, which couples the energy failure of the penumbra to neuronal death. In rodent focal ischemia, mitochondria in the ischemic focus lose respiratory capacity, and succinate that accumulates during ischemia is re-oxidized on reperfusion, driving the reactive oxygen species burst by reverse electron transport at complex I. This is an acute injury process, not the age-related decline the conformed module describes; the shared element is the bioenergetic-failure and oxidative-stress state. Mechanistic support is almost entirely from rodents, and the one randomized human test of targeting the pore (cyclosporine) missed its primary endpoint, so the causal weight of this node in human stroke is unsettled.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
Oxidative Phosphorylation GO:0006119 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Oxidative Phosphorylation (GO:0006119). GO:0006119 is a biological process from the Gene Ontology. Reactive Oxygen Species Metabolism GO:0072593 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Reactive Oxygen Species Metabolism, annotated with reactive oxygen species metabolic process (GO:0072593). GO:0072593 is a biological process from the Gene Ontology.
Cerebral cortex UBERON:0000956 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Cerebral cortex (UBERON:0000956). UBERON:0000956 is an anatomical location from the Uberon multi-species anatomy ontology. Striatum UBERON:0002435 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Striatum (UBERON:0002435). UBERON:0002435 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Excitotoxic and oxidative neuronal injury Mitochondrial ROS generation and permeability transition contribute to the oxidative and apoptotic-like neuronal death modeled in that node. Persistent mitochondrial failure is not required for infarction after shorter ischemia.
Microglial NLRP3 Inflammasome Activation in the Ischemic Penumbra Mitochondrial dysfunction after ischemia-reperfusion activates the NLRP3 inflammasome in microglia.
Show evidence (8 references)
PMID:8571432 SUPPORT Model Organism
"reactive oxygen species generated by mitochondrial electron transport escape cellular antioxidant defenses and promote highly damaging hydroxyl radical activity after transient brain ischemia in the rat"
Rat global ischemia/reperfusion data showing mitochondrial ROS generation; not human evidence.
PMID:16103352 SUPPORT Model Organism
"CypD-deficient mice displayed a dramatic reduction in brain infarct size after acute middle cerebral artery occlusion and reperfusion"
Mouse knockout evidence that the mitochondrial permeability transition pore contributes to infarct size after focal ischemia.
PMID:21130757 SUPPORT INDIRECT Human Clinical
"Levels of plasma nuclear and mitochondrial DNA in patients with acute ischemic stroke were significantly higher than those in the controls"
Human biomarker association consistent with release of mitochondrial material after cerebral infarction; it does not show that mitochondrial dysfunction causes the injury.
+ 5 more references
Neurovascular inflammation and barrier disruption
Ischemic injury engages endothelial cells, astrocytes, neurons, microglia, and peripheral immune cells; inflammatory signaling, protease activation, and matrix injury can disrupt the blood-brain barrier and amplify tissue damage.
endothelial cell CL:0000115 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endothelial cell (CL:0000115). CL:0000115 is a cell type from the Cell Ontology. astrocyte CL:0000127 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves astrocyte (CL:0000127). CL:0000127 is a cell type from the Cell Ontology. microglial cell CL:0000129 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves microglial cell (CL:0000129). CL:0000129 is a cell type from the Cell Ontology.
inflammatory response GO:0006954 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. cell-cell signaling GO:0007267 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal cell-cell signaling (GO:0007267). GO:0007267 is a biological process from the Gene Ontology.
Downstream
Microglial NLRP3 Inflammasome Activation in the Ischemic Penumbra Microglial and vascular inflammatory signaling within the neurovascular unit provides the priming and danger signals for NLRP3 inflammasome assembly in the peri-infarct penumbra.
Show evidence (2 references)
PMID:21738161 SUPPORT Human Clinical
"Inflammatory signaling is involved in all stages of the ischemic cascade, from the early damaging events triggered by arterial occlusion"
This supports inflammation as a contributor from early post-occlusion injury through later repair.
PMID:21628695 SUPPORT Human Clinical
"The BBB homeostasis is remarkably dependent on endothelial-astrocyte-matrix interactions"
This supports endothelial-astrocyte-matrix interactions as central to blood-brain barrier integrity after stroke.
Post-Ischemic Autophagic-Lysosomal Dysfunction
Macroautophagy is activated within the ischemic penumbra after arterial occlusion, with autophagosome numbers and autophagy-marker (Beclin-1, LC3B) levels rising early and then declining over the following days as autophagic flux weakens. In parallel, the lysosomal protease cathepsin D (CTSD) is progressively lost, and this lysosomal dysfunction, rather than autophagy induction itself, is the step this node conforms to: loss of CTSD is sufficient to cause lysosomal dysfunction and aggravates neuronal death under oxygen-glucose deprivation, while restoring CTSD activity protects neurons.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
CTSD hgnc:2529 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CTSD (hgnc:2529). hgnc:2529 is a gene from the HUGO Gene Nomenclature Committee. BECN1 hgnc:1034 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves BECN1 (hgnc:1034). hgnc:1034 is a gene from the HUGO Gene Nomenclature Committee.
Macroautophagy GO:0016236 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Macroautophagy (GO:0016236). GO:0016236 is a biological process from the Gene Ontology.
Downstream
Excitotoxic and oxidative neuronal injury Loss of cathepsin D-dependent lysosomal function aggravates, and its restoration protects against, oxygen-glucose deprivation-induced neuronal cell death, adding a lysosomal-clearance-failure route to excitotoxic and oxidative neuronal injury.
Show evidence (2 references)
PMID:33974897 SUPPORT Model Organism
"autophagy was activated within 7 d of tMCAO induction, and it strengthened at 1 d and then weakened steadily from 3 to 7 d"
Primary rodent time-course evidence for early activation and subsequent decline of autophagic flux after ischemic stroke.
PMID:32450052 SUPPORT Model Organism
"Our results show a time-dependent decrease in CTSD protein levels and activity in the mouse brain after stroke and neurons following OGD, with concurrent defects in lysosomal function."
Primary MCAO and oxygen-glucose-deprivation evidence for progressive loss of lysosomal (autophagic-clearance) function after ischemia, distinct from the review (PMID:42419491) that first proposed this axis as a hypothesis.
Astrocyte and Cerebral Endothelial Cell Senescence
Middle cerebral artery occlusion triggers acute cellular senescence in astrocytes and cerebral endothelial cells within the ischemic hemisphere, marked by p16INK4a upregulation and a senescence-associated secretory phenotype (SASP) of MMP-3, IL-1alpha, and IL-6. Senolytic clearance of these senescent cells, whether systemic (ABT-263) or local (targeted lenti-INK-ATTAC), reduces SASP factor levels and improves neurological and locomotor outcomes after occlusion. A senescence-associated blood gene-expression signature is independently associated with worse 90-day functional outcome in acute ischemic stroke patients.
astrocyte CL:0000127 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves astrocyte (CL:0000127). CL:0000127 is a cell type from the Cell Ontology. endothelial cell CL:0000115 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endothelial cell (CL:0000115). CL:0000115 is a cell type from the Cell Ontology.
Cellular senescence GO:0090398 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Cellular senescence (GO:0090398). GO:0090398 is a biological process from the Gene Ontology.
Downstream
Neurovascular inflammation and barrier disruption The senescence-associated secretory phenotype (MMP-3, IL-1alpha, IL-6) released by senescent astrocytes and endothelial cells adds to neurovascular inflammatory signaling and blood-brain barrier injury within the ischemic hemisphere.
Show evidence (3 references)
PMID:37324944 SUPPORT Model Organism
"The treatment of ABT-263 reduced senescence of astrocytes and CECs in MCAO mice."
Pharmacologic senolysis directly reducing astrocyte/endothelial senescence markers in the same MCAO model, supporting a causal (druggable) role rather than a bystander correlation.
PMID:37324944 SUPPORT Model Organism
"localized removal of senescent cells in the injured brain through the stereotaxical injection of lenti-INK-ATTAC viruses generates neuroprotective effects, protecting against acute ischemic brain injury in mice"
Independent genetic (non-pharmacologic) senescent-cell clearance approach converging on the same neuroprotective outcome.
PMID:42479998 SUPPORT Human Clinical
"Patients with poor outcome (mRS > 2) had enriched senescence gene expression compared with those with good outcome (mRS ≤ 2)"
Independent human clinical evidence linking a senescence-associated gene-expression signature to worse functional outcome after acute ischemic stroke, complementing the rodent mechanistic data above.
Microglial NLRP3 Inflammasome Activation in the Ischemic Penumbra
The NLRP3 inflammasome is dramatically activated in the peri-infarct (penumbral) area after cerebral ischemia/reperfusion, and genetic suppression of its upstream regulator TRIM62 ameliorates NLRP3 activation, reduces neuroinflammation and apoptosis, and attenuates infarct outcomes.
microglial cell CL:0000129 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves microglial cell (CL:0000129). CL:0000129 is a cell type from the Cell Ontology.
TRIM62 hgnc:25574 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TRIM62 (hgnc:25574). hgnc:25574 is a gene from the HUGO Gene Nomenclature Committee.
NLRP3 inflammasome complex assembly GO:0044546 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased NLRP3 inflammasome complex assembly (GO:0044546). GO:0044546 is a biological process from the Gene Ontology.
Downstream
Excitotoxic and oxidative neuronal injury NLRP3-driven neuroinflammatory signaling in the peri-infarct area adds a further, innate-immune route to neuronal injury and apoptosis in the ischemic territory.
Show evidence (2 references)
PMID:32703402 SUPPORT Model Organism
"significantly elevated expression of TRIM62 was detected in peri-infarct area of wild type (WT) mice"
Localizes the TRIM62-NLRP3 signaling axis specifically to the peri-infarct (penumbral) region.
PMID:32703402 SUPPORT Model Organism
"nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome was dramatically activated in cerebral ischemia/reperfusion (I/R) conditions, while being ameliorated in TRIM62-KO mice"
Direct primary evidence of NLRP3 inflammasome activation in ischemia/reperfusion, distinct from the review (PMID:42419491) that first proposed this axis as a hypothesis.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Ischemic Stroke Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

5
Cardiovascular 1
Symptomatic central nervous system infarction Ischemic stroke HP:0002140 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ischemic stroke (HP:0002140). HP:0002140 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23652265 SUPPORT Human Clinical
"Ischemic stroke specifically refers to central nervous system infarction accompanied by overt symptoms"
This consensus definition directly supports the diagnostic phenotype.
Digestive 1
Dysphagia HP:0002015 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysphagia (HP:0002015). HP:0002015 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39342159 SUPPORT Human Clinical
"Of 2054 patients with ischemic stroke, 17.2% showed dysphagia at hospital admission."
This acute ischemic stroke cohort supports dysphagia as a clinically important swallowing phenotype.
Nervous System 3
Hemiparesis HP:0001269 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hemiparesis (HP:0001269). HP:0001269 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35204601 SUPPORT Human Clinical
"secondary signs, namely hemiparesis with limb falls (P), aphasia (A), drowsy or worse consciousness (C), and eyeball limitation"
This acute ischemic stroke cohort used hemiparesis with limb falls as a stroke severity sign.
Aphasia HP:0002381 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aphasia (HP:0002381). HP:0002381 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32173230 SUPPORT Human Clinical
"Aphasia is one of the most severe symptoms in stroke patients, affecting one-third of acute stroke patients."
This national inpatient analysis supports aphasia as a major acute ischemic stroke symptom.
Dysarthria HP:0001260 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysarthria (HP:0001260). HP:0001260 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33580596 SUPPORT Human Clinical
"46% (70/151) of participants had dysarthria, of which half recovered completely from their dysarthria within 1 week"
This prospective acute ischemic stroke study supports dysarthria as a common acute speech phenotype.
💊

