Coronary Artery Disease (Coronary Atherosclerosis, MONDO:0021661): A Comprehensive Disease Characterization Report

Summary

Coronary artery disease, defined here strictly as coronary atherosclerosis (MONDO:0021661) — atherosclerotic plaque formation in the intima of the epicardial coronary arteries — is a chronic, polygenic, lipid-initiated and inflammation-amplified disease. The best-supported causal model is a staged process: subendothelial retention of apolipoprotein-B (apoB)-containing lipoproteins at disturbed-flow arterial sites drives endothelial dysfunction, monocyte recruitment, macrophage foam-cell formation with defective apoptotic-cell clearance (efferocytosis), and smooth-muscle-cell (SMC) phenotypic switching. These processes generate plaques whose composition — a lipid/necrotic core beneath a thin fibrous cap — rather than the degree of luminal stenosis, precipitates acute coronary events. Two histologically distinct terminal routes convert stable plaque into coronary thrombosis: plaque rupture (~2/3 of ACS) and superficial erosion (~1/3 of ACS).

The causal centrality of apoB/LDL is established at the highest evidence tier by convergent human genetics (PCSK9 loss-of-function and LPA variants) and randomized outcome and imaging trials (statins, PCSK9 inhibitors, bempedoic acid). Independently, inflammation is causal: IL-1β inhibition (canakinumab, CANTOS) and colchicine reduce coronary events without lowering lipids, isolating an IL-1β→IL-6→CRP axis. Coronary-specific imaging evidence (PROSPECT natural history, NIRS-IVUS/OCT wall-shear-stress studies, MESA coronary artery calcium) anchors the anatomy and prognostic value of plaque burden and composition directly in the coronary bed. Model-organism and in-vitro work (MerTK efferocytosis, SMC lineage tracing, IL-1β-induced LDL transcytosis) supplies mechanism but is labeled by species and vascular bed and does not, alone, establish human coronary causality.

Clinically, CAD is managed by aggressive apoB/LDL lowering, anti-inflammatory therapy in selected patients, and antithrombotics; revascularization relieves symptoms but does not reduce death or MI in stable disease (ISCHEMIA). This report organizes the evidence across the 15 requested domains, maintaining an explicit evidence-directness ladder (human coronary → human systemic → transferable non-coronary plaque → model organism → in vitro → computational) and flagging discordant/null findings.

Evidence Matrix (Directness Ladder Applied)

Directness ladder: T1 = human coronary pathology/imaging (anatomically direct; imaging composition = surrogate); T2 = human coronary-event genetics/biomarker/systemic intervention (clinically relevant, not plaque-localized); T3 = human carotid/aortic/peripheral plaque (transferable, indirect for coronary); T4 = animal in-vivo (MODEL_ORGANISM); T5 = cultured cells/ex-vivo (IN_VITRO); T6 = computational.

1. Disease Information

Coronary atherosclerosis is the accumulation of atherosclerotic plaque — lipid, inflammatory cells, smooth-muscle cells, extracellular matrix, calcification and necrotic debris — within the intima of the epicardial coronary arteries, progressively narrowing the lumen and/or destabilizing to cause thrombosis. It is the dominant substrate of ischemic heart disease and the leading cause of death worldwide.

Key identifiers: - Mondo: MONDO:0021661 (coronary atherosclerosis) — the locked disease identity. MONDO:0004975, broad ASCVD, and "all coronary disorders" are explicitly excluded. - MeSH: Coronary Artery Disease (D003324); Coronary Atherosclerosis - ICD-10: I25.1 (atherosclerotic heart disease of native coronary artery) - ICD-11: BA80 (ischaemic heart disease block) - SNOMED CT: 53741008 (coronary arteriosclerosis)

Synonyms / near-terms (with scope caveats): coronary atherosclerosis, atherosclerotic heart disease, coronary arteriosclerosis. Not exact synonyms: stable angina, acute coronary syndrome (ACS), and myocardial infarction (MI) are manifestations/complications. Excluded differentials: spontaneous coronary artery dissection (SCAD), coronary vasospasm, congenital coronary anomalies, coronary embolism, isolated coronary microvascular dysfunction, and type-2 MI.

Data provenance: This report synthesizes aggregated disease-level resources (RCTs, cohort studies, GWAS meta-analyses, imaging natural-history studies), not individual patient EHR records.

