🏷

Classifications

Harrison's Part

⚙

Pathophysiology

7

Endothelial Dysfunction and Subendothelial LDL Retention

In the peripheral arterial intima, endothelial injury and dysfunction permit infiltration and retention of apoB-containing lipoproteins in the subendothelial space. Retained and modified lipoproteins initiate local inflammation and monocyte recruitment. This plaque-initiation node is distinct from the downstream vasodilation and ischemic-angiogenesis defect.

Endothelial Cell CL:0000115

Cholesterol Homeostasis GO:0042632 ↕ DYSREGULATED

Downstream

Monocyte Recruitment and Macrophage Foam Cell Formation

Show evidence (1 reference)

PMID:26844337 SUPPORT Other

"infiltration and retention of apoB containing lipoproteins in the artery wall is a critical initiating event that sparks an inflammatory response and promotes the development of atherosclerosis."

Establishes arterial-wall apoB retention as the initiating event; peripheral arterial intima is the disease-specific location represented here.

Monocyte Recruitment and Macrophage Foam Cell Formation

In the peripheral arterial intima, recruited monocytes become macrophages and internalize retained apoB-containing lipoproteins, forming lipid-laden foam cells. Their inflammatory feed-forward loop promotes further lipoprotein oxidation, endothelial activation, monocyte recruitment, and foam-cell formation.

Macrophage CL:0000235 Foam Cell CL:0000891

Foam Cell Differentiation GO:0090077 ↑ INCREASED Inflammatory Response GO:0006954 ↑ INCREASED

Downstream

Atherosclerosis

Show evidence (2 references)

PMID:26844337 SUPPORT Other

"Internalization of the apoB containing lipoproteins by macrophages promotes foam cell formation, which is the hallmark of the fatty streak phase of atherosclerosis."

Directly supports macrophage uptake of apoB lipoproteins and foam-cell formation in the fatty streak.

PMID:26844337 SUPPORT Other

"Macrophage inflammation results in enhanced oxidative stress and cytokine/chemokine secretion, causing more LDL/remnant oxidation, endothelial cell activation, monocyte recruitment, and foam cell formation."

Documents the macrophage inflammatory loop that amplifies foam-cell formation.

Atherosclerosis

In the inflamed peripheral arterial intima, vascular smooth muscle cells switch to a synthetic, migratory phenotype, proliferate, and organize extracellular matrix to build the fibrofatty plaque and its fibrous cap. This is the atomic smooth-muscle-cell and matrix assembly step.

Vascular Smooth Muscle Cell CL:0000359

Smooth Muscle Cell Proliferation GO:0048661 ↑ INCREASED Extracellular Matrix Organization GO:0030198 ↑ INCREASED

Downstream

Advanced Atheroma with Necrotic Core and Fibrous Cap Continued lipid accumulation, foam-cell death, and matrix remodeling intervene between initial fibrofatty plaque assembly and advanced atheroma.

Show evidence (1 reference)

PMID:37595697 SUPPORT Other

"vascular smooth muscle cell phenotypic switching through transdifferentiation and stem/progenitor cell activation resulting in the promotion of inflammation, calcification, and secretion of extracellular matrix, altering fibrous cap structure, and necrotic core growth."

Directly supports smooth-muscle-cell phenotypic switching and extracellular-matrix secretion in plaque assembly.

Endothelial Dysfunction

Impaired endothelium-dependent vasodilation reduces blood flow reserve. Decreased nitric oxide production and increased endothelin contribute.

Endothelial Cell CL:0000115

Vasodilation GO:0042311

Show evidence (2 references)

PMID:38961103 SUPPORT

"It was observed that serum IL-6, IL-8, ICAM and VCAM levels in type II diabetes mellitus (T2DM) with PAD patients were increased significantly (85.93, 597.08, 94.80 and 80.66) as compared to T2DM patients (59.52, 231.34, 56.88 and 50.19) and healthy individuals (4.81, 16.93, 5.55 and 5.16)."

Demonstrates marked elevation of endothelial activation markers (ICAM, VCAM) in PAD patients, indicating severe endothelial dysfunction.

PMID:38182796 SUPPORT

"We have previously shown that VEGF165b, an alternatively spliced anti-angiogenic VEGF-A isoform, inhibits the VEGFR-STAT3 pathway in ischemic endothelial cells (ECs) to decrease their angiogenic capacity."

Describes impaired angiogenic signaling in ischemic endothelial cells in PAD, contributing to endothelial dysfunction and inadequate collateral formation.

Advanced Atheroma with Necrotic Core and Fibrous Cap

Continued lipid accumulation, foam-cell death, and matrix remodeling produce a mature peripheral arterial atheroma with a necrotic lipid core beneath a fibrous cap. Local plaque changes can destabilize the cap and create a rupture-prone lesion.

Vascular Smooth Muscle Cell CL:0000359

Extracellular Matrix Organization GO:0030198 ↑ INCREASED

Artery UBERON:0001637

Downstream

Thrombosis

Show evidence (1 reference)

PMID:37595697 SUPPORT Other

"the local arterial microenvironment of a stable atheroma promotes destabilizing conditions that result in the transition to an unstable atheroma."

Human histopathology and vascular-imaging evidence supports transition of a mature stable atheroma to an unstable lesion; peripheral artery is the disease-specific location substituted here.

Thrombosis

In the atherosclerotic PAD branch, plaque rupture-related thrombosis is reported more often above the knee. PAD also includes occlusive thrombosis without significant plaque, so this node records a qualified association rather than a universal plaque-rupture consequence or an asserted acute limb-ischemia outcome.

Platelet CL:0000233

Thrombosis GO:0007596 ↑ INCREASED

Show evidence (3 references)

DOI:10.3389/fcvm.2023.1271100 SUPPORT Other

"atherosclerotic plaque rupture-related thrombosis was more common above the knee."

