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Classifications

Harrison's Part

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Mechanistic Hypotheses

3

Amplification of polygenic CAD risk in adverse contexts via shared endothelial-dysfunction convergence

pgs_context_amplification EMERGING

Evidence balance 2 support

Polygenic-score-by-context (PGS×C) interactions reported for coronary artery disease in the UK Biobank appear to be driven not by different causal variants acting in different environments, but by amplification: the same susceptibility loci (e.g. the 9p21 locus, APOE, LDLR, PCSK9) exert systematically larger effects in disease-promoting contexts. This entry proposes that the amplification arises because the polygenic liability and adverse exposures such as tobacco smoking converge on a shared upstream pathophysiology node — Endothelial Dysfunction — so their joint effect is super-additive on the liability-threshold scale rather than additive. Nagpal & Gibson (Nat Genet 2026, PMID:42443528) report that in past smokers with low omega-6 fatty acid levels the majority of CAD genetic effects are nearly perfectly correlated with, but up to twofold larger in magnitude than, those in non-smokers with higher omega-6 fatty acids, alongside an ~8% higher SNP-heritability — the signature of amplification rather than uncorrelated context-specific effects.

EMERGING hypothesis motivated by population-scale PGS×context analyses (primary source PMID:42443528; general amplification mechanism corroborated by PMID:37228747, which also documents testosterone-mediated amplification). The convergence claim (genetic liability + smoking → Endothelial Dysfunction) is a mechanistic interpretation and is not itself established as causal — see the reverse-causation knowledge gap under discussions.

Show evidence (2 references)

PMID:42443528 SUPPORT Computational

"The predominant mechanism for PGS×C is the amplification of genetic effects in adverse contexts, such as low polyunsaturated fatty acids or social determinants of ill health"

Direct source (Nagpal & Gibson 2026): across seven UK Biobank diseases and 75 contexts, amplification of genetic effects in adverse contexts is identified as the predominant mechanism of PGS×context interaction — the mechanism applied in this hypothesis.

PMID:37228747 SUPPORT Computational

"GxSex is pervasive but acts primarily through systematic sex differences in the magnitude of many genetic effects"

Establishes amplification — systematic differences in the magnitude of polygenic effects rather than in the identity of causal variants — as the primary mode of gene-by-context interaction. Sex is among the contexts showing the strongest PGS×context amplification for CAD, so this supports amplification as the mechanism underlying the CAD PGS×C interactions modelled here.

Icosapent Ethyl Coronary Plaque-Remodeling Model

icosapent_ethyl_coronary_plaque_remodeling_model EMERGING

Evidence balance 5 support

In statin-treated people with coronary atherosclerosis and persistent hypertriglyceridemia, icosapent ethyl may contribute to the observed cardiovascular-event contrast by altering coronary plaque composition or progression rather than through isolated change in circulating triglyceride concentration. EVAPORATE reported a randomized between-arm imaging signal, but its cached abstract reports 80 enrolled without the paired-scan analytic denominator or baseline plaque balance, and the reported multivariable model did not adjust for baseline plaque. Missing-scan and regression-to-the-mean sensitivity therefore remain unresolved. The trial also used a mineral-oil comparator and a surrogate endpoint and did not test whether plaque change mediated clinical events.

This is a small 80-patient surrogate imaging hypothesis, not a treatment-to-pathophysiology edge. REDUCE-IT tested a high-risk ASCVD-or-diabetes population broader than coronary artery disease; EVAPORATE is the coronary-specific lead and did not test clinical outcomes or mediation. Focused research must compare plaque remodeling with: remnant- and apolipoprotein-B particle number, composition, trafficking, and arterial retention; platelet activation and thromboxane biology; specialized inflammatory-resolution lipid mediators rather than generic C-reactive-protein lowering; endothelial nitric-oxide and vascular-function effects; membrane stabilization, lipid peroxidation, and oxidized-lipid effects; and biomarker increases observed in mineral-oil-assigned participants. Achieved-EPA concentrations and other postrandomization biomarker associations may reflect adherence, absorption, or metabolism and cannot identify a mediator without prespecified temporal causal-mediation analysis. Distinguish a causal mediator from a baseline effect modifier, parallel pharmacodynamic marker, surrogate correlate, or comparator artifact.

Deep research

OpenScientist citations 29 citations 2026-07-26T10:36:09.068894

Show evidence (5 references)

PMID:32860032 SUPPORT Human Clinical

"A total of 80 patients were enrolled in this randomized, double-blind, placebo-controlled trial."

EVAPORATE enrolled only 80. The cached abstract does not report how many participants contributed interpretable paired scans, so the effective analysis size and missing-scan sensitivity are not established by this exact evidence.

PMID:32860032 SUPPORT Human Clinical

"There was a significant reduction in the primary endpoint as IPE reduced LAP plaque volume by 17%, while in the placebo group LAP plaque volume more than doubled (+109%) (P = 0.0061)."

The reported randomized contrast supports differential change in a CT-defined coronary plaque surrogate, not mediation of cardiovascular events or a specific cellular mechanism.

PMID:32860032 SUPPORT Human Clinical

"When further adjusted for age, sex, diabetes status, hypertension, and baseline TG, plaque volume changes between groups remained significantly different, P < 0.01."

Persistence after adjustment for baseline triglyceride is compatible with more than baseline-risk imbalance, but it is not a randomized mediation analysis of triglyceride response. The quoted adjustment list does not include baseline plaque, and the cached abstract does not report baseline plaque balance, so regression-to-the-mean sensitivity remains unresolved.

+ 2 more references

Icosapent Ethyl Atherogenic Particle-Lowering Model

icosapent_ethyl_atherogenic_particle_lowering_model EMERGING

Evidence balance 1 support

In statin-treated people with persistent triglyceride elevation, icosapent ethyl may contribute to plaque or event effects by lowering concentrations of atherogenic VLDL and LDL particles, thereby reducing arterial exposure or retention of apoB-containing particles. A short-duration ANCHOR analysis establishes pharmacodynamic change but did not measure coronary plaque, clinical events, or treatment-to-particle-to-event mediation.

The particle-lowering model can be upstream of the plaque-remodeling model rather than mutually exclusive. Randomized biomarker change is established; the proposed particle-retention and particle-to-plaque-to-event links remain unconfirmed.

Show evidence (1 reference)

PMID:26073397 SUPPORT Human Clinical

"Compared with placebo (n = 211), IPE 4 g/day (n = 216) significantly reduced concentrations of: total (12.2%, P = .0002), large (46.4%, P < .0001), and medium (12.1%, P = .0068) very-low-density lipoprotein (VLDL) particles; total (7.7%, P = .0017) and small (13.5%, P < .0001) LDL particles"

This prespecified exploratory 12-week NMR analysis supports an IPE-versus-placebo contrast in atherogenic particle concentrations, but it did not test coronary plaque, clinical events, or mediation. Without an inert third arm, it does not separate direct IPE action from comparator behavior.

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Discussions and Knowledge Gaps

2

Are the CAD PGS×context interactions driven by adverse exposures causally amplifying genetic risk, or are some "contexts" actually downstream readouts of incipient disease (reverse causation)?

KNOWLEDGE GAP OPEN cad_pgsxc_reverse_causation

Attached to

pathophysiology#Endothelial Dysfunction biochemical#LDL Cholesterol biochemical#C-Reactive Protein environmental#Smoking

Population PGS×context analyses (Nagpal & Gibson 2026, PMID:42443528) are largely unable to establish the causality of specific contexts. dismech separates true environmental exposures (smoking, high-fat diet, sedentary lifestyle) from biochemical readouts (LDL, HDL, C-reactive protein); the biochemical "contexts" are prime reverse-causation suspects, since they may be partly downstream of the atherosclerotic process rather than upstream drivers, and behavioural contexts such as reduced physical activity may be rapid responses to incipient angina rather than causes. Distinguishing genuine amplification of genetic effects from reverse causation determines whether the modelled interventions (e.g. lowering cholesterol in high-PGS smokers) would actually reduce risk.

Proposed experiments

Mendelian randomization of exposure-to-CAD direction across PGS strata

cad_pgsxc_mr_direction

Use bidirectional / multivariable Mendelian randomization to test whether each candidate context (LDL, HDL, C-reactive protein, smoking) causally affects CAD versus being a consequence of subclinical disease, and whether the causal effect estimate scales with polygenic liability as the amplification model predicts.

Decision criterion

A context is retained as a causal amplifier if MR supports exposure-to-disease directionality and the exposure-attributable risk difference increases across increasing PGS strata; it is flagged as a reverse-causation suspect otherwise.

Prospective incident-CAD analysis restricted to pre-diagnosis exposure windows

cad_pgsxc_prospective_temporal

Restrict exposures to measurements taken well before diagnosis and repeat the PGS×context liability-threshold modelling on incident cases only, to reduce the chance that exposure values reflect behavioural responses to early disease.

Decision criterion

Amplification is supported if the PGS×context deviation from additivity persists when only pre-diagnosis exposure windows and incident cases are used.

Which, if any, pathway beyond change in circulating triglyceride concentration causally mediates the cardiovascular-event contrast observed with high-dose icosapent ethyl: coronary plaque remodeling; altered apolipoprotein-B/remnant burden, composition, trafficking, or retention; platelet effects; inflammatory resolution; endothelial effects; or membrane stabilization and reduced lipid oxidation? How much of the contrast reflects the mineral-oil comparator?

KNOWLEDGE GAP OPEN gap_icosapent_ethyl_event_reduction_mechanism

Attached to

treatments#Icosapent Ethyl mechanistic_hypotheses#icosapent_ethyl_coronary_plaque_remodeling_model mechanistic_hypotheses#icosapent_ethyl_atherogenic_particle_lowering_model pathophysiology#Atherosclerotic Plaque Formation pathophysiology#Endothelial Dysfunction pathophysiology#Plaque Rupture and Thrombosis biochemical#C-Reactive Protein

REDUCE-IT established an ischemic-event contrast between icosapent ethyl and a mineral-oil comparator but did not identify a mediator. The seed review explicitly states that triglyceride lowering does not fully explain the benefit. The small 80-patient EVAPORATE trial observed differential CT-plaque change against mineral oil after adjustment for baseline triglyceride, but plaque is a surrogate and the study did not test treatment-to-plaque-to-event mediation. In the REDUCE-IT biomarker substudy, icosapent ethyl produced minimal change in several inflammatory and lipid-oxidation markers while those markers increased among participants assigned to mineral oil; without an inert third arm, relative biomarker differences do not establish direct icosapent lowering or mineral-oil causation. Focused research found a lower-dose EPA plaque-volume signal in CHERRY, no overall fibrous-cap-thickness benefit in a separate three-arm trial, and short-term IPE-associated atherogenic-particle reductions in ANCHOR; none tested clinical mediation. A post hoc REDUCE-IT prior-PCI subgroup supports transfer of the event contrast to coronary disease but remains a subgroup analysis against mineral oil. RESPECT-EPA, an open-label 1.8-g/day Japanese stable-CAD trial without an oil placebo, reported a nonsignificant primary endpoint, a significant secondary coronary composite, and more new-onset atrial fibrillation; it supplies a coronary signal from a comparison that did not use mineral oil but does not establish a mechanism. STRENGTH found no event benefit for a distinct EPA/DHA carboxylic-acid formulation against corn oil intended as an inert comparator. That result constrains class-wide omega-3 inference but does not directly test purified IPE or distinguish its candidate pathways. Plaque remodeling; remnant-particle composition, number, trafficking, and arterial retention; platelet biology; specialized inflammatory resolution; endothelial function; and membrane or lipid-oxidation effects remain candidates rather than established mechanisms. Baseline-subgroup, achieved-EPA, and other postrandomization associations cannot substitute for randomized temporal mediation.