2. Etiology

Disease causal factors

CAD is a multifactorial, polygenic disease. The initiating causal factor is subendothelial retention of apoB-containing lipoproteins (LDL, remnant/triglyceride-rich lipoproteins, and Lp(a)), superimposed on hemodynamic (disturbed-flow) and inflammatory contributors.

Human-genetic proof of LDL causality (F009): In ARIC (15-yr follow-up), PCSK9 nonsense mutations (2.6% of Black participants) conferred a 28% lower LDL-C and 88% lower CHD risk (HR 0.11, 95% CI 0.02–0.81); a PCSK9 variant in White participants gave 15% lower LDL-C and 47% lower CHD risk (HR 0.50, 95% CI 0.32–0.79). "these mutations were associated with a 28 percent reduction in mean LDL cholesterol and an 88 percent reduction in the risk of CHD" (PMID: 16554528). This natural experiment demonstrates that lifelong lower apoB exposure yields disproportionately large CHD reduction.

Genetic risk factors (F006, F010)

• 9p21.3 / CDKN2A/B (rs1333049) — the most replicated common CAD locus; also a shared T2DM–CAD signal (strongest local genetic correlation; T2DM–CAD rg=0.39, P=1.43×10⁻⁷⁵) (PMID: 38062574).
• LPA / lipoprotein(a) (rs10455872) — one of the two strongest CAD risk loci (PMID: 30482443); Mendelian randomization confirms Lp(a) causally raises risk of CHD, large-artery stroke, PAD and aortic stenosis: "Mendelian randomization confirms causal relationships with coronary heart disease, large-artery stroke, peripheral artery disease, and aortic stenosis" (PMID: 41789317). Lp(a) is 70–90% genetically determined and elevated in ~20% of the global population.
• CDKN2B (9p21.3) also replicated as an ankle-brachial-index/PAD–CAD locus (PMID: 41252360).

Environmental / lifestyle risk factors (F015)

INTERHEART (52 countries, ~27,098 participants) found nine modifiable risk factors account for >90% of MI population-attributable risk (women 96% vs men 93%): abnormal lipids (ApoB:ApoA1), current smoking, hypertension, diabetes, abdominal obesity, psychosocial stress, low fruit/vegetable intake, physical inactivity, and no/low alcohol. "The population attributable risk (PAR) of all nine risk factors exceeded 94%, and was similar among women and men (96 vs. 93%)" (PMID: 18334475).

Protective factors

• Genetic: PCSK9 loss-of-function alleles (F009); constitutionally low-Lp(a) genotypes.
• Environmental: the inverse of the INTERHEART factors — physical activity, fruit/vegetable intake, moderate alcohol, non-smoking. Pharmacologic LDL lowering is protective regardless of mechanism (F013).

Gene–environment interactions

The T2DM–CAD relationship is bidirectional and partly genetic (rg largely BMI-independent, 0.31), mediated substantially by systolic blood pressure and statin use (PMID: 38062574). CHIP illustrates a somatic-genetic × inflammatory-environment interaction (F005).

3. Phenotypes

CAD is asymptomatic during plaque development (subclinical for decades) and becomes clinically manifest through ischemic syndromes. Per the scope guardrails, these are manifestations/complications, not synonyms.

Age of onset: typically adult/late-onset, with earlier clinical onset in men (median first MI 56 vs 65 yr in women) (F015). Severity/progression: variable and generally progressive but modifiable; long asymptomatic phase punctuated by acute episodes. QoL impact: angina limits daily functioning; captured by disease-specific tools (Seattle Angina Questionnaire) and generic measures (EQ-5D, SF-36). In stable disease, revascularization's main benefit is angina relief rather than event reduction (F017).

4. Genetic / Molecular Information

CAD is polygenic/multifactorial, not a Mendelian single-gene disorder, except that monogenic hypercholesterolemias greatly accelerate coronary atherosclerosis (familial hypercholesterolemia: LDLR, APOB, PCSK9 gain-of-function).