Medical Actions

5
Intravenous t-PA thrombolysis
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: alteplase NCIT:C39607 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses alteplase (NCIT:C39607). NCIT:C39607 is a therapeutic agent from the NCI Thesaurus.
Intravenous tissue plasminogen activator can restore perfusion in eligible early-presenting patients, improving 3-month functional outcome while increasing symptomatic intracerebral hemorrhage risk.
Mechanism Target:
INHIBITS Cerebral arterial occlusion — Thrombolysis aims to dissolve the occluding thrombus and restore cerebral perfusion.
Show evidence (2 references)
PMID:7477192 SUPPORT Human Clinical
"treatment with intravenous t-PA within three hours of the onset of ischemic stroke improved clinical outcome at three months."
This randomized trial established early IV t-PA benefit in acute ischemic stroke.
PMID:36123777 SUPPORT Other
"Consistent with this weak recommendation, optimal patient management will likely often include co-treatment with intravenous alteplase, depending on local circumstances and patient presentation."
The clinical practice guideline supports co-treatment with intravenous alteplase (t-PA) alongside endovascular thrombectomy in acute large-vessel-occlusion ischemic stroke.
Endovascular thrombectomy
Action: surgical procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surgical procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
Endovascular clot retrieval improves disability outcomes in selected patients with acute ischemic stroke caused by proximal anterior-circulation large-vessel occlusion.
Mechanism Target:
INHIBITS Cerebral arterial occlusion — Mechanical clot retrieval removes the proximal occlusion and restores blood flow in large-vessel ischemic stroke.
Show evidence (1 reference)
PMID:26898852 SUPPORT Human Clinical
"Endovascular thrombectomy led to significantly reduced disability at 90 days compared with control"
This pooled randomized-trial analysis supports thrombectomy for selected large-vessel ischemic stroke.
Antiplatelet secondary prevention
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: Antiplatelet Agent NCIT:C1327 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Antiplatelet Agent (NCIT:C1327). NCIT:C1327 is a therapeutic agent from the NCI Thesaurus.
Antiplatelet therapy reduces recurrent ischemic events after non-cardioembolic ischemic stroke or high-risk transient ischemic attack, with duration and intensity balanced against bleeding risk.
Mechanism Target:
MODULATES Cerebral arterial occlusion — Platelet inhibition reduces recurrent thrombotic arterial occlusion risk after qualifying ischemic stroke presentations.
Show evidence (1 reference)
PMID:34024115 SUPPORT Human Clinical
"DAPT was more effective than SAPT for prevention of secondary ischemic stroke when initiated early after the onset of minor stroke/high-risk transient ischemic attack and treatment duration was <90 days."
This systematic review supports antiplatelet therapy as secondary prevention after selected ischemic stroke or high-risk TIA presentations.
Anticoagulation for atrial fibrillation-associated stroke prevention
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: Anticoagulant Agent NCIT:C263 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Anticoagulant Agent (NCIT:C263). NCIT:C263 is a therapeutic agent from the NCI Thesaurus.
Anticoagulation, particularly direct oral anticoagulant therapy when appropriate, is used after ischemic stroke associated with atrial fibrillation to reduce recurrent embolic events while managing hemorrhage risk.
Mechanism Target:
MODULATES Cerebral arterial occlusion — Anticoagulation reduces cardioembolic clot formation that can occlude cerebral arteries in atrial fibrillation-associated ischemic stroke.
Show evidence (1 reference)
PMID:31984228 SUPPORT Human Clinical
"In patients with atrial fibrillation and previous stroke or transient ischemic attack, oral anticoagulants reduce the risk of recurrence over antiplatelets or no antithrombotic treatment."
This guideline supports oral anticoagulation for secondary prevention in atrial fibrillation-associated ischemic stroke or TIA.
Primary prevention through vascular risk-factor control
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Stroke prevention focuses on cardiovascular and brain-health domains including diet, activity, weight, sleep, glycemic control, blood pressure, lipids, and tobacco avoidance.
Mechanism Target:
MODULATES Cerebral arterial occlusion — Risk-factor control reduces the vascular conditions that promote thrombotic and embolic stroke.
Show evidence (1 reference)
PMID:39429201 SUPPORT Human Clinical
"These recommendations align with the American Heart Association's Life's Essential 8 for optimizing cardiovascular and brain health"
This guideline supports multi-domain vascular risk-factor control for primary stroke prevention.
🌍

Environmental Factors

1
Vascular and metabolic risk-factor burden
Smoking, high-sodium diet, hypertension, high LDL cholesterol, kidney dysfunction, hyperglycemia, and high BMI are major modifiable contributors to ischemic stroke burden.
Show evidence (1 reference)
PMID:37197995 SUPPORT Computational
"2 behavioral factors, smoking and diet in high sodium, and 5 metabolic factors, including high systolic blood pressure"
This GBD risk-factor analysis supports behavioral and metabolic contributors to ischemic stroke burden.
📊

Prevalence

1
Global, all ages
GBD 2021 estimated about 69.9 million prevalent ischemic stroke cases globally, with an age-standardized prevalence rate of 819.5 per 100,000.
Show evidence (1 reference)
PMID:39157811 SUPPORT Computational
"Data for this study was obtained from the 2021 Global Burden of Diseases, Injuries, and Risk Factors Study (GBD). To quantify temporal patterns and assess trends in age-standardized rates of ischemic stroke prevalence (ASPR), incidence (ASIR), mortality (ASDR), and DALYs, estimated annual..."
The GBD 2021 analysis estimates approximately 69.9 million prevalent ischemic-stroke cases worldwide and an age-standardized prevalence rate of 819.5 per 100,000. It analyzes 20 age groups and 204 countries/territories.
📊

Related Datasets

6
Transfer RNAs, not microRNAs, are linked to ischemic stroke and major bleeding in patients with end-stage kidney disease geo:GSE272125
Background: Patients with end-stage kidney disease (ESKD) are at very high risk for thromboembolism and bleeding. This study aimed to identify small non-coding RNAs (sncRNAs), specifically microRNAs and transfer-RNA (tRNA)-derived fragments (tRFs), as potential novel biomarkers for predicting thromboembolism and bleeding in this high-risk population. Methods: In this sncRNA discovery research, we leveraged the VIVALDI cohort, consisting of 625 ESKD patients on hemodialysis, to conduct two nested case-control studies, each comprising 18 participants. The primary outcomes were ischemic stroke in the first study and major bleeding in the second.
human BULK RNA SEQ n=34
PMID:39260398
Identified by GEO DataSets index search for Ischemic Stroke (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
Ischemic stroke accelerates atherosclerosis progression via FTO-mediated epigenetic modification [RNA-Seq] geo:GSE308369
Residual risk of stroke recurrence persists despite the administration of the prevention measures. The recurrent risk is particularly high in patients with atherosclerosis. However, the underlying mechanisms leading to atherosclerosis progression and recurrent stroke have not been fully understood. We found that stroke accelerated atherosclerosis progression.
human BULK RNA SEQ n=8
Identified by GEO DataSets index search for Ischemic Stroke (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
Ischemic stroke accelerates atherosclerosis progression via FTO-mediated epigenetic modification geo:GSE307081
Residual risk of stroke recurrence persists despite the administration of the prevention measures. The recurrent risk is particularly high in patients with atherosclerosis. However, the underlying mechanisms leading to atherosclerosis progression and recurrent stroke have not been fully understood. We found that stroke accelerated atherosclerosis progression.FTO overexpression suppressed atheroprogression after stroke via inhibiting autophagy-dependent ferroptosis.
human BULK RNA SEQ n=7
Identified by GEO DataSets index search for Ischemic Stroke (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
A genome-wide meta analysis on stroke and ischemic stroke within four populations ega:EGAS00000000060
In this analysis a genome-wide meta-analysis was performed on all stroke and ischemic stroke.
human
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Ischemic Stroke"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
Ischemic stroke in a Swedish case-control study. ega:EGAS00001000936
Background. Genetic risk scores (GRS), summing up the total effect of several single nucleotide polymorphisms (SNPs) in genes associated with either coronary risk or cardiovascular risk factors, have been tested for association with ischemic stroke with conflicting results. Recently an association was found between a GRS, based on 29 SNPs discovered by genome-wide association studies (GWAS) and hypertension. The aim of our study was to investigate the possible association of the same GRS with ischemic stroke on top of other “traditional risk factors”, also testing its potential improvement in indices of discrimination and reclassification, in a Swedish case-control study.
human
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Ischemic Stroke"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
Ischemic Stroke Genetics Study (ISGS) dbgap:phs000102
The third leading cause of death in the United States, stroke is an acute neurological event leading to death of neural tissues. Although the majority of strokes are ischemic strokes, meaning there is oxygen deprivation to the brain, almost 20% of strokes are hemorrhagic, resulting from bleeding into the brain. Stroke is a complex disorder and likely multigenic in nature, resulting from a combination of genetic and environmental factors.
Located via OmicsDI, which aggregates across omics repositories; this record comes from dbgap. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Ischemic Stroke"). Retrieved 2026-08-02.
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Source YAML