Proposed experiments

Multi-comparator icosapent trial with prospective temporal mediation

randomized temporal causal-mediation trial

exp_icosapent_multicomparator_temporal_mediation_trial

Embed an independently analyzed mechanistic substudy in an adequately powered, double-blind cardiovascular-outcome trial of icosapent ethyl 4 g/day versus a metabolically inert, non-mineral-oil matched placebo. Enroll people with documented coronary atherosclerosis, persistent triglyceride elevation, stable lipid-lowering and antiplatelet therapy, and prespecified diabetes, sex, renal-function, and baseline-plaque strata. Add a randomized, chemically distinct triglyceride-lowering comparator arm, powered for mechanistic and plaque contrasts and prospectively titrated to approximate the icosapent arm's triglyceride trajectory. Where ethics and safety oversight permit, include a time-limited mineral-oil calibration arm to estimate short-term comparator effects on biomarkers. That calibration cannot determine mineral oil's contribution to a multi-year clinical-event contrast.

Perturbations

Icosapent ethyl 4 g/day

treatments#Icosapent Ethyl

Randomize purified icosapent ethyl with adherence measured independently of achieved eicosapentaenoic-acid concentration.

Readouts

Atherogenic-particle and remnant trajectories

mechanistic_hypotheses#icosapent_ethyl_atherogenic_particle_lowering_model

Measure triglycerides, apolipoprotein B and particle number, remnant cholesterol and composition, and proteoglycan binding before plaque or event divergence.

longitudinal lipoprotein particle and remnant profiling

Direction: NEGATIVE

Prespecified non-particle mediator trajectories

mechanistic_hypotheses#icosapent_ethyl_coronary_plaque_remodeling_model

Measure EPA/arachidonic-acid lipid mediators, specialized pro-resolving mediators, high-sensitivity C-reactive protein, interleukin-6, endothelial function, platelet COX-1/thromboxane activity and reactivity, membrane lipid order and oxidative susceptibility, oxidized LDL, and achieved EPA before plaque or event divergence.

longitudinal lipidomic, lipoprotein, and membrane-biophysics profiling inflammatory-resolution and platelet functional assay

Direction: THRESHOLD DEPENDENT

Coronary plaque change

pathophysiology#Atherosclerotic Plaque Formation

Quantify low-attenuation, noncalcified, and total plaque with a blinded central CCTA core and a prespecified OCT or IVUS substudy.

serial coronary computed tomographic angiography intravascular plaque imaging

Direction: NEGATIVE

Adjudicated cardiovascular and safety outcomes

treatments#Icosapent Ethyl

Adjudicate myocardial infarction, stroke, revascularization, cardiovascular death, atrial fibrillation or flutter, and serious bleeding without using a surrogate as the clinical endpoint.

blinded cardiovascular event adjudication

Direction: THRESHOLD DEPENDENT

Controls

Inert matched placebo

Use a sensory-matched comparator shown in a run-in study not to alter lipids, inflammatory biomarkers, renal function, or platelet assays.

Triglyceride-matched active comparator

Randomize a chemically distinct triglyceride-lowering intervention and use blinded dose adaptation to approximate the icosapent arm's triglyceride trajectory without matching achieved EPA exposure. Analyze apolipoprotein-B and remnant-particle differences explicitly rather than assuming that triglyceride matching equalizes them.

Time-limited mineral-oil calibration control

If approved, randomize a short mechanistic calibration arm with stopping rules. Use it only to estimate short-term biomarker effects, not to attribute the long-term clinical-event contrast.

Background-therapy and implementation controls

Standardize statin, antiplatelet, diet, and diabetes therapy; monitor placebo and active-comparator effects, adherence, renal function, and treatment crossover.

Mediation-analysis controls

Prespecify temporal ordering, multiplicity correction, missing-data handling, exposure-induced mediator-outcome confounding, and sensitivity analyses that do not condition only on achieved EPA levels.

Decision criterion

A candidate mediator is supported only if randomization changes it versus the inert comparator before plaque or clinical divergence and a prespecified treatment-to-mediator-to-endpoint indirect effect replicates. If mineral oil worsens a marker while icosapent and inert placebo do not differ, comparator worsening explains that short-term marker contrast, while its contribution to long-term events remains unresolved. A lipid-mediated explanation requires prespecified interventional indirect- and direct-effect estimands, explicit identification assumptions, and sensitivity analyses to be consistent with full mediation and little or no residual direct effect; ordinary adjustment for postrandomization triglyceride, apolipoprotein-B, remnant, or achieved-EPA measures is insufficient. If plaque trajectories are similar to the triglyceride-matched active comparator, that weakens evidence for an icosapent-specific effect but does not refute icosapent-induced remodeling without prespecified equivalence margins, adequate precision, and assumptions excluding the comparator's own plaque effects. Refute this hypothesis only if the icosapent-versus-inert contrast excludes a prespecified clinically meaningful plaque effect or a well-identified mediation analysis excludes a clinically meaningful plaque-mediated indirect effect. No biomarker or imaging association alone establishes mediation.

Would support

mechanistic_hypotheses#icosapent_ethyl_coronary_plaque_remodeling_model mechanistic_hypotheses#icosapent_ethyl_atherogenic_particle_lowering_model

Would refute

mechanistic_hypotheses#icosapent_ethyl_coronary_plaque_remodeling_model mechanistic_hypotheses#icosapent_ethyl_atherogenic_particle_lowering_model

Show evidence (7 references)

PMID:42397965 SUPPORT Other

"Icosapent ethyl has demonstrated reductions in major adverse cardiovascular events, although the mechanism of benefit remains incompletely understood and is not explained entirely by triglyceride lowering."

The seed review directly defines the unresolved mechanism but does not establish any proposed mediator.

PMID:35762321 SUPPORT Human Clinical

"Among participants in REDUCE-IT, allocation to icosapent ethyl had minimal effects on a series of biomarkers associated with atherosclerotic disease, whereas levels increased among those allocated to mineral oil."

Randomized longitudinal biomarker data show that relative inflammatory differences cannot be interpreted as direct biomarker lowering by icosapent ethyl.

PMID:35762321 SUPPORT Human Clinical

"The effect of these findings on interpretation of the overall risk reductions in clinical events observed within REDUCE-IT is uncertain."

The investigators explicitly preserve uncertainty about how mineral-oil biomarker changes affect interpretation of the event contrast.

+ 4 more references

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Pathophysiology

6

Endothelial Dysfunction

At atherosclerosis-prone arterial sites, disturbed flow is associated with endothelial stress and senescence, while reduced endothelial nitric-oxide biosynthesis represents the vasomotor dysfunction that impairs dilation. This nonconforming coronary endothelial-function branch is modeled separately from the conserved subendothelial apoB-retention trigger. The cited disturbed-flow evidence derives from mouse carotid arteries and human carotid plaques, so its transfer to coronary endothelial dysfunction is explicitly partial.

Endothelial Cell CL:0000115

Nitric Oxide Production GO:0006809 ↓ DECREASED

Downstream

Coronary Endothelial Injury and Subendothelial LDL Retention Connects the vasomotor and disturbed-flow endothelial branch to the conserved retention trigger without asserting that reduced nitric oxide alone is sufficient for apoB retention.

Show evidence (2 references)

PMID:40594772 SUPPORT Model Organism

"CD36 + positive ECs exhibited significant senescence phenotypes following disturbed flow stimulation."

Supports disturbed-flow-associated endothelial senescence as one component of endothelial dysfunction. It does not directly measure nitric-oxide biosynthesis and comes from a mouse carotid model, so it is not treated as direct coronary or nitric-oxide evidence.

PMID:40594772 SUPPORT Model Organism

"Atherosclerosis tends to occur in regions of disturbed blood flow. This study explored how disturbed flow aggravates atherosclerosis using single-cell RNA-seq (scRNA-seq) datasets from mouse carotid arteries under disturbed flow and human carotid artery plaques."

Supports disturbed flow as a regional context for atherosclerosis and endothelial dysfunction. It does not directly establish reduced nitric-oxide biosynthesis or a coronary-specific effect.

Coronary Endothelial Injury and Subendothelial LDL Retention

In the coronary 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, providing the coronary trigger for atheroma formation.

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; coronary arterial intima is the disease-specific location represented here.

Monocyte Recruitment and Macrophage Foam Cell Formation

In the coronary 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 Arterial Wall Lipid Accumulation GO:0019915 ↑ INCREASED Inflammatory Response GO:0006954 ↑ INCREASED

Downstream

Atherosclerotic Plaque Formation

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.

Atherosclerotic Plaque Formation

In the inflamed coronary 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 of coronary atheroma formation.

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 (2 references)

PMID:39518492 SUPPORT Other

"We examine the cellular and molecular processes that drive the formation of calcified plaques, highlighting the roles of inflammation, lipid accumulation, and smooth muscle cell proliferation."

Supports lipid accumulation, inflammation, and smooth-muscle-cell proliferation as contributors to coronary plaque formation. It does not by itself establish the specific phenotypic-switching or matrix-assembly sequence represented by this node.

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.

Advanced Atheroma with Necrotic Core and Fibrous Cap

Continued lipid accumulation, foam-cell death, and matrix remodeling produce a mature coronary atheroma with a necrotic lipid core beneath a fibrous cap. Expansion of the core and local plaque microenvironment can destabilize the cap and create a rupture-prone coronary lesion.

Vascular Smooth Muscle Cell CL:0000359

Extracellular Matrix Organization GO:0030198 ↑ INCREASED

Coronary Artery UBERON:0001621

Downstream

Plaque Rupture and Thrombosis

Show evidence (4 references)

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 stable mature atheroma to an unstable lesion; coronary artery is the disease-specific location substituted here.

PMID:38639096 SUPPORT Human Clinical

"Advanced stages of atherosclerosis progression and symptomatic carotid plaques were largely characterized by 3 smooth muscle cells (SMCs), and 3 macrophage subtype clusters with extracellular matrix organization/osteogenic (SMC), and M1-type proinflammatory/Trem2-high lipid-associated..."

Supports the smooth-muscle-cell, extracellular-matrix, and lipid-associated macrophage composition of advanced human atherosclerotic plaque. The tissue studied was carotid plaque, so this is partial support for conserved advanced-atheroma biology rather than direct coronary evidence.

PMID:40594772 SUPPORT Model Organism

"Notable increases in VEGFA+ macrophages were discovered in the disturbed flow stimulation group, displaying a pronounced M1 pro-inflammatory phenotype associated with the severity of atherosclerosis and plaque stability."

Supports an inflammatory macrophage phenotype associated with plaque severity and stability, not rupture or thrombosis. The disturbed-flow comparison is from a mouse carotid model, so support for coronary advanced atheroma is partial.

+ 1 more reference

Plaque Rupture and Thrombosis

Rupture of an unstable coronary atheroma, or endothelial erosion over it, exposes thrombogenic material and triggers platelet activation, coagulation, and thrombotic coronary occlusion, causing acute coronary syndrome and myocardial infarction.