Key genes / loci: - PCSK9 (HGNC:20001) — loss-of-function is protective (F009); gain-of-function causes FH. Functional consequence: LoF → increased hepatic LDLR → lower LDL. - LDLR — the classic FH gene; central to LDL clearance. - LPA (HGNC:6667) — determines Lp(a); causal for CAD (F010). - CDKN2A/CDKN2B (9p21.3) — strongest common susceptibility locus (F006); non-coding regulatory effect on vascular SMC biology. - TCF21 — coronary-disease GWAS gene modulating SMC phenotype (anchor 31359001, mixed human/model evidence).

Modifier / acquired genetic drivers — CHIP (F005): Somatic mutations in hematopoietic stem cells. DNMT3A and TET2 are the two most frequently mutated CHIP genes (PMID: 36097025). In UK Biobank (n=13,129 with ASCVD): "any CHIP and large CHIP at baseline were associated with adjusted HRs of 1.23 (95% CI: 1.10-1.38; P < 0.001) and 1.34 (95% CI: 1.17-1.53; P < 0.001), respectively, for the primary outcome" (PMID: 37197843); large TET2 HR 1.89, large spliceosome HR 3.02. Murine Tet2/Dnmt3a loss-of-function supports an IL-1β/inflammasome-mediated causal mechanism (PMID: 31345433).

Epigenetics: DNMT3A and TET2 CHIP produce distinct, directionally opposing genome-wide DNA-methylation patterns; Mendelian randomization suggests some DNAm alterations promote CAD risk (PMID: 36097025).

Chromosomal abnormalities: Not a defining feature of coronary atherosclerosis. The most relevant "large-scale" genetic contributor is clonal expansion of mutant hematopoietic clones (CHIP), not aneuploidy.

Variant classification / population frequency: PCSK9 protective LoF alleles (e.g., Y142X, C679X) are more frequent in individuals of African ancestry (~2–3%); classified benign-protective. FH-causing LDLR/APOB/PCSK9-GoF variants span missense, nonsense, frameshift, and splice-site classes (pathogenic/likely pathogenic per ACMG/AMP in ClinVar). All germline; CHIP mutations are somatic.

5. Environmental Information

• Lifestyle factors (F015): smoking, atherogenic diet (high saturated fat/refined carbohydrate), physical inactivity, abdominal obesity, and psychosocial stress. Current smoking and abnormal lipids are among the strongest INTERHEART contributors.
• Environmental exposures: ambient air pollution (particulate matter) is an established population risk factor for ischemic heart disease.
• Metabolic environment: diabetes/hyperglycemia (bidirectional with CAD, PMID: 38062574) and hypertension.
• Infectious agents: CAD is not an infectious disease. Chronic low-grade inflammation (not a specific pathogen) is the operative inflammatory driver; the causal inflammatory axis is IL-1β→IL-6→CRP (F011, F012), not a microbe.

6. Mechanism / Pathophysiology

Staged causal model

apoB-lipoprotein entry & proteoglycan retention  (CAUSAL: PCSK9/LPA genetics, LDL RCTs)
        │  (amplified at disturbed-flow / low wall-shear-stress sites)
        ▼
Endothelial dysfunction & activation  (↓eNOS/NO GO:0006809; ↑adhesion molecules)
        │  IL-1β can induce LDLR/Rab27a-dependent LDL transcytosis (IN VITRO/mouse)
        ▼
Leukocyte recruitment → monocyte entry
        ▼
Macrophage foam-cell formation (CD36/oxLDL uptake; GO:0019915 lipid storage)
        ▼
Defective efferocytosis (MerTK)  →  secondary necrosis  (MODEL ORGANISM: Apoe−/− mice)
        ▼
Necrotic core expansion + SMC phenotypic switching (contractile→synthetic/
   macrophage-like/osteogenic; CL:0000359) → fibrous cap thinning
        ▼
Calcification, neovascularization, intraplaque hemorrhage → plaque growth/remodeling
        ▼
   ┌─────────────────────────────┬──────────────────────────────┐
   ▼ TERMINAL ROUTE 1            ▼ TERMINAL ROUTE 2
 Plaque RUPTURE (~2/3 ACS)     Superficial EROSION (~1/3 ACS)
 thin cap + large necrotic     intact cap, less necrosis/
 core + inflammation           inflammation, larger lumen
        └──────────────┬───────────────┘
                       ▼
        Platelet/coagulation activation → CORONARY THROMBOSIS → MI / sudden death

     (Non-thrombotic route: progressive stenosis → demand ischemia → stable angina)