PAD-specific histopathology summarized by this review directly supports rupture-related thrombosis in above-knee disease and defines the qualified atherosclerotic branch represented by this node.

PMID:38401035 SUPPORT

"Continuous release of NETs in response to external stimuli leads to activation of surrounding platelets and monocytes/macrophages, resulting in damage to endothelial cells (EC) and vascular smooth muscle cells (VSMC)."

Supports platelet-activating and vascular-injury context in atherosclerosis, but does not directly establish plaque rupture-related thrombosis in PAD.

PMID:37452714 SUPPORT

"NETs not only capture pathogens in innate immunity but also respond to sterile inflammatory stimuli in atherosclerosis, such as lipoproteins and inflammatory cytokines."

Supports NET responses to sterile atherosclerotic stimuli, but does not directly establish thrombosis or a PAD-specific rupture event.

Inflammation

Chronic inflammation drives plaque progression and instability. Elevated CRP and inflammatory markers predict cardiovascular events.

Inflammatory Response GO:0006954

Show evidence (3 references)

PMID:38003290 SUPPORT

"Peripheral artery disease (PAD), coronary artery disease (CAD), and cerebrovascular disease (CeVD) are characterized by atherosclerosis and inflammation as their underlying mechanisms."

Establishes inflammation as a core mechanism underlying PAD pathophysiology.

PMID:37452714 SUPPORT

"Neutrophil extracellular traps (NETs) are network-like structures of chromatin filaments decorated by histones, granules, and cytoplasmic-derived proteins expelled by activated neutrophils under multiple pathogenic conditions."

Describes neutrophil-driven inflammatory mechanisms involving NET formation in atherosclerosis.

PMID:38401035 SUPPORT

"Continuous release of NETs in response to external stimuli leads to activation of surrounding platelets and monocytes/macrophages, resulting in damage to endothelial cells (EC) and vascular smooth muscle cells (VSMC)."

Demonstrates how neutrophil-mediated inflammation causes vascular cell damage in atherosclerotic disease.

⬡

Pathograph

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

●

Phenotypes

4

Integument 2

Non-Healing Wounds OCCASIONAL Poor wound healing HP:0001058

Critical limb ischemia

Show evidence (1 reference)

PMID:38961103 SUPPORT

"The most serious long-term effects of diabetes is peripheral artery disease (PAD) which increases the chance of developing diabetic foot ulcers, gangrene and even lower limb amputation."

Demonstrates that PAD leads to non-healing wounds including diabetic foot ulcers and gangrene, particularly in diabetes patients.

Skin Changes FREQUENT Abnormality of the skin HP:0000951

Hair loss, shiny skin, thickened nails

Constitutional 2

Intermittent Claudication VERY_FREQUENT Limb pain HP:0009763

Leg pain with walking, relieved by rest

Show evidence (1 reference)

PMID:38961103 SUPPORT

"The clinical manifestations of PAD which are typically not revealed until symptoms like intermittent claudication, rest pain and ischemic gangrene develop, are not present in majority of diabetes mellitus patients with PAD due to diabetic peripheral neuropathy."

Identifies intermittent claudication as a key clinical manifestation of PAD, though noting it may be masked in diabetic patients.

Rest Pain OCCASIONAL Chronic pain HP:0012532

Indicates critical limb ischemia

🧬

Genetic Associations

3

9p21.3 locus (Risk Factor)

PCSK9 (Risk Factor)

Gene: PCSK9 hgnc:20001

LPA (Risk Factor)

Gene: LPA hgnc:6667

💊

Medical Actions

7

Smoking Cessation

Action: tobacco cessation counseling Ontology label: Tobacco Cessation Counseling NCIT:C101244

Most important intervention, reduces progression.

Show evidence (1 reference)

PMID:25282696 SUPPORT

"During follow-up to 5 years, patients who quit smoking had significantly lower all-cause mortality (14% vs 31%; hazard ratio, 0.40; 95% confidence interval, 0.18-0.90) and improved amputation-free survival (81% vs 60%; hazard ratio, 0.43, 95% confidence interval, 0.22-0.86) compared with..."

Demonstrates that smoking cessation in PAD patients significantly reduces mortality and improves amputation-free survival.

Antiplatelet Therapy

Action: platelet aggregation inhibitor therapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: antiplatelet agent NCIT:C1327

Aspirin or clopidogrel to reduce cardiovascular events.

Statins

Action: Pharmacotherapy NCIT:C15986

Agent: statin CHEBI:87631

LDL lowering, plaque stabilization.

Show evidence (1 reference)

PMID:34389230 SUPPORT

"Higher dosing of statins confers a significant improvement in patient outcomes, especially ACM and amputations, although the quality of the evidence was variable."

Meta-analysis demonstrating statins significantly reduce mortality and amputations in PAD patients.

ACE Inhibitors

Action: Pharmacotherapy NCIT:C15986

Agent: ACE inhibitor NCIT:C247

Cardiovascular risk reduction.

Supervised Exercise Therapy

Action: aerobic exercise therapy Ontology label: Physical Therapy NCIT:C15302

First-line for claudication, improves walking distance.

Show evidence (2 references)

PMID:28874320 SUPPORT

"A meta-analysis of 25 randomized trials demonstrated a 180-meter increase in treadmill walking distance in response to supervised exercise interventions compared with a nonexercising control group."

Meta-analysis of 25 RCTs demonstrates supervised exercise significantly improves walking distance in PAD patients.

PMID:42248619 SUPPORT Other

"The update consistently emphasises supervised exercise therapy and best medical therapies as first line treatment."

The ESVS focused update emphasises supervised exercise therapy, alongside best medical therapy, as first-line treatment for intermittent claudication.