Platelet CL:0000233

Thrombosis GO:0007596 ↑ INCREASED

Show evidence (2 references)

PMID:37595697 SUPPORT Other

"Destabilization is characterized by several different plaque phenotypes that cause major clinical events such as acute coronary syndrome and cerebrovascular strokes."

Histopathology and vascular-imaging evidence directly connects unstable atheroma phenotypes with acute coronary syndrome, supporting this terminal coronary consequence.

PMID:37595697 SUPPORT Other

"Endothelial erosion without rupture has more recently been shown to be a common phenotype to promote thrombosis as well."

Directly supports endothelial erosion as a thrombosis-promoting alternative to fibrous-cap rupture in the coronary consequence node.

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Pathograph

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Phenotypes

3

Cardiovascular 2

Angina Pectoris FREQUENT HP:0001681

Chest pain due to myocardial ischemia

Myocardial Infarction OCCASIONAL HP:0001658

Acute complication of plaque rupture

Show evidence (1 reference)

PMID:24902970 SUPPORT Other

"may suddenly cause life-threatening coronary thrombosis presenting as an acute coronary syndrome"

Directly links rupture of a coronary atherosclerotic plaque to acute coronary syndrome, the mechanism by which myocardial infarction arises as a complication of coronary artery disease.

Respiratory 1

Dyspnea on Exertion FREQUENT HP:0002094

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Genetic Associations

4

APOE (Risk Factor)

Gene: APOE hgnc:613

Show evidence (1 reference)

PMID:17878422 SUPPORT Human Clinical

"Compared with epsilon3/epsilon3, the odds ratio for coronary disease was 0.80 (95% CI, 0.70-0.90) in epsilon2 carriers and was 1.06 (95% CI, 0.99-1.13) in epsilon4 carriers."

Meta-analysis of 121 studies (37,850 coronary cases) quantifies the APOE genotype-coronary risk association, with epsilon2 carriers at lower risk than the epsilon3/epsilon3 reference.

LDLR (Risk Factor)

Gene: LDLR hgnc:6547

Show evidence (1 reference)

PMID:28444290 SUPPORT Other

"Rare genetic mutations that cause reduced LDL receptor function lead to markedly higher LDL-C and a dose-dependent increase in the risk of ASCVD"

EAS consensus statement establishes that loss of LDL-receptor function raises LDL-C and increases atherosclerotic cardiovascular risk in a dose-dependent manner.

PCSK9 (Risk Factor)

Gene: PCSK9 hgnc:20001

Show evidence (1 reference)

PMID:16554528 SUPPORT Human Clinical

"these mutations were associated with a 28 percent reduction in mean LDL cholesterol and an 88 percent reduction in the risk of CHD"

ARIC cohort shows PCSK9 nonsense variants lower LDL cholesterol and substantially reduce coronary heart disease incidence, establishing PCSK9 as a causal modifier of coronary risk.

9p21 Locus (Risk Factor)

Show evidence (1 reference)

PMID:17478681 SUPPORT Human Clinical

"Homozygotes for the risk allele make up 20 to 25% of Caucasians and have a approximately 30 to 40% increased risk of CHD."

Genome-wide association scanning identified the chromosome 9p21 interval as a common CHD risk locus, quantifying the effect size in risk-allele homozygotes.

💊

Medical Actions

7

Statins

Action: statin therapy Ontology label: Pharmacotherapy NCIT:C15986

Lower LDL cholesterol and stabilize atherosclerotic plaques.

Show evidence (1 reference)

PMID:40787973 SUPPORT Other

"The guidelines recommend that all patients with chronic coronary artery disease receive high-intensity lipid-lowering treatment, with a target LDL level of less than 1.4 mmol/L."

The ESC chronic-coronary-syndrome guidelines recommend high-intensity lipid-lowering therapy (statins) for all patients, targeting LDL below 1.4 mmol/L.

Icosapent Ethyl

Action: Pharmacotherapy NCIT:C15986

Agent: icosapent ethyl CHEBI:84883

In REDUCE-IT, adjunctive icosapent ethyl 4 g/day reduced composite ischemic events versus a mineral-oil comparator in selected statin-treated adults with established cardiovascular disease or diabetes plus risk factors and persistent triglyceride elevation. Hospitalization for atrial fibrillation or flutter was more frequent. The trial population was broader than coronary artery disease alone, and neither the mediating mechanism nor the benefit magnitude versus an inert non-mineral-oil comparator is established.

Show evidence (4 references)

PMID:30415628 SUPPORT Human Clinical

"A primary end-point event occurred in 17.2% of the patients in the icosapent ethyl group, as compared with 22.0% of the patients in the placebo group"

REDUCE-IT directly establishes the randomized composite-event contrast in its selected high-risk, statin-treated population.

PMID:35261279 SUPPORT Human Clinical

"Among patients treated with icosapent ethyl versus placebo, there was a 34% reduction in the primary composite end point"

This post hoc analysis of 3408 REDUCE-IT participants with prior PCI reported HR 0.66 (95% CI, 0.58-0.76) for this endpoint, supporting applicability of the randomized event contrast to a coronary subgroup. It does not identify a mediator, was not a separate randomized trial of coronary disease, and retains the parent trial's mineral-oil comparison.

PMID:30415628 SUPPORT Human Clinical

"A larger percentage of patients in the icosapent ethyl group than in the placebo group were hospitalized for atrial fibrillation or flutter (3.1% vs. 2.1%, P=0.004)."

The randomized safety result bounds an unqualified cardioprotective interpretation.

+ 1 more reference

Antiplatelet Therapy

Action: antiplatelet therapy Ontology label: Pharmacotherapy NCIT:C15986

Aspirin and P2Y12 inhibitors reduce thrombotic risk.

Show evidence (1 reference)

PMID:11786451 SUPPORT Human Clinical

"allocation to antiplatelet therapy reduced the combined outcome of any serious vascular event by about one quarter; non-fatal myocardial infarction was reduced by one third, non-fatal stroke by one quarter, and vascular mortality by one sixth"

Collaborative meta-analysis of randomised trials quantifies the reduction in serious vascular events, myocardial infarction, and vascular mortality achieved by antiplatelet therapy in high-risk patients.

ACE Inhibitors

Action: ACE inhibitor therapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: ACE inhibitor NCIT:C247

Provide cardiovascular protection beyond blood pressure lowering.

Beta Blockers

Action: beta-blocker therapy Ontology label: Pharmacotherapy NCIT:C15986

Reduce myocardial oxygen demand and prevent angina.

Percutaneous Coronary Intervention

Action: percutaneous coronary intervention Ontology label: Percutaneous Coronary Intervention NCIT:C99521

Angioplasty with stenting to restore coronary blood flow.

Coronary Artery Bypass Grafting

Action: coronary artery bypass grafting Ontology label: Coronary Artery Bypass Surgery NCIT:C51998

Surgical revascularization for severe multivessel disease.

🌍

Environmental Factors

4

Smoking

Major modifiable risk factor, with a dose-response relationship to myocardial infarction risk.

Show evidence (2 references)

PMID:15364185 SUPPORT Human Clinical

"Smoking (odds ratio 2.87 for current vs never, PAR 35.7% for current and former vs never)"

INTERHEART, a standardised case-control study of acute myocardial infarction across 52 countries with 15152 cases and 14820 controls. Establishes smoking as one of the largest modifiable contributors to population attributable risk.

PMID:16920470 SUPPORT Human Clinical

"risk increased by 5.6% for every additional cigarette smoked"

The tobacco-specific INTERHEART analysis. Quoted for the dose-response relationship, which is the part of the note the odds ratio alone does not establish.

High-Fat Diet

Dietary saturated fat raises serum cholesterol and cardiovascular event risk. The measured effect on LDL specifically is small; the robust finding is the reduction in combined cardiovascular events when saturated fat is reduced.

Show evidence (1 reference)

PMID:32428300 SUPPORT Human Clinical

"Meta-regression suggested that greater reductions in saturated fat (reflected in greater reductions in serum cholesterol) resulted in greater reductions in risk of CVD events, explaining most heterogeneity between trials"

Cochrane review of 15 randomised controlled trials with about 59000 participants. Note this source qualifies the original note rather than simply confirming it: the same abstract reports only small reductions in LDL cholesterol from reducing saturated fat, so LDL elevation is a weaker claim than the cardiovascular event effect, and the note was rewritten accordingly.

Sedentary Lifestyle

Physical inactivity is an independent contributor to myocardial infarction risk. Low physical activity is associated with metabolic syndrome, but sedentary behaviour measured as screen time is not, so the metabolic-syndrome route is not a settled mechanism for this exposure.

Show evidence (2 references)

PMID:15364185 SUPPORT Human Clinical

"regular physical activity (0.86, PAR 12.2%)"

INTERHEART reports regular physical activity as protective against myocardial infarction with a population attributable risk of 12.2 percent for its absence, which is the evidence that inactivity is a risk factor for this disease.

PMID:27997601 SUPPORT Human Clinical

"for sedentary behavior, represented by screen time > 2 hours/day, a significant association was not identified"

Cited as a caveat, not support. This meta-analysis of eighteen studies found low physical activity significantly associated with metabolic syndrome, but sedentary behaviour measured as screen time was NOT significantly associated overall - only on weekends in subgroup analysis. It is an adolescent population, so it does not settle the question in adults, but it is enough to show the metabolic-syndrome mechanism should not be stated flatly.

Obesity

Abdominal obesity is an independent contributor to myocardial infarction risk.

Show evidence (1 reference)

PMID:15364185 SUPPORT Human Clinical

"abdominal obesity (1.12 for top vs lowest tertile and 1.62 for middle vs lowest tertile, PAR 20.1% for top two tertiles vs lowest tertile)"

INTERHEART. Note the measure is abdominal obesity by waist/hip ratio rather than body mass index, which is a more specific claim than the entry name suggests.

🔬

Biochemical Markers

3

LDL Cholesterol (Elevated)

Context: Major risk factor for plaque formation

Show evidence (1 reference)

PMID:28444290 SUPPORT Other

"Consistent evidence from numerous and multiple different types of clinical and genetic studies unequivocally establishes that LDL causes ASCVD."

EAS consensus statement concludes that LDL is causal for atherosclerotic cardiovascular disease, supporting elevated LDL cholesterol as a major risk factor for coronary plaque formation.

HDL Cholesterol (Decreased)

Context: Protective factor when adequate

C-Reactive Protein (Elevated)

Context: Marker of inflammation

Show evidence (1 reference)

PMID:20031199 SUPPORT Human Clinical

"Risk ratios (RRs) for coronary heart disease per 1-SD higher log(e) CRP concentration (three-fold higher) were 1.63 (95% CI 1.51-1.76) when initially adjusted for age and sex only, and 1.37 (1.27-1.48) when adjusted further for conventional risk factors"

Individual-participant meta-analysis quantifies the association between circulating C-reactive protein and incident coronary heart disease, supporting CRP as an inflammatory risk marker in coronary artery disease.

📊

Related Datasets

9

Differential Gene Expression related to Telomere Length in Arterial Wall Tissues and Granulocytes of Patients with Coronary Artery Disease geo:GSE289957

Shortened telomere length (TL) in blood cells is associated with atherosclerotic coronary artery disease (CAD). However, the mechanistic pathways underlying TL attrition in arterial wall tissues for patients with CAD remain unclear. In this study, we evaluated TL in arterial wall tissues and granulocytes and correlated these measurements with data on gene expressions in the arterial wall tissues of patients with CAD.

human BULK RNA SEQ n=34

PMID:42211145

Identified by GEO DataSets index search for Coronary Artery Disease (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.