Molecular pathways & cellular processes

• Lipid retention & foam-cell formation: apoB-lipoprotein subendothelial retention; scavenger-receptor (CD36) uptake of oxLDL; lipid storage (GO:0019915). In vitro, oxLDL downregulates the PPARγ/LXRα/MerTK efferocytosis axis and upregulates competitive receptor CD300a, driving CD36-mediated foam-cell formation (PMID: 36721069).
• Endothelial mechanotransduction: low wall shear stress downregulates eNOS / nitric-oxide biosynthesis (GO:0006809) and upregulates E-selectin/ICAM-1, promoting leukocyte adhesion (in-vitro HUVEC/microfluidic, PMID: 34948110); NRP2/PARP1 mediate low-shear endothelial apoptosis in mouse aorta (PMID: 35028975).
• Efferocytosis / apoptotic-cell clearance (F008): In Mertk-kinase-dead;Apoe⁻/⁻ mice, lesions accumulated apoptotic cells and became more necrotic — "mutation of the phagocytic Mertk receptor promotes the accumulation of apoptotic cells" (PMID: 18451332). Species: mouse; site: aortic root — not coronary.
• SMC plasticity (F004): Contractile vascular-associated SMCs (CL:0000359) dedifferentiate to synthetic, macrophage-like, osteoblast-like states. "most of lesional macrophages... are derived from macrophage-like cells (MLCs) dedifferentiated from the VSMCs lineage... promoting... necrotic core expansion and fibrous cap thinning" (PMID: 41165871). IRF7 is proposed as a checkpoint for maladaptive switching, upregulated in unstable human plaques (PMID: 41625231). Dual SMC/EC lineage tracing shows endothelial-to-SMC and SMC-loss dynamics under vascular stress (PMID: 41648299).
• Inflammation is causal (F011): IL-1β→IL-6→CRP axis. Mechanistically, IL-1β induces LDL transcytosis by human coronary artery endothelial cells via an LDLR/Rab27a pathway (PMID: 38989581), linking inflammation to early lipid entry.

Upstream vs downstream

• Upstream (initiation): apoB retention, disturbed-flow endothelial dysfunction.
• Midstream (progression): foam cells, defective efferocytosis, SMC switching, necrotic-core growth.
• Downstream (terminal): cap thinning → rupture or endothelial erosion → thrombosis.

GO / CL term suggestions

• GO:0019915 lipid storage; GO:0006809 nitric oxide biosynthetic process; GO:0043277 apoptotic cell clearance (efferocytosis); GO:0033344 cholesterol efflux; GO:0006954 inflammatory response.
• CL:0000359 vascular associated smooth muscle cell; CL:0000235 macrophage/foam cell; CL:0000071 blood vessel endothelial cell; CL:0000775 neutrophil (erosion).

7. Anatomical Structures Affected

• Organ level: Heart — specifically the epicardial coronary arteries (UBERON:0001621; left anterior descending, left circumflex, right coronary). Secondary organ: myocardium (UBERON:0002349) via ischemia/infarction. Body system: cardiovascular system.
• Tissue level: arterial tunica intima (UBERON:0004638; primary plaque site), tunica media (SMC source). Tissue types: endothelium, connective tissue/ECM, vascular smooth muscle.
• Cell level: endothelial cells (CL:0000071), monocyte-derived macrophages/foam cells (CL:0000235), vascular-associated smooth muscle cells (CL:0000359), T lymphocytes, neutrophils (prominent in erosion), platelets (terminal thrombosis).
• Subcellular level: lysosomes/late endosomes (lipid handling, efferocytic degradation, Rab27a vesicles, PMID: 38989581); endoplasmic reticulum (lipid synthesis/stress); mitochondria (oxidative stress). GO CC: GO:0005764 lysosome; GO:0005783 ER.
• Localization / lateralization: Multifocal, bilateral (multiple coronary arteries); plaques preferentially form at branch points and inner curvatures where wall shear stress is low/oscillatory (F007).