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name: Ischemic Stroke
creation_date: "2026-05-06T03:10:37Z"
description: >-
  Ischemic stroke is an acute symptomatic central nervous system infarction
  caused by interruption of cerebral blood flow, usually from thrombosis,
  embolism, or proximal large-vessel occlusion, leading to ischemic tissue
  injury and focal neurological deficits.
category: Complex
disease_term:
  preferred_term: Ischemic stroke
  term:
    id: MONDO:1060198
    label: ischemic stroke
parents:
- Cerebrovascular disorder
- stroke disorder
synonyms:
- Cerebral infarction
- Ischaemic stroke
- Acute ischemic stroke
prevalence:
- population: Global, all ages
  notes: >-
    GBD 2021 estimated about 69.9 million prevalent ischemic stroke cases
    globally, with an age-standardized prevalence rate of 819.5 per 100,000.
  evidence:
  - reference: PMID:39157811
    reference_title: "Global, regional, and national burden of ischemic stroke, 1990-2021: an analysis of data from the global burden of disease study 2021."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Data for this study was obtained from the 2021 Global Burden of Diseases, Injuries, and Risk
      Factors Study (GBD). To quantify temporal patterns and assess trends in age-standardized rates
      of ischemic stroke prevalence (ASPR), incidence (ASIR), mortality (ASDR), and DALYs, estimated
      annual percentage changes (EAPCs) were computed over the study period. The analyses were
      disaggregated by gender, 20 age categories, 21 GBD regions, 204 nations/territories, and 5 SDI
      quintiles. ... In 2021, the global burden of ischemic stroke remained substantial, with a
      total of 69,944,884.8 cases with an ASPR of 819.5 cases per 100,000 individuals (95% UI:
      760.3-878.7).
    explanation: >-
      The GBD 2021 analysis estimates approximately 69.9 million prevalent ischemic-stroke cases
      worldwide and an age-standardized prevalence rate of 819.5 per 100,000. It analyzes 20 age
      groups and 204 countries/territories.
pathophysiology:
- name: Chronic Low-Grade Systemic Inflammation
  conforms_to: "inflammaging#Chronic Low-Grade Sterile Inflammation"
  biological_scale: ORGANISM
  description: >-
    Persistently raised circulating inflammatory markers, chiefly interleukin-6
    and C-reactive protein, mark a higher risk of a first ischemic stroke and of
    recurrence after one. Genetic evidence that lower IL-6 signaling lowers the
    risk of large-artery and small-vessel stroke, but not cardioembolic stroke,
    suggests the IL-6 axis is causal rather than only a marker. In aged mice,
    age-related changes in blood-cell production generate atypical neutrophils
    that worsen the inflammatory response to stroke, and related neutrophil
    subsets track with worse reperfusion in elderly patients. Most of the human
    evidence concerns inflammation in general rather than inflammation driven by
    ageing, so this node is a disease-specific use of the inflammaging module.
    Anti-inflammatory treatment has not yet been shown to prevent stroke: low-dose
    colchicine did not reduce early recurrence in a large trial.
  biological_processes:
  - preferred_term: Inflammatory response
    modifier: INCREASED
    term:
      id: GO:0006954
      label: inflammatory response
  - preferred_term: Cytokine production
    modifier: INCREASED
    term:
      id: GO:0001816
      label: cytokine production
  downstream:
  - target: Cerebral arterial occlusion
    description: >-
      Chronic IL-6-driven inflammation is associated with large-artery and
      small-vessel ischemic stroke, plausibly through atherosclerosis and
      small-vessel disease. The causal link rests on genetic evidence, and
      anti-inflammatory treatment has not yet been shown to prevent recurrence.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32397738
      reference_title: "Interleukin-6 Signaling Effects on Ischemic Stroke and Other Cardiovascular Outcomes: A Mendelian Randomization Study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Two-sample inverse-variance weighted MR analyses showed genetically downregulated IL-6 signaling to be associated with lower risks of ischemic stroke"
      explanation: >-
        Mendelian randomization using IL6R-region variants in MEGASTROKE
        (34,217 cases) links lower lifelong IL-6 signaling to lower ischemic
        stroke risk, supporting a causal role for the IL-6 axis.
    - reference: PMID:32397738
      reference_title: "Interleukin-6 Signaling Effects on Ischemic Stroke and Other Cardiovascular Outcomes: A Mendelian Randomization Study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We further found associations with lower risks of large artery and small vessel stroke, but not cardioembolic stroke"
      explanation: >-
        Restricts the genetic association to the large-artery and small-vessel
        subtypes, consistent with an atherosclerotic route rather than a
        cardioembolic one.
    - reference: PMID:38925803
      reference_title: "Colchicine in patients with acute ischaemic stroke or transient ischaemic attack (CHANCE-3): multicentre, double blind, randomised, placebo controlled trial."
      supports: REFUTE
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Stroke occurred within 90 days in 264 patients (6.3%) in the colchicine group and 270 patients (6.5%) in the placebo group"
      explanation: >-
        In 8,343 patients with minor-to-moderate non-cardioembolic stroke or TIA
        and high-sensitivity CRP of at least 2 mg/L, low-dose colchicine did not
        reduce new stroke within 90 days. The drug response bears on the
        mechanism only indirectly, and colchicine does not target IL-6 directly.
  - target: Neurovascular inflammation and barrier disruption
    description: >-
      In ageing, the bone-marrow response to stroke produces atypical,
      pro-oxidant and procoagulant neutrophils that plug the ischemic
      microcirculation and worsen injury.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37188941
      reference_title: "Age-induced alterations of granulopoiesis generate atypical neutrophils that aggravate stroke pathology."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "aged mice had increased neutrophil clogging of the ischemic brain microcirculation, leading to worse no-reflow and outcomes"
      explanation: >-
        Compared with young mice, aged mice show more neutrophil plugging of
        the ischemic microcirculation after experimental stroke.
    - reference: PMID:37188941
      reference_title: "Age-induced alterations of granulopoiesis generate atypical neutrophils that aggravate stroke pathology."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Hematopoietic stem cell rejuvenation reverted aging-associated neutropoiesis and improved stroke outcome"
      explanation: >-
        Reversing the age-related change in neutrophil production improved
        outcome, supporting a causal role for the aged immune state.
    - reference: PMID:37188941
      reference_title: "Age-induced alterations of granulopoiesis generate atypical neutrophils that aggravate stroke pathology."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In elderly patients with ischemic stroke, single-cell proteome profile of blood leukocytes identified CD62Llo neutrophil subsets associated with worse reperfusion and outcome"
      explanation: >-
        The neutrophil subsets identified in aged mice are associated with worse
        reperfusion and outcome in elderly stroke patients.
  evidence:
  - reference: PMID:20031199
    reference_title: "C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CRP concentration has continuous associations with the risk of coronary heart disease, ischaemic stroke, vascular mortality, and death from several cancers and lung disease that are each of broadly similar size."
    explanation: >-
      Pooled prospective data link higher CRP to ischemic stroke risk. The
      association is shared with non-vascular deaths and depends considerably
      on conventional risk factors, so on its own it does not show that
      inflammation causes stroke.
  - reference: PMID:37026458
    reference_title: "C-Reactive Protein, Interleukin-6, and Vascular Recurrence After Stroke: An Individual Participant Data Meta-Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Blood markers of inflammation were independently associated with vascular recurrence after stroke"
    explanation: >-
      In pooled individual-patient data, baseline IL-6 and high-sensitivity
      CRP predicted recurrent vascular events and recurrent stroke after
      adjustment for vascular risk factors and treatment.
- name: Cerebral arterial occlusion
  description: >-
    In situ thrombosis, artery-to-artery embolism, cardioembolism, or proximal
    large-vessel occlusion interrupts cerebral blood flow and initiates the
    ischemic cascade.
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: blood coagulation
    modifier: INCREASED
    term:
      id: GO:0007596
      label: blood coagulation
  - preferred_term: platelet aggregation
    modifier: INCREASED
    term:
      id: GO:0070527
      label: platelet aggregation
  evidence:
  - reference: PMID:20670828
    reference_title: "The science of stroke: mechanisms in search of treatments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This can develop either as a consequence of thrombosis in situ or
      following embolic occlusion of a cerebral blood vessel
    explanation: >-
      This review supports thrombosis and embolic vascular occlusion as
      proximal ischemic-stroke mechanisms.
  downstream:
  - target: Ischemic penumbra and energy failure
    description: >-
      Occlusion creates a severely hypoperfused core and a potentially
      salvageable penumbra with residual perfusion.
- name: Ischemic penumbra and energy failure
  description: >-
    Severe flow deficits rapidly deplete ATP in the ischemic core, while
    residual perfusion in the surrounding penumbra allows slower active cell
    death and creates a time-sensitive target for reperfusion therapy.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: response to hypoxia
    modifier: INCREASED
    term:
      id: GO:0001666
      label: response to hypoxia
  - preferred_term: cell death
    modifier: INCREASED
    term:
      id: GO:0008219
      label: cell death
  evidence:
  - reference: PMID:21628695
    reference_title: Cellular mechanisms of neurovascular damage and repair after stroke.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In ischemic strokes, severe blood flow deficits in the core rapidly
      decrease ATP levels and energy stores.
    explanation: >-
      This supports energy failure as an early consequence of ischemic core
      hypoperfusion.
  - reference: PMID:20670828
    reference_title: "The science of stroke: mechanisms in search of treatments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The ischemic penumbra then denotes an “at risk” region that is
      functionally impaired, but potentially salvageable.
    explanation: >-
      This supports the penumbra as an at-risk but potentially salvageable
      tissue compartment.
  downstream:
  - target: Post-Ischemic Mitochondrial Dysfunction
    description: >-
      Energy failure and the return of oxygen at reperfusion load neuronal
      mitochondria with calcium and reactive oxygen species.
    evidence:
    - reference: PMID:25383517
      reference_title: "Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "selective accumulation of the citric acid cycle intermediate succinate is a universal metabolic signature of ischaemia in a range of tissues and is responsible for mitochondrial ROS production during reperfusion"
      explanation: >-
        In vivo metabolomics links the ischemic phase, through succinate
        accumulation, to the mitochondrial ROS produced on reperfusion.
  - target: Excitotoxic and oxidative neuronal injury
    description: >-
      Energy failure disrupts ionic gradients and glutamate handling,
      triggering calcium overload, oxidative injury, and cell death.
  - target: Neurovascular inflammation and barrier disruption
    description: >-
      Ischemic injury activates vascular, glial, and immune responses in the
      neurovascular unit.
  - target: Post-Ischemic Autophagic-Lysosomal Dysfunction
    description: >-
      Energy failure activates macroautophagy within hours of occlusion, with
      autophagosome numbers and autophagy-marker levels in the ischemic
      penumbra rising over the following days.
    evidence:
    - reference: PMID:33974897
      reference_title: "Dynamic changes in Beclin-1, LC3B and p62 at various time points in mice with temporary middle cerebral artery occlusion and reperfusion (tMCAO)."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Beclin-1, LC3B, ROS, 4-HNE, 8-OHDG, GFAP, TNF-α and IL-6 levels increased (P < 0.01), while p62 and IL-10 levels decreased (P < 0.01) after tMCAO compared to those in the sham group."
      explanation: >-
        Directly ties post-occlusion energy/oxidative stress to the induction
        of autophagy markers (Beclin-1 up, p62 down) in this same tMCAO model.
  - target: Astrocyte and Cerebral Endothelial Cell Senescence
    description: >-
      Astrocytes and cerebral endothelial cells within the ischemic territory
      undergo acute cellular senescence following arterial occlusion.
    evidence:
    - reference: PMID:37324944
      reference_title: "Ability of Local Clearance of Senescent Cells in Ipsilateral Hemisphere to Mitigate Acute Ischemic Brain Injury in Mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "acute senescence is triggered by middle cerebral artery occlusion (MCAO) surgery, particularly in astrocytes and cerebral endothelial cells (CECs)"
      explanation: >-
        Establishes this specific edge: MCAO-induced ischemia triggers acute
        senescence in astrocytes and cerebral endothelial cells.
- name: Excitotoxic and oxidative neuronal injury
  description: >-
    Energy failure and impaired glutamate reuptake promote excitotoxic calcium
    influx, oxidative and nitrative stress, mitochondrial dysfunction, and
    apoptotic-like cell death in neurons and neighboring neurovascular cells.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: response to oxidative stress
    modifier: INCREASED
    term:
      id: GO:0006979
      label: response to oxidative stress
  - preferred_term: apoptotic process
    modifier: INCREASED
    term:
      id: GO:0006915
      label: apoptotic process
  evidence:
  - reference: PMID:21628695
    reference_title: Cellular mechanisms of neurovascular damage and repair after stroke.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      accumulated data over the past two decades have implicated excitotoxicity,
      oxidative stress and in some circumstances, apoptotic-like pathways
    explanation: >-
      This supports excitotoxic, oxidative, and apoptotic-like injury processes
      in acute stroke cell death.
  - reference: PMID:28417216
    reference_title: Pathogenic mechanisms following ischemic stroke.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain injury following stroke results from a complex series of
      pathophysiological events including excitotoxicity, oxidative and nitrative
      stress, inflammation, and apoptosis.
    explanation: >-
      This review independently supports the multi-mechanism cellular injury
      cascade after ischemic stroke.
- name: Post-Ischemic Mitochondrial Dysfunction
  conforms_to: "mitochondrial_dysfunction#Bioenergetic Decline and Oxidative Stress"
  biological_scale: CELLULAR
  description: >-
    After arterial occlusion and reperfusion, neuronal mitochondria generate
    reactive oxygen species and open the permeability transition pore, which
    couples the energy failure of the penumbra to neuronal death. In rodent
    focal ischemia, mitochondria in the ischemic focus lose respiratory
    capacity, and succinate that accumulates during ischemia is re-oxidized on
    reperfusion, driving the reactive oxygen species burst by reverse electron
    transport at complex I. This is an acute injury process, not the age-related decline the conformed module
    describes; the shared element is the bioenergetic-failure and oxidative-stress
    state. Mechanistic support is almost entirely from rodents, and the one
    randomized human test of targeting the pore (cyclosporine) missed its
    primary endpoint, so the causal weight of this node in human stroke is
    unsettled.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: Oxidative Phosphorylation
    modifier: DECREASED
    term:
      id: GO:0006119
      label: oxidative phosphorylation
  - preferred_term: Reactive Oxygen Species Metabolism
    modifier: INCREASED
    term:
      id: GO:0072593
      label: reactive oxygen species metabolic process
  locations:
  - preferred_term: Cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  - preferred_term: Striatum
    term:
      id: UBERON:0002435
      label: striatum
  evidence:
  - reference: PMID:8571432
    reference_title: Mitochondrial generation of reactive oxygen species after brain ischemia in the rat.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      reactive oxygen species generated by mitochondrial electron transport
      escape cellular antioxidant defenses and promote highly damaging hydroxyl
      radical activity after transient brain ischemia in the rat
    explanation: >-
      Rat global ischemia/reperfusion data showing mitochondrial ROS generation;
      not human evidence.
  - reference: PMID:16103352
    reference_title: Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      CypD-deficient mice displayed a dramatic reduction in brain infarct size
      after acute middle cerebral artery occlusion and reperfusion
    explanation: >-
      Mouse knockout evidence that the mitochondrial permeability transition
      pore contributes to infarct size after focal ischemia.
  - reference: PMID:21130757
    reference_title: The value of serial plasma nuclear and mitochondrial DNA levels in patients with acute ischemic stroke.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Levels of plasma nuclear and mitochondrial DNA in patients with acute
      ischemic stroke were significantly higher than those in the controls
    explanation: >-
      Human biomarker association consistent with release of mitochondrial
      material after cerebral infarction; it does not show that mitochondrial
      dysfunction causes the injury.
  - reference: PMID:25948727
    reference_title: Cyclosporine in acute ischemic stroke.
    supports: REFUTE
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: Cyclosporine was generally not effective in reducing infarct size.
    explanation: >-
      The randomized trial of the pore-targeting drug missed its primary
      infarct-volume endpoint, so targeting this node did not show benefit
      overall.
  - reference: PMID:25948727
    reference_title: Cyclosporine in acute ischemic stroke.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a smaller infarct size was observed in patients with proximal cerebral
      artery occlusion and efficient recanalization
    explanation: >-
      Subgroup-only result in the same trial; a therapeutic response cited as
      weak support for the targeted mechanism, not a mechanism demonstration.
  - reference: PMID:10461911
    reference_title: "Mitochondrial respiratory function and cell death in focal cerebral ischemia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "During ischemia, substantial reductions developed in both ADP-stimulated and uncoupled respiration in tissue from the focus of the affected area in the striatum and cortex."
    explanation: >-
      Mitochondria isolated from rat brain during middle cerebral artery
      occlusion lose respiratory capacity in the ischemic focus. Unlike the
      global-ischemia study above, this is a focal stroke model.
  - reference: PMID:10461911
    reference_title: "Mitochondrial respiratory function and cell death in focal cerebral ischemia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "impairment of the functional capacity of mitochondria from all three regions was seen in the first 3 h of reperfusion following 3 h of ischemia"
    explanation: >-
      After longer ischemia, the respiratory deficit persists into
      reperfusion in the focus and the perifocal tissue.
  - reference: PMID:25383517
    reference_title: "Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "After reperfusion, the accumulated succinate is rapidly re-oxidized by succinate dehydrogenase, driving extensive ROS generation by reverse electron transport at mitochondrial complex I."
    explanation: >-
      Identifies the source of the reperfusion ROS burst in vivo, supporting
      the oxidative stress arm of the node.
  downstream:
  - target: Excitotoxic and oxidative neuronal injury
    description: >-
      Mitochondrial ROS generation and permeability transition contribute to
      the oxidative and apoptotic-like neuronal death modeled in that node.
      Persistent mitochondrial failure is not required for infarction after
      shorter ischemia.
    evidence:
    - reference: PMID:25383517
      reference_title: "Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Decreasing ischaemic succinate accumulation by pharmacological inhibition is sufficient to ameliorate in vivo ischaemia-reperfusion injury in murine models of heart attack and stroke."
      explanation: >-
        Blocking the succinate-driven mitochondrial ROS source reduces injury
        in a mouse stroke model.
    - reference: PMID:10461911
      reference_title: "Mitochondrial respiratory function and cell death in focal cerebral ischemia."
      supports: REFUTE
      evidence_source: MODEL_ORGANISM
      snippet: "Thus, mitochondrial impairment during the first 3 h of reperfusion was apparently not essential for tissue infarction to develop."
      explanation: >-
        After 2 h of rat focal ischemia, respiration recovered on reperfusion
        yet the tissue still infarcted, so persistent mitochondrial failure is
        not required for infarction in that setting.
  - target: Microglial NLRP3 Inflammasome Activation in the Ischemic Penumbra
    description: >-
      Mitochondrial dysfunction after ischemia-reperfusion activates the NLRP3
      inflammasome in microglia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30153825
      reference_title: "Mitochondrial dysfunction induces NLRP3 inflammasome activation during cerebral ischemia/reperfusion injury."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "mitochondrial dysfunction played an important role in activating NLRP3 inflammasomes in microglia after OGD/R"
      explanation: >-
        In a co-culture system under oxygen-glucose deprivation and
        reoxygenation, microglial NLRP3 activation depended on mitochondrial
        dysfunction.
    - reference: PMID:30153825
      reference_title: "Mitochondrial dysfunction induces NLRP3 inflammasome activation during cerebral ischemia/reperfusion injury."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "mitochondrial protector could inhibit the activation of NLRP3 inflammasomes in cerebral I/R rats"
      explanation: >-
        Protecting mitochondria suppressed NLRP3 activation in rats after
        transient middle cerebral artery occlusion.
- name: Neurovascular inflammation and barrier disruption
  description: >-
    Ischemic injury engages endothelial cells, astrocytes, neurons, microglia,
    and peripheral immune cells; inflammatory signaling, protease activation,
    and matrix injury can disrupt the blood-brain barrier and amplify tissue
    damage.
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  - preferred_term: microglial cell
    term:
      id: CL:0000129
      label: microglial cell
  biological_processes:
  - preferred_term: inflammatory response
    modifier: INCREASED
    term:
      id: GO:0006954
      label: inflammatory response
  - preferred_term: cell-cell signaling
    modifier: ABNORMAL
    term:
      id: GO:0007267
      label: cell-cell signaling
  evidence:
  - reference: PMID:21738161
    reference_title: "The immunology of stroke: from mechanisms to translation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Inflammatory signaling is involved in all stages of the ischemic cascade,
      from the early damaging events triggered by arterial occlusion
    explanation: >-
      This supports inflammation as a contributor from early post-occlusion
      injury through later repair.
  - reference: PMID:21628695
    reference_title: Cellular mechanisms of neurovascular damage and repair after stroke.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The BBB homeostasis is remarkably dependent on endothelial-astrocyte-matrix
      interactions
    explanation: >-
      This supports endothelial-astrocyte-matrix interactions as central to
      blood-brain barrier integrity after stroke.
  downstream:
  - target: Microglial NLRP3 Inflammasome Activation in the Ischemic Penumbra
    description: >-
      Microglial and vascular inflammatory signaling within the neurovascular
      unit provides the priming and danger signals for NLRP3 inflammasome
      assembly in the peri-infarct penumbra.
- name: Post-Ischemic Autophagic-Lysosomal Dysfunction
  conforms_to: "disabled_macroautophagy#Failure of Cytoplasmic Quality Control"
  biological_scale: CELLULAR
  description: >-