Cilostazol

Action: Pharmacotherapy NCIT:C15986

Agent: cilostazol CHEBI:31401

Phosphodiesterase inhibitor for claudication symptoms.

Show evidence (1 reference)

PMID:12480040 SUPPORT

"Cilostazol therapy increased maximal and pain-free walking distances by 50% and 67%, respectively."

Meta-analysis of 8 RCTs showing cilostazol significantly improves walking distances in claudication patients.

Revascularization

Action: invasive revascularization therapy Ontology label: Invasive Revascularization Therapy NCIT:C191567

Endovascular or surgical for severe disease.

Show evidence (1 reference)

PMID:42248619 SUPPORT Other

"Endovascular revascularisation is recommended only for persistent lifestyle limiting symptoms despite conservative therapy."

The ESVS focused update restricts endovascular revascularisation to patients with persistent lifestyle-limiting symptoms despite conservative therapy.

🌍

Environmental Factors

5

Smoking

Strongest modifiable risk factor

Show evidence (1 reference)

PMID:23915883 SUPPORT Human Clinical

"Smoking was an important risk factor in both HIC and LMIC, with meta-OR for current smoking of 2·72"

Meta-analysis across 34 community studies (112,027 participants). Smoking carries the largest effect of the 15 risk factors assessed -- meta-OR 2.72 in high-income countries -- which is what makes it the strongest; diabetes, hypertension and hypercholesterolaemia follow in that order.

Diabetes

Major risk factor

Show evidence (1 reference)

PMID:23915883 SUPPORT Human Clinical

"in LMIC, followed by diabetes (1·88"

Diabetes has the second-largest effect of the 15 risk factors meta-analysed. The quoted OR 1.88 is the high-income estimate; the low/middle-income estimate is 1.47, in the bracketed continuation the validator strips.

Hypertension

Contributes to atherosclerosis

Show evidence (1 reference)

PMID:24881994 SUPPORT Human Clinical

"raised systolic blood pressure had a greater effect on angina, myocardial infarction, and peripheral arterial disease"

CALIBER cohort of 1.25 million initially cardiovascular-disease-free patients; pulse pressure showed its strongest association of any of the twelve endpoints with peripheral arterial disease. PARTIAL because it evidences the association, not the atherogenic mechanism the note asserts -- for that, see the atherogenesis module.

Dyslipidemia

LDL elevation

Show evidence (1 reference)

PMID:33221847 SUPPORT Human Clinical

"LDL-cholesterol has a causal effect on risk of peripheral arterial disease"

Supports the LDL fraction specifically, which is what this annotation names, and states it causally rather than as an association -- the review synthesises Mendelian randomization and trial evidence.

Sedentary Lifestyle

Lack of exercise

Show evidence (1 reference)

PMID:42537768 SUPPORT Human Clinical

"Participants in the highest SB tertile had a 43% increased risk of symptomatic PAD"

Prospective cohort of 87,490 adults with device-measured rather than self-reported activity, removing the recall bias that weakens most sedentary-behaviour evidence; median follow-up 7.9 years.

🔬

Biochemical Markers

4

ABI (Ankle-Brachial Index) (Decreased)

Context: <0.9 diagnostic

LDL Cholesterol (Elevated)

Context: Major risk factor

HbA1c (Elevated)

Context: Diabetes is major risk factor

CRP (Elevated)

Context: Inflammation marker

📊

Related Datasets

5

Whole Blood Transcriptomics Differentiates Circulating Gene Expression Between Coronary Artery Disease and Peripheral Artery Disease geo:GSE310095

Coronary artery disease (CAD) and peripheral artery disease (PAD) are prevalent atherosclerotic disorders that exhibit distinct clinical and pathological presentations. We used whole-blood RNA sequencing to investigate circulating transcriptomic differences between PAD and CAD. Whole-blood RNA sequencing was performed in 71 subjects 40-65 years of age with symptomatic PAD (n=20) or CAD (n=51). Patients with concomitant PAD and CAD were excluded. Differential expression analysis was performed to compare circulating gene expression in patients with PAD and patients with CAD. We identified 106 genes differentially expressed between PAD and CAD (p adj. < 0.1).

human BULK RNA SEQ n=71

PMID:41661212

Identified by GEO DataSets index search for Peripheral Artery Disease (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

Multiomics identifies unique modulators of calf muscle pathophysiology in peripheral artery disease and chronic kidney disease geo:GSE287118

This project aimed to map transcriptome changes in the skeletal muscle of patients with and without PAD (peripheral artery disease) and CKD (chronic kidney disease)

human BULK RNA SEQ n=86

PMID:39963788

Identified by GEO DataSets index search for Peripheral Artery Disease (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

Multi-omics Analysis of Skeletal Muscle Identifies Dysregulation of Hypoxia-Induced Genes in Peripheral Artery Disease [RRBS] geo:GSE289575

Epigenetic modifications such as DNA methylation play a critical role in hypoxic cell programs. However, no previous studies have investigated the epigenetic regulation of gene expression in peripheral artery disease (PAD), a condition characterized by intermittent ischemia. In this study, we used reduced representation bisulphite sequencing (RRBS) to investigate how PAD affects the DNA methylome in skeletal muscle of PAD patients with intermittent claudication (IC) or critical limb ischemia (CLI) compared to non-PAD controls. We also used small and bulk RNA-sequencing (RNA-seq), which allowed for data integration.

human METHYLATION n=40

PMID:41025488

Identified by GEO DataSets index search for Peripheral Artery Disease (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

Maternal Hypoxemia and oxidative stress in the fetus, newborn, and adult. exercise training for peripheral artery disease metabolomics_workbench:ST000872

Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. 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 ("Peripheral Artery Disease"). Retrieved 2026-08-02.

Maternal Hypoxemia and oxidative stress in the fetus, newborn, and adult. exercise training for peripheral artery disease (part II) metabolomics_workbench:ST000873

Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. 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 ("Peripheral Artery Disease"). Retrieved 2026-08-02.