8. Temporal Development

• Onset: Subclinical plaque begins in early adulthood (fatty streaks even earlier); clinical onset typically adult/geriatric. Onset of events is often acute superimposed on chronic, insidious plaque growth.
• Progression / stages: fatty streak → fibroatheroma → thin-cap fibroatheroma (TCFA, high-risk) → complicated/ruptured or eroded plaque with thrombosis. Progression is variable and modifiable; low wall shear stress accelerates lipid-rich plaque growth over ~1 year — "Exposure to low WSS was associated with a higher plaque progression" (PMID: 36575921).
• Course pattern: chronic, lifelong, generally progressive but regressable with intensive LDL lowering (GLAGOV IVUS regression, F002; PACMAN-AMI lesion-level regression showing PAV change −4.86% alirocumab vs −2.78% placebo, PMID: 39221516).
• Natural history (F001): In PROSPECT, most nonculprit lesions causing future events were angiographically mild at baseline (mean diameter stenosis 32.3±20.6%) yet had high-risk features — "nonculprit lesions associated with recurrent events were more likely... to be characterized by a plaque burden of 70% or greater (hazard ratio, 5.03; 95% confidence interval [CI], 2.51 to 10.11; P<0.001) or a minimal luminal area of 4.0 mm(2) or less" (PMID: 21247313). This establishes composition/burden, not stenosis, as the driver of events.
• Critical intervention windows: LDL lowering and anti-inflammatory therapy alter trajectory at any stage; the post-MI period is a high-residual-risk window (CANTOS, colchicine).

9. Inheritance and Population

• Epidemiology: Ischemic heart disease is the leading global cause of death and DALYs. GBD 2021 shows rising incidence/prevalence even in young adults (aged 20–24), with ischemic heart disease dominating mortality/DALYs and males bearing greater mortality/DALY burden (PMID: 42483021). CAC prevalence is ~50% in adults aged 45–84 (MESA, F014).
• Inheritance: Polygenic/multifactorial, not Mendelian. Heritability estimates ~40–60%. Dominant common-variant contributors: 9p21.3, LPA (F006, F010); ~300+ GWAS loci total.
• Penetrance/expressivity: Genetic liability is probabilistic (polygenic risk scores), strongly modified by environment (F015). Lp(a) is highly penetrant for elevated risk when very high.
• Founder effects: PCSK9 protective variants have population-specific frequencies (F009).
• Population demographics / sex: Median first-MI age higher in women (65 vs 56 yr); hypertension (OR 2.95 vs 2.32) and diabetes (OR 4.26 vs 2.67) are more strongly associated in women, while several factors are similar across sexes (F015). Low/low-middle sociodemographic-index regions bear the highest young-adult burden (PMID: 42483021).

10. Diagnostics

• Laboratory tests/biomarkers: Lipid panel (LDL-C, apoB, non-HDL-C); Lp(a) (2024 NLA Class I recommendation for universal one-time measurement; F010); high-sensitivity cardiac troponin (HP:0410174) for MI; hs-CRP for residual inflammatory risk (CANTOS entry criterion ≥2 mg/L; F012) — "High-sensitivity C-reactive protein is a practical and reliable biomarker for assessing low-grade chronic inflammation" (PMID: 41936433). Serum urate independently predicts MACE/CV death even under IL-1β blockade (HR 1.66 for MACE, PMID: 39862678).
• Imaging (coronary-direct, tier 1):
• Coronary artery calcium (CAC) score by non-contrast CT (Agatston method) — MESA: "those with annual progression of ≥300 units had adjusted HRs of 3.8 (1.5 to 9.6) for total" CHD events (PMID: 23500326). AI-enhanced CAC scans add chamber-volume and hepatic-steatosis prognostics (PMID: 38664073, PMID: 40221147, PMID: 41591983).
• Coronary CT angiography (CCTA) — anatomy and plaque composition.
• Invasive intracoronary imaging: IVUS (plaque burden/volume; GLAGOV/PROSPECT), NIRS (lipid-core burden), OCT (thin-cap fibroatheroma; the only modality able to identify erosion in vivo, F003).
• Low endothelial shear stress adds incremental risk beyond morphology (HR 4.34, PMID: 28917684).
• Functional tests: exercise/pharmacologic stress testing, fractional flow reserve (FFR); ECG.
• Clinical criteria / differential diagnosis: ACC/AHA and ESC guidelines. Differentials to exclude (per scope): SCAD, vasospasm, congenital anomalies, embolism, isolated microvascular dysfunction, type-2 MI.
• Genetic/omics testing: Not routine for common CAD; polygenic risk scores and Lp(a) are emerging risk-stratification tools. FH gene panels (LDLR/APOB/PCSK9) apply to monogenic hypercholesterolemia.
• Screening: CAC scoring for intermediate-risk asymptomatic adults; universal one-time Lp(a).

