Atherogenesis Module

Module atherogenesis 8 disorders Pathograph 6

A conserved pathophysiology module representing the formation of an atheroma (atherosclerotic plaque), the lipid-rich intimal lesion that recurs across coronary artery disease, ischemic stroke, peripheral artery disease, and aortic atherosclerosis. Endothelial dysfunction increases arterial-wall permeability and permits retention of apoB-containing lipoproteins (LDL) in the subendothelial space - the critical initiating event. Retained, modified LDL recruits monocytes that become macrophages and internalize the lipoproteins to form foam cells, the hallmark of the fatty streak, amid a self-amplifying inflammatory response. Vascular smooth muscle cells switch phenotype, migrate into the intima, proliferate, and secrete extracellular matrix, building a fibrofatty plaque with a lipid/necrotic core beneath a fibrous cap. Advanced plaques may destabilize; cap rupture or endothelial erosion can expose thrombogenic material and trigger luminal thrombosis, causing acute ischemic events. The module captures the shared core across atherosclerotic vascular disorders. Conforming disorder branches substitute the disease-specific driver (LDL burden and apoB in familial hypercholesterolemia, hyperglycemia/AGEs in diabetic atherosclerosis, hypertension-associated endothelial injury, smoking) while preserving the core LDL retention -> foam cell -> SMC/extracellular-matrix fibrofatty plaque chain. Advanced atheroma, rupture/thrombosis, stenosis, and ischemia are optional stage consequences; they are not required for every conforming branch.

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Pathophysiology Nodes

5 shared nodes are defined in this module.

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Cell Types

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Biological Processes

cholesterol homeostasis GO:0042632 DYSREGULATED foam cell differentiation GO:0090077 INCREASED inflammatory response GO:0006954 INCREASED smooth muscle cell proliferation GO:0048661 INCREASED extracellular matrix organization GO:0030198 INCREASED

Notes

This is a mechanism module, not a specific disease. It is a pathological structure-formation ("Xogenesis") module. Xogenesis anchor: the terminal output is an atheroma / atherosclerotic plaque, an OGMS:0000078 pathological anatomical structure produced by an OGMS:0000081 pathological derivation (a new intimal lesion); process genus OGMS:0000061 pathological bodily process; site UBERON:0001637 artery. MPATH represents the lesion as MPATH:28 (atherosclerosis) but has no distinct "atheroma"/"atherosclerotic plaque" continuant class, a noted OBO gap. SNOMED "Morphologically abnormal structure" (49755003) is used only as an external census/gap guide and is not bound here. Disorder entries reference individual nodes via conforms_to (for example, "atherogenesis#Smooth Muscle Cell Switching and Fibrofatty Plaque Formation"). The module defines the expected pathophysiology structure; conforming nodes in disorder files should include the corresponding cell types, biological processes, and causal edges, specialized to their disease context. A pathophysiology branch is within scope when it explicitly represents formation of an arterial-intimal atheroma through (1) retention of apoB-containing lipoprotein in the arterial intima, with oxidative or enzymatic modification as a possible specialization, (2) monocyte/macrophage foam-cell biology, and (3) vascular-smooth-muscle-cell and extracellular-matrix assembly of a fibrofatty plaque. This core three-stage chain is the operational necessary-and-sufficient curation boundary for module conformance; it is a prose guardrail, not a formal grouping criterion. Advanced necrotic core/fibrous cap, rupture or erosion with thrombosis, stenosis, and ischemia may be mapped when the disorder explicitly represents those later stages, but none is required and none is sufficient alone. Exclude hyperlipidemia or vascular risk without an explicit arterial plaque-forming branch, foam cells outside arterial atheroma, nonatherosclerotic stenosis, dissection or thrombosis, and terminal ischemia without modeled plaque formation. Because conformance is node-level, an explicit atherosclerotic branch of a mixed-etiology disorder may qualify without asserting that every disease mechanism is atherogenic. Familial hypercholesterolemia substitutes a high LDL/apoB burden at the retention trigger; diabetic atherosclerosis substitutes hyperglycemia and advanced glycation end-products; the terminal rupture/thrombosis node feeds the thrombogenesis module. Mechanism nodes bind GO, CL, and UBERON terms where appropriate and do not use chemical (CHEBI) or disease (MONDO) term bindings, except in the treatments block where the therapeutic agent carries an ontology identifier per the treatment schema.