{ }

Source YAML

click to show

name: Peripheral Artery Disease
creation_date: '2025-12-18T17:01:35Z'
description: >-
  Peripheral artery disease (PAD) is atherosclerotic narrowing of the arteries
  supplying the limbs, most often the lower extremities. Endothelial dysfunction,
  plaque accumulation, inflammation, and thrombosis progressively reduce distal
  perfusion, producing a supply-demand mismatch that manifests as intermittent
  claudication and, in advanced disease, rest pain, ulceration, and critical limb
  ischemia. PAD also marks elevated systemic cardiovascular risk.
category: Complex
parents:
- Cardiovascular Disease
disease_term:
  preferred_term: peripheral arterial disease
  term:
    id: MONDO:0005386
    label: peripheral arterial disease
pathophysiology:
- name: Endothelial Dysfunction and Subendothelial LDL Retention
  conforms_to: "atherogenesis#Endothelial Dysfunction and Subendothelial LDL Retention"
  role: trigger
  description: >-
    In the peripheral arterial intima, endothelial injury and dysfunction permit
    infiltration and retention of apoB-containing lipoproteins in the
    subendothelial space. Retained and modified lipoproteins initiate local
    inflammation and monocyte recruitment. This plaque-initiation node is
    distinct from the downstream vasodilation and ischemic-angiogenesis defect.
  cell_types:
  - preferred_term: Endothelial Cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: Cholesterol Homeostasis
    term:
      id: GO:0042632
      label: cholesterol homeostasis
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:26844337
    reference_title: The Role of Lipids and Lipoproteins in Atherosclerosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      infiltration and retention of apoB containing lipoproteins in the artery
      wall is a critical initiating event that sparks an inflammatory response
      and promotes the development of atherosclerosis.
    explanation: >-
      Establishes arterial-wall apoB retention as the initiating event;
      peripheral arterial intima is the disease-specific location represented
      here.
  downstream:
  - target: Monocyte Recruitment and Macrophage Foam Cell Formation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26844337
      reference_title: The Role of Lipids and Lipoproteins in Atherosclerosis.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Arterial injury causes endothelial dysfunction promoting modification of
        apoB containing lipoproteins and infiltration of monocytes into the
        subendothelial space.
      explanation: >-
        Directly links endothelial injury and modified apoB lipoproteins to
        monocyte entry into the subendothelial space.
- name: Monocyte Recruitment and Macrophage Foam Cell Formation
  conforms_to: "atherogenesis#Monocyte Recruitment and Macrophage Foam Cell Formation"
  role: amplifier
  description: >-
    In the peripheral arterial intima, recruited monocytes become macrophages and
    internalize retained apoB-containing lipoproteins, forming lipid-laden foam
    cells. Their inflammatory feed-forward loop promotes further lipoprotein
    oxidation, endothelial activation, monocyte recruitment, and foam-cell
    formation.
  cell_types:
  - preferred_term: Macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: Foam Cell
    term:
      id: CL:0000891
      label: foam cell
  biological_processes:
  - preferred_term: Foam Cell Differentiation
    term:
      id: GO:0090077
      label: foam cell differentiation
    modifier: INCREASED
  - preferred_term: Inflammatory Response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  evidence:
  - reference: PMID:26844337
    reference_title: The Role of Lipids and Lipoproteins in Atherosclerosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Internalization of the apoB containing lipoproteins by macrophages promotes
      foam cell formation, which is the hallmark of the fatty streak phase of
      atherosclerosis.
    explanation: >-
      Directly supports macrophage uptake of apoB lipoproteins and foam-cell
      formation in the fatty streak.
  - reference: PMID:26844337
    reference_title: The Role of Lipids and Lipoproteins in Atherosclerosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Macrophage inflammation results in enhanced oxidative stress and
      cytokine/chemokine secretion, causing more LDL/remnant oxidation,
      endothelial cell activation, monocyte recruitment, and foam cell formation.
    explanation: >-
      Documents the macrophage inflammatory loop that amplifies foam-cell
      formation.
  downstream:
  - target: Atherosclerosis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26844337
      reference_title: The Role of Lipids and Lipoproteins in Atherosclerosis.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Macrophage inflammatory chemoattractants stimulate infiltration and
        proliferation of smooth muscle cells. Smooth muscle cells produce the
        extracellular matrix providing a stable fibrous barrier between plaque
        prothrombotic factors and platelets.
      explanation: >-
        Connects macrophage inflammation to smooth-muscle-cell proliferation and
        extracellular-matrix production, the next core stage.
- name: Atherosclerosis
  conforms_to: "atherogenesis#Smooth Muscle Cell Switching and Fibrofatty Plaque Formation"
  role: central_effector
  description: >-
    In the inflamed peripheral arterial intima, vascular smooth muscle cells
    switch to a synthetic, migratory phenotype, proliferate, and organize
    extracellular matrix to build the fibrofatty plaque and its fibrous cap.
    This is the atomic smooth-muscle-cell and matrix assembly step.
  cell_types:
  - preferred_term: Vascular Smooth Muscle Cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  biological_processes:
  - preferred_term: Smooth Muscle Cell Proliferation
    term:
      id: GO:0048661
      label: positive regulation of smooth muscle cell proliferation
    modifier: INCREASED
  - preferred_term: Extracellular Matrix Organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  evidence:
  - reference: PMID:37595697
    reference_title: The microenvironment of the atheroma expresses phenotypes of plaque instability.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      vascular smooth muscle cell phenotypic switching through
      transdifferentiation and stem/progenitor cell activation resulting in the
      promotion of inflammation, calcification, and secretion of extracellular
      matrix, altering fibrous cap structure, and necrotic core growth.
    explanation: >-
      Directly supports smooth-muscle-cell phenotypic switching and