11. Outcome / Prognosis

• Mortality: Ischemic heart disease is the leading cause of death globally (GBD 2021). Acute MI and sudden cardiac death are the principal fatal outcomes.
• Prognostic factors (coronary-direct): plaque burden ≥70%, minimal luminal area ≤4.0 mm², and thin-cap fibroatheroma morphology independently predict nonculprit events (PROSPECT, F001); low endothelial shear stress adds risk (PMID: 28917684); CAC progression predicts hard CHD (F014).
• Prognostic biomarkers: LDL-C/apoB (modifiable driver), Lp(a), hs-CRP (residual inflammatory risk), troponin, serum urate.
• Modifiability: Prognosis is strongly improved by LDL lowering (−21% MVE per 1 mmol/L, F013), anti-inflammatory therapy (F011/F012), and antithrombotics.
• Complications: MI, heart failure (predictable from CAC-derived chamber ratios, PMID: 41591983), arrhythmia, sudden death.

12. Treatment

Pharmacotherapy — lipid lowering (causal, LDL-dependent; MAXO:0000262 lipid-lowering agent therapy)

Benefit tracks the absolute magnitude of LDL-C reduction regardless of mechanism and holds in patients ≥75 yr (RR 0.74 per 1 mmol/L; PMID: 33186535).

Anti-inflammatory therapy (causal, lipid-independent)

• Canakinumab (anti-IL-1β): CANTOS reduced events without lowering lipids — "Canakinumab did not reduce lipid levels from baseline" (PMID: 28845751); total-event rate ratios ~0.78–0.80 (PMID: 33004131).
• Colchicine (0.5 mg/day, FDA-approved 2023): COLCOT and LoDoCo2 reduced MACE — "randomised colchicine trials such as COLCOT and LoDoCo2 showed reductions in major adverse cardiovascular events in patients with recent myocardial infarction and chronic coronary disease, respectively" (PMID: 42454467).
• Discordant/null control: low-dose methotrexate (CIRT) was null (PMID: 23874021 rationale), showing the effective axis is specifically IL-1β→IL-6→CRP, not anti-inflammation broadly (F011).

RNA-based / emerging

• Lp(a)-lowering: olpasiran (siRNA, OCEAN(a), NCT05581303) and pelacarsen (ASO, Lp(a) HORIZON, NCT04023552) in outcome trials (PMID: 42016317).

Antithrombotic

Antiplatelet therapy (aspirin, P2Y12 inhibitors) and anticoagulation address the terminal thrombotic route (MAXO: antiplatelet therapy).

Surgical / interventional (MAXO: percutaneous coronary intervention; coronary artery bypass grafting)

• PCI with drug-eluting stents and CABG. Key nuance (F017): in stable CAD with moderate–severe ischemia, "an initial invasive strategy does not reduce cardiovascular mortality or myocardial infarction compared with optimized medical therapy" (PMID: 42099494); benefit is symptom relief (also sham-controlled ORBITA). Revascularization remains indicated for ACS, left-main, high-risk anatomy, and refractory symptoms. Chronic-total-occlusion PCI is a specialized subset with distinct procedural profiles (PMID: 42309488).

13. Prevention

• Primary prevention: risk-factor modification targeting the nine INTERHEART factors (F015) — smoking cessation, lipid/apoB lowering, blood-pressure and glycemic control, weight/diet/activity. Lp(a) measurement for risk stratification.
• Secondary prevention: intensive LDL lowering to very low targets, anti-inflammatory therapy (colchicine) in selected post-MI/chronic coronary patients, antithrombotics, cardiac rehabilitation.
• Tertiary prevention: guideline-directed medical therapy to prevent recurrent events and heart failure; hs-CRP-guided identification of residual inflammatory risk.
• Screening / risk stratification: CAC scoring (MESA-validated, F014); polygenic risk scores (emerging); universal one-time Lp(a).
• Behavioral / public health: population-level tobacco control, dietary policy, physical-activity promotion — urgent in low-SDI regions with rising young-adult burden (PMID: 42483021).
• Not applicable: immunization (no infectious etiology).