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 Coronary Artery Disease (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.

RNA-seq analysis of human monocytes in patients with and without coronary atherosclerosis geo:GSE282042

We conducted RNA-Seq transcriptome profiling on monocytes isolated from patients undergoing coronary angiography. After the procedure, patients were divided into two groups: those without coronary artery stenosis ("w.o. CA", n=11) and those with coronary artery stenosis ("w. CA", n=9). All patients were men, aged 61±6 years. CD14+ monocytes were isolated, and RNA-seq was performed on the Illumina NextSeq 2000 platform. This data was analyzed to identify changes in gene expression profiles associated with coronary atherosclerosis. Transcriptome analysis revealed an upregulation of numerous inflammatory genes.

human BULK RNA SEQ n=20

PMID:40350260

Identified by GEO DataSets index search for Coronary Artery Disease (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.

WTCCC case-control study for Coronary Artery Disease ega:EGAS00000000003

WTCCC genome-wide case-control association study for Bipolar disorder (CAD) using the 1958 British Birth Cohort and the UK National Blood Service collections as controls.

human

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Coronary Artery Disease"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

WTCCC case-control study for Coronary Artery Disease - Combined Controls ega:EGAS00000000004

WTCCC genome-wide case-control association study for Coronary Artery Disease (CAD) using six disease collections together with the 1958 British Birth Cohort and the UK National Blood Service collections as controls.

human

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Coronary Artery Disease"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

WTCCC case-control study for Coronary Artery Disease, Hypertension, T2D - combined cases ega:EGAS00000000005

WTCCC genome-wide case-control association study using the cardiovascular disease CAD, HT and T2D as combined case collection and the 1958 British Birth Cohort and the UK National Blood Service collections as controls.

human

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Coronary Artery Disease"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

Metabolomics Approach to Identify Molecules and Pathways Involved in the Development of Atherosclerotic Coronary Artery Disease metabolomics_workbench:ST000306

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 ("Coronary Artery Disease"). Retrieved 2026-08-02.

TAILS identifies candidate substrates and biomarkers of ADAMTS7, a therapeutic protease target in coronary artery disease massive:MSV000088508

MacDonald BT, Keshishian H, Mundorff CC, Arduini A, Lai D, Bendinelli K, Popp NR, Bhandary B, Clauser KR, Specht H, Elowe NH, Laprise D, Xing Y, Kaushik VK, Carr SA, Ellinor PT. Loss-of-function mutations in the secreted enzyme ADAMTS7 (a disintegrin and metalloproteinase with thrombospondin motifs 7) are associated with protection for coronary artery disease (CAD). ADAMTS7 catalytic inhibition has been proposed as a therapeutic strategy for treating CAD; however, the lack of an endogenous substrate has hindered the development of activity-based biomarkers.

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

Lipidomics-based algorithms can enhance prediction of obstructive coronary artery disease massive:MSV000095097

Lipidomics-based algorithms can enhance prediction of obstructive coronary artery disease

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

🔬

Clinical Trials

1

NCT05018247 NOT_APPLICABLE

Prospective randomized study comparing early revascularization guided by PET-quantified coronary flow capacity versus optimal medical therapy alone in stable ischemic heart disease.

Show evidence (1 reference)

clinicaltrials:NCT05018247 SUPPORT Human Clinical

"To compare the impact of revascularization and Optimal Medical Treatment (OMT) on the extent of severely reduced coronary flow capacity in stable ischemic heart disease."

The trial directly tests a revascularization strategy for stable ischemic coronary disease, informing interventional management.