      extracellular-matrix secretion in plaque assembly.
  downstream:
  - target: Advanced Atheroma with Necrotic Core and Fibrous Cap
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - continued lipid accumulation
    - foam-cell apoptosis/death with defective efferocytosis and necrotic-core growth
    - vascular smooth muscle cell and extracellular-matrix remodeling
    description: >-
      Continued lipid accumulation, foam-cell death, and matrix remodeling
      intervene between initial fibrofatty plaque assembly and advanced atheroma.
    evidence:
    - reference: PMID:26844337
      reference_title: The Role of Lipids and Lipoproteins in Atherosclerosis.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Unresolved inflammation results in formation of vulnerable plaques
        characterized by enhanced macrophage apoptosis and defective efferocytosis
        of apoptotic cells resulting in necrotic cell death leading to increased
        smooth muscle cell death, decreased extracellular matrix production, and
        collagen degradation by macrophage proteases.
      explanation: >-
        Identifies macrophage/foam-cell death and extracellular-matrix remodeling
        as known intermediates in progression toward vulnerable advanced plaque.
- name: Endothelial Dysfunction
  description: >
    Impaired endothelium-dependent vasodilation reduces blood flow
    reserve. Decreased nitric oxide production and increased
    endothelin contribute.
  cell_types:
  - preferred_term: Endothelial Cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: Vasodilation
    term:
      id: GO:0042311
      label: vasodilation
  evidence:
  - reference: PMID:38961103
    reference_title: "An evaluation of inflammatory and endothelial dysfunction markers as determinants of peripheral arterial disease in those with diabetes mellitus."
    supports: SUPPORT
    snippet: "It was observed that serum IL-6, IL-8, ICAM and VCAM levels in type II diabetes mellitus (T2DM) with PAD patients were increased significantly (85.93, 597.08, 94.80 and 80.66) as compared to T2DM patients (59.52, 231.34, 56.88 and 50.19) and healthy individuals (4.81, 16.93, 5.55 and 5.16)."
    explanation: Demonstrates marked elevation of endothelial activation markers (ICAM, VCAM) in PAD patients, indicating severe endothelial dysfunction.
  - reference: PMID:38182796
    reference_title: "Inhibiting anti-angiogenic VEGF165b activates a miR-17-20a-Calcipressin-3 pathway that revascularizes ischemic muscle in peripheral artery disease."
    supports: SUPPORT
    snippet: "We have previously shown that VEGF165b, an alternatively spliced anti-angiogenic VEGF-A isoform, inhibits the VEGFR-STAT3 pathway in ischemic endothelial cells (ECs) to decrease their angiogenic capacity."
    explanation: Describes impaired angiogenic signaling in ischemic endothelial cells in PAD, contributing to endothelial dysfunction and inadequate collateral formation.
- name: Advanced Atheroma with Necrotic Core and Fibrous Cap
  conforms_to: "atherogenesis#Advanced Atheroma with Necrotic Core and Fibrous Cap"
  role: effector
  description: >-
    Continued lipid accumulation, foam-cell death, and matrix remodeling produce
    a mature peripheral arterial atheroma with a necrotic lipid core beneath a
    fibrous cap. Local plaque changes can destabilize the cap and create a
    rupture-prone lesion.
  cell_types:
  - preferred_term: Vascular Smooth Muscle Cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  locations:
  - preferred_term: Artery
    term:
      id: UBERON:0001637
      label: artery
  biological_processes:
  - preferred_term: Extracellular Matrix Organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  evidence:
  - reference: PMID:37595697
    reference_title: The microenvironment of the atheroma expresses phenotypes of plaque instability.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the local arterial microenvironment of a stable atheroma promotes
      destabilizing conditions that result in the transition to an unstable
      atheroma.
    explanation: >-
      Human histopathology and vascular-imaging evidence supports transition of
      a mature stable atheroma to an unstable lesion; peripheral artery is the
      disease-specific location substituted here.
  downstream:
  - target: Thrombosis
    causal_link_type: DIRECT
    evidence:
    - reference: DOI:10.3389/fcvm.2023.1271100
      reference_title: Lower limb arterial calcification and its clinical relevance with peripheral arterial disease
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        atherosclerotic plaque rupture-related thrombosis was more common above
        the knee.
      explanation: >-
        PAD-specific histopathology summarized by this review directly supports
        plaque rupture leading to thrombosis in the above-knee atherosclerotic
        branch; it does not generalize to every PAD occlusion.
- name: Thrombosis
  description: >-
    In the atherosclerotic PAD branch, plaque rupture-related thrombosis is
    reported more often above the knee. PAD also includes occlusive thrombosis
    without significant plaque, so this node records a qualified association
    rather than a universal plaque-rupture consequence or an asserted acute
    limb-ischemia outcome.
  cell_types:
  - preferred_term: Platelet
    term:
      id: CL:0000233
      label: platelet
  biological_processes:
  - preferred_term: Thrombosis
    term:
      id: GO:0007596
      label: blood coagulation
    modifier: INCREASED
  evidence:
  - reference: DOI:10.3389/fcvm.2023.1271100
    reference_title: Lower limb arterial calcification and its clinical relevance with peripheral arterial disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      atherosclerotic plaque rupture-related thrombosis was more common above the
      knee.
    explanation: >-
      PAD-specific histopathology summarized by this review directly supports
      rupture-related thrombosis in above-knee disease and defines the qualified
      atherosclerotic branch represented by this node.
  - reference: PMID:38401035
    reference_title: "Neutrophil extracellular traps: a catalyst for atherosclerosis."
    supports: SUPPORT
    snippet: "Continuous release of NETs in response to external stimuli leads to activation of surrounding platelets and monocytes/macrophages, resulting in damage to endothelial cells (EC) and vascular smooth muscle cells (VSMC)."
    explanation: Supports platelet-activating and vascular-injury context in atherosclerosis, but does not directly establish plaque rupture-related thrombosis in PAD.
  - reference: PMID:37452714