    Macroautophagy is activated within the ischemic penumbra after arterial
    occlusion, with autophagosome numbers and autophagy-marker (Beclin-1,
    LC3B) levels rising early and then declining over the following days as
    autophagic flux weakens. In parallel, the lysosomal protease cathepsin D
    (CTSD) is progressively lost, and this lysosomal dysfunction, rather than
    autophagy induction itself, is the step this node conforms to: loss of
    CTSD is sufficient to cause lysosomal dysfunction and aggravates neuronal
    death under oxygen-glucose deprivation, while restoring CTSD activity
    protects neurons.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: Macroautophagy
    modifier: ABNORMAL
    term:
      id: GO:0016236
      label: macroautophagy
  genes:
  - preferred_term: CTSD
    term:
      id: hgnc:2529
      label: CTSD
  - preferred_term: BECN1
    term:
      id: hgnc:1034
      label: BECN1
  downstream:
  - target: Excitotoxic and oxidative neuronal injury
    description: >-
      Loss of cathepsin D-dependent lysosomal function aggravates, and its
      restoration protects against, oxygen-glucose deprivation-induced
      neuronal cell death, adding a lysosomal-clearance-failure route to
      excitotoxic and oxidative neuronal injury.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32450052
      reference_title: "Restoration of CTSD (cathepsin D) and lysosomal function in stroke is neuroprotective."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "CTSD knockdown further aggravates lysosomal dysfunction and cell death in OGD-exposed neurons."
      explanation: >-
        Direct loss-of-function evidence that impaired lysosomal
        (autophagic-clearance) function worsens ischemic neuronal death. This
        specific result is from oxygen-glucose-deprived primary cortical
        neuron culture (the paper's in vitro arm), distinct from the
        MCAO-mouse evidence cited at the node level.
    - reference: PMID:32450052
      reference_title: "Restoration of CTSD (cathepsin D) and lysosomal function in stroke is neuroprotective."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Restoration of CTSD protein levels via lentiviral transduction increases CTSD activity in neurons and, thus, renders resistance to OGD-mediated defects in lysosomal function and cell death."
      explanation: >-
        Complementary gain-of-function evidence that restoring the
        autophagic-lysosomal clearance step is directly protective, supporting
        a causal (not merely correlative) role for this node. Also from the
        oxygen-glucose-deprivation cell-culture arm of this study.
  evidence:
  - reference: PMID:33974897
    reference_title: "Dynamic changes in Beclin-1, LC3B and p62 at various time points in mice with temporary middle cerebral artery occlusion and reperfusion (tMCAO)."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "autophagy was activated within 7 d of tMCAO induction, and it strengthened at 1 d and then weakened steadily from 3 to 7 d"
    explanation: >-
      Primary rodent time-course evidence for early activation and subsequent
      decline of autophagic flux after ischemic stroke.
  - reference: PMID:32450052
    reference_title: "Restoration of CTSD (cathepsin D) and lysosomal function in stroke is neuroprotective."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our results show a time-dependent decrease in CTSD protein levels and activity in the mouse brain after stroke and neurons following OGD, with concurrent defects in lysosomal function."
    explanation: >-
      Primary MCAO and oxygen-glucose-deprivation evidence for progressive
      loss of lysosomal (autophagic-clearance) function after ischemia,
      distinct from the review (PMID:42419491) that first proposed this axis
      as a hypothesis.
- name: Astrocyte and Cerebral Endothelial Cell Senescence
  conforms_to: "cellular_senescence#Senescent Cell Accumulation"
  biological_scale: CELLULAR
  description: >-
    Middle cerebral artery occlusion triggers acute cellular senescence in
    astrocytes and cerebral endothelial cells within the ischemic
    hemisphere, marked by p16INK4a upregulation and a senescence-associated
    secretory phenotype (SASP) of MMP-3, IL-1alpha, and IL-6. Senolytic
    clearance of these senescent cells, whether systemic (ABT-263) or local
    (targeted lenti-INK-ATTAC), reduces SASP factor levels and improves
    neurological and locomotor outcomes after occlusion. A
    senescence-associated blood gene-expression signature is independently
    associated with worse 90-day functional outcome in acute ischemic stroke
    patients.
  cell_types:
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: Cellular senescence
    modifier: INCREASED
    term:
      id: GO:0090398
      label: cellular senescence
  downstream:
  - target: Neurovascular inflammation and barrier disruption
    description: >-
      The senescence-associated secretory phenotype (MMP-3, IL-1alpha, IL-6)
      released by senescent astrocytes and endothelial cells adds to
      neurovascular inflammatory signaling and blood-brain barrier injury
      within the ischemic hemisphere.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - senescence-associated secretory phenotype
    evidence:
    - reference: PMID:37324944
      reference_title: "Ability of Local Clearance of Senescent Cells in Ipsilateral Hemisphere to Mitigate Acute Ischemic Brain Injury in Mice."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The upregulation of p16INK4a and senescence-associated secretory phenotype (SASP) factors including matrix metalloproteinase-3, interleukin-1 alpha and -6 were observed in oxygen-glucose deprivation-treated astrocytes and CECs."
      explanation: >-
        Identifies the specific SASP factors (a matrix protease and two
        proinflammatory cytokines) released by senescent astrocytes/CECs that
        would be expected to feed forward into neurovascular inflammation and
        barrier disruption. This measurement is from oxygen-glucose-deprived
        cell culture, distinct from the MCAO-mouse in vivo evidence cited
        elsewhere on this node.
  evidence:
  - reference: PMID:37324944
    reference_title: "Ability of Local Clearance of Senescent Cells in Ipsilateral Hemisphere to Mitigate Acute Ischemic Brain Injury in Mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The treatment of ABT-263 reduced senescence of astrocytes and CECs in MCAO mice."
    explanation: >-
      Pharmacologic senolysis directly reducing astrocyte/endothelial
      senescence markers in the same MCAO model, supporting a causal
      (druggable) role rather than a bystander correlation.
  - reference: PMID:37324944
    reference_title: "Ability of Local Clearance of Senescent Cells in Ipsilateral Hemisphere to Mitigate Acute Ischemic Brain Injury in Mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "localized removal of senescent cells in the injured brain through the stereotaxical injection of lenti-INK-ATTAC viruses generates neuroprotective effects, protecting against acute ischemic brain injury in mice"
    explanation: >-
      Independent genetic (non-pharmacologic) senescent-cell clearance
      approach converging on the same neuroprotective outcome.
  - reference: PMID:42479998
    reference_title: "Senescence Gene Expression Profiles and 90-Day Outcome in Stroke Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with poor outcome (mRS > 2) had enriched senescence gene expression compared with those with good outcome (mRS ≤ 2)"
    explanation: >-
      Independent human clinical evidence linking a senescence-associated
      gene-expression signature to worse functional outcome after acute
      ischemic stroke, complementing the rodent mechanistic data above.
- name: Microglial NLRP3 Inflammasome Activation in the Ischemic Penumbra
  conforms_to: "nlrp3_inflammasome_activation#NLRP3 Inflammasome Assembly and Caspase-1 Activation"
  biological_scale: MOLECULAR
  description: >-
    The NLRP3 inflammasome is dramatically activated in the peri-infarct
    (penumbral) area after cerebral ischemia/reperfusion, and genetic
    suppression of its upstream regulator TRIM62 ameliorates NLRP3 activation,
    reduces neuroinflammation and apoptosis, and attenuates infarct outcomes.
  cell_types:
  - preferred_term: microglial cell
    term:
      id: CL:0000129
      label: microglial cell
  biological_processes:
  - preferred_term: NLRP3 inflammasome complex assembly
    modifier: INCREASED
    term:
      id: GO:0044546
      label: NLRP3 inflammasome complex assembly
  genes:
  - preferred_term: TRIM62
    term:
      id: hgnc:25574
      label: TRIM62
  downstream:
  - target: Excitotoxic and oxidative neuronal injury
    description: >-
      NLRP3-driven neuroinflammatory signaling in the peri-infarct area adds a
      further, innate-immune route to neuronal injury and apoptosis in the
      ischemic territory.
    evidence:
    - reference: PMID:32703402
      reference_title: "TRIM62 knockout protects against cerebral ischemic injury in mice by suppressing NLRP3-regulated neuroinflammation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The TRIM62 knockout (KO) mice exhibited alleviated apoptosis and neuroinflammation in the ischemic brain, eventually attenuating the stroke outcomes."
      explanation: >-
        Suppressing NLRP3-regulated neuroinflammation (via TRIM62 knockout)
        directly reduces neuronal apoptosis and improves stroke outcome,
        supporting a causal contribution to neuronal injury.
  evidence:
  - reference: PMID:32703402
    reference_title: "TRIM62 knockout protects against cerebral ischemic injury in mice by suppressing NLRP3-regulated neuroinflammation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "significantly elevated expression of TRIM62 was detected in peri-infarct area of wild type (WT) mice"
    explanation: >-
      Localizes the TRIM62-NLRP3 signaling axis specifically to the
      peri-infarct (penumbral) region.
  - reference: PMID:32703402
    reference_title: "TRIM62 knockout protects against cerebral ischemic injury in mice by suppressing NLRP3-regulated neuroinflammation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome was dramatically activated in cerebral ischemia/reperfusion (I/R) conditions, while being ameliorated in TRIM62-KO mice"
    explanation: >-
      Direct primary evidence of NLRP3 inflammasome activation in
      ischemia/reperfusion, distinct from the review (PMID:42419491) that
      first proposed this axis as a hypothesis.
phenotypes:
- category: Neurological
  name: Symptomatic central nervous system infarction
  diagnostic: true
  description: >-
    Overt neurological symptoms with tissue evidence of ischemic infarction
    define ischemic stroke.
  phenotype_term:
    preferred_term: Ischemic stroke
    term:
      id: HP:0002140
      label: Ischemic stroke
  evidence:
  - reference: PMID:23652265
    reference_title: "An updated definition of stroke for the 21st century: a statement for healthcare professionals from the American Heart Association/American Stroke Association."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ischemic stroke specifically refers to central nervous system infarction
      accompanied by overt symptoms
    explanation: >-
      This consensus definition directly supports the diagnostic phenotype.
- category: Neurological
  name: Hemiparesis
  description: >-
    Unilateral weakness occurs when infarction affects corticospinal motor
    pathways and is a common acute stroke sign.
  phenotype_term:
    preferred_term: Hemiparesis
    term:
      id: HP:0001269
      label: Hemiparesis
  evidence:
  - reference: PMID:35204601
    reference_title: "Rapid Identification of Patients Eligible for Direct Emergent Computed Tomography Angiography during Acute Ischemic Stroke: The DARE-PACE Assessment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      secondary signs, namely hemiparesis with limb falls (P), aphasia (A),
      drowsy or worse consciousness (C), and eyeball limitation
    explanation: >-
      This acute ischemic stroke cohort used hemiparesis with limb falls as a
      stroke severity sign.
- category: Neurological
  name: Aphasia
  description: >-
    Dominant-hemisphere ischemic stroke can impair language production or
    comprehension.
  phenotype_term:
    preferred_term: Aphasia
    term:
      id: HP:0002381
      label: Aphasia
  evidence:
  - reference: PMID:32173230
    reference_title: Prevalence and Impact of Aphasia among Patients Admitted with Acute Ischemic Stroke.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Aphasia is one of the most severe symptoms in stroke patients, affecting
      one-third of acute stroke patients.
    explanation: >-
      This national inpatient analysis supports aphasia as a major acute
      ischemic stroke symptom.
- category: Neurological
  name: Dysarthria
  description: >-
    Motor speech impairment can occur during the acute phase after ischemic
    stroke.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: PMID:33580596
    reference_title: "Dysarthria following acute ischemic stroke: Prospective evaluation of characteristics, type and severity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      46% (70/151) of participants had dysarthria, of which half recovered
      completely from their dysarthria within 1 week
    explanation: >-
      This prospective acute ischemic stroke study supports dysarthria as a
      common acute speech phenotype.
- category: Neurological
  name: Dysphagia
  description: >-
    Acute swallowing impairment can occur after ischemic stroke and increases
    the need for early screening because of aspiration and nutrition risks.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:39342159
    reference_title: Comorbidities associated with dysphagia after acute ischemic stroke.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of 2054 patients with ischemic stroke, 17.2% showed dysphagia at hospital
      admission.
    explanation: >-
      This acute ischemic stroke cohort supports dysphagia as a clinically
      important swallowing phenotype.
environmental:
- name: Vascular and metabolic risk-factor burden
  notes: >-
    Smoking, high-sodium diet, hypertension, high LDL cholesterol, kidney
    dysfunction, hyperglycemia, and high BMI are major modifiable contributors
    to ischemic stroke burden.
  evidence:
  - reference: PMID:37197995
    reference_title: "Global Burden, Risk Factor Analysis, and Prediction Study of Ischemic Stroke, 1990-2030."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      2 behavioral factors, smoking and diet in high sodium, and 5 metabolic
      factors, including high systolic blood pressure
    explanation: >-
      This GBD risk-factor analysis supports behavioral and metabolic
      contributors to ischemic stroke burden.
treatments:
- name: Intravenous t-PA thrombolysis
  description: >-
    Intravenous tissue plasminogen activator can restore perfusion in eligible
    early-presenting patients, improving 3-month functional outcome while
    increasing symptomatic intracerebral hemorrhage risk.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: alteplase
      term:
        id: NCIT:C39607
        label: Alteplase
  target_mechanisms:
  - target: Cerebral arterial occlusion
    treatment_effect: INHIBITS
    description: >-
      Thrombolysis aims to dissolve the occluding thrombus and restore cerebral
      perfusion.
  evidence:
  - reference: PMID:7477192
    reference_title: Tissue plasminogen activator for acute ischemic stroke.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      treatment with intravenous t-PA within three hours of the onset of ischemic
      stroke improved clinical outcome at three months.
    explanation: >-
      This randomized trial established early IV t-PA benefit in acute ischemic
      stroke.
  - reference: PMID:36123777
    reference_title: "Endovascular thrombectomy and intravenous alteplase in patients with acute ischemic stroke due to large vessel occlusion: A clinical practice guideline."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Consistent with this weak recommendation, optimal patient management will likely often include co-treatment with intravenous alteplase, depending on local circumstances and patient presentation."
    explanation: The clinical practice guideline supports co-treatment with intravenous alteplase (t-PA) alongside endovascular thrombectomy in acute large-vessel-occlusion ischemic stroke.
- name: Endovascular thrombectomy
  description: >-
    Endovascular clot retrieval improves disability outcomes in selected
    patients with acute ischemic stroke caused by proximal anterior-circulation
    large-vessel occlusion.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Cerebral arterial occlusion
    treatment_effect: INHIBITS
    description: >-
      Mechanical clot retrieval removes the proximal occlusion and restores
      blood flow in large-vessel ischemic stroke.
  evidence:
  - reference: PMID:26898852
    reference_title: "Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Endovascular thrombectomy led to significantly reduced disability at 90
      days compared with control
    explanation: >-
      This pooled randomized-trial analysis supports thrombectomy for selected
      large-vessel ischemic stroke.
- name: Antiplatelet secondary prevention
  description: >-
    Antiplatelet therapy reduces recurrent ischemic events after non-cardioembolic
    ischemic stroke or high-risk transient ischemic attack, with duration and
    intensity balanced against bleeding risk.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Antiplatelet Agent
      term:
        id: NCIT:C1327
        label: Antiplatelet Agent
  target_mechanisms:
  - target: Cerebral arterial occlusion
    treatment_effect: MODULATES
    description: >-
      Platelet inhibition reduces recurrent thrombotic arterial occlusion risk
      after qualifying ischemic stroke presentations.
  evidence:
  - reference: PMID:34024115
    reference_title: "Benefits and Risks of Dual Versus Single Antiplatelet Therapy for Secondary Stroke Prevention: A Systematic Review for the 2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DAPT was more effective than SAPT for prevention of secondary ischemic
      stroke when initiated early after the onset of minor stroke/high-risk
      transient ischemic attack and treatment duration was <90 days.
    explanation: >-
      This systematic review supports antiplatelet therapy as secondary
      prevention after selected ischemic stroke or high-risk TIA presentations.
- name: Anticoagulation for atrial fibrillation-associated stroke prevention
  description: >-
    Anticoagulation, particularly direct oral anticoagulant therapy when
    appropriate, is used after ischemic stroke associated with atrial
    fibrillation to reduce recurrent embolic events while managing hemorrhage
    risk.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Anticoagulant Agent
      term:
        id: NCIT:C263
        label: Anticoagulant Agent
  target_mechanisms:
  - target: Cerebral arterial occlusion
    treatment_effect: MODULATES
    description: >-
      Anticoagulation reduces cardioembolic clot formation that can occlude
      cerebral arteries in atrial fibrillation-associated ischemic stroke.
  evidence:
  - reference: PMID:31984228
    reference_title: "Antithrombotic treatment for secondary prevention of stroke and other thromboembolic events in patients with stroke or transient ischemic attack and non-valvular atrial fibrillation: A European Stroke Organisation guideline."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In patients with atrial fibrillation and previous stroke or transient
      ischemic attack, oral anticoagulants reduce the risk of recurrence over
      antiplatelets or no antithrombotic treatment.
    explanation: >-
      This guideline supports oral anticoagulation for secondary prevention in
      atrial fibrillation-associated ischemic stroke or TIA.
- name: Primary prevention through vascular risk-factor control
  description: >-
    Stroke prevention focuses on cardiovascular and brain-health domains
    including diet, activity, weight, sleep, glycemic control, blood pressure,
    lipids, and tobacco avoidance.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Cerebral arterial occlusion
    treatment_effect: MODULATES
    description: >-
      Risk-factor control reduces the vascular conditions that promote
      thrombotic and embolic stroke.
  evidence:
  - reference: PMID:39429201
    reference_title: "2024 Guideline for the Primary Prevention of Stroke: A Guideline From the American Heart Association/American Stroke Association."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These recommendations align with the American Heart Association's Life's
      Essential 8 for optimizing cardiovascular and brain health
    explanation: >-
      This guideline supports multi-domain vascular risk-factor control for
      primary stroke prevention.
datasets:
- accession: geo:GSE272125
  title: Transfer RNAs, not microRNAs, are linked to ischemic stroke and major bleeding in patients with end-stage kidney disease
  description: 'Background: Patients with end-stage kidney disease (ESKD) are at very high risk for thromboembolism and bleeding. This study aimed to identify small non-coding RNAs (sncRNAs), specifically microRNAs and transfer-RNA (tRNA)-derived fragments (tRFs), as potential novel biomarkers for predicting thromboembolism and bleeding in this high-risk population. Methods: In this sncRNA discovery research, we leveraged the VIVALDI cohort, consisting of 625 ESKD patients on hemodialysis, to conduct two nested case-control studies, each comprising 18 participants. The primary outcomes were ischemic stroke in the first study and major bleeding in the second.'
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 34
  publication: PMID:39260398
  notes: Identified by GEO DataSets index search for Ischemic Stroke (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE308369
  title: Ischemic stroke accelerates atherosclerosis progression via FTO-mediated epigenetic modification [RNA-Seq]
  description: Residual risk of stroke recurrence persists despite the administration of the prevention measures. The recurrent risk is particularly high in patients with atherosclerosis. However, the underlying mechanisms leading to atherosclerosis progression and recurrent stroke have not been fully understood. We found that stroke accelerated atherosclerosis progression.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 8
  notes: Identified by GEO DataSets index search for Ischemic Stroke (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE307081
  title: Ischemic stroke accelerates atherosclerosis progression via FTO-mediated epigenetic modification
  description: Residual risk of stroke recurrence persists despite the administration of the prevention measures. The recurrent risk is particularly high in patients with atherosclerosis. However, the underlying mechanisms leading to atherosclerosis progression and recurrent stroke have not been fully understood. We found that stroke accelerated atherosclerosis progression.FTO overexpression suppressed atheroprogression after stroke via inhibiting autophagy-dependent ferroptosis.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 7
  notes: Identified by GEO DataSets index search for Ischemic Stroke (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: ega:EGAS00000000060
  title: A genome-wide meta analysis on stroke and ischemic stroke within four populations
  description: In this analysis a genome-wide meta-analysis was performed on all stroke and ischemic stroke.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Ischemic Stroke"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001000936
  title: Ischemic stroke in a Swedish case-control study.
  description: Background. Genetic risk scores (GRS), summing up the total effect of several single nucleotide polymorphisms (SNPs) in genes associated with either coronary risk or cardiovascular risk factors, have been tested for association with ischemic stroke with conflicting results. Recently an association was found between a GRS, based on 29 SNPs discovered by genome-wide association studies (GWAS) and hypertension. The aim of our study was to investigate the possible association of the same GRS with ischemic stroke on top of other “traditional risk factors”, also testing its potential improvement in indices of discrimination and reclassification, in a Swedish case-control study.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Ischemic Stroke"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: dbgap:phs000102
  title: Ischemic Stroke Genetics Study (ISGS)
  description: The third leading cause of death in the United States, stroke is an acute neurological event leading to death of neural tissues. Although the majority of strokes are ischemic strokes, meaning there is oxygen deprivation to the brain, almost 20% of strokes are hemorrhagic, resulting from bleeding into the brain. Stroke is a complex disorder and likely multigenic in nature, resulting from a combination of genetic and environmental factors.
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from dbgap. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Ischemic Stroke"). Retrieved 2026-08-02.
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Evaluations and curation notes (1)