14. Other Species / Natural Disease

• Taxonomy: Naturally occurring coronary atherosclerosis with thrombosis is largely a human condition; rare in most laboratory species. Relevant orthologs in Mus musculus (NCBI:txid10090): Apoe (Gene ID 11816), Ldlr (16835), Pcsk9 (100102). Lpa has no rodent ortholog (F016).
• Larger animals with true coronary lesions: WHHL rabbit (LDLR-mutant), Ossabaw/Yucatan pigs, and nonhuman primates develop coronary atherosclerosis more analogous to humans (F016).
• Comparative pathology: Rodent lesions form at the aortic root/arch and brachiocephalic artery and rarely rupture or thrombose spontaneously, limiting fidelity to human coronary events.
• Zoonotic potential: none (non-infectious, non-transmissible).

15. Model Organisms

Standard models (F016): hyperlipidemia-driven mice — Apoe⁻/⁻ and Ldlr⁻/⁻ on Western/pro-atherogenic diets, and humanized APOE*3-Leiden.CETP (human-like lipoprotein metabolism); PCSK9-AAV overexpression induces atherogenesis without germline editing. "APOE3-Leiden.CETP mice, a well-established model for human-like lipoprotein metabolism"* (PMID: 40460236).

Applications: dissecting apoB retention, foam-cell biology, efferocytosis (MerTK), SMC lineage plasticity (dual lineage tracing, PMID: 41648299), and hemodynamic endothelial dysfunction. Limitations: the dominant murine models do not produce spontaneous coronary plaque rupture or MI, so terminal-route mechanisms (rupture vs erosion) are studied primarily by human coronary OCT in vivo (F003). Negative-control model result: PUFA-synthesis-deficient (fads2⁻/⁻) mice remain atherosclerosis-prone when crossed to Apoe⁻/⁻/Ldlr⁻/⁻ — hypercholesterolemia dominates (PMID: 34530175).

Resources: MGI, IMPC/KOMP, IMSR, Alliance of Genome Resources.

Mechanistic Model / Interpretation

The synthesis across 17 findings supports a staged, multi-arm causal model in which initiation, progression, stability, and acute thrombosis are distinct processes with distinct evidence:

1. Initiation is apoB-driven and hemodynamically localized. Human genetics (PCSK9 LoF, F009; LPA, F010) and randomized LDL-lowering (F013, F002) establish apoB/LDL causality at the highest tier; direct human coronary imaging (F007) shows low wall shear stress plus lipid content accelerates coronary plaque growth. These converge on a strong causal edge: apoB retention + disturbed flow → coronary plaque.

2. Progression is governed by cellular handling of lipid and dead cells. Defective MerTK efferocytosis (mouse, F008) and oxLDL-driven foam-cell formation (in vitro, F008) expand the necrotic core; SMC-to-macrophage-like transdifferentiation (mouse/human, F004) thins the fibrous cap. These are mechanistically compelling but anatomically indirect (mouse aorta, cultured cells) — they explain how human coronary composition arises without proving coronary causality alone.

3. Inflammation is an independent causal arm. CANTOS (F011) and colchicine trials (F012) reduce human coronary events without lipid change, while the null CIRT/methotrexate result isolates the IL-1β→IL-6→CRP axis. IL-1β can also feed back on initiation by inducing coronary-endothelial LDL transcytosis (in vitro/mouse, PMID: 38989581).

4. Terminal events are composition-, not stenosis-, dependent, with two routes. PROSPECT (F001) shows angiographically mild lesions cause future events when plaque burden/necrotic-core/thin-cap features are present; human coronary OCT (F003) resolves rupture (~2/3) vs erosion (~1/3) as biologically distinct triggers of thrombosis.

5. Therapeutic corollary: because stenosis is not the driver of hard events, revascularization relieves symptoms but does not reduce death/MI in stable CAD (ISCHEMIA, F017), whereas systemic apoB lowering and anti-inflammation modify the biology and reduce events.