{ }

Source YAML

click to show

name: Coronary Artery Disease
creation_date: '2025-12-18T17:01:35Z'
description: >-
  Coronary artery disease (CAD) is the narrowing or obstruction of the coronary
  arteries by atherosclerotic plaque, driven by endothelial dysfunction, lipid
  accumulation, and chronic vascular inflammation. Progressive luminal stenosis
  produces a mismatch between myocardial oxygen supply and demand, causing
  angina, while plaque rupture with superimposed thrombosis precipitates acute
  coronary syndromes and myocardial infarction.
category: Complex
parents:
- Cardiovascular Disease
- Atherosclerotic Disease
disease_term:
  preferred_term: coronary atherosclerosis
  term:
    id: MONDO:0021661
    label: coronary atherosclerosis
pathophysiology:
- name: Endothelial Dysfunction
  description: >-
    At atherosclerosis-prone arterial sites, disturbed flow is associated with
    endothelial stress and senescence, while reduced endothelial nitric-oxide
    biosynthesis represents the vasomotor dysfunction that impairs dilation.
    This nonconforming coronary endothelial-function branch is modeled
    separately from the conserved subendothelial apoB-retention trigger. The
    cited disturbed-flow evidence derives from mouse carotid arteries and human
    carotid plaques, so its transfer to coronary endothelial dysfunction is
    explicitly partial.
  cell_types:
  - preferred_term: Endothelial Cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: Nitric Oxide Production
    term:
      id: GO:0006809
      label: nitric oxide biosynthetic process
    modifier: DECREASED
  evidence:
  - reference: PMID:40594772
    reference_title: "Single-cell RNA-seq analysis of mouse carotid artery under disturbed flow and human carotid plaques identifies key cell populations in atherosclerosis development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "CD36 + positive ECs exhibited significant senescence phenotypes following disturbed flow stimulation."
    explanation: >-
      Supports disturbed-flow-associated endothelial senescence as one component
      of endothelial dysfunction. It does not directly measure nitric-oxide
      biosynthesis and comes from a mouse carotid model, so it is not treated as
      direct coronary or nitric-oxide evidence.
  - reference: PMID:40594772
    reference_title: "Single-cell RNA-seq analysis of mouse carotid artery under disturbed flow and human carotid plaques identifies key cell populations in atherosclerosis development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Atherosclerosis tends to occur in regions of disturbed blood flow. This study explored how disturbed flow aggravates atherosclerosis using single-cell RNA-seq (scRNA-seq) datasets from mouse carotid arteries under disturbed flow and human carotid artery plaques."
    explanation: >-
      Supports disturbed flow as a regional context for atherosclerosis and
      endothelial dysfunction. It does not directly establish reduced
      nitric-oxide biosynthesis or a coronary-specific effect.
  downstream:
  - target: Coronary Endothelial Injury and Subendothelial LDL Retention
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - increased endothelial permeability and apoB-lipoprotein entry
    - subendothelial lipoprotein modification and retention
    description: >-
      Connects the vasomotor and disturbed-flow endothelial branch to the
      conserved retention trigger without asserting that reduced nitric oxide
      alone is sufficient for apoB retention.
    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: >-
        Links arterial injury and endothelial dysfunction to subendothelial apoB
        modification and monocyte entry, but does not isolate nitric-oxide loss
        or directly establish every intermediate in lipoprotein retention.
- name: Coronary Endothelial Injury and Subendothelial LDL Retention
  conforms_to: "atherogenesis#Endothelial Dysfunction and Subendothelial LDL Retention"
  role: trigger
  description: >-
    In the coronary 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, providing the coronary trigger for
    atheroma formation.
  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; coronary
      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 coronary 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: Arterial Wall Lipid Accumulation
    term:
      id: GO:0019915
      label: lipid storage
    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: Atherosclerotic Plaque 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: >-
        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: Atherosclerotic Plaque Formation
  conforms_to: "atherogenesis#Smooth Muscle Cell Switching and Fibrofatty Plaque Formation"
  role: central_effector
  description: >-
    In the inflamed coronary 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 of coronary atheroma formation.
  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:39518492
    reference_title: "From Cells to Plaques: The Molecular Pathways of Coronary Artery Calcification and Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "We examine the cellular and molecular processes that drive the formation of calcified plaques, highlighting the roles of inflammation, lipid accumulation, and smooth muscle cell proliferation."
    explanation: >-
      Supports lipid accumulation, inflammation, and smooth-muscle-cell
      proliferation as contributors to coronary plaque formation. It does not
      by itself establish the specific phenotypic-switching or matrix-assembly
      sequence represented by this node.
  - 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: 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 coronary atheroma with a necrotic lipid core beneath a fibrous cap.
    Expansion of the core and local plaque microenvironment can destabilize the
    cap and create a rupture-prone coronary lesion.
  cell_types:
  - preferred_term: Vascular Smooth Muscle Cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  locations:
  - preferred_term: Coronary Artery
    term:
      id: UBERON:0001621
      label: coronary 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 stable mature atheroma to an unstable lesion; coronary artery is the
      disease-specific location substituted here.
  - reference: PMID:38639096
    reference_title: "Single-Cell Gene-Regulatory Networks of Advanced Symptomatic Atherosclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Advanced stages of atherosclerosis progression and symptomatic carotid plaques were largely characterized by 3 smooth muscle cells (SMCs), and 3 macrophage subtype clusters with extracellular matrix organization/osteogenic (SMC), and M1-type proinflammatory/Trem2-high lipid-associated (macrophage) phenotypes."
    explanation: >-
      Supports the smooth-muscle-cell, extracellular-matrix, and lipid-associated
      macrophage composition of advanced human atherosclerotic plaque. The tissue
      studied was carotid plaque, so this is partial support for conserved
      advanced-atheroma biology rather than direct coronary evidence.
  - reference: PMID:40594772
    reference_title: "Single-cell RNA-seq analysis of mouse carotid artery under disturbed flow and human carotid plaques identifies key cell populations in atherosclerosis development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Notable increases in VEGFA+ macrophages were discovered in the disturbed flow stimulation group, displaying a pronounced M1 pro-inflammatory phenotype associated with the severity of atherosclerosis and plaque stability."
    explanation: >-
      Supports an inflammatory macrophage phenotype associated with plaque
      severity and stability, not rupture or thrombosis. The disturbed-flow
      comparison is from a mouse carotid model, so support for coronary advanced
      atheroma is partial.
  - reference: PMID:38639096
    reference_title: "Single-Cell Gene-Regulatory Networks of Advanced Symptomatic Atherosclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By identifying and integrating the most gene-rich single-cell subclusters of atherosclerosis to date with a coronary artery disease framework of GRNs, GRN39 was identified and independently validated as being critical for the transformation of contractile SMCs into an osteogenic phenotype promoting advanced, symptomatic atherosclerosis."
    explanation: >-
      Supports smooth-muscle-cell transformation in advanced symptomatic
      atherosclerosis. It does not directly demonstrate plaque rupture or
      thrombosis, so it is retained here as partial support for the advanced
      plaque stage.
  downstream:
  - target: Plaque Rupture and Thrombosis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37595697
      reference_title: The microenvironment of the atheroma expresses phenotypes of plaque instability.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        There are several rupture-associated phenotypes causing thrombotic
        vascular occlusion including simple fibrous cap rupture of an atheroma,
        fibrous cap rupture at site of previous rupture-and-repair of an atheroma,
        and nodular calcification with rupture.
      explanation: >-
        Directly supports the causal transition from advanced atheroma rupture to
        thrombotic vascular occlusion.
- name: Plaque Rupture and Thrombosis
  conforms_to: "atherogenesis#Plaque Rupture, Thrombosis, and Ischemic Events"
  role: consequence
  description: >-
    Rupture of an unstable coronary atheroma, or endothelial erosion over it,
    exposes thrombogenic material and triggers platelet activation, coagulation,
    and thrombotic coronary occlusion, causing acute coronary syndrome and
    myocardial infarction.
  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: PMID:37595697
    reference_title: The microenvironment of the atheroma expresses phenotypes of plaque instability.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Destabilization is characterized by several different plaque phenotypes
      that cause major clinical events such as acute coronary syndrome and
      cerebrovascular strokes.
    explanation: >-
      Histopathology and vascular-imaging evidence directly connects unstable
      atheroma phenotypes with acute coronary syndrome, supporting this terminal
      coronary consequence.
  - reference: PMID:37595697
    reference_title: The microenvironment of the atheroma expresses phenotypes of plaque instability.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Endothelial erosion without rupture has more recently been shown to be a
      common phenotype to promote thrombosis as well.
    explanation: >-
      Directly supports endothelial erosion as a thrombosis-promoting alternative
      to fibrous-cap rupture in the coronary consequence node.
mechanistic_hypotheses:
- hypothesis_group_id: pgs_context_amplification
  hypothesis_label: Amplification of polygenic CAD risk in adverse contexts via shared endothelial-dysfunction convergence
  status: EMERGING
  description: >-
    Polygenic-score-by-context (PGS×C) interactions reported for coronary artery
    disease in the UK Biobank appear to be driven not by different causal
    variants acting in different environments, but by amplification: the same
    susceptibility loci (e.g. the 9p21 locus, APOE, LDLR, PCSK9) exert
    systematically larger effects in disease-promoting contexts. This entry
    proposes that the amplification arises because the polygenic liability and
    adverse exposures such as tobacco smoking converge on a shared upstream
    pathophysiology node — Endothelial Dysfunction — so their joint effect is
    super-additive on the liability-threshold scale rather than additive. Nagpal
    & Gibson (Nat Genet 2026, PMID:42443528) report that in past
    smokers with low omega-6 fatty acid levels the majority of CAD genetic
    effects are nearly perfectly correlated with, but up to twofold larger in
    magnitude than, those in non-smokers with higher omega-6 fatty acids,
    alongside an ~8% higher SNP-heritability — the signature of amplification
    rather than uncorrelated context-specific effects.
  evidence:
  - reference: PMID:42443528
    reference_title: "Pervasive interactions between exposures and polygenic risk can inform more effective clinical and behavioral interventions."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: The predominant mechanism for PGS×C is the amplification of genetic effects in adverse contexts, such as low polyunsaturated fatty acids or social determinants of ill health
    explanation: >-
      Direct source (Nagpal & Gibson 2026): across seven UK Biobank diseases and
      75 contexts, amplification of genetic effects in adverse contexts is
      identified as the predominant mechanism of PGS×context interaction — the
      mechanism applied in this hypothesis.
  - reference: PMID:37228747
    reference_title: "Amplification is the primary mode of gene-by-sex interaction in complex human traits."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: GxSex is pervasive but acts primarily through systematic sex differences in the magnitude of many genetic effects
    explanation: >-
      Establishes amplification — systematic differences in the magnitude of
      polygenic effects rather than in the identity of causal variants — as the
      primary mode of gene-by-context interaction. Sex is among the contexts
      showing the strongest PGS×context amplification for CAD, so this supports
      amplification as the mechanism underlying the CAD PGS×C interactions
      modelled here.
  notes: >-
    EMERGING hypothesis motivated by population-scale PGS×context analyses
    (primary source PMID:42443528; general amplification mechanism corroborated
    by PMID:37228747, which also documents testosterone-mediated amplification).
    The convergence claim (genetic liability + smoking → Endothelial Dysfunction)
    is a mechanistic interpretation and is not itself established as causal — see
    the reverse-causation knowledge gap under discussions.
- hypothesis_group_id: icosapent_ethyl_coronary_plaque_remodeling_model
  hypothesis_label: Icosapent Ethyl Coronary Plaque-Remodeling Model
  status: EMERGING
  description: >-
    In statin-treated people with coronary atherosclerosis and persistent
    hypertriglyceridemia, icosapent ethyl may contribute to the observed
    cardiovascular-event contrast by altering coronary plaque composition or
    progression rather than through isolated change in circulating triglyceride
    concentration. EVAPORATE reported a randomized between-arm imaging signal,
    but its cached abstract reports 80 enrolled without the paired-scan analytic
    denominator or baseline plaque balance, and the reported multivariable model
    did not adjust for baseline plaque. Missing-scan and regression-to-the-mean
    sensitivity therefore remain unresolved. The trial also used a mineral-oil
    comparator and a surrogate endpoint and did not test whether plaque change
    mediated clinical events.
  evidence:
  - reference: PMID:32860032
    reference_title: "Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: final results of the EVAPORATE trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A total of 80 patients were enrolled in this randomized, double-blind,
      placebo-controlled trial.
    explanation: >-
      EVAPORATE enrolled only 80. The cached abstract does not report how many
      participants contributed interpretable paired scans, so the effective
      analysis size and missing-scan sensitivity are not established by this
      exact evidence.
  - reference: PMID:32860032
    reference_title: "Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: final results of the EVAPORATE trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There was a significant reduction in the primary endpoint as IPE reduced