Add autophagy/senescence/inflammasome pathophysiology nodes · 2026-09-15T23:59:38Z · View source

Addressed issue #11902 (leftover from #6189/#5847, PMID:42419491 Ellappan et al. 2026 axis handoff). Added three new pathophysiology nodes evidenced with primary literature (not the review, which is background-only): (1) Post-Ischemic Autophagic-Lysosomal Dysfunction, conforms_to disabled_macroautophagy#Failure of Cytoplasmic Quality Control, cited to PMID:33974897 (mouse tMCAO time-course showing Beclin-1/LC3B induction then decline) and PMID:32450052 (mouse MCAO+OGD, cathepsin D/lysosomal-function loss aggravates and restoration rescues neuronal death); (2) Astrocyte and Cerebral Endothelial Cell Senescence, conforms_to cellular_senescence#Senescent Cell Accumulation, cited to PMID:37324944 (mouse MCAO, p16INK4a/SASP induction in astrocytes and cerebral endothelial cells, senolytic and localized senescent-cell clearance both neuroprotective) and PMID:42479998 (human clinical cohort, blood senescence gene-expression signature associated with worse 90-day mRS outcome); (3) Microglial NLRP3 Inflammasome Activation in the Ischemic Penumbra, conforms_to nlrp3_inflammasome_activation#NLRP3 Inflammasome Assembly and Caspase-1 Activation, cited to PMID:32703402 (mouse MCAO, NLRP3 dramatically activated in the peri-infarct/penumbral area, TRIM62 knockout suppresses it and improves outcome). All three nodes are wired into the existing pathograph via new downstream edges from Cerebral arterial occlusion / Ischemic penumbra and energy failure / Neurovascular inflammation and barrier disruption, and downstream to Excitotoxic and oxidative neuronal injury or back into Neurovascular inflammation and barrier disruption, most with their own edge-level evidence distinct from node-level evidence. Researched via manual PubMed E-utilities search (NCBI esearch/efetch), not a just research-disorder deep-research run, since this was a targeted literature search for three specific mechanisms rather than a full disease research pass. Validated with just validate-disorders (schema+terms+references, 33/33 snippets verified), just check-entity-refs, just check-causal-targets (0 new dangling targets), just check-duplicate-keys, just check-qualifier-terms, just check-enum-values, and just list-gene-term-mismatches (0 mismatches).