    reference_title: "Neutrophil extracellular traps contributing to atherosclerosis: From pathophysiology to clinical implications."
    supports: SUPPORT
    snippet: "NETs not only capture pathogens in innate immunity but also respond to sterile inflammatory stimuli in atherosclerosis, such as lipoproteins and inflammatory cytokines."
    explanation: Supports NET responses to sterile atherosclerotic stimuli, but does not directly establish thrombosis or a PAD-specific rupture event.
- name: Inflammation
  description: >
    Chronic inflammation drives plaque progression and instability.
    Elevated CRP and inflammatory markers predict cardiovascular events.
  biological_processes:
  - preferred_term: Inflammatory Response
    term:
      id: GO:0006954
      label: inflammatory response
  evidence:
  - reference: PMID:38003290
    reference_title: "Current Medical Therapy and Revascularization in Peripheral Artery Disease of the Lower Limbs: Impacts on Subclinical Chronic Inflammation."
    supports: SUPPORT
    snippet: "Peripheral artery disease (PAD), coronary artery disease (CAD), and cerebrovascular disease (CeVD) are characterized by atherosclerosis and inflammation as their underlying mechanisms."
    explanation: Establishes inflammation as a core mechanism underlying PAD pathophysiology.
  - reference: PMID:37452714
    reference_title: "Neutrophil extracellular traps contributing to atherosclerosis: From pathophysiology to clinical implications."
    supports: SUPPORT
    snippet: "Neutrophil extracellular traps (NETs) are network-like structures of chromatin filaments decorated by histones, granules, and cytoplasmic-derived proteins expelled by activated neutrophils under multiple pathogenic conditions."
    explanation: Describes neutrophil-driven inflammatory mechanisms involving NET formation in atherosclerosis.
  - reference: PMID:38401035
    reference_title: "Neutrophil extracellular traps: a catalyst for atherosclerosis."
    supports: SUPPORT
    snippet: "Continuous release of NETs in response to external stimuli leads to activation of surrounding platelets and monocytes/macrophages, resulting in damage to endothelial cells (EC) and vascular smooth muscle cells (VSMC)."
    explanation: Demonstrates how neutrophil-mediated inflammation causes vascular cell damage in atherosclerotic disease.
phenotypes:
- name: Intermittent Claudication
  category: Musculoskeletal
  frequency: VERY_FREQUENT
  diagnostic: true
  notes: Leg pain with walking, relieved by rest
  phenotype_term:
    preferred_term: Limb Pain
    term:
      id: HP:0009763
      label: Limb pain
  evidence:
  - reference: PMID:38961103
    reference_title: "An evaluation of inflammatory and endothelial dysfunction markers as determinants of peripheral arterial disease in those with diabetes mellitus."
    supports: SUPPORT
    snippet: "The clinical manifestations of PAD which are typically not revealed until symptoms like intermittent claudication, rest pain and ischemic gangrene develop, are not present in majority of diabetes mellitus patients with PAD due to diabetic peripheral neuropathy."
    explanation: Identifies intermittent claudication as a key clinical manifestation of PAD, though noting it may be masked in diabetic patients.
- name: Rest Pain
  category: Musculoskeletal
  frequency: OCCASIONAL
  notes: Indicates critical limb ischemia
  phenotype_term:
    preferred_term: Limb Pain at Rest
    term:
      id: HP:0012532
      label: Chronic pain
- name: Non-Healing Wounds
  category: Dermatological
  frequency: OCCASIONAL
  notes: Critical limb ischemia
  phenotype_term:
    preferred_term: Impaired Wound Healing
    term:
      id: HP:0001058
      label: Poor wound healing
  evidence:
  - reference: PMID:38961103
    reference_title: "An evaluation of inflammatory and endothelial dysfunction markers as determinants of peripheral arterial disease in those with diabetes mellitus."
    supports: SUPPORT
    snippet: "The most serious long-term effects of diabetes is peripheral artery disease (PAD) which increases the chance of developing diabetic foot ulcers, gangrene and even lower limb amputation."
    explanation: Demonstrates that PAD leads to non-healing wounds including diabetic foot ulcers and gangrene, particularly in diabetes patients.
- name: Skin Changes
  category: Dermatological
  frequency: FREQUENT
  notes: Hair loss, shiny skin, thickened nails
  phenotype_term:
    preferred_term: Skin Changes
    term:
      id: HP:0000951
      label: Abnormality of the skin
biochemical:
- name: ABI (Ankle-Brachial Index)
  presence: Decreased
  context: <0.9 diagnostic
- name: LDL Cholesterol
  presence: Elevated
  context: Major risk factor
- name: HbA1c
  presence: Elevated
  context: Diabetes is major risk factor
- name: CRP
  presence: Elevated
  context: Inflammation marker
genetic:
- name: 9p21.3 locus
  association: Risk Factor
  notes: Same as CAD
- name: PCSK9
  gene_term:
    preferred_term: PCSK9
    term:
      id: hgnc:20001
      label: PCSK9
  association: Risk Factor
- name: LPA
  gene_term:
    preferred_term: LPA
    term:
      id: hgnc:6667
      label: LPA
  association: Risk Factor
  notes: Lipoprotein(a)
environmental:
- name: Smoking
  exposure_term:
    preferred_term: exposure to tobacco smoking
    term:
      id: ECTO:6000029
      label: exposure to tobacco smoking
  notes: Strongest modifiable risk factor
  evidence:
  - reference: PMID:23915883
    reference_title: "Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Smoking was an important risk factor in both HIC and LMIC, with meta-OR for current smoking of 2·72"
    explanation: "Meta-analysis across 34 community studies (112,027 participants). Smoking carries the largest effect of the 15 risk factors assessed -- meta-OR 2.72 in high-income countries -- which is what makes it the strongest; diabetes, hypertension and hypercholesterolaemia follow in that order."
- name: Diabetes
  notes: Major risk factor
  evidence:
  - reference: PMID:23915883
    reference_title: "Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in LMIC, followed by diabetes (1·88"
    explanation: "Diabetes has the second-largest effect of the 15 risk factors meta-analysed. The quoted OR 1.88 is the high-income estimate; the low/middle-income estimate is 1.47, in the bracketed continuation the validator strips."
- name: Hypertension
  notes: Contributes to atherosclerosis
  evidence:
  - reference: PMID:24881994
    reference_title: "Blood pressure and incidence of twelve cardiovascular diseases: lifetime risks, healthy life-years lost, and age-specific associations in 1.25 million people"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "raised systolic blood pressure had a greater effect on angina, myocardial infarction, and peripheral arterial disease"