      LAP plaque volume by 17%, while in the placebo group LAP plaque volume more
      than doubled (+109%) (P = 0.0061).
    explanation: >-
      The reported randomized contrast supports differential change in a
      CT-defined coronary plaque surrogate, not mediation of cardiovascular
      events or a specific cellular mechanism.
  - reference: PMID:32860032
    reference_title: "Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: final results of the EVAPORATE trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      When further adjusted for age, sex, diabetes status, hypertension, and
      baseline TG, plaque volume changes between groups remained significantly
      different, P < 0.01.
    explanation: >-
      Persistence after adjustment for baseline triglyceride is compatible with
      more than baseline-risk imbalance, but it is not a randomized mediation
      analysis of triglyceride response. The quoted adjustment list does not
      include baseline plaque, and the cached abstract does not report baseline
      plaque balance, so regression-to-the-mean sensitivity remains unresolved.
  - reference: PMID:28863874
    reference_title: A randomized controlled trial of eicosapentaenoic acid in patients with coronary heart disease on statins.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The PTV/EPA group showed a greater reduction in total atheroma volume
      compared to PTV group. IB-IVUS analyses revealed that lipid volume was
      significantly decreased during follow-up period in only PTV/EPA group.
    explanation: >-
      CHERRY supplies an independent randomized coronary-imaging signal without
      the EVAPORATE mineral-oil comparison, but its open-label protocol tested
      EPA 1.8 g/day plus pitavastatin in 193 Japanese post-PCI patients for only
      6–8 months, not IPE 4 g/day or event mediation.
  - reference: PMID:32805184
    reference_title: "Effects of Fatty Acid Therapy in Addition to Strong Statin on Coronary Plaques in Acute Coronary Syndrome: An Optical Coherence Tomography Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There were no significant differences in the percent change for minimum
      FCT between the EPA or EPA+DHA group and the control group.
    explanation: >-
      This 130-patient, three-arm trial limits the cap-stabilization version of
      the model because neither EPA 1.8 g/day nor mixed EPA/DHA produced a
      significantly greater overall minimum-FCT increase than statin-only
      control. The abstract reports a favorable minimum-FCT change in the
      subgroup below the median baseline FCT, but that subgroup does not
      overturn the null overall comparison. The trial does not refute the
      narrower plaque-volume signal or test IPE 4 g/day.
  notes: >-
    This is a small 80-patient surrogate imaging hypothesis, not a
    treatment-to-pathophysiology edge. REDUCE-IT tested a high-risk
    ASCVD-or-diabetes population broader than coronary artery disease;
    EVAPORATE is the coronary-specific lead and did not test clinical outcomes
    or mediation. Focused research must compare plaque remodeling with:
    remnant- and apolipoprotein-B particle number, composition, trafficking, and
    arterial retention; platelet activation and thromboxane biology;
    specialized inflammatory-resolution lipid mediators rather than generic
    C-reactive-protein lowering; endothelial nitric-oxide and vascular-function
    effects; membrane stabilization, lipid peroxidation, and oxidized-lipid
    effects; and biomarker increases observed in mineral-oil-assigned
    participants. Achieved-EPA
    concentrations and other postrandomization biomarker associations may
    reflect adherence, absorption, or metabolism and cannot identify a mediator
    without prespecified temporal causal-mediation analysis. Distinguish a
    causal mediator from a baseline effect modifier, parallel pharmacodynamic
    marker, surrogate correlate, or comparator artifact.
- hypothesis_group_id: icosapent_ethyl_atherogenic_particle_lowering_model
  hypothesis_label: Icosapent Ethyl Atherogenic Particle-Lowering Model
  status: EMERGING
  description: >-
    In statin-treated people with persistent triglyceride elevation, icosapent
    ethyl may contribute to plaque or event effects by lowering concentrations
    of atherogenic VLDL and LDL particles, thereby reducing arterial exposure or
    retention of apoB-containing particles.
    A short-duration ANCHOR analysis establishes pharmacodynamic change but did
    not measure coronary plaque, clinical events, or
    treatment-to-particle-to-event mediation.
  evidence:
  - reference: PMID:26073397
    reference_title: Effects of icosapent ethyl on lipoprotein particle concentration and size in statin-treated patients with persistent high triglycerides (the ANCHOR Study).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Compared with placebo (n = 211), IPE 4 g/day (n = 216) significantly
      reduced concentrations of: total (12.2%, P = .0002), large (46.4%, P <
      .0001), and medium (12.1%, P = .0068) very-low-density lipoprotein (VLDL)
      particles; total (7.7%, P = .0017) and small (13.5%, P < .0001) LDL
      particles
    explanation: >-
      This prespecified exploratory 12-week NMR analysis supports an
      IPE-versus-placebo contrast in atherogenic particle concentrations, but it
      did not test coronary plaque, clinical events, or mediation. Without an
      inert third arm, it does not separate direct IPE action from comparator
      behavior.
  notes: >-
    The particle-lowering model can be upstream of the plaque-remodeling model
    rather than mutually exclusive. Randomized biomarker change is established;
    the proposed particle-retention and particle-to-plaque-to-event links remain
    unconfirmed.
phenotypes:
- name: Angina Pectoris
  category: Cardiovascular
  frequency: FREQUENT
  diagnostic: true
  notes: Chest pain due to myocardial ischemia
  phenotype_term:
    preferred_term: Angina Pectoris
    term:
      id: HP:0001681
      label: Angina pectoris
- name: Dyspnea on Exertion
  category: Respiratory
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
- name: Myocardial Infarction
  category: Cardiovascular
  frequency: OCCASIONAL
  notes: Acute complication of plaque rupture
  phenotype_term:
    preferred_term: Myocardial Infarction
    term:
      id: HP:0001658
      label: Myocardial infarction
  evidence:
  - reference: PMID:24902970
    reference_title: "Mechanisms of plaque formation and rupture."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "may suddenly cause life-threatening coronary thrombosis presenting as an acute coronary syndrome"
    explanation: Directly links rupture of a coronary atherosclerotic plaque to acute coronary syndrome, the mechanism by which myocardial infarction arises as a complication of coronary artery disease.
biochemical:
- name: LDL Cholesterol
  presence: Elevated
  context: Major risk factor for plaque formation
  evidence:
  - reference: PMID:28444290
    reference_title: "Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Consistent evidence from numerous and multiple different types of clinical and genetic studies unequivocally establishes that LDL causes ASCVD."
    explanation: EAS consensus statement concludes that LDL is causal for atherosclerotic cardiovascular disease, supporting elevated LDL cholesterol as a major risk factor for coronary plaque formation.
- name: HDL Cholesterol
  presence: Decreased
  context: Protective factor when adequate
- name: C-Reactive Protein
  presence: Elevated
  context: Marker of inflammation
  evidence:
  - reference: PMID:20031199
    reference_title: "C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Risk ratios (RRs) for coronary heart disease per 1-SD higher log(e) CRP concentration (three-fold higher) were 1.63 (95% CI 1.51-1.76) when initially adjusted for age and sex only, and 1.37 (1.27-1.48) when adjusted further for conventional risk factors"
    explanation: Individual-participant meta-analysis quantifies the association between circulating C-reactive protein and incident coronary heart disease, supporting CRP as an inflammatory risk marker in coronary artery disease.
genetic:
- name: APOE
  gene_term:
    preferred_term: APOE
    term:
      id: hgnc:613
      label: APOE
  association: Risk Factor
  evidence:
  - reference: PMID:17878422
    reference_title: "Association of apolipoprotein E genotypes with lipid levels and coronary risk."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Compared with epsilon3/epsilon3, the odds ratio for coronary disease was 0.80 (95% CI, 0.70-0.90) in epsilon2 carriers and was 1.06 (95% CI, 0.99-1.13) in epsilon4 carriers."
    explanation: Meta-analysis of 121 studies (37,850 coronary cases) quantifies the APOE genotype-coronary risk association, with epsilon2 carriers at lower risk than the epsilon3/epsilon3 reference.
- name: LDLR
  gene_term:
    preferred_term: LDLR
    term:
      id: hgnc:6547
      label: LDLR
  association: Risk Factor
  evidence:
  - reference: PMID:28444290
    reference_title: "Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Rare genetic mutations that cause reduced LDL receptor function lead to markedly higher LDL-C and a dose-dependent increase in the risk of ASCVD"
    explanation: EAS consensus statement establishes that loss of LDL-receptor function raises LDL-C and increases atherosclerotic cardiovascular risk in a dose-dependent manner.
- name: PCSK9
  gene_term:
    preferred_term: PCSK9
    term:
      id: hgnc:20001
      label: PCSK9
  association: Risk Factor
  evidence:
  - reference: PMID:16554528
    reference_title: "Sequence variations in PCSK9, low LDL, and protection against coronary heart disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "these mutations were associated with a 28 percent reduction in mean LDL cholesterol and an 88 percent reduction in the risk of CHD"
    explanation: ARIC cohort shows PCSK9 nonsense variants lower LDL cholesterol and substantially reduce coronary heart disease incidence, establishing PCSK9 as a causal modifier of coronary risk.
- name: 9p21 Locus
  association: Risk Factor
  evidence:
  - reference: PMID:17478681
    reference_title: "A common allele on chromosome 9 associated with coronary heart disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Homozygotes for the risk allele make up 20 to 25% of Caucasians and have a approximately 30 to 40% increased risk of CHD."
    explanation: Genome-wide association scanning identified the chromosome 9p21 interval as a common CHD risk locus, quantifying the effect size in risk-allele homozygotes.
environmental:
- name: Smoking
  exposure_term:
    preferred_term: exposure to tobacco smoking
    term:
      id: ECTO:6000029
      label: exposure to tobacco smoking
  notes: Major modifiable risk factor, with a dose-response relationship to
    myocardial infarction risk.
  review_notes: The prior note also asserted that smoking promotes endothelial
    damage. That mechanism is not carried by either epidemiologic source cited here
    and is not evidenced in this entry; it belongs in pathophysiology with its own
    citation rather than as an unsourced clause on an exposure.
  evidence:
  - reference: PMID:15364185
    reference_title: "Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Smoking (odds ratio 2.87 for current vs never, PAR 35.7% for current and former vs never)"
    explanation: "INTERHEART, a standardised case-control study of acute myocardial infarction across 52 countries with 15152 cases and 14820 controls. Establishes smoking as one of the largest modifiable contributors to population attributable risk."
  - reference: PMID:16920470
    reference_title: "Tobacco use and risk of myocardial infarction in 52 countries in the INTERHEART study: a case-control study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "risk increased by 5.6% for every additional cigarette smoked"
    explanation: "The tobacco-specific INTERHEART analysis. Quoted for the dose-response relationship, which is the part of the note the odds ratio alone does not establish."
- name: High-Fat Diet
  exposure_term:
    preferred_term: high dietary lipid exposure
    modifier: INCREASED
    term:
      id: ECTO:0090010
      label: exposure to lipid in food
  notes: Dietary saturated fat raises serum cholesterol and cardiovascular event
    risk. The measured effect on LDL specifically is small; the robust finding is
    the reduction in combined cardiovascular events when saturated fat is reduced.
  review_notes: The bound exposure term is broader than the cited evidence. The term
    is total dietary lipid, while the citation concerns saturated fat specifically -
    a distinction that matters, because trials reducing total fat do not show the
    same event reduction. ECTO was searched for a saturated-fat-specific exposure
    term and has none; the available matches are CHEBI and CDNO chemical classes,
    which are not exposure classes and would not validate against the exposure-term
    enum. The note therefore says saturated fat explicitly so the claim is scoped
    correctly even though the term is not.
  evidence:
  - reference: PMID:32428300
    reference_title: "Reduction in saturated fat intake for cardiovascular disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Meta-regression suggested that greater reductions in saturated fat (reflected in greater reductions in serum cholesterol) resulted in greater reductions in risk of CVD events, explaining most heterogeneity between trials"
    explanation: "Cochrane review of 15 randomised controlled trials with about 59000 participants. Note this source qualifies the original note rather than simply confirming it: the same abstract reports only small reductions in LDL cholesterol from reducing saturated fat, so LDL elevation is a weaker claim than the cardiovascular event effect, and the note was rewritten accordingly."
- name: Sedentary Lifestyle
  exposure_term:
    preferred_term: sedentary lifestyle
    term:
      id: ECTO:6000004
      label: exposure to sedentary lifestyle
  notes: Physical inactivity is an independent contributor to myocardial infarction
    risk. Low physical activity is associated with metabolic syndrome, but sedentary
    behaviour measured as screen time is not, so the metabolic-syndrome route is not
    a settled mechanism for this exposure.
  review_notes: The prior note read simply that a sedentary lifestyle contributes to
    metabolic syndrome. The cited meta-analysis separates low physical activity from
    sedentary behaviour and finds only the former significantly associated with
    metabolic syndrome, so the note was split accordingly rather than left as a flat
    claim. That meta-analysis is in adolescents and does not settle the question in
    adults; it is enough to show the claim needs qualifying, not enough to refute it.
  evidence:
  - reference: PMID:15364185
    reference_title: "Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "regular physical activity (0.86, PAR 12.2%)"
    explanation: "INTERHEART reports regular physical activity as protective against myocardial infarction with a population attributable risk of 12.2 percent for its absence, which is the evidence that inactivity is a risk factor for this disease."
  - reference: PMID:27997601
    reference_title: "Physical Activity, Sedentary Behavior, Cardiorespiratory Fitness and Metabolic Syndrome in Adolescents: Systematic Review and Meta-Analysis of Observational Evidence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "for sedentary behavior, represented by screen time > 2 hours/day, a significant association was not identified"