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Ischemic Stroke (Complex Disease) — Disease Characteristics Research Report
Edison Scientific Literature 25 citations 2026-05-05T23:25:09.211664

Ischemic Stroke (Complex Disease) — Disease Characteristics Research Report

Executive summary

Ischemic stroke (IS) is brain tissue infarction due to occlusion of cerebral blood flow (thrombosis/embolism), producing acute focal neurologic deficits and major global disability and mortality burden. Contemporary evidence highlights (i) persistently high absolute global burden despite improvements in age-standardized rates, (ii) hypertension and dyslipidemia (especially high systolic blood pressure and high LDL-cholesterol) as leading modifiable contributors to disability-adjusted life-years (DALYs), and (iii) large, real-world improvements in evidence-based acute care and secondary prevention processes in organized stroke systems (e.g., Get With The Guidelines–Stroke in the US). (zhu2025globalandregional pages 1-5, liu2025globalregionaland pages 1-2, bushnell20242024guidelinefor pages 2-3, li2024globalregionaland pages 1-2, xian2024twentyyearsof pages 3-4)

Domain Metric Value Population/setting Year(s) Source (include DOI URL) Notes
Burden Prevalent ischemic stroke cases 69,944,884.8 cases Global; GBD 2021 ischemic stroke estimates 2021 Li et al., eClinicalMedicine (2024), https://doi.org/10.1016/j.eclinm.2024.102758 (li2024globalregionaland pages 1-2) Absolute prevalent case count
Burden Age-standardized prevalence rate (ASPR) 819.5 per 100,000 Global; GBD 2021 2021 Li et al., eClinicalMedicine (2024), https://doi.org/10.1016/j.eclinm.2024.102758 (li2024globalregionaland pages 1-2) 95% UI 760.3–878.7
Burden Age-standardized incidence rate (ASIR) 92.4 per 100,000 Global; GBD 2021 2021 Li et al., eClinicalMedicine (2024), https://doi.org/10.1016/j.eclinm.2024.102758 (li2024globalregionaland pages 1-2) 95% UI 79.8–105.8
Burden Age-standardized death rate (ASDR) 44.2 per 100,000 Global; GBD 2021 2021 Li et al., eClinicalMedicine (2024), https://doi.org/10.1016/j.eclinm.2024.102758 (li2024globalregionaland pages 1-2) Mortality rate
Burden Age-standardized DALY rate 837.4 per 100,000 Global; GBD 2021 2021 Li et al., eClinicalMedicine (2024), https://doi.org/10.1016/j.eclinm.2024.102758 (li2024globalregionaland pages 1-2) 95% UI 763.7–905
Prevention Antihypertensive therapy intensity needed for BP control ~30% controlled with a single antihypertensive; most required 2–3 medications Randomized trial evidence summarized in AHA/ASA primary prevention guideline Evidence summarized through 2024 Bushnell et al., Stroke (2024), https://doi.org/10.1161/STR.0000000000000475 (bushnell20242024guidelinefor pages 2-3) Supports guideline emphasis on aggressive BP control as a primary stroke-prevention strategy
Care quality Anticoagulation for atrial fibrillation/flutter at discharge 55.7% → 97.2% U.S. GWTG-Stroke registry; eligible acute ischemic stroke patients 2003 → 2022 Xian et al., Stroke (2024), https://doi.org/10.1161/STROKEAHA.124.048174 (xian2024twentyyearsof pages 1-2, xian2024twentyyearsof pages 3-4) Major improvement in secondary prevention quality metric
Care quality Door-to-needle time ≤60 min 19.0% → 75.3% U.S. GWTG-Stroke registry; thrombolysis-treated acute ischemic stroke 2003 → 2022 Xian et al., Stroke (2024), https://doi.org/10.1161/STROKEAHA.124.048174 (xian2024twentyyearsof pages 1-2, xian2024twentyyearsof pages 3-4) Time-to-treatment benchmark improved ~4-fold
Care quality Arrive-by-3.5 h / treat-by-4.5 h 15.2% → 92.9% U.S. GWTG-Stroke registry; eligible early-arriving acute ischemic stroke 2003 → 2022 Xian et al., Stroke (2024), https://doi.org/10.1161/STROKEAHA.124.048174 (xian2024twentyyearsof pages 1-2, xian2024twentyyearsof pages 3-4) Reflects expansion and uptake of timely IV thrombolysis workflows
Care quality Smoking cessation counseling 44.7% → 97.8% U.S. GWTG-Stroke registry; eligible stroke/TIA patients who smoke 2003 → 2022 Xian et al., Stroke (2024), https://doi.org/10.1161/STROKEAHA.124.048174 (xian2024twentyyearsof pages 1-2, xian2024twentyyearsof pages 3-4) Prevention-focused discharge quality measure
Care quality Dysphagia screening 53.8% → 83.5% U.S. GWTG-Stroke registry; eligible acute ischemic stroke patients 2003 → 2022 Xian et al., Stroke (2024), https://doi.org/10.1161/STROKEAHA.124.048174 (xian2024twentyyearsof pages 1-2, xian2024twentyyearsof pages 3-4) Important complication-prevention and safety process measure
Care quality In-hospital mortality for ischemic stroke 5.8% → 4.2% U.S. GWTG-Stroke registry; hospitalized ischemic stroke 2003 → 2022 Xian et al., Stroke (2024), https://doi.org/10.1161/STROKEAHA.124.048174 (xian2024twentyyearsof pages 4-5) Risk-adjusted outcomes improved over time
Care quality Discharge to home after ischemic stroke 44.1% → 50.6% U.S. GWTG-Stroke registry; hospitalized ischemic stroke 2003 → 2022 Xian et al., Stroke (2024), https://doi.org/10.1161/STROKEAHA.124.048174 (xian2024twentyyearsof pages 5-8) Suggests improved short-term functional/disposition outcomes
Care quality Discharge to skilled nursing facility after ischemic stroke 20.9% → 13.6% U.S. GWTG-Stroke registry; hospitalized ischemic stroke 2003 → 2022 Xian et al., Stroke (2024), https://doi.org/10.1161/STROKEAHA.124.048174 (xian2024twentyyearsof pages 5-8) Decline consistent with better acute care and discharge outcomes