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Used By Disorder Entries

Autosomal Dominant Hypercholesterolemia 3 via Subendothelial Retention of ApoB-Containing Lipoproteins → Endothelial Dysfunction and Subendothelial LDL Retention , Macrophage Foam Cell Formation → Monocyte Recruitment and Macrophage Foam Cell Formation , Smooth Muscle Cell Switching and Fibrofatty Plaque Formation , Advanced Atheroma with Necrotic Core and Fibrous Cap , Plaque Rupture, Thrombosis, and Ischemic Events

Carotid Artery Occlusion via Carotid Intimal ApoB Lipoprotein Retention → Endothelial Dysfunction and Subendothelial LDL Retention , Carotid Monocyte Recruitment and Macrophage Foam Cell Formation → Monocyte Recruitment and Macrophage Foam Cell Formation , Atherosclerotic carotid plaque formation → Smooth Muscle Cell Switching and Fibrofatty Plaque Formation , Advanced carotid atheroma with necrotic core and fibrous cap → Advanced Atheroma with Necrotic Core and Fibrous Cap

Carotid Stenosis via Carotid Intimal ApoB Lipoprotein Retention → Endothelial Dysfunction and Subendothelial LDL Retention , Carotid Monocyte Recruitment and Macrophage Foam Cell Formation → Monocyte Recruitment and Macrophage Foam Cell Formation , Atherosclerotic carotid plaque formation → Smooth Muscle Cell Switching and Fibrofatty Plaque Formation , Vulnerable plaque instability → Advanced Atheroma with Necrotic Core and Fibrous Cap , Thromboembolic cerebral and retinal ischemia → Plaque Rupture, Thrombosis, and Ischemic Events

Coronary Artery Disease via Coronary Endothelial Injury and Subendothelial LDL Retention → Endothelial Dysfunction and Subendothelial LDL Retention , Monocyte Recruitment and Macrophage Foam Cell Formation , Atherosclerotic Plaque Formation → Smooth Muscle Cell Switching and Fibrofatty Plaque Formation , Advanced Atheroma with Necrotic Core and Fibrous Cap , Plaque Rupture and Thrombosis → Plaque Rupture, Thrombosis, and Ischemic Events

Familial Defective Apolipoprotein B-100 via Subendothelial Retention of ApoB-Containing Lipoproteins → Endothelial Dysfunction and Subendothelial LDL Retention

Familial Hypercholesterolemia via Oxidized LDL Infiltration of Arterial Intima → Endothelial Dysfunction and Subendothelial LDL Retention , Macrophage-Derived Foam Cell Formation → Monocyte Recruitment and Macrophage Foam Cell Formation , Atherosclerotic Plaque Development → Smooth Muscle Cell Switching and Fibrofatty Plaque Formation , Advanced Atheroma with Necrotic Core and Fibrous Cap , Plaque Rupture, Thrombosis, and Ischemic Events

LDLR-Related Familial Hypercholesterolemia via Endothelial Dysfunction and Subendothelial LDL Retention , Monocyte Recruitment and Macrophage Foam Cell Formation , Premature Atherosclerotic Cardiovascular Events → Plaque Rupture, Thrombosis, and Ischemic Events

Peripheral Artery Disease via Endothelial Dysfunction and Subendothelial LDL Retention , Monocyte Recruitment and Macrophage Foam Cell Formation , Atherosclerosis → Smooth Muscle Cell Switching and Fibrofatty Plaque Formation , Advanced Atheroma with Necrotic Core and Fibrous Cap

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Pathograph

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Pathophysiology

Endothelial Dysfunction and Subendothelial LDL Retention

trigger

The proximal trigger of atherogenesis. Endothelial dysfunction - from disturbed flow, hypercholesterolemia, hypertension, smoking, or hyperglycemia - increases arterial-wall permeability and alters the subendothelial matrix, permitting infiltration and retention of apoB-containing lipoproteins (LDL) in the intima. Retained LDL is oxidatively and enzymatically modified, becoming a pro-inflammatory stimulus. This subendothelial lipoprotein retention is the critical initiating event of the plaque; the disease-specific driver differs but the retained-LDL trigger is shared.

vascular endothelial cell CL:0000115

cholesterol homeostasis GO:0042632 DYSREGULATED

Used by disorders

Autosomal Dominant Hypercholesterolemia 3 as Subendothelial Retention of ApoB-Containing Lipoproteins

Carotid Artery Occlusion as Carotid Intimal ApoB Lipoprotein Retention

Carotid Stenosis as Carotid Intimal ApoB Lipoprotein Retention

Coronary Artery Disease as Coronary Endothelial Injury and Subendothelial LDL Retention