    explanation: "CALIBER cohort of 1.25 million initially cardiovascular-disease-free patients; pulse pressure showed its strongest association of any of the twelve endpoints with peripheral arterial disease. PARTIAL because it evidences the association, not the atherogenic mechanism the note asserts -- for that, see the atherogenesis module."
- name: Dyslipidemia
  notes: LDL elevation
  evidence:
  - reference: PMID:33221847
    reference_title: "LDL-Cholesterol versus Glucose in Microvascular and Macrovascular Disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "LDL-cholesterol has a causal effect on risk of peripheral arterial disease"
    explanation: "Supports the LDL fraction specifically, which is what this annotation names, and states it causally rather than as an association -- the review synthesises Mendelian randomization and trial evidence."
- name: Sedentary Lifestyle
  exposure_term:
    preferred_term: sedentary lifestyle
    term:
      id: ECTO:6000004
      label: exposure to sedentary lifestyle
  notes: Lack of exercise
  evidence:
  - reference: PMID:42537768
    reference_title: "Wearable device-measured sedentary behaviour, physical activity, and incident symptomatic peripheral artery disease: a prospective cohort study of 87,490 adults"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Participants in the highest SB tertile had a 43% increased risk of symptomatic PAD"
    explanation: "Prospective cohort of 87,490 adults with device-measured rather than self-reported activity, removing the recall bias that weakens most sedentary-behaviour evidence; median follow-up 7.9 years."
treatments:
- name: Smoking Cessation
  description: Most important intervention, reduces progression.
  treatment_term:
    preferred_term: tobacco cessation counseling
    term:
      id: NCIT:C101244
      label: Tobacco Cessation Counseling
  evidence:
  - reference: PMID:25282696
    reference_title: "Smoking cessation is associated with decreased mortality and improved amputation-free survival among patients with symptomatic peripheral artery disease."
    supports: SUPPORT
    snippet: "During follow-up to 5 years, patients who quit smoking had significantly lower all-cause mortality (14% vs 31%; hazard ratio, 0.40; 95% confidence interval, 0.18-0.90) and improved amputation-free survival (81% vs 60%; hazard ratio, 0.43, 95% confidence interval, 0.22-0.86) compared with patients who continued smoking"
    explanation: Demonstrates that smoking cessation in PAD patients significantly reduces mortality and improves amputation-free survival.
- name: Antiplatelet Therapy
  description: Aspirin or clopidogrel to reduce cardiovascular events.
  treatment_term:
    preferred_term: platelet aggregation inhibitor therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: antiplatelet agent
      term:
        id: NCIT:C1327
        label: Antiplatelet Agent
- name: Statins
  description: LDL lowering, plaque stabilization.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: statin
      term:
        id: CHEBI:87631
        label: statin
  evidence:
  - reference: PMID:34389230
    reference_title: "Effects of Statin Therapy and Dose on Cardiovascular and Limb Outcomes in Peripheral Arterial Disease: A Systematic Review and Meta-analysis."
    supports: SUPPORT
    snippet: "Higher dosing of statins confers a significant improvement in patient outcomes, especially ACM and amputations, although the quality of the evidence was variable."
    explanation: Meta-analysis demonstrating statins significantly reduce mortality and amputations in PAD patients.
- name: ACE Inhibitors
  description: Cardiovascular risk reduction.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ACE inhibitor
      term:
        id: NCIT:C247
        label: ACE Inhibitor
- name: Supervised Exercise Therapy
  description: First-line for claudication, improves walking distance.
  treatment_term:
    preferred_term: aerobic exercise therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:28874320
    reference_title: "Exercise training for intermittent claudication."
    supports: SUPPORT
    snippet: "A meta-analysis of 25 randomized trials demonstrated a 180-meter increase in treadmill walking distance in response to supervised exercise interventions compared with a nonexercising control group."
    explanation: Meta-analysis of 25 RCTs demonstrates supervised exercise significantly improves walking distance in PAD patients.
  - reference: PMID:42248619
    reference_title: "Editor's Choice - Focused Update on Paclitaxel Coated Technologies, from the 2024 European Society for Vascular Surgery (ESVS) Guidelines on the Management of Asymptomatic Peripheral Arterial Disease and Intermittent Claudication."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The update consistently emphasises supervised exercise therapy and best medical therapies as first line treatment."
    explanation: The ESVS focused update emphasises supervised exercise therapy, alongside best medical therapy, as first-line treatment for intermittent claudication.
- name: Cilostazol
  description: Phosphodiesterase inhibitor for claudication symptoms.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: cilostazol
      term:
        id: CHEBI:31401
        label: cilostazol
  evidence:
  - reference: PMID:12480040
    reference_title: "Meta-analysis of results from eight randomized, placebo-controlled trials on the effect of cilostazol on patients with intermittent claudication."
    supports: SUPPORT
    snippet: "Cilostazol therapy increased maximal and pain-free walking distances by 50% and 67%, respectively."
    explanation: Meta-analysis of 8 RCTs showing cilostazol significantly improves walking distances in claudication patients.
- name: Revascularization
  description: Endovascular or surgical for severe disease.
  treatment_term:
    preferred_term: invasive revascularization therapy
    term:
      id: NCIT:C191567
      label: Invasive Revascularization Therapy
  evidence:
  - reference: PMID:42248619
    reference_title: "Editor's Choice - Focused Update on Paclitaxel Coated Technologies, from the 2024 European Society for Vascular Surgery (ESVS) Guidelines on the Management of Asymptomatic Peripheral Arterial Disease and Intermittent Claudication."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Endovascular revascularisation is recommended only for persistent lifestyle limiting symptoms despite conservative therapy."
    explanation: The ESVS focused update restricts endovascular revascularisation to patients with persistent lifestyle-limiting symptoms despite conservative therapy.

classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
datasets:
- accession: geo:GSE310095
  title: Whole Blood Transcriptomics Differentiates Circulating Gene Expression Between Coronary Artery Disease and Peripheral Artery Disease
  description: Coronary artery disease (CAD) and peripheral artery disease (PAD) are prevalent atherosclerotic disorders that exhibit distinct clinical and pathological presentations. We used whole-blood RNA sequencing to investigate circulating transcriptomic differences between PAD and CAD. Whole-blood RNA sequencing was performed in 71 subjects 40-65 years of age with symptomatic PAD (n=20) or CAD (n=51). Patients with concomitant PAD and CAD were excluded. Differential expression analysis was performed to compare circulating gene expression in patients with PAD and patients with CAD. We identified 106 genes differentially expressed between PAD and CAD (p adj. < 0.1).
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 71
  publication: PMID:41661212
  notes: Identified by GEO DataSets index search for Peripheral Artery Disease (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE287118
  title: Multiomics identifies unique modulators of calf muscle pathophysiology in peripheral artery disease and chronic kidney disease
  description: This project aimed to map transcriptome changes in the skeletal muscle of patients with and without PAD (peripheral artery disease) and CKD (chronic kidney disease)
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 86
  publication: PMID:39963788
  notes: Identified by GEO DataSets index search for Peripheral Artery Disease (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE289575
  title: Multi-omics Analysis of Skeletal Muscle Identifies Dysregulation of Hypoxia-Induced Genes in Peripheral Artery Disease [RRBS]
  description: Epigenetic modifications such as DNA methylation play a critical role in hypoxic cell programs. However, no previous studies have investigated the epigenetic regulation of gene expression in peripheral artery disease (PAD), a condition characterized by intermittent ischemia. In this study, we used reduced representation bisulphite sequencing (RRBS) to investigate how PAD affects the DNA methylome in skeletal muscle of PAD patients with intermittent claudication (IC) or critical limb ischemia (CLI) compared to non-PAD controls. We also used small and bulk RNA-sequencing (RNA-seq), which allowed for data integration.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: METHYLATION
  sample_count: 40
  publication: PMID:41025488
  notes: Identified by GEO DataSets index search for Peripheral Artery Disease (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: metabolomics_workbench:ST000872
  title: Maternal Hypoxemia and oxidative stress in the fetus, newborn, and adult. exercise training for peripheral artery disease
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. 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 ("Peripheral Artery Disease"). Retrieved 2026-08-02.
- accession: metabolomics_workbench:ST000873
  title: Maternal Hypoxemia and oxidative stress in the fetus, newborn, and adult. exercise training for peripheral artery disease (part II)
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. 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 ("Peripheral Artery Disease"). Retrieved 2026-08-02.
references:
- reference: DOI:10.1038/s41598-023-50751-8
  title: Association of immunologic findings of atheromatous plaques with subsequent cardiovascular events in patients with peripheral artery disease
  findings: []
- reference: DOI:10.1038/s41598-024-65188-w
  title: An evaluation of inflammatory and endothelial dysfunction markers as determinants of peripheral arterial disease in those with diabetes mellitus
  findings: []
- reference: DOI:10.1038/s43856-023-00431-5
  title: Inhibiting anti-angiogenic VEGF165b activates a miR-17-20a-Calcipressin-3 pathway that revascularizes ischemic muscle in peripheral artery disease
  findings: []
- reference: DOI:10.1093/eurheartj/ehad562
  title: 'Critical limb-threatening ischaemia and microvascular transformation: clinical implications'
  findings: []
- reference: DOI:10.1101/2025.09.23.678171
  title: Generation and Validation of a Lower Limb Muscle Single-Cell RNA Sequencing Data Set Identifies Pathogenic Endothelial Metabolism in Peripheral Arterial Disease
  findings: []
- reference: DOI:10.3389/fcvm.2023.1271100
  title: Lower limb arterial calcification and its clinical relevance with peripheral arterial disease
  findings: []
- reference: DOI:10.3390/genes15010135
  title: Translational Relevance of Advanced Age and Atherosclerosis in Preclinical Trials of Biotherapies for Peripheral Artery Disease
  findings: []
- reference: DOI:10.3390/ijms242216099
  title: 'Current Medical Therapy and Revascularization in Peripheral Artery Disease of the Lower Limbs: Impacts on Subclinical Chronic Inflammation'
  findings: []
- reference: PMID:37595697
  title: The microenvironment of the atheroma expresses phenotypes of plaque instability.
  findings: []
- reference: PMID:26844337
  title: The Role of Lipids and Lipoproteins in Atherosclerosis.
  findings: []

📚

References & Deep Research

References

10

DOI:10.1038/s41598-023-50751-8

Association of immunologic findings of atheromatous plaques with subsequent cardiovascular events in patients with peripheral artery disease