Table: This table compiles recent quantitative ischemic stroke burden estimates and selected prevention/care-quality metrics from major 2024 sources. It is useful for quickly comparing global burden with real-world U.S. improvements in evidence-based stroke care delivery.

1. Disease Information

1.1 Definition / overview (current understanding)

Ischemic stroke (also termed cerebral infarction) is caused primarily by thrombotic obstruction or embolic occlusion of cerebral vessels, leading to brain ischemia and tissue necrosis/infarction. (zhu2025globalandregional pages 1-5)

A widely used clinical/epidemiologic definition (as used in Global Burden of Disease [GBD] analyses aligned to WHO criteria) describes ischemic stroke as rapidly developing clinical signs of cerebral dysfunction due to occlusion of cerebral blood flow by thrombus/embolus, typically lasting >24 hours or leading to death; GBD also references the tissue-based concept of infarction-driven neurological dysfunction. (liu2025globalregionaland pages 1-2, liu2025epidemiologyandfuture pages 11-12)

1.2 Key identifiers (available from retrieved sources)

This run did not retrieve OMIM/Orphanet/MeSH/ICD records directly; therefore, formal code mappings are not provided here and should be added from ontology resources (e.g., MeSH D-codes; ICD-10 I63.).*

Identifiers and abbreviations commonly used in the epidemiology literature include: IS (ischemic stroke), DALYs, ASIR (age-standardized incidence rate), ASMR (age-standardized mortality rate), ASDR (age-standardized DALY rate). (zhu2025globalandregional pages 16-19)

1.3 Common synonyms / alternative names

  • Ischemic stroke (IS) (liu2025globalregionaland pages 1-2)
  • Cerebral infarction (zhu2025globalandregional pages 1-5)

1.4 Source of information

The evidence synthesized here is primarily from: - Aggregated, disease-level epidemiologic resources (GBD 2021–based analyses). (li2024globalregionaland pages 1-2, liu2025globalregionaland pages 1-2) - Aggregated clinical quality-improvement registry data (Get With The Guidelines–Stroke). (xian2024twentyyearsof pages 3-4) - Evidence-synthesizing clinical guideline documents (AHA/ASA 2024 primary prevention guideline). (bushnell20242024guidelinefor pages 2-3)

2. Etiology

2.1 Disease causal factors (mechanistic framing)

The proximal cause of ischemic stroke is cerebral blood flow interruption due to intravascular occlusion (thrombus/embolus), leading to ischemia and infarction/necrosis of downstream brain tissue. (zhu2025globalandregional pages 1-5, liu2025globalregionaland pages 1-2)

2.2 Risk factors (recent quantitative summaries)

GBD 2021–based analyses consistently identify metabolic/vascular risks as dominant contributors to ischemic stroke burden. - High systolic blood pressure and high LDL-cholesterol were the leading modifiable contributors to DALYs over 1990–2021 in a GBD 2021 systematic analysis. (liu2025globalregionaland pages 1-2) - A GBD 2019–based analysis (Neurology, 2023) identified seven major attributable risk factors: smoking and high-sodium diet (behavioral), plus high systolic blood pressure, high LDL cholesterol, kidney dysfunction, high fasting plasma glucose, and high BMI (metabolic). (fan2023globalburdenrisk pages 1-2)

Environmental and behavioral factors are also highlighted in GBD-based syntheses, including air pollution and smoking. (liu2025epidemiologyandfuture pages 11-12, zhu2025globalandregional pages 16-19)

2.3 Protective factors

AHA/ASA’s 2024 primary prevention guideline endorses Mediterranean dietary patterns (with nuts and olive oil highlighted in the evidence synthesis) for stroke risk reduction. (bushnell20242024guidelinefor pages 2-3)

2.4 Gene–environment interactions

Not established from the retrieved evidence in this run. GBD and guideline sources emphasize risk-factor synergy (e.g., metabolic + behavioral risks) but do not provide specific validated gene–environment interaction effect estimates in the extracted passages. (fan2023globalburdenrisk pages 1-2, bushnell20242024guidelinefor pages 2-3)

3. Phenotypes

The present run did not retrieve dedicated phenotype frequency studies or HPO-mapped clinical series; thus, phenotype frequencies and detailed HPO mapping are incomplete.

3.1 Core phenotype concept (high-level)

The defining clinical phenotype is an acute episode of neurological dysfunction due to focal infarction (classically focal deficits corresponding to vascular territory). (liu2025epidemiologyandfuture pages 11-12)

3.2 Quality-of-life impact (system-level proxy)

Large registry data show temporal improvements in discharge disposition after ischemic stroke (a proxy for early functional outcome): discharge to home increased from 44.1% (2003) to 50.6% (2022) and discharge to skilled nursing facilities decreased from 20.9% to 13.6% in GWTG-Stroke hospitals. (xian2024twentyyearsof pages 5-8)

3.3 Suggested HPO terms (placeholders; not evidence-mapped in this run)

  • Hemiparesis (HP:0001269)
  • Aphasia (HP:0002381)
  • Dysarthria (HP:0001260)
  • Dysphagia (HP:0002015)
  • Visual field defect (HP:0001123)

These should be verified and frequency-annotated from primary clinical cohorts.

4. Genetic / Molecular Information

This run did not retrieve OMIM/ClinVar/HGMD/ClinGen evidence for monogenic stroke syndromes; therefore, causal genes/variants and ACMG classifications are not provided.

4.1 Current understanding (complex genetics)

Ischemic stroke is described as a complex, multifactorial disorder with both environmental and heritable components; epidemiology sources emphasize that GBD-based analyses do not capture all genetic contributors. (fan2023globalburdenrisk pages 1-2, zhu2025globalandregional pages 16-19)

5. Environmental Information

5.1 Environmental factors

Environmental pollution is repeatedly identified as a major contributor alongside hypertension and LDL-cholesterol in GBD-based ischemic stroke risk-attribution summaries. (zhu2025globalandregional pages 1-5, zhu2025globalandregional pages 12-16)

5.2 Lifestyle factors

Lifestyle and metabolic risks highlighted include smoking, high BMI, and high-sodium diet. (fan2023globalburdenrisk pages 1-2)

6. Mechanism / Pathophysiology

6.1 Causal chain (macro-to-micro)

A canonical upstream-to-downstream chain supported by the retrieved evidence is: 1) Thrombotic/embolic occlusion of cerebral blood flow → 2) focal cerebral ischemia → 3) tissue infarction/necrosis → 4) acute neurological dysfunction and disability. (zhu2025globalandregional pages 1-5, liu2025globalregionaland pages 1-2)

6.2 Biological processes and cell types (ontology suggestions; limited direct evidence in this run)

Because this run emphasized epidemiology/guidelines, mechanistic molecular pathways (e.g., excitotoxicity, oxidative stress, BBB disruption) were not extracted from primary mechanistic papers here.

Suggested GO biological process terms (to be evidence-validated): - GO:0006954 inflammatory response - GO:0008219 cell death - GO:0006281 DNA repair (secondary injury context)

Suggested CL cell types (to be evidence-validated): - Microglial cell (CL:0000129) - Astrocyte (CL:0000127) - Brain microvascular endothelial cell (CL:2000064)

7. Diagnostics

This run did not retrieve primary imaging guideline text or biomarker performance statistics; diagnostic details should be supplemented from acute stroke guideline documents and radiology literature.

8. Treatment

8.1 Real-world implementation and systems of care

The US Get With The Guidelines–Stroke (GWTG-Stroke) registry demonstrates large real-world improvements in evidence-based acute ischemic stroke workflows and secondary prevention processes from 2003–2022, including: - Anticoagulation for atrial fibrillation/flutter: 55.7% → 97.2%. - Smoking cessation counseling: 44.7% → 97.8%. - Dysphagia screening: 53.8% → 83.5%. - Arrive-by-3.5h/treat-by-4.5h thrombolysis measure: 15.2% → 92.9%. - Door-to-needle ≤60 min: 19.0% → 75.3%. These changes occurred across 7,837,849 stroke/TIA admissions from 2,865 hospitals and are presented as sustained improvements across performance measures. (xian2024twentyyearsof pages 3-4, xian2024twentyyearsof pages 1-2)

A figure depicting these temporal trends in key acute ischemic stroke care performance measures is provided in the source paper. (xian2024twentyyearsof media e6f60d86)

8.2 MAXO terms (suggested; not formally mapped in this run)

  • Thrombolysis (MAXO:0001294)
  • Mechanical thrombectomy / endovascular thrombectomy (MAXO term to be confirmed)
  • Anticoagulant therapy (MAXO:0000436)
  • Antiplatelet therapy (MAXO:0000435)
  • Dysphagia screening/intervention (MAXO term to be confirmed)

9. Prevention

9.1 Primary prevention (AHA/ASA 2024 guideline highlights)

The AHA/ASA 2024 primary prevention guideline organizes prevention around the American Heart Association’s “Life’s Essential 8” domains: diet, physical activity, weight, sleep, blood sugar, blood pressure, lipids, and tobacco. (bushnell20242024guidelinefor pages 2-3)

Selected evidence-based prevention statements extracted from the guideline include: - Mediterranean diet is endorsed for stroke risk reduction (with nuts and olive oil emphasized in the evidence synthesis), while low-fat diets have shown little impact on stroke risk. (bushnell20242024guidelinefor pages 2-3) - Sedentary behavior: a new recommendation is to screen for sedentary behavior and counsel patients to avoid prolonged sedentary time. (bushnell20242024guidelinefor pages 2-3) - Blood pressure: randomized trial evidence summarized indicates single-drug BP control occurred in only ~30% of participants and most required 2–3 medications; accordingly, ≥2 antihypertensive medications are recommended when needed to achieve targets. (bushnell20242024guidelinefor pages 2-3)

9.2 Population-health rationale from burden data

Despite declining age-standardized mortality and DALY rates in many regions, absolute ischemic stroke case counts have increased substantially over 1990–2021 due to population growth and aging. (liu2025globalregionaland pages 1-2, zhu2025globalandregional pages 12-16)

10. Other Species / Natural Disease

Not established from retrieved evidence.