Familial Defective Apolipoprotein B-100 as Subendothelial Retention of ApoB-Containing Lipoproteins

Familial Hypercholesterolemia as Oxidized LDL Infiltration of Arterial Intima

LDLR-Related Familial Hypercholesterolemia

Peripheral Artery Disease

Downstream

Monocyte Recruitment and Macrophage Foam Cell Formation

Monocyte Recruitment and Macrophage Foam Cell Formation

amplifier

Retained, modified LDL and activated endothelium recruit circulating monocytes into the intima, where they differentiate into macrophages and internalize the lipoproteins through scavenger receptors, becoming lipid-laden foam cells - the hallmark of the fatty streak. Foam-cell macrophage inflammation amplifies oxidative stress and cytokine secretion, driving further LDL oxidation, endothelial activation, and monocyte recruitment in a feed-forward loop. This is the amplifying step of atherogenesis.

foam cell (lipid-laden macrophage) CL:0000235

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

Used by disorders

Autosomal Dominant Hypercholesterolemia 3 as Macrophage Foam Cell Formation

Carotid Artery Occlusion as Carotid Monocyte Recruitment and Macrophage Foam Cell Formation

Carotid Stenosis as Carotid Monocyte Recruitment and Macrophage Foam Cell Formation

Coronary Artery Disease

Familial Hypercholesterolemia as Macrophage-Derived Foam Cell Formation

LDLR-Related Familial Hypercholesterolemia

Peripheral Artery Disease

Downstream

Smooth Muscle Cell Switching and Fibrofatty Plaque Formation

Smooth Muscle Cell Switching and Fibrofatty Plaque Formation

central effector

The rate-limiting central effector of atheroma formation. In the inflamed, lipid-rich intima, vascular smooth muscle cells undergo phenotypic switching from a contractile to a synthetic/migratory state, migrate into the intima, proliferate, and secrete extracellular matrix. Together with foam cells and a growing lipid/necrotic core, this builds the organized fibrofatty plaque capped by a smooth-muscle- and matrix-rich fibrous cap. This SMC-driven plaque assembly is the disorder-agnostic step that converts a fatty streak into an atheroma and is the key conformance target of the module.

vascular smooth muscle cell CL:0000192

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

Used by disorders

Autosomal Dominant Hypercholesterolemia 3

Carotid Artery Occlusion as Atherosclerotic carotid plaque formation

Carotid Stenosis as Atherosclerotic carotid plaque formation

Coronary Artery Disease as Atherosclerotic Plaque Formation

Familial Hypercholesterolemia as Atherosclerotic Plaque Development

Peripheral Artery Disease as Atherosclerosis

Downstream

Advanced Atheroma with Necrotic Core and Fibrous Cap

Advanced Atheroma with Necrotic Core and Fibrous Cap

effector

Continued lipid accumulation, foam-cell death, and matrix remodeling enlarge the plaque into an advanced atheroma with a soft necrotic lipid core walled off by a fibrous cap. Local microenvironmental changes - neovascularization from the vasa vasorum, intraplaque hemorrhage, and necrotic-core expansion - promote the transition from a stable to an unstable (vulnerable) atheroma. This is the mature pathological structure the module produces.

vascular smooth muscle cell CL:0000192

extracellular matrix organization GO:0030198 INCREASED

Used by disorders

Autosomal Dominant Hypercholesterolemia 3

Carotid Artery Occlusion as Advanced carotid atheroma with necrotic core and fibrous cap

Carotid Stenosis as Vulnerable plaque instability

Coronary Artery Disease

Familial Hypercholesterolemia

Peripheral Artery Disease

Downstream

Plaque Rupture, Thrombosis, and Ischemic Events

Plaque Rupture, Thrombosis, and Ischemic Events

consequence

The clinical end state of the module. Fibrous-cap rupture (or endothelial erosion) of an unstable atheroma exposes the thrombogenic necrotic core and subendothelial matrix to flowing blood, triggering luminal thrombosis (see the thrombogenesis module). The resulting thrombotic vascular occlusion causes acute ischemic events - acute coronary syndrome, myocardial infarction, and ischemic stroke - the consequence of the conserved atherogenesis chain.

Used by disorders

Autosomal Dominant Hypercholesterolemia 3

Carotid Stenosis as Thromboembolic cerebral and retinal ischemia

Coronary Artery Disease as Plaque Rupture and Thrombosis

Familial Hypercholesterolemia

LDLR-Related Familial Hypercholesterolemia as Premature Atherosclerotic Cardiovascular Events