    explanation: "Cited as a caveat, not support. This meta-analysis of eighteen studies found low physical activity significantly associated with metabolic syndrome, but sedentary behaviour measured as screen time was NOT significantly associated overall - only on weekends in subgroup analysis. It is an adolescent population, so it does not settle the question in adults, but it is enough to show the metabolic-syndrome mechanism should not be stated flatly."
- name: Obesity
  notes: Abdominal obesity is an independent contributor to myocardial infarction risk.
  review_notes: Two separate caveats. First, obesity is a disease entity with its own
    MONDO identity, not an environmental exposure, so this entry is modelling a host
    state in the environmental block - the pattern tracked by issue 8551. It is cited
    here rather than left bare because the evidence is real and moves with the entry
    if it is later re-homed. Second, the prior note asserted association with
    dyslipidemia and inflammation; the cited source establishes the association with
    myocardial infarction, not that mechanism, so the note was narrowed.
  evidence:
  - reference: PMID:15364185
    reference_title: "Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "abdominal obesity (1.12 for top vs lowest tertile and 1.62 for middle vs lowest tertile, PAR 20.1% for top two tertiles vs lowest tertile)"
    explanation: "INTERHEART. Note the measure is abdominal obesity by waist/hip ratio rather than body mass index, which is a more specific claim than the entry name suggests."
treatments:
- name: Statins
  description: Lower LDL cholesterol and stabilize atherosclerotic plaques.
  treatment_term:
    preferred_term: statin therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:40787973
    reference_title: "Chronic coronary syndrome - new ESC guidelines."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The guidelines recommend that all patients with chronic coronary artery disease receive high-intensity lipid-lowering treatment, with a target LDL level of less than 1.4 mmol/L."
    explanation: The ESC chronic-coronary-syndrome guidelines recommend high-intensity lipid-lowering therapy (statins) for all patients, targeting LDL below 1.4 mmol/L.
- name: Icosapent Ethyl
  description: >-
    In REDUCE-IT, adjunctive icosapent ethyl 4 g/day reduced composite ischemic
    events versus a mineral-oil comparator in selected statin-treated adults
    with established cardiovascular disease or diabetes plus risk factors and
    persistent triglyceride elevation. Hospitalization for atrial fibrillation
    or flutter was more frequent. The trial population was broader than
    coronary artery disease alone, and neither the mediating mechanism nor the
    benefit magnitude versus an inert non-mineral-oil comparator is established.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: icosapent ethyl
      term:
        id: CHEBI:84883
        label: ethyl (5Z,8Z,11Z,14Z,17Z)-icosapentaenoate
  evidence:
  - reference: PMID:30415628
    reference_title: Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A primary end-point event occurred in 17.2% of the patients in the
      icosapent ethyl group, as compared with 22.0% of the patients in the
      placebo group
    explanation: >-
      REDUCE-IT directly establishes the randomized composite-event contrast in
      its selected high-risk, statin-treated population.
  - reference: PMID:35261279
    reference_title: "Treatment With Icosapent Ethyl to Reduce Ischemic Events in Patients With Prior Percutaneous Coronary Intervention: Insights From REDUCE-IT PCI."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among patients treated with icosapent ethyl versus placebo, there was a
      34% reduction in the primary composite end point
    explanation: >-
      This post hoc analysis of 3408 REDUCE-IT participants with prior PCI
      reported HR 0.66 (95% CI, 0.58-0.76) for this endpoint, supporting
      applicability of the randomized event contrast to a coronary subgroup.
      It does not identify a mediator, was not a separate randomized trial of
      coronary disease, and retains the parent trial's mineral-oil comparison.
  - reference: PMID:30415628
    reference_title: Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A larger percentage of patients in the icosapent ethyl group than in the
      placebo group were hospitalized for atrial fibrillation or flutter (3.1%
      vs. 2.1%, P=0.004).
    explanation: >-
      The randomized safety result bounds an unqualified cardioprotective
      interpretation.
  - reference: PMID:38873793
    reference_title: Randomized Trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy-Statin and Eicosapentaenoic Acid (RESPECT-EPA).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Adverse events did not differ between the groups, but the rate of
      new-onset atrial fibrillation was significantly higher in the EPA group
      (3.1% versus 1.6%; P=0.017).
    explanation: >-
      This randomized, open-label Japanese stable-CAD comparison of EPA 1.8
      g/day with control independently supports an atrial-fibrillation safety
      signal without a mineral-oil placebo. Its different dose and design limit
      quantitative transfer to REDUCE-IT.
- name: Antiplatelet Therapy
  description: Aspirin and P2Y12 inhibitors reduce thrombotic risk.
  treatment_term:
    preferred_term: antiplatelet therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:11786451
    reference_title: "Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "allocation to antiplatelet therapy reduced the combined outcome of any serious vascular event by about one quarter; non-fatal myocardial infarction was reduced by one third, non-fatal stroke by one quarter, and vascular mortality by one sixth"
    explanation: Collaborative meta-analysis of randomised trials quantifies the reduction in serious vascular events, myocardial infarction, and vascular mortality achieved by antiplatelet therapy in high-risk patients.
- name: ACE Inhibitors
  description: Provide cardiovascular protection beyond blood pressure lowering.
  treatment_term:
    preferred_term: ACE inhibitor therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ACE inhibitor
      term:
        id: NCIT:C247
        label: ACE Inhibitor
- name: Beta Blockers
  description: Reduce myocardial oxygen demand and prevent angina.
  treatment_term:
    preferred_term: beta-blocker therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: Percutaneous Coronary Intervention
  description: Angioplasty with stenting to restore coronary blood flow.
  treatment_term:
    preferred_term: percutaneous coronary intervention
    term:
      id: NCIT:C99521
      label: Percutaneous Coronary Intervention
- name: Coronary Artery Bypass Grafting
  description: Surgical revascularization for severe multivessel disease.
  treatment_term:
    preferred_term: coronary artery bypass grafting
    term:
      id: NCIT:C51998
      label: Coronary Artery Bypass Surgery
clinical_trials:
- name: NCT05018247
  phase: NOT_APPLICABLE
  description: Prospective randomized study comparing early revascularization guided by PET-quantified coronary flow capacity versus optimal medical therapy alone in stable ischemic heart disease.
  evidence:
  - reference: clinicaltrials:NCT05018247
    reference_title: "A Prospective, Randomized Trial of Early Revascularization in Stable Ischemic Heart Disease Guided by Positron Emission Tomography of Artery Specific Integrated Comprehensive Quantitative Myocardial Perfusion"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: To compare the impact of revascularization and Optimal Medical Treatment (OMT) on the extent of severely reduced coronary flow capacity in stable ischemic heart disease.
    explanation: The trial directly tests a revascularization strategy for stable ischemic coronary disease, informing interventional management.
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
discussions:
- discussion_id: cad_pgsxc_reverse_causation
  prompt: >-
    Are the CAD PGS×context interactions driven by adverse exposures causally
    amplifying genetic risk, or are some "contexts" actually downstream readouts
    of incipient disease (reverse causation)?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Endothelial Dysfunction
  - biochemical#LDL Cholesterol
  - biochemical#C-Reactive Protein
  - environmental#Smoking
  rationale: >-
    Population PGS×context analyses (Nagpal & Gibson 2026,
    PMID:42443528) are largely unable to establish the
    causality of specific contexts. dismech separates true environmental
    exposures (smoking, high-fat diet, sedentary lifestyle) from biochemical
    readouts (LDL, HDL, C-reactive protein); the biochemical "contexts" are prime
    reverse-causation suspects, since they may be partly downstream of the
    atherosclerotic process rather than upstream drivers, and behavioural
    contexts such as reduced physical activity may be rapid responses to
    incipient angina rather than causes. Distinguishing genuine amplification of
    genetic effects from reverse causation determines whether the modelled
    interventions (e.g. lowering cholesterol in high-PGS smokers) would actually
    reduce risk.
  proposed_experiments:
  - experiment_id: cad_pgsxc_mr_direction
    name: Mendelian randomization of exposure-to-CAD direction across PGS strata
    description: >-
      Use bidirectional / multivariable Mendelian randomization to test whether
      each candidate context (LDL, HDL, C-reactive protein, smoking) causally
      affects CAD versus being a consequence of subclinical disease, and whether
      the causal effect estimate scales with polygenic liability as the
      amplification model predicts.
    decision_criterion: >-
      A context is retained as a causal amplifier if MR supports
      exposure-to-disease directionality and the exposure-attributable risk
      difference increases across increasing PGS strata; it is flagged as a
      reverse-causation suspect otherwise.
  - experiment_id: cad_pgsxc_prospective_temporal
    name: Prospective incident-CAD analysis restricted to pre-diagnosis exposure windows
    description: >-
      Restrict exposures to measurements taken well before diagnosis and repeat
      the PGS×context liability-threshold modelling on incident cases only, to
      reduce the chance that exposure values reflect behavioural responses to
      early disease.
    decision_criterion: >-
      Amplification is supported if the PGS×context deviation from additivity
      persists when only pre-diagnosis exposure windows and incident cases are
      used.
- discussion_id: gap_icosapent_ethyl_event_reduction_mechanism
  prompt: >-
    Which, if any, pathway beyond change in circulating triglyceride
    concentration causally mediates the cardiovascular-event contrast observed
    with high-dose icosapent ethyl: coronary plaque remodeling; altered
    apolipoprotein-B/remnant burden, composition, trafficking, or retention;
    platelet effects; inflammatory resolution; endothelial effects; or membrane
    stabilization and reduced lipid oxidation? How much of the contrast reflects
    the mineral-oil comparator?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - treatments#Icosapent Ethyl
  - mechanistic_hypotheses#icosapent_ethyl_coronary_plaque_remodeling_model
  - mechanistic_hypotheses#icosapent_ethyl_atherogenic_particle_lowering_model
  - pathophysiology#Atherosclerotic Plaque Formation
  - pathophysiology#Endothelial Dysfunction
  - pathophysiology#Plaque Rupture and Thrombosis
  - biochemical#C-Reactive Protein
  rationale: >-
    REDUCE-IT established an ischemic-event contrast between icosapent ethyl and
    a mineral-oil comparator but did not identify a mediator. The seed review
    explicitly states that triglyceride lowering does not fully explain the
    benefit. The small 80-patient EVAPORATE trial observed differential
    CT-plaque change against mineral oil after adjustment for baseline
    triglyceride, but plaque is a surrogate and the study did not test
    treatment-to-plaque-to-event mediation. In the REDUCE-IT biomarker substudy,
    icosapent ethyl produced minimal change in several inflammatory and
    lipid-oxidation markers while those markers increased among participants
    assigned to mineral oil; without an inert third arm, relative biomarker
    differences do not establish direct icosapent lowering or mineral-oil
    causation. Focused research found a lower-dose EPA plaque-volume signal in
    CHERRY, no overall fibrous-cap-thickness benefit in a separate three-arm
    trial, and short-term IPE-associated atherogenic-particle reductions in
    ANCHOR; none tested clinical mediation. A post hoc REDUCE-IT prior-PCI
    subgroup supports transfer of the event contrast to coronary disease but
    remains a subgroup analysis against mineral oil. RESPECT-EPA, an open-label
    1.8-g/day Japanese stable-CAD trial without an oil placebo, reported a
    nonsignificant primary endpoint, a significant secondary coronary composite,
    and more new-onset atrial fibrillation; it supplies a coronary signal from a
    comparison that did not use mineral oil but does not establish a mechanism.
    STRENGTH found no event benefit for a distinct EPA/DHA carboxylic-acid
    formulation against corn oil intended as an inert comparator. That result
    constrains class-wide omega-3 inference but does not directly test purified
    IPE or distinguish its candidate pathways.
    Plaque remodeling; remnant-particle composition, number, trafficking, and
    arterial retention; platelet biology; specialized inflammatory resolution;
    endothelial function; and membrane or lipid-oxidation effects remain
    candidates rather than established mechanisms. Baseline-subgroup,
    achieved-EPA, and other postrandomization associations cannot substitute
    for randomized temporal mediation.
  proposed_experiments:
  - experiment_id: exp_icosapent_multicomparator_temporal_mediation_trial
    name: >-
      Multi-comparator icosapent trial with prospective temporal mediation
    description: >-
      Embed an independently analyzed mechanistic substudy in an adequately
      powered, double-blind cardiovascular-outcome trial of icosapent ethyl
      4 g/day versus a metabolically inert, non-mineral-oil matched placebo.
      Enroll people with documented coronary atherosclerosis, persistent
      triglyceride elevation, stable lipid-lowering and antiplatelet therapy,
      and prespecified diabetes, sex, renal-function, and baseline-plaque
      strata.
      Add a randomized, chemically distinct triglyceride-lowering comparator
      arm, powered for mechanistic and plaque contrasts and prospectively
      titrated to approximate the icosapent arm's triglyceride trajectory.
      Where ethics and safety oversight permit, include a time-limited
      mineral-oil calibration arm to estimate short-term comparator effects on
      biomarkers. That calibration cannot determine mineral oil's contribution
      to a multi-year clinical-event contrast.
    experiment_type:
      preferred_term: randomized temporal causal-mediation trial
    perturbations:
    - name: Icosapent ethyl 4 g/day
      target: treatments#Icosapent Ethyl
      description: >-
        Randomize purified icosapent ethyl with adherence measured independently
        of achieved eicosapentaenoic-acid concentration.
    readouts:
    - name: Atherogenic-particle and remnant trajectories
      target: mechanistic_hypotheses#icosapent_ethyl_atherogenic_particle_lowering_model
      description: >-
        Measure triglycerides, apolipoprotein B and particle number, remnant
        cholesterol and composition, and proteoglycan binding before plaque or