11. Model organisms

This run retrieved some model-system papers but did not extract detailed evidence passages on model recapitulation/limitations.

12. Outcomes / Prognosis

12.1 Registry-based short-term outcome trends (US)

In-hospital mortality for ischemic stroke in GWTG-Stroke hospitals declined from 5.8% to 4.2% across 2003–2022, alongside shifting discharge patterns (more direct home discharge, fewer SNF discharges). (xian2024twentyyearsof pages 4-5, xian2024twentyyearsof pages 5-8)

13–15. Remaining template elements

Several requested knowledge-base fields (MONDO ID, ICD/MeSH codes, detailed phenotype frequencies with HPO mapping, causal genes/variants with ClinVar/gnomAD allele frequencies, and comprehensive diagnostics/treatment trial effect sizes) were not retrievable from the specific documents accessed in this run. The report should be extended by targeted retrieval from ontology databases (MONDO/MeSH/ICD), clinical guidelines for acute management, and primary genetics/biomarker studies.

Direct quotes from abstracts (for key statements)

  • AHA/ASA 2024 prevention guideline aim: “Ischemic and hemorrhagic strokes lead to significant disability but, most important, are preventable.” (bushnell20242024guidelinefor pages 2-3)
  • GWTG-Stroke scale and performance improvement: the registry included “7,837,849 stroke cases… [and] sustained improvement in all performance metrics” with examples including “anticoagulation for atrial fibrillation (55.7% in 2003 to 97.2% in 2022)” and “door-to-needle time within 60 minutes (19.0%–75.3%).” (xian2024twentyyearsof pages 3-4)

Key URLs and publication dates (from retrieved sources)

  • Li et al. “Global, regional, and national burden of ischemic stroke, 1990–2021…” eClinicalMedicine; published Sep 2024. https://doi.org/10.1016/j.eclinm.2024.102758 (li2024globalregionaland pages 1-2)
  • Bushnell et al. “2024 Guideline for the Primary Prevention of Stroke…” Stroke; published Dec 2024. https://doi.org/10.1161/str.0000000000000475 (bushnell20242024guidelinefor pages 2-3)
  • Xian et al. “Twenty Years of Sustained Improvement…” Stroke; published Nov 2024. https://doi.org/10.1161/strokeaha.124.048174 (xian2024twentyyearsof pages 3-4)

References

  1. (zhu2025globalandregional pages 1-5): Weimin Zhu, Xiaxia He, Daochao Huang, Yiqing Jiang, Weijun Hong, Shaofa Ke, En Wang, Feng Wang, Xianwei Wang, Renfei Shan, Suzhi Liu, Yinghe Xu, and Yongpo Jiang. Global and regional burden of ischemic stroke disease from 1990 to 2021: an age-period-cohort analysis. Translational stroke research, Dec 2025. URL: https://doi.org/10.1007/s12975-024-01319-9, doi:10.1007/s12975-024-01319-9. This article has 32 citations and is from a peer-reviewed journal.

  2. (liu2025globalregionaland pages 1-2): Sibo Liu, Yanzhao Li, Xiaoyan Lan, Long Wang, Hang Li, Dean Gu, Mengxing Wang, and Jinjie Liu. Global, regional, and national trends in ischaemic stroke burden and risk factors among adults aged 20 + years (1990–2021): a systematic analysis of data from the global burden of disease study 2021 with projections into 2050. Frontiers in Public Health, Apr 2025. URL: https://doi.org/10.3389/fpubh.2025.1567275, doi:10.3389/fpubh.2025.1567275. This article has 23 citations.

  3. (bushnell20242024guidelinefor pages 2-3): Cheryl Bushnell, Walter N. Kernan, Anjail Z. Sharrief, Seemant Chaturvedi, John W. Cole, William K. Cornwell, Christine Cosby-Gaither, Sarah Doyle, Larry B. Goldstein, Olive Lennon, Deborah A. Levine, Mary Love, Eliza Miller, Mai Nguyen-Huynh, Jennifer Rasmussen-Winkler, Kathryn M. Rexrode, Nicole Rosendale, Satyam Sarma, Daichi Shimbo, Alexis N. Simpkins, Erica S. Spatz, Lisa R. Sun, Vin Tangpricha, Dawn Turnage, Gabriela Velazquez, and Paul K. Whelton. 2024 guideline for the primary prevention of stroke: a guideline from the american heart association/american stroke association. Stroke, Dec 2024. URL: https://doi.org/10.1161/str.0000000000000475, doi:10.1161/str.0000000000000475. This article has 332 citations and is from a highest quality peer-reviewed journal.

  4. (li2024globalregionaland pages 1-2): Xin-yu Li, Xiang-meng Kong, Cheng-hao Yang, Zhi-feng Cheng, Jia-jie Lv, Hong Guo, and Xiao-hong Liu. Global, regional, and national burden of ischemic stroke, 1990–2021: an analysis of data from the global burden of disease study 2021. eClinicalMedicine, 75:102758, Sep 2024. URL: https://doi.org/10.1016/j.eclinm.2024.102758, doi:10.1016/j.eclinm.2024.102758. This article has 309 citations and is from a peer-reviewed journal.

  5. (xian2024twentyyearsof pages 3-4): Ying Xian, Shen Li, Tian Jiang, Chandler D. Beon, Remy Poudel, Kathie Thomas, Mathew J. Reeves, Eric E. Smith, Jeffrey L. Saver, Kevin N. Sheth, Steven R. Messé, Lee H. Schwamm, and Gregg C. Fonarow. Twenty years of sustained improvement in quality of care and outcomes for patients hospitalized with stroke or transient ischemic attack: data from the get with the guidelines-stroke program. Stroke, 55:2599-2610, Nov 2024. URL: https://doi.org/10.1161/strokeaha.124.048174, doi:10.1161/strokeaha.124.048174. This article has 23 citations and is from a highest quality peer-reviewed journal.

  6. (xian2024twentyyearsof pages 1-2): Ying Xian, Shen Li, Tian Jiang, Chandler D. Beon, Remy Poudel, Kathie Thomas, Mathew J. Reeves, Eric E. Smith, Jeffrey L. Saver, Kevin N. Sheth, Steven R. Messé, Lee H. Schwamm, and Gregg C. Fonarow. Twenty years of sustained improvement in quality of care and outcomes for patients hospitalized with stroke or transient ischemic attack: data from the get with the guidelines-stroke program. Stroke, 55:2599-2610, Nov 2024. URL: https://doi.org/10.1161/strokeaha.124.048174, doi:10.1161/strokeaha.124.048174. This article has 23 citations and is from a highest quality peer-reviewed journal.

  7. (xian2024twentyyearsof pages 4-5): Ying Xian, Shen Li, Tian Jiang, Chandler D. Beon, Remy Poudel, Kathie Thomas, Mathew J. Reeves, Eric E. Smith, Jeffrey L. Saver, Kevin N. Sheth, Steven R. Messé, Lee H. Schwamm, and Gregg C. Fonarow. Twenty years of sustained improvement in quality of care and outcomes for patients hospitalized with stroke or transient ischemic attack: data from the get with the guidelines-stroke program. Stroke, 55:2599-2610, Nov 2024. URL: https://doi.org/10.1161/strokeaha.124.048174, doi:10.1161/strokeaha.124.048174. This article has 23 citations and is from a highest quality peer-reviewed journal.

  8. (xian2024twentyyearsof pages 5-8): Ying Xian, Shen Li, Tian Jiang, Chandler D. Beon, Remy Poudel, Kathie Thomas, Mathew J. Reeves, Eric E. Smith, Jeffrey L. Saver, Kevin N. Sheth, Steven R. Messé, Lee H. Schwamm, and Gregg C. Fonarow. Twenty years of sustained improvement in quality of care and outcomes for patients hospitalized with stroke or transient ischemic attack: data from the get with the guidelines-stroke program. Stroke, 55:2599-2610, Nov 2024. URL: https://doi.org/10.1161/strokeaha.124.048174, doi:10.1161/strokeaha.124.048174. This article has 23 citations and is from a highest quality peer-reviewed journal.

  9. (liu2025epidemiologyandfuture pages 11-12): Jiayu Liu, Aoxi Xu, Zhifeng Zhao, Bin Ren, Zhao Gao, Dandong Fang, Bo Hei, Junzhao Sun, Xiangyang Bao, Lin Ma, Xiaoque Zheng, Yuxin Wang, Hecheng Ren, Guan Wang, Li Zhu, and Jianning Zhang. Epidemiology and future trend predictions of ischemic stroke based on the global burden of disease study 1990–2021. Communications Medicine, Jul 2025. URL: https://doi.org/10.1038/s43856-025-00939-y, doi:10.1038/s43856-025-00939-y. This article has 35 citations and is from a peer-reviewed journal.

  10. (zhu2025globalandregional pages 16-19): Weimin Zhu, Xiaxia He, Daochao Huang, Yiqing Jiang, Weijun Hong, Shaofa Ke, En Wang, Feng Wang, Xianwei Wang, Renfei Shan, Suzhi Liu, Yinghe Xu, and Yongpo Jiang. Global and regional burden of ischemic stroke disease from 1990 to 2021: an age-period-cohort analysis. Translational stroke research, Dec 2025. URL: https://doi.org/10.1007/s12975-024-01319-9, doi:10.1007/s12975-024-01319-9. This article has 32 citations and is from a peer-reviewed journal.

  11. (fan2023globalburdenrisk pages 1-2): Jiahui Fan, Xiaoguang Li, Xueying Yu, Zhenqiu Liu, Yanfeng Jiang, Yibin Fang, Ming Zong, Chen Suo, Qiuhong Man, and Lize Xiong. Global burden, risk factor analysis, and prediction study of ischemic stroke, 1990–2030. Neurology, Jul 2023. URL: https://doi.org/10.1212/wnl.0000000000207387, doi:10.1212/wnl.0000000000207387. This article has 433 citations and is from a highest quality peer-reviewed journal.

  12. (zhu2025globalandregional pages 12-16): Weimin Zhu, Xiaxia He, Daochao Huang, Yiqing Jiang, Weijun Hong, Shaofa Ke, En Wang, Feng Wang, Xianwei Wang, Renfei Shan, Suzhi Liu, Yinghe Xu, and Yongpo Jiang. Global and regional burden of ischemic stroke disease from 1990 to 2021: an age-period-cohort analysis. Translational stroke research, Dec 2025. URL: https://doi.org/10.1007/s12975-024-01319-9, doi:10.1007/s12975-024-01319-9. This article has 32 citations and is from a peer-reviewed journal.

  13. (xian2024twentyyearsof media e6f60d86): Ying Xian, Shen Li, Tian Jiang, Chandler D. Beon, Remy Poudel, Kathie Thomas, Mathew J. Reeves, Eric E. Smith, Jeffrey L. Saver, Kevin N. Sheth, Steven R. Messé, Lee H. Schwamm, and Gregg C. Fonarow. Twenty years of sustained improvement in quality of care and outcomes for patients hospitalized with stroke or transient ischemic attack: data from the get with the guidelines-stroke program. Stroke, 55:2599-2610, Nov 2024. URL: https://doi.org/10.1161/strokeaha.124.048174, doi:10.1161/strokeaha.124.048174. This article has 23 citations and is from a highest quality peer-reviewed journal.