Terminal-route detail: rupture vs erosion

Genuine competing hypotheses

• "Response-to-retention" (apoB-centric) vs "inflammation-primary": the evidence supports these as complementary, both causal arms. Best synthesis: apoB is the initiating cause; inflammation is a required amplifier (Lp(a) mediates only 1.3–4.8% of the IL-6→ASCVD effect, PMID: 41932221, arguing for independence).
• Rupture-dominant vs erosion-inclusive paradigm: OCT data force inclusion of erosion as a mechanistically separate, potentially antithrombotic-manageable route.
• Macrophage origin: whether lesional "macrophages" are monocyte- vs SMC-derived (F004) remains partly unresolved and matters for target selection.

Evidence Base (Key Literature)

Suggested Ontology Terms

Limitations and Knowledge Gaps

1. Vascular-bed indirectness. Much mechanistic detail (efferocytosis, SMC switching, shear-endothelial signaling) derives from mouse aorta or cultured cells, not epicardial coronary tissue. Per the scope guardrails, carotid/aortic human plaque and mouse-carotid disturbed-flow work (e.g., 38639096, 40594772) remain transferable atherosclerosis evidence only, not human coronary evidence.
2. Imaging surrogates ≠ cellular mechanism. IVUS/OCT/NIRS/CAC quantify composition and predict events but do not prove a specific cellular mediator; GLAGOV/PACMAN show plaque regression, not a demonstrated causal cell type.
3. Erosion biology underexplored. The ~1/3 of ACS due to erosion has fewer mechanistic and therapeutic data than rupture; targeted therapy is nascent.
4. Model fidelity. Dominant murine models lack spontaneous coronary rupture/thrombosis (F016); terminal-route mechanisms rest primarily on human in-vivo OCT and pathology.
5. CHIP and SMC-origin questions. Causality in humans for CHIP is association + mouse mechanism; the monocyte- vs SMC-derived macrophage question (F004) is unresolved.
6. Residual risk. Even with excellent LDL control, events persist (motivating Lp(a) and inflammation targeting); the full mediator set of residual risk is incompletely defined.
7. Citation caveat. One snippet (30482443) flagged a quote-validation mismatch and should be re-verified before KB ingestion.

Proposed Follow-up Experiments / Actions

1. Coronary-specific causal localization: apply spatial transcriptomics and genetic-lineage inference to human epicardial coronary plaques (not carotid/aortic surrogates) to test whether SMC-to-macrophage transitions and IRF7 activity localize to coronary rupture/erosion sites.
2. Erosion-directed intervention trial: OCT-guided randomization of antithrombotic-only vs stenting in confirmed erosion (extending EROSION-concept designs) with hard endpoints.
3. Lp(a)-lowering outcome readout: analyze OCEAN(a) (olpasiran) and Lp(a) HORIZON (pelacarsen) to test whether genetically causal Lp(a) reduction reduces coronary events, with plaque-composition endpoints.
4. Inflammation × lipid factorial trials: test IL-6-pathway inhibition (e.g., ziltivekimab) plus intensive LDL lowering to quantify additive coronary benefit, exploiting the demonstrated independence of the two arms (PMID: 41932221).
5. Efferocytosis restoration: test pro-efferocytic agents (MerTK-stabilizing or CD47-axis modulators) in large-animal coronary models (pig/NHP) with necrotic-core imaging endpoints.
6. CHIP-stratified anti-inflammatory therapy: prospectively test whether TET2/DNMT3A CHIP carriers derive enhanced benefit from IL-1β/IL-6 inhibition.
7. CAC/AI imaging integration: validate AI-derived CAC-scan biomarkers (chamber ratios, hepatic steatosis) for coronary + heart-failure risk in prospective trials.

Bottom line

Coronary atherosclerosis (MONDO:0021661) is an apoB-initiated, shear-patterned, inflammation-amplified intimal disease whose composition — not stenosis — governs acute risk through two distinct terminal routes (rupture and erosion). The causal backbone (apoB via PCSK9/LPA genetics and LDL trials; IL-1β/IL-6 via CANTOS/colchicine) is proven in humans, while the cellular mechanism (SMC switching, efferocytosis, foam-cell biology) is robustly established in models/carotid tissue and awaits coronary-localized confirmation.

Report scope locked to MONDO:0021661 coronary atherosclerosis. Evidence tiers, vascular beds, and null/discordant results are stated explicitly per the issue-specific guardrails; reviews were treated as orientation and primary studies anchor each claim.