        event divergence.
      assays:
      - preferred_term: longitudinal lipoprotein particle and remnant profiling
      direction: NEGATIVE
    - name: Prespecified non-particle mediator trajectories
      target: mechanistic_hypotheses#icosapent_ethyl_coronary_plaque_remodeling_model
      description: >-
        Measure EPA/arachidonic-acid lipid mediators, specialized pro-resolving
        mediators, high-sensitivity C-reactive protein, interleukin-6,
        endothelial function, platelet COX-1/thromboxane activity and
        reactivity, membrane lipid order and oxidative susceptibility, oxidized
        LDL, and achieved EPA before plaque or event divergence.
      assays:
      - preferred_term: longitudinal lipidomic, lipoprotein, and membrane-biophysics profiling
      - preferred_term: inflammatory-resolution and platelet functional assay
      direction: THRESHOLD_DEPENDENT
    - name: Coronary plaque change
      target: pathophysiology#Atherosclerotic Plaque Formation
      description: >-
        Quantify low-attenuation, noncalcified, and total plaque with a blinded
        central CCTA core and a prespecified OCT or IVUS substudy.
      assays:
      - preferred_term: serial coronary computed tomographic angiography
      - preferred_term: intravascular plaque imaging
      direction: NEGATIVE
    - name: Adjudicated cardiovascular and safety outcomes
      target: treatments#Icosapent Ethyl
      description: >-
        Adjudicate myocardial infarction, stroke, revascularization,
        cardiovascular death, atrial fibrillation or flutter, and serious
        bleeding without using a surrogate as the clinical endpoint.
      assays:
      - preferred_term: blinded cardiovascular event adjudication
      direction: THRESHOLD_DEPENDENT
    controls:
    - name: Inert matched placebo
      description: >-
        Use a sensory-matched comparator shown in a run-in study not to alter
        lipids, inflammatory biomarkers, renal function, or platelet assays.
    - name: Triglyceride-matched active comparator
      description: >-
        Randomize a chemically distinct triglyceride-lowering intervention and
        use blinded dose adaptation to approximate the icosapent arm's
        triglyceride trajectory without matching achieved EPA exposure. Analyze
        apolipoprotein-B and remnant-particle differences explicitly rather than
        assuming that triglyceride matching equalizes them.
    - name: Time-limited mineral-oil calibration control
      description: >-
        If approved, randomize a short mechanistic calibration arm with stopping
        rules. Use it only to estimate short-term biomarker effects, not to
        attribute the long-term clinical-event contrast.
    - name: Background-therapy and implementation controls
      description: >-
        Standardize statin, antiplatelet, diet, and diabetes therapy; monitor
        placebo and active-comparator effects, adherence, renal function, and
        treatment crossover.
    - name: Mediation-analysis controls
      description: >-
        Prespecify temporal ordering, multiplicity correction, missing-data
        handling, exposure-induced mediator-outcome confounding, and sensitivity
        analyses that do not condition only on achieved EPA levels.
    decision_criterion: >-
      A candidate mediator is supported only if randomization changes it versus
      the inert comparator before plaque or clinical divergence and a
      prespecified treatment-to-mediator-to-endpoint indirect effect replicates.
      If mineral oil worsens a marker while icosapent and inert placebo do not
      differ, comparator worsening explains that short-term marker contrast,
      while its contribution to long-term events remains unresolved. A
      lipid-mediated explanation requires prespecified interventional indirect-
      and direct-effect estimands, explicit identification assumptions, and
      sensitivity analyses to be consistent with full mediation and little or
      no residual direct effect; ordinary adjustment for postrandomization
      triglyceride, apolipoprotein-B, remnant, or achieved-EPA measures is
      insufficient. If plaque trajectories are similar to the
      triglyceride-matched active comparator, that weakens evidence for an
      icosapent-specific effect but does not refute icosapent-induced remodeling
      without prespecified equivalence margins, adequate precision, and
      assumptions excluding the comparator's own plaque effects. Refute this
      hypothesis only if the icosapent-versus-inert contrast excludes a
      prespecified clinically meaningful plaque effect or a well-identified
      mediation analysis excludes a clinically meaningful plaque-mediated
      indirect effect. No biomarker or imaging association alone establishes
      mediation.
    would_support:
    - mechanistic_hypotheses#icosapent_ethyl_coronary_plaque_remodeling_model
    - mechanistic_hypotheses#icosapent_ethyl_atherogenic_particle_lowering_model
    would_refute:
    - mechanistic_hypotheses#icosapent_ethyl_coronary_plaque_remodeling_model
    - mechanistic_hypotheses#icosapent_ethyl_atherogenic_particle_lowering_model
  evidence:
  - reference: PMID:42397965
    reference_title: Rethinking triglycerides in the management of ASCVD.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Icosapent ethyl has demonstrated reductions in major adverse cardiovascular
      events, although the mechanism of benefit remains incompletely understood
      and is not explained entirely by triglyceride lowering.
    explanation: >-
      The seed review directly defines the unresolved mechanism but does not
      establish any proposed mediator.
  - reference: PMID:35762321
    reference_title: "Effects of Randomized Treatment With Icosapent Ethyl and a Mineral Oil Comparator on Interleukin-1β, Interleukin-6, C-Reactive Protein, Oxidized Low-Density Lipoprotein Cholesterol, Homocysteine, Lipoprotein(a), and Lipoprotein-Associated Phospholipase A2: A REDUCE-IT Biomarker Substudy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among participants in REDUCE-IT, allocation to icosapent ethyl had minimal
      effects on a series of biomarkers associated with atherosclerotic disease,
      whereas levels increased among those allocated to mineral oil.
    explanation: >-
      Randomized longitudinal biomarker data show that relative inflammatory
      differences cannot be interpreted as direct biomarker lowering by
      icosapent ethyl.
  - reference: PMID:35762321
    reference_title: "Effects of Randomized Treatment With Icosapent Ethyl and a Mineral Oil Comparator on Interleukin-1β, Interleukin-6, C-Reactive Protein, Oxidized Low-Density Lipoprotein Cholesterol, Homocysteine, Lipoprotein(a), and Lipoprotein-Associated Phospholipase A2: A REDUCE-IT Biomarker Substudy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The effect of these findings on interpretation of the overall risk
      reductions in clinical events observed within REDUCE-IT is uncertain.
    explanation: >-
      The investigators explicitly preserve uncertainty about how mineral-oil
      biomarker changes affect interpretation of the event contrast.
  - reference: PMID:38873793
    reference_title: Randomized Trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy-Statin and Eicosapentaenoic Acid (RESPECT-EPA).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Icosapent ethyl treatment resulted in a numerically lower risk of
      cardiovascular events that did not reach statistical significance in
      patients with chronic coronary artery disease, a low EPA/AA ratio, and
      statin treatment.
    explanation: >-
      This 1.8-g/day, open-label Japanese stable-CAD trial reported a
      nonsignificant primary endpoint. Its direction is compatible with a
      product effect outside the REDUCE-IT comparison, but it neither
      establishes a mechanism nor quantifies any mineral-oil contribution.
  - reference: PMID:38873793
    reference_title: Randomized Trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy-Statin and Eicosapentaenoic Acid (RESPECT-EPA).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Meanwhile, the secondary composite end point of coronary events in the EPA
      group was significantly lower
    explanation: >-
      The reported HR was 0.73 (95% CI, 0.55-0.97). This significant secondary
      coronary composite supplies event evidence from a comparison that did not
      use mineral oil in chronic CAD, but it was a secondary endpoint in an
      open-label Japanese trial of EPA 1.8 g/day and did not test mediation.
  - reference: PMID:33190147
    reference_title: "Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk: The STRENGTH Randomized Clinical Trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Participants were randomized to receive 4 g/d of omega-3 CA (n = 6539) or
      corn oil, which was intended to serve as an inert comparator (n = 6539),
      in addition to usual background therapies, including statins.
    explanation: >-
      STRENGTH supplies a comparison that did not use mineral oil, although corn
      oil was intended rather than independently proven to be inert.
  - reference: PMID:33190147
    reference_title: "Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk: The STRENGTH Randomized Clinical Trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among statin-treated patients at high cardiovascular risk, the addition of
      omega-3 CA, compared with corn oil, to usual background therapies resulted
      in no significant difference in a composite outcome of major adverse
      cardiovascular events.
    explanation: >-
      The neutral event result constrains a formulation-agnostic omega-3
      cardioprotection claim. STRENGTH tested an EPA/DHA carboxylic-acid
      formulation rather than purified IPE, so it does not refute an
      IPE-specific mechanism.
datasets:
- accession: geo:GSE289957
  title: Differential Gene Expression related to Telomere Length in Arterial Wall Tissues and Granulocytes of Patients with Coronary Artery Disease
  description: Shortened telomere length (TL) in blood cells is associated with atherosclerotic coronary artery disease (CAD). However, the mechanistic pathways underlying TL attrition in arterial wall tissues for patients with CAD remain unclear. In this study, we evaluated TL in arterial wall tissues and granulocytes and correlated these measurements with data on gene expressions in the arterial wall tissues of patients with CAD.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 34
  publication: PMID:42211145
  notes: Identified by GEO DataSets index search for Coronary Artery Disease (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: geo: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 Coronary Artery Disease (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE282042
  title: RNA-seq analysis of human monocytes in patients with and without coronary atherosclerosis
  description: 'We conducted RNA-Seq transcriptome profiling on monocytes isolated from patients undergoing coronary angiography. After the procedure, patients were divided into two groups: those without coronary artery stenosis ("w.o. CA", n=11) and those with coronary artery stenosis ("w. CA", n=9). All patients were men, aged 61±6 years. CD14+ monocytes were isolated, and RNA-seq was performed on the Illumina NextSeq 2000 platform. This data was analyzed to identify changes in gene expression profiles associated with coronary atherosclerosis. Transcriptome analysis revealed an upregulation of numerous inflammatory genes.'
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 20
  publication: PMID:40350260
  notes: Identified by GEO DataSets index search for Coronary Artery Disease (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: ega:EGAS00000000003
  title: WTCCC case-control study for Coronary Artery Disease
  description: WTCCC genome-wide case-control association study for Bipolar disorder (CAD) using the 1958 British Birth Cohort and the UK National Blood Service collections as controls.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Coronary Artery Disease"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00000000004
  title: WTCCC case-control study for Coronary Artery Disease - Combined Controls
  description: WTCCC genome-wide case-control association study for Coronary Artery Disease (CAD) using six disease collections together with the 1958 British Birth Cohort and the UK National Blood Service collections as controls.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Coronary Artery Disease"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00000000005
  title: WTCCC case-control study for Coronary Artery Disease, Hypertension, T2D - combined cases
  description: WTCCC genome-wide case-control association study using the cardiovascular disease CAD, HT and T2D as combined case collection and the 1958 British Birth Cohort and the UK National Blood Service collections as controls.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Coronary Artery Disease"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: metabolomics_workbench:ST000306
  title: Metabolomics Approach to Identify Molecules and Pathways Involved in the Development of Atherosclerotic Coronary 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 ("Coronary Artery Disease"). Retrieved 2026-08-02.
- accession: massive:MSV000088508
  title: TAILS identifies candidate substrates and biomarkers of ADAMTS7, a therapeutic protease target in coronary artery disease
  description: MacDonald BT, Keshishian H, Mundorff CC, Arduini A, Lai D, Bendinelli K, Popp NR, Bhandary B, Clauser KR, Specht H, Elowe NH, Laprise D, Xing Y, Kaushik VK, Carr SA, Ellinor PT. Loss-of-function mutations in the secreted enzyme ADAMTS7 (a disintegrin and metalloproteinase with thrombospondin motifs 7) are associated with protection for coronary artery disease (CAD). ADAMTS7 catalytic inhibition has been proposed as a therapeutic strategy for treating CAD; however, the lack of an endogenous substrate has hindered the development of activity-based biomarkers.
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. 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 ("Coronary Artery Disease"). Retrieved 2026-08-02.
- accession: massive:MSV000095097
  title: Lipidomics-based algorithms can enhance prediction of obstructive coronary artery disease
  description: Lipidomics-based algorithms can enhance prediction of obstructive coronary artery disease
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. 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 ("Coronary Artery Disease"). Retrieved 2026-08-02.
references:
- reference: DOI:10.1038/s41598-025-07395-7
  title: Single-cell RNA-seq analysis of mouse carotid artery under disturbed flow and human carotid plaques identifies key cell populations in atherosclerosis development
  findings: []
- reference: DOI:10.1101/2024.09.11.612431
  title: Integrated single-cell atlas of human atherosclerotic plaques
  findings: []
- reference: DOI:10.1161/circresaha.123.323184
  title: Single-Cell Gene-Regulatory Networks of Advanced Symptomatic Atherosclerosis
  findings: []
- reference: DOI:10.3390/cells14110770
  title: 'Understanding Atherosclerotic Plaque Cellular Composition: Recent Advances Driven by Single Cell Omics'
  findings: []
- reference: DOI:10.3390/jcm13216352
  title: 'From Cells to Plaques: The Molecular Pathways of Coronary Artery Calcification and Disease'
  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

7

DOI:10.1038/s41598-025-07395-7

Single-cell RNA-seq analysis of mouse carotid artery under disturbed flow and human carotid plaques identifies key cell populations in atherosclerosis development